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ff05dbed01d5d1154b2749097325b95225c881c2

Effect of salmeterol on allergen-induced airway inflammation in mild allergic asthma.

A previous study suggested that the long-acting beta2-adrenergic agonist salmeterol (SM) had inhibitory effects on bronchial mucosal inflammation 6 hours after allergen exposure. To further evaluate the influence of SM on allergen-induced airway inflammation. We studied, in a randomized, double-blind, cross-over trial, 16 mild asthmatic patients who had a dual asthmatic response to allergen inhalation. Subjects received 50 microg of SM or placebo (P), twice daily for 1 week each, separated by a 2-week wash-out period. At the end of each treatment period, after withholding SM for 24 h, they had a methacholine inhalation test (medication was resumed after the test), followed 24 h later by an AC with the concentration of allergen that had induced a LAR at baseline. Airway inflammation was assessed 24 h after the AC by bronchoalveolar lavage (BAL) (n = 16) and bronchial biopsies (n = 13). As expected, SM improved baseline FEV1 and PC20 (P < or = 0.009) and decreased the allergen-induced early bronchoconstrictive response. There were no significant differences in BAL cell counts after the two treatments. On bronchial biopsies, numbers (median, mm2) of submucosal CD45 (P: 43 +/- 23; SM: 161 +/- 43, P = 0.031), CD45Ro (P: 37 +/- 19; SM: 126 +/- 41, P = 0.047) and AA1 positive cells (P: 38 +/- 6, SM: 65 +/- 17, P = 0.006) were significantly higher after SM than P treatment. The numbers of CD4 (P: 11 +/- 10; SM: 32 +/- 7, P = 0.085), HLA-DR (P: 65 +/- 30; SM: 116 +/- 36, P = 0.079) and EG2 positive cells (P: 25 +/- 15; SM: 38 +/- 26, P = 0.09) tended to increase with SM treatment. In summary, compared to placebo, 1 week of regular use of SM is associated with an increase in bronchial inflammatory cells 24 h after AC. This is in keeping with the recommendation that salmeterol should only be used with an anti-inflammatory agent, particularly in the context of significant allergen exposure.

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The esophageal detector device: accuracy and reliability in difficult airway settings.

INTRODUCTION The esophageal detector device (EDD) recently has been found to assess endotracheal (ET) tube placement accurately. This study describes the reliability of the EDD in determining the position of the ET tube in clinical airway situations that are difficult. METHODS This was a prospective, randomized, single-blinded, controlled laboratory investigation. Two airway managers (an emergency-medicine attending physician and a resident) determined ET-tube placement using the EDD in five swine in respiratory arrest. The ET tube was place in the following clinical airway situations: 1) esophagus; 2) esophagus with 1 liter of air instilled; 3) trachea; 4) trachea with 5 ml/kg water instilled; and 5) right mainstem bronchus. Anatomic location of the tube was verified by thoracotomy of the left side of the chest. RESULTS There was 100% correlation between the resident and attending physician's use of the EDD. The EDD was 100% accurate in the determining tube placement in the esophagus, in the esophagus with 1 liter of air instilled, in the trachea, and in the right mainstem bronchus. The airway managers were only 80% accurate in detecting tracheal intubations when fluid was present. CONCLUSIONS The EDD is an accurate and reliable device for detecting ET-tube placement in most clinical situations. Tube placement in fluid-filled trachea, lungs, or both, which occurs in pulmonary edema and drowning, may not be detected using this device.

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Fluctuation analysis of lung function as a predictor of long-term response to beta2-agonists.

The response to beta(2)-agonists differs between asthmatics and has been linked to subsequent adverse events, even death. Possible determinants include beta(2)-adrenoceptor genotype at position 16, lung function and airway hyperresponsiveness. Fluctuation analysis provides a simple parameter alpha measuring the complex correlation properties of day-to-day peak expiratory flow. The present study investigated whether alpha predicts clinical response to beta(2)-agonist treatment, taking into account other conventional predictors. Analysis was performed on previously published twice-daily peak expiratory flow measurements in 66 asthmatic adults over three 6-month randomised order treatment periods: placebo, salbutamol and salmeterol. Multiple linear regression was used to determine the association between alpha during the placebo period and response to treatment (change in the number of days with symptoms), taking into account other predictors namely beta(2)-adrenoceptor genotype, lung function and its variability, and airway hyperresponsiveness. The current authors found that alpha measured during the placebo period considerably improved the prediction of response to salmeterol treatment, taking into account genotype, lung function or its variability, or airway hyperresponsiveness. The present study provides further evidence that response to beta(2)-agonists is related to the time correlation properties of lung function in asthma. The current authors conclude that fluctuation analysis of lung function offers a novel predictor to identify patients who may respond well or poorly to treatment.

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Controversies in the surgical management of thyroid follicular neoplasms. Retrospective analysis of 721 patients.

The most appropriate surgical management of "follicular neoplasm/suspicious for follicular neoplasm" lesions, is still controversial. Analysing and comparing the experience of two units for endocrine surgery, we retrospectively evaluated 721 patients, surgically treated after a follicular neoplasm diagnosis. Total thyroidectomy was routinely performed in one Institution, while in the other one it was selectively carried out. The main criteria leading to hemythyroidectomy were a single nodule, the age ≤45 years, the absence of thyroiditis or clinical/intraoperative suspicion of malignancy. Total thyroidectomy was performed in 402/721 patients (55.7%), hemythyroidectomy in 319/721 cases (44.2%) and a completion thyroidectomy in 51/319 cases (15.9%). The overall malignancy rate was 24% (176/721 patients), respectively 16% (51/319 patients) following hemythyroidectomy, and 31% (125/402 patients) following total thyroidectomy. Definitive recurrent laryngeal nerve paralysis and permanent hypoparathyroidism were not reported in hemythyroidectomy patients in which lower mean hospitalization and costs were observed. Considering the low-risk of follicular neoplasm solitary lesions, hemythyroidectomy is still the safest standard of care with lower hospitalization and costs. In case of multiglandular disease or thyroiditis, that might be associated with a higher risk of cancer, total thyroidectomy should be recommended. Further investigation is warranted to achieve a better preoperative follicular neoplasm diagnostic accuracy in order to reduce the amount of unnecessary surgical operations with a diagnostic aim.

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Impact of quality circles for improvement of asthma care: results of a randomized controlled trial

RATIONALE AND AIMS Quality circles (QCs) are well established as a means of aiding doctors. New quality improvement strategies include benchmarking activities. The aim of this paper was to evaluate the efficacy of QCs for asthma care working either with general feedback or with an open benchmark. METHODS Twelve QCs, involving 96 general practitioners, were organized in a randomized controlled trial. Six worked with traditional anonymous feedback and six with an open benchmark; both had guided discussion from a trained moderator. Forty-three primary care practices agreed to give out questionnaires to patients to evaluate the efficacy of QCs. RESULTS A total of 256 patients participated in the survey, of whom 185 (72.3%) responded to the follow-up 1 year later. Use of inhaled steroids at baseline was high (69%) and self-management low (asthma education 27%, individual emergency plan 8%, and peak flow meter at home 21%). Guideline adherence in drug treatment increased (P = 0.19), and asthma steps improved (P = 0.02). Delivery of individual emergency plans increased (P = 0.008), and unscheduled emergency visits decreased (P = 0.064). There was no change in asthma education and peak flow meter usage. High medication guideline adherence was associated with reduced emergency visits (OR 0.24; 95% CI 0.07-0.89). Use of theophylline was associated with hospitalization (OR 7.1; 95% CI 1.5-34.3) and emergency visits (OR 4.9; 95% CI 1.6-14.7). There was no difference between traditional and benchmarking QCs. CONCLUSIONS Quality circles working with individualized feedback are effective at improving asthma care. The trial may have been underpowered to detect specific benchmarking effects. Further research is necessary to evaluate strategies for improving the self-management of asthma patients.

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Real-time frame rate up-conversion for video games: or how to get from 30 to 60 fps for "free"

Currently in the video game industry, the holy grail of rendering is achieving ultra realistic visual quality while maintaining a consistent 60 frames per second. However, the cost of doing so means having half the time to construct an image when compared to simply running at 30 fps. Most 30 fps games roughly split up their rendering time in half, standard scene and alpha rendering, and all the other glamorous post processing effects and shadows. This inevitably makes it extremely difficult for game studios to achieve high quality visual images with post processing and dynamic shadows while maintaining a consistent 60 frames per second. Video games that run at 30 fps suffer from very noticeable motion "flickering" artifacts due to fast movements of objects and/or the camera. One common technique to help remedy this flickering artifact is to introduce motion blur. In one way this technique helps smooth out the perceived motion of objects, but is only able to compensate properly relative to the virtual camera. In other words, the game does not know where the user's eyes are focused to and tracking, so in practice in interactive applications, the images tend to be more blurry all the time even in areas where the user's eye is tracking an object's motion and expecting it to be sharp. Running an application at 60 fps on a 60 hertz display eliminates multiple expositions of a single frame to the eye, reducing "flickering" artifacts and increasing sharpness of the moving objects under the eye tracking conditions. Motion blur only needs to be added to compensate for motions in the image that move faster then the eye can track. Figure 1 shows the difference in motion from a 30 fps rendering image, 30 fps with motion blur, and the 60 fps respectively on a 60 hertz display. Film typically has an easier work around to this problem because of the nature of the entertainment medium not being user interactive. The presentation of shots, usage of depth of field, and limiting the use of fast motions around the focal point are common techniques that are used because the user's eye can be guided to focus on certain parts of the image. Each shot is tuned specifically assuming the user's eye is focusing on certain material, thus avoiding the problem completely. The proposed solution is a novel technique that combines the best of both high quality rendering at 30 fps with the natural motion of objects refreshing at 60 fps, introducing very minimal overhead in terms of memory and performance. The basic concept is to approximate the middle frame between what has previously rendered and what is currently being constructed and present it as the new "predicted" image exactly in the middle of rendering at a 30 fps rate, thus empowering a product to still "feel" as if it is refreshing at 60. Televisions use a similar trick to achieve refresh rates near 120 hertz. However, for video games, more information is present regarding the frames construction, such as depth and velocity, and creating the predicted frame can be significantly simplified. This proposed technique is useful for all real-time user interactive applications to help guarantee that a very high quality of rendering is achieved, by allowing more time to construct a frame, but still refresh at a higher rate such as 60 frames per second. Additionally, further techniques are considered such as rendering more static / slow moving parts of the scene at an even lower refresh rate, such as 15 fps, because some tests have shown that the predicted images are "good enough" approximations of the slower moving data from the user's perspective. This would thereby increase the time an application would have to construct a frame, and still maintain 60 frames per second. Also, always maintaining 60 fps by automatically presenting more predicted frames during the instances that the game slows down. This would additionally balance visual quality of fast moving objects with refresh rate consistency.

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Hypnosis Treatment for Severe Irritable Bowel Syndrome: Investigation of Mechanism and Effects on Symptoms

Hypnosis improves irritable bowel syndrome (IBS), but the mechanism is unknown. Possible physiological and psychological mechanisms were investigated in two studies. Patients with severe irritable bowel syndrome received seven biweekly hypnosis sessions and used hypnosis audiotapes at home. Rectal pain thresholds and smooth muscle tone were measured with a barostat before and after treatment in 18 patients (study I), and treatment changes in heart rate, blood pressure, skin conductance, finger temperature, and forehead electromyographic activity were assessed in 24 patients (study II). Somatization, anxiety, and depression were also measured. All central IBS symptoms improved substantially from treatment in both studies. Rectal pain thresholds, rectal smooth muscle tone, and autonomic functioning (except sweat gland reactivity) were unaffected by hypnosis treatment. However, somatization and psychological distress showed large decreases. In conclusion, hypnosis improves IBS symptoms through reductions in psychological distress and somatization. Improvements were unrelated to changes in the physiological parameters measured.

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Abrupt cessation of short-term continuous treatment with isosorbide dinitrate may cause a rebound increase in silent myocardial ischaemia in patients with stable angina pectoris.

OBJECTIVE To examine by Holter electrocardiographic monitoring the effect of abruptly stopping nitrate treatment in patients with stable angina pectoris. PATIENTS 12 men with confirmed ischaemic heart disease and stable exertional class 3 angina (Canadian). All had episodes of horizontal or down sloping ST segment depression during 24 hour electrocardiographic monitoring. All were nitrate responders. DESIGN Each patient was given isosorbide dinitrate (10-30 mg four times a day) and placebo (four times a day) for three days in a randomised crossover trial. There was a washout period of 3-5 days between the two treatment periods. Holter monitoring was performed on the third day of isosorbide dinitrate and placebo administration and on the first day of their withdrawal. RESULTS When treatment with isosorbide dinitrate was stopped there was a significant increase in the total number and duration of painless episodes of myocardial ischaemia. During placebo and isosorbide dinitrate administration 8 patients had episodes of painless myocardial ischaemia whereas after isosorbide dinitrate cessation they were recorded in all 12 patients. Episodes of silent myocardial ischaemia at rest appeared in 4 patients after isosorbide dinitrate withdrawal. CONCLUSION Abrupt cessation of short-term continuous nitrate treatment in patients with severe angina may cause a rebound increase in myocardial ischaemia which is predominantly silent.

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Consideration of high-sensitivity troponin values below the 99th percentile at presentation: does it improve diagnostic accuracy?

BACKGROUND The introduction of high-sensitivity cardiac troponin (hs-cTn) assays allows the assessment of clinical decision values below the 99th percentile. METHODS Final diagnosis and one-year mortality were adjudicated in a multicenter, prospective cohort of 1181 patients presenting with acute chest pain to the emergency department. Hs-cTnT (Roche) and cTnI-ultra (Siemens) were measured in a blinded fashion. RESULTS At presentation hs-cTnT and cTnI-ultra were below the limit of blank (LOB) in 201 (17%) and 549 (47%) patients, below the 75th percentile in 379 (32%) and 623 (53%) patients, below the 95th percentile in 603 (51%) and 808 (68%), and below the 99th percentile in 748 (63%) and 913 (77%), respectively. Sensitivities for the diagnosis of AMI were 100.0% and 96.8% respectively for hs-cTnT and cTnI-ultra (LOB as cut-off value), 99.5% and 96.2% (75th percentile), 96.8% and 93.0% (95th percentile), and 94.1% and 88.1% (99th percentile). The proportion of patients correctly classified as having or not AMI increased from 32.9% (LOB as cut-off value) to 47.8% (75th percentile), 65.9% (95th percentile) and 77.3% (99th percentile) for hs-cTnT and from 61.2% to 67.3%, 81.9% and 89.3% respectively for cTnI-ultra. At 1 year, all-cause mortality was very low and similar for patients below all of these cut-off levels (between 0.7% and 1.5%, p=0.748 for all-groups comparison). CONCLUSION cTn should be considered as a continuous variable. Decision values below the 99th percentile (e.g. the 75th percentile) are associated with a very high NPV for the diagnosis of AMI, but have a lower accuracy than the 99th percentile.

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Comparative risk of hospitalized infection between biological agents in rheumatoid arthritis patients: A multicenter retrospective cohort study in Japan

OBJECTIVE Knowing the risk of hospitalized infection associated with individual biological agents is an important factor in selecting the best treatment option for patients with rheumatoid arthritis (RA). This study examined the comparative risk of hospitalized infection between biological agents in a routine care setting. METHODS We used data for all RA patients who had first begun biological therapy at rheumatology divisions of participating community hospitals in Japan between January 2009 and December 2014. New treatment episodes with etanercept, infliximab, adalimumab, abatacept, or tocilizumab were included. Patients were allowed to contribute multiple treatment episodes with different biological agents. Incidence rates (IRs) of hospitalized infection during the first year of follow-up were examined. Cox regression analysis was used to calculate hazard ratios (HRs) for overall hospitalized infection and for pulmonary hospitalized infection, adjusting for possible confounders. RESULTS A total of 1596 new treatment episodes were identified. The incidence of overall hospitalized infection during the first year was 86 with 1239 person-years (PYs), yielding a crude IR of 6.9 per 100 PYs (95% confidence interval [CI], 5.6-8.6). After correction for confounders, no significant difference in risk of hospitalized infection was observed between treatment groups: adjusted HRs (95% CI) were 1.54 (0.78-3.04) for infliximab, 1.72 (0.88-3.34) for adalimumab, 1.11 (0.55-2.21) for abatacept, and 1.02 (0.55-1.87) for tocilizumab compared with etanercept. Patient-specific factors such as age, RA functional class, body mass index (BMI), prednisolone use, and chronic lung disease contributed more to the risk of hospitalized infection than specific biological agents. The incidence of pulmonary hospitalized infection was 50 and a crude IR of 4.0 per 100 PYs (95% CI, 3.1-5.3). After adjustment for confounders, adalimumab had a significantly higher HR for pulmonary hospitalized infection compared with tocilizumab: an adjusted HR (95% CI) was 4.43 (1.72-11.37) for adalimumab. BMI, prednisolone use, diabetes mellitus, and chronic lung disease were also significant factors associated with the risk of pulmonary hospitalized infection. CONCLUSIONS The magnitude of the risk of overall hospitalized infection was not determined by the type of biological agents, and patient-specific risk factors had more impact on the risk of hospitalized infection. For pulmonary hospitalized infections, the use of adalimumab was significantly associated with a greater risk of this complication than tocilizumab use.

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Clinical classifications of atrial fibrillation poorly reflect its temporal persistence: insights from 1,195 patients continuously monitored with implantable devices.

OBJECTIVES This study aimed to identify how accurately the current clinical atrial fibrillation (AF) classifications reflect its temporal persistence. BACKGROUND Clinical classification of AF is employed to communicate its persistence, to select appropriate therapies, and as inclusion criterion for clinical trials. METHODS Cardiac rhythm histories of 1,195 patients (age 73.0 ± 10.1 years, follow-up: 349 ± 40 days) with implantable devices were reconstructed and analyzed. Patients were classified as having paroxysmal or persistent AF by physicians at baseline in accordance with current guidelines. AF burden, measured as the proportion of time spent in AF, was obtained from the device. Additionally we evaluated the agreement between clinical and device-derived AF classifications. RESULTS Patients within the same clinical class were highly heterogeneous with regards to AF temporal persistence. Agreement between the clinical AF classification and the objective device-derived assessments of AF temporal persistence was poor (Cohen's kappa: 0.12 [95% CI: 0.05 to 0.18]). Patient characteristics influenced the clinical decision to classify AF as paroxysmal or persistent. Higher ejection fraction (odds ratio: 0.97/per unit [95% CI: 0.95 to 0.98/per unit]; p < 0.0001) and presence of coronary artery disease (odds ratio: 0.53 [95% CI: 0.32 to 0.88]; p = 0.01) were independently associated with a lower probability of being classified as persistent AF for the same AF burden level. CONCLUSIONS The currently used clinical AF classifications poorly reflect AF temporal persistence. Patient characteristics significantly influence the physician's classification of AF. Patients classified in identical clinical categories may be inherently heterogeneous with regard to AF temporal persistence. Further study is required to determine if patient selection on the basis of objective criteria derived from rigorous AF monitoring can improve reported outcomes and better identify responders and non-responders to treatments. (OMNI Study-Assessing Therapies in Medtronic Pacemaker, Defibrillator, and Cardiac Resynchronization Therapy Devices; NCT00277524; TRENDS: A Prospective Study of the Clinical Significance of Atrial Arrhythmias Detected by Implanted Device Diagnostics; NCT00279981).

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Aortic regurgitation quantification using cardiovascular magnetic resonance: association with clinical outcome.

BACKGROUND Current indications for surgery in patients with significant aortic regurgitation (AR) focus on symptoms and left ventricular dilation/dysfunction. However, prognosis is already reduced by this stage, and earlier identification of patients for surgery could be beneficial. Quantifying the regurgitation may help, but there are limited data on its link with outcome. Cardiovascular magnetic resonance (CMR) can accurately quantify AR, and we examined whether this was associated with the future need for surgery. METHODS AND RESULTS One hundred thirteen patients with echocardiographic moderate or severe AR were monitored for up to 9 years (mean 2.6 ± 2.1 years) following a CMR scan, and the progression to symptoms or other indications for surgery was monitored. AR quantification identified outcome with high accuracy: 85% of the 39 subjects with regurgitant fraction >33% progressed to surgery (mostly within 3 years) in comparison with 8% of 74 subjects with regurgitant fraction ≤ 33% (P<0.0001); the area under the curve on receiver operating characteristic analysis was 0.93 (P<0.0001). This ability remained strong on time-dependent Kaplan-Meier survival curves. CMR-derived left ventricular end-diastolic volume >246 mL had good, although lower, discriminatory ability (area under the curve 0.88), but the combination of this measure with regurgitant fraction provided the best discriminatory power. CONCLUSIONS High degrees of CMR-quantified AR were associated with the development of symptoms or other indications for surgery. Quantifying AR showed slightly better discriminatory ability than "gold standard" CMR ventricular volume assessment. This could provide a new paradigm for the timing of surgical intervention but requires confirmation in a clinical trial.

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Standardized Ki67 Diagnostics Using Automated Scoring--Clinical Validation in the GeparTrio Breast Cancer Study.

PURPOSE Scoring proliferation through Ki67 immunohistochemistry is an important component in predicting therapy response to chemotherapy in patients with breast cancer. However, recent studies have cast doubt on the reliability of "visual" Ki67 scoring in the multicenter setting, particularly in the lower, yet clinically important, proliferation range. Therefore, an accurate and standardized Ki67 scoring is pivotal both in routine diagnostics and larger multicenter studies. EXPERIMENTAL DESIGN We validated a novel fully automated Ki67 scoring approach that relies on only minimal a priori knowledge on cell properties and requires no training data for calibration. We applied our approach to 1,082 breast cancer samples from the neoadjuvant GeparTrio trial and compared the performance of automated and manual Ki67 scoring. RESULTS The three groups of autoKi67 as defined by low (≤ 15%), medium (15.1%-35%), and high (>35%) automated scores showed pCR rates of 5.8%, 16.9%, and 29.5%, respectively. AutoKi67 was significantly linked to prognosis with overall and progression-free survival P values P(OS) < 0.0001 and P(PFS) < 0.0002, compared with P(OS) < 0.0005 and P(PFS) < 0.0001 for manual Ki67 scoring. Moreover, automated Ki67 scoring was an independent prognosticator in the multivariate analysis with P(OS) = 0.002, P(PFS) = 0.009 (autoKi67) versus P(OS) = 0.007, PPFS = 0.004 (manual Ki67). CONCLUSIONS The computer-assisted Ki67 scoring approach presented here offers a standardized means of tumor cell proliferation assessment in breast cancer that correlated with clinical endpoints and is deployable in routine diagnostics. It may thus help to solve recently reported reliability concerns in Ki67 diagnostics.

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Clinician judgment vs formal scales for predicting intracerebral hemorrhage outcomes.

OBJECTIVE To compare the performance of formal prognostic instruments vs subjective clinical judgment with regards to predicting functional outcome in patients with spontaneous intracerebral hemorrhage (ICH). METHODS This prospective observational study enrolled 121 ICH patients hospitalized at 5 US tertiary care centers. Within 24 hours of each patient's admission to the hospital, one physician and one nurse on each patient's clinical team were each asked to predict the patient's modified Rankin Scale (mRS) score at 3 months and to indicate whether he or she would recommend comfort measures. The admission ICH score and FUNC score, 2 prognostic scales selected for their common use in neurologic practice, were calculated for each patient. Spearman rank correlation coefficients (r) with respect to patients' actual 3-month mRS for the physician and nursing predictions were compared against the same correlation coefficients for the ICH score and FUNC score. RESULTS The absolute value of the correlation coefficient for physician predictions with respect to actual outcome (0.75) was higher than that of either the ICH score (0.62, p = 0.057) or the FUNC score (0.56, p = 0.01). The nursing predictions of outcome (r = 0.72) also trended towards an accuracy advantage over the ICH score (p = 0.09) and FUNC score (p = 0.03). In an analysis that excluded patients for whom comfort care was recommended, the 65 available attending physician predictions retained greater accuracy (r = 0.73) than either the ICH score (r = 0.50, p = 0.02) or the FUNC score (r = 0.42, p = 0.004). CONCLUSIONS Early subjective clinical judgment of physicians correlates more closely with 3-month outcome after ICH than prognostic scales.

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Whole breast irradiation for small-sized breasts after conserving surgery: is the field-in-field technique optimal?

BACKGROUND To determine the optimal whole breast irradiation technique in patients with small-sized breasts, tangential and field-in-field IMRT (FIF) techniques were compared. METHODS Sixteen patients with ≤3 cm breast height and ≤350 cc volume were included. Seven patients had 4D CTs performed. The planning target volumes (PTV), editing 5 and 2 mm from the surface on the whole breast, were delineated and called PTV(5) and PTV(2), respectively. Dose-volume histograms of tangential techniques with open beam (OT) and wedge filter (WT), conventional FIF (cFIF), and modified FIF (mFIF) blocking out the lung were produced. Various dose-volume parameters, the dose heterogeneity index (DHtrI), dose homogeneity index (DHmI), and PTV dose improvement (PDI) were calculated. RESULTS OT compared with WT showed a significantly favorable V 90 of the heart and lung, and PTV(5)-dose distribution. Comparing OT and cFIF, OT showed significant improvement in the V 95 of PTV(2), whereas cFIF showed significant improvement in the V 95, DHtrI, DHmI, and PDI of the PTV(5). In comparing cFIF and mFIF, mFIF showed improved dose distributions of the heart and lung, while cFIF presented the better V 95, DHtrI, DHmI, and PDI of the PTV(5). Respiratory influences on the absolute dose were mostly within 1 %. The ratio of free breathing and each respiratory phase was similar among OT, cFIF, and mFIF. CONCLUSIONS cFIF has favorable dose conformity and is suggested to be an optimal method for small-sized breasts. However, OT for dose coverage close to the skin and mFIF for normal tissue may also be potential alternatives. Respiratory effects are minimal.

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Oral paricalcitol versus oral calcitriol in continuous ambulatory peritoneal dialysis patients with secondary hyperparathyroidism

Secondary hyperparathyroidism (SHPT) is common in end-stage renal disease. Our primary objective was to evaluate the efficacy of oral paricalcitol versus oral calcitriol on serum intact parathyroid hormone (iPTH) and mineral bone parameters in continuous ambulatory peritoneal dialysis (CAPD) patients with SHPT. The secondary objective was to analyze highly sensitive C-reactive protein (hsCRP) and peritoneal membrane function in both groups. This was a prospective randomized control trial. CAPD patients with SHPT were randomized to paricalcitol or calcitriol for 15 weeks. Serum intact iPTH, calcium, phosphate and alkaline phosphatase (ALP) were measured at baseline and every 3 weeks. Serum hsCRP and peritoneal membrane functions were measured at baseline and at week 15. A total of 26 patients were enrolled and randomized—12 to paricalcitol and 14 to calcitriol. Serum iPTH reduced significantly in both groups and there was no difference in the incidence of ≥50 % reduction of iPTH between both groups. There was a significant increase in serum calcium in both groups but there were no differences in serum phosphorus across the visits. The incidence of hypercalcemia was the same in both groups. Serum calcium–phosphorus (Ca × P) product increased in the paricalcitol group but decreased in the calcitriol group. Serum ALP decreased significantly in both groups. There were also no differences in pre- and post-treatment serum hsCRP and peritoneal function test (PFT) in both groups. Both oral paricalcitol and calcitriol were equally efficacious in reducing serum iPTH but were associated with significantly higher serum calcium. Serum Ca × P product increased in the paricalcitol group and decreased in the calcitriol group. Serum hsCRP level and PFT were not affected by either treatment. A larger randomized controlled trial is indicated to confirm these initial findings.

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Use of screening phase data to evaluate observer variation of sputum cytodiagnosis as an outcome measure in a chemoprevention trial.

Sputum samples obtained during the screening phase of a chemoprevention trial in heavy smokers were evaluated independently by trained cytotechnologists and classified for degree of cellular atypia according to the method of Saccommano et al. (G. Saccommano et al., Cancer (Phila.), 33: 256-270, 1974). The level of agreement within and between Observers A and B was calculated as the percentage of agreement and, in addition, a statistic was used (kappa) to correct for chance-expected agreement. Between observer agreement on 300 specimens from 130 subjects was 68% (204 of 300) (kappa = 0.58). Of the 96 disagreements, only 17 were of more than one category in the six-category classification. Within observer agreement for both Observers A and B was evaluated on a subset of 60 specimens from 49 subjects examined on two separate occasions by each observer. The percentage of within observer agreement was 80% for Observer A (kappa = 0.73) and 62% for Observer B (kappa = 0.49) (P less than 0.04). Altogether, 71% (25 of 35) of within observer discordant readings were confined to only one category. These data, obtained from the screening phase of the study, will allow us to refine the outcome measure for the trial without introducing bias that could result from knowledge of the actual study results. The failure of conventional cancer treatments to impact significantly on overall cancer mortality has led to an emphasis on prevention. If premalignant changes can be reliably detected at a time when the malignant process is reversible, then it may be feasible to intervene to prevent the occurrence of some cancers. The appropriate selection of subjects for such intervention trials and the subsequent demonstration of the efficacy of chemoprevention strategies are therefore crucial.

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Comparison of frequency of radial artery occlusion after 4Fr versus 6Fr transradial coronary intervention (from the Novel Angioplasty USIng Coronary Accessor Trial).

The frequency of radial artery occlusion was compared between patients receiving 4Fr versus 6Fr transradial coronary interventions (TRIs) in an open-label randomized trial (ClinicalTrials.gov identifier: NCT00815997). The primary outcome measure was radial artery occlusion on the day after TRI. The secondary outcome measures were the procedural success, major advanced cardiac events, access site-related complications, procedural times, fluoroscopy times, and contrast dye usage. A total of 160 patients were included. The procedure was successful in 79 of 80 patients (99%) in both groups. Whereas the 4Fr group showed no access site-related complications, the 6Fr developed 5 (6%), including 3 radial artery occlusions and 2 bleedings (1 radial artery perforation and 1 massive hematoma; p = 0.02). Although the radial artery occlusion rate was lower in the 4Fr versus the 6Fr groups, the difference was not significant (0% vs 4%, p = 0.08). The mean hemostasis time was significantly shorter in the 4Fr than in the 6Fr groups (237 ± 105 vs 320 ± 238 minutes, p = 0.007). In conclusion, these findings suggest that 4Fr TRI may become a less invasive alternative to 6Fr TRI in treating coronary artery diseases.

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A randomized, double-blind, placebo-controlled trial and open-label extension study to evaluate the efficacy and safety of pregabalin in the treatment of neuropathic pain associated with human immunodeficiency virus neuropathy

The objective of these studies was to assess the efficacy and safety of pregabalin in the treatment of human immunodeficiency virus (HIV)-associated neuropathic pain. Patients with HIV-associated distal sensory polyneuropathy (DSP) were randomized to treatment with flexible-dose pregabalin (150-600 mg/day) or placebo for 17 weeks in a single-blind, placebo lead-in, randomized, double-blind, parallel-group, placebo-controlled multinational trial. The primary efficacy outcome was the change in mean pain score on an 11-point numeric rating scale (NRS) from baseline to study endpoint. Participants who completed this trial were invited to participate in a 6-month open-label extension study with pregabalin. Of the 377 patients enrolled in the randomized controlled trial (pregabalin, n=183; placebo, n=194), 68.4% completed treatment. In the open-label extension, 217 patients were treated and 59.4% completed treatment. Both studies were terminated by the sponsor after a preplanned interim analysis indicated trial futility. At endpoint, the change from baseline in least-squares mean NRS pain scores in the intent-to-treat population was -2.04 for pregabalin versus -2.11 for placebo (P=.709). There were no significant differences between the pregabalin and placebo groups in the secondary efficacy measures. Incidence of adverse events was lower than seen in previous pregabalin studies. Overall, this trial did not show pregabalin to be more efficacious than placebo in treating HIV-associated DSP. Studies such as these, which fail to support their primary hypotheses, may be important in informing the methodology of future trials, especially when novel approaches to limit variability in the control group are included. ClinicalTrials.gov identifiers: NCT01049217 and NCT01145417.

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Enhanced Psychosocial Support for Caregiver Burden for Patients With Chronic Kidney Failure Choosing Not to Be Treated by Dialysis or Transplantation: A Pilot Randomized Controlled Trial.

BACKGROUND Family caregivers of patients with chronic kidney failure have increased burden, as reflected by their high frequency of physical and mental disturbances. The impact of enhanced psychosocial support to caregivers of patients with chronic kidney failure remains unclear. STUDY DESIGN Open-label randomized controlled trial. SETTING & PARTICIPANTS All new patients referred to the renal palliative clinic were screened. Caregivers of patients who met the following criteria were recruited: (1) chronic kidney failure as defined by creatinine clearance < 15 mL/min, (2) opted for conservative management by nephrology team or patient, (3) never treated with dialysis or transplantation, and (4) able to provide informed consent. INTERVENTIONS Random assignment to treatment with enhanced psychosocial support or standard renal care (control). Enhanced psychosocial support included counseling and psychosocial interventions by an on-site palliative care nurse and designated social worker. Each caregiver was followed up at 2- to 4-week intervals for up to 6 months. OUTCOMES Zarit Burden Inventory (ZBI) and Hospital Anxiety and Depression Scale (HADS) in caregivers and McGill Quality of Life scores in patients of both groups were compared. RESULTS 29 pairs of family caregivers/patients with chronic kidney failure were randomly assigned (intervention, n=14; control, n=15). Mean ages of patients and caregivers were 81.6 ± 5.1 and 59.8 ± 14.2 (SD) years, respectively. The intervention group showed significantly lower ZBI scores than the control group at 1 and 3 months (22.0 ± 5.3 vs 31.6 ± 9.5 and 21.3 ± 6.6 vs 33.4 ± 7.2; P=0.006 and P=0.009, respectively). HADS anxiety scores of caregivers who received the intervention were significantly lower than those of controls at 1 and 3 months (7.1 ± 3.2 vs 10.1 ± 2.2 and 6.5 ± 4.5 vs 11.0 ± 3.1; P=0.01 and P=0.03, respectively). Insignificant reductions in ZBI and HADS scores were found at 6 months. 19 patients died (intervention, n=10; control, n=9) during the study period. LIMITATIONS The study is limited by a relatively small sample size and short duration. CONCLUSIONS Enhanced psychosocial support program in patients with chronic kidney failure and caregivers resulted in an early significant reduction in caregiver burden and anxiety.

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Comparison of the immunogenicity and safety of pentavalent vaccine Quinvaxem in a compact prefilled auto-disabled (cPAD) injection system versus single-dose vials in healthy infants: a phase 3, open-label, randomized, parallel-group, non-inferiority study.

OBJECTIVE To evaluate non-inferiority of three doses of Quinvaxem in a compact prefilled auto-disabled (cPAD) injection system versus Quinvaxem in a single-dose vial administered with conventional syringe in terms of seroconversion/seroprotection rates for all antibodies (anti-hepatitis B (HB), anti-Haemophilus influenzae type b polyribosylribitol phosphate (Hib PRP), anti-diphtheria, anti-tetanus, anti-Bordetella pertussis) at 1 month after primary vaccination. METHODS Four hundred healthy infants aged 42-65 days were randomized (1:1) to receive Quinvaxem in cPAD or single-dose vial at 6, 10, and 12 weeks of age. Blood samples were collected before vaccination and at 1 month after the third dose to determine seroconversion/seroprotection rates. Safety was assessed from solicited and unsolicited adverse events and serious adverse events (SAEs). RESULTS Of the 400 infants randomized, 395 (98.8%) received all three vaccine doses. In the cPAD vs. single-dose vial groups, seroprotection rates against Hib PRP (both 98.5%), HB (92.9% vs. 93.4%), diphtheria (100% vs. 99%), and tetanus toxoids (both 100%), and seroconversion against B. pertussis (95.4% vs. 97%) were ≥92% at 1 month after the third vaccination (lower limits of 95% confidence intervals simultaneously greater than -10%). Geometric mean concentrations exceeded seroprotection/seroconversion thresholds by large margins. The incidences of induration and erythema were comparable between the groups; tenderness was slightly higher in the cPAD group (85.5% vs. 76.5%). No vaccine-related SAEs occurred. CONCLUSIONS Quinvaxem in cPAD was non-inferior to single-dose vial with respect to seroprotection/seroconversion rates for all antibodies. Both presentations were well-tolerated.

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Mechanisms of stent thrombosis analysed by optical coherence tomography: insights from the national PESTO French registry.

AIMS Angiography has limited value for identifying the causes of stent thrombosis (ST). We studied a large cohort of patients by optical coherence tomography (OCT) to explore ST characteristics and mechanisms. METHODS AND RESULTS A prospective multicentre registry was screened for patients with confirmed ST. Optical coherence tomography was performed after initial intervention to the culprit lesion (in 69% of cases in a deferred procedure). Stent thrombosis was classified as acute (AST), sub-acute (SAST), late (LST), and very late (VLST). Optical coherence tomography records were analysed in a central core lab. The analysis included 120 subjects aged 61.7 [51.4-70.7]; 89% male. Very late ST was the clinical presentation in 75%, LST in 6%, SAST in 15%, and AST in 4% of patients. Bare metal stents (BMS) were used in 39%, drug-eluting stents (DES) in 59% and bioresorbable vascular scaffolds in 2% of the cases. Optical coherence tomography identified an underlying morphological abnormality in 97% of cases, including struts malapposition (34%), neoatherosclerotic lesions (22%), major stent underexpansion (11%), coronary evagination (8%), isolated uncovered struts (8%), edge-related disease progression (8%), and neointimal hyperplasia (4%). Ruptured neoatherosclerotic lesions were more frequent with BMS than with DES (36 vs. 14%, P = 0.005), whereas coronary evaginations were more frequent with DES than with BMS (12 vs. 2%, P = 0.04). LST + VLST were mainly related to malapposition (31%) and neoatherosclerosis (28%), while prominent mechanisms for AST + SAST were malapposition (48%) and underexpansion (26%). CONCLUSION In patients with confirmed ST, OCT imaging identified an underlying morphological abnormality in 97% of cases.

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Prospective comparison of two Sengstaken tubes in the management of patients with variceal haemorrhage.

To compare the efficacy of two oesophageal tamponade tubes, 28 patients with endoscopically proven actively bleeding varices were randomly allocated to be intubated with either a newly available 4-lumen tube incorporating an extra lumen for oesophageal suction, or the modified 3-lumen Sengstaken tube. The patients and the nursing staff preferred using the 4-lumen tube and both aspiration pneumonias and balloon dysfunction occurred less frequently. Variceal haemorrhage was successfully controlled for the first 12 hours in most patients in the two treatment groups, although the incidence of re-bleeding at 48 hours after the tube had been deflated was high.

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Comparison of interactive voice response, patient mailing, and mailed registry to encourage screening for osteoporosis: a randomized controlled trial

Guidelines recommend screening for osteoporosis with bone mineral density (BMD) testing in menopausal women, particularly those with additional risk factors for fracture. Many eligible women remain unscreened. This randomized study demonstrates that a single outreach interactive voice response phone call improves rates of BMD screening among high-risk women age 50–64. Osteoporotic fractures are a major cause of disability and mortality. Guidelines recommend screening with BMD for menopausal women, particularly those with additional risk factors for fracture. However, many women remain unscreened. We examined whether telephonic interactive voice response (IVR) or patient mailing could increase rates of BMD testing in high risk, menopausal women. We studied 4,685 women age 50–64 years within a not-for-profit health plan in the United States. All women had risk factors for developing osteoporosis and no prior BMD testing or treatment for osteoporosis. Patients were randomly allocated to usual care, usual care plus IVR, or usual care plus mailed educational materials. To avoid contamination, patients within a single primary care physician practice were randomized to receive the same intervention. The primary endpoint was BMD testing at 12 months. Secondary outcomes included BMD testing at 6 months and medication use at 12 months. Mean age was 57 years. Baseline demographic and clinical characteristics were similar across the three study groups. In adjusted analyses, the incidence of BMD screening was 24.6 % in the IVR group compared with 18.6 % in the usual care group (P < 0.001). There was no difference between the patient mailing group and the usual care group (P = 0.3). In this large community-based randomized trial of high risk, menopausal women age 50–64, IVR, but not patient mailing, improved rates of BMD screening. IVR remains a viable strategy to incorporate in population screening interventions.

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Autoantigen-specific regulatory T cells induced in patients with type 1 diabetes mellitus by insulin B-chain immunotherapy.

There is a growing body of evidence to suggest that the autoimmunity observed in type 1 diabetes mellitus (T1DM) is the result of an imbalance between autoaggressive and regulatory cell subsets. Therapeutics that supplement or enhance the existing regulatory subset are therefore a much sought after goal in this indication. Here, we report the results of a double blind, placebo controlled, phase I clinical trial of a novel antigen-specific therapeutic in 12 subjects with recently diagnosed T1DM. Our primary objective was to test its safety. The study drug, human insulin B-chain in incomplete Freund's adjuvant (IFA) was administered as a single intramuscular injection, with subjects followed for 2 years. All subjects completed therapy and all follow-up visits. The therapy was generally safe and well-tolerated. Mixed meal stimulated C-peptide responses, measured every 6 months, showed no statistical differences between arms. All patients vaccinated with the autoantigen, but none who received placebo, developed robust insulin-specific humoral and T cell responses. Up to two years following the single injection, in peripheral blood from subjects in the experimental arm, but not the control arm, insulin B-chain-specific CD4+ T cells could be isolated and cloned that showed phenotypic and functional characteristics of regulatory T cells. The induction of a lasting, robust immune response generating autoantigen-specific regulatory T cells provides strong justification for further testing of this therapy in type 1 diabetes. (clinicaltrials.gov identifier NCT00057499).

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Totaled health risks in vascular events score predicts clinical outcome and symptomatic intracranial hemorrhage in chinese patients after thrombolysis.

BACKGROUND AND PURPOSE The performance of the Totaled Health Risks in Vascular Events (THRIVE) score in predicting clinical outcomes in Chinese patients with acute ischemic stroke post intravenous thrombolysis is unknown. METHODS Data from the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China) study was used to compare the THRIVE score with other scores used to predict clinical outcomes and symptomatic intracranial hemorrhage after intravenous thrombolysis. RESULTS Among the 1128 patients with acute ischemic stroke who were included in this study, areas under the curve of the THRIVE score for symptomatic intracranial hemorrhage, 3-month poor functional outcomes, and death rate were 0.69, 0.71, and 0.78, respectively. The increased THRIVE score was related to the higher risk of developing symptomatic intracranial hemorrhage, poor functional outcomes, or death in patients with acute ischemic stroke at 3 months after thrombolysis. CONCLUSIONS The THRIVE score predicted reliably the risks of developing symptomatic intracranial hemorrhage, poor functional outcome, or death after intravenous thrombolysis therapy in Chinese patients with acute ischemic stroke.

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Crushed prednisolone tablets or oral solution for acute asthma?

In a randomised trial, treatment with prednisolone in two formulations (oral solution or crushed tablets) was compared in 78 young children with acute asthma. Prednisolone oral solution was better tolerated than crushed tablets (less vomiting, superior taste); clinical resolution was similar.

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Effectiveness of focused meditation for patients with chronic low back pain-A randomized controlled clinical trial.

OBJECTIVES We aimed to evaluate the effectiveness of an 8-week meditation program (focused meditation) in patients with chronic low-back pain. DESIGN A randomized clinical trial was conducted on 68 patients (55 years;75% female) with chronic low-back pain who scored >40mm on a 100mm Visual-Analogue-Scale. Subjects were allocated to an 8-week meditation program (focused meditation) with weekly 75min classes or to a self-care exercise program with a wait-list offer for meditation. Both groups were instructed to practice at home. Outcomes were assessed baseline and after 4 and 8 weeks. The primary outcome measure was the change in mean back pain at rest after 8 weeks. Secondary outcomes included function, pain-related bothersomeness, perceived stress, quality-of-life (QOL), and psychological outcomes. RESULTS Twelve (meditation) and 4 (exercise) patients were lost to follow-up. The primary outcome, pain at rest after 8 weeks, was reduced from 59.3±13.9mm to 40.8±21.8mm with meditation vs. 52.9±11.8mm to 37.3±18.2mm with exercise (adjusted group difference: -1.4 (95%CI:11.6;8.8;p=n.s.) Perceived stress was significantly more reduced with meditation (p=0.011). No significant treatment effects were found for other secondary outcomes as pain-related bothersomeness, function, quality-of-life and psychological scores, although the meditation group consistently showed non-significant better improvements compared to the exercise group. CONCLUSIONS Focused meditation and self-care exercise lead to comparable, symptomatic improvements in patients with chronic low back pain. Future studies should include longer-term follow-ups and develop guided meditation programs to support compliance.

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Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus.

Diabetes mellitus and depressive disorders are both common chronic diseases that increase functional disability and social burden. Cognitive impairment is a potentially debilitating feature of depression. Previous evidence indicates that the antidiabetic drug metformin could be suitable for diabetic patients with cognitive impairment. However, there is no direct evidence from clinical studies that metformin treatment improves cognitive function in diabetic patients suffering from depression. In the present study, 58 participants diagnosed with depression and type 2 diabetes mellitus (T2DM) were recruited and divided into two groups, one treated with metformin and the other treated with placebo for 24 weeks. Cognitive function, depressive behaviour and diabetes improvement were evaluated. Chronic treatment with metformin for 24 weeks improved cognitive performance, as assessed by the Wechsler Memory Scale-Revised, in depressed patients with T2DM. In addition, metformin significantly improved depressive performance and changed the glucose metabolism in depressed patients with diabetes. Depressive symptoms were negatively correlated with cognitive performance in metformin-treated participants. Furthermore, associations were observed between the parameters of blood glucose metabolism and the depression phenotype. These findings suggest that chronic treatment with metformin has antidepressant behavioural effects and that improved cognitive function is involved in the therapeutic outcome of metformin. The results of the present study also raise the possibility that supplementary administration of antidiabetic medications may enhance the recovery of depression, comorbid with T2DM, through improvements in cognitive performance.

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Rapid Protection against Hepatitis A and B Using an Accelerated Vaccination Schedule

1 Department of Infectious Diseases and Tropical Medicine, Ludwig-Maximilians University, Munich, Germany 2 Department of Medicine, Bernhard-Nocht Institute for Tropical Medicine, Hamburg, Germany 3 Academic Centre for Travel Medicine & Vaccines, Royal Free and University College Medical School, University College London, London, UK 4 Institute of Tropical Medicine, University Hospital, Tübingen, Germany 5 University Hospital and Medical Center, Ulm, Germany 6 GlaxoSmithKline GmbH & Co. KG, Munich, Germany SHORT COMMUNICATION Biodrugs 2003; 17 Suppl. 1: 15-18 1173-8804/03/0001-0015/$30.00/0

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Inaccurate early assessment of neurological severity in head injury.

Intubation, which requires sedation and myorelaxants, may lead to inaccurate neurological evaluation of severely head-injured patients. Aims of this study were to describe the early clinical evolution of traumatic brain injured (TBI) patients admitted to intensive care unit (ICU), to identify cases of over-estimated neurological severity, and to quantify the risk factors for this over-estimation. A total of 753 TBI patients consecutively admitted to ICU of three academic neurosurgical hospitals (NSH) were assessed. Cases whose severity was potentially over-estimated were identified by four criteria and indicated as "mistakenly severe" (MS): (1) no surgical intracranial masses; (2) could not follow commands at neurological assessment; (3) were dismissed from the ICU in < or =3 days to a regular ward; and (4) had regained the ability to obey commands. A total of 675 patients were intubated and/or sedated-paralyzed at the post-stabilization evaluation. In all, 304 patients had surgically treated intracranial masses. Among the 449 non-surgical cases, 58 patients fulfilling the criteria for MS were identified. The main features distinguishing MS from truly severe cases were younger age, higher Glasgow Coma Scale (GCS) score at all time points, Marshall classification of Computerized Tomographic (CT) scan mostly Diffuse Injury I and II, fewer pupillary abnormalities, and a lower frequency of hypoxia, hypotension, and extra-cranial injuries. In a certain proportion of non-surgical TBI patients, mostly intubated and sedated, neurological examination is difficult and severity can be over-estimated. Risk factors for this inaccurate evaluation can be identified, and clinical decisions should be based on further examination.

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The effect of literacy on oral language processing: Implications for aphasia tests.

Most studies investigating the impact of literacy on oral language processing have shown that literacy provides phonological awareness skills in the processing of oral language. The implications of these results on aphasia tests could be significant and pose questions on the adequacy of such tools for testing non-literate individuals. Aiming at examining the impact of literacy on oral language processing and its implication on aphasia tests, this study tested 12 non-literate and 12 literate individuals with a modified Amharic version of the Bilingual Aphasia Test (Paradis and Amberber, 1991, Bilingual Aphasia Test. Amharic version. Hillsdale, NJ: Lawrence Erlbaum.). The problems of phonological awareness skills in oral language processing in non-literates are substantiated. In addition, compared with literate participants, non-literate individuals demonstrated difficulties in the word/sentence-picture matching tasks. This study has also revealed that the Amharic version of the Bilingual Aphasia Test may be viable for testing Amharic-speaking non-literate individuals with aphasia when modifications are incorporated.

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Evaluation of the cost of home care for terminally ill cancer patients

 The aim of this work was to carry out a cost evaluation of the home care programme for terminally ill cancer patients run by the Istituto Oncologico Romagnolo (I.O.R.) in the areas of Forlì, Cesena, Ravenna and Rimini (Romagna, Italy). To determine effective home care direct costs, we first selected 1 week of care as an observation unit. We then proceeded to assess the medical and nursing care units together with the clinical protocols administered for each patient. The Karnofsky Performance Status (KPS) was also assessed weekly. In this way, we calculated care costs for each patient and for each week as the sum of medical costs, nursing costs, treatment costs and other costs. A consecutive series of 574 patients were involved in the study from 1 April 1994 to 31 March 1995. A total of 5164 patient-weeks of care was provided, with an average cost per week of 177.6 Ecu. This weekly cost increased in the last 100 days of life (week –15=179.5 Ecu; week –8=188.3 Ecu; week –2=221.0 Ecu;P<0.001). When single components were analysed in relation to total cost (treatment protocols, physician and nursing care) the increased global cost was found to be mainly attributable to the intensification in nursing care (21.8% of costs in week –15 vs 27.3% of costs in week –2). Examination of the relation between the cost of 1 week of care and KPS values clearly shows that healthcare costs increased as KPS decreased (from 152.2 Ecu with KPS ≥60 to 292.6 Ecu with KPS ≤20;P<0.001). Home care costs were also seen to vary with some clinical characteristics and symptoms present when patients entered the study: asthenia, anorexia, nausea/vomiting, bedsores. Given the good results of home care for cancer patients in terms of quality of life, this method of cost accounting for home-care providers can help to monitor the rising cost of assistance and confirm the cost effectiveness of this type of care.

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Multiplanar MRI–CT fusion neuronavigation-guided serial stereotactic biopsy of human brain tumors: proof of a strong correlation between tumor imaging and histopathology by a new technical approach

Serial stereotactic biopsy is a diagnostic procedure, used when open biopsy or tumor bulk removal seems to be associated with a too high risk of new neurological deficits in tumors of eloquent regions or tumors of deep localizations or in anticipated high surgery related morbidity even in the older patient group. Shortcomings of this method are recognized to be the missed pathohistological information from untargeted areas in heterogeneous tumors. This study shows for the first time a collection of patients with brain tumors with their associated multiplanar MRI–CT fusion imaging during stereotaxis and the histopathological features of serial tumor biopsies along exact trajectorial sites towards the tumor center. Thirteen patients were included. Stereotactic biopsy was performed and neuronavigation was correlated to histopathological features. Reactive tissue, endothelial hyperplasia, and diffusely scattered tumor cells occur outside the contrast-enhancing tumor in glioblastomas. Within the contrast-enhancing area, endothelial hyperplasia and diffuse tumor tissue were seen as compared to endothelial proliferations and the dense tumor as well as necroses in the image-defined center. Serial stereotactic biopsy is a reliable means. Strong correlations with the imaging characteristics of the lesions could be evaluated.

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Relevance of Stereotyped B-Cell Receptors in the Context of the Molecular, Cytogenetic and Clinical Features of Chronic Lymphocytic Leukemia

Highly homologous B-cell receptors, characterized by non-random combinations of immunoglobulin heavy-chain variable (IGHV) genes and heavy-chain complementarity determining region-3 (HCDR3), are expressed in a recurrent fraction of patients affected by chronic lymphocytic leukemia (CLL). We investigated the IGHV status of 1131 productive IG rearrangements from a panel of 1126 CLL patients from a multicenter Italian study group, and correlated the presence and class of HCDR3 stereotyped subsets with the major cytogenetic alterations evaluated by FISH, molecular prognostic factors, and the time to first treatment (TTFT) of patients with early stage disease (Binet A). Stereotyped HCDR3 sequences were found in 357 cases (31.7%), 231 of which (64.7%) were unmutated. In addition to the previously described subsets, 31 new putative stereotypes subsets were identified. Significant associations between different stereotyped HCDR3 sequences and molecular prognostic factors, such as CD38 and ZAP-70 expression, IGHV mutational status and genomic abnormalities were found. In particular, deletion of 17p13 was significantly represented in stereotype subset #1. Notably, subset #1 was significantly correlated with a substantially reduced TTFT compared to other CLL groups showing unmutated IGHV, ZAP-70 or CD38 positivity and unfavorable cytogenetic lesions including del(17)(p13). Moreover, subset #2 was strongly associated with deletion of 13q14, subsets #8 and #10 with trisomy 12, whereas subset #4 was characterized by the prevalent absence of the common cytogenetic abnormalities. Our data from a large and representative panel of CLL patients indicate that particular stereotyped HCDR3 sequences are associated with specific cytogenetic lesions and a distinct clinical outcome.

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Community-Based Screening by Colonoscopy or Computed Tomographic Colonography in Asymptomatic Average-Risk Subjects

OBJECTIVES:Visualizing the entire colorectum in screening is an advantage of colonoscopy, and also computed tomographic (CT) colonography, another potentially suitable screening test. Our objective was to compare screening CT colonography and colonoscopy in an asymptomatic average-risk population, and to determine whether providing a choice of tests increased participation.METHODS:One thousand and four hundred subjects from the general community, randomly selected from the parliamentary electoral roll, were allocated one of three screening groups: colonoscopy, CT colonography, or a choice of these tests, and were sent an institutional letter of invitation. Those with symptoms, colorectal cancer in first-degree relatives, or colonoscopy within 5 yr were ineligible. Outcome measures were participation, acceptability of screening, and yield for advanced colorectal neoplasia in participants.RESULTS:Of the subjects, 24.9% were ineligible; the overall participation rate was 18.2% (184/1,009). Participation in each screening group was not different. Both tests were accompanied by the same high levels of acceptability; most participants found colonoscopy (87%) and CT colonography (67%, p < 0.001) less unpleasant than expected. About 29% (26/89) CT colonography subjects had a positive screening test. The yield of advanced colorectal neoplasia was 8.7% (95% CI 5–14%), with no difference in yield between tests.CONCLUSION:Colorectal neoplasia screening by colonoscopy or CT colonography was associated with modest participation, high levels of acceptability, and similar yield for advanced colorectal neoplasia. Providing a choice of test did not increase participation.

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Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial.

CONTEXT The scarcity of data addressing the health effects of popular diets is an important public health concern, especially since patients and physicians are interested in using popular diets as individualized eating strategies for disease prevention. OBJECTIVE To assess adherence rates and the effectiveness of 4 popular diets (Atkins, Zone, Weight Watchers, and Ornish) for weight loss and cardiac risk factor reduction. DESIGN, SETTING, AND PARTICIPANTS A single-center randomized trial at an academic medical center in Boston, Mass, of overweight or obese (body mass index: mean, 35; range, 27-42) adults aged 22 to 72 years with known hypertension, dyslipidemia, or fasting hyperglycemia. Participants were enrolled starting July 18, 2000, and randomized to 4 popular diet groups until January 24, 2002. INTERVENTION A total of 160 participants were randomly assigned to either Atkins (carbohydrate restriction, n=40), Zone (macronutrient balance, n=40), Weight Watchers (calorie restriction, n=40), or Ornish (fat restriction, n=40) diet groups. After 2 months of maximum effort, participants selected their own levels of dietary adherence. MAIN OUTCOME MEASURES One-year changes in baseline weight and cardiac risk factors, and self-selected dietary adherence rates per self-report. RESULTS Assuming no change from baseline for participants who discontinued the study, mean (SD) weight loss at 1 year was 2.1 (4.8) kg for Atkins (21 [53%] of 40 participants completed, P = .009), 3.2 (6.0) kg for Zone (26 [65%] of 40 completed, P = .002), 3.0 (4.9) kg for Weight Watchers (26 [65%] of 40 completed, P < .001), and 3.3 (7.3) kg for Ornish (20 [50%] of 40 completed, P = .007). Greater effects were observed in study completers. Each diet significantly reduced the low-density lipoprotein/high-density lipoprotein (HDL) cholesterol ratio by approximately 10% (all P<.05), with no significant effects on blood pressure or glucose at 1 year. Amount of weight loss was associated with self-reported dietary adherence level (r = 0.60; P<.001) but not with diet type (r = 0.07; P = .40). For each diet, decreasing levels of total/HDL cholesterol, C-reactive protein, and insulin were significantly associated with weight loss (mean r = 0.36, 0.37, and 0.39, respectively) with no significant difference between diets (P = .48, P = .57, P = .31, respectively). CONCLUSIONS Each popular diet modestly reduced body weight and several cardiac risk factors at 1 year. Overall dietary adherence rates were low, although increased adherence was associated with greater weight loss and cardiac risk factor reductions for each diet group.

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Osteoporosis detection in postmenopausal women using axial transmission multi-frequency bone ultrasonometer: clinical findings.

The objective of this study was to evaluate if the Bone UltraSonic Scanner (BUSS) can detect osteoporosis in postmenopausal women. BUSS is an axial transmission multi-frequency ultrasonometer for acquisition of wave propagation profiles along the proximal anterior tibia. We derived 10 diagnostically significant BUSS parameters that were then compared with the DXA spine T-score, which was used in this study as the "gold standard" for the assessment of osteoporosis (T-score<-2.5). BUSS wave parameters were studied in 331 postmenopausal women examined by 9 trained operators at 3 clinical sites with use of 3 devices. The efficiency of each BUSS parameter in osteoporosis detection was assessed using a receiver operating characteristic curve analysis. Area under the curve (AUC) for each of 10 parameters ranged from 58.1% to 70.2%. Using these parameters a linear classifier was derived which provided at its output 83.0% AUC, 87.7% sensitivity and 63.2% specificity to DXA-identified osteoporosis. The results of this study confirm BUSS's capability to detect osteoporosis in postmenopausal women.

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Multicenter phase 2 trial of thalidomide in relapsed/refractory multiple myeloma: adverse prognostic impact of advanced age.

Relapsed or refractory multiple myeloma has a poor outlook. Some patients respond to thalidomide; however, criteria for predicting response have not been conclusively identified. We initiated a prospective multicenter phase 2 trial in patients with relapsed/refractory myeloma using thalidomide up to the maximum dose, 800 mg/d. Interferon-alpha-2B (1.5-3.0 x 10(6) U, subcutaneously, 3 times per week) was added at week 12 if disease was responsive or stable. Patients intolerant of interferon continued thalidomide alone. Thalidomide with or without interferon was continued until disease progression. Objectives were to determine toxicity, response rate (RR), progression-free survival (PFS), and overall survival (OS) and to elucidate relevant prognostic factors. We enrolled 75 patients, with median age 64 years (range, 36-83 years). Median individual maximum-tolerated dose of thalidomide was 600 mg/d; 41% reached 800 mg/d. Overall RR was 28%, and 55% stable disease (SD). The only predictor for response was age 65 years or younger (38% versus 17%; P =.043). At 18 months median follow-up, the actuarial median PFS and OS were 5.5 and 14.6 months, respectively. Multivariate analysis for OS demonstrated age exceeding 65 years (median, 9.2 months versus longer than 26 months; P =.011), raised serum lactate dehydrogenase (P =.002), and raised serum creatinine (P =.007) predicted inferior outcomes. Nineteen patients received interferon. Ten discontinued owing to toxicity. Four of 12 patients who received interferon for longer than 4 weeks were converted from SD to partial response. Our findings confirm substantial activity of thalidomide in relapsed/refractory myeloma. Interferon may improve response in selected patients, but is often not tolerated. The inferior outcome demonstrated in those with the identified prognostic factors is important in planning management for such patients.

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Norepinephrine and cardiovascular responses to maximal exercise in Parkinson's disease on and off medication.

The aim of this experiment is to understand how Parkinson's disease (PD) medication affects the autonomic responses of individuals during an acute exercise stress test. Fourteen people with PD and fifteen healthy individuals age-matched between 50 and 80 years performed a modified Bruce protocol. Subjects with PD performed the test once off medication (PD-off) and then 1 week later on medication (PD-on). Heart rate (HR), blood pressure (BP), VO(2), and norepinephrine (NE) levels were taken at rest and at peak exercise. At peak exercise HR, BP, and NE values for the PD-on and PD-off group were all significantly lower than healthy controls, regardless of whether subjects were on their medication. Autonomic abnormalities during exercise in this population appear to be disease manifested and not impacted by medications used to treat PD. We can assume, both on and off medication, this population will show markedly lower BP, HR, and NE responses.

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Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study.

PURPOSE From 1986 to 1992, "eight-drugs-in-one-day" (8-in-1) chemotherapy both before and after radiation therapy (XRT) (54 Gy tumor/36 Gy neuraxis) was compared with vincristine, lomustine (CCNU), and prednisone (VCP) after XRT in children with untreated, high-stage medulloblastoma (MB). PATIENTS AND METHODS Two hundred three eligible patients with an institutional diagnosis of MB were stratified by local invasion and metastatic stage (Chang T/M) and randomized to therapy. Median time at risk from study entry was 7.0 years. RESULTS Survival and progression-free survival (PFS) +/- SE at 7 years were 55%+/-5% and 54%+/-5%, respectively. VCP was superior to 8-in-1 chemotherapy, with 5-year PFS rates of 63%+/-5% versus 45%+/-5%, respectively (P = .006). Upon central neuropathology review, 188 patients were confirmed as having MB and were the subjects for analyses of prognostic factors. Children aged 1.5 to younger than 3 years had inferior 5-year estimates of PFS, compared with children 3 years old or older (P = .0014; 32%+/-10% v 58%+/-4%, respectively). For MB patients 3 years of age or older, the prognostic effect of tumor spread (MO v M1 v M2+) on PFS was powerful (P = .0006); 5-year PFS rates were 70%+/-5%, 57%+/-10%, and 40%+/-8%, respectively. PFS distributions at 5 years for patients with M0 tumors with less than 1.5 cm2 of residual tumor, versus > or = 1.5 cm2 of residual tumor by scan, were significantly different (P = .023; 78%+/-6% v 54%+/-11%, respectively). CONCLUSION VCP plus XRT is a superior adjuvant combination compared with 8-in-1 chemotherapy plus XRT. For patients with M0 tumors, residual tumor bulk (not extent of resection) is a predictor for PFS. Patients with M0 tumors, > or = 3 years with < or = 1.5 cm2 residual tumor, had a 78%+/-6% 5-year PFS rate. Children younger than 3 years old who received a reduced XRT dosage had the lowest survival rate.

ff8b8869a827d387f6b9c3dc80f8d78f4d862837

Predictive factors for anti-HBs status after 1 booster dose of hepatitis B vaccine

In Taiwan, infants need to receive 3 doses of hepatitis B virus (HBV) vaccine under the public health policy from the government. However, there are many young adults who even though received complete HBV vaccination in their childhood would lose the positive response of anti-hepatitis B surface antibody (HBs) and need the booster dose of HBV vaccine. The aim of our study is to determine the powerful predictive factor for screening the candidates who need only 1 booster dose of HB vaccine then they can regain positive postbooster anti-HBs status (≧10 mIU/mL) or protective postbooster anti-HBs status (≧100 mIU/mL).We recruited 103 university freshmen who were born after July 1986 with complete HBV vaccination in childhood, but displayed negative results for hepatitis B surface antigen and anti-HBs levels at their health examinations upon university entry. They received 1 booster dose of HB vaccine, and their anti-HBs titers were rechecked 4 weeks after the booster administration. Multivariate analysis logistic regression for positive postbooster anti-HBs status (≧10 mIU/mL, model 1) and protective postbooster anti-HBs status (≧100 mIU/mL, model 2) was done with predictive factors of prebooster anti-HBs level, body mass index, serum glutamate pyruvate transaminase level, and sex.Twenty-four students got positive postbooster anti-HBs status (10-100 mIU/mL) and 50 students got protective postbooster anti-HBs status (≧100 mIU/mL). In the model of multivariate analysis logistic regression for positive postbooster anti-HBs status (≧10 mIU/mL), prebooster anti-HBs level was the strongest predictive factor. The odds ratio was 218.645 and the P value was 0.001. Even in the model of multivariate analysis logistic regression for protective postbooster anti-HBs status (≧100 mIU/mL), prebooster anti-HBs level was still the strongest predictive factor, but the odds ratio of a protective booster effect was 2.143, with 95% confidence interval between 1.552 and 2.959, and the P value was less than 0.001.Prebooster anti-HBs level can be the powerful predictive factor for positive postbooster anti-HBs status (≧10 mIU/mL) and protective postbooster anti-HBs status (≧100 mIU/mL). According to the result of this study, if someone received complete HBV vaccination in childhood, but displayed negative results for hepatitis B surface antigen and anti-HBs levels around 2 decades later, 1 booster dose of HBV vaccine could help him or her to regain positive postbooster anti-HBs status (≧10 mIU/mL) under the strong predictive factor of prebooster anti-HBs level higher than 1 mIU/mL. The other 2 HBV vaccines could be saved and the case could also save money and time.

ff8c533cf443ee20c28d65c462ff5b9d43e789dc

Oral mucositis in paediatric patients after chemotherapy for cancer.

Oral mucositis (OM) can aggravate the paediatric patients’ clinical condition and elicit multiple debilitating oral symptoms that irrevocably alter patients’ quality of life.1,2 Nonetheless, the full spectrum of pathogenesis and factors in the development of OM remains poorly understood, in particular in the paediatric cancer population. This study aimed to determine the factors associated with OM in paediatric patients undergoing chemotherapy for cancer, and to compare the outcomes in paediatric patients with and without OM.

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Exercise and fractures in postmenopausal women: 12-year results of the Erlangen Fitness and Osteoporosis Prevention Study (EFOPS)

This trial is the first exercise study that focuses on fracture incidence as a primary study endpoint. Although we marginally failed to determine significant effects on “overall” fracture risk (p = .074) or rate ratio (p = .095), our findings further increased the evidence that exercise relevantly prevents fractures in the elderly. The purpose of this study is to determine the effect of strictly supervised long-term exercise training on “overall” fracture incidence and bone mineral density (BMD) in postmenopausal osteopenic women. Eighty-five early postmenopausal (1–8 years), osteopenic women living in the area of Erlangen–Nuremberg, Germany without any medication or diseases affecting bone metabolism were assessed after 12 years of supervised exercise (EG) or unvarying lifestyle (control, CG). Exercisers were encouraged to perform two group sessions/week and two home training sessions/week. Calcium and vitamin D supplementation was provided for both groups. “Overall” fractures were determined by questionnaires and structured interviews. The BMD was assessed at lumbar spine and proximal femur by dual-energy X-ray absorptiometry. “Overall” fracture risk ratio in the EG was 0.32 (95% confidence interval (CI), 0.08 to 1.05; p = .074), and the rate ratio for “overall” fractures was 0.38 (95% CI, 0.11 to 1.15; p = .095). BMD changes at lumbar spine (EG, −0.8%; 95% CI, 0.8% to −2.7% vs. CG, −4.0%; 95% CI, −2.4% to −5.7%; p = .011) and femoral neck (EG, −3.7%; 95% CI, −2.4% to −5.0% vs. CG, −6.7%; 95% CI, −5.3% to −8.2%; p = .003) significantly differed between both groups. Although we marginally failed to determine significant effects on overall fracture risk or rate ratio, our study increased the body of evidence for the fracture prevention efficiency of exercise programs, with special regard on bone strength (as assessed by bone mineral density measurement). Future studies should focus on subjects more prone to fractures to generate enough statistical power to clearly determine this issue.

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An open-label study of lapatinib in women with HER-2-negative early breast cancer: the lapatinib pre-surgical study (LPS study).

BACKGROUND This phase II, open-label, multicentre study aimed to evaluate changes in cell proliferation and biomarkers, as well as efficacy of lapatinib in treatment-naïve patients with HER-2-negative primary breast cancer. PATIENTS AND METHODS Patients received 1500 mg lapatinib for 28-42 days before surgery with repeat biopsies and measurements. The primary end point was inhibition of cell proliferation measured by Ki67; the secondary end points included clinical response, adverse events and changes in FOXO3a, FOXM1, p-AKT and HER-3. RESULTS Overall, there was no significant reduction in Ki67 with treatment (assessment carried out in 28 of 31 subjects enrolled). However, four patients (14%) showed a reduction in Ki67 ≥50%. Four of 25 patients (16%) had a partial response to treatment judged by sequential ultrasound measurements. Response, in terms of either Ki67 or ultrasound, did not relate to changes in any biomarker assessed at baseline, including the estrogen receptor (ER) and epidermal growth factor receptor (EGFR). However, all four clinical responders were HER-3 positive, as were three of four Ki67 responders. CONCLUSIONS Overall, a pre-surgical course of lapatinib monotherapy had little effect on this group of patients; however, in subsets of patients, especially those with HER-3-positive tumors, we observed either reduction in proliferation (Ki67) or tumor size; EGFR/ER status had no impact.

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Lack of benefit of a primary care-based nurse-led education programme for people with osteoarthritis of the knee

Osteoarthritis (OA) is the commonest cause of locomotor disability and forms a major element of the workload of the primary care team. There is evidence that patient education may improve quality of life, physical functioning, mental health and coping as well as reducing health service use. The aim of this study was to evaluate the effectiveness of a primary care-based patient education programme (PEP) using a randomised controlled trial. A cluster randomised controlled trial, involving 22 practices, was used to determine the efficacy of a nurse-led education programme. The programme consisted of a home visit and four 1-h teaching sessions. Patients were assessed at baseline and then 1, 3, 6 and 12 months post intervention using 36-item Short Form (SF-36), Western Ontario and McMaster Universities Arthritis Index (WOMAC), arthritis helplessness index and a patient knowledge questionnaire. Direct interviews were used at baseline and at the 12-month follow-up. There were no differences in depression, OA knowledge, pain or physical ability at either 1 month or 1 year between the two groups. Control practices (65 patients from 12 practices) recruited significantly fewer patients than intervention practices (105 patients from ten practices, p=0.02). Control practices had more doctors (p=0.02), more non-white patients (p=0.007), fewer patients living alone (p=0.005) and lower levels of disability (p=0.008). We detected a lack of benefit of PEP for people with OA of the knee. This was thought to be due in part to the short intervention time employed and the heterogeneous nature of the disease and the population studied.

ff9cef8ea6fa80d7ad82afa77438bb59992865ad

Short-term Results of Birmingham Hip Resurfacing in the United States.

Previous data on the survivorship of the Birmingham Hip Resurfacing (BHR) implant have come from design surgeons and large national databases outside of the United States, and there is a lack of reported outcomes of surface replacement arthroplasty from US centers. A retrospective study was undertaken of 1271 hips treated with a BHR system (Smith & Nephew, Memphis, Tennessee) between June 2006 and September 2008 at 6 high-volume total joint centers in the United States. Demographic features, Harris Hip Score (HHS), and radiographic findings were recorded. Patients who did not have a 2-year follow-up visit were contacted by telephone. All patients were asked about complications, reoperations, or failure of the implants. Of the treated hips, 1144 (90%) had a minimum of 2 years of clinical follow-up (mean, 2.9 years; range, 1.8-4.2 years). Mean age was 52.3 years, and 75% of patients were men. Mean HHS improved from 55.8 preoperatively to 97.4 at the most recent follow-up (P<.001). There were 16 (1.4%) revisions to total hip arthroplasty (THA) for fracture (7), early dislocation (3), acetabular component malpositioning with pain (3; 1 with metallosis), infection (1), femoral loosening (1), and pseudotumor (1). There were 9 additional complications (0.8%) that did not require revision, including 3 dislocations treated with closed reduction, 2 fractures, 3 nerve injuries, and 1 pseudotumor. At 2 to 4 years of follow-up, the revision rate and the major complication rate with the BHR system were similar to those in previous reports of primary THA. Excellent clinical results were observed, but further follow-up is necessary to assess mid- and long-term results with the BHR system in US patients.

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Leptin before and after insulin therapy in children with new-onset type 1 diabetes.

Serum leptin levels reflect the amount of body fat. However, several reports suggest that insulin may also regulate serum leptin levels. This study was aimed at testing whether leptin levels are low in newly diagnosed patients with type 1 diabetes and increase after institution of insulin therapy. Nineteen children with new-onset type 1 diabetes were studied. Serum leptin levels were measured at presentation before insulin therapy was initiated (day 0), 1 day after insulin therapy (day 1), 3-5 days after insulin therapy (day 3-5), and at 3 months of follow-up (3 months). The control group consisted of 19 healthy children matched for age and body mass index. On day 0 leptin levels were lower in the patients compared with those in controls (3.3 +/- 0.2 vs. 6.2 +/- 0.9 ng/mL; P < 0.005). After insulin therapy, leptin levels increased significantly by day 1 without significant weight change and became comparable to control values by days 3-5. Before insulin therapy, leptin did not correlate with weight, body mass index, or hemoglobin A1c. After insulin therapy, leptin levels on days 3-5 correlated with insulin dose (r = 0.43; P = 0.03). The results of this study demonstrate that children with new-onset type 1 diabetes have low leptin levels before insulin therapy. Leptin levels increase within 24 h of insulin therapy and become comparable to nondiabetic levels by 3-5 days. This rapid increase in leptin after 24 h of insulinization is independent of changes in body weight and is postulated to be due to a stimulatory effect of insulin on leptin production, nutritional replenishment, or both factors together.

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Preventing depression and promoting resilience: feasibility study of a school-based cognitive-behavioural intervention.

BACKGROUND The limited reach and effectiveness of psychological treatments for adolescent depression have fuelled interest in alternative approaches designed to promote resilience. Schools offer a convenient location for the widespread delivery of depression prevention programmes, although little research has evaluated the feasibility of delivering interventions in this setting. AIMS To investigate the feasibility of delivering and evaluating a universal school-based depression prevention programme for children aged 12-16 years. METHOD A three-arm pilot study was conducted in one UK secondary school (n = 834). RESULTS Interventions had good reach (96%), with high rates of consent (89%) and reasonable retention (78%). The majority of intervention sessions were delivered as intended, with 85% of students attending seven or more sessions. The programme was acceptable to students and teachers, with the specific content of the active intervention being rated differently from the control programmes. CONCLUSIONS Delivering and undertaking methodologically robust evaluations of universal school-based depression programmes is feasible.

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Comparison of conventional and real-time RT-PCR for the quantitation of jun protooncogene mRNA and analysis of junB mRNA expression in synovial membranes and isolated synovial fibroblasts from rheumatoid arthritis patients

AP-1 dependent genes, e.g., matrix-metallo-proteinases, are involved in the pathogenesis of rheumatoid arthritis (RA). Therefore, the transcription factor AP-1 and its subunits, proteins of the Jun and Fos proto-oncogene families, are interesting targets for analysis in RA. In this study, we analyzed the mRNA expression of junB in synovial membrane (SM) samples and isolated synovial fibroblasts of patients with RA, osteoarthritis (OA), and normal, non-inflammatory controls. To address the suitability of real-time RT-PCR for the quantitation of Jun proto-oncogene family members, conventional RTPCR and real-time PCR were comparatively applied for junD, a gene representing a major challenge because of its high GC-content (70%, increasing the probability of secondary structures interfering with the PCR) and its sequence homology to other Jun proto-oncogenes. In addition, a comparison was performed concerning the precision, reproducibility, costs, as well as labor and time consumption of the two PCR methods. Real-time RT-PCR proved superior to conventional PCR in terms of precision (mean deviation of measured from employed concentration 58% for real-time PCR vs 225% for conventional PCR), reproducibility, as well as labor and time consumption (4 times less for real-time RT-PCR). Experimental cDNA normalization for equivalent cDNA concentrations by sample dilution was more reliable than mathematical cDNA normalization. However, real-time PCR was 3.6-fold more expensive. Applying the more reliable real-time RT-PCR for the ex vivo analysis of junB mRNA-expression, no significantly different expression of junB was observed in SM or isolated synovial fibroblasts from RA as compared to OA. Interestingly, however, junBmRNA expression was significantly lower in RA SM and borderline significantly lower in OA SM than in normal/non-inflammatory SM, with potential effects on the functional properties of the resulting AP-1 complexes. Immunohistochemical staining of the SM with JunB-specific antibodies showed comparable JunB protein expression in SFB (collagen III mRNA-positive) of RA and OA samples. Thus, real-time RT-PCR appears suitable and time-saving for the quantitation of jun proto-oncogene mRNA-expression in tissue and cell samples with high precision and reproducibility. AP-1-abhängige Gene, z. B. Matrix-Metallo- Proteinasen, sind an der Pathogenese der rheumatoiden Arthritis (RA) beteiligt. Deshalb sind der Transkriptionsfaktor AP-1 und seine Untereinheiten – die Proteine der Jun- und Fos-Proto-Onkogen-Familien – interessante Ziele für die Analyse in der RA. In dieser Studie wurde die mRNA-Expression von JunB in Synovialmembran-Gewebeproben (SM) und primären synovialen Fibroblasten von Patienten mit RA und Osteoarthritis (OA), sowie normalen, nicht entzündlichen Kontrollen analysiert. Um die Eignung der Real-time PCR für die Quantifizierung von Mitgliedern der Jun-Genfamilie zu überprüfen, wurde ein Vergleich der konventionellen RT-PCR mit der Real-time PCR für das Gen junD durchgeführt. Dieses stellt aufgrund seines hohen GC-Gehaltes (70%, wodurch die mögliche Bildung von mit der Polymerase- Reaktion interferierenden Sekundärstrukturen deutlich erhöht wird) und der Sequenzhomologien zu anderen Jun-Genen eine große methodische Herausforderung dar. Außerdem wurde in die Untersuchung ein Vergleich in Hinblick auf die Präzision, die Reproduzierbarkeit, die Kosten, sowie den Arbeits- und Zeitaufwand der beiden Methoden einbezogen. Die Real-time PCR erwies sich der konventionellen PCR in den Punkten Präzision (die mittlere Abweichung der gemessenen von der eingesetzten Konzentration betrug bei der Real-time PCR 58% gegenüber 225% bei der konventionellen PCR), Reproduzierbarkeit und Arbeits-/Zeitaufwand (4-fach geringer bei der Real-time RT-PCR) überlegen. Eine experimentelle Normalisierung durch Verdünnung der untersuchten cDNA-Proben auf äquivalente cDNA-Konzentrationen stellte sich gegenüber einer rein mathematischen Normalisierung als genauer heraus. Allerdings waren die Kosten der Realtime PCR 3,6-mal so hoch wie die der konventionellen PCR. Die zuverlässigere Real-time PCR wurde anschließend zur Ex-vivo- Analyse der junB mRNA-Expression eingesetzt. Dabei konnten keine signifikanten Unterschiede zwischen den Expressionsniveaus von junB in SM oder primären synovialen Fibroblasten von RA- und OA-Patienten nachgewiesen werden. Interessanterweise wurde allerdings eine signifikant niedrigere junB-Expression in der RA-SM und eine grenzwertig signifikant niedrigere junB-Expression in der OA-SM im Vergleich zu den Normalkontrollen beobachtet, was die Funktion der resultierenden AP-1 Komplexe beeinflussen könnte. Die immunhistologische Färbung der SM mit JunB-spezifischen Antikörpern zeigte eine vergleichbare JunB Proteinexpression in SFB (Kollagen III mRNA positiv) bei RA- und OA-Proben. Insgesamt erwies sich die Realtime RT-PCR in dieser Studie als eine geeignete und zeitsparende Methode für die Quantifizierung der mRNA-Expression von jun- Proto-Onkogenen in Gewebe und Zellproben mit hoher Präzision und Reproduzierbarkeit.

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Care evaluation scale-patient version: measuring the quality of the structure and process of palliative care from the patient's perspective.

CONTEXT Recently, greater emphasis has been placed on patient-reported outcomes. However, there are only a few measures to evaluate the quality of care from the patient's perspective. OBJECTIVES To report the development of a scale to measure the quality of the structure and process in palliative care from the patient's perspective and examine the reliability and validity of the scale. METHODS A cross-sectional anonymous questionnaire was administered to cancer patients who were being treated on an oncology inpatient ward, who visited an oncology outpatient clinic at Saitama Medical University International Medical Center, or who were in an inpatient palliative unit in Japan between August 2007 and March 2008. RESULTS A total of 405 cancer patients participated in the study. Factor analysis revealed that the Care Evaluation Scale-Patient version (CES-P) consisted of 23 items with eight subscales: physical care by physicians, physical care by nurses, psychoexistential care, help with decision making for patients, environment, cost, availability, and coordination/consistency. The total CES-P score was correlated with satisfaction (r = 0.63) but not with quality of life (r = 0.18). The Cronbach α coefficient of the total score was 0.97, and the intraclass correlation coefficient of the total score was 0.67. The CES-P total score was not significantly correlated with the self-reported Eastern Cooperative Oncology Group performance status (ρ = -0.05). CONCLUSION The CES-P has sufficient validity and reliability. In addition, this scale is independent of the general physical condition of the patient.

ffaffcc2570a4dd892a4d4ed992e4876a065fd38

Regional and seasonal influence in patient’s toxicity to adjuvant chemotherapy for early breast cancer

Results from multinational clinical trials are globally adopted into the routine clinical practice in most countries. Changes in the natural history and incidence of certain diseases as well as in drugs toxicities related to yearly seasons have been reported, however, variations related to climate have never been described. In our study, we assessed whether yearly seasons and climate could influence the chemotherapy toxicity profile. We analyzed the toxicities recorded in the phase III GEICAM 9906 study which was run in different geographically and climatically/seasonally regions in Spain. In this trial 1246 patients were randomized and eligible to receive FEC90 ×6 cycles or FEC90 ×4 cycles followed by eight doses of weekly paclitaxel (T). The results showed differences in hematological and non-hematological toxicities in relation to the season of the year and the climate of the area in which the treatment was administered. We found a higher hematological toxicity in warm seasons (spring and summer) and in Oceanic climate regions (Neutropenia G4: 7.8 vs. 1.0 vs. 1.0%, P < 0.0001). Asthenia was greater frequency in the summer period (FEC90: 21.1%, T: 15.3%) as well as in the Mediterranean areas (FEC: 28% T: 27.2%). Also we observed liver transaminase elevations were more frequent in the summer and in the Oceanic areas. Myalgias and secondary sensory neuropathy to paclitaxel were recorded more frequently during autumn. Climate should be considered a significant variable in toxicity to chemotherapy.

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PREVENTION OF INTRAVENTRICULAR HAEMORRHAGE IN PRETERM INFANTS BY PHENOBARBITONE: A Controlled Trial

Sixty infants with birth-weights less than 1500 g and who were less than 6 h old were randomly assigned to a group given phenobarbitone or a control group. Intravenous phenobarbitone was given in doses sufficient to achieve anticonvulsant serum levels within 12-18 h. Maintenance therapy was continued for one week. Periventricular/intraventricular haemorrhage (IVH) occurred in 13.3% (4/30) of the phenobarbitone group and in 46.7% (14/30) of the control group. The occurrence of risk factors related to IVH was similar in the two groups. Phenobarbitone may reduce the incidence of IVH in small preterm infants.

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Response Prediction in Chronic Hepatitis C by Assessment of IP-10 and IL28B-Related Single Nucleotide Polymorphisms

BACKGROUND High baseline levels of IP-10 predict a slower first phase decline in HCV RNA and a poor outcome following interferon/ribavirin therapy in patients with chronic hepatitis C. Several recent studies report that single nucleotide polymorphisms (SNPs) adjacent to IL28B predict spontaneous resolution of HCV infection and outcome of treatment among HCV genotype 1 infected patients. METHODS AND FINDINGS In the present study, we correlated the occurrence of variants at three such SNPs (rs12979860, rs12980275, and rs8099917) with pretreatment plasma IP-10 and HCV RNA throughout therapy within a phase III treatment trial (HCV-DITTO) involving 253 Caucasian patients. The favorable SNP variants (CC, AA, and TT, respectively) were associated with lower baseline IP-10 (P = 0.02, P = 0.01, P = 0.04) and were less common among HCV genotype 1 infected patients than genotype 2/3 (P<0.0001, P<0.0001, and P = 0.01). Patients carrying favorable SNP genotypes had higher baseline viral load than those carrying unfavorable variants (P = 0.0013, P = 0.029, P = 0.0004 respectively). Among HCV genotype 1 infected carriers of the favorable C, A, or T alleles, IP-10 below 150 pg/mL significantly predicted a more pronounced reduction of HCV RNA from day 0 to 4 (first phase decline), which translated into increased rates of RVR (62%, 53%, and 39%) and SVR (85%, 76%, and 75% respectively) among homozygous carriers with baseline IP-10 below 150 pg/mL. In multivariate analyses of genotype 1-infected patients, baseline IP-10 and C genotype at rs12979860 independently predicted the first phase viral decline and RVR, which in turn independently predicted SVR. CONCLUSIONS Concomitant assessment of pretreatment IP-10 and IL28B-related SNPs augments the prediction of the first phase decline in HCV RNA, RVR, and final therapeutic outcome.

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Using computer based data acquisition and analysis system for nasal potential difference measurement in cystic fibrosis.

Nasal potential difference (PD) measurement has been used as a diagnostic test for cystic fibrosis (CF). It has been shown that large differences in reproducibility of nasal PD measurement can exist between different study sites. These differences reduce the validity of studies. In our study we tried to measure nasal PD values for a group of Turkish CF patients by using a computer based data acquisition system, which could eliminate the bias due to using different voltmeters. The CF group (n=40, mean age 9.3 years) value was -39.21+/-1.74 mV, and the control group (n=36, mean age 17.08 years) value was -18.24+/-1.48 mV (mean+/-SEM). Using the electronic data acquisition and analysis systems gave reliable results with high specificity (92%), sensitivity (79%), positive predictive value (95%) and negative predictive value (72%). Computer based data acquisition and analysis system provides suitable monitoring and continuous recording during measurements and facilitates repeat readings at the same distances along the nasal floor. Using electronic data acquisition may help to minimize the subjectivity in voltmeter measurements and hand analysis.

ffb5bd0b13ec20894d444f341b86e0f08c36198a

Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A/C Mutation Carriers.

BACKGROUND Mutations in LMNA are variably expressed and may cause cardiomyopathy, atrioventricular block (AVB), or atrial arrhythmias (AAs) and ventricular arrhythmias (VA). Detailed natural history studies of LMNA-associated arrhythmic and nonarrhythmic outcomes are limited, and the prognostic significance of the index cardiac phenotype remains uncertain. OBJECTIVES This study sought to describe the arrhythmic and nonarrhythmic outcomes of LMNA mutation carriers and to assess the prognostic significance of the index cardiac phenotype. METHODS The incidence of AVB, AA, sustained VA, left ventricular systolic dysfunction (LVD) (= left ventricular ejection fraction ≤50%), and end-stage heart failure (HF) was retrospectively determined in 122 consecutive LMNA mutation carriers followed at 5 referral centers for a median of 7 years from first clinical contact. Predictors of VA and end-stage HF or death were determined. RESULTS The prevalence of clinical manifestations increased broadly from index evaluation to median follow-up: AVB, 46% to 57%; AA, 39% to 63%; VA, 16% to 34%; and LVD, 44% to 57%. Implantable cardioverter-defibrillators were placed in 59% of patients for new LVD or AVB. End-stage HF developed in 19% of patients, and 13% died. In patients without LVD at presentation, 24% developed new LVD, and 7% developed end-stage HF. Male sex (p = 0.01), nonmissense mutations (p = 0.03), and LVD at index evaluation (p = 0.004) were associated with development of VA, whereas LVD was associated with end-stage HF or death (p < 0.001). Mode of presentation (with isolated or combination of clinical features) did not predict sustained VA or end-stage HF or death. CONCLUSIONS LMNA-related heart disease was associated with a high incidence of phenotypic progression and adverse arrhythmic and nonarrhythmic events over long-term follow-up. The index cardiac phenotype did not predict adverse events. Genetic diagnosis and subsequent follow-up, including anticipatory planning for therapies to prevent sudden death and manage HF, is warranted.

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A phase I dose-escalation and pharmacokinetic study of enzastaurin and erlotinib in patients with advanced solid tumors

Enzastaurin, an oral serine/threonine kinase inhibitor, targets the protein kinase C and AKT pathways with anti-tumor and anti-angiogenic effects. Erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, has activity in solid tumors. Based on the promising combination of EGFR inhibitors and anti-angiogenic agents, this phase I trial was initiated. This single-institution, open-label, non-randomized trial used a standard 3 + 3 dose-escalation model in patients with advanced solid malignancies including non-small-cell lung cancer (NSCLC). Two dose levels of enzastaurin (with loading doses) were explored: 250 mg daily and 500 mg daily. Erlotinib was given at 150 mg daily. Sixteen patients were enrolled in this study (median age, 64 years). Most patients were heavily pre-treated, female, and Caucasian and had NSCLC. The highest dose of enzastaurin, 500 mg daily, was tolerated with no unexpected adverse events and no alteration in the pharmacokinetics of either drug at this dose level. The mean clearance was 5.75 L/h for erlotinib and 53.8 L/h for enzastaurin. The most common possibly drug-related grade 3–4 adverse events included diarrhea (25.0%), neurologic symptoms (18.8%), and vomiting (18.8%). Activity was noted, with a partial response in one patient and prolonged disease stability for >12 cycles in three patients. The combination of enzastaurin 500 mg daily and erlotinib 150 mg daily is well tolerated and does not alter the pharmacokinetics of the individual drugs, with clinical activity seen. A phase II trial of this combination has been initiated in patients with advanced-stage NSCLC.

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Cost-effectiveness of a nurse-based intervention (AIMS) to improve adherence among HIV-infected patients: design of a multi-centre randomised controlled trial

BACKGROUND Non-adherence to HIV-treatment can have a negative impact on patients treatment success rates, quality of life, infectiousness, and life expectancy. Few adherence interventions have shown positive effects on adherence and/or virologic outcomes. The theory- and evidence-based Adherence Improving self-Management Strategy (AIMS) is an intervention that has been demonstrated to improve adherence and viral suppression rates in a randomised controlled trial. However, evidence of its cost-effectiveness is lacking. Following a recent review suggesting that cost-effectiveness evaluations of adherence interventions for chronic diseases are rare, and that the methodology of such evaluations is poorly described in the literature, this manuscript presents the study protocol for a multi-centre trial evaluating the effectiveness and cost-effectiveness of AIMS among a heterogeneous sample of patients. METHODS/DESIGN The study uses a multi-centre randomised controlled trial design to compare the AIMS intervention to usual care from a societal perspective. Embedded in this RCT is a trial-based and model-based economic evaluation. A planned number of 230 HIV-infected patients are randomised to receive either AIMS or usual care. The relevant outcomes include changes in adherence, plasma viral load, quality of life, and societal costs. The time horizon for the trial-based economic evaluation is 12-15 months. Costs and effects are extrapolated to a lifetime horizon for the model-based economic evaluation. DISCUSSION The present multicentre RCT is designed to provide sound methodological evidence regarding the effectiveness and cost-effectiveness of a nurse-based counselling intervention (AIMS) to support treatment adherence among a large and heterogeneous sample of HIV-infected patients in the Netherlands. The objective of the current paper is to describe the trial protocol in sufficient detail to allow full evaluation of the quality of the study design. It is anticipated that, if proven cost-effective, AIMS can contribute to improved evidence-based counselling guidelines for HIV-nurses and other health care professionals. TRIAL REGISTRATION The study has been registered on clinicaltrials.gov (Identifier: NCT01429142).

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A randomized controlled behavioral intervention trial to improve medication adherence in adult stroke patients with prescription tailored Short Messaging Service (SMS)-SMS4Stroke study

BACKGROUND The effectiveness of mobile technology to improve medication adherence via customized Short Messaging Service (SMS) reminders for stroke has not been tested in resource poor areas. We designed a randomized controlled trial to test the effectiveness of SMS on improving medication adherence in stroke survivors in Pakistan. METHODS This was a parallel group, assessor-blinded, randomized, controlled, superiority trial. Participants were centrally randomized in fixed block sizes. Adult participants on multiple medications with access to a cell phone and stroke at least 4 weeks from onset (Onset as defined by last seen normal) were eligible. The intervention group, in addition to usual care, received reminder SMS for 2 months that contained a) Personalized, prescription tailored daily medication reminder(s) b) Twice weekly health information SMS. The Health Belief Model and Social Cognitive theory were used to design the language and content of messages. Frontline SMS software was used for SMS delivery. Medication adherence was self-reported and measured on the validated Urdu version of Morisky Medication Adherence Questionnaire. Multiple linear regression was used to model the outcome against intervention and other covariates. Analysis was conducted by intention-to-treat principle. RESULTS Two hundred participants were enrolled. 38 participants were lost to follow-up. After 2 months, the mean medication score was 7.4 (95 % CI: 7.2-7.6) in the intervention group while 6.7 (95 % CI: 6.4-7.02) in the control group. The adjusted mean difference (Δ) was 0.54 (95 % CI: 0.22-0.85). The mean diastolic blood pressure in the intervention group was 2.6 mmHg (95 % CI; -5.5 to 0.15) lower compared to the usual care group. CONCLUSION A short intervention of customized SMS can improve medication adherence and effect stroke risk factors like diastolic blood pressure in stroke survivors with complex medication regimens living in resource poor areas. TRIAL REGISTRATION Clinicaltrials.gov NCT01986023 last accessed at https://clinicaltrials.gov/ct2/show/NCT01986023.

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The pediatric asthma intervention: a comprehensive cost-effective approach to asthma management in a disadvantaged inner-city community.

OBJECTIVE To compare three pediatric asthma interventions for their impact on improving the health status of inner-city asthmatic children and in achieving cost savings. STUDY DESIGN A total of 212 children 1 to 16 years of age were randomized into three groups: group 1 (n = 74) received one individualized asthma education session; group 2 (n = 68) received reinforced asthma education; group 3 (n = 70) received reinforced asthma education plus case management. Asthma-related health resource utilization and cost were primary outcomes. The cost-benefit analysis sought to estimate the expected cost savings to the Illinois Department of Healthcare and Family Services (Medicaid administrator) associated with the intervention. RESULTS Participants in all three groups used significantly fewer emergency health care services in the follow-up year. Averaged across all three groups, the magnitudes of declines were substantial: 81% for hospitalizations, 69% for hospital days, 64% for emergency department visits, and 58% for clinic visits. Although there were no statistically significant differences between study groups for three of the four main outcome measures, group 3 participants consistently improved to the greatest degree. All three interventions were associated with considerable cost savings ranging from $4,021/child/year for group 1 to $4,503/child/year for group 3. CONCLUSION Asthma education with or without case management services enhances the health of children with asthma thereby reducing associated costs.

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Prevention of Heel Pressure Injuries and Plantar Flexion Contractures With Use of a Heel Protector in High-Risk Neurotrauma, Medical, and Surgical Intensive Care Units: A Randomized Controlled Trial.

PURPOSE The purpose of this study was to compare the use of a heel protector to standard of care (pillows) in the prevention of hospital-acquired pressure injuries (HAPI) of the heels and prevention of plantar flexion contractures. DESIGN Randomized controlled trial. SUBJECTS AND SETTING The study took place on a surgical intensive care unit, medical intensive care unit, and neurotrauma intensive care unit. Inclusion criteria were a minimum of 5 days of sedation related to care for a critical illness, immobility for 6 to 8 hours before study initiation, a Braden Scale for Pressure Sore Risk score 18 or less, and a mobility subscale score 2 or less. Patients were included if they had preexisting heel pressure injury or plantar flexion contracture. The sample comprised 54 subjects; 37 were randomly allocated to the intervention group and 17 to the control group. Their average age-mean (standard deviation)-was 40.7 (14.96) years in the control group and 44.6 (17.15) years in the intervention group. METHODS Data were collected from patients' electronic medical records. We recorded subject demographics, presence of diabetes mellitus or peripheral vascular disease, Glasgow Coma Scale scores (every shift), Braden Scale for Pressure Sore Risk scores (every shift), heel skin assessments (every shift), goniometric measurements (every other day), and adverse events (every shift). Assessments and measurements were continued until the patient was discharged from the study. RESULTS None of the patients in the intervention group developed HAPI of the heels, as compared to 7 in the control group (0% vs 41%, P < .001). Patients in the intervention group had a significantly greater decrease in goniometric scores (mean decrease = 1.4 ± 2.25) compared to the control group by day 3 (mean decrease = 0.1 ± 0.52 P = .004) and the last study day (mean decrease = 2.0 ± 3.02 for the intervention group vs 0.07 ± 0.96 for the control group; P < .001). CONCLUSIONS Study findings indicate that a heel protector that ensures off-loading and maintains the foot in a neutral position is more effective for prevention of HAPI of the heel and contractures as compared to standard care using pillows to position the heel and redistribute pressure.

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Effect of cyclosporine on reperfusion injury in acute myocardial infarction.

BACKGROUND Experimental evidence suggests that cyclosporine, which inhibits the opening of mitochondrial permeability-transition pores, attenuates lethal myocardial injury that occurs at the time of reperfusion. In this pilot trial, we sought to determine whether the administration of cyclosporine at the time of percutaneous coronary intervention (PCI) would limit the size of the infarct during acute myocardial infarction. METHODS We randomly assigned 58 patients who presented with acute ST-elevation myocardial infarction to receive either an intravenous bolus of 2.5 mg of cyclosporine per kilogram of body weight (cyclosporine group) or normal saline (control group) immediately before undergoing PCI. Infarct size was assessed in all patients by measuring the release of creatine kinase and troponin I and in a subgroup of 27 patients by performing magnetic resonance imaging (MRI) on day 5 after infarction. RESULTS The cyclosporine and control groups were similar with respect to ischemia time, the size of the area at risk, and the ejection fraction before PCI. The release of creatine kinase was significantly reduced in the cyclosporine group as compared with the control group (P=0.04). The release of troponin I was not significantly reduced (P=0.15). On day 5, the absolute mass of the area of hyperenhancement (i.e., infarcted tissue) on MRI was significantly reduced in the cyclosporine group as compared with the control group, with a median of 37 g (interquartile range, 21 to 51) versus 46 g (interquartile range, 20 to 65; P=0.04). No adverse effects of cyclosporine administration were detected. CONCLUSIONS In our small, pilot trial, administration of cyclosporine at the time of reperfusion was associated with a smaller infarct by some measures than that seen with placebo. These data are preliminary and require confirmation in a larger clinical trial.

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Effect of a six month gemfibrozil treatment and dietary recommendations on the metabolic risk profile of visceral obese men

OBJECTIVE: The aim of the present study was to investigate the effects of a 6 month gemfibrozil treatment.SUBJECTS: A sample of 64 visceral obese men (age 46±6 y; body mass index 31±3 kg/m2; waist circumference 104±7 cm; mean±s.d.) who received dietary recommendations.METHODS: Subjects were randomly assigned to receive a placebo (n=32) or gemfibrozil (1200 mg/day) (n=32).RESULTS: In both placebo and gemfibrozil treated groups, significant reductions were noted in body weight, fat mass, waist circumference and visceral adipose tissue area measured by computed tomography (0.0001<P<0.05). Plasma cholesterol (CHOL) and apolipoprotein B (apo B) levels were also decreased in both groups (P<0.01) whereas plasma high density lipoprotein (HDL) and HDL-3-CHOL levels were only significantly (P<0.01) increased in the gemfibrozil-treated group. After the 6 month treatment period, gemfibrozil-treated men displayed significantly lower plasma triglycerides (TG) levels, compared to those who received the placebo (P<0.01). Finally, both fasting plasma insulin concentration and insulin area measured during an oral glucose load were significantly decreased only in the placebo group (P<0.05). Taken together, these results suggest that the improvement in plasma lipid/lipoprotein profile observed in gemfibrozil treated visceral obese men seems to be independent from changes in adipose tissue mass and in visceral fat accumulation. Furthermore, improvements in the plasma lipoprotein profile produced by gemfibrozil therapy appear to be independent from changes in indices of plasma glucose–insulin homeostasis.

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Evaluation of hypertension control in Greek primary care units. The VANK study

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A cluster randomized controlled trial to determine the efficacy of Trauma Risk Management (TRiM) in a military population.

Trauma Risk Management is a peer-support program that aims to promote help-seeking in the aftermath of traumatic events. Prior to its implementation, the British military conducted a randomized controlled trial of Trauma Risk Management against standard care in 12 warships; 6 were randomized to use Trauma Risk Management after collecting baseline measurements. Follow up after 12-18 months found no significant change in psychological health or stigma scores in either group; however, the studied vessels only encountered low numbers of critical incidents. Additionally, measurements of organizational functioning were modestly better in the Trauma Risk Management ships. The authors conclude that within organizations using Trauma Risk Management may be beneficial and may, in time, lead to a valuable cultural shift.

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Cluster ing of insul in resistance , total and central abdominal fat : same genes or same envi ronment ?

Obesi ty, insul in resistance and disturbed glucose metabol ism cluster wi thin the Insul in Resistance Syndrome (IRS). Whether this reflects shared genetic or envi ronmental factors detectable in ‘normal ’ populations (not selected for IRS features) is unknown. This study estimated (i ) genetic influences on IRS trai ts and (i i ) shared and specific genetic and envi ronmental factors on the relationships between these trai ts in heal thy female twins. Fasting insul in, glucose, total and central fat were measured in 59 monozygotic (MZ) and 51 dizygotic (DZ) female twin pai rs aged ( ± SD) 52 ± 13 years. Body fat was measured by dual -energy X-ray absorptiometry, insul in resistance and secretion by a modified homeostasis model assessment. Using intraclass correlation coefficients and univar iate model -fi tting analyses, genetic influences were found in total fat, central fat, insul in resistance, fasting glucose and insul in secretion, wi th genetic factors explaining 64, 57, 59, 75 and 68% of thei r var iance, respectively, using the latter technique. In matched analysis intra-pai r di fferences in total and central fat related to intra-pai r di fferences in insul in resistance (r 2 = 0.19, P < 0.001). Mul tivar iate model -fi tting showed a close genetic relationship between total and central fat (r = 0.88). The genetic correlation between IR and central fat (0.41) was significantly greater than that for total fat (0.24), suggesting that central fat is not only a predictor of, but shares considerable genetic influence wi th, insul in resistance. In Cholesky analysis, these genetic influences were separate from those shared between central and total fat. In conclusion, both shared and specific genetic factors regulate components of the IRS in heal thy females. However, there were discrete genetic influences on -cel l insul in secretion, not shared wi th other IRS components, suggesting that a separate genetic propensi ty exists for Type2 diabetes. These findings suggest we may understand the genetic and envi ronmental influences on IRS from the study of the normal population.

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An open-label randomized trial comparing itraconazole oral solution with fluconazole oral solution for primary prophylaxis of fungal infections in patients with haematological malignancy and profound neutropenia.

OBJECTIVES This trial studied the efficacy and safety of itraconazole and fluconazole in the prevention of invasive fungal infections in neutropenic patients with haematological malignancies. PATIENTS AND METHODS An 8 week, open-label, randomized, parallel-group, multicentre trial comparing itraconazole oral solution (2.5 mg/kg twice daily; N=248) with fluconazole oral solution or capsules (400 mg daily; N=246) in 494 patients with anticipated profound neutropenia (i.e. neutrophil count expected to be <500 cells/mm3 for at least 10 days) from tertiary care centres. RESULTS Invasive fungal infections were reported for 4 out of 248 patients (1.6%) in the itraconazole group and 5 out of 246 patients (2.0%) in the fluconazole group. Invasive Aspergillus infections were proven for 2 out of 248 patients (0.8%) in the itraconazole group and 3 out of 246 patients (1.2%) in the fluconazole group. For both the ITT and profoundly neutropenic populations, no differences were detected between treatment groups in proven or suspected invasive fungal infections or other endpoints. The mortality rates owing to proven invasive fungal infections were 2 out of 248 patients (0.8%) for the itraconazole group and 3 out of 246 patients (1.2%) for the fluconazole group. There was also no difference between treatment groups in the number of patients who recovered from neutropenia or in the duration of neutropenia. More discontinuation of drug intake owing to nausea and more hypokalaemia occurred in the itraconazole group, other adverse events and the total number of adverse events were similar in both groups. CONCLUSIONS In this study there were no differences in the efficacy and safety of itraconazole and fluconazole prophylaxis in neutropenic patients with haematological malignancies.

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Under-diagnosis of smear-positive pulmonary tuberculosis in Nairobi, Kenya.

SETTING Nairobi City Council Chest Clinic, Nairobi, Kenya. OBJECTIVE To determine if under-reading of sputum smears is a contributing factor in the disproportionate increase in smear-negative tuberculosis in Nairobi, Kenya. METHODOLOGY Between October 1997 and November 1998, patients fulfilling the local programme definition of smear-negative presumed pulmonary tuberculosis were enrolled in the study. Two further sputum specimens were collected for examination in a research laboratory by fluorescence microscopy. RESULTS Of 163 adult subjects enrolled, 55% were seropositive for the human immunodeficiency virus type 1 (HIV-1). One hundred subjects had had two pre-study sputum smears assessed before recruitment and produced two further sputum specimens for re-examination in the research laboratory; of these 19 (19%) were sputum smear-positive on re-examination and a further seven (7%) became smear-positive on second re-examination. CONCLUSIONS Of those patients with smear-negative presumed pulmonary tuberculosis by the local programme definition, 26% were smear-positive when reexamined carefully with two repeat sputum smears. This suggests that the high rates of smear-negative tuberculosis being seen may in part be due to under-reading. This is probably as a result of the overwhelming burden of tuberculosis leading to over rapid and inaccurate sputum examination. Retraining of existing technicians and training of more technicians is likely to reduce underreading and increase the yield of smear-positive tuberculosis. This finding also stresses the need for regular quality assurance.

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Comparison of olmesartan combined with a calcium channel blocker or a diuretic in elderly hypertensive patients (COLM Study): safety and tolerability

The cardiovascular effects of combined therapy with the angiotensin receptor blocker (olmesartan) and a dihydropyridine calcium channel blocker (CCB) or a diuretic were compared in high-risk elderly Japanese hypertensive patients by performing a randomized, open label, blinded-endpoint study of morbidity and mortality (the COLM study). Here we report the results obtained with respect to safety and tolerability. High-risk hypertensive patients aged 65–84 years were enrolled and were randomized to receive olmesartan combined with either a CCB (amlodipine or azelnidipine) or a low-dose diuretic for at least 3 years. The primary endpoint was a composite of fatal and non fatal cardiovascular events, whereas adverse events (AEs) and the percentage of patients who discontinued the allocated treatment were evaluated as secondary endpoints. A total of 5141 patients were randomized. Both combination regimens achieved a similar reduction of cardiovascular morbidity and mortality. The incidences of AEs, serious AEs, drug-related serious AEs and discontinuation due to serious AEs were lower in the olmesartan plus CCB group than in the olmesartan plus diuretic group. Serum levels of uric acid and creatinine were significantly higher in the olmesartan plus diuretic group than in the olmesartan plus CCB group. Olmesartan combined with a CCB was significantly superior to olmesartan plus a diuretic with regard to the frequency of AEs and discontinuation of treatment.

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Role of angiotensin II in plasma PAI-1 changes induced by imidapril or candesartan in hypertensive patients with metabolic syndrome

To evaluate the relationship between plasma plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (Ang II) changes during treatment with imidapril and candesartan in hypertensive patients with metabolic syndrome. A total of 84 hypertensive patients with metabolic syndrome were randomized to imidapril 10 mg or candesartan 16 mg for 16 weeks. At weeks 4 and 8, there was a dose titration to imidapril 20 mg and candesartan 32 mg in nonresponders (systolic blood pressure (SBP) >140 and/or diastolic blood pressure (DBP) >90 mm Hg). We evaluated, at baseline and after 2, 4, 8, 12 and 16 weeks, clinic blood pressure, Ang II and PAI-1 antigen. Both imidapril and candesartan induced a similar SBP/DBP reduction (−19.4/16.8 and −19.5/16.3 mm Hg, respectively, P<0.001 vs. baseline). Both drugs decreased PAI-1 antigen after 4 weeks of treatment, but only the PAI-1 lowering effect of imidapril was sustained throughout the 16 weeks (−9.3 ng ml−1, P<0.01 vs. baseline), whereas candesartan increased PAI-1 (+6.5 ng ml−1, P<0.05 vs. baseline and P<0.01 vs. imidapril). Imidapril significantly decreased Ang II levels (−14.6 pg ml−1 at week 16, P<0.05 vs. baseline), whereas candesartan increased them (+24.2 pg ml−1, P<0.01 vs. baseline and vs. imidapril). In both groups there was a positive correlation between Ang II and PAI-1 changes (r=0.61, P<0.001 at week 16 for imidapril, and r=0.37, P<0.005 at week 16 for candesartan). Imidapril reduced plasma PAI-1 and Ang II levels, whereas candesartan increased them. This suggests that the different effect of angiotensin-converting enzyme inhibitors and Ang II blockers on Ang II production has a role in their different influence on fibrinolysis.

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Factors that influence cancer patients' anxiety following a medical consultation: impact of a communication skills training programme for physicians.

BACKGROUND No study has yet assessed the impact of physicians' skills acquisition after a communication skills training programme on the evolution of patients' anxiety following a medical consultation. This study aimed to compare the impact, on patients' anxiety, of a basic communication skills training programme (BT) and the same programme consolidated by consolidation workshops (CW), and to investigate physicians' communication variables associated with patients' anxiety. PATIENTS AND METHODS Physicians, after attending the BT, were randomly assigned to CW or to a waiting list. The control group was not a non-intervention group. Consultations with a cancer patient were recorded. Patients' anxiety was assessed with the State Trait Anxiety Inventory before and after a consultation. Communication skills were analysed according to the Cancer Research Campaign Workshop Evaluation Manual. RESULTS No statistically significant change over time and between groups was observed. Mixed-effects modelling showed that a decrease in patients' anxiety was linked with screening questions (P = 0.045), physicians' satisfaction about support given (P = 0.004) and with patients' distress (P < 0.001). An increase in anxiety was linked with breaking bad news (P = 0.050) and with supportive skills (P = 0.013). No impact of the training programme was observed. CONCLUSIONS This study shows the influence of some communication skills on the evolution of patients' anxiety. Physicians should be aware of these influences.

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Is adjuvant chemotherapy indicated in stage I pure immature ovarian teratoma (IT)? A multicentre Italian trial in ovarian cancer (MITO-9).

OBJECTIVE Conservative surgery followed by platinum-based chemotherapy is considered the standard approach for stage I immature ovarian teratoma (IT), except for stage IA G1. Nevertheless the use of chemotherapy in stage IA G2-3 and IB-IC is controversial. The aim of this study was to evaluate the outcome of patients with IT in order to define the role of chemotherapy in stage I disease. METHODS Twenty-eight patients with stage I IT treated in MITO centers were retrospectively reviewed. Grade, stage, age, surgical and postoperative treatment were analyzed using χ(2) test and T test looking for association with recurrence. RESULTS Median age was 25.5. Twenty-four patients underwent fertility-sparing surgery. FIGO stages were 19 IA, 2 IB, and 7 IC. Nine patients had grade 1 tumor, 12 grade 2, and 7 grade 3. Nine patients received adjuvant chemotherapy. Overall recurrence rate was 21.4% (2 in chemotherapy group and 4 in the group without treatment). No patients with G1 had recurrence, whereas 25% of G2 and 42.9% of G3 relapsed. Recurrence rate was not significantly different according to stage, grade or adjuvant chemotherapy, whereas it was greater in the group not operated in a MITO center, not staged and of age lower than 20 years, with statistical significance. At recurrence 4 patients presenting with mature teratoma were treated with surgery alone, whereas 2 recurring with IT were treated with surgery plus chemotherapy. After a median follow-up of 59 months all patients are NED. CONCLUSIONS Our study suggests that chemotherapy may be withheld for primary therapy and utilized only for recurrence.

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Relationship between PCO2 and unfavorable outcome in infants with moderate-to-severe hypoxic ischemic encephalopathy

Background:Abnormal PCO2 is common in infants with hypoxic ischemic encephalopathy (HIE). The objective was to determine whether hypocapnia was independently associated with unfavorable outcome (death or severe neurodevelopmental disability at 18 mo) in infants with moderate-to-severe HIE.Methods:This was a post hoc analysis of the CoolCap Study in which infants were randomized to head cooling or standard care. Blood gases were measured at prespecified times after randomization. PCO2 and follow-up data were available for 196 of 234 infants. Analyses were performed to investigate the relationship between hypocapnia in the first 72 h after randomization and unfavorable outcome.Results:After adjusting for pH, amplitude-integrated electroencephalogram background and seizures, birth weight, Apgar score at 5 min, cooling status, and Sarnat stage, PCO2 was inversely associated with unfavorable outcome (P < 0.001). The probability of unfavorable outcome was 0.20 ± 0.1 (point estimate ± SE), 0.53 ± 0.23 and 0.89 ± 0.16 for a PCO2 of 40, 30, and 20 mm Hg respectively and was greater in infants with severe HIE than with moderate HIE.Conclusions:Hypocapnia in infants with moderate-to-severe HIE was independently associated with unfavorable outcome. Future studies of controlled normocapnia will be important.