Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001.

PURPOSE: To compare clinical benefit response (CBR) and quality of life (QOL) in patients receiving gemcitabine (Gem) plus capecitabine (Cap) versus single-agent Gem for advanced/metastatic pancreatic cancer. PATIENTS AND METHODS: Patients were randomly assigned to receive GemCap (oral Cap 650 mg/m(2) twice daily on days 1 through 14 plus Gem 1,000 mg/m(2) in a 30-minute infusion on days 1 and 8 every 3 weeks) or Gem (1,000 mg/m(2) in a 30-minute infusion weekly for 7 weeks, followed by a 1-week break, and then weekly for 3 weeks every 4 weeks) for 24 weeks or until progression. CBR criteria and QOL indicators were assessed over this period. CBR was defined as improvement from baseline for >or= 4 consecutive weeks in pain (pain intensity or analgesic consumption) and Karnofsky performance status, stability in one but improvement in the other, or stability in pain and performance status but improvement in weight. RESULTS: Of 319 patients, 19% treated with GemCap and 20% treated with Gem experienced a CBR, with a median duration of 9.5 and 6.5 weeks, respectively (P < .02); 54% of patients treated with GemCap and 60% treated with Gem had no CBR (remaining patients were not assessable). There was no treatment difference in QOL (n = 311). QOL indicators were improving under chemotherapy (P < .05). These changes differed by the time to failure, with a worsening 1 to 2 months before treatment failure (all P < .05). CONCLUSION: There is no indication of a difference in CBR or QOL between GemCap and Gem. Regardless of their initial condition, some patients experience an improvement in QOL on chemotherapy, followed by a worsening before treatment failure.

CT dose optimization when changing to CT multi-detector row technology

The purpose of this article was to review the strategies to control patient dose in adult and pediatric computed tomography (CT), taking into account the change of technology from single-detector row CT to multi-detector row CT. First the relationships between computed tomography dose index, dose length product, and effective dose in adult and pediatric CT are revised, along with the diagnostic reference level concept. Then the effect of image noise as a function of volume computed tomography dose index, reconstructed slice thickness, and the size of the patient are described. Finally, the potential of tube current modulation CT is discussed.

Combined written and oral information prior to gastrointestinal endoscopy compared with oral information alone: a randomized trial.

BACKGROUND: Little is known about how to most effectively deliver relevant information to patients scheduled for endoscopy. METHODS: To assess the effects of combined written and oral information, compared with oral information alone on the quality of information before endoscopy and the level of anxiety. We designed a prospective study in two Swiss teaching hospitals which enrolled consecutive patients scheduled for endoscopy over a three-month period. Patients were randomized either to receiving, along with the appointment notice, an explanatory leaflet about the upcoming examination, or to oral information delivered by each patient's doctor. Evaluation of quality of information was rated on scales between 0 (none received) and 5 (excellent). The analysis of outcome variables was performed on the basis of intention to treat-analysis. Multivariate analysis of predictors of information scores was performed by linear regression analysis. RESULTS: Of 718 eligible patients 577 (80%) returned their questionnaire. Patients who received written leaflets (N = 278) rated the quality of information they received higher than those informed verbally (N = 299), for all 8 quality-of-information items. Differences were significant regarding information about the risks of the procedure (3.24 versus 2.26, p < 0.001), how to prepare for the procedure (3.56 versus 3.23, p = 0.036), what to expect after the procedure (2.99 versus 2.59, p < 0.001), and the 8 quality-of-information items (3.35 versus 3.02, p = 0.002). The two groups reported similar levels of anxiety before procedure (p = 0.66), pain during procedure (p = 0.20), tolerability throughout the procedure (p = 0.76), problems after the procedure (p = 0.22), and overall rating of the procedure between poor and excellent (p = 0.82). CONCLUSION: Written information led to more favourable assessments of the quality of information and had no impact on patient anxiety nor on the overall assessment of the endoscopy. Because structured and comprehensive written information is perceived as beneficial by patients, gastroenterologists should clearly explain to their patients the risks, benefits and alternatives of endoscopic procedures. Trial registration: Current Controlled trial number: ISRCTN34382782.

Effect of a lifestyle intervention on adiposity and fitness in socially disadvantaged subgroups of preschoolers: a cluster-randomized trial (Ballabeina).

OBJECTIVE: A multidimensional lifestyle intervention performed in 652 preschoolers (72% of migrant, 38% of low educational level (EL) parents) reduced body fat, but not BMI and improved fitness. The objective of this study is to examine whether the intervention was equally effective in children of migrant and/or low EL parents.¦METHODS: Cluster-randomized controlled single blinded trial, conducted in 2008/09 in 40 randomly selected preschools in Switzerland. The culturally tailored intervention consisted of a physical activity program and lessons on nutrition, media use and sleep. Primary outcomes included BMI and aerobic fitness. Secondary outcomes included %body fat, waist circumference and motor agility.¦RESULTS: Children of migrant parents benefitted similarly from the intervention compared to their counterparts (p for interaction≥ 0.09). However, children of low EL parents benefitted less, although these differences did not reach statistical significance (p for interaction≥ 0.06). Average intervention effect sizes for BMI were -0.10, -0.05, -0.11 and 0.04 kg/m(2) and for aerobic fitness were 0.55, 0.20, 0.37 and -0.05 stages for children of non-migrant, migrant, middle/high EL and low EL parents, respectively.¦CONCLUSIONS: This intervention was similarly effective among preschoolers of migrant parents compared to their counterparts, while children of low EL parents benefitted less.

Optimization of snowmaking in high mountains ski resort

Ski resorts are deploying more and more systems of artificial snow. These tools are necessary to ensure an important economic activity for the high alpine valleys. However, artificial snow raises important environmental issues that can be reduced by an optimization of its production. This paper presents a software prototype based on artificial intelligence to help ski resorts better manage their snowpack. It combines on one hand a General Neural Network for the analysis of the snow cover and the spatial prediction, with on the other hand a multiagent simulation of skiers for the analysis of the spatial impact of ski practice. The prototype has been tested on the ski resort of Verbier (Switzerland).

Does altering inclination alter effectiveness of treadmill training for gait impairment after stroke? A randomized controlled trial.

Objective: To assess whether a downhill walking training programme is more effective than the same amount of training applied uphill in chronic stroke survivors. Design: Randomized, single-blind study. Setting: Outpatient rehabilitation service. Methods: Thirty-eight adults with hemiplegia from stroke lasting more than three months were randomly allocated to one of the two groups: 'UP' - 45 minutes of physical therapy + 30 minutes of treadmill with 5% ascending slope; and 'DOWN' - 45 minutes of physical therapy + 30 minutes of treadmill with 5% descending slope. Both groups were treated 5 times a week for six weeks. Patients were evaluated before treatment, at the end of treatment and after three months. Outcome measures: Primary outcome measure was the number of patients showing an improvement in 6-minute walking test (6MWT) greater than 50 m. Secondary outcome measures were: (1) number of patients showing a clinically relevant improvement of gait speed during 10-m walking test (10mWT); (2) number of patients showing an improvement in timed up and go (TUG) greater than minimal detectable change. Results: Both groups had a significant improvement after treatment and at follow-up. At the end of treatment, compared to UP group, more patients in the DOWN group showed clinically significant improvements in primary and secondary outcomes (16/19 patients for 6MWT, 11/19 patients for 10mWT and 9/19 patients for TUG compared with 3/19, 4/19 and 2/19 patients, respectively, P < 0.01). At follow-up, results were similar except for 10mWT. Conclusions: In chronic stroke patients, downhill treadmill training produces a bigger effect than uphill training.

Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis.

BACKGROUND: Interleukin-1 is pivotal in the pathogenesis of systemic juvenile idiopathic arthritis (JIA). We assessed the efficacy and safety of canakinumab, a selective, fully human, anti-interleukin-1β monoclonal antibody, in two trials. METHODS: In trial 1, we randomly assigned patients, 2 to 19 years of age, with systemic JIA and active systemic features (fever; ≥2 active joints; C-reactive protein, >30 mg per liter; and glucocorticoid dose, ≤1.0 mg per kilogram of body weight per day), in a double-blind fashion, to a single subcutaneous dose of canakinumab (4 mg per kilogram) or placebo. The primary outcome, termed adapted JIA ACR 30 response, was defined as improvement of 30% or more in at least three of the six core criteria for JIA, worsening of more than 30% in no more than one of the criteria, and resolution of fever. In trial 2, after 32 weeks of open-label treatment with canakinumab, patients who had a response and underwent glucocorticoid tapering were randomly assigned to continued treatment with canakinumab or to placebo. The primary outcome was time to flare of systemic JIA. RESULTS: At day 15 in trial 1, more patients in the canakinumab group had an adapted JIA ACR 30 response (36 of 43 [84%], vs. 4 of 41 [10%] in the placebo group; P<0.001). In trial 2, among the 100 patients (of 177 in the open-label phase) who underwent randomization in the withdrawal phase, the risk of flare was lower among patients who continued to receive canakinumab than among those who were switched to placebo (74% of patients in the canakinumab group had no flare, vs. 25% in the placebo group, according to Kaplan-Meier estimates; hazard ratio, 0.36; P=0.003). The average glucocorticoid dose was reduced from 0.34 to 0.05 mg per kilogram per day, and glucocorticoids were discontinued in 42 of 128 patients (33%). The macrophage activation syndrome occurred in 7 patients; infections were more frequent with canakinumab than with placebo. CONCLUSIONS: These two phase 3 studies show the efficacy of canakinumab in systemic JIA with active systemic features. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT00889863 and NCT00886769.).

Thérapie cellulaire en cardiologie: bilan des premiers essais cliniques randomisés [Cell therapies in cardiology: results from the first randomized clinical trials]

Following acute myocardial infarction, necrotic cardiac tissue is replaced by scar leading to ventricular remodeling and pump failure. Transplantation of autologous bone marrow-derived cells into the heart, early post-infarct, aims to prevent ventricular remodeling. This strategy has been evaluated in four controlled, randomized clinical trials, which provided mixed results. A transient improvement in ventricular function was observed in one trial, and a modest improvement (the duration of which remains to be determined) in an additional trial, whereas two trials showed negative results. A modest benefit of bone marrow cell transplantation was also observed in patients with chronic ischemic heart disease. Despite mixed results reported so far, cell therapy of heart disease still is in its infancy and has considerable room for improvement.

How Much Does It Cost? Optimization of Costs in Sequence Analysis of Social Science Data

One major methodological problem in analysis of sequence data is the determination of costs from which distances between sequences are derived. Although this problem is currently not optimally dealt with in the social sciences, it has some similarity with problems that have been solved in bioinformatics for three decades. In this article, the authors propose an optimization of substitution and deletion/insertion costs based on computational methods. The authors provide an empirical way of determining costs for cases, frequent in the social sciences, in which theory does not clearly promote one cost scheme over another. Using three distinct data sets, the authors tested the distances and cluster solutions produced by the new cost scheme in comparison with solutions based on cost schemes associated with other research strategies. The proposed method performs well compared with other cost-setting strategies, while it alleviates the justification problem of cost schemes.

Ecological-economic optimization of biodiversity conservation under climate change

Substantial investment in climate change research has led to dire predictions of the impacts and risks to biodiversity. The Intergovernmental Panel on Climate Change fourth assessment report(1) cites 28,586 studies demonstrating significant biological changes in terrestrial systems(2). Already high extinction rates, driven primarily by habitat loss, are predicted to increase under climate change(3-6). Yet there is little specific advice or precedent in the literature to guide climate adaptation investment for conserving biodiversity within realistic economic constraints(7). Here we present a systematic ecological and economic analysis of a climate adaptation problem in one of the world's most species-rich and threatened ecosystems: the South African fynbos. We discover a counterintuitive optimal investment strategy that switches twice between options as the available adaptation budget increases. We demonstrate that optimal investment is nonlinearly dependent on available resources, making the choice of how much to invest as important as determining where to invest and what actions to take. Our study emphasizes the importance of a sound analytical framework for prioritizing adaptation investments(4). Integrating ecological predictions in an economic decision framework will help support complex choices between adaptation options under severe uncertainty. Our prioritization method can be applied at any scale to minimize species loss and to evaluate the robustness of decisions to uncertainty about key assumptions.

EADock: docking of small molecules into protein active sites with a multiobjective evolutionary optimization.

In recent years, protein-ligand docking has become a powerful tool for drug development. Although several approaches suitable for high throughput screening are available, there is a need for methods able to identify binding modes with high accuracy. This accuracy is essential to reliably compute the binding free energy of the ligand. Such methods are needed when the binding mode of lead compounds is not determined experimentally but is needed for structure-based lead optimization. We present here a new docking software, called EADock, that aims at this goal. It uses an hybrid evolutionary algorithm with two fitness functions, in combination with a sophisticated management of the diversity. EADock is interfaced with the CHARMM package for energy calculations and coordinate handling. A validation was carried out on 37 crystallized protein-ligand complexes featuring 11 different proteins. The search space was defined as a sphere of 15 A around the center of mass of the ligand position in the crystal structure, and on the contrary to other benchmarks, our algorithm was fed with optimized ligand positions up to 10 A root mean square deviation (RMSD) from the crystal structure, excluding the latter. This validation illustrates the efficiency of our sampling strategy, as correct binding modes, defined by a RMSD to the crystal structure lower than 2 A, were identified and ranked first for 68% of the complexes. The success rate increases to 78% when considering the five best ranked clusters, and 92% when all clusters present in the last generation are taken into account. Most failures could be explained by the presence of crystal contacts in the experimental structure. Finally, the ability of EADock to accurately predict binding modes on a real application was illustrated by the successful docking of the RGD cyclic pentapeptide on the alphaVbeta3 integrin, starting far away from the binding pocket.

Motivational intervention to reduce cannabis use in young people with psychosis: a randomized controlled trial.

Background: Cannabis use has a negative impact on psychosis. Studies are needed to explore the efficacy of psychological interventions to reduce cannabis use in psychosis. Our aim is to study the efficacy of a specific motivational intervention on young cannabis users suffering from psychosis. Methods: Participants (aged less than 35 years) were randomly assigned to treatment as usual (TAU) alone, or treatment as usual plus motivational intervention (MI + TAU). TAU was comprehensive and included case management, early intervention and mobile team when needed. Assessments were completed at baseline and at 3, 6 and12 months follow-up. Results: Sixty-two participants (32 TAU and 30 MI + TAU) were included in the study. Cannabis use decreased in both groups at follow-up. Participants who received MI in addition to TAU displayed both a greater reduction in number of joints smoked per week and greater confidence to change cannabis use at 3 and 6 months follow-up, but differences between groups were nonsignificant at 12 months. Conclusions: MI is well accepted by patients suffering from psychosis and has a short-term impact on cannabis use when added to standard care. However, the differential effect was not maintained at 1-year follow-up. MI appears to be a useful active component to reduce cannabis use which should be integrated in routine clinical practice.

Early mobilization out of bed after ischaemic stroke reduces severe complications but not cerebral blood flow: a randomized controlled pilot trial.

OBJECTIVE: To evaluate whether early mobilization after acute ischaemic stroke is better than delayed mobilization with regard to medical complications and if it is safe in relation to neurological function and cerebral blood flow. DESIGN: Randomized controlled pilot trial of early versus delayed mobilization out of bed with incidence of severe complications as the primary outcome. SETTING: Acute stroke unit in the neurology department of a University Hospital. PARTICIPANTS: Fifty patients after ischaemic stroke with a National Institutes of Health Stroke Scale (NIHSS) score >6 were recruited. INTERVENTION: All patients were treated with physiotherapy immediately after their admission. In the early protocol patients were mobilized out of bed after 52 hours, in the delayed protocol after seven days. RESULTS: Eight out of 50 randomized patients were excluded from the per-protocol analysis because of early transfer to other hospitals. There were 2 (8%) severe complications in the 25 early mobilization patients and 8 (47%) in the 17 delayed mobilization patients (P < 0.006). There were no differences in the total number of complications or in clinical outcome. In the 26 patients (62%) who underwent serial transcranial Doppler ultrasonography, no blood flow differences were found. CONCLUSION: We found an apparent reduction in severe complications and no increase in total complications with an early mobilization protocol after acute ischaemic stroke. No influence on neurological three-month outcomes or on cerebral blood flow was seen. These results justify larger trials comparing mobilization protocols with possibly even faster mobilization out of bed than explored here.