The difficulties of reproducing conventionally derived results through 500k-chip technology

Based on a "training" sample of 1,042 subjects genotyped for 5,728 single-nucleotide polymorphisms (SNPs) of a conventional 0.4-Mb genome scan and a "test" sample of 746 subjects genotyped for 545,080 SNPs on a 500k-chip, we investigated the extent to which the subjects' immunoglobulin M levels can be reproducibly predicted from a multilocus genotype. We were specifically interested in the reproducibility of predictors across populations (1,042 versus 746 subjects) and across SNP sets (conventional genome scan versus anonymous 500k-chip) because this is a prerequisite for clinical application. For the training sample, neural network (NN) analysis yielded classifiers that predicted immunoglobulin M levels from the subjects' multilocus genotypes at acceptable error rates through a configuration of 15 genomic loci (61 SNPs). With the test sample (746 subjects) we addressed the question of reproducibility across populations and across SNP sets by means of a novel "competitive SNP set" approach. However, the chip data contained several sources of distortion, including greatly elevated noise levels and artifact-prone SNP regions, thus complicating attempts to verify the reproducibility of NN predictors. Though 5 of 15 genomic loci from the training samples appeared to be reproducible, the NN classifiers derived so far from the test samples are insufficiently compatible with the training samples. Nonetheless, our results are promising enough to justify further investigations. Because the underlying algorithm can easily be split into parallel tasks, the proposed "competitive SNP set" approach has turned out to be well suited for computers with today's 64-bit multiprocessor architectures and to offer a valuable extension to genome-wide association analyses

No association of a set of candidate genes on haloperidol side effects

We previously investigated a sample of patients during an active phase of psychosis in the search for genetic predictors of haloperidol induced side effects. In the present work we extend the genetic association analysis to a wider panel of genetic variations, including 508 variations located in 96 genes. The original sample included 96 patients. An independent group of 357 patients from the CATIE study served as a replication sample. Outcomes in the investigation sample were the variation through time of: 1) the ESRS and UKU total scores 2) ESRS and UKU subscales (neurologic and psychic were included) related to tremors and 3) ESRS and UKU subscales that do not relate to tremors. Outcome in the replication sample was the presence vs absence of motoric side effects from baseline to visit 1 ( 3c one month of treatment) as assessed by the AIMS scale test. Rs2242480 located in the CYP3A4 was associated with a different distribution of the UKU neurologic scores through time (permutated p\u200a=\u200a0.047) along with a trend for a different haloperidol plasma levels (lower in CC subjects). This finding was not replicated in the CATIE sample. In conclusion, we did not find conclusive evidence for a major association between the investigated variations and haloperidol induced motoric side effect

Detecting depression in dyadic conversations with multimodal narratives and visualizations

Conversations contain a wide spectrum of multimodal information that gives us hints about the emotions and moods of the speaker. In this paper, we developed a system that supports humans to analyze conversations. Our main contribution is the identification of appropriate multimodal features and the integration of such features into verbatim conversation transcripts. We demonstrate the ability of our system to take in a wide range of multimodal information and automatically generated a prediction score for the depression state of the individual. Our experiments showed that this approach yielded better performance than the baseline model. Furthermore, the multimodal narrative approach makes it easy to integrate learnings from other disciplines, such as conversational analysis and psychology. Lastly, this interdisciplinary and automated approach is a step towards emulating how practitioners record the course of treatment as well as emulating how conversational analysts have been analyzing conversations by hand.Comment: 12 page

Idiosyncratic deals for older workers: increased heterogeneity among older workers enhance the need for i-Deals

The rapid aging of the workforce throughout the Western world and parts of Asia, including Japan and China, poses many challenges on contemporary organizations (European Commission, 2010 ; Wang & Shultz, 2010 ). The Babyboom generation, consisting of workers born between 1945 and 1965, constitutes a large part of the current workforce. Due to decreased fertility rates, there are fewer younger workers entering the labor market, as a consequence of which the percentage of older workers is rapidly increasing (Truxillo & Fraccaroli, 2013 ). Consequently, organizations are increasingly aware that the employee population is changing, and that strategies to employ, motivate, and retain workers have to be adapted accordingly. It is no longer suffi cient for organizations to focus on employing younger workers (e.g., through designing traineeships for graduates), because the infl ux of younger workers in the labor market is stagnating, which is in particular present in certain sectors, such as technical occupations and health care (Polat, Bal, & Jansen, 2012 ). Hence, organizations increasingly will have to rely on older workers, and try to retain older workers, and motivate them to stay longer in the workforce. Similarly, governments across Europe are also increasing offi cial retirement ages, and making it fi nancially less attractive for older workers to retire early (European Commission)

Rationale and design of the randomised clinical trial comparing early medication change (EMC) strategy with treatment as usual (TAU) in patients with Major Depressive Disorder - the EMC trial

<p>Abstract</p> <p>Background</p> <p>In Major Depressive Disorder (MDD), the traditional belief of a delayed onset of antidepressants' effects has lead to the concept of current guidelines that treatment durations should be between 3-8 weeks before medication change in case of insufficient outcome. Post hoc analyses of clinical trials, however, have shown that improvement usually occurs within the first 10-14 days of treatment and that such early improvement (Hamilton Depression Rating Scale [HAMD] decrease ≥20%) has a substantial predictive value for final treatment outcome. Even more important, non-improvement (HAMD decrease <20%) after 14 days of treatment was found to be highly predictive for a poor final treatment outcome.</p> <p>Methods/Design</p> <p>The EMC trial is a phase IV, multi-centre, multi-step, randomized, observer-blinded, actively controlled parallel-group clinical trial to investigate for the first time prospectively, whether non-improvers after 14 days of antidepressant treatment with an early medication change (EMC) are more likely to attain remission (HAMD-17 ≤7) on treatment day 56 compared to patients treated according to current guideline recommendation (treatment as usual; TAU). In level 1 of the EMC trial, non-improvers after 14 days of antidepressant treatment will be randomised to an EMC strategy or TAU. The EMC strategy for this study schedules a first medication change on day 15; in case of non-improvement between days 15-28, a second medication change will be performed. TAU schedules the first medication change after 28 days in case of non-response (HAMD-17 decrease <50%). Both interventions will last 42 days. In levels 2 and 3, EMC strategies will be compared with TAU strategies in improvers on day 14, who experience a stagnation of improvement during the course of treatment. The trial is supported by the German Federal Ministry of Education and Research (BMBF) and will be conducted in cooperation with the BMBF funded Interdisciplinary Centre Clinical Trials (IZKS) at the University Medical Centre Mainz and at six clinical trial sites in Germany.</p> <p>Discussion</p> <p>If the EMC strategies lead to significantly more remitters, changes of clinical practice, guidelines for the treatment of MDD as well as research settings can be expected.</p> <p>Trial Registration</p> <p><b>Clincaltrials.gov Identifier</b>: NCT00974155; <b>EudraCT</b>: 2008-008280-96.</p

Peripheral blood and neuropsychological markers for the onset of action of antidepressant drugs in patients with Major Depressive Disorder

<p>Abstract</p> <p>Background</p> <p>In Major Depressive Disorder (MDD), treatment outcomes with currently available strategies are often disappointing. Therefore, it is sensible to develop new strategies to increase remission rates in acutely depressed patients. Many studies reported that true drug response can be observed within 14 days (early improvement) of antidepressant treatment. The identical time course of symptom amelioration after early improvement in patients treated with antidepressants of all classes or with placebo strongly suggests a common biological mechanism, which is not specific for a particular antidepressant medication. However, the biology underlying early improvement and final treatment response is not understood and there is no established biological marker as yet, which can predict treatment response for the individual patient before initiation or during the course of antidepressant treatment. Peripheral blood markers and executive functions are particularly promising candidates as markers for the onset of action and thus the prediction of final treatment outcome in MDD.</p> <p>Methods/Design</p> <p>The present paper presents the rationales, objectives and methods of a multi-centre study applying close-meshed repetitive measurements of peripheral blood and neuropsychological parameters in patients with MDD and healthy controls during a study period of eight weeks for the identification of biomarkers for the onset of antidepressants' action in patients with MDD. Peripheral blood parameters and depression severity are assessed in weekly intervals from baseline to week 8, executive performance in bi-weekly intervals. Patients are participating in a randomized controlled multi-level clinical trial, healthy controls are matched according to mean age, sex and general intelligence.</p> <p>Discussion</p> <p>This investigation will help to identify a biomarker or a set of biomarkers with decision-making quality in the treatment of MDD in order to increase the currently disappointing remission rates of antidepressant treatment.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00974155">NCT00974155</a></p

The ladies trial: laparoscopic peritoneal lavage or resection for purulent peritonitisA and Hartmann's procedure or resection with primary anastomosis for purulent or faecal peritonitisB in perforated diverticulitis (NTR2037)

Background: Recently, excellent results are reported on laparoscopic lavage in patients with purulent perforated diverticulitis as an alternative for sigmoidectomy and ostomy. The objective of this study is to determine whether LaparOscopic LAvage and drainage is a safe and effective treatment for patients with purulent peritonitis (LOLA-arm) and to determine the optimal resectional strategy in patients with a purulent or faecal peritonitis (DIVA-arm: perforated DIVerticulitis: sigmoidresection with or without Anastomosis). Methods/Design: In this multicentre randomised trial all patients with perforated diverticulitis are included. Upon laparoscopy, patients with purulent peritonitis are treated with laparoscopic lavage and drainage, Hartmann's procedure or sigmoidectomy with primary anastomosis in a ratio of 2:1:1 (LOLA-arm). Patients with faecal peritonitis will be randomised 1:1 between Hartmann's procedure and resection with primary anastomosis (DIVA-arm). The primary combined endpoint of the LOLA-arm is major morbidity and mortality. A sample size of 132:66:66 patients will be able to detect a difference in the primary endpoint from 25% in resectional groups compared to 10% in the laparoscopic lavage group (two sided alpha = 5%, power = 90%). Endpoint of the DIVA-arm is stoma free survival one year after initial surgery. In this arm 212 patients are needed to significantly demonstrate a difference of 30% (log rank test two sided alpha = 5% and powe

Regulatory T cells and their role in rheumatic diseases: a potential target for novel therapeutic development

Regulatory T cells have an important role in limiting immune reactions and are essential regulators of self-tolerance. Among them, CD4+CD25high regulatory T cells are the best-described subset. In this article, we summarize current knowledge on the phenotype, function, and development of CD4+CD25high regulatory T cells. We also review the literature on the role of these T cells in rheumatic diseases and discuss the potential for their use in immunotherapy

Study protocol for a Multi-centre, Investigator-initiated, Randomized Controlled Trial to Compare the Effects of Prehospital Antibiotic Treatment for Sepsis Patients with Usual Care after Training Emergency Medical Services (EMS) Personnel in Early Recognition (- The Prehospital ANTibiotics Against Sepsis (PHANTASi) trial

INTRODUCTION: Sepsis is one of the most frequent reasons for referral to emergency departments (EDs) worldwide. Sepsis becomes more serious when left untreated with a high mortality rate, exceeding even those of myocardial infarction and stroke. Therefore, much effort has been put in to start with appropriate therapy as early as possible. Emergency medical services (EMS) personnel have already made a significant difference in improving care for patients with acute coronary syndrome, multiple trauma and stroke. Patients with severe sepsis or septic shock could also benefit from timely prehospital care. Earlier recognition and initiation of treatment by EMS personnel may improve survival of these critically ill patients. Methods and analysis: The Prehospital Antibiotics against Sepsis (PHANTASi) trial is an investigator- initiated, multicentre, randomized controlled open-label clinical trial nested within a step wedge design. This study compares the effects of usual care to that of training EMS personnel in recognizing and initiating treatment in the prehospital setting together with early administration of antibiotics for patients suspected of (severe) sepsis and septic shock. Primary outcome is 28 day mortality. Secondary outcomes include, length of hospital stay and admission to intensive care units. Ethics and dissemination: This study has been approved by the research ethics committee of VU University Medical Centre, Amsterdam, The Netherlands (Protocol 2013.458/ NL 42001.029.13). The results of the study will be disseminated at several research conferences and international peer reviewed journals. The study will be implemented and reported in line with the CONSORT statement