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Introduction: Animal and clinical studies suggest complementary effects of magnesium and high-dose pyridoxine (vitamin B6) on stress reduction. This is the first randomized trial evaluating the effects of combined magnesium and vitamin B6 supplementation on stress in a stressed population with low magnesemia using a validated measure of perceived stress., Methods: In this Phase IV, investigator-blinded trial (EudraCT: 2015-003749-24), healthy adults with Depression Anxiety Stress Scales (DASS-42) stress subscale score >18 and serum magnesium concentration 0.45 mmol/L-0.85 mmol/L, were randomized 1:1 to magnesium-vitamin B6 combination (Magne B6 [Mg-vitamin B6]; daily dose 300 mg and 30 mg, respectively) or magnesium alone (Magnespasmyl [Mg]; daily dose 300 mg). Outcomes included change in DASS-42 stress subscale score from baseline to Week 8 (primary endpoint) and Week 4, and incidence of adverse events (AEs)., Results: In the modified intention-to-treat analysis (N = 264 subjects), both treatment arms substantially reduced DASS-42 stress subscale score from baseline to Week 8 (Mg-vitamin B6, 44.9%; Mg 42.4%); no statistical difference between arms was observed (p>0.05). An interaction (p = 0.0097) between baseline stress level and treatment warranted subgroup analysis (as per statistical plan); adults with severe/extremely severe stress (DASS-42 stress subscale score ≥25; N = 162) had a 24% greater improvement with Mg-vitamin B6 versus Mg at Week 8 (3.16 points, 95% CI 0.50 to 5.82, p = 0.0203). Consistent results were observed in the per protocol analysis and at Week 4. Overall, 12.1% of Mg-vitamin B6 treated and 17.4% of Mg-treated subjects experienced AEs potentially treatment related., Conclusions: These findings suggest oral Mg supplementation alleviated stress in healthy adults with low magnesemia and the addition of vitamin B6 to Mg was not superior to Mg supplementation alone. With regard to subjects with severe/extremely severe stress, this study provides clinical support for greater benefit of Mg combined with vitamin B6., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests to declare: CD reports no conflict of interest. AM reports consultancy fees from Sanofi, unrelated to this publication. LD has received research funding from Sanofi and consultancy payments unrelated to this publication. JH was employed by Daacro at the time of this study, and has also received consultancy fees and performed saliva analyses for Sanofi, unrelated to this publication. Daacro is a private contract research and saliva analysis laboratory. Daacro did not play any role in funding the study design, data collection, decision to publish, or preparation of the manuscript, however, research materials and the laboratory premises were used to analyse saliva samples for this trial and the company was reimbursed for any time or materials used relating to this study. EP, MK-A and LN are employees of Sanofi. LN was employed by Metabrain Research during the conduction of the trial and the early stages of the development of this manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Unlabelled: This French multicenter prospective cohort study recruited 391 patients to investigate the risk factors for persistent pain after elective cesarean delivery, focusing on psychosocial aspects adjusted for other known medical factors. Perioperative data were collected and specialized questionnaires were completed to assess reports of pain at the site of surgery. Three dependent outcomes were considered: pain at the third month after surgery (M3, n = 268; risk = 28%), pain at the sixth month after surgery (M6, n = 239; risk = 19%), and the cumulative incidence (up to M6) of neuropathic pain, as assessed using the Douleur Neuropathique 4 questionnaire (n = 218; risk = 24.5%). The neuropathic aspect of reported pain changed over time in more than 60% of cases, pain being more intense if associated with neuropathic features. Whatever the dependent outcome, a high mental component of quality of life (SF-36) was protective. Pain at M3 was also predicted by pain reported during current pregnancy and a history of miscarriage. Pain at M6 was also predicted by report of a postoperative complication. Incident neuropathic pain was predicted by pain reported during current pregnancy, a previous history of a peripheral neuropathic event, and preoperative anxiety., Trial Registration: ClinicalTrials.gov, NCT00812734., Perspective: Persistent pain after cesarean delivery has a relatively frequent neuropathic aspect but this is less stable than that after other surgeries. When comparing the risk factor analyses with published data for hysterectomy, the influence of preoperative psychological factors seems less important, possibly because of the different context and environment., (Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.)

In May 2014, the European Union Parliament and Council published a new regulation on clinical trials on medicinal products for human use, which is designed to replace Directive 2001/20/EC. It will not come into effect until 2016. Nevertheless, it is essential to examine its relationship with national legislation, i.e. the Jardé Act, whose implementation has been delayed pending publication of the European regulation. The Giens workshop identified and examined the various issues that this relationship is bound to raise. In particular, it looked at trial methodology assessment procedures, the working relationship between the French National Agency of Drug Safety and Health Products (Agence Nationale de Sécurité du Médicament et des Produits de Santé, ANSM) and ethics committees during the authorization application evaluation phase, review of post-authorization/registration studies on medicinal products and medical devices, and data transparency., (© 2015 Société Française de Pharmacologie et de Thérapeutique.)

Background: Chronic heart failure, is increasing due to the aging population and improvements in heart disease detection and management. The prevalence is estimated at ~10% of the French general practice patient population over 59 years old. The primary objective of this study is to improve the quality of life for heart failure patients though a complex intervention involving patient and general practitioner (GP) education in primary care., Methods: A randomised, cluster controlled trial, stratified over 4 areas of the Auvergne region in France comparing intervention and control groups. The inclusion criteria are: patients older than 50 years with New York Heart Association (NYHA) stage I, II, or III heart failure, with reduced ejection fraction or with preserved ejection fraction. Heart failure should be confirmed by the patient's cardiologist according to the European Society of Cardiology guidelines criteria. The exclusion criteria include: severe cognitive disorders, living in an institution, participating in another clinical trial, having NYHA stage IV heart failure, or a lack of French language skills. The complex intervention consists of training at the GP practice with an interactive 2-day workshop to provide a patient's education programme. GPs are trained to perform case management, lifestyle counselling and motivational interviewing, to educate patients on the main topics including clinical alarm signs, physical activity, diet and cardiovascular risk factors. The patients' education sessions are scheduled at 1, 4, 7, 10, 13 and 19 months following the start of the trial. The primary outcome to be assessed is the impact on the quality of life as determined using two questionnaires: the Minnesota Living with Heart Failure Questionnaire and SF-36. To detect a difference in the mean quality of life at 19 months, we anticipate studying a minimum of 400 patients from 80 GPs., Discussion: This trial will provide insight into the effectiveness of a complex intervention to educate patients with heart failure including a 2-day GP workshop and patients' education programme in the setting of a GP consultation to improve the quality of life in patients with chronic heart failure. This complex intervention tool could be used during initial and further medical training., Trial Registration: ETIC is a cluster-randomised, controlled trial registered on ClinicalTrials.gov [ NCT01065142 , 2010, Feb 8] and the French drug agency [Agence Nationale de Sécurité du Médicament et des produits de santé; registration number: 2009-A01142-55, on March 5th, 2010].

Background: Cannabis is the most consumed illegal substance in France. General practitioners (GPs) are the health professionals who are most consulted by adolescents. Brief intervention (BI) is a promising care initiative for the consumption of cannabis, and could be a tool for GPs in caring for adolescents who consume cannabis. The aim of the CANABIC study is to measure the impact of a BI carried out by a GP on the consumption of cannabis by adolescents of 15 to 25 years of age., Methods: A randomized clustered controlled trial, stratified over three areas (Auvergne, Languedoc-Roussillon, and Rhône - Alpes), comparing an intervention group, which carries out the BI in consultation, and a control group, which ensures routine medical care. The main assessment criterion is the consumption of cannabis by amount of joints per month, at 12 months. The amount necessary to highlight a significant difference between the two groups of 30% of consumption at 12 months is 250 patients (50 GPs, 5 patients per GP; risk α = 5%; power = 90%; intra-cluster correlation coefficient ρ = 0.2; Hawthorne effect = 15%; lost to follow-up rates for GPs = 10% and for patients = 20%). This plan is replicated for the three areas, and therefore a total of 750 patients are expected.The secondary criteria for judgment are the associated consumption of tobacco and alcohol, the perception of the consequences of consumption, and the driving of a vehicle following consumption., Discussion: Research about BI for young cannabis users is underway. The aim of the CANABIC study is to validate a BI suited to adolescents who consume cannabis, which may be performed in the general practice. This would provide a tool for their treatment by a GP, which could be widely distributed during initial or further medical training., Trial Registration: CANABIC is a randomized clustered trial (NCT01433692, registered 2011 Sept 12), PHRC funded: Clinical Research Hospital Program (Governmental Fund, Health Ministry). Date first patient randomized: March 2012.

Medical devices are many and various, ranging from tongue spatulas to implantable or invasive devices and imaging machines; their lifetimes are short, between 18 months and 5 years, due to incessant incremental innovation; and they are operator-dependent: in general, the clinical user performs a fitting procedure (hip implant or pacemaker), a therapeutic procedure using a non-implantable invasive device (arrhythmic site ablation probe, angioplasty balloon, extension spondyloplasty system, etc.) or follow-up of an active implanted device (long-term follow-up of an implanted cardiac defibrillator or of a deep brain stimulator in Parkinson's patients). A round-table held during the XXVIII(th) Giens Workshops meeting focused on the methodology of scientific evaluation of medical devices and the associated procedures with a view to their pricing and financing by the French National Health Insurance system. The working hypothesis was that the available data-set was sufficient for and compatible with scientific evaluation with clinical benefit. Post-registration studies, although contributing to the continuity of assessment, were not dealt with. Moreover, the focus was restricted to devices used in health establishments, where the association between devices and technical medical procedures is optimally representative. An update of the multiple regulatory protocols governing medical devices and procedures is provided. Issues more specifically related to procedures as such, to non-implantable devices and to innovative devices are then dealt with, and the proposals and discussion points raised at the round-table for each of these three areas are presented., (© 2013 Société Française de Pharmacologie et de Thérapeutique.)

Background and Aim of the Study: In this single-center French study, the conventional management of patients receiving vitamin K antagonists (VKAs) was compared with an International Normalized Ratio (INR) self-testing program. The aim was to determine the reliability of self-testing devices, and to estimate the variability of the self-measured INR within the therapeutic and target range., Methods: A total of 206 patients who had undergone valve replacement with a mechanical prosthesis, with or without myocardial revascularization, between May 2004 and September 2007 was randomized into two groups. Group 1 patients (n = 103) underwent INR monitoring at a laboratory, while Group 2 patients (n = 103) underwent self-testing INR using either the CoaguChek (Roche) (Group 2A; n = 55) or INRatio (Hemosense) (Group 2B; n = 48) system. Patients in Group 1 underwent at least once-monthly INR measurement, while those in Group 2 carried out once-weekly self-testing, and also underwent once-monthly INR measurement at the laboratory. The large majority of patients (97.9%) were treated with fluindione., Results: The mean follow up period was 49.0 +/- 10.3 weeks. Self-testing was reliable, with a correlation coefficient between device- and laboratory-measured INRs of 0.80 [CI: 0.78, 0.82] (p < 0.0001). The proportion of time spent within the INR target range was significantly higher for Group 2 (61.5 +/- 19.3% versus 55.5 +/- 19.9%; p < 0.05), while the absolute mean deviation of INR from the target range was higher in Group 1 (60.1 +/- 70.2% versus 47.4 +/- 51.5%). Adverse events were reported by seven patients in Group 1, but by no patients in Group 2 (p < 0.01)., Conclusion: INR self-testing devices are reliable and beneficial. Moreover, INR self-monitoring allows an enhanced stability within a target range, and also helps to prevent serious postoperative complications.

Objective: Patients with painful conditions often suffer from sleep disturbances. However, changes in sleep pattern per se could also influence pain tolerance. Untreated obstructive sleep apnea (OSA) causes major disturbances in sleep pattern. The aim of this study was to assess whether continuous positive airway pressure (CPAP) treatment in elderly patients with OSA would result in improved pain tolerance., Design: Randomized, double-blind crossover study., Setting: Geriatric sleep center based in Antoine Charial University Hospital (Lyon, France)., Participants: A total of 13 consecutive OSA patients aged 70 and older randomly assigned CPAP treatment (lowCPAP versus highCPAP). Eleven patients completed the study., Measurements: Overnight sleep recording, electrical pain tolerance assessment, and visual analog scale for sleep quality were performed., Results: Both low- and highCPAP treatment significantly improved respiratory parameters. However, compared with baseline, the electrical pain tolerance score was significantly enhanced (analgesic effect) only under highCPAP treatment (21.2 ± 10.9 versus 28.4 ± 16.0; P = .03)., Conclusion: The treatment of OSA with CPAP would have an analgesic effect. This would represent a unique outcome attributed to CPAP treatment. Given the high prevalence of both OSA and chronic pain conditions in the elderly; our findings could hold many implications for very large segments of the elderly population., (Copyright © 2010 American Medical Directors Association. Published by Elsevier Inc. All rights reserved.)

Objective: French law on biomedical research does not apply to non-interventional researches. A favourable advice of an IRB (Institutional Review Board) is required. This article describes the setting up of a Clinical Research Centers Ethics Committee., Methods: The Clinical Research Centers Ethics Committee (CRCEC) was created in November, 2006. To guarantee a better objectivity Grenoble's projects are reviewed in Clermont-Ferrand board and conversely. Recommendations are given according to the compliance of research with laws and regulations in effect in France., Results: Twenty eight projects were submitted to the CRCEC during a 18 months period, mainly observation studies in a hospital setting. Four projects were redirected towards a formal French Ethic Committees (CPP) submission. Requests of modifications concerned a lack of information relative to data confidentiality., Conclusion: This committee is useful but its voluntary and "unofficial" nature questions about its perpetuation. We suggest that non interventional research be submitted to official CPP.

The purpose of the clinical trial guidelines is to harmonise legislation in order to ensure consistency within Europe and thereby promote Europe's attractiveness for clinical research while maintaining or improving the protection of subjects who agree to participate. The French administrative system has hitherto been relatively favourable (with simple notification to a single Ethics Committee per study); it is thus important to maintain competitiveness in these respects, given that, in other areas (the time it takes to establish agreements, recruitment, etc.), other countries have the advantage. At the moment, this Directive has not been entirely transposed into French law. The pilot period established by the Afssaps (French drug agency) has made it possible to determine very quickly how to set things up. For Ethics Committees, the situation is more critical in that many points remain that need to be finalised (selection of members, internal rules, Competent Authority/Ethics Committee relationship, etc.). The Giens workshop issued a number of proposals and it hopes, through the Afssaps)/DGS (French agency of health in government)/LEEM Steering Group (French pharmaceutical companies association), to be able to help establish an efficient system which also correctly protect the patient.

To date, biomedical research using nominal data files for the data collection, data acquisition or data processing has had to comply with 2 French laws (Law of December, 20, 1988, modified, relating to the protection of patients participating in biomedical research, and the Law of January, 6, 1978, completed by the Law of July 1, 1994 n degrees 94-548, chapter V bis). This later law dictates rules not only for the establishment of nominal data files, but also confer individual rights to filed persons. These regulations concern epidemiological research, clinical trials, drug watch studies and economic health research. In this note, we describe the obligations and specific general and simplified procedure required for conducting biomedical research. Included in the requirements are an information and authorization procedure with the local and national consultative committees on data processing in biomedical research (CCTIRS, Comité Consultatif sur le Traitement de l'Information en Recherche Biomédicale, and CNIL, Commission Nationale Informatique et Libertés).