Peer Review of Grant Applications: A Simple Method to Identify Proposals with Discordant Reviews

Grant proposals submitted for funding are usually selected by a peer-review rating process. Some proposals may result in discordant peer-review ratings and therefore require discussion by the selection committee members. The issue is which peer-review ratings are considered as discordant. We propose a simple method to identify such proposals. Our approach is based on the intraclass correlation coefficient, which is usually used in assessing agreement in studies with continuous ratings

Ultrastructural and quantitative analysis of the lipid droplet clustering induced by hepatitis C virus core protein.: HCV-induced lipid droplet clustering

International audienceHepatitis C virus (HCV) release is linked to the formation of lipid droplet (LD) clusters in the perinuclear area of infected cells, induced by the core protein. We used electron microscopy (EM) to monitor and compare the number and size of LD in cells producing the mature and immature forms of the HCV core protein, and 3D EM to reconstruct whole cells producing the mature core protein. Only the mature protein coated the LD and induced their clustering and emergence from endoplasmic reticulum membranes enriched in this protein. We found no particular association between LD clusters and the centrosome in reconstructed cells. The LD clustering induced by the mature core protein was associated with an increase in LD synthesis potentially due, at least in part, to the ability of this protein to coat the LD. These observations provide useful information for further studies of the mechanisms involved in HCV-induced steatosis

Neuromuscular blockade during therapeutic hypothermia after cardiac arrest: Observational study of neurological and infectious outcomes

AbstractIntroductionNeuromuscular blockade (NMB) is widely used during therapeutic hypothermia (TH) after cardiac arrest but its effect on patient outcomes is unclear. We compared the effects of NMB on neurological outcomes and frequency of early-onset pneumonia in cardiac-arrest survivors managed with TH.MethodsWe retrospectively studied consecutive adult cardiac-arrest survivors managed with TH in a tertiary-level intensive care unit between January 2008 and July 2013. Patients given continuous NMB for persistent shivering were compared to those managed without NMB. Cases of early-onset pneumonia and vital status at ICU discharge were recorded. To avoid bias due to between-group baseline differences, we adjusted the analysis on a propensity score.ResultsOf 311 cardiac-arrest survivors, 144 received TH, including 117 with continuous NMB and 27 without NMBs. ICU mortality was lower with NMB (hazard ratio [HR], 0.54 [0.32; 0.89], p=0.016) but the difference was not significant after adjustment on the propensity score (HR, 0.70 [0.39; 1.25], p=0.22). The proportion of patients with good neurological outcomes was not significantly different (36% with and 22% without NMB, p=0.16). Early-onset pneumonia was more common with NMB (HR, 2.36 [1.24; 4.50], p=0.009) but the difference was not significant after adjustment on the propensity score (HR, 1.68 [0.90; 3.16], p=0.10).ConclusionsContinuous intravenous NMB during TH after cardiac arrest has potential owns effects on ICU survival with a trend increase in the frequency of early-onset pneumonia. Randomised controlled trials are needed to define the role for NMB among treatments for TH-induced shivering

Viral sequence variation in chronic carriers of hepatitis C virus has a low impact on liver steatosis.: HCV variability and steatosis

International audienceMost clinical studies suggest that the prevalence and severity of liver steatosis are higher in patients infected with hepatitis C virus (HCV) genotype 3 than in patients infected with other genotypes. This may reflect the diversity and specific intrinsic properties of genotype 3 virus proteins. We analyzed the possible association of particular residues of the HCV core and NS5A proteins known to dysregulate lipid metabolism with steatosis severity in the livers of patients chronically infected with HCV. We used transmission electron microscopy to quantify liver steatosis precisely in a group of 27 patients, 12 of whom were infected with a genotype 3 virus, the other 15 being infected with viruses of other genotypes. We determined the area covered by lipid droplets in liver tissues and analyzed the diversity of the core and NS5A regions encoded by the viral variants circulating in these patients. The area covered by lipid droplets did not differ significantly between patients infected with genotype 3 viruses and those infected with other genotypes. The core and NS5A protein sequences of the viral variants circulating in patients with mild or severe steatosis were evenly distributed throughout the phylogenic trees established from all the collected sequences. Thus, individual host factors seem to play a much greater role than viral factors in the development of severe steatosis in patients chronically infected with HCV, including those infected with genotype 3 viruses

Impact of early enteral versus parenteral nutrition on mortality in patients requiring mechanical ventilation and catecholamines: study protocol for a randomized controlled trial (NUTRIREA-2)

BACKGROUND: Nutritional support is crucial to the management of patients receiving invasive mechanical ventilation (IMV) and the most commonly prescribed treatment in intensive care units (ICUs). International guidelines consistently indicate that enteral nutrition (EN) should be preferred over parenteral nutrition (PN) whenever possible and started as early as possible. However, no adequately designed study has evaluated whether a specific nutritional modality is associated with decreased mortality. The primary goal of this trial is to assess the hypothesis that early first-line EN, as compared to early first-line PN, decreases day 28 all-cause mortality in patients receiving IMV and vasoactive drugs for shock. METHODS/DESIGN: The NUTRIREA-2 study is a multicenter, open-label, parallel-group, randomized controlled trial comparing early PN versus early EN in critically ill patients requiring IMV for an expected duration of at least 48 hours, combined with vasoactive drugs, for shock. Patients will be allocated at random to first-line PN for at least 72 hours or to first-line EN. In both groups, nutritional support will be started within 24 hours after IMV initiation. Calorie targets will be 20 to 25 kcal/kg/day during the first week, then 25 to 30 kcal/kg/day thereafter. Patients receiving PN may be switched to EN after at least 72 hours in the event of shock resolution (no vasoactive drugs for 24 consecutive hours and arterial lactic acid level below 2 mmol/L). On day 7, all patients receiving PN and having no contraindications to EN will be switched to EN. In both groups, supplemental PN may be added to EN after day 7 in patients with persistent intolerance to EN and inadequate calorie intake. We plan to recruit 2,854 patients at 44 participating ICUs. DISCUSSION: The NUTRIREA-2 study is the first large randomized controlled trial designed to assess the hypothesis that early EN improves survival compared to early PN in ICU patients. Enrollment started on 22 March 2013 and is expected to end in November 2015. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01802099 (registered 27 February 2013)

Participant informed consent in cluster randomized trials: review.

BACKGROUND: The Nuremberg code defines the general ethical framework of medical research with participant consent as its cornerstone. In cluster randomized trials (CRT), obtaining participant informed consent raises logistic and methodologic concerns. First, with randomization of large clusters such as geographical areas, obtaining individual informed consent may be impossible. Second, participants in randomized clusters cannot avoid certain interventions, which implies that participant informed consent refers only to data collection, not administration of an intervention. Third, complete participant information may be a source of selection bias, which then raises methodological concerns. We assessed whether participant informed consent was required in such trials, which type of consent was required, and whether the trial was at risk of selection bias because of the very nature of participant information. METHODS AND FINDINGS: We systematically reviewed all reports of CRT published in MEDLINE in 2008 and surveyed corresponding authors regarding the nature of the informed consent and the process of participant inclusion. We identified 173 reports and obtained an answer from 113 authors (65.3%). In total, 23.7% of the reports lacked information on ethics committee approval or participant consent, 53.1% of authors declared that participant consent was for data collection only and 58.5% that the group allocation was not specified for participants. The process of recruitment (chronology of participant recruitment with regard to cluster randomization) was rarely reported, and we estimated that only 56.6% of the trials were free of potential selection bias. CONCLUSIONS: For CRTs, the reporting of ethics committee approval and participant informed consent is less than optimal. Reports should describe whether participants consented for administration of an intervention and/or data collection. Finally, the process of participant recruitment should be fully described (namely, whether participants were informed of the allocation group before being recruited) for a better appraisal of the risk of selection bias

Mechanical cervicAl ripeninG for Women with PrOlongedPregnancies (MAGPOP): Protocol for a Randomised Controlled Trial of a Silicone Double Balloon Catheter versus the Propess System for the Slow Release of Dinoprostone for Cervical Ripening of Prolonged Pregnancies

International audienceINTRODUCTION: Induction of labour for prolonged pregnancies (PP) when the cervix is unfavourable is a challenging situation. Cervical ripening by pharmacological or mechanical techniques before oxytocin administration is used to increase the likelihood of vaginal delivery. Both techniques are equally effective in achieving vaginal delivery but excessive uterine activity, which induces fetal heart rate (FHR) anomalies, is more frequent after the pharmacological intervention. We hypothesised that mechanical cervical ripening could reduce the caesarean rate for non-reassuring FHR especially in PP where fetuses are already susceptible to this. METHODS AND ANALYSIS: A multicentre, superiority, open-label, parallel-group, randomised controlled trial that aims to compare cervical ripening with a mechanical device (Cervical Ripening Balloon, Cook-Medical Europe, Ireland) inserted in standardised manner for 24\,hours to pharmacological cervical ripening (Propess system for slow release system of 10\,mg of dinoprostone, Ferring SAS, France) before oxytocin administration. Women (n=1220) will be randomised in a 1:1 ratio in 15 French units. Participants will be women with a singleton pregnancy, a vertex presentation, a term ≥q41+0\,and≤q42+0\,week's gestation, and for whom induction of labour is planned. Women with a Bishop score ≥q6, a prior caesarean delivery, premature rupture of membranes or with any contraindication for vaginal delivery will be excluded. The primary endpoint is the caesarean rate for non-reassuring FHR. Secondary outcomes are related to delivery and perinatal morbidity. As study investigators and patients cannot be masked to treatment assignment, to compensate for the absence of blinding, an independent endpoint adjudication committee, blinded to group allocation, will determine whether the caesarean for non-reassuring FHR was justified. ETHICS AND DISSEMINATION: Written informed consent will be obtained from all participants. The Tours Research ethics committee has approved this study (2016-R23, 29 November 2016). Study findings will be submitted for publication and presented at relevant conferences. TRIAL REGISTRATION NUMBER: NCT02907060; pre-results

Méthode danalyse ultrasonore des transformations mécaniques du sang coagulant : Effets des antiagrégants plaquettaires et des anticoagulants

National audienceAu cours détudes antérieures une méthode ultrasonore dexploration in vitro des propriétés mécaniques du sang total lors de la coagulation a été mise au point. Cette méthode originale s'appuie sur la mesure simultanée de paramètres ultrasonores haute-fréquence (transmission et rétrodiffusion) et permet lidentification de transformations mécaniques et biochimiques lors de la coagulation du sang total. Lagrégation des hématies, la polymérisation du fibrinogène en fibrine ainsi que la rétraction du caillot sanguin sont ainsi mises en évidence. Le présent article porte sur une étude clinique pilote (PHRC CHU Tours 2008) menée afin de confronter les résultats du test ultrasonore à ceux des tests de routines biochimiques. Les paramètres ultrasonores obtenus sur des patients témoins sains (25) ont été comparés à leurs données biologiques. Une analyse statistique a permis de montrer dans quelle mesure le test ultrasonore permet de différencier les modifications de coagulation induites par la prise d'antiagrégants plaquettaires et d'anticoagulants. En particulier, la prise danticoagulants modifie de manière significative la dynamique de coagulation et souligne la corrélation entre fibrinoformation, rétraction du caillot et vitesse ultrasonore

Embedding a COVID-19 group sequential clinical trial within an ongoing trial: lessons from an unusual experience

International audienceThe Cape-Covid trial is an embedded clinical trial within the ongoing Cape-Cod trial. The Covid-19 pandemic appeared while we were conducting a randomized trial assessing the effectiveness of corticosteroids in severe community-acquired pneumonia. We took advantage of this ongoing trial to embed a sub-trial assessing hydrocortisone in SARS-CoV-2 infected patients. In this manuscript, we wish to share our experience when we needed to make fast and robust methodological decisions during the Covid-19 pandemic in a two weeks period of time