Search

Correction to: Intensive Care Med (2017) DOI 10.1007/s00134-017-4891-0.

Purpose: The relative merits of immediate extubation versus terminal weaning for mechanical ventilation withdrawal are controversial, particularly regarding the experience of patients and relatives., Methods: This prospective observational multicentre study (ARREVE) was done in 43 French ICUs to compare terminal weaning and immediate extubation, as chosen by the ICU team. Terminal weaning was a gradual decrease in the amount of ventilatory assistance and immediate extubation was extubation without any previous decrease in ventilatory assistance. The primary outcome was posttraumatic stress symptoms (Impact of Event Scale Revised, IES-R) in relatives 3 months after the death. Secondary outcomes were complicated grief, anxiety, and depression symptoms in relatives; comfort of patients during the dying process; and job strain in staff., Results: We enrolled 212 (85.5%) relatives of 248 patients with terminal weaning and 190 relatives (90.5%) of 210 patients with immediate extubation. Immediate extubation was associated with airway obstruction and a higher mean Behavioural Pain Scale score compared to terminal weaning. In relatives, IES-R scores after 3 months were not significantly different between groups (31.9 ± 18.1 versus 30.5 ± 16.2, respectively; adjusted difference, -1.9; 95% confidence interval, -5.9 to 2.1; p = 0.36); neither were there any differences in complicated grief, anxiety, or depression scores. Assistant nurses had lower job strain scores in the immediate extubation group., Conclusions: Compared to terminal weaning, immediate extubation was not associated with differences in psychological welfare of relatives when each method constituted standard practice in the ICU where it was applied. Patients had more airway obstruction and gasps with immediate extubation., Trial Registration: ClinicalTrials.gov identifier: NCT01818895.

Aim: To prospectively evaluate the performance of Doppler-ultrasonography (US) for the detection of transjugular intrahepatic portosystemic shunt (TIPS) dysfunction within a multicenter cohort of cirrhotic patients., Methods: This study was conducted in 10 french teaching hospitals. After TIPS insertion, angiography and liver Doppler-US were carried out every six months to detect dysfunction (defined by a portosystemic gradient ≥ 12 mmHg and/or a stent stenosis ≥ 50%). The association between ultrasonographic signs and dysfunction was studied by logistic random-effects models, and the diagnostic performance of each Doppler criterion was estimated by the bootstrap method. This study was approved by the ethics committee of Tours., Results: Two hundred and eighteen pairs of examinations performed on 87 cirrhotic patients were analyzed. Variables significantly associated with dysfunction were: The speed of flow in the portal vein ( P = 0.008), the reversal of flow in the right ( P = 0.038) and left ( P = 0.049) portal branch, the loss of modulation of portal flow by the right atrium ( P = 0.0005), ascites ( P = 0.001) and the overall impression of the operator ( P = 0.0001). The diagnostic performances of these variables were low; sensitivity was < 58% and negative predictive value was < 73%. Therefore, dysfunction cannot be ruled out from Doppler-US., Conclusion: The performance of Doppler-US for the detection of TIPS dysfunction is poor compared to angiography. New tools are needed to improve diagnosis of TIPS dysfunction., Competing Interests: Conflict-of-interest statement: The authors of this manuscript having no conflicts of interest to disclose.

Introduction: 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 ≥41+0 and≤42+0 week's gestation, and for whom induction of labour is planned. Women with a Bishop score ≥6, 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., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background/aims The use of the stepped wedge cluster randomized design is rapidly increasing. This design is commonly used to evaluate health policy and service delivery interventions. Stepped wedge cluster randomized trials have unique characteristics that complicate their ethical interpretation. The 2012 Ottawa Statement provides comprehensive guidance on the ethical design and conduct of cluster randomized trials, and the 2010 CONSORT extension for cluster randomized trials provides guidelines for reporting. Our aims were to assess the adequacy of the ethical conduct and reporting of stepped wedge trials to date, focusing on research ethics review and informed consent. Methods We conducted a systematic review of stepped wedge cluster randomized trials in health research published up to 2014 in English language journals. We extracted details of study intervention and data collection procedures, as well as reporting of research ethics review and informed consent. Two reviewers independently extracted data from each trial; discrepancies were resolved through discussion. We identified the presence of any research participants at the cluster level and the individual level. We assessed ethical conduct by tabulating reporting of research ethics review and informed consent against the presence of research participants. Results Of 32 identified stepped wedge trials, only 24 (75%) reported review by a research ethics committee, and only 16 (50%) reported informed consent from any research participants-yet, all trials included research participants at some level. In the subgroup of 20 trials with research participants at cluster level, only 4 (20%) reported informed consent from such participants; in 26 trials with individual-level research participants, only 15 (58%) reported their informed consent. Interventions (regardless of whether targeting cluster- or individual-level participants) were delivered at the group level in more than two-thirds of trials; nine trials (28%) had no identifiable data collected from any research participants. Overall, only three trials (9%) indicated that a waiver of consent had been granted by a research ethics committee. When considering the combined requirement of research ethics review and informed consent (or a waiver), only one in three studies were compliant. Conclusion The ethical conduct and reporting of key ethical protections in stepped wedge trials, namely, research ethics review and informed consent, are inadequate. We recommend that stepped wedge trials be classified as research and reviewed and approved by a research ethics committee. We also recommend that researchers appropriately identify research participants (which may include health professionals), seek informed consent or appeal to an ethics committee for a waiver of consent, and include explicit details of research ethics approval and informed consent in the trial report.

Objective: The study aims to evaluate the accuracy of combining uterine artery Doppler (UAD), PlGF and sFlt-1 in the first trimester for preeclampsia screening., Methods: Prospectively enrolled women at high risk of preeclampsia were included. Transabdominal UAD measurements and serum biomarkers were collected between 11 and 13 weeks of gestation in three university hospitals and in one general hospital. The main outcome was preeclampsia. UAD parameters and biomarker levels among women with preeclampsia were compared with those of women in the unaffected group in univariate and multivariate analyses., Results: Out of 226 women included from May 2007 to January 2011, 27 (11.9%) women developed preeclampsia. Among women affected by preeclampsia, the lowest pulsatility index was higher (p = 0.02), bilateral notching was more frequent (p = 0.01), and PlGF was lower (p < 0.001). No significant differences were observed for other indicators. The multivariate model, adjusted for laboratory and sonographic indicators, had an area under the curve (AUC) estimated at 0.76, which was not significantly different from the AUC of the univariate model adjusted only for PlGF (p = 0.7)., Conclusion: In a high-risk population, PlGF in the first trimester is useful for predicting preeclampsia, but neither sFlt-1 nor any UAD indices improved the prediction of preeclampsia.

Background and Objectives: In developed countries, where omphalitis has become rare and related mortality nil, benefits of antiseptic use in umbilical cord care have not been demonstrated. We aimed to assess the noninferiority of dry care compared with antiseptics in France where antiseptic use is widespread., Methods: We conducted a noninferiority, cluster-randomized, 2-period crossover trial, in 6 French university maternity units including all infants born after 36 weeks' gestation. Maternity units were randomly assigned to provide either their usual antiseptic care or a dry care umbilical cord method for a 4-month period, and then units switched to the alternate cord cleansing method for a 4-month period. The primary outcome was neonatal omphalitis, adjudicated by an independent blinded committee based on all available photographs, clinical, and bacteriological data. We used a noninferiority margin of 0.4%. Analysis was performed per protocol and by intention to treat., Results: Among 8698 participants, omphalitis occurred in 3 of 4293 (0.07%) newborns in the dry care group and in none of the 4404 newborns in the antiseptic care group (crude difference: 0.07; 95% confidence interval: -0.03 to 0.21). Late neonatal infection, parental appreciation of difficulty in care, and time to separation of the cord were not significantly different between the 2 groups., Conclusions: Dry cord was noninferior to the use of antiseptics in preventing omphalitis in full-term newborns in a developed country. Antiseptic use in umbilical cord care is therefore unnecessary, constraining, and expensive in high-income countries and may be replaced by dry care., (Copyright © 2017 by the American Academy of Pediatrics.)

In cluster randomized trials, clusters of subjects are randomized rather than subjects themselves, and missing outcomes are a concern as in individual randomized trials. We assessed strategies for handling missing data when analysing cluster randomized trials with a binary outcome; strategies included complete case, adjusted complete case, and simple and multiple imputation approaches. We performed a simulation study to assess bias and coverage rate of the population-averaged intervention-effect estimate. Both multiple imputation with a random-effects logistic regression model or classical logistic regression provided unbiased estimates of the intervention effect. Both strategies also showed good coverage properties, even slightly better for multiple imputation with a random-effects logistic regression approach. Finally, this latter approach led to a slightly negatively biased intracluster correlation coefficient estimate but less than that with a classical logistic regression model strategy. We applied these strategies to a real trial randomizing households and comparing ivermectin and malathion to treat head lice., (© The Author(s) 2014.)

Parents are increasingly placing amber necklaces on their infants or toddlers to prevent teething pain. The use of the necklaces can pose a risk of death by strangulation, however, there are no data on the potential infectious risk linked to bacterial colonisation associated with the necklaces. We aimed to analyse bacterial colonisation of amber necklaces worn by children during hospital consultations. This prospective observational study included all children wearing a teething necklace at consultation in the Paediatric Dermatology and the Paediatric Emergency Department of our hospital from April to December 2014. The study included 27 children (median age: 10.7 months; 70.4% female). The surface of necklaces underwent bacteriological analyses using three different agar cultures. Parents completed a brief questionnaire to provide reasons for using necklaces and express awareness of risks. One child had a history of impetigo. All necklaces were colonised by bacteria (median: four species per necklace [range: 1-9]); 32 different species were found, the most frequent being coagulase-negative staphylococci (Staphylococcus epidermidis in 88.9% of cases). In three cases, methicillin-sensitive Staphylococcus aureus was found. The most frequent reason for wearing a necklace was to prevent teething pain (n = 17; 63.0%); the necklace was judged effective (moderately/highly effective) in 74.1% of cases, however, 70.4% of parents considered the use of the necklace to be risky. Amber necklaces may be highly colonised by commensal germs of the skin, mainly coagulase-negative staphylococci. Although these bacteria are saprophytes, they may become pathogenic in particular conditions.

Objectives: The Core Outcome Measures in Effectiveness Trial initiative aims at developing core outcome set (COS) for research. Consensus on a COS for renoprotection research is lacking. We performed a systematic review (SR) of SRs of renoprotection to identify outcomes used in renoprotection research and to assess how frequently these outcomes could be meta-analyzed in the SRs., Study Design and Setting: We searched for SRs with meta-analyses of renoprotection treatments in the Database of Abstracts of Reviews of Effects and in MEDLINE and collected outcomes that were meta-analyzed. For each outcome and SR, we assessed the proportion of trials/patients that could be meta-analyzed., Results: We retrieved 66 SRs. A total of 609 outcomes were extracted for 20 distinct renoprotection outcomes. The median (interquartile range) proportion of SRs in which these outcomes had been meta-analyzed was 8% (2%, 27%) (range 2-50%). The proportion of trials that had been aggregated was >75% for only 36% of the outcomes., Conclusion: The outcomes meta-analyzed in renoprotection trials are heterogeneous, with a low proportion of trials or patients pooled for each outcome and each SR. A COS is needed in renoprotection research to limit this waste of research. The outcomes identified in the present work could be a basis for this COS., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Sample sizes for randomized controlled trials are typically based on power calculations. They require us to specify values for parameters such as the treatment effect, which is often difficult because we lack sufficient prior information. The objective of this paper is to provide an alternative design which circumvents the need for sample size calculation. In a simulation study, we compared a meta-experiment approach to the classical approach to assess treatment efficacy. The meta-experiment approach involves use of meta-analyzed results from 3 randomized trials of fixed sample size, 100 subjects. The classical approach involves a single randomized trial with the sample size calculated on the basis of an a priori-formulated hypothesis. For the sample size calculation in the classical approach, we used observed articles to characterize errors made on the formulated hypothesis. A prospective meta-analysis of data from trials of fixed sample size provided the same precision, power and type I error rate, on average, as the classical approach. The meta-experiment approach may provide an alternative design which does not require a sample size calculation and addresses the essential need for study replication; results may have greater external validity.

Mammalian target of rapamycin (mTOR) inhibitors are a promising new treatment in vascular anomalies, but no published randomized controlled trials are available. The aim of this systematic review of all reported cases was to assess the efficacy and safety of mTOR inhibitors in all vascular anomalies, except cancers, in children and adults. In November 2014 MEDLINE, CENTRAL, LILACS and EMBASE were searched for studies of mTOR inhibitors in any vascular condition, except for malignant lesions, in humans. Fourteen publications and 9 posters, with data on 25 and 59 patients, respectively, all < 18 years old were included. Of these patients, 35.7% (n = 30) had vascular tumours, and 64.3% (n = 54) had malformations. Sirolimus was the most frequent mTOR inhibitor used (98.8%, n = 83). It was efficient in all cases, at a median time of 2 weeks (95% confidence interval 1-10 weeks). Sirolimus was well tolerated, the main side-effect being mouth sores, which led to treatment withdrawal in one case. The dosage of sirolimus was heterogeneous, the most common being 1.6 mg/m2/day.

Introduction: Postoperative wound seroma is common after mastectomy. This complication is associated with significant impact on patient outcomes and healthcare costs. The optimal closure approach for seroma prevention remains unknown but some evidence suggests that quilting suture of the dead space could lower the incidence of seroma. The aim of this trial is to compare seroma formation using quilting suture versus conventional closure with drainage in patients undergoing mastectomy., Methods and Analysis: This is a multicentre, superiority, randomised controlled trial in women undergoing mastectomy with or without axillary involvement. Exclusion criteria include indication of bilateral mastectomy or immediate reconstruction and any physical or psychiatric condition that could impair patient's ability to cooperate with postoperative data collection or that do not allow an informed consent. 320 participants will be randomised in a 1:1 ratio to receive either quilting suture or conventional wound closure with drain. The primary outcome is seroma requiring either aspiration or surgical intervention within 21 days following mastectomy. Secondary outcomes include seroma regardless of whether or not it requires an intervention, surgical site infection, pain score, cosmetic result, patient's quality of life, costs and cost-effectiveness. The primary analysis will be an intention-to treat analysis performed with a χ(2) test (or Fisher's exact test)., Ethics and Dissemination: Written informed consent will be obtained from all participants. This study was approved by Tours Research ethics committee (CPP TOURS-Region Centre-Ouest 1, 2014-R20, 16 December 2014). Study findings will be published in peer-reviewed journals and presented at relevant national and international breast cancer conferences., Trial Registration Number: NCT02263651., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Confounding factors are commonly encountered in observational studies. Several confounder-adjusted tests to compare survival between differently exposed subjects were proposed. However, only few studies have compared their performances regarding type I error rates, and no study exists evaluating their type II error rates. In this paper, we performed a comparative simulation study based on two different applications in kidney transplantation research. Our results showed that the propensity score-based inverse probability weighting (IPW) log-rank test proposed by Xie and Liu (2005) can be recommended as a first descriptive approach as it provides adjusted survival curves and has acceptable type I and II error rates. Even better performance was observed for the Wald test of the parameter corresponding to the exposure variable in a multivariable-adjusted Cox model. This last result is of primary interest regarding the exponentially increasing use of propensity score-based methods in the literature., (Copyright © 2015 John Wiley & Sons, Ltd.)

We examine the properties of principal scores methods to estimate the causal marginal odds ratio of an intervention for compliers in the context of a randomized controlled trial with non-compliers. The two-stage estimation approach has been proposed for a linear model by Jo and Stuart (Statistics in Medicine 2009; 28:2857-2875) under a principal ignorability (PI) assumption. Using a Monte Carlo simulation study, we compared the performance of several strategies to build and use principal score models and the robustness of the method to violations of underlying assumptions, in particular PI. Results showed that the principal score approach yielded unbiased estimates of the causal marginal log odds ratio under PI but that the method was sensitive to violations of PI, which occurs in particular when confounders are omitted from the analysis. For principal score analysis, probability weighting performed slightly better than full matching or 1:1 matching. Concerning the variables to be included in principal score models, the lowest mean squared error was generally obtained when using the true confounders. Using variables associated with the outcome only but not compliance however yielded very similar performance., (Copyright © 2015 John Wiley & Sons, Ltd.)

Although numerous perioperative samples and culture media are required to diagnose prosthetic joint infection (PJI), their exact number and types have not yet been definitely determined with a high level of proof. We conducted a prospective multicenter study to determine the minimal number of samples and culture media required for accurate diagnosis of PJI. Over a 2-year period, consecutive patients with clinical signs suggesting PJI were included, with five perioperative samples per patient. The bacteriological and PJI diagnosis criteria were assessed using a random selection of two, three, or four samples and compared with those obtained using the recommended five samples (references guidelines). The results obtained with two or three culture media were then compared with those obtained with five culture media for both criteria. The times-to-positivity of the different culture media were calculated. PJI was confirmed in 215/264 suspected cases, with a bacteriological criterion in 192 (89%). The PJI was monomicrobial (85%) or polymicrobial (15%). Percentages of agreement of 98.1% and 99.7%, respectively, for the bacteriological criterion and confirmed PJI diagnosis were obtained when four perioperative samples were considered. The highest percentages of agreement were obtained with the association of three culture media, a blood culture bottle, a chocolate agar plate, and Schaedler broth, incubated for 5, 7, and 14 days, respectively. This new procedure leads to significant cost saving. Our prospective multicenter study showed that four samples seeded on three culture media are sufficient for diagnosing PJI., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Fear of corticosteroid use among patients and parents of children with atopic dermatitis (AD) may be increased by professional caregiver's mistrust to corticosteroids and a lack of consistency in information provision. This study used a French national survey to assess mistrust among pharmacists of the use of topical steroids for treatment of AD in children. From all pharmacies in France, a random sample of 500 (approximately 2%) was selected to receive a postal survey comprising a standardized questionnaire of 50 items exploring trust, knowledge, beliefs and practices related to the use of topical steroids for children with AD. The main outcome was self-assessment of pharmacists' confidence in topical steroids on a 0-10 visual analogue scale. The mean confidence was 4.46 (95% confidence interval 4.11-4.82). This study highlights that pharmacists have only moderate confidence in topical steroids. This lack of trust may have a high impact on maintaining fear of corticosteroids in parents and patients.

Meta-epidemiological studies are used to compare treatment effect estimates between randomized clinical trials with and without a characteristic of interest. To our knowledge, there is presently nothing to help researchers to a priori specify the required number of meta-analyses to be included in a meta-epidemiological study. We derived a theoretical power function and sample size formula in the framework of a hierarchical model that allows for variation in the impact of the characteristic between trials within a meta-analysis and between meta-analyses. A simulation study revealed that the theoretical function overestimated power (because of the assumption of equal weights for each trial within and between meta-analyses). We also propose a simulation approach that allows for relaxing the constraints used in the theoretical approach and is more accurate. We illustrate that the two variables that mostly influence power are the number of trials per meta-analysis and the proportion of trials with the characteristic of interest. We derived a closed-form power function and sample size formula for estimating the impact of trial characteristics in meta-epidemiological studies. Our analytical results can be used as a 'rule of thumb' for sample size calculation for a meta-epidemiologic study. A more accurate sample size can be derived with a simulation study., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background: Despite randomization, baseline imbalance and confounding bias may occur in cluster randomized trials (CRTs). Covariate imbalance may jeopardize the validity of statistical inferences if they occur on prognostic factors. Thus, the diagnosis of a such imbalance is essential to adjust statistical analysis if required., Methods: We developed a tool based on the c-statistic of the propensity score (PS) model to detect global baseline covariate imbalance in CRTs and assess the risk of confounding bias. We performed a simulation study to assess the performance of the proposed tool and applied this method to analyze the data from 2 published CRTs., Results: The proposed method had good performance for large sample sizes (n =500 per arm) and when the number of unbalanced covariates was not too small as compared with the total number of baseline covariates (≥40% of unbalanced covariates). We also provide a strategy for pre selection of the covariates needed to be included in the PS model to enhance imbalance detection., Conclusion: The proposed tool could be useful in deciding whether covariate adjustment is required before performing statistical analyses of CRTs.

Purpose: This study was designed to compare conventional closure with a drain and quilting suture of mastectomy dead space for preventing wound seroma., Methods: Consecutive patients undergoing mastectomy for breast cancer were included in this retrospective observational study. Patients received conventional closure with drainage or quilting suture for wound closure. Propensity score (PS) matching was performed based on potential confounders to minimize selection bias. The primary outcome was the rate of type 2 or 3 wound seroma according to the common terminology criteria for adverse events (CTCAE) definition., Results: A total of 119 patients were included (quilting suture n = 59; conventional closure n = 60). Type 2 or 3 seroma was observed in 6.8 % of the quilting suture group and 21.7 % of the conventional closure group (crude odds ratio 0.26; 95 % confidence interval 0.08-0.86; p = 0.03). The overall seroma rate was 15.2 % in the quilting suture group and 51.7 % in the conventional closure group (p < 0.001). Persistent pain at days 15-21 was significantly less frequent in the quilting suture group than in the conventional suture group. PS matched analysis confirmed these findings, in particular the lower rate of type 2 or 3 seroma in the quilting suture group than in the conventional closure group (PS-matched odds ratio 0.16; 95 % confidence interval 0.04-0.72; p = 0.02)., Conclusions: Quilting suture of the mastectomy dead space is associated with significantly less frequent seroma than conventional closure with drain.

Background: Late recognition plays an important role in prognosis associated with kidney disease; thus, information transfer at hospital discharge regarding kidney disease is crucial. Whether it is notified in patients' hospital discharge summary (HDS) is presently largely unknown., Study Design: Cross-sectional., Setting and Participants: The prevalence of kidney dysfunction [estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2)] and its reporting to primary-care physicians from 26 units [11 surgery, 11 medical, 4 intensive care units (ICUs)] of a university hospital were analyzed in 14,000 hospitalizations., Predictor: eGFR., Outcome: Notification of kidney dysfunction in HDS., Measurements: GFR was estimated from serum creatinine using the Modification of Diet in Renal Disease formula., Results: Kidney dysfunction was frequent (27.2 %) but infrequently notified in the main-body of the HDS (overall 25.3 %, medical 25 %, surgical 16.3 %, ICU 48.4 %) even when severe (eGFR 15-29.9 ml/min/1.73 m(2) was notified in 68.8, 38.5, and 79.8 % of HDSs in medical, surgical and ICUs, respectively). Notification in the HDS conclusion was rare (overall 11.4 %, medical 9.8 %, surgical 8.4 %, ICU 27.5 %). Reporting remained low when eGFR remained abnormal at discharge (medical 35.8 %, surgical 22.5 %, ICU 62.2 %) but was worse for acute kidney injury (16.0, 17.1, and 37.7 %, respectively). The optimal eGFR cut-off for reporting was 39 ml/min/1.73 m(2). Longer durations of hospitalization, greater numbers of creatinine measurements and of abnormal eGFR were associated with notification, regardless of the type of unit., Limitations: Lack of data to define acute or chronic kidney injury with precision., Conclusions: Kidney dysfunction is frequent in hospitalized patients but is usually not notified, even when severe or still present at discharge, suggesting that it is not considered important to disclose to primary-care physicians. This lack of information may decrease physicians' awareness, and may affect continuity of care in patients with kidney dysfunction.

Background: Incomplete reporting is a frequent waste in research. Our aim was to evaluate the impact of a writing aid tool (WAT) based on the CONSORT statement and its extension for non-pharmacologic treatments on the completeness of reporting of randomized controlled trials (RCTs)., Methods: We performed a 'split-manuscript' RCT with blinded outcome assessment. Participants were masters and doctoral students in public health. They were asked to write, over a 4-hour period, the methods section of a manuscript based on a real RCT protocol, with a different protocol provided to each participant. Methods sections were divided into six different domains: 'trial design', 'randomization', 'blinding', 'participants', 'interventions', and 'outcomes'. Participants had to draft all six domains with access to the WAT for a random three of six domains. The random sequence was computer-generated and concealed. For each domain, the WAT comprised reminders of the corresponding CONSORT item(s), bullet points detailing all the key elements to be reported, and examples of good reporting. The control intervention consisted of no reminders. The primary outcome was the mean global score for completeness of reporting (scale 0-10) for all domains written with or without the WAT., Results: Forty-one participants wrote 41 different manuscripts of RCT methods sections, corresponding to 246 domains (six for each of the 41 protocols). All domains were analyzed. For the primary outcome, the mean (SD) global score for completeness of reporting was higher with than without use of the WAT: 7.1 (1.2) versus 5.0 (1.6), with a mean (95 % CI) difference 2.1 (1.5-2.7; P <0.01). Completeness of reporting was significantly higher with the WAT for all domains except for blinding and outcomes., Conclusion: Use of the WAT could improve the completeness of manuscripts reporting the results of RCTs., Trial Registration: Clinicaltrials.gov ( http://clinicaltrials.gov NCT02127567 , registration date first received April 29, 2014).

Objectives: We aimed to assess whether the clinical equipoise principle is satisfied in unbalanced randomized controlled trials (RCTs) (i.e., with an unequal probability of subjects being allocated to one group than another)., Study Design and Setting: Observational and comparative study between unbalanced and balanced RCTs. We searched the "core clinical journals" of MEDLINE to identify reports of two-parallel group superiority unbalanced RCTs published between January 2009 and December 2010. For each unbalanced RCT, we identified a maximum of four reports (to maximize power) of matched balanced RCTs dealing with the same population. Our primary outcome was the proportion of positive RCTs [i.e., with statistically significant results for the primary outcome (P < 0.05), showing greater efficacy with the new treatment than the control treatment]., Results: We selected 46 reports of unbalanced RCTs and 164 of balanced RCTs; 65.2% unbalanced RCTs and 43.9% of balanced RCTs were positive (odds ratio, 2.38; 95% confidence interval: 1.23, 4.63). As compared with balanced RCTs, unbalanced RCTs were more often industry funded and their control treatments were more often inactive. Adjusting for these latter variables did not modify the results., Conclusion: This result questions the respect of clinical equipoise in unbalanced RCTs., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We aimed to examine the extent to which inaccurate assumptions for nuisance parameters used to calculate sample size can affect the power of a randomized controlled trial (RCT). In a simulation study, we separately considered an RCT with continuous, dichotomous or time-to-event outcomes, with associated nuisance parameters of standard deviation, success rate in the control group and survival rate in the control group at some time point, respectively. For each type of outcome, we calculated a required sample size N for a hypothesized treatment effect, an assumed nuisance parameter and a nominal power of 80%. We then assumed a nuisance parameter associated with a relative error at the design stage. For each type of outcome, we randomly drew 10,000 relative errors of the associated nuisance parameter (from empirical distributions derived from a previously published review). Then, retro-fitting the sample size formula, we derived, for the pre-calculated sample size N, the real power of the RCT, taking into account the relative error for the nuisance parameter. In total, 23%, 0% and 18% of RCTs with continuous, binary and time-to-event outcomes, respectively, were underpowered (i.e., the real power was < 60%, as compared with the 80% nominal power); 41%, 16% and 6%, respectively, were overpowered (i.e., with real power > 90%). Even with proper calculation of sample size, a substantial number of trials are underpowered or overpowered because of imprecise knowledge of nuisance parameters. Such findings raise questions about how sample size for RCTs should be determined.

Background: Meta-analyses of nonrandomized studies have provided conflicting data on therapeutic hypothermia, or targeted temperature management (TTM), at 33°C in patients successfully resuscitated after nonshockable cardiac arrest. Nevertheless, the latest recommendations issued by the International Liaison Committee on Resuscitation and by the European Resuscitation Council recommend therapeutic hypothermia. New data are available on the adverse effects of therapeutic hypothermia, notably infectious complications. The risk/benefit ratio of therapeutic hypothermia after nonshockable cardiac arrest is unclear., Methods: HYPERION is a multicenter (22 French ICUs) trial with blinded outcome assessment in which 584 patients with successfully resuscitated nonshockable cardiac arrest are allocated at random to either TTM between 32.5 and 33.5°C (therapeutic hypothermia) or TTM between 36.5 and 37.5°C (therapeutic normothermia) for 24 hours. Both groups are managed with therapeutic normothermia for the next 24 hours. TTM is achieved using locally available equipment. The primary outcome is day-90 neurological status assessed by the Cerebral Performance Categories (CPC) Scale with dichotomization of the results (1 + 2 versus 3 + 4 + 5). The primary outcome is assessed by a blinded psychologist during a semi-structured telephone interview of the patient or next of kin. Secondary outcomes are day-90 mortality, hospital mortality, severe adverse events, infections, and neurocognitive performance. The planned sample size of 584 patients will enable us to detect a 9% absolute difference in day-90 neurological status with 80% power, assuming a 14% event rate in the control group and a two-sided Type 1 error rate of 4.9%. Two interim analyses will be performed, after inclusion of 200 and 400 patients, respectively., Discussion: The HYPERION trial is a multicenter, randomized, controlled, assessor-blinded, superiority trial that may provide an answer to an issue of everyday relevance, namely, whether TTM is beneficial in comatose patients resuscitated after nonshockable cardiac arrest. Furthermore, it will provide new data on the tolerance and adverse events (especially infectious complications) of TTM at 32.5-33.5°C., Trial Registration: ClinicalTrials.gov: NCT01994772 .

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).

Background: Cervical cancer screening coverage remains insufficient in most countries. Our objective was to assess whether in-home vaginal self-sampling with a dry swab for high-risk human papillomavirus (HR-HPV) testing is effective and cost-effective in increasing participation in cervical cancer screening., Methods: In March 2012, 6000 unscreened women aged 30-65 years, living in a French region covered by a screening programme, who had not responded to an initial invitation to have a Pap smear were equally randomised to three groups: 'no intervention'; 'recall', women received a letter to have a Pap smear; and 'self-sampling', women received a self-sampling kit to return to a centralised virology laboratory for PCR-based HPV testing., Results: Participation was higher in the 'self-sampling' than in the 'no intervention' group (22.5% vs 9.9%, P<0.0001; OR 2.64) and 'recall' group (11.7%, P<0.0001; OR 2.20). In the 'self-sampling' group, 320 used the self-sampling kit; for 44 of these women with positive HR-HPV test results, 40 had the recommended triage Pap smear. The ICER per extra screened woman was 77.8[euro ] and 63.2[euro ] for the 'recall' and 'self-sampling' groups, respectively, relative to the 'no intervention' group., Conclusions: Offering an in-home, return-mail kit for vaginal self-sampling with a dry swab is more effective and cost-effective than a recall letter in increasing participation in cervical cancer screening.

There is no standard method for the diagnosis of prosthetic joint infection (PJI). The contribution of 16S rRNA gene PCR sequencing on a routine basis remains to be defined. We performed a prospective multicenter study to assess the contributions of 16S rRNA gene assays in PJI diagnosis. Over a 2-year period, all patients suspected to have PJIs and a few uninfected patients undergoing primary arthroplasty (control group) were included. Five perioperative samples per patient were collected for culture and 16S rRNA gene PCR sequencing and one for histological examination. Three multicenter quality control assays were performed with both DNA extracts and crushed samples. The diagnosis of PJI was based on clinical, bacteriological, and histological criteria, according to Infectious Diseases Society of America guidelines. A molecular diagnosis was modeled on the bacteriological criterion (≥ 1 positive sample for strict pathogens and ≥ 2 for commensal skin flora). Molecular data were analyzed according to the diagnosis of PJI. Between December 2010 and March 2012, 264 suspected cases of PJI and 35 control cases were included. PJI was confirmed in 215/264 suspected cases, 192 (89%) with a bacteriological criterion. The PJIs were monomicrobial (163 cases [85%]; staphylococci, n = 108; streptococci, n = 22; Gram-negative bacilli, n = 16; anaerobes, n = 13; others, n = 4) or polymicrobial (29 cases [15%]). The molecular diagnosis was positive in 151/215 confirmed cases of PJI (143 cases with bacteriological PJI documentation and 8 treated cases without bacteriological documentation) and in 2/49 cases without confirmed PJI (sensitivity, 73.3%; specificity, 95.5%). The 16S rRNA gene PCR assay showed a lack of sensitivity in the diagnosis of PJI on a multicenter routine basis., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Objectives: To assess the reporting of the unequal randomization ratio in reports of trials with this design and to identify the justification for the design., Study Design and Setting: Systematic review of reports of trials with unequal randomization. We selected all original reports of two parallel-group randomized controlled trials with unequal randomization, which were published in 2009 and 2010 in core clinical journals in MEDLINE on the basis of the abstract (and full text, if necessary). Additional information was collected by an author survey., Results: We retrieved 106 reports (prevalence, 4.7%). The randomization ratio was not stated in 8.5% of reports and 51.9% of abstracts. Sample size calculation was reported in 70 reports, with unequal randomization not taken into account in 25.7% (n = 18). Justification for unequal randomization was not reported in 77.4% (n = 82) of reports. Combining information from reports and author surveys, we had justification for 41 trials. The main justification was safety issues for 20 trials. In 11 of those latter 20 reports, adverse events were not fully reported., Conclusion: A better reporting of the randomization ratio, sample size calculation, and justification to unequal randomization could help readers appraise the quality and risk of bias of such trials., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Despite randomization, selection bias may occur in cluster randomized trials. Classical multivariable regression usually allows for adjusting treatment effect estimates with unbalanced covariates. However, for binary outcomes with low incidence, such a method may fail because of separation problems. This simulation study focused on the performance of propensity score (PS)-based methods to estimate relative risks from cluster randomized trials with binary outcomes with low incidence. The results suggested that among the different approaches used (multivariable regression, direct adjustment on PS, inverse weighting on PS, and stratification on PS), only direct adjustment on the PS fully corrected the bias and moreover had the best statistical properties., (Copyright © 2014 John Wiley & Sons, Ltd.)

Objectives: Primary objective was to identify leukocyte subsets that could predict the early evolution of sepsis at 48 hours (i.e., deterioration or stability/improvement). Secondary objectives were to evaluate the prognostic value of leukocyte subsets on mortality and immunosuppressive properties of immature granulocytes., Design: Twenty-three peripheral blood leukocyte subsets were analyzed using a new-generation 10-color flow cytometry. T-cell killing activity of immature granulocytes was explored using a sorting method specifically developed., Setting: ICUs and emergency departments., Patients: All patients admitted to emergency department and ICU for sepsis ongoing for less than 24 hours were eligible. Exclusion criteria were pregnancy, age less than 18 years, solid tumors, HIV infection, hematological or inflammatory conditions, and immunosuppressive drugs. Finally, 177 patients were included., Interventions: None., Measurements and Main Results: The two most salient features of sepsis were decreased CD10 (CD10) and CD16 (CD16) expressions on granulocytes. With a threshold of 90% of CD10 and 15% of CD16 granulocytes, these immunophenotypic features, which are those of immature granulocytes, predicted sepsis deterioration at 48 hours with a sensitivity of 57% and 70% and a specificity of 78% and 82%, respectively. Survival rate at day 30 was 99% for patients without CD10 and CD16, 85% for patients with increased CD16 only, and 63% for patients with increased CD16 and CD10 granulocytes (p < 0.001). Among CD16 immature granulocytes, we identified a CD14/CD24 myeloid-derived suppressor cell subset with the capability of killing activated T cells. Consistently, an excess of CD16 immature granulocytes was associated with both CD3 and CD4 T-cell lymphopenia in deteriorating patients., Conclusions: Circulating immature granulocytes predicted early sepsis deterioration and were enriched in myeloid-derived suppressor cells which could be responsible for immunosuppression through the induction of T-cell lymphopenia.

Background: Echocardiography is routinely used to identify potential cardiac sources of embolism (CSE) in the acute phase of ischemic stroke (IS). We know that transoesophageal echography (TEE) is superior to detect CSE than transthoracic echography (TTE). However, the indications of each technique remain controversial. We aimed to evaluate the diagnostic yield (DY) and the therapeutic impact (TI) of echocardiography (both techniques combined) in IS and to analyze impact of clinical factors on these values., Methods: We included consecutive IS patients over a period of 22 months. All patients underwent TTE, and selected patients (young or with a high suspicion of cardioembolic origin) then underwent TEE. DY (detection of CSE) and TI (introduction of oral anticoagulant, closure of patent foramen ovale and targeted cardiologic consultation) were systematically evaluated., Results: We analyzed 300 patients (mean age 61 years). All patients underwent TTE and 127 patients underwent TTE and TEE. Echocardiography overall detected CSE in 22% of patients with a TI in 11% of all cases. The TI was higher in patients less than or equal to 55 years of age. In contrast to other studies, the DY and TI of echocardiography were not associated with vascular risk factors., Conclusions: Echocardiography, as currently practiced in our stroke unit, allows detection of CSE in one patient in five, and leads to change in therapy in half of these cases. Our results suggest that TTE should be used for all patients admitted for IS, and to limit the use of TEE to younger patients., (Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Objective: Cervical cancer screening coverage remains insufficient in most countries. Testing self-collected samples for high-risk human papillomavirus (HR-HPV) could be an alternative to the Pap smear, but costs, sampling methods and transport issues hamper its wide use. Our objective was to compare diagnostic accuracy of 2 vaginal self-collection methods, a dry swab (vsc-DRY) or swab in liquid medium (vsc-LIQ), for detecting HR-HPV cervical infection assessed by a cervical clinician-collected sample in liquid medium (ccc-LIQ)., Methods: Women 20 to 65 years attending a Pap smear were recruited between September, 2009 and March, 2011. Each sample (3 per woman) underwent HPV DNA testing. Samples were classified as HR-HPV+ with detection of at least one HR-HPV or probable HR-HPV type., Results: Of 734 women included, 722 had complete HPV data. HR-HPV was detected in 20.9% of ccc-LIQ samples. Estimated sensitivity and specificity to detect HR-HPV in vsc-DRY samples were 88.7% and 92.5%, respectively, and in vsc-LIQ samples, 87.4% and 90.9%. Cytology findings were abnormal for 79 women (10.9%): among 27 samples of low-grade squamous intraepithelial lesions, 25 were HR-HPV+ in vsc-DRY, vsc-LIQ and ccc-LIQ samples. Among 6 samples of high-grade squamous intraepithelial lesions, all were HR-HPV+ in vsc-DRY samples, 1 was HR-HPV- in vsc-LIQ samples and 1 was HR-HPV- in ccc-LIQ samples., Conclusions: Vaginal self-sampling with a dry swab is accurate to detect HR-HPV infection as compared with cervical clinician-collection and accurate as compared with cytology results. This cheap and easy-to-ship sampling method could be widely used in a cervical cancer screening program., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Patients are at risk of drug-related problems (DRPs) at transition points during hospitalization. The community pharmacist (CP) is often the first healthcare professional patients visit after discharge. CPs lack sufficient information about the patient and so they may be unable to identify problems in medications, which may lead to dispensing the wrong drugs or dosage, and/or giving wrong information. We aim to assess the impact of a complex intervention comprising of medication reconciliation performed at discharge by a hospital pharmacist (HP) with communication between the HP and CP on DRPs during the seven days following discharge., Methods/design: The study is a cluster randomized crossover trial involving 46 care units (each unit corresponding to a cluster) in 22 French hospitals during two consecutive 14-day periods, randomly assigned as 'experimental' or 'control' (usual care) periods. We will recruit patients older than 18 years of age and visiting the same CP for at least three months. We will exclude patients with a hospital length of stay of more than 21 days, who do not return home or those in palliative care. During the experimental period, the HP will perform a medications reconciliation that will be communicated to the patient. The HP will inform the patient's CP about the patient's drug therapy (modification in home medication, acute drugs prescribed, nonprescription treatments, and/or lab results). The primary outcome will be a composite outcome of any kind of drug misuse during the seven days following discharge assessed at day seven (±2) post-discharge by a pharmacist in charge of the study who will contact both patients and CPs by phone. The secondary outcome will be unplanned hospitalizations assessed by phone contact at day 35 (±5) after discharge. We plan to recruit 1,176 patients., Discussion: This study will assess the impact of a reconciliation of medications performed at patient discharge followed by communication between the HP and the patient's CP. It will allow for identifying the type of patients in France for which the intervention is most relevant., Trial Registration: This study was registered with ClinicalTrials.gov (number: NCT02006797) on 5 December 2013.

Background & Aims: The first studies comparing covered stents (CS) and bare stents (BS) to achieve Transjugular Intrahepatic Portosystemic Shunt (TIPS) were in favor of CS, but only one randomized study has been performed. Our aim was to compare the primary patency of TIPS performed with CS and BS., Methods: The study was planned as a multicenter, pragmatic (with centers different in size and experience), randomized, single-blinded (with blinding of patients only), parallel group trial. The primary endpoint was TIPS dysfunction defined as either a portocaval gradient ⩾12mmHg, or a stent lumen stenosis ⩾50%. A transjugular angiography with portosystemic pressure gradient measurement was scheduled every 6months after TIPS insertion., Results: 137 patients were randomized: 66 to receive CS, and 71 BS. Patients who were found to have a hepato-cellular carcinoma, or whose procedure was cancelled were excluded, giving a sample of 129 patients (62 vs. 67). Median follow-up for CS and BS were 23.6 and 21.8months, respectively. Compared to BS, the risk of TIPS dysfunction with CS was 0.60 95% CI [0.38-0.96], (p=0.032). The 2-year rate of shunt dysfunction was 44.0% for CS vs. 63.6% for BS. Early post TIPS complications (22.4% vs. 34.9%), risk of hepatic encephalopathy (0.89 [0.53-1.49]) and 2-year survival (70% vs. 67.5%) did not differ in the two groups. The 2-year cost/patient was 20k€ [15.9-27.5] for CS vs. 23.4k€ [18-37] for BS (p=0.52)., Conclusions: CS provided a significant 39% reduction in dysfunction compared to BS. We did not observe any significant difference with regard to hepatic encephalopathy or death., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Head-louse infestation remains a public health problem. Despite published randomized-controlled trials, no consensus-based clinical practice guidelines for its management emerged because of the heterogeneity of trial methodologies. Our study was undertaken to attempt to find an optimal trial framework: minimizing the risk of bias, while taking feasibility into account. To do so, we used the vignette-based method. A systematic review first identified trials on head-louse infestation; 49 were selected and their methodological constraints assessed. Methodological features were extracted and combined by arborescence to generate a broad spectrum of potential designs, called vignettes, yielding 357 vignettes. A panel of 48 experts then rated one-on-one comparisons of those vignettes to obtain a ranking of the designs. Methodological items retained for vignette generation were income level of the population, types of treatments compared, randomization unit, blinding, treatment-administration site, diagnosis method and criteria, and primary outcome measure. The expert panel selected vignettes with cluster randomization, centralized treatment administration, and blinding of the outcome assessor. The vignette method identified optimal designs to standardize future head-louse treatment trials, thereby obtaining valid conclusions and comparable data from future trials, and appears to be a reliable way to generate evidence-based guidelines.

Purpose: The blood glucose target range and optimal method to reach this range remain a matter of debate in the intensive care unit (ICU). A computer decision support system (CDSS) might improve the outcome of ICU patients through facilitation of a tighter blood glucose control., Methods: We conducted a multi-center randomized trial in 34 French ICU. Adult patients expected to require treatment in the ICU for at least 3 days were randomly assigned without blinding to undergo tight computerized glucose control with the CDSS (TGC) or conventional glucose control (CGC), with blood glucose targets of 4.4-6.1 and <10.0 mmol/L, respectively. The primary outcome was all-cause death within 90 days after ICU admission., Results: Of the 2,684 patients who underwent randomization to the TGC and CGC treatment groups, primary outcome was available for 1,335 and 1,311 patients, respectively. The baseline characteristics of these treatment groups were similar in terms of age (61 ± 16 years), SAPS II (51 ± 19), percentage of surgical admissions (40.0%) and proportion of diabetic patients (20.3%). A total of 431 (32.3%) patients in the TGC group and 447 (34.1%) in the CGC group had died by day 90 (odds ratio for death in the TGC 0.92; 95% confidence interval 0.78-1.78; p = 0.32). Severe hypoglycemia (<2.2 mmol/L) occurred in 174 of 1,317 patients (13.2%) in the TGC group and 79 of 1,284 patients (6.2%) in the CGC group (p < 0.001)., Conclusions: Tight computerized glucose control with the CDSS did not significantly change 90-day mortality and was associated with more frequent severe hypoglycemia episodes in comparison with conventional glucose control.

Hepatitis C virus (HCV) remains a challenging public health problem worldwide. The identification of viral variants establishing de novo infections and definition of the phenotypic requirements for transmission would facilitate the design of preventive strategies. We explored the transmission of HCV variants in three cases of acute hepatitis following needlestick accidents. We used single-genome amplification of glycoprotein E1E2 gene sequences to map the genetic bottleneck upon transmission accurately. We found that infection was likely established by a single variant in two cases and six variants in the third case. Studies of donor samples showed that the transmitted variant E1E2 amino acid sequences were identical or closely related to those of variants from the donor virus populations. The transmitted variants harbored a common signature site at position 394, within hypervariable region 1 of E2, together with additional signature amino acids specific to each transmission pair. Surprisingly, these E1E2 variants conferred no greater capacity for entry than the E1E2 derived from nontransmitted variants in lentiviral pseudoparticle assays. Mutants escaping the antibodies of donor sera did not predominate among the transmitted variants either. The fitness parameters affecting the selective outgrowth of HCV variants after transmission in an immunocompetent host may thus be more complex than those suggested by mouse models. Human antibodies directed against HCV envelope effectively cross-neutralized the lentiviral particles bearing E1E2 derived from transmitted variants. These findings provide insight into the molecular mechanisms underlying HCV transmission and suggest that viral entry is a potential target for the prevention of HCV infection.

Background: Heterogeneity and its causes must be assessed using meta-analyses (meta-analysis). Especially in meta-analysis dealing with treatment of acute postoperative pain, the type of surgery is a source of heterogeneity. We aimed to assess whether the type of surgery is considered a source of heterogeneity in meta-analysis and how it is taken into account in meta-analysis evaluating the efficacy of treatment of acute postoperative pain. We further compared meta-analysis that pooled trials of surgeries with highly heterogeneous postoperative pain levels, the heterogeneous group, with meta-analysis that pooled trials involving surgeries with homogeneous pain levels, the homogenous group., Methods: The meta-analysis reports available in Issue 3, 2011 of the electronic database of the Cochrane library and pooling results of randomized or quasi-randomized controlled trials that assessed the efficacy of treatment of acute postoperative pain alone were considered. A survey of experts established a rating of the postoperative pain levels for the type of surgery. For each meta-analysis, the different pain level ratings associated with the trials included in the meta-analysis were considered and the standard deviation (sd) of these ratings calculated. From the distribution of sd values, we defined the heterogeneous and homogeneous groups., Results: Sixty-one meta-analyses were included; all assessed heterogeneity. Twenty-six meta-analyses considered the type of surgery as a subgroup (50% vs 38% in the homogeneous group vs heterogeneous group). Forty-four reports discussed the type of surgery as a source of clinical heterogeneity (85% vs 62% for the homogeneous vs heterogeneous group). Twenty-nine meta-analyses compared 'postoperative pain from dental surgery' to 'other type of surgery'., Conclusions: Meta-analyses evaluating treatment of postoperative pain should explore clinical heterogeneity associated with the type of surgery for better implications for practice.

Objective: This study aimed to determine if screening for preeclampsia could be improved between 20 and 24 weeks of gestation by uterine artery Doppler (UAD), biomarkers and lipid-related markers., Method: Women at high risk of preeclampsia according to obstetric and medical characteristics and history were prospectively enrolled. Transabdominal UAD, serum biomarkers (placenta growth factor (PlGF), soluble Fms-like tyrosine kinase-1 and sEndoglin) and lipid-related markers (total and high-density lipoprotein cholesterol, triglycerides and leptin) were prospectively collected between 20 and 24 weeks of gestation. The main endpoint was preeclampsia. UAD indices and biomarker levels were compared for the groups with and without preeclampsia. Multivariate analyses took into account the laboratory and ultrasound variables significantly associated with preeclampsia in the univariate analysis and age and nulliparity., Results: The study at Tours University Hospital took place from March 2003 to February 2008 and included 235 women: 56 (23.8%) developed preeclampsia, 42 were severe (17.8%) and 14 occurred before 34 weeks of gestation (5.9%). The group with preeclampsia had a higher UAD pulsatility index (p = 0.0003), more frequent bilateral notches (p = .0001), lower PlGF levels (239.90 vs 302.00 pg/mL; p = 0.0015), and higher triglyceride (1.95 vs 1.70 mmol/l; p = 0.0068) and leptin levels (37.40 vs 22.55 ng/mL; p = < 0.001). No significant differences were observed for other markers. Screening for preeclampsia using these Doppler and laboratory findings produced an area under the curve of 0.795., Conclusion: Second-trimester UAD findings, and PlGF, triglyceride and leptin levels could help to predict preeclampsia., (© 2013 John Wiley & Sons, Ltd.)

Cluster randomized trials (CRTs) are often prone to selection bias despite randomization. Using a simulation study, we investigated the use of propensity score (PS) based methods in estimating treatment effects in CRTs with selection bias when the outcome is quantitative. Of four PS-based methods (adjustment on PS, inverse weighting, stratification, and optimal full matching method), three successfully corrected the bias, as did an approach using classical multivariable regression. However, they showed poorer statistical efficiency than classical methods, with higher standard error for the treatment effect, and type I error much smaller than the 5% nominal level., (Copyright © 2013 John Wiley & Sons, Ltd.)

Background: The recommended first-line therapy of chronic urticaria is second-generation antihistamines, but the modalities of treatment remains unclear. Numerous recommendations with heterogeneous conclusions have been published. We wondered whether such heterogeneous conclusions were linked to the quality of published studies and their reporting., Objective: To review the study design and quality of reporting of randomized control trials investigating pharmacological treatment of autoimmune or idiopathic chronic urticaria., Methodology/principal Findings: MEDLINE and EMBASE were searched for pharmacological randomized controlled trials involving patients with chronic autoimmune or idiopathic urticaria, with the main outcome being treatment efficacy. Data were collected on general characteristics of the studies, internal validity, studied treatments, design of the trial, outcome measures and "spin" strategy in interpreting results. Spin was defined as use of specific reporting strategies to highlight that the experimental treatment is beneficial, despite statistically nonsignificant results. We evaluated 52 articles that met our criteria. Patients were reported as blinded in 42 articles (81%) and the outcome assessor was blinded in 37 (71%). A placebo was the only comparator in 13 (25%) studies. The study duration was <8 weeks in 39 articles (75%), with no follow-up after discontinuation of treatment in 37 (71%). In 4 articles (8%), blinding was clear because they described blinding of the outcome assessor, the treatment was not recognizable (identical or double-dummy) or had no major secondary effects, and computed randomization was centralized. The primary outcome was specified in 33 articles (63%) and was a score in 31. In total, 15 different scores were used. A spin strategy was used for 10 of 12 studies with a nonsignificant primary outcome., Conclusion: For establishing guidelines in treatment of chronic urticaria, studies should focus on choosing clinically relevant and reproducible primary outcomes, long-term follow-up, limited use of placebo and avoiding spin strategies.

Objective: Outcome Measures in Rheumatology promotes standardized outcome measures. No such organization exists for nephrology. We compared the reporting and homogeneity of outcome measures in registered protocols of randomized trials in rheumatology and nephrology., Study Design and Setting: Data were extracted from protocols for rheumatoid arthritis or nephroprotection registered in ClinicalTrials.gov. We rated five outcome items (domain, specific measurement, specific metric, method of aggregating data, and time frame) to obtain a 5-point score. We split outcomes into clusters that could be pooled for meta-analysis, and assessed the proportion of trials and patients by cluster., Results: We selected 75 protocols for rheumatology and 66 for nephrology. A high adjusted score for outcomes was associated with rheumatology protocols (odds ratio, 4.2; 95% confidence interval, 2.39, 7.39). We retained 13 clusters of outcomes for rheumatology, and one of one outcome (American College Rheumatology Criteria) could pool 87.1% of trials and 92.8% of patients. We retained eight clusters for nephrology, and one of four outcomes (assessing proteinuria) could pool 83.1% of trials and 44.7% of patients., Conclusions: The reporting and homogeneity of outcomes is better in registered protocols of rheumatology than nephrology. The presence of international guidelines on outcome measurement may explain the differences., (Copyright © 2013 Elsevier Inc. All rights reserved.)