Implementation of the WHO Tricycle protocol for surveillance of extended-spectrum ß-lactamase producing Escherichia coli in humans, chickens, and the environment in Madagascar: a prospective genomic epidemiology study.

BACKGROUND: Antimicrobial resistance (AMR) is a major public health threat, affecting not only people but also animals and the environment. The One Health dimension of AMR is well known; however, data are lacking on the circulation of resistance-conferring genes, particularly in low-income countries. In 2017, WHO proposed a protocol called Tricycle, focusing on extended-spectrum ß-lactamase (ESBL)-Escherichia coli surveillance in the three sectors (humans, animals, and the environment). We implemented Tricycle in Madagascar to assess ESBL-E coli prevalence and describe intrasector and intersector circulation of ESBL-E coli and plasmids. METHODS: In this prospective study, we collected blood culture data from hospitalised patients with a suspected bloodstream infection processed from May 1, 2018, to April 30, 2019, and rectal swabs from healthy pregnant women from July 30, 2018, to April 27, 2019, both from three hospitals in Antananarivo, Madagascar; and caeca from farm chickens and surface waters from the Ikopa river, wastewater, and slaughterhouse effluents in the Antananarivo area, Madagascar, from April 9, 2018, to April 30, 2019. All samples were tested for ESBL-E coli. The genomes of all isolates were sequenced using a short-read method on NextSeq 500 and NovaSeq 6000 platforms (Illumina, San Diego, CA, USA) and those carrying plasmid replicons using an additional long-read method on a MinION platform (Oxford Nanopore Technologies, Oxford, UK). We characterised genomes of isolated strains (sequence type, resistance and virulence gene content, and plasmid replicons). We then compared isolates using the variant calling method (single-nucleotide polymorphism). FINDINGS: Data from 1056 blood cultures were collected and 289 pregnant women, 246 chickens, and 28 surface waters were sampled. Of the blood cultures, 18 contained E coli, of which seven (39%) were ESBL. ESBL-E coli was present in samples from 86 (30%) of 289 pregnant women, 140 (57%) of 246 chickens, and 28 (100%) of 28 surface water samples. The wet season (November to April) was associated with higher rates of carriage in humans (odds ratio 3·08 [1·81-5·27]) and chickens (2·79 [1·65-4·81]). Sequencing of 277 non-duplicated isolates (82 from pregnant women, 118 from chickens, and 77 from environmental samples) showed high genetic diversity (90 sequence types identified) with sector-specific genomic features. Single nucleotide polymorphism (SNP) analysis revealed that 169 (61%) of 277 isolates grouped into 44 clusters (two or more isolates) of closely related isolates (<40 SNPs), of which 24 clusters contained isolates from two sectors and five contained isolates from all three sectors. ESBL genes were all blaCTX-M variants (215 [78%] of 277 being blaCTX-M-15) and were located on a plasmid in 113 (41%) of 277 isolates. These ESBL-carrying plasmids were mainly IncF (63 [55%] of 114; one strain carried two plasmids) and IncY (42 [37%] of 114). The F31/36:A4:B1 (n=13) and F-:A-:B53 (n=8) pMLST subtypes, and the IncY plasmids, which were all highly conserved, were observed in isolates of differing genetic backgrounds from all sectors and were transferable in vitro by conjugation. INTERPRETATION: Despite sector-specific population structures, both ESBL-E coli strains and plasmids are circulating among humans, chickens, and the environment in Antananarivo, Madagascar. The Tricycle protocol can be implemented in a low-income country and represents a powerful tool for investigating dissemination of AMR from a One Health perspective. FUNDING: Fondation Mérieux and INSERM, Université Paris Cité.

Metrology of two wearable sleep trackers against polysomnography in patients with sleep complaints.

Sleep trackers are used widely by patients with sleep complaints, however their metrological validation is often poor and relies on healthy subjects. We assessed the metrological validity of two commercially available sleep trackers (Withings Activité/Fitbit Alta HR) through a prospective observational monocentric study, in adult patients referred for polysomnography (PSG). We compared the total sleep time (TST), REM time, REM latency, nonREM1 + 2 time, nonREM3 time, and wake after sleep onset (WASO). We report absolute and relative errors, Bland-Altman representations, and a contingency table of times spent in sleep stages with respect to PSG. Sixty-five patients were included (final sample size 58 for Withings and 52 for Fitbit). Both devices gave a relatively accurate sleep start time with a median absolute error of 5 (IQR -43; 27) min for Withings and -2.0 (-12.5; 4.2) min for Fitbit but both overestimated TST. Withings tended to underestimate WASO with a median absolute error of -25.0 (-61.5; -8.5) min, while Fitbit tended to overestimate it (median absolute error 10 (-18; 43) min. Withings underestimated light sleep and overestimated deep sleep, while Fitbit overestimated light and REM sleep and underestimated deep sleep. The overall kappas for concordance of each epoch between PSG and devices were low: 0.12 (95%CI 0.117-0.121) for Withings and VPSG indications 0.07 (95%CI 0.067-0.071) for Fitbit, as well as kappas for each VPSG indication 0.07 (95%CI 0.067-0.071). Thus, commercially available sleep trackers are not reliable for sleep architecture in patients with sleep complaints/pathologies and should not replace actigraphy and/or PSG.

Development of a model to predict the age at breast cancer diagnosis in a global population.

Knowing the mean age at diagnosis of breast cancer (BC) in a country is important for setting up an efficient BC screening program. The aim of this study was to develop and validate a model to predict the mean age at diagnosis of BC at the country level. To develop the model, we used the CI5plus database from the IARC, which contains incidence data for 122 selected populations for a minimum of 15 consecutive years from 1993 to 2012 and data from the World Bank. The standard model was fitted with a generalized linear model with the age of the population, growth domestic product per capita (GDPPC) and fertility rate as fixed effects and continent as a random effect. The model was validated in registries of the Cancer Incidence in Five Continents that are not included in the CI5plus database (1st validation set: 1950-2012) and in the most recently released volume (2nd validation set: 2013-2017). The intercept of the model was 30.9 (27.8-34.1), and the regression coefficients for population age, GDPPC and fertility rate were 0.55 (95% CI: 0.53-0.58, p < 0.001), 0.46 (95% CI: 0.26-0.67, p < 0.001) and 1.62 (95% CI: 1.42-1.88, p < 0.001), respectively. The marginal R2 and conditional R2 were 0.22 and 0.81, respectively, suggesting that 81% percent of the variance in the mean age at diagnosis of BC was explained by the variance in population age, GDPPC and fertility rate through linear relationships. The model was highly accurate, as the correlations between the predicted age from the model and the observed mean age at diagnosis of BC were 0.64 and 0.89, respectively, and the mean relative error percentage errors were 5.2 and 3.1% for the 1st and 2nd validation sets, respectively. We developed a robust model based on population age and continent to predict the mean age at diagnosis of BC in populations. This tool could be used to implement BC screening in countries without prevention programs.

Perturbation and resilience of the gut microbiome up to 3 months after ß-lactams exposure in healthy volunteers suggest an important role of microbial ß-lactamases.

BACKGROUND: Antibiotics notoriously perturb the gut microbiota. We treated healthy volunteers either with cefotaxime or ceftriaxone for 3 days, and collected in each subject 12 faecal samples up to day 90. Using untargeted and targeted phenotypic and genotypic approaches, we studied the changes in the bacterial, phage and fungal components of the microbiota as well as the metabolome and the ß-lactamase activity of the stools. This allowed assessing their degrees of perturbation and resilience. RESULTS: While only two subjects had detectable concentrations of antibiotics in their faeces, suggesting important antibiotic degradation in the gut, the intravenous treatment perturbed very significantly the bacterial and phage microbiota, as well as the composition of the metabolome. In contrast, treatment impact was relatively low on the fungal microbiota. At the end of the surveillance period, we found evidence of resilience across the gut system since most components returned to a state like the initial one, even if the structure of the bacterial microbiota changed and the dynamics of the different components over time were rarely correlated. The observed richness of the antibiotic resistance genes repertoire was significantly reduced up to day 30, while a significant increase in the relative abundance of ß-lactamase encoding genes was observed up to day 10, consistent with a concomitant increase in the ß-lactamase activity of the microbiota. The level of ß-lactamase activity at baseline was positively associated with the resilience of the metabolome content of the stools. CONCLUSIONS: In healthy adults, antibiotics perturb many components of the microbiota, which return close to the baseline state within 30 days. These data suggest an important role of endogenous ß-lactamase-producing anaerobes in protecting the functions of the microbiota by de-activating the antibiotics reaching the colon. Video Abstract.

Early morning immune checkpoint blockade and overall survival of patients with metastatic cancer: An In-depth chronotherapeutic study.

INTRODUCTION: Recent retrospective studies suggest potential large patient's benefit through proper timing of immune checkpoint blockers (ICB). The association between ICB treatment timing and patient survival, neoplastic response and toxicities was investigated, together with interactions with performance status (PS) and sex. METHODS: A cohort of patients with metastatic or locally advanced solid tumors, who received pembrolizumab, nivolumab, atezolizumab, durvalumab, or avelumab, alone or with concomitant chemotherapy, between November 2015 and March 2021, at the Centre Leon Bérard (France), was retrospectively studied. RESULTS: 361 patients were investigated (80% non-small cell lung cancer patients, mean [SD] age: 63 [11] years, 39% of women, 83% PS0-1 at first infusion, 19% received concomitant chemotherapy). ICB were administered from 07:25 to 17:21 and optimal morning/afternoon cut-off was 11:37. Morning infusions were associated with increased OS as compared to afternoon (median 30.3 vs 15.9 months, p = 0.0024; HR 1.56 [1.17-2.1], p = 0.003). A strong PS-timing interaction was found (PS0-1 patients, HR=1.53 [1.10-2.12], p = 0.011; PS2-3 patients, HR=0.50 [0.25-0.97], p = 0.042). Morning PS0-1 patients displayed increased OS (median 36.7 vs 21.3 months, p = 0.023), partial/complete response rate (58% vs 41%, p = 0.027), and grade1-3 toxicities (49% vs 34%, p = 0.028). Mortality risk ratio between infusions at worst time-of-day, estimated at 13:36 [12:48-14:23], and in early morning was equal to 4.8 ([2.3-10.1], p = 0.008). Timing differences in toxicities resulted significant only in female patients (women vs men: p < 0.001 vs 0.4). CONCLUSIONS: Early morning ICB infusion was associated with increased OS, response, and toxicities in patients with PS0-1 as compared to later infusions within the day. Prospective randomized trials are needed to confirm this retrospective study.

Extending the code in the open-source saemix package to fit joint models of longitudinal and time-to-event data.

BACKGROUND AND OBJECTIVE: Joint modeling of longitudinal and time-to-event data has gained attention over recent years with extensive developments including nonlinear models for longitudinal outcomes and flexible time-to-event models for survival outcomes, possibly involving competing risks. However, in popular software such as R, the function used to describe the biomarker dynamic is mainly linear in the parameters, and the survival submodel relies on pre-implemented functions (exponential, Weibull, ...). The objective of this work is to extend the code from the saemix package (version 3.1 on CRAN) to fit parametric joint models where longitudinal submodels are not necessary linear in their parameters, with full user control over the model function. METHODS: We used the saemix package, designed to fit nonlinear mixed-effects models (NLMEM) through the Stochastic Approximation Expectation Maximization (SAEM) algorithm, and extended the main functions to joint model estimation. To compute standard errors (SE) of parameter estimates, we implemented a recently developed stochastic algorithm. A simulation study was proposed to assess (i) the performances of parameter estimation, (ii) the SE computation and (iii) the type I error when testing independence between the two submodels. Four joint models were considered in the simulation study, combining a linear or nonlinear mixed-effects model for the longitudinal submodel, with a single terminal event or a competing risk model. RESULTS: For all simulation scenarios, parameters were precisely and accurately estimated with low bias and uncertainty. For complex joint models (with NLMEM), increasing the number of chains of the algorithm was necessary to reduce bias, but earlier censoring in the competing risk scenario still challenged the estimation. The empirical SE of parameters obtained over all simulations were very close to those computed with the stochastic algorithm. For more complex joint models (involving NLMEM), some estimates of random effects variances had higher uncertainty and their SE were moderately under-estimated. Finally, type I error was controlled for each joint model. CONCLUSIONS: saemix is a flexible open-source package and we adapted it to fit complex parametric joint models that may not be estimated using standard tools. Code and examples to help users get started are freely available on Github.

Multivariate joint model under competing risks to predict death of hospitalized patients for SARS-CoV-2 infection.

During the coronavirus disease 2019 (COVID-19) pandemic, several clinical prognostic scores have been proposed and evaluated in hospitalized patients, relying on variables available at admission. However, capturing data collected from the longitudinal follow-up of patients during hospitalization may improve prediction accuracy of a clinical outcome. To answer this question, 327 patients diagnosed with COVID-19 and hospitalized in an academic French hospital between January and July 2020 are included in the analysis. Up to 59 biomarkers were measured from the patient admission to the time to death or discharge from hospital. We consider a joint model with multiple linear or nonlinear mixed-effects models for biomarkers evolution, and a competing risks model involving subdistribution hazard functions for the risks of death and discharge. The links are modeled by shared random effects, and the selection of the biomarkers is mainly based on the significance of the link between the longitudinal and survival parts. Three biomarkers are retained: the blood neutrophil counts, the arterial pH, and the C-reactive protein. The predictive performances of the model are evaluated with the time-dependent area under the curve (AUC) for different landmark and horizon times, and compared with those obtained from a baseline model that considers only information available at admission. The joint modeling approach helps to improve predictions when sufficient information is available. For landmark 6 days and horizon of 30 days, we obtain AUC [95% CI] 0.73 [0.65, 0.81] and 0.81 [0.73, 0.89] for the baseline and joint model, respectively (p = 0.04). Statistical inference is validated through a simulation study.

Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression.

OBJECTIVE: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD. METHOD: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system. RESULTS: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD. CONCLUSIONS: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).

Prevalence of sexual dysfunction after breast cancer compared to controls, a study from CONSTANCES cohort.

PURPOSE: Sexuality, a substantial factor in quality of life, may be altered after breast cancer (BC) treatments as they intimately afflict femininity. This study aimed to assess the prevalence of sexual dysfunction in women with a history of BC and to compare it with women without a BC history. METHODS: The French general epidemiological cohort CONSTANCES includes more than 200,000 adults. All inclusion questionnaires from CONSTANCES non-virgin adult female participants were analyzed. Women reporting a history of BC were compared to controls in univariate analysis. Multivariate analysis was performed to highlight any demographic risk factor for sexual dysfunction. RESULTS: Among the 2,680 participants who had a history of BC, 34% did not engage in sexual intercourse (SI) in the month preceding the completion of the questionnaire (n = 911), 34% had pain during SI (n = 901) and 30% were not satisfied with their sex life (n = 803). Sexual dysfunction was significantly more frequent in women who had a history of BC: they had less sexual interest (OR 1.79 [1.65;1.94], p < 0.001), experienced more pain during SI (OR 1.10 [1.02;1.19], p < 0.001) and were more dissatisfied with their sex life (OR 1.58 [1.47;1.71], p < 0.001). This stayed true after adjustment on multiple demographic factors such as age, menopausal status, body mass index and depression. CONCLUSIONS: Overall, in this real-life study in a large national cohort, history of BC appeared to be a risk factor for sexual disorders. IMPLICATIONS FOR CANCER SURVIVORS: Efforts to detect sexual disorders in BC survivors and offer quality support must be pursued.

eOSCE stations live versus remote evaluation and scores variability.

BACKGROUND: Objective structured clinical examinations (OSCEs) are known to be a fair evaluation method. These recent years, the use of online OSCEs (eOSCEs) has spread. This study aimed to compare remote versus live evaluation and assess the factors associated with score variability during eOSCEs. METHODS: We conducted large-scale eOSCEs at the medical school of the Université de Paris Cité in June 2021 and recorded all the students' performances, allowing a second evaluation. To assess the agreement in our context of multiple raters and students, we fitted a linear mixed model with student and rater as random effects and the score as an explained variable. RESULTS: One hundred seventy observations were analyzed for the first station after quality control. We retained 192 and 110 observations for the statistical analysis of the two other stations. The median score and interquartile range were 60 out of 100 (IQR 50-70), 60 out of 100 (IQR 54-70), and 53 out of 100 (IQR 45-62) for the three stations. The score variance proportions explained by the rater (ICC rater) were 23.0, 16.8, and 32.8%, respectively. Of the 31 raters, 18 (58%) were male. Scores did not differ significantly according to the gender of the rater (p = 0.96, 0.10, and 0.26, respectively). The two evaluations showed no systematic difference in scores (p = 0.92, 0.053, and 0.38, respectively). CONCLUSION: Our study suggests that remote evaluation is as reliable as live evaluation for eOSCEs.

Joint modeling under competing risks: Application to survival prediction in patients admitted in Intensive Care Unit for sepsis with daily Sequential Organ Failure Assessment score assessments.

Joint models of longitudinal process and time-to-event data have recently gained attention, notably to provide individualized dynamic predictions. In the presence of competing risks, models published mostly involve cause-specific hazard functions jointly estimated with a linear or generalized linear model. Here we propose to extend the modeling to full parametric joint estimation of a nonlinear mixed-effects model and a subdistribution hazard model. We apply this approach on 6046 patients admitted in intensive care unit (ICU) for sepsis with daily Sequential Organ Failure Assessment (SOFA) score measurements. The joint model is built on a randomly selected training set of two thirds of patients and links the current predicted SOFA measurement to the instantaneous risks of ICU death and discharge from ICU, both adjusted on the patient age. Stochastic Approximation Expectation Maximization algorithm in Monolix is used for estimation. SOFA evolution is significantly associated with both risks: 0.37, 95% confidence interval (CI) = [0.35, 0.39] for the risk of death and -0.38, 95% CI = [-0.39, -0.36] for the risk of discharge. A simulation study, inspired from the real data, shows the good estimation properties of the parameters. We assess on the validation set the added value of modeling the longitudinal SOFA follow-up for the prediction of death compared with a model that includes only SOFA at baseline. Time-dependent receiver operating characteristic area under the curve and Brier scores show that when enough longitudinal individual information is available, joint modeling provides better predictions. The methodology can easily be applied to other clinical applications because of the general form of the model.

Extended prone positioning duration for COVID-19-related ARDS: benefits and detriments.

BACKGROUND: During the COVID-19 pandemic, many more patients were turned prone than before, resulting in a considerable increase in workload. Whether extending duration of prone position may be beneficial has received little attention. We report here benefits and detriments of a strategy of extended prone positioning duration for COVID-19-related acute respiratory distress syndrome (ARDS). METHODS: A eetrospective, monocentric, study was performed on intensive care unit patients with COVID-19-related ARDS who required tracheal intubation and who have been treated with at least one session of prone position of duration greater or equal to 24 h. When prone positioning sessions were initiated, patients were kept prone for a period that covered two nights. Data regarding the incidence of pressure injury and ventilation parameters were collected retrospectively on medical and nurse files of charts. The primary outcome was the occurrence of pressure injury of stage ≥ II during the ICU stay. RESULTS: For the 81 patients included, the median duration of prone positioning sessions was 39 h [interquartile range (IQR) 34-42]. The cumulated incidence of stage ≥ II pressure injuries was 26% [95% CI 17-37] and 2.5% [95% CI 0.3-8.8] for stages III/IV pressure injuries. Patients were submitted to a median of 2 sessions [IQR 1-4] and for 213 (94%) prone positioning sessions, patients were turned over to supine position during daytime, i.e., between 9 AM and 6 PM. This increased duration was associated with additional increase in oxygenation after 16 h with the PaO2/FiO2 ratio increasing from 150 mmHg [IQR 121-196] at H+ 16 to 162 mmHg [IQR 124-221] before being turned back to supine (p = 0.017). CONCLUSION: In patients with extended duration of prone position up to 39 h, cumulative incidence for stage ≥ II pressure injuries was 26%, with 25%, 2.5%, and 0% for stage II, III, and IV, respectively. Oxygenation continued to increase significantly beyond the standard 16-h duration. Our results may have significant impact on intensive care unit staffing and patients' respiratory conditions. TRIAL REGISTRATION: Institutional review board 00006477 of HUPNVS, Université Paris Cité, APHP, with the reference: CER-2021-102, obtained on October 11th 2021. Registered at Clinicaltrials (NCT05124197).

Extended antibiotic prophylaxis after pancreatoduodenectomy reduces postoperative abdominal infection in high-risk patients: Results from a retrospective cohort study.

BACKGROUND: Preoperative biliary stenting before pancreatoduodenectomy is associated with a greater risk of bacteribilia and thus could lead to more frequent and severe surgical site infections. We hypothesized that an extended antibiotic prophylaxis could reduce the risk of surgical site infections for these high-risk patients compared with standard antibiotic prophylaxis. METHODS: All consecutive patients who underwent pancreatoduodenectomy between January 1, 2010 and December 31, 2016 were included in a tricentric retrospective cohort and classified according to the risk of surgical site infections (high or low) and the type of antibiotic prophylaxis (standard or extended). Extended antibiotic prophylaxis was defined by the use of high-rank ß-lactams >2 days after surgery. Standard antibiotic prophylaxis concerned all single dose of low-rank ß-lactams antibiotic prophylaxis. The primary outcome was postoperative surgical site infections. RESULTS: Three hundred and eight patients were included; 146 (47%) were high-risk patients, and 81 (55%) received extended antibiotic prophylaxis, mostly composed of piperacilline-tazobactam and gentamicin. There were significantly fewer surgical site infections in high-risk patients receiving extended antibiotic prophylaxis versus standard antibiotic prophylaxis (odds ratio = 0.4; 95% confidence interval, 0.2-0.8; P = .011), even after adjusting on age, sex, and duration of the surgical procedure (adjusted odds ratio = 0.3; 95% confidence interval, 0.1-0.7; P = .0071). There was no statistical difference in 28-day mortality (P = .32) or 90-day mortality (P = .13). Microorganisms identified in bile culture were more often sensitive to antibiotic prophylaxis in high-risk extended antibiotic prophylaxis group than in high-risk standard antibiotic prophylaxis group (64% versus 38%; P = .01). CONCLUSION: Extended antibiotic prophylaxis is associated with a reduced risk of surgical site infections for high-risk patients with no significant reduction on 28-day mortality. Additional studies are required to determine the optimal duration of extended antibiotic prophylaxis for these patients.

Controlling for human population stratification in rare variant association studies.

Population stratification is a confounder of genetic association studies. In analyses of rare variants, corrections based on principal components (PCs) and linear mixed models (LMMs) yield conflicting conclusions. Studies evaluating these approaches generally focused on limited types of structure and large sample sizes. We investigated the properties of several correction methods through a large simulation study using real exome data, and several within- and between-continent stratification scenarios. We considered different sample sizes, with situations including as few as 50 cases, to account for the analysis of rare disorders. Large samples showed that accounting for stratification was more difficult with a continental than with a worldwide structure. When considering a sample of 50 cases, an inflation of type-I-errors was observed with PCs for small numbers of controls (≤ 100), and with LMMs for large numbers of controls (≥ 1000). We also tested a novel local permutation method (LocPerm), which maintained a correct type-I-error in all situations. Powers were equivalent for all approaches pointing out that the key issue is to properly control type-I-errors. Finally, we found that power of analyses including small numbers of cases can be increased, by adding a large panel of external controls, provided an appropriate stratification correction was used.

Added value of rapid respiratory syndromic testing at point of care versus central laboratory testing: a controlled clinical trial.

BACKGROUND: Virus-associated respiratory infections are in the spotlight with the emergence of SARS-CoV-2 and the expanding use of multiplex PCR (mPCR). The impact of molecular testing as a point-of-care test (POCT) in the emergency department (ED) is still unclear. OBJECTIVES: To compare the impact of a syndromic test performed in the ED as a POCT and in the central laboratory on length of stay (LOS), antibiotic use and single-room assignment. METHODS: From 19 November 2019 to 9 March 2020, adults with acute respiratory illness seeking care in the ED of a large hospital were enrolled, with mPCR performed with a weekly alternation in the ED as a POCT (week A) or in the central laboratory (week B). RESULTS: 474 patients were analysed: 275 during A weeks and 199 during B weeks. Patient characteristics were similar. The hospital LOS (median 7 days during week A versus 7 days during week B, P = 0.29), the proportion of patients with ED-LOS <1 day (63% versus 60%, P = 0.57) and ED antibiotic prescription (59% versus 58%, P = 0.92) were not significantly different. Patients in the POCT arm were more frequently assigned a single room when having a positive PCR for influenza, respiratory syncytial virus and metapneumovirus [52/70 (74%) versus 19/38 (50%) in the central testing arm, P = 0.012]. CONCLUSIONS: Syndromic testing performed in the ED compared with the central laboratory failed to reduce the LOS or antibiotic consumption in patients with acute respiratory illness, but was associated with an increased single-room assignment among patients in whom a significant respiratory pathogen was detected.

Childhood Trauma and Perinatal Depression: Data From the IGEDEPP Cohort.

Background: Childhood trauma (CT) is associated with an increased risk of major depressive disorder, but little is known about the impact of CT on depression during pregnancy and the early and late postpartum period. The present study assesses whether CT is associated with perinatal depression, considering different types of CT.Methods: This study used data from the Interaction of Gene and Environment of Depression in PostPartum (IGEDEPP), a French multicenter prospective cohort study, including 3,252 women who completed the Childhood Trauma Questionnaire at the maternity department between November 2011 and June 2016. Depression during pregnancy was assessed retrospectively at the maternity department using DSM-5 criteria. Early- and late-onset postpartum depression were assessed at 2 months and 1 year postpartum, respectively.Results: Among the 3,252 women, 298 (9.2%) reported at least 1 CT. Women with CT had a higher risk of depression (OR = 2.2; 95% CI, 1.7-2.7), anxiety (OR = 2.3; 95% CI, 1.7-3.0), and suicide attempts (OR = 5.4; 95% CI, 3.5-8.4) than women without CT. Perinatal depression was more frequent in women with CT than in women without CT, after adjustment for sociodemographic characteristics and personal history of major depressive episode and consideration of the timing of onset (pregnancy, early or late postpartum) (P < .001). There was a dose effect between the number of CT types and the risk of perinatal depression.Conclusions: These results show that CT is associated with a depressive episode during adulthood, specifically in the perinatal period. These findings may lead to special prenatal care for women abused or neglected during childhood, to better screen and treat perinatal depression.Trial registration: ClinicalTrials.gov identifier: NCT01648816.

Taking population stratification into account by local permutations in rare-variant association studies on small samples.

Many methods for rare variant association studies require permutations to assess the significance of tests. Standard permutations assume that all individuals are exchangeable and do not take population stratification (PS), a known confounding factor in genetic studies, into account. We propose a novel strategy, LocPerm, in which individual phenotypes are permuted only with their closest ancestry-based neighbors. We performed a simulation study, focusing on small samples, to evaluate and compare LocPerm with standard permutations and classical adjustment on first principal components. Under the null hypothesis, LocPerm was the only method providing an acceptable type I error, regardless of sample size and level of stratification. The power of LocPerm was similar to that of standard permutation in the absence of PS, and remained stable in different PS scenarios. We conclude that LocPerm is a method of choice for taking PS and/or small sample size into account in rare variant association studies.

Prospective external validation of a new non-invasive test for the diagnosis of non-alcoholic steatohepatitis in patients with type 2 diabetes.

BACKGROUND: One of the unmet needs in patients with type 2 diabetes mellitus (T2DM) is the prediction of non-alcoholic liver disease by non-invasive blood tests, for each of the three main histological features, fibrosis, non-alcoholic steatohepatitis (NASH) and steatosis. AIMS: To validate externally the performances of a recent panel, Nash-FibroTest, for the assessment of the severity of fibrosis stages, NASH grades and steatosis grades. METHODS: We prospectively analysed 272 patients with T2DM. Standard definitions of stages and grades were used, and analyses were centralised and blinded. The performances of the FibroTest, NashTest-2 and SteatoTest-2 were assessed using the Obuchowski measure (OM), the main outcome recommended as a summary measure of accuracy includeing all pairwise stages and grades comparisons, which is not provided par the extensively used binary area under the ROC curve. RESULTS: The diagnostic performance of each component of the panel was significant. OM (SE; significance) of the FibroTest, the NashTest-2 and the SteatoTest-2 was 0.862 (0.012; P < 0.001), 0.827 (0.015; P < 0.001) and 0.794 (0.020; P < 0.01), respectively. For ballooning and lobular inflammation, OM was 0.794 (0.021; P < 0.001) and 0.821 (0.017; P < 0.001), respectively. In a post hoc analysis the FibroTest outperformed VCTE by 4.1% (2.5-6.5; P < 0.001) for reliability, with a non-significant difference for OM for fibrosis staging, 0.859 (0.012) for FibroTest vs 0.870 (0.009) for VCTE. CONCLUSIONS: From a single blood sample, the panel provides non-invasive diagnosis of the stages of fibrosis, and the grades of NASH and steatosis in patients with T2DM. TRIAL REGISTRATION NUMBER: NCT03634098.

Dynamics of extended-spectrum beta-lactamase-producing Enterobacterales colonization in long-term carriers following travel abroad.

Travel to tropical regions is associated with high risk of acquiring extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) that are typically cleared in less than 3 months following return. The conditions leading to persistent carriage that exceeds 3 months in some travellers require investigation. Whole-genome sequencing (Illumina MiSeq) was performed on the 82 ESBL-E isolates detected upon return and 1, 2, 3, 6 and 12 months later from the stools of 11 long-term (>3 months) ESBL-E carriers following travel abroad. One to five different ESBL Escherichia coli strains were detected per traveller upon return, and this diminished to one after 3 months. Long-term carriage was due to the presence of the same ESBL E. coli strain, for more than 3 months, in 9 out of 11 travellers, belonging to epidemic sequence type complexes (STc 10, 14, 38, 69, 131 and 648). The mean carriage duration of strains belonging to phylogroups B2/D/F, associated with extra-intestinal virulence, was higher than that for commensal-associated A/B1/E phylogroups (3.5 vs 0.5 months, P=0.021). Genes encoding iron capture systems (fyuA, irp), toxins (senB, sat), adhesins (flu, daaF, afa/nfaE, pap, ecpA) and colicin (cjrA) were more often present in persistent strains than in transient ones. Single-nucleotide polymorphism (SNP) analysis in persistent strains showed a maximum divergence of eight SNPs over 12 months without signs of adaptation. Genomic plasticity was observed during the follow-up with the loss or gain of mobile genetic elements such as plasmids, integrons and/or transposons that may contain resistance genes at different points in the follow-up. Long-term colonization of ESBL-E following travel is primarily due to the acquisition of E. coli strains belonging to epidemic clones and harbouring 'virulence genes', allowing good adaptation to the intestinal microbiota.