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Abstract Introduction With the emergence of targeted therapies, there is a need to accurately identify more tumor biomarkers. The EXOMA trial was designed to offer tumor and germline exome sequencing (ES) to patients with solid malignant tumors and facing therapeutic failure. As hereditary cancer predispositions could be identified, with genetic counseling and health management implications, a genetic consultation was systematically established. This design needs to be discussed as genetic human resources are limited and indication of theranostic tests will increase. Methods Genetic counseling was conducted within 15 days following inclusion in the study for patients recruited between December 2015 and July 2019. In silico analyses from theranostic ES were limited to 317 genes involved in oncogenesis, from both tumor and blood DNA. Results Six hundred and sixty six patients had a genetic consultation before ES. In 65/666 patients, 66 germline pathogenic or likely pathogenic (P/LP) variants were identified in 16 actionable genes and seven non‐actionable genes according to French guidelines. 24/65 patients had previously received genetic analysis for diagnostic purposes, and for 17 of them, a P/LP variant had already been identified. Among the 48/65 remaining cases for which the EXOMA protocol revealed a previously unknown P/LP variant, only 19 met the criteria for genetic testing for inherited cancer risk after familial survey. These criteria had not been identified by the oncologist in 10 cases. In 21/65 cases, the variant was considered incidental. Discussion In 7.4% of patients, an undiagnosed hereditary genetic predisposition was identified, whether or not related to the clinical presentation, and germline analysis impacted oncological management for only 6.3% of the cohort. This low percentage should be weighed against the burden of systematic genetic consultation and urgent circuits. Information or training tools to form oncologists to the prescription of germline genetic analyses should be explored, as well as information supports and patient preferences.

Abstract Background This substudy of the randomized IDEAL-ICU trial assessed whether the timing of renal replacement therapy (RRT) initiation has a differential effect on 90-day mortality, according to the criteria used to diagnose acute kidney injury (AKI), in patients with early-stage septic shock. Methods Three groups were considered according to the criterion defining AKI: creatinine elevation only (group 1), reduced urinary output only (group 2), creatinine elevation plus reduced urinary output (group 3). Primary outcome was 90-day all-cause death. Secondary endpoints were RRT-free days, RRT dependence and renal function at discharge. We assessed the interaction between RRT strategy (early vs. delayed) and group, and the association between RRT strategy and mortality in each group by logistic regression. Results Of 488 patients enrolled, 205 (42%) patients were in group 1, 174 (35%) in group 2, and 100 (20%) in group 3. The effect of RRT initiation strategy on 90-day mortality across groups showed significant heterogeneity (adjusted interaction p = 0.021). Mortality was 58% vs. 42% for early vs. late RRT initiation, respectively, in group 1 (p = 0.028); 57% vs. 67%, respectively, in group 2 (p = 0.18); and 58% vs. 55%, respectively, in group 3 (p = 0.79). There was no significant difference in secondary outcomes. Conclusion The timing of RRT initiation has a differential impact on outcome according to AKI diagnostic criteria. In patients with elevated creatinine only, early RRT initiation was associated with significantly increased mortality. In patients with reduced urine output only, late RRT initiation was associated with a nonsignificant, 10% absolute increase in mortality.

Pneumocystis pneumonia (PcP) remains life-threatening in kidney transplant recipients (KTR). Our study investigated risk factors one-year before PcP. We conducted a monocentric, case-control study including all KTR at the Dijon University Hospital (France) with a diagnosis of PcP between 2005 and 2022 (cases), and matched control KTR with no history of PcP (3 controls/case). Among all 1,135 KTR, 57 cases (5%) and 169 matched-controls were included. PcP was associated with 18% mortality. Compared to controls, cases were older, with a higher immunological risk, and CMV infection was more frequent in the year preceding the occurrence of PcP (23% vs. 4%; p < 0.001). As early as 1 year before PcP, lymphocyte counts were lower and serum creatinine levels were higher in cases, but immunosuppressive regimens were not significantly different. Multivariable analysis identified lymphocyte count, serum creatinine level, being treated by immunosuppressive therapy other than anti-rejection drugs, and CMV infection in the year preceding the time PcP as independently associated with the occurrence of PcP. PcP was associated with an increased risk of subsequent chronic rejection (27% vs. 3%; p = 0.001) and return to dialysis (20% vs. 3%; p = 0.002). The occurrence of CMV infection and a low lymphocyte count could redefine the indications for continuation or reinitiation of anti-Pneumocystis prophylaxis.

Background The leading cause of acute bacterial meningitis in adults is Streptococcus pneumoniae. This infection is associated with high rates of mortality and morbidity related, among other factors, to the excessive host response to the pneumococcal lysis. Experimental in vitro and in vivo data show that the combination of corticosteroids/third-generation cephalosporins and the non-lytic antibiotic, daptomycin, has synergistic effects with (1) a rapid cerebrospinal fluid sterilisation, (2) less brain damages and (3) less loss of cognitive performances. Despite these encouraging results, daptomycin has never been evaluated in adult patients with pneumococcal meningitis.Methods and analysis The AddaMAP trial is a phase II, open-label, Simon’s two-stage, multicentre trial that has been designed to assess the efficacy and safety of adding daptomycin (10 mg/kg/d for 8 days) to the recommended treatment (corticosteroids+third generation cephalosporin) in adults with confirmed pneumococcal meningitis. The main endpoint is the disability-free survival (defined as modified Rankin Scale mRS≤2) at day 30. Secondary outcomes are overall mortality, disability at D30 and D90 (mRS, Glasgow Coma Scale and Glasgow Outcome Scales, mini-mental score), hearing loss (Hearing Handicap Inventory Test at D30 and D90, routine audiometric test and Hearing-it test at D30), and quality of life (12-item Short Form Survey and WHO QOL BREF). Seventy-two analysable patients are required.Ethics and dissemination The study protocol was approved by the Institutional Review Board of the IDF 1 of the ethics committee on 16 January 2018, and authorisation was obtained from the Agence Nationale de Securité des Médicaments et des Produits de Santé on 22 September 2017. The results will be submitted for publication in a peer-reviewed journal.Trial registration number NCT03480191.

IntroductionWhether a delayed diagnosis of community-acquired pneumonia (CAP) in the emergency department (ED) is associated with worse outcome is uncertain. We sought factors associated with a delayed diagnosis of CAP in the ED and those associated with in-hospital mortality.MethodsRetrospective study including all inpatients admitted to an ED (Dijon University Hospital, France) from 1 January to 31 December 2019, and hospitalized with a diagnosis of CAP. Patients diagnosed with CAP in the ED (n = 361, early diagnosis) were compared with those diagnosed later, in the hospital ward, after the ED visit (n = 74, delayed diagnosis). Demographic, clinical, biological and radiological data were collected upon admission to the ED, as well as administered therapies and outcomes including in-hospital mortality.Results435 inpatients were included: 361 (83%) with an early and 74 (17%) with a delayed diagnosis. The latter less frequently required oxygen (54 vs. 77%; p

Introduction: Prenatal ultrasound (US) anomalies are detected in around 5%–10% of pregnancies. In prenatal diagnosis, exome sequencing (ES) diagnostic yield ranges from 6% to 80% depending on the inclusion criteria. We describe the first French national multicenter pilot study aiming to implement ES in prenatal diagnosis following the detection of anomalies on US.Patients and methods: We prospectively performed prenatal trio-ES in 150 fetuses with at least two US anomalies or one US anomaly known to be frequently linked to a genetic disorder. Trio-ES was only performed if the results could influence pregnancy management. Chromosomal microarray (CMA) was performed before or in parallel.Results: A causal diagnosis was identified in 52/150 fetuses (34%) with a median time to diagnosis of 28 days, which rose to 56/150 fetuses (37%) after additional investigation. Sporadic occurrences were identified in 34/56 (60%) fetuses and unfavorable vital and/or neurodevelopmental prognosis was made in 13/56 (24%) fetuses. The overall diagnostic yield was 41% (37/89) with first-line trio-ES versus 31% (19/61) after normal CMA. Trio-ES and CMA were systematically concordant for identification of pathogenic CNV.Conclusion: Trio-ES provided a substantial prenatal diagnostic yield, similar to postnatal diagnosis with a median turnaround of approximately 1 month, supporting its routine implementation during the detection of prenatal US anomalies.

Abstract Background In France, the Ministry of Health has implemented a comprehensive program for rare diseases (RD) that includes an epidemiological program as well as the establishment of expert centers for the clinical care of patients with RD. Since 2007, most of these centers have entered the data for patients with developmental disorders into the CEMARA population-based registry, a national online data repository for all rare diseases. Through the CEMARA web portal, descriptive demographic data, clinical data, and the chronology of medical follow-up can be obtained for each center. We address the interest and ongoing challenges of this national data collection system 10 years after its implementation. Methods Since 2007, clinicians and researchers have reported the “minimum dataset (MDS)” for each patient presenting to their expert center. We retrospectively analyzed administrative data, demographic data, care organization and diagnoses. Results Over 10 years, 228,243 RD patients (including healthy carriers and family members for whom experts denied any suspicion of RD) have visited an expert center. Among them, 167,361 were patients affected by a RD (median age 11 years, 54% children, 46% adults, with a balanced sex ratio), and 60,882 were unaffected relatives (median age 37 years). The majority of patients (87%) were seen no more than once a year, and 52% of visits were for a diagnostic procedure. Among the 2,869 recorded rare disorders, 1,907 (66.5%) were recorded in less than 10 patients, 802 (28%) in 10 to 100 patients, 149 (5.2%) in 100 to 1,000 patients, and 11 (0.4%) in > 1,000 patients. Overall, 45.6% of individuals had no diagnosis and 6.7% had an uncertain diagnosis. Children were mainly referred by their pediatrician (46%; n = 55,755 among the 121,136 total children referrals) and adults by a medical specialist (34%; n = 14,053 among the 41,564 total adult referrals). Given the geographical coverage of the centers, the median distance from the patient’s home was 25.1 km (IQR = 6.3 km-64.2 km). Conclusions CEMARA provides unprecedented support for epidemiological, clinical and therapeutic studies in the field of RD. Researchers can benefit from the national scope of CEMARA data, but also focus on specific diseases or patient subgroups. While this endeavor has been a major collective effort among French RD experts to gather large-scale data into a single database, it provides tremendous potential to improve patient care.

Abstract Background We investigated the impact of the COVID-19 crisis on mental health of professionals working in the intensive care unit (ICU) according to the intensity of the epidemic in France. Methods This cross-sectional survey was conducted in 77 French hospitals from April 22 to May 13 2020. All ICU frontline healthcare workers were eligible. The primary endpoint was the mental health, assessed using the 12-item General Health Questionnaire. Sources of stress during the crisis were assessed using the Perceived Stressors in Intensive Care Units (PS-ICU) scale. Epidemic intensity was defined as high or low for each region based on publicly available data from Santé Publique France. Effects were assessed using linear mixed models, moderation and mediation analyses. Results In total, 2643 health professionals participated; 64.36% in high-intensity zones. Professionals in areas with greater epidemic intensity were at higher risk of mental health issues (p

Abstract COVID-19 pneumonia has specific features and outcomes that suggests a unique immunopathogenesis. Severe forms of COVID-19 appear to be more frequent in obese patients, but an association with metabolic disorders is not established. Here, we focused on lipoprotein metabolism in patients hospitalized for severe pneumonia, depending on COVID-19 status. Thirty-four non-COVID-19 and 27 COVID-19 patients with severe pneumonia were enrolled. Most of them required intensive care. Plasma lipid levels, lipoprotein metabolism, and clinical and biological (including plasma cytokines) features were assessed. Despite similar initial metabolic comorbidities and respiratory severity, COVID-19 patients displayed a lower acute phase response but higher plasmatic concentrations of non-esterified fatty acids (NEFAs). NEFA profiling was characterised by higher level of polyunsaturated NEFAs (mainly linoleic and arachidonic acids) in COVID-19 patients. Multivariable analysis showed that among severe pneumonia, COVID-19-associated pneumonia was associated with higher NEFAs, lower apolipoprotein E and lower high-density lipoprotein cholesterol concentrations, independently of body mass index, sequential organ failure (SOFA) score, and C-reactive protein levels. NEFAs and PUFAs concentrations were negatively correlated with the number of ventilator-free days. Among hospitalized patients with severe pneumonia, COVID-19 is independently associated with higher NEFAs (mainly linoleic and arachidonic acids) and lower apolipoprotein E and HDL concentrations. These features might act as mediators in COVID-19 pathogenesis and emerge as new therapeutic targets. Further investigations are required to define the role of NEFAs in the pathogenesis and the dysregulated immune response associated with COVID-19. Trial registration: NCT04435223.

Background Intensive care units (ICU) are among the healthcare services most affected by the COVID-19 crisis. Stressors related to insecurity, unpredictability, patient death and family distress are significant, and put healthcare workers (HCWs) at high risk of post-traumatic stress disorder (PTSD). The aims of this study were to measure the prevalence of post-traumatic stress disorder in HCWs and to identify risk factors and protective factors during the epidemic in France. Methods During the first peak of the epidemic (from 22 April to 13 May 2020), we assessed sources of stress (PS-ICU scale), mental health (GHQ-12) and coping strategies (Brief-COPE). Three months later (03 June to 6 July 2020), PTSD was assessed using the IES-R scale, with additional questions about sources of support. Data were collected using self-report questionnaires administered online. Results Among 2153 professionals who participated in the study, 20.6% suffered from potential PTSD, mostly intrusion symptoms. Risk factors for the development of PTSD were having experienced additional difficult events during the crisis, having a high level of psychological distress, a high level of perceived stress related to the workload and human resources issues, the emotional burden related to the patient and family, and stressors specific to COVID-19 during the first peak of the crisis. The use of positive thinking coping strategies decreased the relationship between perceived stress and the presence of PTSD, while social support seeking strategies increased the relationship. Finally, the HCWs preferred to use support from colleagues, relatives and/or a psychologist, and very few used the telephone hotlines. Conclusion The epidemic has had a strong traumatic impact on intensive care HCWs. Given the risk of PTSD, we need to consider implementing easily-accessible support services that focus on positive thinking coping strategies, during and after the crisis.

IntroductionWhile QuantiFERON-TB gold (QFT) is frequently used, little attention is paid to the mitogen response. How it could be impacted and associated with outcomes is poorly known.MethodsRetrospective, case-control study in hospitalized patients who underwent QFT testing in two hospitals between 2016 and 2019. We defined two groups of cases with either negative [interferon (IFN)-γ ≤ 0.5 IU/ml, official threshold] or weak (0.5–2 IU/ml) mitogen response, and one group of controls with normal (>2 IU/ml) mitogen response.ResultsA total of 872 patients were included. An ongoing infection was independently associated with both a negative (RR = 4.34; 95% CI = 2.94–6.41) and a weak mitogen response (RR = 2.44; 95% CI = 1.66–3.58). Among tuberculosis patients, a weak mitogen response was associated with a false-negative QFT result (75%) compared to a normal response (20%). Decreasing mitogen response (normal, weak and negative, respectively) was associated with increasing length of hospital stay [median (interquartile range) 5 (3–13), 11 (5–21) and 15 (10–30) days; p < 0.001] and increasing hospital mortality (3, 7, and 15%; p < 0.001).ConclusionClinicians should take notice of the mitogen response since IFN-γ concentrations lower than

Abstract Background As cancer treatment, biotherapies can be as effective as chemotherapy while reducing the risk of secondary effects, so that they can be taken over longer periods than conventional chemotherapy. Thus, some trials aimed at assessing the benefit of maintaining biotherapies during chemotherapy-free intervals (CFI). For example, the recent PRODIGE9 trial assessed the effect of maintaining bevacizumab during CFI in metastatic colorectal cancer (mCRC) patients. However, its analysis was hindered by a small difference of exposure to the treatment between the randomized groups and by a large proportion of early drop outs, leading to a potentially unbalanced distribution of confounding factors among the trial completers. To address these limitations, we re-analyzed the PRODIGE9 data to assess the effects of different exposure metrics on all-cause mortality of patients with mCRC using methods originally developed for observational studies. Methods To account for the actual patterns of drug use by individual patients and for possible cumulative effects, we used five alternative time-varying exposure metrics: (i) cumulative dose, (ii) quantiles of the cumulative dose, (iii) standardized cumulative dose, (iv) Theoretical Blood Concentration (TBC), and (v) Weighted Cumulative Exposure (WCE). The last two metrics account for the timing of drug use. Treatment effects were estimated using adjusted Hazard Ratio from multivariable Cox proportional hazards models. Results After excluding 112 patients who died during the induction period, we analyzed data on 382 patients, among whom 320 (83.8%) died. All time-varying exposures improved substantially the model’s fit to data, relative to using only the time-invariant randomization group. All exposures indicated a protective effect for higher cumulative bevacizumab doses. The best-fitting WCE and TBC models accounted for both the cumulative effects and the different impact of doses taken at different times. Conclusions All time-varying analyses, regardless of the exposure metric used, consistently suggested protective effects of higher cumulative bevacizumab doses. However, the results may partly reflect the presence of a confusion bias. Complementing the main ITT analysis of maintenance trials with an analysis of potential cumulative effects of treatment actually taken can provide new insights, but the results must be interpreted with caution because they do not benefit from the randomization. Trial registration clinicaltrials.gov, NCT00952029 . Registered 8 August 2009.

Abstract Background Although immune modulation is a promising therapeutic avenue in coronavirus disease 2019 (COVID-19), the most relevant targets remain to be found. COVID-19 has peculiar characteristics and outcomes, suggesting a unique immunopathogenesis. Methods Thirty-six immunocompetent non-COVID-19 and 27 COVID-19 patients with severe pneumonia were prospectively enrolled in a single center, most requiring intensive care. Clinical and biological characteristics (including T cell phenotype and function and plasma concentrations of 30 cytokines) and outcomes were compared. Results At similar baseline respiratory severity, COVID-19 patients required mechanical ventilation for significantly longer than non-COVID-19 patients (15 [7–22] vs. 4 (0–15) days; p = 0.0049). COVID-19 patients had lower levels of most classical inflammatory cytokines (G-CSF, CCL20, IL-1β, IL-2, IL-6, IL-8, IL-15, TNF-α, TGF-β), but higher plasma concentrations of CXCL10, GM-CSF and CCL5, compared to non-COVID-19 patients. COVID-19 patients displayed similar T-cell exhaustion to non-COVID-19 patients, but with a more unbalanced inflammatory/anti-inflammatory cytokine response (IL-6/IL-10 and TNF-α/IL-10 ratios). Principal component analysis identified two main patterns, with a clear distinction between non-COVID-19 and COVID-19 patients. Multivariate regression analysis confirmed that GM-CSF, CXCL10 and IL-10 levels were independently associated with the duration of mechanical ventilation. Conclusion We identified a unique cytokine response, with higher plasma GM-CSF and CXCL10 in COVID-19 patients that were independently associated with the longer duration of mechanical ventilation. These cytokines could represent the dysregulated immune response in severe COVID-19, as well as promising therapeutic targets. ClinicalTrials.gov: NCT03505281.

Abstract Background COVID-19-related ARDS has unique features when compared with ARDS from other origins, suggesting a distinctive inflammatory pathogenesis. Data regarding the host response within the lung are sparse. The objective is to compare alveolar and systemic inflammation response patterns, mitochondrial alarmin release, and outcomes according to ARDS etiology (i.e., COVID-19 vs. non-COVID-19). Methods Bronchoalveolar lavage fluid and plasma were obtained from 7 control, 7 non-COVID-19 ARDS, and 14 COVID-19 ARDS patients. Clinical data, plasma, and epithelial lining fluid (ELF) concentrations of 45 inflammatory mediators and cell-free mitochondrial DNA were measured and compared. Results COVID-19 ARDS patients required mechanical ventilation (MV) for significantly longer, even after adjustment for potential confounders. There was a trend toward higher concentrations of plasma CCL5, CXCL2, CXCL10, CD40 ligand, IL-10, and GM-CSF, and ELF concentrations of CXCL1, CXCL10, granzyme B, TRAIL, and EGF in the COVID-19 ARDS group compared with the non-COVID-19 ARDS group. Plasma and ELF CXCL10 concentrations were independently associated with the number of ventilator-free days, without correlation between ELF CXCL-10 and viral load. Mitochondrial DNA plasma and ELF concentrations were elevated in all ARDS patients, with no differences between the two groups. ELF concentrations of mitochondrial DNA were correlated with alveolar cell counts, as well as IL-8 and IL-1β concentrations. Conclusion CXCL10 could be one key mediator involved in the dysregulated immune response. It should be evaluated as a candidate biomarker that may predict the duration of MV in COVID-19 ARDS patients. Targeting the CXCL10-CXCR3 axis could also be considered as a new therapeutic approach. Trial registration ClinicalTrials.gov, NCT03955887

Introduction: Like other countries, France has invested in a national medical genomics program. Among the four pilot research studies, the DEFIDIAG project focuses on the use of whole genome sequencing (WGS) for patients with intellectual disability (ID), a neurodevelopmental condition affecting 1–3% of the general population but due to a plethora of genes. However, the access to genomic analyses has many potential individual and societal issues in addition to the technical challenges. In order to help decision-makers optimally introduce genomic testing in France, there is a need to identify the socio-economic obstacles and leverages associated with the implementation of WGS.Methods and Analysis: This humanities and social sciences analysis is part of the DEFIDIAG study. The main goal of DEFIDIAG is to compare the percentage of causal genetic diagnoses obtained by trio WGS (including the patient and both parents) (WGST) to the percentage obtained using the minimal reference strategy currently used in France (Fragile-X testing, chromosomal microarray analysis, and gene panel strategy including 44 ID genes) for patients with ID having their first clinical genetics consultation. Additionally, four complementary studies will be conducted. First, a cost-effectiveness analysis will be undertaken in a subsample of 196 patients consulting for the first time for a genetic evaluation; in a blinded fashion, WGST and solo (index case, only) genomic analysis (WGSS) will be compared to the reference strategy. In addition, quantitative studies will be conducted: the first will estimate the cost of the diagnostic odyssey that could potentially be avoidable with first-line WGST in all patients previously investigated in the DEFIDIAG study; the second will estimate changes in follow-up of the patients in the year after the return of the WGST analysis compared to the period before inclusion. Finally, through semi-directive interviews, we will explore the expectations of 60 parents regarding genomic analyses.Discussion: Humanities and social sciences studies can be used to demonstrate the efficiency of WGS and assess the value that families associate with sequencing. These studies are thus expected to clarify trade-offs and to help optimize the implementation of genomic sequencing in France.Ethics Statement: The protocol was approved by the Ethics Committee Sud Méditerranée I (June 2019)—identification number: 2018-A00680-55 and the French data privacy commission (CNIL, authorization 919361).Clinical Trial Registration: (ClinicalTrials.gov), identifier (NCT04154891).

Introduction: Intellectual Disability (ID) is the most common cause of referral to pediatric genetic centers, as it affects around 1–3% of the general population and is characterized by a wide genetic heterogeneity. The Genome Sequencing (GS) approach is expected to achieve a higher diagnostic yield than exome sequencing given its wider and more homogenous coverage, and, since theoretically, it can more accurately detect variations in regions traditionally not well captured and identify structural variants, or intergenic/deep intronic putatively pathological events. The decreasing cost of sequencing, the progress in data-management and bioinformatics, prompted us to assess GS efficiency as the first line procedure to identify the molecular diagnosis in patients without obvious ID etiology. This work is being carried out in the framework of the national French initiative for genomic medicine (Plan France Médecine Génomique 2025).Methods and Analysis: This multidisciplinary, prospective diagnostic study will compare the diagnostic yield of GS trio analysis (index case, father, mother) with the French core minimal reference strategy (Fragile-X testing, chromosomal microarray analysis and Gene Panel Strategy of 44 selected ID genes). Both strategies are applied in a blinded fashion, in parallel, in the same population of 1275 ID index cases with no obvious diagnosis (50% not previously investigated). Among them, a subgroup of 196 patients are randomized to undergo GS proband analysis in addition to GS trio analysis plus the French core minimal reference strategy, in order to compare their efficiency. The study also aims to identify the most appropriate strategy according to the clinical presentation of the patients, to evaluate the impact of deployment of GS on the families’ diagnostic odyssey and the modification of their care, and to identify the advantages/difficulties for the patients and their families.Ethics Statement: The protocol was approved by the Ethics Committee Sud Méditerranée I and the French data privacy commission (CNIL, authorization 919361).Trial Registration:ClinicalTrials.gov identifier NCT04154891 (07/11/2019).

Abstract Background The influence of socioeconomic status on patient outcomes is unclear. We assessed the impact of socioeconomic deprivation on severity of illness at intensive care unit (ICU) admission, and on the risk of death at 3 months after ICU admission. Methods The IVOIRE study was a prospective, observational, multicentre cohort study in the ICU of 8 participating hospitals in France, including patients aged ≥ 18 years admitted to the ICU and receiving at least one life support therapy for organ failure. The primary outcomes were severity at admission (assessed by SAPSII score), and mortality at 3 months. Socioeconomic data were obtained from interviews with patients or family. Deprivation was assessed using the EPICES score. Results Among 1294 patents included between 2013 and 2016, 629 (48.6%) were classed as deprived and differed significantly from non-deprived subjects in terms of sociodemographic characteristics and pre-existing conditions. The mean SAPS II score at admission was 50.1 ± 19.4 in deprived patients and 52.3 ± 17.3 in non-deprived patients, with no significant difference by multivariable analysis (β = − 1.85 [95% CI − 3.86; + 0.16, p = 0.072]). The proportion of death was 31.1% at 3 months, without significant differences between deprived and non-deprived patients, even after adjustment for confounders. Conclusions Deprivation is frequent in patients admitted to the ICU and is not associated with disease severity at admission, or with mortality at 3 months between deprived and non-deprived patients. Trial registration The IVOIRE cohort is registered with ClinicalTrials.gov under the identifier NCT01907581, registration date 17/7/2013

BackgroundIntensive care unit (ICU) staff have faced unprecedented levels of stress, in the context of profound upheaval of their working environment due to the COVID-19 pandemic. We explored the perceptions of frontline ICU staff about the first wave of the COVID-19 pandemic, and how this experience impacted their personal and professional lives.MethodsIn a qualitative study as part of the PsyCOVID-ICU project, we conducted semi-structured interviews with a random sample of nurses and nurses' aides from 5 centres participating in the main PsyCOVID study. Interviews were recorded and fully transcribed, and analysed by thematic analysis.ResultsA total of 18 interviews were performed from 13 August to 6 October 2020; 13 were nurses, and 5 were nurses' aides. Thematic analysis revealed three major themes, namely: (1) Managing the home life; (2) Conditions in the workplace; and (3) the meaning of their profession.ConclusionIn this qualitative study investigating the experiences and perceptions of healthcare workers caring for critically ill patients during the first COVID-19 wave in France, the participants reported that the crisis had profound repercussions on both their personal and professional lives. The main factors affecting the participants were a fear of contamination, and the re-organisation of working conditions, against a background of a media "infodemic".

The COVID-19 pandemic has led to significant re-organisation of healthcare delivery in hospitals, with repercussions on all professionals working in healthcare. We aimed to assess the impact of the pandemic on the mental health of professionals working in health care institutions and to identify individual and environmental factors influencing the risk of mental health disorders. From 4 June to 22 September 2020, a total of 4370 professionals responded to an online questionnaire evaluating psychological distress, severity of post-traumatic stress symptoms, stress factors, and coping strategies. About 57% of the professionals suffered from psychological distress, and 21% showed symptoms of potential post-traumatic stress. Professionals working in radiology, those working in quality/hygiene/security and nurses' aides were the most affected groups. The media focus on the crisis, and a high workload were the most prevalent stress factors, followed by uncertainty regarding the possibility of containing the epidemic, the constantly changing hygiene recommendations/protocols, and the lack of personal protective equipment. The use of coping strategies, notably positive thinking, helped to mitigate the relation between perceived stress and mental health disorders. The COVID-19 pandemic has had far-reaching negative repercussions for all professionals, with some sectors more markedly affected. To prevent mental health disorders in professionals during a public health crisis, support services and management strategies within hospitals should take account of the importance of positive thinking and social support.

PurposeDuring the COVID pandemic, many hospitals had to mobilize reinforcement healthcare workers, especially in intensive care (ICUs). We investigated the perceptions and experiences of reinforcement workers deployed to ICUs, and the impact of deployment on their personal and professional lives.MethodsFor this qualitative study, a random sample of 30 reinforcement workers was drawn from 4 centres participating in the larger PsyCOVID-ICU study. Individual semi-structured interviews were held, recorded, transcribed and analyzed by thematic analysis.ResultsThirty interviews were performed from April to May 2021 (22 nurses, 2 anesthesiology nurses, 6 nurses' aides). Average age was 36.8±9.5 years; 7 participants had no ICU experience. Four major themes emerged, namely: (1) Difficulties with integration, especially for those with no ICU experience; (2) lack of training; (3) difficulties with management, notably a feeling of insufficient communication; (4) Mental distress relating to the unusual work and fear of contaminating their entourage.ConclusionHealthcare workers deployed as reinforcements to ICUs at the height of the pandemic had a unique experience of the crisis, and identified important gaps in organisation and preparation. They also suffered from a marked lack of training, given the stakes in the management of critically ill patients in the ICU.

Rationale: COVID-19 displays distinct characteristics that suggest a unique pathogenesis. The objective of this study was to compare biomarkers of coagulopathy and outcomes in COVID-19 and non-COVID-19 patients with severe pneumonia.Methods: Thirty-six non-COVID-19 and 27 COVID-19 non-immunocompromised patients with severe pneumonia were prospectively enrolled, most requiring intensive care. Clinical and biological characteristics (including plasma biomarkers of coagulopathy) were compared.Results: At similar baseline severity, COVID-19 patients required mechanical ventilation (MV) for significantly longer than non-COVID-19 patients (p = 0.0049) and more frequently developed venous thrombotic complications (p = 0.031). COVID-19 patients had significantly higher plasma concentrations of soluble VCAM1 (sVCAM1) (5,739 ± 3,293 vs. 3,700 ± 2,124 ng/ml; p = 0.009), but lower levels of D-dimers, vWF-A2, sICAM1, sTREM1, VEGF, and P-selectin, compared to non-COVID-19 patients. Principal component analysis identified two main patterns, with a clear distinction between non-COVID-19 and COVID-19 patients. Multivariable regression analysis confirmed that sVCAM1 rising levels were independently associated with a longer duration of MV. Finally, we identified close correlations between sVCAM1 and some features of COVID-19 immune dysregulation (ie. CXCL10, GM-CSF, and IL-10).Conclusion: We identified specific features of the coagulopathy signature in severe COVID-19 patients, with higher plasma sVCAM1 levels, that were independently associated with the longer duration of mechanical ventilation.Clinical Trial Registration:ClinicalTrials.gov, identifier: NCT03505281.

Abstract Objectives To assess the efficacy of several repurposed drugs to prevent hospitalisation or death in patients aged 65 or more with recent symptomatic SARS-CoV-2 infection (COVID-19) and no criteria for hospitalisation. Trial design Phase III, multi-arm (5) and multi-stage (MAMS), randomized, open-label controlled superiority trial. Participants will be randomly allocated 1:1:1:1:1 to the following strategies: Arm 1: Control arm Arms 2 to 5: Experimental treatment arms Planned interim analyses will be conducted at regular intervals. Their results will be reviewed by an Independent Data and Safety Monitoring Board. Experimental arms may be terminated for futility, efficacy or toxicity before the end of the trial. New experimental arms may be added if new evidence suggests that other treatments should be tested. A feasibility and acceptability substudy as well as an immunological substudy will be conducted alongside the trial. Participants Inclusion criteria are: 65-year-old or more; Positive test for SARS-CoV-2 on a nasopharyngeal swab; Symptoms onset within 3 days before diagnosis; No hospitalisation criteria; Signed informed consent; Health insurance. Exclusion criteria are: Inability to make an informed decision to participate (e.g.: dementia, guardianship); Rockwood Clinical Frailty Scale ≥7; Long QT syndrome; QTc interval > 500 ms; Heart rate 5.5 mmol/L or

Abstract Background Non-tunneled hemodialysis catheters are currently used for critically ill patients with acute kidney injury requiring extracorporeal renal replacement therapy. Strategies to prevent catheter dysfunction and infection with catheter locks remain controversial. Methods In a multicenter, randomized, controlled, double-blind trial, we compared two strategies for catheter locking of non-tunneled hemodialysis catheters, namely trisodium citrate at 4% (intervention group) versus unfractionated heparin (control group), in patients aged 18 years or older admitted to the intensive care unit and in whom a first non-tunneled hemodialysis catheter was to be inserted by the jugular or femoral vein. The primary endpoint was length of event-free survival of the first non-tunneled hemodialysis catheter. Secondary endpoints were: rate of fibrinolysis, incidence of catheter dysfunction and incidence of catheter-related bloodstream infection (CRBSI), all per 1000 catheter-days; number of hemorrhagic events requiring transfusion, length of stay in intensive care and in hospital; 28-day mortality. Results Overall, 396 randomized patients completed the trial: 199 in the citrate group and 197 in the heparin group. There was no significant difference in baseline characteristics between groups. The duration of event-free survival of the first non-tunneled hemodialysis catheter was not significantly different between groups: 7 days (IQR 3–10) in the citrate group and 5 days (IQR 3–11) in the heparin group (p = 0.51). Rates of catheter thrombosis, CRBSI, and adverse events were not statistically different between groups. Conclusions In critically ill patients, there was no significant difference in the duration of event-free survival of the first non-tunneled hemodialysis catheter between trisodium citrate 4% and heparin as a locking solution. Catheter thrombosis, catheter-related infection, and adverse events were not statistically different between the two groups. Trial registration Registered with Clinicaltrials.gov under the number NCT01962116. Registered 14 October 2013.

French authorities created mental health support services to accompany HCWs during the pandemic. We aimed to obtain feedback from staff providing these mental health support services within French hospitals to identify positive and negative features and avenues for improvement. A mixed-methods study was performed between 1 April and 30 June 2020. We contacted 77 centres to identify those providing mental health support services. We developed a questionnaire containing questions about the staff providing the service (quantitative part), with open questions to enable feedback from service providers (qualitative part). Of the 77 centres, 36 had mental health support services; 77.8% were created specifically for the epidemic. Services were staffed principally by psychologists, mainly used a telephone platform, and had a median opening time of 8 h/day. Thirty-seven professionals provided feedback, most aged 35–49 years. For 86.5%, it was their first time providing such support. Median self-reported comfort level was 8 (interquartiles 3–10), and 95% would do it again. Respondents reported (i) difficulties with work organisation, clinical situations, and lack of recognition and (ii) a desire for training. This study suggests that mental health support needs to be adapted to the needs of HCWs, both in terms of the content of the service and the timing of delivery.

PurposeTo investigate the association between the characteristics of the retinal vascular network in the elderly and retinal nerve fiber layer (RNFL) thickness in a population-based study.MethodsWe conducted a population-based study, the Montrachet study (Maculopathy Optic Nerve, nuTRition neurovAsCular, and HEarT disease), in participants aged ≥ 75 years. RNFL thickness was assessed with spectral-domain optical coherence tomography (SD-OCT). Analysis of the retinal vascular network was performed by means of the Singapore "I" Vessel Assessment (SIVA) software based on fundus photography.ResultsData from 970 participants were suitable for analysis. Patients with optic neuropathy were excluded. In multivariable analysis, each standard deviation (SD) decrease in the caliber of the six largest arterioles and veins in zone B and the six largest arterioles and veins in zone C was associated with a decrease in global RNFL thickness (β = -1.62 μm, P = 0.001; β = -2.39 μm, P < 0.001; β = -1.56 μm, P = 0.002; and β = -2.64 μm, P < 0.001, respectively).ConclusionsOur study found that decreased retinal vessels caliber were associated with a decreased RNFL thickness in the elderly without optic neuropathy.

BackgroundMultiple approaches have been proposed to measure low socio-economic status. In France the concept of precariousness, akin to social deprivation, was developed and is widely used. EPICES is a short questionnaire that was developed to measure this concept. This study aimed to evaluate Differential Item Functioning (DIF) in the EPICES questionnaire between contrasted areas: mainland France, French West Indies (FWI) and French Guiana (FG).MethodsThe population was taken from the INDIA study, which aimed to evaluate the impact of social inequalities on stroke characteristics and prognosis. Eligible people were patients referred to neurology or emergency departments for a suspicion of stroke. We assessed the DIF using hybrid ordinal logistic regression method, derived from item response theory.ResultsWe analysed 1 553 stroke patients, including 768 from FWI (49.5%), 289 from FG (18.6%) and 496 from mainland (31.9%). We identified five items with a moderate to large DIF in area comparisons: "meeting with a social worker", "complementary health insurance", "home-owning", "financial difficulties" and "sport activities". Correlation between EPICES score and the latent variable was strong (r = 0.84).ConclusionThis is the first attempt to assess the DIF of the EPICES score between different French populations. We found several items with DIF, which can be explained by individual interpretation or local context. However, the DIFs did not lead to a large difference between the latent variable and the EPICES score, which indicates that it can be used to assess precariousness and social deprivation between contrasted areas.

Exosomes are nanovesicles released by all cells that can be found in the blood. A key point for their use as potential biomarkers in cancer is to differentiate tumour-derived exosomes from other circulating nanovesicles. Heat shock protein-70 (HSP70) has been shown to be abundantly expressed by cancer cells and to be associated with bad prognosis. We previously showed that exosomes derived from cancer cells carried HSP70 in the membrane while those from non-cancerous cells did not. In this work, we opened a prospective clinical pilot study including breast and lung cancer patients to determine whether it was possible to detect and quantify HSP70 exosomes in the blood of patients with solid cancers. We found that circulating exosomal HSP70 levels, but not soluble HSP70, reflected HSP70 content within the tumour biopsies. Circulating HSP70 exosomes increased in metastatic patients compared to non-metastatic patients or healthy volunteers. Further, we demonstrated that HSP70-exosome levels correlated with the disease status and, when compared with circulating tumour cells, were more sensitive tumour dissemination predictors. Finally, our case studies indicated that HSP70-exosome levels inversely correlated with response to the therapy and that, therefore, monitoring changes in circulating exosomal HSP70 might be useful to predict tumour response and clinical outcome.

Objective: The evaluation of the disease severity in hip osteoarthritis (OA) patients being currently based on subjective instruments. It would be of interest to develop more objective instruments, for example based on gait analysis. The aims of this study were to explore if pelvis-thorax coordination parameters could be valuable instrument outcomes to achieve this evaluation by assessing their reliability, discriminant capacity and responsiveness.Methods: Three groups of subjects; healthy, hip OA patients with severe disease (defined as indication to surgery), hip OA patients with less severe disease (no indication to surgery) were included. Hip OA patients with severe disease were evaluated before and 6 months after surgery. Subjects had to perform a gait analysis at comfortable speed, and pelvis-thorax coordination was evaluated. The correlations with clinical and structural parameters, as well as reliability, discriminant capacities and responsiveness, were assessed.Results: The pelvis-thorax coordination in the coronal plane during walking was correlated to clinical and to structural severity in hip OA patients (R2 = 0.13). The coronal plane coordination allowed to discriminate healthy subjects from all hip OA patients (sensibility = 0.86; specificity = 0.59). Moreover, when comparing OA patients only, coronal plane coordination allows to discriminate patients with indication of surgery from those with no indication of surgery (sensibility = 0.72; specificity = 0.72). Moreover, the pelvis-thorax coordination demonstrated an excellent reliability and a good responsiveness.Conclusion: Changes in the pelvis-thorax coordination might refer to different mechanisms, from analgesia to motor control plasticity, and might be a possible explanation for the weak correlation between structure and symptoms in hip OA patients. Moreover, such parameter might be used as an objective outcome in hip OA clinical trials.Clinical Trials Registration:www.ClinicalTrials.gov, identifier: NCT02042586 and NCT01907503.

Abstract Background Testicular germ cell tumor such as seminoma is strongly associated with male reproductive problems commonly associated with the alteration of sperm parameters as described in testicular dysgenesis syndrome. Interestingly, numerous studies have reported that the precursor of germ cell cancer, germ cell neoplasia in situ (GCNIS), present similarities to fetal gonocytes, specifically characterized by global DNA hypomethylation particularly on imprinting sequences. These disorders may have a common origin derived from perturbations of embryonal programming during fetal development. Presently, there is no available information concerning the sperm DNA methylation patterns of testicular cancer patients. For the first time, we evaluated the sperm imprinting of seminoma patients. A total of 92 cryopreserved sperm samples were included, 31 before seminoma treatment (S): 23 normozoospermic (SN) and 8 oligozoospermic (SO) and 61 sperm controls samples: 31 normozoospermic (N) and 30 oligozoospermic (O). DNA methylation levels of seven differentially methylated regions (DMRs) of imprinted genes [H19/IGF2: IG-DMR (CTCF3 and CTCF6 of H19 gene); IGF2-DMRs (DMR0 and DMR2); MEG3/DLK1:IG-DMR; SNURF:TSS-DMR; KCNQ1OT1:TSS-DMR] were assessed by pyrosequencing. All comparative analyses were adjusted for age. Results Comparisons of sperm DNA methylation levels between seminoma (S) and normozoospermic (N) samples showed a significant difference for the SNURF sequence (p = 0.017), but after taking into account the sperm parameters, no difference was observed. However, we confirmed a significant association between oligozoospermia (O) and imprinting defects for H19/IGF2-CTCF6 (p = 0.001), MEG3/DLK1 (p = 0.017), IGF2-DMR2 (p = 0.022), and SNURF (p = 0.032) in comparison with control groups (N). Conclusions This study highlights the high risk of sperm imprinting defects in cases of oligozoospermia and shows for the first time that seminoma patients with normal spermatogenesis present sperm imprinting integrity. These data suggest a low probability of the involvement of a common imprinting defect in fetal cells leading to both TGCT and subfertility.

An amendment to this paper has been published and can be accessed via the original article.

BackgroundCongenital Toxoplasmosis (CT) can have severe consequences. France, Austria, and Slovenia have prenatal screening programs whereas some other countries are considering universal screening to reduce congenital transmission and severity of infection in children. The efficiency of such programs is debated increasingly as seroprevalence among pregnant women and incidence of congenital toxoplasmosis show a steady decrease. In addition, uncertainty remains regarding the effectiveness of pre- and postnatal treatments.MethodTo identify cost-effective strategies, prenatal and neonatal screenings were compared using a decision-analytic model based on French guidelines and current knowledge of long-term evolution of the disease in treated children. Epidemiological data were extracted from the scientific literature and clinical data from the French Lyon cohort. Strategies were compared at one year of age, when infection can be definitively evaluated, and at 15 years of age, after which validated outcome data become scarce. The analysis was performed from the French Health Insurance System perspective and included direct medical costs for pregnant women and their children.ResultsThe 1-year Incremental Cost-Effectiveness Ratio showed that prenatal screening would require investing €14,826 to avoid one adverse event (liveborn with CT, fetal loss, neonatal death or pregnancy termination) compared to neonatal screening. Extra investment increased up to €21,472 when considering the 15-year endpoint.ConclusionsPrenatal screening is cost-effective as compared to neonatal screening in moderate prevalence areas with predominant Type II strains. In addition, prenatal screening, by providing closer follow-up of women at risk increases the number of occasions for education avoiding toxoplasmosis.

An amendment to this paper has been published and can be accessed via the original article.

BACKGROUND:We aimed to determine participation rates and factors associated with participation in colorectal (fecal occul blood test) and cervical cancer (Pap-smear) screening among a population of women participating in breast cancer screening. METHODS:From August to October 2015, a self-administered questionnaire was sent by post to 2 900 women aged 50-65, living in Côte-d'Or, France, and who were up to date with mammogram screening. Polytomic logistic regression was used to identify correlates of participation in both cervical and colorectal cancer screenings. Participation in all 3 screenings was chosen as the reference. RESULTS:Study participation rate was 66.3% (n = 1856). Besides being compliant with mammogram, respectively 78.3% and 56.6% of respondents were up to date for cervical and colorectal cancer screenings, while 46.2% were compliant with the 3 screenings. Consultation with a gynecologist in the past year was associated with higher chance of undergoing the 3 screenings or female cancer screenings (p59 and yearly flu vaccine were associated with a lower involvement in cervical cancer screening. Women from high socio-economic classes were more likely to attend only female cancer screenings (p = 0.009). Finally, a low level of physical activity and tobacco use were associated with higher risk of no additional screening participation (p

To identify patterns summarizing the retinal vascular network in the elderly and to investigate the relationship of these vascular patterns with cardiovascular history.We conducted a population-based study, the Montrachet study (Maculopathy Optic Nerve nuTRition neurovAsCular and HEarT diseases), in participants older than 75 years. The history of cardiovascular disease and a score-based estimation of their 10-year risk of cardiovascular mortality (Heart SCORE) were collected. Retinal vascular network analysis was performed by means of Singapore "I" Vessel Assessment (SIVA) software. Principal component analysis was used to condense the information contained in the high number of variables provided and to identify independent retinal vascular patterns.Overall, 1069 photographs (1069 participants) were reviewed with SIVA software. The mean age was 80.0 ± 3.8 years. We extracted three vascular patterns summarizing 41.3% of the vascular information. The most clinically relevant pattern, Sparse vascular network, accounted for 17.4% of the total variance. It corresponded to a lower density in the vascular network and higher variability in vessel width. Diabetic participants with hypoglycemic treatment had a sparser vascular network pattern than subjects without such treatment (odds ratio, [OR], 1.68; 95% CI, 1.04-2.72; P = 0.04). Participants with no history of cardiovascular disease who had a sparser vascular network were associated with a higher Heart SCORE (OR, 1.76; 95% CI, 1.08-2.25; P = 0.02).Three vascular patterns were identified. The Sparse vascular network pattern was associated with having a higher risk profile for cardiovascular mortality risk at 10 years.

We investigated incidence, risk factors for new-onset atrial fibrillation (NAF), and prognostic impact during septic shock in medical Intensive Care Unit (ICU) patients.Prospective, observational study in a university hospital. Consecutive patients from 03/2011 to 05/2013 with septic shock were eligible. Exclusion criteria were age 30 seconds. Patient characteristics, infection criteria, cardiovascular parameters, severity of illness, support therapies were recorded.Among 66 patients, 29(44%) developed NAF; 10 (34%) would not have been diagnosed without Holter ECG monitoring. NAF patients were older, with more markers of heart failure (troponin and NT-pro-BNP), lower left ventricular ejection fraction (LVEF), longer QRS duration and more nonsustained supra ventricular arrhythmias (

OBJECTIVE: We aimed to investigate the predictive value for severe adverse outcome of plasma protein measurements on day one of life in very preterm infants and to compare total plasma protein levels with the validated illness severity scores CRIB, CRIB-II, SNAP-II and SNAPPE-II, regarding their predictive ability for severe adverse outcome. METHODS: We analyzed a cohort of infants born at 24-31 weeks gestation, admitted to the tertiary intensive care unit of a university hospital over 10.5 years. The outcome measure was "severe adverse outcome" defined as death before discharge or severe neurological injury on cranial ultrasound. The adjusted odd ratio (aOR) and 95% confidence interval (95% CI) of severe adverse outcome for hypoproteinemia (total plasma protein level