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Summary Background Patients with COVID-19 pneumonia can have increased inflammation and elevated cytokines, including interleukin (IL)-6, which might be deleterious. Thus, sarilumab, a high-affinity anti-IL-6 receptor antibody, might improve the outcome of patients with moderate-to-severe COVID-19 pneumonia. Methods We did a multicentric, open-label, Bayesian randomised, adaptive, phase 2/3 clinical trial, nested within the CORIMUNO-19 cohort, to test a superiority hypothesis. Patients 18 years or older hospitalised with COVID-19 in six French centres, requiring at least 3L/min of oxygen but without ventilation assistance and a WHO Clinical Progression Scale [CPS] score of 5 were enrolled. Patients were randomly assigned (1:1) via a web-based system, according to a randomisation list stratified on centre and with blocks randomly selected among 2 and 4, to receive usual care plus 400 mg of sarilumab intravenously on day 1 and on day 3 if clinically indicated (sarilumab group) or usual care alone (usual care group). Primary outcomes were the proportion of patients with WHO-CPS scores greater than 5 on the 10-point scale on day 4 and survival without invasive or non-invasive ventilation at day 14. This completed trial is closed to new participants and is registered with ClinicalTrials.gov , NCT04324073 . Findings 165 patients were recruited from March 27 to April 6, 2020, and 148 patients were randomised (68 patients to the sarilumab group and 80 to the usual care group) and followed up for 90 days. Median age was 61·7 years [IQR 53·0–71·1] in the sarilumab group and 62·8 years [56·0–71·7] in the usual care group. In the sarilumab group 49 (72%) of 68 were men and in the usual care group 59 (78%) of 76 were men. Four patients in the usual care group withdrew consent and were not analysed. 18 (26%) of 68 patients in the sarilumab group had a WHO-CPS score greater than 5 at day 4 versus 20 (26%) of 76 in the usual care group (median posterior absolute risk difference 0·2%; 90% credible interval [CrI] −11·7 to 12·2), with a posterior probability of absolute risk difference greater than 0 of 48·9%. At day 14, 25 (37%) patients in the sarilumab and 26 (34%) patients in the usual care group needed ventilation or died, (median posterior hazard ratio [HR] 1·10; 90% CrI 0·69–1·74) with a posterior probability HR greater than 1 of 37·4%. Serious adverse events occurred in 27 (40%) patients in the sarilumab group and 28 (37%) patients in the usual care group (p=0·73). Interpretation Sarilumab treatment did not improve early outcomes in patients with moderate-to-severe COVID-19 pneumonia. Further studies are warranted to evaluate the effect of sarilumab on long-term survival. Funding Assistance publique—Hopitaux de Paris

Environmental flows are generally characterized by complex bed morphology and high current speeds. Such configurations favor the formation of vortex structures that strongly affect hydrody-namics and sediment transport. Large-Eddy Simulation (LES) enables investigation of the dynam-ics of the largest turbulence scales and, thanks to enhanced calculation resources, has now become applicable for simulating environmental flows. In this paper, a LES approach is developed in a CFD code (TELEMAC-3D), which was originally developed to simulate free surface flows using RANS methods. The present developments involve implementing subgrid models, boundary con-ditions and numerical schemes suitable for LES. The LES version of TELEMAC-3D was validated by comparing results on the model with experimental data for flow past a cylinder. Then, the model was applied to a test case representing flow over dunes. After validating the hydrodynamics, the model was used to assess the bottom shear stress, using both a RANS and a LES approach. Com-parison highlighted the potential contribution of LES to investigating the hydrodynamic forces acting on the bottom.

Jocelyne Just,1– 3 Celine Thonnelier,4 Melisande Bourgoin-Heck,5 Laurence Mala,4 Mathieu Molimard,6 Marc Humbert7– 9 On behalf of the STELLAIR Investigators1Groupe Hospitalier Trousseau-La Roche Guyon, Service d’Allergologie, Paris, France; 2Université Paris Sorbonne, Paris, France; 3UMR 1153 - Centre de Recherche en Épidémiologie et Statistiques (CRESS), Paris, France; 4Novartis Pharma, Rueil Malmaison, France; 5Hôpital Trousseau, Service d’Allergologie, Paris, France; 6CHU de Bordeaux, Service de Pharmacologie Médicale, Bordeaux, France; 7Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France; 8AP-HP, Service de Pneumologie, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; 9INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, FranceCorrespondence: Jocelyne JustService d’Allergologie, Groupe hospitalier Trousseau-La Roche Guyon, 26 Avenue du Dr. Arnold Netter, Paris, 75012, FranceTel +33 1 71 73 68 47Fax +33 1 44 73 53 15Email jocelyne.just@aphp.frBackground: Immunoglobulin (Ig) E-mediated pathophysiological mechanisms are common in allergic diseases including severe allergic asthma (SAA). The anti-IgE monoclonal antibody omalizumab may be particularly beneficial for patients with SAA and multiple allergic comorbidities (AC) including perennial/seasonal rhinitis, conjunctivitis, atopic dermatitis (AD), and food allergy.Methods: We conducted a post-hoc analysis of the patients from the STELLAIR study (n=872, 149 minors and 723 adults). The patients were classified based on the presence of multiple AC (≥ 3 AC or < 3 AC) or AD as assessed by questionnaire. Response to omalizumab was assessed after 4– 6 months (T4– 6) and after 12 months (T12). Asthma response at T4– 6 was based on global evaluation of treatment effectiveness, reduction of ≥ 40% in annual exacerbation rate, and a combination of both. Asthma response at T12 was based on change in yearly exacerbation and hospitalization rates. AC improvement at T12 was based on patient perception.Results: Patients with ≥ 3 AC demonstrated a higher combined response to omalizumab (74.7% vs 58.3%) at T4– 6 and had reduced yearly exacerbation and hospitalization rates (88.9% vs 77.4% and − 94.0% vs − 70.5%, respectively). Patients with ≥ 3 AC were more likely to show an improvement in their AC (85.3% vs 51.9%) at T12. Results were similar in minors and adults. The presence of AD was associated with greater omalizumab effectiveness at T4– 6 and a greater AC improvement at T12. Improvement of AD and food allergies at T12 were 73.2% and 38.7%, respectively, in the population overall.Conclusion: This post-hoc analysis of the STELLAIR study shows that omalizumab is beneficial for all SAA patients and especially for patients with multiple AC or AD. In patients with ≥ 3 AC, omalizumab also improved AC outcomes.Keywords: Ig-E, multiple allergic comorbidities, omalizumab, severe allergic asthma

Background: In France, from 30% to 35% of children suffer from multiple food allergies (MFA). The gold standard to diagnosis a food allergy is the oral food challenge (OFC) which is conducted in a hospital setting due to risk of anaphylaxis. The aim of this study was to evaluate an algorithm to predict OFCs at low risk of anaphylaxis that could safely be performed in an office-based setting. Methods: Children with MFA and at least one open OFC reactive or non-reactive to other allergens were included. The algorithm was based on multiple clinical and biological parameters related to food allergens, and designed mainly to predict “low-risk” OFCs i.e., practicable in an office-based setting. The algorithm was secondarily tested in a validation cohort. Results: Ninety-one children (median age 9 years) were included; 94% had at least one allergic comorbidity with an average of three OFCs per child. Of the 261 OFCs analyzed, most (192/261, 74%) were non-reactive. The algorithm failed to correctly predict 32 OFCs with a potentially detrimental consequence but among these only three children had severe symptoms. One hundred eighty-four of the 212 “low-risk” OFCs, (88%) were correctly predicted with a high positive predictive value (87%) and low negative predictive value (44%). These results were confirmed with a validation cohort giving a specificity of 98% and negative predictive value of 100%. Conclusion: This study suggests that the algorithm we present here can predict “low-risk” OFCs in children with MFA which could be safely conducted in an office-based setting. Our results must be confirmed with an algorithm-based machine-learning approach.

Purpose Early prognostication of neurologic outcome in neonates and children supported with extra-corporeal membrane oxygenation (ECMO) is challenging. Amplitude-integrated EEG (aEEG) offers the advantages of continuous monitoring and 24-hours availability at the bedside for intensive care unit providers. The objective of this study was to describe the early electrophysiological background patterns of neonates and children undergoing ECMO and their association with neurologic outcomes. Methods This was a retrospective review of neonates and children undergoing ECMO and monitored with aEEG. Amplitude-integrated EEG was summarized as an aEEG background score determined within the first 24 hours of ECMO and divided in 3-hour periods. Screening for electrical seizures was performed throughout the full ECMO duration. Neurologic outcome was defined by the Pediatric Cerebral Performance Category score at hospital discharge. Results Seventy-three patients (median age 79 days [8-660], median weight 4.78 kg [3.24-10.02]) were included in the analysis. Thirty-two patients had a favorable neurologic outcome and 41 had an unfavorable neurologic outcome group at hospital discharge. A 24-hour aEEG background score >17 was associated with an unfavorable outcome with a sensitivity of 44%, a specificity of 97%, a positive predictive value of 95%, and a negative predictive value of 57%. In multivariate analysis, 24-hour aEEG background score was associated with unfavorable outcome (hazard ratio, 6.1; p = 0.001; 95% confidence interval, 2.31-16.24). The presence of seizures was not associated with neurologic outcome at hospital discharge. Conclusions Continuous aEEG provides accurate neurologic prognostication in neonates and children supported with ECMO. Early aEEG monitoring may help intensive care unit providers to guide clinical care and family counseling.

Introduction. Septic shock is a systemic inflammatory response syndrome associated with organ failures. Earlier clinical diagnosis would be of benefit to a decrease in the mortality rate. However, there is currently a lack of predictive biomarkers. The secretome is the set of proteins secreted by a cell, tissue, or organism at a given time and under certain conditions. The plasma secretome is easily accessible from biological fluids and represents a good opportunity to discover new biomarkers that can be studied with nontargeted “omic” strategies. Aims. To identify relevant deregulated proteins (DEP) in the secretome of a rat endotoxemic shock model. Methods. Endotoxemic shock was induced in rats by intravenous injection of lipopolysaccharides (LPS, S. enterica typhi, 0.5 mg/kg) and compared to controls (Ringer Lactate, iv). Under isoflurane anesthesia, carotid cannulation allowed mean arterial blood pressure (MAP) and heart rate (HR) monitoring and blood sampling at different time points (T0 and T50 or T0 and T90, with EDTA and protease inhibitor). Samples were prepared for large-scale tandem mass spectrometry (MS-MS) based on a label-free quantification to allow identification of the proteins deregulated upon endotoxemic conditions. A Gene Ontology (GO) analysis defined several clusters of biological processes (BP) in which the DEP are involved. Results. Ninety minutes after shock induction, the LPS group presents a reduction in MAP (-45%, p < 0.05 ) and increased lactate levels (+27.5%, p < 0.05 ) compared to the control group. Proteomic analyses revealed 10 and 33 DEP in the LPS group, respectively, at 50 and 90 minutes after LPS injection. At these time points, GO-BP showed alterations in pathways involved in oxidative stress response and coagulation. Conclusion. This study proposes an approach to identify relevant DEP in septic shock and brings new insights into the understanding of the secretome adaptations upon sepsis.

The impact of cervical cannulation on neurologic outcome has not been yet studied among children receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO) in the context of severe sepsis or septic shock. A retrospective cohort study was performed using the extracorporeal life support organization (ELSO) registry. A total of 559 children weighing less than 20 kg with a primary or secondary diagnosis of severe sepsis, septic shock or toxic shock syndrome were included between January 1, 2010, and December 31, 2019. Cervical cannulation was performed in 485 children (87%) and central cannulation in 74 children (13%). The prevalence of acute neurologic event (ANE) was 32%, including clinical and/or electroencephalographic seizures, cerebral infarction, cerebral hemorrhage, and/or brain death. In multivariable analysis, we did not find an association between cervical cannulation and greater/lesser odds of ANE during ECMO (adjusted odds ratio [aOR] = 1.39, 95% confidence interval [CI] 0.72-2.65; P = 0.326). Only pre-ECMO acidosis was independently associated with the development of ANE (pH < 6.99; aOR = 2.71, 95% CI 1.34-5.49; P = 0.006; pH 6.99 to

The 2020 update of the Canadian Stroke Best Practice Recommendations (CSBPR) for the Secondary Prevention of Stroke includes current evidence-based recommendations and expert opinions intended for use by clinicians across a broad range of settings. They provide guidance for the prevention of ischemic stroke recurrence through the identification and management of modifiable vascular risk factors. Recommendations address triage, diagnostic testing, lifestyle behaviors, vaping, hypertension, hyperlipidemia, diabetes, atrial fibrillation, other cardiac conditions, antiplatelet and anticoagulant therapies, and carotid and vertebral artery disease. This update of the previous 2017 guideline contains several new or revised recommendations. Recommendations regarding triage and initial assessment of acute transient ischemic attack (TIA) and minor stroke have been simplified, and selected aspects of the etiological stroke workup are revised. Updated treatment recommendations based on new evidence have been made for dual antiplatelet therapy for TIA and minor stroke; anticoagulant therapy for atrial fibrillation; embolic strokes of undetermined source; low-density lipoprotein lowering; hypertriglyceridemia; diabetes treatment; and patent foramen ovale management. A new section has been added to provide practical guidance regarding temporary interruption of antithrombotic therapy for surgical procedures. Cancer-associated ischemic stroke is addressed. A section on virtual care delivery of secondary stroke prevention services in included to highlight a shifting paradigm of care delivery made more urgent by the global pandemic. In addition, where appropriate, sex differences as they pertain to treatments have been addressed. The CSBPR include supporting materials such as implementation resources to facilitate the adoption of evidence into practice and performance measures to enable monitoring of uptake and effectiveness of recommendations.

OBJECTIVES Diaphragmatic paralysis following congenital cardiac surgery is associated with significant morbidity and mortality. Spontaneous recovery of diaphragmatic function has been described, contrasting with centres providing early diaphragmatic plication. We aimed to describe the outcomes of a conservative approach, as well as to identify factors associated with a failure of the strategy. METHODS This is a retrospective study of patients admitted after cardiac surgery and suffering unilateral diaphragmatic paralysis within 2 French Paediatric Cardiac Surgery Centers. The conservative approach, defined by the prolonged use of ventilation until successful weaning from respiratory support, was the primary strategy adopted in both centres. In case of unsuccessful evolution, a diaphragmatic plication was scheduled. Total ventilation time included invasive and non-invasive ventilation. Diaphragm asymmetry was defined by the number of posterior rib segments counted between the 2 hemi-diaphragms on the chest X-ray after cardiac surgery. RESULTS Fifty-one neonates and infants were included in the analysis. Patients’ median age was 12.0 days at cardiac surgery (5.0–82.0), and median weight was 3.5 kg (2.8–4.9). The conservative approach was successful for 32/51 patients (63%), whereas 19/51 patients (37%) needed diaphragm plication. There was no difference in patients’ characteristics between groups. Respiratory support prolonged for 21 days or more and diaphragm asymmetry more than 2 rib segments were independently associated with the failure of the conservative strategy [odds ratio (OR) 6.9 (1.29–37.3); P = 0.024 and OR 6.0 (1.4–24.7); P = 0.013, respectively]. CONCLUSIONS The conservative approach was successful for 63% of the patients. We identified risk factors associated with the strategy’s failure.

Background Lingual microcystic lymphatic malformations (LMLMs) are rare congenital vascular malformations presenting as clusters of cysts filled with lymph fluid or blood. Even small well-limited lesions can be responsible for a heavy burden, inducing pain, aesthetic prejudice, or oozing, bleeding, infections. The natural history of LMLMs is progressive worsening punctuated by acute flares. Therapeutic options include surgery, laser excision, and radiofrequency ablation but all are potentially detrimental and expose to local relapse. Therefore, the management frequently relies on a “watchful waiting” approach. In complicated LMLMs, treatment with oral sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is often used. Topical applications of sirolimus on the buccal mucosae have been reported in other oral diseases with good tolerance and none to slight detectable blood sirolimus concentrations. We aim to evaluate the efficacy and safety of a 1 mg/mL sirolimus solution applied once daily on LMLM of any stage in children and adults after 4, 8, 12, 16, 20, and 24 weeks of treatment compared to usual care (no treatment). Methods This is a randomized, multicentric study using an individually randomized stepped-wedge design over 24 weeks to evaluate topical application of a 1 mg/mL sirolimus solution once daily, on LMLM, versus usual care (no treatment), the control condition. Participants begin with an observational period and later switch to the intervention at a randomized time (week 0, 4, 8, or 12). Visits occur every 4 weeks, either in the study center or by teleconsulting. The primary outcome will be the evaluation of global severity of the LMLM on monthly standardized photographs by 3 independent blinded experts using the physical global assessment (PGA) 0 to 5 scale. Secondary outcomes will include lesion size measurement and quality of life assessment, investigator, and patient-assessed global disease and specific symptoms (oozing, bleeding, sialorrhea, eating impairment, taste modification, aesthetic impairment, pain, and global discomfort) assessment. A biological monitoring will be performed including residual blood sirolimus concentration and usual laboratory parameters. Discussion Given the disappointing state of current treatment options in LMLMs, topical sirolimus could become firstline therapy in treating LMLMs if its efficacy and safety were to be demonstrated. Trial registration ClinicalTrials.gov NCT04128722. Registered on 24 September 2019. EudraCT: EUCTR2019-001530-33-FR Sponsor (University Hospital Center of Tours – CHRU Tours): DR190041-TOPGUN French regulatory authorities: ID RCB: 2019-001530-33

Background Pollen food allergy syndrome (PFAS) is a frequently underdiagnosed disease due to diverse triggers, clinical presentations, and test results. This is especially relevant in geographic areas with a broad spectrum of pollen sensitization, such as Southern Europe. Objectives To elucidate similarities and differences of PFAS in nine Southern European centers and identify associated characteristics and unique markers of PFAS. Methods As part of the @IT.2020 Multicenter Study, 815 patients with seasonal allergic rhinitis (SAR), aged 10-60 years, were recruited in seven countries. They completed questionnaires regarding SAR, comorbidities, family history, and PFAS, and underwent skin prick testing (SPT) and serum IgE testing. Results Of the 815 patients, 167 (20.5%) reported PFAS reactions. Most commonly, eliciting foods were kiwi (58, 34.7%), peach (43, 25.7%), and melon (26, 15.6%). Reported reactions were mostly local (216/319, 67.7%), occurring within 5 min of contact with elicitors (209/319, 65.5%). Associated characteristics included positive IgE to at least one panallergen (profilin, PR-10, or nsLTP) (p = 0.007), maternal PFAS (OR: 3.716, p = 0.026), and asthma (OR: 1.752, p = 0.073). Between centers, heterogeneity in prevalence (Marseille: 7.5% vs. Rome: 41.4%, p < 0.001) and of clinical characteristics was apparent. Cypress played a limited role, with only 1/22 SPT mono-sensitized patients reporting a food reaction (p < 0.073). Conclusions PFAS is a frequent comorbidity in Southern European SAR patients. Significant heterogeneity of clinical characteristics in PFAS patients among the centers was observed and may be related to the different pollen sensitization patterns in each geographic area. IgE to panallergen(s), maternal PFAS, and asthma could be PFAS-associated characteristics., EAACI Fellowship Award of the European Academy of Allergology and Clinical Immunology; Euroimmun [118583], SA was supported by the EAACI Fellowship Award of the European Academy of Allergology and Clinical Immunology. The study has been supported by an unrestricted grant from Euroimmun (grant number 118583). The ESEP assay has been provided by Euroimmun. The Informatics Platform AllergyCARD (TM) and the app AllergyMonitor (R) have been provided by TPS Production.

International audience; BackgroundOver the last few decades, the level of pollen from birch and homologous trees has increased in parts of Europe. Sensitization to birch pollen allergens (principally Bet v 1) has been associated with food cross‐reactivity called pollen‐food‐allergy syndrome (PFAS).ObjectiveTo evaluate changes in allergic diseases due to IgE sensitization over 25 years in asthmatic children.MethodsThis was a cross‐sectional retrospective study conducted in Paris. We analyzed two cohorts of asthmatic children with similar characteristics explored between 1993‐1999 (old cohort=OC) and 2012‐2018 (recent cohort=RC).Results121 children were in the OC and 120 in the RC. An increase in sensitization to tree pollens was found especially for birch pollen which was 11.6% in the OC and 31% in the RC (p=0.0002). Allergic rhinitis prevalence was significantly higher in the RC than in the OC (96% vs 52%, respectively, p

Background and Purpose: Research suggests that women and men may present with different transient ischemic attack (TIA) and stroke symptoms. We aimed to explore symptoms and features associated with a definite TIA/stroke diagnosis and whether those associations differed by sex. Methods: We completed a retrospective cohort study of patients referred to The Ottawa Hospital Stroke Prevention Clinic in 2015. Exploratory multinomial logistic regression was used to evaluate candidate variables associated with diagnosis and patient sex. Backwards elimination of the interaction terms with a significance level for staying in the model of 0.25 was used to arrive at a more parsimonious model. Results: Based on 1770 complete patient records, sex-specific differences were noted in TIA/stroke diagnosis based on features such as duration of event, suddenness of symptom onset, unilateral sensory loss, and pain. Conclusions: This preliminary work identified sex-specific differences in the final diagnosis of TIA/stroke based on common presenting symptoms/features. More research is needed to understand if there are biases or sex-based differences in TIA/stroke manifestations and diagnosis.

International guidelines recommend carotid revascularization within 14 days for patients with a symptomatic transient ischemic attack (TIA) or stroke event. However, significant delays in care persist, with only 9% of outpatients and 36% of inpatients in Ontario meeting this target. The study objective was to explore the influence of health system factors on carotid revascularization timelines.We conducted a retrospective chart review of all symptomatic TIA/stroke patients undergoing carotid endarterectomy or stenting at The Ottawa Hospital (2015-2016). The primary outcome was time from TIA/stroke to carotid revascularization. Health system variables of interest included location and timing of patient presentation, timelines to vascular imaging, and same-day collaboration between key services such as emergency, neurology, and surgery. Descriptive statistics and univariate analysis were used to determine statistically significant differences between groups.A total of 228 records met the inclusion criteria. The median time from TIA/stroke to carotid revascularization was 10 days, with 58% of patients meeting the 14-day guideline. Prompt patient presentation to emergency demonstrated significantly shorter timelines to surgery (7 days; P .001). Early vascular imaging was strongly correlated with early revascularization (4-5 days; P .001). In addition, collaboration from two or more care services enhanced timelines to surgery ranging from 2.0 to 6.5 days (P .001-.008).Early/emergency response to stroke symptoms was pivotal in achieving best practice recommendations for rapid carotid revascularization, emphasizing the need for ongoing public awareness. Emergency and ambulatory strategies to facilitate urgent vascular imaging, as well as mechanisms for same-day communication between teams require optimization to promote early revascularization.

International audience; BACKGROUND: As infant feeding may influence allergy development, we aimed to identify groups of infants based on feeding practices and to examine their associations with respiratory health/allergy at 8 years in the PARIS birth cohort. METHODS: Data on breastfeeding, consumption of infant formula (regular, pre-/probiotics, partially hydrolysed with hypoallergenic label [pHF-HA], extensively hydrolysed [eHF], soya) and solid food introduction were collected using repeated questionnaires at 1, 3, 6, 9 and 12 months. Infants with similar feeding practices over the first year of life were grouped using multidimensional longitudinal cluster analysis. Respiratory/allergic morbidity was studied at 8 years as symptoms, doctor's diagnoses (asthma, hay fever, eczema, food allergy), and measurement of lung function, FeNO and specific IgE. Associations between feeding-related clusters and respiratory/allergic morbidity were investigated using multivariable logistic and linear regression models adjusted for potential confounders including early respiratory/allergic outcomes and parental history of allergy. RESULTS: Five clusters were identified among 3,446 infants: Cluster 1 (45%) mainly fed with regular formula, Cluster 2 (27%) exclusively breastfed during the first 3 months, and three other clusters consuming different types of formula (pre-/probiotics for Cluster 3 [17%], pHF-HA for Cluster 4 [7%], eHF/soya for Cluster 5 [4%]). Compared to Cluster 1, children from Cluster 2 tended to have a lower risk of asthma and children from Cluster 4 had a significant lower lung function (FEV1 , FVC), higher FeNO and higher risk of sensitisation at 8 years. CONCLUSION: Early pHF-HA use was negatively associated with objective measures of respiratory/allergic morbidity at school age, while children breastfed for at least 3 months seem protected against asthma at 8 years old.

Cerebral autoregulation (CA) impairment may pose a risk factor for neurological complications among children supported by extracorporeal membrane oxygenation (ECMO). Our first objective was to investigate the feasibility of CA continuous monitoring during ECMO treatment and to describe its evolution over time. The second objective was to analyze the association between CA impairment and neurological outcome. Observational prospective study. Twenty-nine children treated with veno-arterial or veno-venous ECMO in the PICU of Nantes University Hospital, France, and the PICU of the IRCCS Giannina Gaslini Institute in Genoa, Italy. A correlation coefficient between the variations of regional cerebral oxygen saturation and the variations of mean arterial blood pressure (MAP) was calculated as an index of CA (cerebral oxygenation reactivity index, COx). A COx > 0.3 was considered as indicative of autoregulation impairment. COx—MAP plots were investigated allowing determining optimal MAP (MAPopt) and limits of autoregulation: lower (LLA) and upper (ULA). Neurological outcome was assessed by the onset of an acute neurological event (ANE) after ECMO start. We included 29 children (median age 84 days, weight 4.8 kg). MAPopt, LLA, and ULA were detected in 90.8% (84.3–93.3) of monitoring time. Mean COx was significantly higher during day 1 of ECMO compared to day 2 [0.1 (0.02–0.15) vs. 0.01 (− 0.05 to 0.1), p = 0.002]. Twelve children experienced ANE (34.5%). The mean COx and the percentage of time spent with a COx > 0.3 were significantly higher among ANE+ compared to ANE− patients [0.09 (0.01–0.23) vs. 0.04 (− 0.02 to 0.06), p = 0.04 and 33.3% (24.8–62.1) vs. 20.8% (17.3–23.7) p = 0.001]. ANE+ patients spent significantly more time with MAP below LLA [17.2% (6.5–32.9) vs. 5.6% (3.6–9.9), p = 0.02] and above ULA [13% (5.3–38.4) vs. 4.2% (2.7–7.4), p = 0.004], respectively. CA assessment is feasible in pediatric ECMO. The first 24 h following ECMO represents the most critical period regarding CA. Impaired autoregulation is significantly more severe among patients who experience ANE.

International audience; Objectives: Decreased expression of human leukocyte antigen-DR on monocytes (mHLA-DR) is recognized as the most appropriate marker for the monitoring of immune alterations in septic patients and critically ill subjects. Its measurement has been established for years by flow cytometry, but remains under-used due to pre-analytical constraints. The objectives of the present work were to develop a rapid and robust one-step protocol. Methods: A novel, simplified protocol has been developed to measure mHLA-DR in whole blood using flow cytometry. It is a one-step procedure that includes red cell lysis, antibodies, and fixative reagents. It has been compared to the standardized routine protocol in two consecutive cohorts of septic shock patients (n = 37). Finally, the protocol was applied to a few subjects in point-of-care settings, by collecting capillary blood from fingerpricks. Results: Strong correlation was observed between the one-step method and routine protocol in 24 patients. After testing several stabilizing agents, the procedure was further optimized by adding a low-dose formaldehyde to the stain and lyse solution. This improved method was tested in a second cohort of 13 patients, and again strongly correlated to the routine protocol. Finally, the fingerprick and venous puncture samples were shown to provide similar results. Conclusions: The present work demonstrates the feasibility of a bedside protocol for flow cytometry measurement of mHLA-DR in critically ill subjects. This helps overcome pre-analytical constraints previously identified, which have limited wider use of this biomarker in intensive care units. In addition, preliminary results from fingerprick samples are promising.

We reviewed stroke care delivery during the COVID-19 pandemic at our stroke center and provincial telestroke system. We counted referrals to our prevention clinic, code strokes, thrombolysis, endovascular thrombectomies, and activations of a provincial telestroke system from February to April of 2017–2020. In April 2020, there was 28% reduction in prevention clinic referrals, 32% reduction in code strokes, and 26% reduction in telestroke activations compared to prior years. Thrombolysis and endovascular thrombectomy rates remained constant. Fewer patients received stroke services across the spectrum from prevention, acute care to telestroke care in Ontario, Canada, during the COVID-19 pandemic.

Children supported by extracorporeal membrane oxygenation present a high risk of neurological complications. Although carotid cannulation is known to be associated with neurologic injury, conflicting data exist with regard to the predominance of right- or left-sided lesions. We describe here two infants requiring veno-arterial extracorporeal membrane oxygenation for septic shock who encountered right watershed infarction ipsilateral to carotid artery cannulation. Hemodynamic failure seems to be the most probable underlying mechanism. The asymmetry of transcranial Doppler metrics in one case and the low right regional cerebral oxygen saturation value observed soon after right cannulation in both cases suggest an insufficient cerebral collateral flow compensation. The risk of ipsilateral watershed injury should be considered before cervical cannulation, notably in the context of sepsis and an evaluation of the cerebral collateral blood flow before and just after cannulation may be interesting in order to identify infants with higher risk of ipsilateral ischemic lesions.

Clonal hematopoiesis of indeterminate potential (CHIP) is predictive of hematological cancers and cardiovascular diseases, but the etiology of CHIP initiation and clonal expansion is unknown. Several lines of evidence suggest that proinflammatory cytokines may favor mutated hematopoietic stem cell expansion. To investigate the potential link between inflammation and CHIP, we performed targeted deep sequencing of 11 genes previously implicated in CHIP in 1887 subjects aged >70 years from the Montreal Heart Institute Biobank, of which 1359 had prior coronary artery disease (CAD), and 528 controls did not. We assessed association of CHIP with log transformed high-sensitivity C-reactive protein (hs-CRP), a validated biomarker of inflammation. CHIP was identified in 427 of the 1887 subjects (22.6%). CHIP mutations were more frequently identified in DNMT3A (11.6%) and TET2 (6.1%), with a higher proportion of TET2 mutations occurring in controls than in patients with CAD (9.0% vs 4.9%, P < .001). CHIP carriers had 21% higher hs-CRP levels compared with their noncarrier counterparts (eβ = 1.21, 95% confidence interval [CI]: 1.08 to 1.36; P = .001). A similar effect was observed in the subgroup of patients with known CAD (eβ = 1.22, 95% CI: 1.06 to 1.41; P = .005). These findings confirm the association between inflammation and CHIP. This association may open investigational avenues aimed at documenting mechanisms linking inflammation to clonal progression and ultimately supports prevention interventions to attenuate CHIP’s impact on cardiovascular disease and cancer.

Resume Introduction Quelques cas de melanomes sur tatouages ont ete rapportes. Le role du tatouage dans le developpement de tumeurs cutanees malignes est cependant tres discute. Nous rapportons deux nouvelles observations de melanomes se developpant sur des tatouages, completees d’une revue systematique de la litterature. Observations Cas 1. Un patient de 61 ans, de phototype IV, consultait pour une lesion nodulaire pigmentee de 4,5 × 3 cm apparue depuis un an, developpee sur un tatouage noir et rouge du dos. L’examen histologique de la lesion objectivait un melanome de type nodulaire ulcere, indice de Breslow a 7 mm. Le bilan d’extension ne trouvait pas de localisations secondaires. Cas 2. Un patient de 39 ans, de phototype II, portant un tatouage noir du bras consultait pour une lesion pigmentee cliniquement suspecte evoluant depuis plusieurs mois. L’exerese etait d’emblee realisee, confirmant le diagnostic de melanome de type SSM, developpe sur naevus preexistant, indice de Breslow 0,9 mm. Une reprise a 1 cm etait realisee et, avec un recul de 9 ans, il n’etait pas note de recidive. Discussion La revue systematique de la litterature trouvait 34 cas de melanomes survenus sur tatouage. Il existait une forte prevalence masculine (90,3 %) et un âge moyen relativement jeune (45,9 ans). Il s’agissait majoritairement de tatouages monochromes noir/bleu fonce (71,0 %). Le delai moyen entre la realisation du tatouage et l’apparition du melanome etait de 13,2 ans. La localisation la plus frequente du melanome etait le membre superieur (53,1 %) suivi du tronc (34,4 %). A l’examen anatomopathologique, il s’agissait dans 2 cas de melanomes in situ, et dans 13 cas, l’indice de Breslow etait inferieur ou egal a 1 mm. Dans 5 observations, une metastase ganglionnaire macroscopique ou microscopique (ganglion sentinelle) etait trouvee au diagnostic et dans une de ces observations etaient aussi observees des metastases cutanees en transit au diagnostic. L’hypothetique role du tatouage dans la carcinogenese est discute.

Background and Purpose: The diagnosis of transient ischemic attack (TIA) is largely dependent on a process of clinical decision-making that remains poorly characterized in the absence of a validated and accessible biomarker or imaging test. We performed a retrospective chart review to identify variables associated with a final neurologist diagnosis of TIA/stroke. Methods: Records for all patients seen in The Ottawa Hospital’s Stroke Prevention Clinic in 2015 were analyzed for patient and referral characteristics, features of the presenting neurological event, and final diagnosis by a stroke neurologist (classified as definite, possible, or definite not TIA/stroke). Multinomial logistic regression analysis with backward elimination was used to identify variables associated with the final diagnosis. Results: Our inclusion criteria were met by 1894 patients. After backward elimination, 23 potentially important variables were identified, including monocular vision loss (odds ratio [OR]: 30.4, 95% confidence interval [CI]: 14.6-63.3), symptoms of sudden onset (OR: 28.3, 95% CI: 14.2-56.2), unilateral weakness affecting 2 or 3 of face, arm, or leg (OR: 17.7, 95% CI: 9.8-31.7), and homonymous hemianopia (OR: 16.6, 95% CI: 8.1-34.0). Conclusions: Accurate diagnosis of TIA is essential to initiating appropriate secondary stroke prevention therapies. A focus on elements of the patient history most commonly associated with a final diagnosis of TIA/stroke may help to identify patients in greatest need of urgent SPC assessment and allow for the provision of effective and efficient stroke prevention services.

OBJECTIVES To assess the ability of amplitude-integrated electroencephalography monitoring within 24 hours of the return of spontaneous circulation to prognosticate neurologic outcomes in children following cardiac arrest DESIGN:: Retrospective review of prospectively recorded data. An amplitude-integrated electroencephalography background score was calculated according to background activity during the first 24 hours after return of spontaneous circulation, a higher score correlating with more impaired background activity. The primary endpoint was the neurologic outcome as defined by the Pediatric Cerebral Performance Category at PICU discharge (Pediatric Cerebral Performance Category 1-3: a good neurologic outcome; Pediatric Cerebral Performance Category 4-6: a poor neurologic outcome). SETTING A referral PICU. PATIENTS Thirty children with a median age of 10 months (2-38 mo) and a male/female sex ratio of 1.3 were included. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Eighteen patients were assigned to the favorable outcome group and 12 to the unfavorable outcome group. The median time between return of spontaneous circulation and amplitude-integrated electroencephalography initiation was 4 hours (3-9 hr). The amplitude-integrated electroencephalography score within 24 hours after return of spontaneous circulation was significantly higher in the children with poor outcomes compared with those with good outcomes (12 ± 4 vs 25 ± 8; p < 0.001). Background activity during amplitude-integrated electroencephalography monitoring was able to predict poor neurologic outcomes at PICU discharge, with an area under the receiver operating characteristic curve of 0.91 (95% CI, 0.81-1.00). CONCLUSIONS Early amplitude-integrated electroencephalography monitoring may help predict poor neurologic outcomes in children within 24 hours following cardiac arrest.

OBJECTIVES To describe the frequency and outcomes on the use of extracorporeal membrane oxygenation (ECMO) among critically ill neonates and children within a structured pediatric critical care network in the West of France. To assess the optimality of decision-making process for patients primarily admitted in non-ECMO centers. DESIGN Observational prospective population-based study from January 2015 to December 2019. PATIENTS Neonates over 34 weeks of gestational age, weighing more than 2,000 g and children under 15 years and 3 months old admitted in one of the 10 units belonging to a Regional Pediatric Critical Care Network. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Eight-thousand one hundred eighty-nine children and 3,947 newborns were admitted within one of the 10 units of the network over the study period. Sixty-five children (8.1% [95% CI, 6.2-10‰]) and 35 newborns (9.4% [95% CI, 6.4-12%]) required ECMO support. Of these patients, 31 were first admitted to a non-ECMO center, where 20 were cannulated in situ (outside the regional ECMO center) and 11 after transfer to the ECMO regional center. Cardiogenic shock, highest serum lactate level, and cardiac arrest prior to first phone call with the regional ECMO center were associated with higher rate of in situ cannulation. During the study period, most of the patients were cannulated for underlying cardiac issue (42/100), postoperative cardiac surgery instability (38/100), and pediatric (10/100) and neonatal (10/100) respiratory distress syndrome. Patients primarily admitted in non-ECMO centers or not had similar 28-day post-ICU survival rates compared with those admitted in the referral ECMO center (58% vs 51%; p = 0.332). Pre-ECMO cardiac arrest, ECMO, and lower pH at ECMO onset were associated with lower 28-day post-ICU survival. CONCLUSIONS Our local results suggest that a structured referral network for neonatal and pediatric ECMO in the region of Western France facilitated escalation of care with noninferior (or similar) early mortality outcome. Our data support establishing referral networks in other equivalent regions.

Importance Sirolimus is increasingly being used to treat various vascular anomalies, although evidence of its efficacy is lacking. Objective To assess the efficacy and safety of sirolimus for children with slow-flow vascular malformations to better delineate the indications for treatment. Design, setting and participants This multicenter, open-label, observational-phase randomized clinical trial included 59 children aged 6 to 18 years with a slow-flow vascular malformation who were recruited between September 28, 2015, and March 22, 2018, in 11 French tertiary hospital centers. Statistical analysis was performed on an intent-to-treat basis from December 4, 2019, to November 10, 2020. Interventions Patients underwent an observational period, then switched to an interventional period when they received oral sirolimus (target serum levels, 4-12 ng/mL). The switch time was randomized from month 4 to month 8, and the whole study period lasted 12 months for each patient. Main outcomes and measures The primary outcome was change in the volume of vascular malformations detected on magnetic resonance imaging scan (with centralized interpretation) per unit of time (ie, between the interventional period and the observational period). Secondary outcomes included subjective end points: pain, bleeding, oozing, quality of life, and safety. Results Among the participants (35 girls [59.3%]; mean [SD] age, 11.6 [3.8] years), 22 (37.3%) had a pure venous malformation, 18 (30.5%) had a cystic lymphatic malformation, and 19 (32.2%) had a combined malformation, including syndromic forms. Variations in the volume of vascular malformations detected on magnetic resonance imaging scans associated with the duration period were not overall significantly different between the interventional period and the observational period (all vascular malformations: mean [SD] difference, -0.001 [0.007]; venous malformations: mean [SD] difference, 0.001 [0.004]; combined malformations: mean [SD] difference, 0.001 [0.009]). However, a significant decrease in volume was observed for children with pure lymphatic malformations (mean [SD] difference, -0.005 [0.005]). Overall, sirolimus had positive effects on pain, especially for combined malformations, and on bleeding, oozing, self-assessed efficacy, and quality of life. During sirolimus treatment, 56 patients experienced 231 adverse events (5 serious adverse events, none life-threatening). The most frequent adverse event was an oral ulcer (29 patients [49.2%]). Conclusions and relevance This observational-phase randomized clinical trial allows for clarifying the goals of patients and families when starting sirolimus therapy for children older than 6 years. Pure lymphatic malformations seem to be the best indication for sirolimus therapy because evidence of decreasing lymphatic malformation volume per unit of time, oozing, and bleeding and increasing quality of life was found. In combined malformations, sirolimus significantly reduced pain, oozing, and bleeding. Benefits seemed lower for pure venous malformations than for the 2 other subgroups, also based on symptoms. Trial registration ClinicalTrials.gov Identifier: NCT02509468; clinicaltrialsregister.eu Identifier: 2015-001096-43.

Background & Aims Next-generation sequencing (NGS) was recently approved by the United States Food and Drug Administration to detect microsatellite instability (MSI) arising from defective mismatch repair (dMMR) in patients with metastatic colorectal cancer (mCRC) before treatment with immune checkpoint inhibitors (ICI). In this study, we aimed to evaluate and improve the performance of NGS to identify MSI in CRC, especially dMMR mCRC treated with ICI. Methods CRC samples used in this post hoc study were reassessed centrally for MSI and dMMR status using the reference methods of pentaplex polymerase chain reaction and immunohistochemistry. Whole-exome sequencing (WES) was used to evaluate MSISensor, the Food and Drug Administration-approved and NGS-based method for assessment of MSI. This was performed in (1) a prospective, multicenter cohort of 102 patients with mCRC (C1; 25 dMMR/MSI, 24 treated with ICI) from clinical trials NCT02840604 and NCT033501260, (2) an independent retrospective, multicenter cohort of 113 patients (C2; 25 mCRC, 88 non-mCRC, all dMMR/MSI untreated with ICI), and (3) a publicly available series of 118 patients with CRC from The Cancer Genome Atlas (C3; 51 dMMR/MSI). A new NGS-based algorithm, namely MSICare, was developed. Its performance for assessment of MSI was compared with MSISensor in C1, C2, and C3 at the exome level or after downsampling sequencing data to the MSK-IMPACT gene panel. MSICare was validated in an additional retrospective, multicenter cohort (C4) of 152 patients with new CRC (137 dMMR/MSI) enriched in tumors deficient in MSH6 (n = 35) and PMS2 (n = 9) after targeted sequencing of samples with an optimized set of microsatellite markers (MSIDIAG). Results At the exome level, MSISensor was highly specific but failed to diagnose MSI in 16% of MSI/dMMR mCRC from C1 (4 of 25; sensitivity, 84%; 95% confidence interval [CI], 63.9%–95.5%), 32% of mCRC (8 of 25; sensitivity, 68%; 95% CI, 46.5%–85.1%), and 9.1% of non-mCRC from C2 (8 of 88; sensitivity, 90.9%; 95% CI, 82.9%–96%), and 9.8% of CRC from C3 (5 of 51; sensitivity, 90.2%; 95% CI, 78.6%–96.7%). Misdiagnosis included 4 mCRCs treated with ICI, of which 3 showed an overall response rate without progression at this date. At the exome level, reevaluation of the MSI genomic signal using MSICare detected 100% of cases with true MSI status among C1 and C2. Further validation of MSICare was obtained in CRC tumors from C3, with 96.1% concordance for MSI status. Whereas misdiagnosis with MSISensor even increased when analyzing downsampled WES data from C1 and C2 with microsatellite markers restricted to the MSK-IMPACT gene panel (sensitivity, 72.5%; 95% CI, 64.2%–79.7%), particularly in the MSH6-deficient setting, MSICare sensitivity and specificity remained optimal (100%). Similar results were obtained with MSICare after targeted NGS of tumors from C4 with the optimized microsatellite panel MSIDIAG (sensitivity, 99.3%; 95% CI, 96%–100%; specificity, 100%). Conclusions In contrast to MSISensor, the new MSICare test we propose performs at least as efficiently as the reference method, MSI polymerase chain reaction, to detect MSI in CRC regardless of the defective MMR protein under both WES and targeted NGS conditions. We suggest MSICare may rapidly become a reference method for NGS-based testing of MSI in CRC, especially in mCRC, where accurate MSI status is required before the prescription of ICI.

To date, efforts to reduce hospital readmissions have centered largely on hospitals. In a recently published environmental scan, we examined the literature focusing on primary care–based efforts to reduce readmissions. While rigorous studies on interventions arising from primary care are limited, we found that multi-component care transitions programs that are initiated early in the hospitalization and are part of broader primary care practice transformation appear most promising. However, policy changes are necessary to spur innovation and support effective primary care–led transitions interventions. Though more rigorous research is needed, our findings suggest that primary care can and should lead future efforts for reducing hospital readmissions.

Receptor activator of NF-κB ligand (RANKL) activates, while osteoprotegerin (OPG) inhibits, osteoclastogenesis. A neutralizing Ab against RANKL, denosumab, improves bone strength in osteoporosis. OPG also improves muscle strength in mouse models of Duchenne’s muscular dystrophy (mdx) and denervation-induced atrophy, but its role and mechanisms of action on muscle weakness in other conditions remain to be investigated. We investigated the effects of RANKL inhibitors on muscle in osteoporotic women and mice that either overexpress RANKL (HuRANKLTg(+)), or lack Pparb and concomitantly develop sarcopenia (Pparb(–/–)). In women, taking denosumab for more than 3 years improved appendicular lean mass and handgrip strength compared with no treatment, whereas bisphosphonate did not. HuRANKLTg(+) mice displayed lower limb force and maximal speed, while their leg muscle mass was diminished, with a lower number of type I and II fibers. Both OPG and denosumab increased limb force proportionally to the increase in muscle mass. They markedly improved muscle insulin sensitivity and glucose uptake, and decreased antimyogenic and inflammatory gene expression in muscle, such as myostatin and protein tyrosine phosphatase receptor-γ. Similarly, in Pparb(–/–), OPG increased muscle volume and force while also normalizing insulin signaling and higher expression of inflammatory genes in skeletal muscle. In conclusion, RANKL deteriorates while its inhibitors improve muscle strength and insulin sensitivity in osteoporotic mice and humans. Hence, denosumab could represent a novel therapeutic approach for sarcopenia.

Monitoring forest degradation at fine scale over large area is critical from an environmental point of view since it provides crucial information for many ecological applications. We introduce an automatic method based on optical Landsat time series (2000–2017) to detect and quantify forest disturbances and to identify the causes of forest degradation. The method is based on i) an automatic spectral unmixing to detect forest's disturbances and on ii) landscape metrics and temporal indicators to detect the causes of forest degradation. We applied the approach in the Brazilian Amazon municipality of Paragominas to map forested areas affected by reduced impact logging, conventional logging or illegal logging and fires.

International audience; The identification of a bacterial, viral, or even noninfectious cause is essential in the management of febrile syndrome in the emergency department (ED), especially in epidemic contexts such as flu or CoVID-19. The aim was to assess discriminative performances of two biomarkers, CD64 on neutrophils (nCD64) and CD169 on monocytes (mCD169), using a new flow cytometry procedure, in patients presenting with fever to the ED during epidemics. Eighty five adult patients presenting with potential infection were included during the 2019 flu season in the ED of La Timone Hospital. They were divided into four diagnostic outcomes according to their clinical records: no-infection, bacterial infection, viral infection and co-infection. Seventy six patients with confirmed SARS-CoV-2 infection were also compared to 48 healthy volunteers. For the first cohort, 38 (45%) patients were diagnosed with bacterial infections, 11 (13%) with viral infections and 29 (34%) with co-infections. mCD169 was elevated in patients with viral infections, with a majority of Flu A virus or Respiratory Syncytial Virus, while nCD64 was elevated in subjects with bacterial infections, with a majority of Streptococcus pneumoniae and Escherichia coli. nCD64 and mCD169 showed 90% and 80% sensitivity, and 78% and 91% specificity, respectively, for identifying patients with bacterial or viral infections. When studied in a second cohort, mCD169 was elevated in 95% of patients with SARS-CoV-2 infections and remained at normal level in 100% of healthy volunteers. nCD64 and mCD169 have potential for accurately distinguishing bacterial and acute viral infections. Combined in an easy and rapid flow cytometry procedure, they constitute a potential improvement for infection management in the ED, and could even help for triage of patients during emerging epidemics.

Background The Mediterranean diet (MD) has known health benefits but its specific impact on allergy development is unclear. As part of the PARIS birth cohort follow-up, we aimed to investigate the adherence of 8 years old children to the MD and its association with allergic/respiratory morbidity at school age. Methods Diet was assessed using a food frequency questionnaire completed by the parents. Adherence to the MD was assessed based on two scores: the KIDMED index and the Mediterranean Diet Score (MDS). Current allergic diseases (asthma, rhinitis, eczema), lung function indices (FEV1 and FVC), FeNO and specific IgE levels were determined during a health check-up at 8 years. Associations between levels of adherence to the MD and respiratory/allergic morbidity were studied using multivariable logistic and linear regression models adjusted for potential confounders. Results A total of 975 children were included in the present study, 35.6% with low adherence to the MD, 55.7% with moderate adherence, and 8.7% with high adherence according to the KIDMED index. High family socioeconomic status, any breastfeeding at 6 months, and consumption of organic food were associated with higher adherence to the MD. Compared to low adherence, high adherence was associated with lower risk of asthma and sensitization at 8 years, as well as higher FEV1 and FVC. Conclusion This study suggests a protective effect of high adherence to the MD on allergic and respiratory morbidity at school age. These results need to be confirmed by further longitudinal analyses. A healthy diet may prevent allergic and respiratory morbidity in school-aged children.

BACKGROUND Asthma is a heterogeneous disease in which the interaction between genetic and environmental factors plays a major role. The significance of blood eosinophil is unclear. The aim of the study was to determine the significance of blood eosinophil count in moderate-to-severe asthmatic children of preschool age and school age. METHODS This was a prospective cross-sectional study performed from 2011 to 2015 including children from the severe asthma molecular phenotype (SAMP) cohort at Trousseau Hospital (Paris, France). We included children with severe and moderate asthma, or severe and moderate recurrent wheeze, aged from 1 to 15 years at the time of exploration. RESULTS We analyzed data from 402 children: 248 of preschool age and 154 of school age. Blood eosinophil count third quartile thresholds were 322 and 600 cells/μL for the preschool- and school-age groups, respectively. In multivariate analysis, a blood eosinophil count over this threshold was associated with elevated total IgE (OR = 5.33, P

International audience; Background: Patients with COVID-19 pneumonia have an excess of inflammation and increased concentrations of cytokines including interleukin-1 (IL-1). We aimed to determine whether anakinra, a recombinant human IL-1 receptor antagonist, could improve outcomes in patients in hospital with mild-to-moderate COVID-19 pneumonia.Methods: In this multicentre, open-label, Bayesian randomised clinical trial (CORIMUNO-ANA-1), nested within the CORIMUNO-19 cohort, we recruited patients from 16 University hospitals in France with mild-to-moderate COVID-19 pneumonia, severe acute respiratory syndrome coronavirus 2 infection confirmed by real-time RT-PCR, requiring at least 3 L/min of oxygen by mask or nasal cannula but without ventilation assistance, a score of 5 on the WHO Clinical Progression Scale (WHO-CPS), and a C-reactive protein serum concentration of more than 25 mg/L not requiring admission to the intensive care unit at admission to hospital. Eligible patients were randomly assigned (1:1) using a web-based secure centralised system, stratified by centre and blocked with varying block sizes (randomly of size two or four), to either usual care plus anakinra (200 mg twice a day on days 1-3, 100 mg twice on day 4, 100 mg once on day 5) or usual care alone. Usual care was provided at the discretion of the site clinicians. The two coprimary outcomes were the proportion of patients who had died or needed non-invasive or mechanical ventilation by day 4 (ie, a score of >5 on the WHO-CPS) and survival without need for mechanical or non-invasive ventilation (including high-flow oxygen) at day 14. All analyses were done on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, NCT04341584, and is now closed to accrual.Findings: Between April 8 and April 26, 2020, we screened 153 patients. The study was stopped early following the recommendation of the data and safety monitoring board, after the recruitment of 116 patients: 59 were assigned to the anakinra group, and 57 were assigned to the usual care group. Two patients in the usual care group withdrew consent and were not analysed. In the analysable population, the median age was 66 years (IQR 59 to 76) and 80 (70%) participants were men. In the anakinra group, 21 (36%) of 59 patients had a WHO-CPS score of more than 5 at day 4 versus 21 (38%) of 55 in the usual care group (median posterior absolute risk difference [ARD] -2·5%, 90% credible interval [CrI] -17·1 to 12·0), with a posterior probability of ARD of less than 0 (ie, anakinra better than usual care) of 61·2%. At day 14, 28 (47%; 95% CI 33 to 59) patients in the anakinra group and 28 (51%; 95% CI 36 to 62) in the usual care group needed ventilation or died, with a posterior probability of any efficacy of anakinra (hazard ratio [HR] being less than 1) of 54·5% (median posterior HR 0·97; 90% CrI 0·62 to 1·52). At day 90, 16 (27%) patients in the anakinra group and 15 (27%) in the usual care group had died. Serious adverse events occurred in 27 (46%) patients in the anakinra group and 21 (38%) in the usual care group (p=0·45).Interpretation: Anakinra did not improve outcomes in patients with mild-to-moderate COVID-19 pneumonia. Further studies are needed to assess the efficacy of anakinra in other selected groups of patients with more severe COVID-19.Funding: The Ministry of Health, Programme Hospitalier de Recherche Clinique, Foundation for Medical Research, and AP-HP Foundation.

International audience; Lung ultrasound is commonly used for the diagnosis of pneumothorax. However, recognition of pleural sliding is subjective and can be difficult for novice. The primary objective was to compare a novices physician's performance in diagnosing pneumothorax from ultrasound (US) scans either with visual evaluation or with maximum longitudinal pleural strain (MLPS). The secondary objective was to compare the diagnostic relevance of US with visual evaluation or MLPS to diagnose pneumothorax with an intermediately experienced and an expert physician.Methods: We conducted a prospective, observational study in two emergency department and two intensive care unit, between February 2019 and June 2020. We included 99 adult patients with suspected pneumothorax, who received a chest computed tomography (CT). Three physicians with different experience of interpreting US scans (a novice physician, an intermediately experienced physician, and an expert) analyzed the US scans of 99 patients with suspected pneumothorax (50 (51%) with confirmed pneumothorax), which were confirmed by CT scan.Results: With a threshold of 5%, the MLPS sensitivity was 94% (95% CI [83%; 98%]), and the specificity was 100% (95% CI [93%; 100%]). The novice physician had an area under the curve (AUC) with visual analysis of 0.75 (95% CI [0.67; 0.83]) vs 0.86 (95% CI [0.79; 0.94]) with MLPS (p = 0.04). The intermediate physician's AUC for diagnosing pneumothorax with visual analysis was 0.93 (95% CI [0.88; 0.99]) vs 1.00 (95% CI [1.00; 1.00]) with MLPS (p < 0.01) and for the expert physician it was 0.98 (95% CI [0.95;1.00]) vs 0.97 (95% CI [0.93; 1.00]), respectively (p = 0.69).Conclusion: In our study, speckle tracking analysis improved the accuracy of US for the novice and the intermediate but not the expert sonographer in the diagnosis of pneumothorax.

Background Shorter telomere length (TL) may indicate premature cellular aging and increased risk for disease. While there is substantial evidence for shorter TL in individuals suffering from psychiatric disorders, data is scarce on maladaptive personality traits related to coronary artery disease (CAD). The purpose of this study was to evaluate the association of TL with hostility and defensiveness in individuals with CAD or other non-cardiovascular illnesses and whether associations were moderated by CAD status and sex. Methods One thousand thirty-six individuals (Mage = 65.40 ± 6.73 years) with and without CAD completed the Marlowe-Crowne Social Desirability Scale and the Cook–Medley Hostility Scale. Relative TL was measured via quantitative polymerase chain reaction of total genomic DNA samples. Analyses involved hierarchical regressions on TL, performed separately for hostility and defensiveness, controlling for pertinent sociodemographic, behavioural, and medical risk factors. Separate analyses were performed on 25 healthy participants. Results A hostility by sex interaction emerged (β = − .08, p = .006) in the patient groups, where greater hostility was associated with shorter TL in women only (p < .01). A Defensiveness by CAD status interaction (β = − .06, p = .049) revealed longer TL in more defensive CAD patients only (p = .06). In healthy men, shorter TL was observed in those with greater defensiveness (β = .52, p = .006) but lower hostility (β = − .43, p = .049). Conclusion Hostility and defensiveness are differentially associated with TL as a function of sex and health status. The implication of these results for health remains to be determined, but propose an additional pathway through which the effect of maladaptive personality traits may contribute to CV and other disease.

The presence of bradycardic arrhythmias during volitional apnea at altitude may be caused by chemoreflex activation/sensitization. We investigated whether bradyarrhythmic episodes became prevalent in apnea following short‐term hypoxia exposure. Electrocardiograms (ECG; lead II) were collected from 22 low‐altitude residents (F = 12; age=25 ± 5 years) at 671 m. Participants were exposed to normobaric hypoxia (Spo 2 ~79 ± 3%) over a 5‐h period. ECG rhythms were assessed during both free‐breathing and maximal volitional end‐expiratory and end‐inspiratory apnea at baseline during normoxia and hypoxia exposure (20 min [AHX]; 5 h [HX5]). Free‐breathing HR became elevated at AHX (78 ± 10 bpm; p, In this study, voluntary apnea was used to determine whether significant chemoreceptor sensitivity develops following 5 h of normobaric hypoxia, as evident through significant bradycardia and arrhythmogenesis. The results showed that bradycardia and the incidence of arrhythmogenesis was similar between initial hypoxia exposures, as well as after 5 h of exposure. These findings demonstrate previously documented bradyarrhythmogenesis is a unique phenomenon to chronic hypoxia exposure (i.e., several days residency at altitude).

The treatment of aseptic osteonecrosis (ON) of the femoral head has been the subject of numerous therapeutic and surgical proposals due to the absence of medical treatment with proven efficacy. For many years, the goal of surgical treatment was to avoid total hip replacement (THR) with uncertain survival in patients considered too young (30-50 years) for this procedure. Numerous conservative treatments were thus proposed: core decompression with numerous variants, non-vascularized and vascularized bone grafts, intertrochanteric and rotational transtrochanteric osteotomies, cementing. The lack of a common classification and a lack of knowledge of natural history complicated the interpretation of the results for a long time. Nevertheless, it appeared that these treatments were effective only in the very early stages and among these in the limited ONs, medial rather than central and especially lateral, with discrepancies according to etiologies apart from sickle cell disease recognized by all as being pejorative. For the same reason, partial arthroplasties have been attempted and abandoned in turn: femoral head total and partial resurfacing and femoral prosthesis. The most recent advances are stem-cell-enhanced core decompression and progress in total arthroplasty, whose reliability has made it possible to extend the indications to increasingly younger patients seeking treatment with guaranteed or near-guaranteed efficacy. Most of the other interventions have disappeared or almost disappeared because of their lack of effectiveness especially in extensive and post-fracture ONs, sometimes because of their complexity and the length of their post-operative management, and also because they complicate and penalize a future total arthroplasty. This argues for early detection of ON at an early stage where the "head can be saved" by stem cell augmented core decompression, a minimally invasive treatment that leaves the chances of success of a THR intact.

We present the results of the first series of successful two-way laser ranging experiments from a ground station, the Lunar Laser Ranging (LLR) station in Grasse, France, to a spacecraft at lunar distance, the Lunar Reconnaissance Orbiter (LRO). A 15 × 18 × 5 cm, 650-g array of twelve 32-mm diameter solid corner cubes is mounted on its anti-nadir deck. Ranging to this small retro-reflector array onboard a lunar orbiter from a ground station was a challenge compared to ranging to larger lunar surface retro-reflectors. Grasse measured 67 returns in two 6-min sessions on September 4, 2018. Clear returns were also recorded during two additional sessions on August 23–24, 2019 for which active slewing by LRO was performed to bring the array in view of the station. The measured echos yielded range residuals less than 3 cm (two-way time-of-flight RMS

BackgroundThe identification of a bacterial, viral or even non-infectious cause is essential in the management of febrile syndrome in the emergency department (ED) setting, especially in epidemic contexts such as flu or CoVID-19.ObjectivesThe aim of this study was to assess discriminative performances of two biomarkers, CD64 on neutrophils (nCD64) and CD169 on monocytes (mCD169), using a new flow cytometry procedure, in patients presenting with fever to the ED. Human leucocyte antigen-DR on monocytes (mHLA-DR), HLA-ABC ratio (rHLA-ABC), and CD64 on monocytes (mCD64) were also assessed.Methods85 adult patients presenting with potential infection were included during the 2019 flu season in the ED of La Timone Hospital. They were divided into four diagnostic outcomes according to their clinical records: no-infection, bacterial infection, viral infection and co-infection.ResultsmCD169 was elevated in patients suffering from Flu A virus or Respiratory Syncytial Virus, while nCD64 was mainly found elevated in subjects with Streptococcus pneumoniae. In total, 38 (45%) patients were diagnosed with bacterial infections, 11 (13%) with viral infections and 29 (34%) with co-infections. nCD64 and mCD169 showed 90% and 80% sensitivity, and 78% and 91% specificity, respectively, for identifying patients with bacterial or viral infections. Other biomarkers had lower discriminative performances.ConclusionsnCD64 and mCD169 have potential for accurately distinguishing bacterial and acute viral infections. Combined in an easy and rapid flow cytometry procedure, they constitute a potential improvement for infection management in the ED setting, and could even help for the triage of patients during emerging epidemics.

Introduction The humerus is the second most common site for metastasis in the peripheral skeleton. These humeral metastases (HM) occur in the midshaft in 42% to 61% of cases and theproximal humerus in 32% to 45% of cases. They are often secondary to primary breast (17–31%), kidney (13–15%) or lung (11–24%) cancer. The optimal surgical treatment between intramedullary (IM) procedures, fixation or arthroplasty is still being debated. Hypothesis We hypothesized that fixation and/or arthroplasty are safe and effective options for controlling pain and improving the patients’ function. Materials and methods Between 2004 and 2016, 11 French hospitals included 112 continuous cases of HM in 54 men (49%) and 57 women (51%). The average age was 63.7 ± 13.4 years (30–94). The HM occurred in the context of primary breast (30%), lung (23%) or kidney (21%) cancers. The HM was proximal in 35% of cases, midshaft in 59% and distal in 7% of cases. Surgery was required in 69% of patients because of a pathological fracture. The surgical procedure consisted of bundle pinning, plate fixation, arthroplasty or locked IM nailing in 6%, 11%, 14% and 69% of patients, respectively. Results Seven patients (6%) had to be reoperated due to surgical site complications including two infections and four fractures (periprosthetic or away from implant). Twelve patients (11%) experienced a general complication. The overall survival was 16.7 months, which was negatively and significantly impacted by the occurrence of a fracture, a diaphyseal location and the type of primary cancer. At the final assessment, 75% had normal or subnormal function and more than 90% were pain-free or had less pain. The final function was not related to the occurrence of a fracture or etiology of the metastasis. In epiphyseal and metaphyseal HM, there was a trend to better function after shoulder arthroplasty than after plate fixation or IM nailing. Conclusions Our initial hypothesis was confirmed. Our findings were consistent with those of other published studies. Based on our findings, we recommend using static locked IM nailing with cementoplasty for mid-shaft lesions and modular arthroplasty for destructive epiphyseal or metaphyso–epiphyseal lesions. The criteria for assessing humeral fracture risk should be updated to allow the introduction of a preventative procedure, which contributes to better survival. Level of evidence IV, retrospective study.

CoVID-19 is an unprecedented epidemic, globally challenging health systems, societies, and economy. Its diagnosis relies on molecular methods, with drawbacks revealed by current use as mass screening. Monocyte CD169 upregulation has been reported as a marker of viral infections, we evaluated a flow cytometry three-color rapid assay of whole blood monocyte CD169 for CoVID-19 screening.Outpatients (n=177) with confirmed CoVID-19 infection, comprising 80 early-stage (≤14 days after symptom onset), 71 late-stage (≥15 days), and 26 asymptomatic patients received whole blood CD169 testing in parallel with SARS-CoV-2 RT-PCR. Upregulation of monocyte CD169 without polymorphonuclear neutrophil CD64 changes was the primary endpoint. Sensitivity was 98% and 100% in early-stage and asymptomatic patients respectively, specificity was 50% and 84%. Rapid whole blood monocyte CD169 evaluation was highly sensitive when compared with RT-PCR, especially in early-stage, asymptomatic patients whose RT-PCR tests were not yet positive.Diagnostic accuracy, easy finger prick sampling and minimal time-to-result (15-30 minutes) rank whole blood monocyte CD169 upregulation as a potential screening and diagnostic support for CoVID-19. Secondary endpoints were neutrophil CD64 upregulation as a marker of bacterial infections and monocyte HLA-DR downregulation as a surrogate of immune fitness, both assisting with adequate and rapid management of non-CoVID cases.

Cerebral autoregulation (CA) impairment is associated with neurological complications among children supported by extracorporeal membrane oxygenation (ECMO). Severe variations of arterial CO2 (PaCO2) and O2 (PaO2) tension after ECMO onset are common and associate with mortality and poor neurological outcome. The impact of gas exchange on CA among critically ill patients is poorly studied. Retrospective analysis of data collected prospectively from 30 children treated with veno-arterial or veno-venous ECMO in the PICU of Nantes University Hospital, France. A correlation coefficient between the variations of regional cerebral oxygen saturation (rSO2) and the variations of mean arterial blood pressure (MAP) was calculated as an index of CA (cerebral oxygenation reactivity index, COx). Cox–MAP plots were investigated allowing determining lower limit of autoregulation (LLA) and upper limit of autoregulation (ULA) limits of autoregulation. Age-based normal blood pressure was used to adjust the MAP, LLA, and ULA data from each patient and then reported as percentage (nMAP, nLLA, and nULA, respectively). RSO2, COx, nMAP, nLLA, and nULA values were averaged over one hour before each arterial blood gas (ABG) sample during ECMO run. Thirty children (median age 4.8 months [Interquartile range (IQR) 0.7–39.1], median weight 5 kg [IQR 4–15]) experiencing 31 ECMO runs were included in the study. Three hundred and ninety ABGs were analyzed. The highest values of COx were observed on day 1 (D1) of ECMO. The relationship between COx and PaCO2 was nonlinear, but COx values tended to be lower in case of hypercapnia compared to normocapnia. During the whole ECMO run, a weak but significant correlation between PaCO2 and nULA was observed (R = 0.432, p = 0.02). On D1 of ECMO, this correlation was stronger (R = 0.85, p = 0.03) and a positive correlation between nLLA and PaCO2 was also found (R = 0.726, p

Introduction and Background Trident is a mission concept to investigate Neptune’s large moon Triton, an exotic candidate ocean world at 30 AU (Prockter et al., 2019, Mitchell et al. 2019). The concept is responsive to recommendations of the recent NASA Roadmap to Ocean Worlds study (Hendrix et al., 2019), and to the 2013 Planetary Decadal Survey’s habitability and workings themes (Squyres et al., 2011). The concept was chosen (Ref. 5) from proposals submitted in 2019, under NASA’s Discovery Program, and is currently in its Phase A, competing for selection with three other mission concepts. Voyager 2 showed that Triton has active resurfacing with the potential for erupting plumes and an atmosphere. Coupled with an ionosphere that can create organic snow and the potential for a subsurface ocean, Triton is an exciting exploration target to understand how habitable worlds may develop in our Solar System and beyond. Using a single flyby, Trident would map Triton, characterize active processes and determine whether the predicted subsurface ocean exists. Nominal mission By launching during 2026, Trident would take advantage of a rare, efficient gravity-assist alignment, to capitalize on a narrow – but closing – observational window that enables assessment of changes in Triton’s plume activity and surface characteristics since Voyager 2’s encounter one Neptune-Triton season ago. We have identified an optimized solution to enable a New Horizons-like fast flyby of Triton in 2038 that was proved to fit within the Discovery 2019 cost cap. The spacecraft has a robust design and uses high heritage instruments: (a) Infra-red spectrometer, (b) Narrow angle camera, (c) Wide-angle camera, (d) Triaxial magnetometer, (e) Radio science and (f) Plasma spectrometer. The mission concept builds on the New Horizons concepts of operation. Our overarching science goals are to determine: (1) if Triton has a subsurface ocean; (2) why Triton has the youngest surface of any icy world in the solar system, and which processes are responsible for this; and (3) why Triton’s ionosphere is so unusually intense. Radio Science Instrument and Objectives The Radio Science Instrument (RSI) is the assembly of the DST-R (Deep Space Transponder and Receiver) and USO (UltraStable Oscillator), see Fig. 1. Fig. 1: Trident’s Block Diagram of the Radio Science Instrument The RSI hardware involves no new technology or advanced development. The DST-Rs are provided by the Italian Space Agency (ASI). Dual USOs identical to the USO provided for the ESA/JUICE mission 3GM radio science experiment, are provided to ASI by the Israel Space Agency. ASI has a wide experience in providing RF instrumentation having led the development of several transponder units for deep space science missions in the last 30 years. The USO feeds the DST-R and generates a stable frequency reference for the uplink radio signals to be recorded on board. The DST-R works at the same time as a phase-coherent Deep Space Transponder at X-band, but also as an on-board Receiver at X- and Ka-band. The RSI contributes to two Trident science questions related to the science goals (1) and (3): “Is Triton an ocean world?” and “Why is Triton’s ionosphere so intense?”. In particular, the RSI provides three physical parameters: (a) the electron density profiles on leading and trailing hemispheres, (b) temperature via neutral atmospheric density profile, and (c) the thickness of the hydrosphere from internal mass distribution. Physical parameters (a) and (b) are estimated through simultaneous, dual frequency (X-and Ka-band) uplink radio occultations while the physical parameter (c) is inferred by gravity science observations carried out via phase-coherent Doppler tracking at X-band. Our quantitative requirements for the three above-mentioned objectives (a), (b) and (c) are as follows: - measure the electron density in the ionosphere of Triton to +/- 10% of the population detected by Voyager, i.e. to a sensitivity of 4E+9 el/m3; - measure the neutral atmosphere density and temperature to a sensitivity of +/- 0.1 Pa and +/- 5 K; - measure the gravity quadrupole coefficient C22 with ≤10% error. This paper shows how an optimal combination of on-board instrumentation, a careful trajectory design and an efficient radio science data processing strategy will lead to exceeding all quantitative radio science requirements listed above, with ample margins. Acknowledgements Authors PT, AB, LGC and MZ acknowledge financial support from Agenzia Spaziale Italiana (ASI), via contract No. 2020-13-HH.0 CUP F34I20000050005. This work was carried out in part at the California Institute of Technology, Jet Propulsion Laboratory under a contract from NASA. It describes a predecisional mission concept, for discussion and planning purposes only. The inputs of the various past and present members of the Trident team are gratefully acknowledged. References [1] L. M. Prockter, et al.: Exploring Triton with TRIDENT: a Discovery-Class Mission, 50th Lunar and Planetary Science Conference 2019 (LPI Contrib. No. 2132), Abstract 3188. [2] K. L. Mitchell, et al.: Implementation of TRIDENT: a Discovery-Class Mission to Triton, 50th Lunar and Planetary Science Conference 2019 (LPI Contrib. No. 2132), Abstract 3200. [3] Hendrix, A. R. et al. (2019) Astrobiology 19(1), doi:10.1089/ast.2018.1955. [4] Squyres, S. W. et al. (2011) Vision and Voyagers for Planetary Science in the Decade 2013-2022, National Academies Press. [5] https://www.nasa.gov/press-release/nasa-selects-four-possible-missions-to-study-the-secrets-of-the-solar-system

Purpose The objective of this study was to assess the morbidity of Anterior Lumbar Interbody Fusion (ALIF) using an intervertebral tantalum implant. Tantulum is an extremely porous metallic material which possesses properties of osseointegration, osteoinduction and osteoconduction while offering superior primary stability, compared to other materials more commonly used (polyether ether ketone or PEEK, titanium). Perioperative morbidity, short-term functional outcomes (2 years) and radiographic impaction of implants were also analysed. Methods This retrospective monocentric study involved 94 patients operated on between 2014 and 2017 for degenerative disc disease (75%), degenerative spondylolisthesis (3%) or isthmic lytic spondylolisthesis (22%). Sixty-five patients (69%) had isolated (“stand-alone”) ALIF procedures, 24 (26%) with associated anterior osteosynthesis and 5 (5%) with associated posterior osteosynthesis. A Kaplan-Meier survival curve was established with surgical revision listed as the main criterion for failure. Perioperative complications were identified. The clinical evaluation at the last follow-up used a Visual Analogue Scale for radicular pain (VAS-R), for lumbar pain (VAS-L) and the Oswestry Disability Index (ODI) score. The impactions, assessed on x-rays, were divided into 2 groups according to severity in order to establish risk factors (RF). Results The primary objective showed a 2-year survival rate of 94% (95% CI [0.88; 0.99]). Two patients had early surgical revision for impaction and 4 patients had late surgical revision for pseudarthrosis. The rate of perioperative complications was 8.5%, mostly due to vascular causes. At the average follow-up of 33 months (24–59), the clinical results were significantly improved and the impaction rate was 36% in the immediate postoperative period (IPO) and 47% at one year. Conclusion ALIF using an intervertebral tantalum implant is a reliable, reproducible and low morbidity technique. However, it is accompanied by a significant rate of immediate and secondary impaction but without any resounding influence on short-term clinical outcomes. Level of evidence IV.

Importance Coronavirus disease 2019 (COVID-19) is associated with severe lung damage. Corticosteroids are a possible therapeutic option. Objective To determine the effect of hydrocortisone on treatment failure on day 21 in critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute respiratory failure. Design, Setting, and Participants Multicenter randomized double-blind sequential trial conducted in France, with interim analyses planned every 50 patients. Patients admitted to the intensive care unit (ICU) for COVID-19–related acute respiratory failure were enrolled from March 7 to June 1, 2020, with last follow-up on June 29, 2020. The study intended to enroll 290 patients but was stopped early following the recommendation of the data and safety monitoring board. Interventions Patients were randomized to receive low-dose hydrocortisone (n = 76) or placebo (n = 73). Main Outcomes and Measures The primary outcome, treatment failure on day 21, was defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy. Prespecified secondary outcomes included the need for tracheal intubation (among patients not intubated at baseline); cumulative incidences (until day 21) of prone position sessions, extracorporeal membrane oxygenation, and inhaled nitric oxide; Pao2:Fio2ratio measured daily from day 1 to day 7, then on days 14 and 21; and the proportion of patients with secondary infections during their ICU stay. Results The study was stopped after 149 patients (mean age, 62.2 years; 30.2% women; 81.2% mechanically ventilated) were enrolled. One hundred forty-eight patients (99.3%) completed the study, and there were 69 treatment failure events, including 11 deaths in the hydrocortisone group and 20 deaths in the placebo group. The primary outcome, treatment failure on day 21, occurred in 32 of 76 patients (42.1%) in the hydrocortisone group compared with 37 of 73 (50.7%) in the placebo group (difference of proportions, –8.6% [95.48% CI, –24.9% to 7.7%];P = .29). Of the 4 prespecified secondary outcomes, none showed a significant difference. No serious adverse events were related to the study treatment. Conclusions and Relevance In this study of critically ill patients with COVID-19 and acute respiratory failure, low-dose hydrocortisone, compared with placebo, did not significantly reduce treatment failure (defined as death or persistent respiratory support) at day 21. However, the study was stopped early and likely was underpowered to find a statistically and clinically important difference in the primary outcome. Trial Registration ClinicalTrials.gov Identifier:NCT02517489