Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Comprehensive assessment of postoperative mobility during the first days after mini-invasive lung surgery: A prospective observational study

Study objective: Postoperative physical therapy and early mobilization are major elements for enhanced recoveryafter surgery. In contrast with supervised physical therapy sessions that can be monitored, self-mobilization isnot easily quantifiable and has so far been estimated mainly through patient auto-reports. This study aimed toperform a comprehensive and objective evaluation of postoperative mobility.Design: Prospective observational study.Setting: Postoperative setting.Patients: Patients undergoing mini-invasive lung surgery.Interventions: Measurement of postoperative mobility during the first five postoperative days using an acceler-ometer (ActiGraph GT3X).Measurements: The primary outcome was the number of daily steps. Secondary outcomes included physical ac-tivity duration and intensity, sedentary time, number of breaks in sedentary time, sedentary patterns, dailyevaluation by physiotherapists, postoperative complications, and acceptability of wearing the accelerometer.Main results: Sixty patients were included in the study, of whom 56 provided at least one day of valid accel-erometry data. There was no significant change during the first four PODs concerning the number of daily stepsnor the mean cadence. One-minute cadence peak, total activity counts, and duration of light-intensity physicalactivity increased over time (p = 0.032, p = 0.001 and p = 0.001, respectively). Sedentary patterns changedfavorably over time, with a decrease in prolonged sedentary bouts (≥ 60 consecutive min) (p < 0.001), and anincrease in shorter bouts (< 10 min) (p ¼ 0.001). Similar results were observed when analysis was adjusted forthe day of the week when the surgery took place. The median acceptability of wearing the accelerometer wasexcellent (median 10 [9-10] on a 10-point Likert scale). Three patients had major complications.Conclusions: Our findings suggest that daily steps may not be the only relevant indicator of early mobilityfollowing thoracic surgery and that accelerometry is suitable to follow patients’ early postoperative activity

Soft matrix maintains the molecular traits of pulmonary basal cells

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2D cell culture on soft hydrogel drives an endoplasmic reticulum stress-dependent S quiescence underlying molecular traits of pulmonary basal cells

By preserving progenitor characteristics, cell culture on soft hydrogel represents a practical tool in regenerative medicine compared with conventional rigid plastic. However, the mechanism by which the mechanical microenvironment determines progenitor phenotype, and its relevance to human biology, remain poorly described. Thanks to an innovation enabling the generation of uniform multi-well hydrogels, we show that 2D culture on mechanomimetic supports leads to an atypical S-phase quiescence and prevents cell drift, while preserving the differentiation capacities of human bronchoepithelial cells. Mechanistically, defects in proteostasis and basal endoplasmic reticulum stress (ERS) underlie the quiescent phenotype and resistance to ERS-induced apoptosis by metabolic stress. Furthermore, analysis of available single cell data of the human lung confirmed that these molecular features are consistent with those of pulmonary basal cells. Overall, this study demonstrates that mechanomimetic supports are relevant devices for characterizing novel molecular events that govern progenitor biology in human tissues

Comment choisir la question de son essai clinique ? Les conseils du Réseau Recherche de la SFAR

National audienceEvery research project begins with a question. As its nature will influence all subsequent steps, including the methodology, the question should be clear and well-defined from the outset. This is therefore a major step in carrying out a research project, which requires expertise and work. It is indeed clinical experience and previous research that lead to a good question. For it to be relevant, it is necessary to master existing literature on the subject, to be open to new ideas, new techniques, new methodologies, imagination and creativity, as well as to pay attention to mentorship and expert advice. This question must meet criteria for feasibility, interest, novelty, ethics, and relevance (the FINER criteria). It should be formulated in a structured way to ensure maximum clarity, for example following the PICOT framework. Therefore, defining the main question of your clinical trial is not just a semantic exercise.Tous les travaux de recherche commencent par une question. Cette question doit être claire et bien définie dès le départ, car sa nature influencera toutes les étapes suivantes, notamment la méthodologie. Il s’agit donc d’une étape majeure dans la réalisation d’un projet de recherche, qui demande de l’expertise et du travail. Une bonne question émerge en effet de l’expérience clinique et des recherches réalisées antérieurement. Elle nécessite pour être pertinente une maîtrise de la littérature existante sur le sujet, une ouverture à de nouvelles idées, de nouvelles techniques, de nouvelles méthodologies, de l’imagination et de la créativité, mais aussi une grande attention aux conseils de ses mentors et des experts établis. Cette question doit répondre à des critères de faisabilité, d’intérêt, de nouveauté, d’éthique et de pertinence (les critères FINER). Elle doit être formulée de manière structurée pour assurer un maximum de clarté, en suivant par exemple le cadre PICOT (pour population, intervention étudiée, contrôle, outcome et timeframe). Choisir et formuler la question principale de son essai clinique n’est donc pas un exercice purement sémantique

Palliative Care in SMA Type 1: A Prospective Multicenter French Study Based on Parents' Reports

International audienceSpinal muscular atrophy type 1 (SMA-1) is a severe neurodegenerative disorder, which in the absence of curative treatment, leads to death before 1 year of age in most cases. Caring for these short-lived and severely impaired infants requires palliative management. New drugs (nusinersen) have recently been developed that may modify SMA-1 natural history and thus raise ethical concerns about the appropriate level of care for patients. The national Hospital Clinical Research Program (PHRC) called "Assessment of clinical practices of palliative care in children with Spinal Muscular Atrophy Type 1 (SMA-1)" was a multicenter prospective study conducted in France between 2012 and 2016 to report palliative practices in SMA-1 in real life through prospective caregivers' reports about their infants' management. Thirty-nine patients were included in the prospective PHRC (17 centers). We also studied retrospective data regarding management of 43 other SMA-1 patients (18 centers) over the same period, including seven treated with nusinersen, in comparison with historical data from 222 patients previously published over two periods of 10 years (1989-2009). In the latest period studied, median age at diagnosis was 3 months [0.6-10.4]. Seventy-seven patients died at a median 6 months of age[1-27]: 32% at home and 8% in an intensive care unit. Eighty-five percent of patients received enteral nutrition, some through a gastrostomy (6%). Sixteen percent had a non-invasive ventilation (NIV). Seventy-seven percent received sedative treatment at the time of death. Over time, palliative management occurred more frequently at home with increased levels of technical supportive care (enteral nutrition, oxygenotherapy, and analgesic and sedative treatments). No statistical difference was found between the prospective and retrospective patients for the last period. However, significant differences were found between patients treated with nusinersen vs. those untreated. Our data confirm that palliative care is essential in management of SMA-1 patients and that parents are extensively involved in everyday patient care. Our data suggest that nusinersen treatment was accompanied by significantly more invasive supportive care, indicating that a re-examination of standard clinical practices should explicitly consider what treatment pathways are in infants' and caregivers' best interest. This study was registered on clinicaltrials.gov under the reference NCT01862042 (https://clinicaltrials.gov/ct2/show/study/NCT01862042?cond=SMA1&rank=8)

Anaesth Crit Care Pain Med

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