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

Etude la croissance dendritique du cuivre dans l'acide oxalique (application au procédé de nettoyage post-CMP en microélectronique)

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Maximum-Score Diversity Selection for Early Drug Discovery

Diversity selection is a common task in early drug discovery. One drawback of current approaches is that usually only the structural diversity is taken into account and activity information is ignored. In this article we present a modified version of diversity selection - which we term "Maximum-Score Diversity Selection" - that additionally takes the estimated or predicted activities of the molecules into account. We show that finding an optimal solution to this problem is computationally very expensive (it is NP-hard) and therefore heuristic approaches are needed.After a discussion of existing approaches we present our new method which is computationally far more efficient but at the same time produces comparable results. We conclude by validating these theoretical differences on several datasets

Muscle loss associated changes of oxylipin signatures during biological aging: an exploratory study from the PROOF cohort

Characterizations of the multiple mechanisms determining biological aging are required to betterunderstand the etiology and identify early biomarkers of sarcopenia. Oxylipins are a large family ofsignaling lipids involved in the regulation of various biological processes that become dysregulatedduring aging.To investigate whether comprehensive oxylipin profiling could provide an integrated and finecharacterisation of the early phases of sarcopenia, we performed a quantitative targetedmetabolomics of oxylipins in plasma of 81-year old subjects from the PROOF cohort with decreased(n=12), stable (n=16) or increased appendicular muscle mass (n=14).Multivariate and univariate analyses identified significant and concordant changes of oxylipin profilesaccording to the muscle status. Of note, 90% of the most discriminant oxylipins were derived fromEPA and DHA and were increased in the sarcopenic subjects. The oxylipins signatures of sarcopenicsubjects revealed subtle activation of inflammatory resolution pathways, coagulation processes andoxidative stress and the inhibition of angiogenesis. Heat maps highlighted relationships betweenoxylipins and the cardiometabolic health parameters which were mainly lost in sarcopenic subjects.This exploratory study supports that targeted metabolomics of oxylipins could provide relevant andsubtle characterization of early disturbances associated with muscle-loss during aging

Muscle loss associated changes of oxylipin signatures during biological aging: an exploratory study from the PROOF cohort

Epub ahead of printCharacterizations of the multiple mechanisms determining biological aging are required to betterunderstand the etiology and identify early biomarkers of sarcopenia. Oxylipins are a large family ofsignaling lipids involved in the regulation of various biological processes that become dysregulatedduring aging.To investigate whether comprehensive oxylipin profiling could provide an integrated and finecharacterisation of the early phases of sarcopenia, we performed a quantitative targetedmetabolomics of oxylipins in plasma of 81-year old subjects from the PROOF cohort with decreased(n=12), stable (n=16) or increased appendicular muscle mass (n=14).Multivariate and univariate analyses identified significant and concordant changes of oxylipin profilesaccording to the muscle status. Of note, 90% of the most discriminant oxylipins were derived fromEPA and DHA and were increased in the sarcopenic subjects. The oxylipins signatures of sarcopenicsubjects revealed subtle activation of inflammatory resolution pathways, coagulation processes andoxidative stress and the inhibition of angiogenesis. Heat maps highlighted relationships betweenoxylipins and the cardiometabolic health parameters which were mainly lost in sarcopenic subjects.This exploratory study supports that targeted metabolomics of oxylipins could provide relevant andsubtle characterization of early disturbances associated with muscle-loss during aging