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

La trousse de secours des guides de haute montagne : contenu réel et usage

The profession of High-mountain guide is to evolve its customers by securing them in a dangerous and isolated environment. For this, his first aid kit is an indispensable and obligatory tool, even if its content is not regulated. We assessed the actual content of the first aid kit of the guides and its use through a questionnaire, and we analyzed the obtained results with regard to the risks of the high mountain and their management recommendations, detailed in the first part of the book. It appears that the composition and the use of this kit depends on each guide, depending on his own experience and type of practice. There is a tendency to privilize first aid and withdraw drugs. Most of the guides adapt the composition of their kit to the planned race and they generally have a good knowledge of the treatments they carry. However, few guides contact a doctor before giving a medical treatment, and just the idea that they do not have the status of health professionals, and therefore can not deliver drugs, is recurrent. So it can be interesting to complete their training via a specific course dealing with the content of the first aid kit, its good management overtime and its use with a medical assistance support.Le métier de guide de haute montagne consiste à faire évoluer ses clients tout en les sécurisant dans un milieu dangereux et isolé. Pour cela sa trousse de secours est un outil indispensable et obligatoire, sans pour autant avoir un contenu réglementé. Nous avons évalué le contenu réel de la trousse de secours des guides ainsi que son utilisation par le biais d’un questionnaire, et nous avons analysé les résultats obtenus au regard des risques de la haute montagne et de leurs recommandations de prise en charge, détaillées en première partie de l'ouvrage. Il en ressort que la composition et l’utilisation de cette trousse varient d’un guide à l’autre, en fonction de son expérience et de son type de pratique. On observe une tendance à privilégier les premiers secours et à retirer les médicaments. La plupart des guides adaptent la composition de leur trousse à la course prévue, et ils ont globalement une bonne connaissance des traitements qu’ils emportent. Cependant, on observe que peu de guides contactent un médecin avant l’administration d’un traitement ; et l’idée qu’ils n'ont pas un statut de professionnels de santé, et par conséquent ne peuvent pas délivrer de médicaments, est récurrente. Il peut donc être intéressant de compléter leur formation via un cours spécifique traitant du contenu de la trousse de secours, de sa bonne gestion au cours du temps, et de son utilisation avec soutien téléphonique médical

Variation pattern of the imprints of the middle meningeal vessels in extant human endocasts

International audienc

Circadian, sleep and caloric intake phenotyping in Type 2 Diabetes patients with rare melatonin receptor 2 mutations and controls: A Pilot Study.

BackgroundMelatonin modulates circadian rhythms in physiology and sleep initiation. Genetic variants of the MTNR1B locus, encoding the melatonin MT2 receptor, have been associated with increased type 2 diabetes (T2D) risk. Carriers of the common intronic MTNR1B rs10830963 T2D risk variant have modified sleep and circadian traits such as changes of the melatonin profile. However, it is currently unknown whether rare variants in the MT2 coding region are also associated with altered sleep and circadian phenotypes, including meal timing. Materials and MethodsIn this pilot study, 28 individuals [50% male; 46-82 years old; 50% with rare MT2 mutations (T2D MT2)] wore actigraphy devices and filled out daily food logs for 4 weeks. We computed circadian, sleep, and caloric intake phenotypes, including sleep duration, timing, and regularity [assessed by the Sleep Regularity Index (SRI)]; composite phase deviations (CPD) as well a sleep timing-based proxy for circadian misalignment; and caloric intake patterns throughout the day. Using regression analyses, we estimated age- and sex-adjusted mean differences (MD) and 95% confidence intervals (95%CI) between the two patient groups. Secondary analyses also compare T2D MT2 to 15 healthy controls. ResultsPatients with rare MT2 mutations had a later sleep onset (MD = 1.23, 95%CI = 0.42;2.04), and midsleep time (MD = 0.91, 95%CI = 0.12;1.70), slept more irregularly (MD in SRI = -8.98, 95%CI = -16.36;-1.60), had higher levels of behavioral circadian misalignment (MD in CPD = 1.21, 95%CI = 0.51;1.92), were more variable in regard to duration between first caloric intake and average sleep offset (MD = 1.08, 95%CI = 0.07;2.08), and had more caloric episodes in a 24 h day (MD = 1.08, 95%CI = 0.26;1.90), in comparison to T2D controls. Secondary analyses showed similar patterns between T2D MT2 and non-diabetic controls. ConclusionThis pilot study suggests that compared to diabetic controls, T2D MT2 patients display a number of adverse sleep, circadian, and caloric intake phenotypes, including more irregular behavioral timing. A prospective study is needed to determine the role of these behavioral phenotypes in T2D onset and severity, especially in view of rare MT2 mutations

Structural Elements Directing G Proteins and β-Arrestin Interactions with the Human Melatonin Type 2 Receptor Revealed by Natural Variants

[Image: see text] G protein-coupled receptors (GPCRs) can engage distinct subsets of signaling pathways, but the structural determinants of this functional selectivity remain elusive. The naturally occurring genetic variants of GPCRs, selectively affecting different pathways, offer an opportunity to explore this phenomenon. We previously identified 40 coding variants of the MTNR1B gene encoding the melatonin MT(2) receptor (MT(2)). These mutations differently impact the β-arrestin 2 recruitment, ERK activation, cAMP production, and Gα(i1) and Gα(z) activation. In this study, we combined functional clustering and structural modeling to delineate the molecular features controlling the MT(2) functional selectivity. Using non-negative matrix factorization, we analyzed the signaling signatures of the 40 MT(2) variants yielding eight clusters defined by unique signaling features and localized in distinct domains of MT(2). Using computational homology modeling, we describe how specific mutations can selectively affect the subsets of signaling pathways and offer a proof of principle that natural variants can be used to explore and understand the GPCR functional selectivity

Identification of Key Regions Mediating Human Melatonin Type 1 Receptor Functional Selectivity Revealed by Natural Variants

International audienceMelatonin is a hormone mainly produced by the pineal gland and MT1 is one of the two G protein-coupled receptors (GPCRs) mediating its action. Despite an increasing number of available GPCR crystal structures, the molecular mechanism of activation of a large number of receptors, including MT1, remains poorly understood. The purpose of this study is to elucidate the structural elements involved in the process of MT1’s activation using naturally occurring variants affecting its function. Thirty-six nonsynonymous variants, including 34 rare ones, were identified in MTNR1A (encoding MT1) from a cohort of 8687 individuals and their signaling profiles were characterized using Bioluminescence Resonance Energy Transfer-based sensors probing 11 different signaling pathways. Computational analysis of the experimental data allowed us to group the variants in clusters according to their signaling profiles and to analyze the position of each variant in the context of the three-dimensional structure of MT1 to link functional selectivity to structure. MT1 variant signaling profiles revealed three clusters characterized by (1) wild-type-like variants, (2) variants with selective defect of βarrestin-2 recruitment, and (3) severely defective variants on all pathways. Our structural analysis allows us to identify important regions for βarrestin-2 recruitment as well as for Gα12 and Gα15 activation. In addition to identifying MT1 domains differentially controlling the activation of the various signaling effectors, this study illustrates how natural variants can be used as tools to study the molecular mechanisms of receptor activation

Discrimination à l’embauche des personnes d’origine supposée maghrébine : quels enseignements d’une grande étude par testing ?

Note IPP, n° 76, novembre 2021De nombreuses études montrent que les Français issus de l’immigration maghrébine se heurtent à des difficultés importantes sur le marché du travail, et ce dès la première étape de recrutement. Les résultats d’un testing récent et de grande ampleur le confirment. La discrimination à l’embauche selon l’origine supposée reste élevée et un élément majeur du marché du travail en France. En moyenne, à qualité comparable, les candidatures dont l’identité suggère une origine maghrébine ont 31,5 % de chances de moins d’être contactées par les recruteurs que celles portant un prénom et nom d’origine française. Si les discriminations liées à l’origine supposée sont fortes et persistantes, elles sont plus faibles, sans s’effacer, parmi les salariés les plus qualifiés. Ces résultats ne varient pas sensiblement entre les femmes et les hommes