Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids

International audienceThe worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary car-cinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low-and high-grade lung neuroendocrine neoplasms

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

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

Evolution of metallicolous populations in a heavy metal tolerant plant Arabidopsis halleri (Brassicaceae) : survey on genome and traits in natural populations

Les milieux métallifères d’origine anthropique sont des habitats particulièrement stressants pour les êtres vivants du fait des fortes concentrations en métaux lourds et des changements environnementaux profonds qui y sont présents. Certaines espèces, dites métallophytes, sont capables de se développer dans ces milieux extrêmes. Parmi ces espèces, les pseudométallophytes (qui peuvent se développer à la fois dans des sites pollués et dans des sites non pollués) constitue des modèles particulièrement intéressants pour étudier l’adaptation locale et l’influence des différences forces évolutives dans la différentiation phénotypique entre populations. Arabidopsis halleri est une espèce pseudométallophyte modèle pour l’étude de la tolérance et de l’hyperaccumulation des métaux du fait de sa proximité avec l’espèce prééminente A. thaliana. Des études préalables sur la tolérance et l’hyperaccumulation du zinc chez cette espèce ont suggéré une possible évolution des populations métallicoles sous l’effet des fortes concentrations en métaux. Notre objectif a donc été de mieux comprendre les mécanismes évolutifs prenant place dans ces populations. Pour cela nous avons proposé d’utiliser la génomique des populations ainsi que l’expérimentation en milieu contrôlé et ce à une échelle locale. Nous avons tout d’abord cherché des traces de sélection dans le génome de cette espèce par une approche de criblage génomique sur 820 marqueurs AFLP. Nous avons pu identifier des locus potentiellement sous sélection dans les populations métallicoles qui constituent de bons candidats pour l’adaptation aux sites métallifères. De manière intéressante, certains candidats sont spécifiques à des populations ce qui suggère une évolution convergente ou des pressions de sélection différentes entre les sites. Une partie de ces candidats a été cartographiée chez A. thaliana dans le but de définir des gènes candidats. Nous avons dans un deuxième temps cherché à comprendre l’influence des différentes forces évolutives dans la distribution de la tolérance au zinc chez A. halleri. La tolérance au zinc de populations a été caractérisée par des mesures morphologiques et physiologiques et l’influence de la sélection par une approche Qst/Fst. Nos résultats suggèrent que, pour les populations échantillonnées, la tolérance au zinc augmente dans les populations métallicoles sous l’effet de la sélection. Cette sélection s’exerçant potentiellement sur la variabilité présente dans les populations non métallicoles ancestrales. Enfin, la dernière partie de cette étude s’intéresse à l’association entre les génotypes et les phénotypes de la tolérance au zinc.Due to the high concentration of heavy metals and the important environmental modifications, ecological conditions of metalliferous sites are very stressing for most organisms. A few plant species, coined “metallophyte”, have acquired the capacity to grow on heavy metal contaminated soils. Among this group, the pseudometallophyte species (able to grow on contaminated as well as on non contaminated soils) constitute highly relevant models to study local adaptation and relative influence of evolutionary forces in shaping phenotypic differentiation among populations The pseudometallophyte plant Arabidopsis halleri is a model species for tolerance and hyperaccumulation of heavy metal because it is a close relative of the pre-eminent species A. thaliana. Previous studies on heavy metal tolerance and hyperaccumulation of A. halleri suggested evolution of metallicolous populations in response to high level of metal exposure. In order to investigate the evolutionary processes in neighboring metallicolous and non-metallicous A. halleri populations, we adopted population genomics and phenotyping approaches. First we explored the A. halleri genome to detect signatures of directional selection. We performed a genome-wide scan analysis using 820 AFLP markers. We identified some loci potentially under selection in metallicolous populations that constitute high-quality candidates for general adaptation to metalliferous sites. Interestingly, some candidates were population specifics, suggesting the possibility of convergent evolution or existence of different selection pressure in the different sites. Some of these candidates were mapped on A. thaliana genome to identify candidate genes. Our second objective was to evaluate the contribution of selection versus other forces in shaping distribution of zinc tolerance in A. halleri. We measured morphological and physiological traits to estimate zinc tolerance and role of selection was inferred using Qst/Fst approach. Our results suggest that, in the sampled populations, zinc tolerance has been increased in metallicolous populations through selection on standing variation within local non-metallicolous ancestral populations. The last part of this study focuses on looking for a link between genotype and phenotype of zinc tolerance

Evolution de l'architecture génétique de la tolérance aux métaux chez l'espèce pseudo-metallophyte Arabidopsis halleri

info:eu-repo/semantics/publishe

Use of the model species Arabidopsis halleri towards phytoextraction of cadmium polluted soils

Phytoremediation consists in treating environmental pollutions through the use of plants and their associated microbes. Phytoremediation can be used for pollutant stabilization, extraction, degradation or volatilization. Cadmium is one of the most toxic trace metallic elements for living organisms and its accumulation in the environment is recognized as a worldwide concern. Plants suitable for efficient pollutant extraction from the soil should combine different characteristics like fast growth, high biomass, high tolerance and high accumulation capacities in harvestable parts. A rare class of plants called hyperaccumulators combines extremely high tolerance degrees and foliar accumulation of trace elements. With regard to cadmium, none of the Cd hyperaccumulators identified has met the criteria for efficient phytoextraction so far. By virtue of genetic engineering it is possible to transfer genes involved in Cd tolerance or accumulation in high biomass plants. Nevertheless, the genetic determinants of Cd hyperaccumulation are far from being understood. It is thus indispensable to acquire more knowledge about these processes. Among Cd hyperaccumulators, Arabidopsis halleri (some populations can hyperaccumulate Cd) is considered as a model species for the study of metal homeostasis and detoxification. This review will summarize our knowledge about Cd tolerance and accumulation acquired in A. halleri and how this knowledge may be used in phytoextraction.info:eu-repo/semantics/publishe

Tolerance to cadmium in plants: the special case of hyperaccumulators

info:eu-repo/semantics/publishe