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

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

Croissance et mue chez le poussin de Manchot royal (Aptenodytes patagonicus) (aspects écophysiologiques)

LYON1-BU Santé (693882101) / SudocPARIS-Museum-Bib zoologie mam. (751052312) / SudocSudocFranceF

Immunogénicité des protéines p24 et gp 120 du VIH-1 adjuvantées par les nanoparticules de poly(acide lactique) et combinaison avec les vecteurs viraux

Notre objectif est d évaluer la formulation et l immunogénicité en primo-vaccination/rappel d un nouveau véhicule de vaccination : les PLA poly(D,L-acide lactique). Ces nanoparticules synthétiques biodégradables présentant des antigènes adsorbés à leur surface, peuvent activer les deux bras de l immunité. Deux antigènes VIH-1 gp120 et p24 peuvent être formulés sur la même particule sans altérer la qualité et l intensité de la réponse immune murine. Ces formulations n induisant pas de réponse contre le vecteur vaccinal, la réponse immune peut être amplifiée et maintenue par des rappels répétés. Ces observations nous ont permis d évaluer une stratégie vaccinale utilisant des PLA-p24, suivies d un rappel par un vecteur recombinant, poxvirus (rMVA), Adénovirus (Ad5), ou de l ADN exprimant le même antigène. L association vecteur synthétique et vecteur viral permet d amplifier les réponses humorales et cellulaires et semble une stratégie vaccinale prometteuse pour les infections chroniquesIn this study, the formulation and the immunogenicity of a new vaccine vehicle, the PLA poly(D,L-lactic acid), were evaluated in prime/boost strategy. These synthetic and biodegradable nanoparticles prepared with antigens adsorded on their surface, could induce both arms of immunity. Two antigens, HIV-1 p24 and gp120 could be formulated onto the same particle without modification of quality and intensity of immune responses in a mouse model. As these formulations induce no anti-vector immune responses, repeated boosting could increase and maintain immunity. Based on these observations, we evaluated a new vaccine strategy using PLA-p24 as a prime and recombinant vector (poxvirus (rMVA), Adenovirus (Ad5) or DNA) expressing the same antigen as a boost. Synthetic vector associated with viral vector is able to increase humoral and cellular immune responses, and seems a promising vaccine strategy against chronic infectionsLYON1-BU.Sciences (692662101) / SudocSudocFranceF

Contribution à l'étude du parasitisme chez le mandrill au Gabon

Les primates non humains sont les hôtes d'une grande variété de parasites, pouvant avoir un effet délétère sur la santé des individus, comme sur la santé humaine. La prévalence, l'abondance et la diversité des parasites externes, gastro-intestinaux et sanguins, en fonction de facteurs environnementaux, physiologiques et sérologiques (statuts SIV et STLV) ont été étudiées au sein de deux colonies de mandrills (Mandrillus sphinx) au Gabon. Sur les 308 échantillons fécaux analysés, Balantidium coli (prévalence 47,3%), Oesophagostomum spp (83,4%), Ancylostoma spp (37,2%), Trichostrongylus spp (27,8%), Strongyloïdes spp (5,5%), Trichuris spp (4,4%), et Mammomonogamus spp (1 échantillon positif) ont été identifiés. Des poux piqueurs ont été trouvés sur 5 des 137 individus et 14% des animaux se sont révélés infectés par l'hémoparasite Hepatocystis spp. L'habitat, la saison, l'âge, le sexe, et les statuts en rétrovirus ont été retrouvés significativement corrélés avec les facteurs étudiés.TOULOUSE-EN Vétérinaire (315552301) / SudocTOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Hormonal responses to extreme fasting in subantarctic fur seal (Arctocephalus tropicalis) pups

Surviving prolonged fasting implies closely regulated alterations in fuel provisioning to meet metabolic requirements, while preserving homeostasis. Little is known, however, of the endocrine regulations governing such metabolic adaptations in naturally fasting free-ranging animals. The hormonal responses to natural prolonged fasting and how they correlate to the metabolic adaptations observed, were investigated in subantarctic fur seal (Arctocephalus tropicalis) pups, which, because of the intermittent pattern of maternal attendance, repeatedly endure exceptionally long fasting episodes throughout their development (1&ndash;3 mo). Phase I fasting was characterized by a dramatic decrease in plasma insulin, glucagon, leptin, and total L-thyroxine (T4) associated with reductions in mass-specific resting metabolic rate (RMR), plasma triglycerides, glycerol, and urea-to-creatine ratio, while nonesterified fatty acids (NEFA) and &beta;-OHB increased. In contrast, the metabolic steady-state of phase II fasting reached within 6 days was associated with minimal concentrations of insulin, glucagon, and leptin; unchanged cortisol and triiodothyronine (T3); and moderately increased T4. The early fall in insulin and leptin may mediate the shift to the strategy of energy conservation, protein sparing, and primary reliance on body lipids observed in response to the cessation of feeding. In contrast to the typical mammalian starvation response, nonelevated cortisol and minimal glucagon levels may contribute to body protein preservation and downregulation of catabolic pathways, in general. Furthermore, thyroid hormones may be involved in a process of energy conservation, independent of pups\u27 nutritional state. These original hormonal settings might reflect an adaptation to the otariid repeated fasting pattern and emphasize the crucial importance of a tight physiological control over metabolism to survive extreme energetic constraints.<br /

Natural simian immunodeficiency virus transmission in mandrills: a family affair?

Remerciements ECOFECTInternational audienceUnderstanding how pathogens spread and persist in the ecosystem is critical for deciphering the epidemiology of diseases of significance for global health and the fundamental mechanisms involved in the evolution of virulence and host resistance. Combining long-term behavioural and epidemiological data collected in a naturally infected mandrill population and a Bayesian framework, the present study investigated unknown aspects of the eco-epidemiology of simian immunodeficiency virus (SIV), the recent ancestor of HIV. Results show that, in contrast to what is expected from aggressive and sexual transmission (i.e. the two commonly accepted transmission modes for SIV), cases of SIVmnd-1 subtype were significantly correlated among related individuals (greater than 30% of the observed cases). Challenging the traditional view of SIV, this finding suggests the inheritance of genetic determinants of susceptibility to SIV and/or a role for behavioural interactions among maternal kin affecting the transmission of the virus, which would highlight the underappreciated role of sociality in the spread of infectious diseases. Outcomes of this study also provide novel insights into the role of host social structure in the evolution of pathogens

Spatial radial maze procedures and setups to dissociate local and distal relational spatial frameworks in humans.

BACKGROUND: Radial maze tasks have been used to assess optimal foraging and spatial abilities in rodents. The spatial performance was based on a capacity to rely on a configuration of local and distant cues. We adapted maze procedures assessing the relative weight of local cues and distant landmarks for arm choice in humans. NEW METHOD: The procedure allowed testing memory of places in four experimental setups: a fingertip texture-groove maze, a tactile screen maze, a virtual radial maze and a walking size maze. During training, the four reinforced positions remained fixed relative to local and distal cues. During subsequent conflict trials, these frameworks were made conflictive in the prediction of reward locations. RESULTS: Three experiments showed that the relative weight of local and distal relational cues is affected by different factors such as cues' nature, visual access to the environment, real vs. virtual environment, and gender. A fourth experiment illustrated how a walking maze can be used with people suffering intellectual disability. COMPARISON WITH EXISTING METHODS: In our procedure, long-term (reference) and short-term (working) memory can be assessed. It is the first radial task adapted to human that enables dissociating local and distal cues, to provides an indication as to their relative salience. Our mazes are moveable and easily used in limited spaces. Tasks are performed with realistic and spontaneous though controlled exploratory movements. CONCLUSION: Our tasks enabled highlighting the use of different strategies. In a clinical perspective, considering the use of compensatory strategies should orient towards adapted behavioural rehabilitation

Monkeys (Sapajus apella and Macaca tonkeana) and great apes (Gorilla gorilla, Pongo abelii, Pan paniscus, and Pan troglodytes) play for the highest bid

Many studies investigate animals’ decisions under risk focussing on individuals’ attitudes towards risk. Yet, little attention has been paid to individuals’ understanding of outcomes’ odd. In a previous gambling task (Pelé et al., 2014), we showed that non-human primates used prospective gains and losses to reach their decision even when 18 different lotteries were used. However, the study offered gradually decreasing chances to win from the beginning to the end of the experiment. We suggest that this probably facilitated the extraction of information about odds at each lottery. In the current experiment, we controlled for this factor by presenting those lotteries in a random order. We tested individuals from four ape and two monkey species to better evaluate potential species differences in the cognitive evaluation of outcome odds. We found little species differences. Subjects were not expected value maximizers but used heuristic decision-making. This heuristic called maximax, involves playing as soon as there is at least one chance to win more than what they already possess whatever the risk. Also, most species took into account outcome frequency, playing more as larger reward frequency increased. We showed little effects of learning and reinforcement through repetition of trials. Together, these results are reminiscent of optimistic behaviour, often seen in human managerial decisions and finance where risk is ignored in favour of potential even if low probability gains. Reducing the complex problem of cognitive evaluation to a maximax heuristics can be found in other species than human beings

Individual details of degree, eigenvector centrality and betweenness for the <i>contact network</i>.

<p>Individual details of degree, eigenvector centrality and betweenness for the <i>contact network</i>.</p