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

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

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

Controle par la dopamine des phenomenes d'expression genique dans le striatum du rat. Etude anatomo-fonctionnelle par hybridation in situ

SIGLEINIST T 75201 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Caractérisation des propriétés motivationnelles du sevrage des opiacés (analyse comparative des substrats neurobiologiques des effets inconditionnés et conditionnés)

Chez le toxicomane, la présentation de situations environnementales précédemment associées au sevrage des opiacés induit un intense désir pour la drogue. Ces stimuli conditionnés pourraient précipiter la rechute en réactivant les circuits neuronaux activés de manière inconditionnée par le sevrage. Nous avons ainsi entrepris, chez l'animal, la caractérisation anatomique et fonctionnelle de ces processus motivationnels qui impliquent la mémoire affective, en utilisant le marqueur de réactivité neuronale c-fos. Nous montrons que les substrats neuronaux sous-jacents à la composante motivationnelle du sevrage des opiacés (qui incluent des structures limbiques) sont dissociés d'un ensemble d'autres régions qui sont en revanche impliquées dans l'expression de la composante somatique du sevrage. Sur la base de l'ensemble de nos résultats, nous proposons un modèle fonctionnel pour la formation et le rappel de la "mémoire du sevrage des opiacés".In former opiate addicts re-exposure to environmental situations previously paired with withdrawal is able to induce strong craving episodes. These conditioned stimuli could precipitate relapse in drug-taking behaviour by re-activating the neurobiological networks engaged in an unconditionned manner by the withdrawal state itself. Thus, we have focused, in animals, on the anatomical characterization of these motivational processes which involve affective memory, by using c-fos as a marker of neuronal reactivity. We show that the neurobiological substrates underlying the motivational component of opiate withdrawal (which include limbic structures) can be dissociated from a number of other structures, which in contrast are involved in the expression of the overt somatic symptoms of withdrawal. On the basis of our results, we propose a functional model for the acquisition and the retrieval of morphine withdrawal memories.BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Sustrats neuronaux des mémoires émotionnelles associées au sevrage des opiacés (analyse des réseaux de l'amygdale et des structures associées)

Dans la dépendance aux opiacés, l'arrêt de la prise de drogue entraîne l'émergence d'un syndrome de sevrage, dont les propriétés aversives peuvent être conditionnées à l'environnement dans lequel il est vécu. D'une manière générale, les stimuli conditionnés associés à la drogue ou à son sevrage sont connus pour influencer les comportements addictifs, via des processus d'apprentissage et de mémoire à long terme. Ces processus impliquent des circuits neuronaux qu'il est nécessaire de caractériser pour mieux comprendre la persistance de cette pathologie. Notre objectif a été par des approches anatomo-fonctionnelles de préciser au niveau de l'amygdale et des structures associées, certains des processus neuronaux sous-tendant les effets conditionnés du sevrage des opiacés chez des animaux dépendants et abstinents. Nous avons utilisé un modèle d'aversion de place conditionnée induite par le sevrage chez le rat morphino-dépendant, permettant l'étude de la mémoire de cet état aversif par la réexposition ultérieure à l'environnement. Nos travaux ont mis en évidence, au cours du conditionnement, des processus de plasticité dans les noyaux de l'amygdale, qui pourraient sous-tendre la formation de la mémoire du sevrage, mais aussi son rappel par la réexposition aux stimuli confitionnés. Nous montrons aussi que la dopamine est impliquée dans ce processus mais, dans l'amygdale, n'est pas nécessaire au conditionnement. Enfin, le rappel de la mémoire du sevrage à long terme chez des rats abstinents, implique des circuits en partie différents de ceux recrutés chez des rats dépendants, suggérant un remodelage des circuits qui sous-tendent cette mémoire en fonction de l'état de dépendance.In opiate addiction, a withdrawal syndrome emerges when stopping drug consumption, and the aversive properties of the withdrawal state can be conditioned to the environment. Indeed, environmental stimuli associated with drug taking or withdrawal are known to influence addictive behaviours, via associative learning and long term memory processes. The processes involved neural networks that must be characterized to better understand the persistence of this pathology. Our work intended to analyze, by using anatomo-functional approaches, the neuronal processes underlying opiate withdrawal conditioning within amygdala nuclei and associated stuctures. For this, we used a conditioned place aversion model induced by opiate withdrawal in morphine-dependent rats that allowed the study of withdrawal aversive state memory by reexposure to the conditioned environment, in both dependent and abstinent rats. During morphine withdrawal conditioning, our data reveal neuronal plasticity processes in the amygdala nuclei which could underlie withdrawal memory formation, but also the retrieval of this memory in dependent rats during reexposure to the conditioned stimuli. We also show a dopaminergic activation in such processes, although it seems not necessary in the amygdala for withdrawal memory formation. Finally, the retrieval aversive memories in abstinent ats involves neuronal networks partly different from those in dependent rats. This suggests an anatomo-functional reorganization of the networks underlying the retrieval memories associated with morphine withdrawal depending on the dependance state.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Des références partagées pour des alternatives au placement du bébé en danger

National audienceUn groupe de recherche exploratoire, formé lors d’une recherche-action menée par le département d’Ille-et-Vilaine et Askoria, a engagé une réflexion sur « l’accompagnement des enfants et de leurs parents de la grossesse à l’âge de 2 ans ». Son objectif visait à construire des références praxéologiques qui, dans des situations de danger avéré pour le bébé, doivent permettre d’envisager des alternatives à son placement. L’enjeu est de constituer un langage commun entre des professionnels de différents secteurs d’activité afin d’orienter, de manière référencée, les pratiques professionnelles

Arc reactivity in accumbens nucleus, amygdala and hippocampus differentiates cue over context responses during reactivation of opiate withdrawal memory

International audienc

Evolution of the dynamic properties of the cortex-basal ganglia network after dopaminergic depletion in rats.

International audienceIt is well established that parkinsonian syndrome is associated with alterations of neuronal activity temporal pattern basal ganglia (BG). An increase in synchronized oscillations has been observed in different BG nuclei in Parkinson's disease patients as well as animal models such as 6-hydroxydopamine treated rats. We recently demonstrated that this increase in oscillatory synchronization is present during high-voltage spindles (HVS) probably underpinned by the disorganization of cortex-BG interactions. Here we investigated the time course of both oscillatory and motor alterations. For that purpose we performed daily simultaneous recordings of neuronal activity in motor cortex, striatum and substantia nigra pars reticulata (SNr), before and after 6-hydroxydopamine lesion in awake rats. After a brief non-dopamine-specific desynchronization, oscillatory activity first increased during HVS followed by progressive motor impairment and the shortening of SNr activation delay. While the oscillatory firing increase reflects dopaminergic depletion, response alteration in SNr neurons is closely related to motor symptom

Neuropsychopharmacology

Depression is highly prevalent worldwide, but its etiology is not fully understood. An overlooked possible contributor to the epidemic of depression is feeding styles, particularly at early age when the brain is intensely changing. We have previously reported that unlimited sucrose consumption during adolescence leads to enduring changes in brain reward function. Here, we tested the hypothesis that sucrose consumption during adolescence would lead to a 'depressive-like' phenotype. Adolescent male rats were given unlimited access to 5% sucrose in their home cages from postnatal day 30 to postnatal day 46 and their emotional behavior was subsequently examined at adulthood. Sucrose consumption during adolescence caused anhedonia, decreased motivation for saccharin, increased immobility in the forced swim test and exacerbated anxiety-like behavior. Additionally, sucrose consumption during adolescence decreased cell proliferation in the hippocampus in adulthood. Chronic treatment with imipramine (10 mg/kg) normalized behavior and restored cell proliferation in the hippocampus of adult rats with a history of sucrose consumption during adolescence. A similar sucrose consumption starting at adulthood only increases immobility in the forced swim test, suggesting that sucrose intake affects also adults' behavior but to a lesser degree. Overall, our findings reveal an unsuspected protracted effect of sucrose consumption on behavior and suggest that unlimited sucrose consumption during critical periods of brain development may play an important role in the etiology of reward-related disorders such as depression