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

Fault Zone Structure and Diagenetic Evolution in Porous Carbonate Rocks, Provence, France

International audienceWe provide an analysis of normal fault zones exceptionally well exposed in porous calcarenites from La Fare les Oliviers (Provence, France). The fault zones crop out along their entire length due to their higher resistance to erosion compared to the porous host rock, and provide excellent exposures for detailed study. This high resistance to erosion is due to significant diagenetical and lithological modifications of the fault damage zone (i.e. pore cementation and sediment infiltration from the surface). The fault core zone is characterized by cataclastic shear and constitutes a vertical path for late gravity-driven oxidant fluids assisting karstification. The fault zone composition and structure is therefore the result of the interplay between the fault zone mechanical behaviour and the the Earth surface environement (marine vs continental)

Fault Zone Structure and Diagenetic Evolution in Porous Carbonate Rocks, Provence, France

International audienceWe provide an analysis of normal fault zones exceptionally well exposed in porous calcarenites from La Fare les Oliviers (Provence, France). The fault zones crop out along their entire length due to their higher resistance to erosion compared to the porous host rock, and provide excellent exposures for detailed study. This high resistance to erosion is due to significant diagenetical and lithological modifications of the fault damage zone (i.e. pore cementation and sediment infiltration from the surface). The fault core zone is characterized by cataclastic shear and constitutes a vertical path for late gravity-driven oxidant fluids assisting karstification. The fault zone composition and structure is therefore the result of the interplay between the fault zone mechanical behaviour and the the Earth surface environement (marine vs continental)

Fault Zone Structure and Diagenetic Evolution in Porous Carbonate Rocks, Provence, France

International audienceWe provide an analysis of normal fault zones exceptionally well exposed in porous calcarenites from La Fare les Oliviers (Provence, France). The fault zones crop out along their entire length due to their higher resistance to erosion compared to the porous host rock, and provide excellent exposures for detailed study. This high resistance to erosion is due to significant diagenetical and lithological modifications of the fault damage zone (i.e. pore cementation and sediment infiltration from the surface). The fault core zone is characterized by cataclastic shear and constitutes a vertical path for late gravity-driven oxidant fluids assisting karstification. The fault zone composition and structure is therefore the result of the interplay between the fault zone mechanical behaviour and the the Earth surface environement (marine vs continental)

Rev-erbalpha2 mRNA encodes a stable protein with a potential role in circadian clock regulation.

International audienceCircadian rhythms are observed in nearly all aspects of physiology and behavior. In mammals, such biological rhythms are supported by a complex network of self-sustained transcriptional loops and posttranslational modifications, which regulate timely controlled production and degradation of critical factors on a 24-h basis. Among these factors, the orphan nuclear receptor rev-erbalpha plays an essential role by linking together positive and negative regulatory loops. As an essential part of the circadian core clock mechanism, REV-ERBalpha expression shows a precisely scheduled oscillation reflecting the tight control of its production and degradation. In previous studies, we identified two alternative transcripts encoding two protein variants referred to as REV-ERBalpha1 and -alpha2. Interestingly, recent work identified structural elements present only in REV-ERBalpha1 that controls its turnover and thereby influences circadian oscillations. In the present work, we comparatively analyze the two variants and show that REV-ERBalpha2 exhibits a half-life incompatible with a circadian function, suggesting that this variant exerts different biological functions. However, our comparative study clearly indicates undistinguishable DNA-binding properties and transcriptional repression activity as well as a similar regulation mechanism. The only consistent difference appears to be the relative expression level of the two transcripts, rev-erbalpha1 being one to 100 times more expressed than alpha2 depending on tissue and circadian time. Taking this finding into consideration, we reassessed REV-ERBalpha2 turnover and were able to show that this variant exhibits a reduced half-life when coexpressed with REV-ERBalpha1. We propose that the relative expression levels of the two REV-ERBalpha variants fine-tune the circadian period length by regulating REV-ERBalpha half-life

Expression Levels of Estrogen Receptor β Are Modulated by Components of the Molecular Clock▿

Circadian regulation of gene expression plays a major role in health and disease. The precise role of the circadian system remains to be clarified, but it is known that circadian proteins generate physiological rhythms in organisms by regulating clock-controlled target genes. The estrogen receptor beta (ERβ) is, together with ERα, a member of the nuclear receptor superfamily and a key mediator of estrogen action. Interestingly, recent studies show that disturbed circadian rhythmicity in humans can increase the risk of reproductive malfunctions, suggesting a link between the circadian system and ER-mediated transcription pathways. Here, we identify a novel level of regulation of estrogen signaling where ERβ, but not ERα, is controlled by circadian clock proteins. We show that ERβ mRNA levels fluctuate in different peripheral tissues following a robust circadian pattern, with a peak at the light-dark transition, which is maintained under free-running conditions. Interestingly, this oscillation is abolished in clock-deficient BMAL1 knockout mice. Circadian control of ERβ expression is exerted through a conserved E-box element in the ERβ promoter region that recruits circadian regulatory factors. Furthermore, using small interfering RNA-mediated knockdown assays, we show that the expression levels of the circadian regulatory factors directly influence estrogen signaling by regulating the intracellular levels of endogenous ERβ

PCR Au fil du plomb de la Seine. Rapport 2021 (coord. M. Robert)

Au cours du XIXe siècle, de nombreux contenants funéraires en plomb d’époque romaine sont découverts dans l’estuaire de la Seine : des vases ossuaires mis au jour à Lillebonne (Seine-Maritime) et ses alentours aux cercueils des environs de Rouen (Seine-Maritime), ils intriguent les érudits locaux et moins locaux, qui relient rapidement la présence de ce métal en grande quantité, dans une région où aucune mine antique n’est connue, à la richesse plombifère de la province proche de Britannia. Trois axes de recherche ont été identifiés les concernant :- Échanges et pratiques commerciales autour du plomb dans l’estuaire.- L'artisanat du plomb estuarien, de la mine au produit fini.- Le plomb dans les pratiques funéraires calètes et véliocasses.À la suite de ces échanges et au regard des premières données rassemblées au cours de l'année probatoire 2020, une réflexion collective a été menée afin de planifier les poursuites de la recherche sur les productions manufacturées en plomb d’époque romaine dans l’estuaire de la Seine. Un programme de recherche triennale a donc débuté en 2021, afin d’étendre la réflexion initiée dans le cadre des axes de recherche du PCR : les différentes enquêtes portant sur la composition et la provenance du métal, tout comme l’étude de la diffusion des contenants en plomb vers et au sein de la région d’étude, ainsi que leur vocation funéraire ne font, en effet, que débuter. Le présent rapport correspond à un bilan des activités de recherches au cours de l’année 2021, première année de la campagne triennale

PCR Au fil du plomb de la Seine. Rapport 2022 (coord. M. Robert)

Au cours du XIXe siècle, de nombreux contenants funéraires en plomb d’époque romaine sont découverts dans l’estuaire de la Seine : des vases ossuaires mis au jour à Lillebonne (Seine-Maritime) et ses alentours aux cercueils des environs de Rouen (Seine-Maritime), ils intriguent les érudits locaux et moins locaux, qui relient rapidement la présence de ce métal en grande quantité, dans une région où aucune mine antique n’est connue, à la richesse plombifère de la province proche de Britannia. Trois axes de recherche ont été identifiés les concernant : - Échanges et pratiques commerciales autour du plomb dans l’estuaire. - L'artisanat du plomb estuarien, de la mine au produit fini. - Le plomb dans les pratiques funéraires calètes et véliocasses. À la suite de ces échanges et au regard des premières données rassemblées au cours de l'année probatoire 2020, une réflexion collective a été menée afin de planifier les poursuites de la recherche sur les productions manufacturées en plomb d’époque romaine dans l’estuaire de la Seine. Un programme de recherche triennale a donc débuté en 2021, afin d’étendre la réflexion initiée dans le cadre des axes de recherche du PCR : les différentes enquêtes portant sur la composition et la provenance du métal, tout comme l’étude de la diffusion des contenants en plomb vers et au sein de la région d’étude, ainsi que leur vocation funéraire ne font, en effet, que débuter. Le présent rapport correspond à un bilan des activités de recherches au cours de l’année 2022, deuxième année de la campagne de recherche triennale