Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders

The Rho-guanine nucleotide exchange factor (RhoGEF) TRIO acts as a key regulator of neuronal migration, axonal outgrowth, axon guidance, and synaptogenesis by activating the GTPase RAC1 and modulating actin cytoskeleton remodeling. Pathogenic variants in TRIO are associated with neurodevelopmental diseases, including intellectual disability (ID) and autism spectrum disorders (ASD). Here, we report the largest international cohort of 24 individuals with confirmed pathogenic missense or nonsense variants in TRIO. The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1. Although all individuals in this cohort present with developmental delay and a neuro-behavioral phenotype, individuals with a pathogenic variant in the seventh spectrin repeat have a more severe ID associated with macrocephaly than do most individuals with GEFD1 variants, who display milder ID and microcephaly. Functional studies show that the spectrin and GEFD1 variants cause a TRIO-mediated hyper- or hypo-activation of RAC1, respectively, and we observe a striking correlation between RAC1 activation levels and the head size of the affected individuals. In addition, truncations in TRIO GEFD1 in the vertebrate model X. tropicalis induce defects that are concordant with the human phenotype. This work demonstrates distinct clinical and molecular disorders clustering in the GEFD1 and seventh spectrin repeat domains and highlights the importance of tight control of TRIO-RAC1 signaling in neuronal development.<br/

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/)

Soins de soutien en néonatologie: effets des facilitations,des positionnements et des manipulations sur ledéveloppement des prématurés

Introduction : Le taux d’enfants prématurés ne cesse d’augmenter et ces naissances précoces ne sont pas sans risques. Ces enfants, et surtout ceux nés avant la 32ème semaine de gestation ont un risque plus élevé de développer des séquelles neuro-développementales. La pratique la plus couramment utilisée dans nos hôpitaux pour y remédier, est celle des soins de soutien au développement. Cependant, ces techniques démontrent des effets controversés et l’objectif de notre revue de la littérature est d’identifier les effets d’un traitement incluant des facilitations, des positionnements et de manipulations, sur le développement moteur des enfants prématurés. Méthode : C’est par l’utilisation des moteurs de recherche tels que PubMed, PsycInfo, PEDro, CINAHL, Otseeker, Cochrane, et Web of Knowledge que nous avons trouvé les articles nécessaires à la réalisation de notre travail. Les articles inclus comprennent une population d’enfants prématurés et une intervention précoce de type Developmental handling ou Neuro-Developmental-Treatment. Résultats : Avec un total de 773 articles, quatre ont été retenus, comprenant deux études de cohorte ainsi que deux études randomisées contrôlées. Trois d’entre elles ont démontré des effets significatifs sur le niveau d’organisation motrice, alors qu’une n’en présente pas. Conclusions : Les manipulations, positionnements et facilitations ont démontré des résultats significativement positifs à un court terme. Cependant, des observations similaires sur un plus long terme auraient été plus pertinentes. En effet, les suivis neurodéveloppementaux ont démontré une latence dans l’apparition des séquelles développementales.Einführung: Die Anzahl der Frühgeburten ist im konstanten Anstieg. Diese Frühgeburten sind aber nicht immer ohne nachteilige Auswirkungen. Diese Kinder, aber hauptsächlich die vor der 32. Schwangerschaftswoche Geborenen sind einem höheren Risiko ausgesetzt, neurologische Störung davonzutragen. Diese werden in unseren Krankenhäusern gebräuchlich durch eine Entwicklungsbehandlung versorgt. Verschiedene Studien zeigen jedoch umstrittene Wirkungen dieser Technik. Das Ziel unserer systematischen Revue ist die Identifizierung der Auswirkungen einer Behandlung, die Facilitation, Positionierungen und Manipulationen in der motorischen Entwicklung des Frühgeborenen einschließt. Methode: Mit Hilfe der Suchmaschinen wie PubMed, PsycInfo, PEDro, CINAHL, Otseeker, Cochrane, et Web of Knowledge, haben wir die nötigen Artikel und Berichte für die Realisierung unserer Arbeit gefunden. Die inklusiven Artikel beinhalten eine Anzahl Frühgeburten und ein frühzeitiges Eingreifen des Developmental handling oder Neuro-Developmental-Treatment. Ergebnisse: Von 773 Artikel wurden vier ausgewählt, davon zwei Kohortenstudien sowie zwei randomisierte kontrollierte Studien. Drei von diesen vier Studien zeigen signifikante Wirkungen, was die motorische Entwicklung betrifft, wogegen bei einer diese Wirkung ausbleibt. Abschluss: Die Manipulationen, die Positionierungen sowie die Facilitation haben kurzfristig signifikant positive Resultate gezeigt. Ähnliche aber langfristige Beobachtungen wären jedoch stichhaltiger gewesen. In der Tat zeigen Weiterverfolgungen, dass die Wachstumsstörungen der früheren Frühgeborenen oft latent sind und im Kleinkindalter beobachtet werden können

Etude théorique de processus radicalaires sur les glaces interstellaires

Aujourd hui le rôle potentiel de la chimie interstellaire dans l apparition des molécules du vivant est considéré attentivement. Synthèse et destruction des molécules organiques complexes dans l espace constituent un sujet brûlant, expérimentalement comme théoriquement. En particulier, pour ces molécules dont la formation en phase gaz dans les conditions usuelles du milieu interstellaire est difficile, tous s interrogent sur le rôle de la glace d eau, constituant solide omniprésent du milieu. Cette thèse traite du rôle multiple de la glace d eau, protecteur, catalyseur ou destructeur au travers des processus suivants : la formation du méthanol par hydrogénations radicalaires successives de CO à la surface d un grain interstellaire glacé, les déshydrogénations de la méthylamine, produit de fragmentation primaire de la glycine, et du méthanol par les radicaux OH issus de l irradiation cosmique de la glace. Les méthodes employées sont celles de la chimie théorique (ab initio, fonctionnelle de la densité). La glace est considérée soit en tant que surface modélisée par un cluster cristallin, soit en tant que volume modélisé avec un continuum polarisable. Le rôle de la glace apparaît complexe et antagoniste. Côté formation, l hydrogénation de CO est indéniablement facilitée par la présence de glace d eau mais très dépendante des conditions environnementales. Côté destruction, la glace impose une structure zwitterionique à la glycine dont l irradiation conduit à une fragmentation partielle (70%) en méthylamine et CO2. La méthylamine, comme le méthanol, est détruite dans une série de réactions exothermiques par les radicaux OH dont le rôle a jusqu ici été peu considéré.The role possibly played by interstellar chemistry in the emergence of the molecules of life is currently investigated with great attention. The synthesis and destruction of complexes organic molecules in space are a permanent challenge for both theory and experiments, especially for these molecules whose formation in the interstellar gas phase is highly questionable. Consequently, chemistry at the interface of dust and gas has now gained the status of a major actor in astrochemistry. This thesis deals with the multiple aspects under which water ice, ubiquitous in space, can act, namely as catalyst, molecular shield or destructive medium. The following processes have been considered: the formation of methanol by successive radical hydrogenations of CO on the surface of water ice, the destructions of methylamine, primary product of the glycine fragmentation, and methanol by the OH radicals created when the icy mantles of the grains are irradiated by the cosmic radiations. The methods used are those of theoretical chemistry (ab initio post Hartree-Fock and Density Functional Theory). The ice surface is modeled by a crystalline cluster and the water ice bulk by a polarizable continuum medium. The role of the ice is complex and antagonist. On the formation side, the CO hydrogenation is undeniably aided by the water ice presence but very dependent of the environment. On the destruction side, the ice forces a zwitterionic structure of glycine whose irradiation leads to a partial fragmentation (70%) into methylamine and CO2. Methylamine as well as methanol is destroyed, in a series of exothermic reactions by the OH radicals whose role has been little considered as of today.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Type 1 Diabetes in People Hospitalized for COVID-19: New Insights From the CORONADO Study

International audienc

The association between macrovascular complications and intensive care admission, invasive mechanical ventilation, and mortality in people with diabetes hospitalized for coronavirus disease-2019 (COVID-19)

International audienceAbstract Background It is not clear whether pre-existing macrovascular complications (ischemic heart disease, stroke or peripheral artery disease) are associated with health outcomes in people with diabetes mellitus hospitalized for COVID-19. Methods We conducted cohort studies of adults with pre-existing diabetes hospitalized for COVID-19 infection in the UK, France, and Spain during the early phase of the pandemic (between March 2020—October 2020). Logistic regression models adjusted for demographic factors and other comorbidities were used to determine associations between previous macrovascular disease and relevant clinical outcomes: mortality, intensive care unit (ICU) admission and use of invasive mechanical ventilation (IMV) during the hospitalization. Output from individual logistic regression models for each cohort was combined in a meta-analysis. Results Complete data were available for 4,106 (60.4%) individuals. Of these, 1,652 (40.2%) had any prior macrovascular disease of whom 28.5% of patients died. Mortality was higher for people with compared to those without previous macrovascular disease (37.7% vs 22.4%). The combined crude odds ratio (OR) for previous macrovascular disease and mortality for all four cohorts was 2.12 (95% CI 1.83–2.45 with an I 2 of 60%, reduced after adjustments for age, sex, type of diabetes, hypertension, microvascular disease, ethnicity, and BMI to adjusted OR 1.53 [95% CI 1.29–1.81]) for the three cohorts. Further analysis revealed that ischemic heart disease and cerebrovascular disease were the main contributors of adverse outcomes. However, proportions of people admitted to ICU (adjOR 0.48 [95% CI 0.31–0.75], I 2 60%) and the use of IMV during hospitalization (adjOR 0.52 [95% CI 0.40–0.68], I 2 37%) were significantly lower for people with previous macrovascular disease. Conclusions This large multinational study of people with diabetes mellitus hospitalized for COVID-19 demonstrates that previous macrovascular disease is associated with higher mortality and lower proportions admitted to ICU and treated with IMV during hospitalization suggesting selective admission criteria. Our findings highlight the importance correctly assess the prognosis and intensive monitoring in this high-risk group of patients and emphasize the need to design specific public health programs aimed to prevent SARS-CoV-2 infection in this subgroup

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

International audienc

Characteristics, management, and prognosis of elderly patients with COVID-19 admitted in the ICU during the first wave: insights from the COVID-ICU study

International audienceBackground: The COVID-19 pandemic is a heavy burden in terms of health care resources. Future decision-making policies require consistent data on the management and prognosis of the older patients (&gt; 70 years old) with COVID-19 admitted in the intensive care unit (ICU). Methods: Characteristics, management, and prognosis of critically ill old patients (&gt; 70 years) were extracted from the international prospective COVID-ICU database. A propensity score weighted-comparison evaluated the impact of intubation upon admission on Day-90 mortality. Results: The analysis included 1199 (28% of the COVID-ICU cohort) patients (median [interquartile] age 74 [72–78] years). Fifty-three percent, 31%, and 16% were 70–74, 75–79, and over 80 years old, respectively. The most frequent comorbidities were chronic hypertension (62%), diabetes (30%), and chronic respiratory disease (25%). Median Clinical Frailty Scale was 3 (2–3). Upon admission, the PaO2/FiO2 ratio was 154 (105–222). 740 (62%) patients were intubated on Day-1 and eventually 938 (78%) during their ICU stay. Overall Day-90 mortality was 46% and reached 67% among the 193 patients over 80 years old. Mortality was higher in older patients, diabetics, and those with a lower PaO2/FiO2 ratio upon admission, cardiovascular dysfunction, and a shorter time between first symptoms and ICU admission. In propensity analysis, early intubation at ICU admission was associated with a significantly higher Day-90 mortality (42% vs 28%; hazard ratio 1.68; 95% CI 1.24–2.27; p &lt; 0·001). Conclusion: Patients over 70 years old represented more than a quarter of the COVID-19 population admitted in the participating ICUs during the first wave. Day-90 mortality was 46%, with dismal outcomes reported for patients older than 80 years or those intubated upon ICU admission

Benefits and risks of noninvasive oxygenation strategy in COVID-19: a multicenter, prospective cohort study (COVID-ICU) in 137 hospitals

International audienceAbstract Rational To evaluate the respective impact of standard oxygen, high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) on oxygenation failure rate and mortality in COVID-19 patients admitted to intensive care units (ICUs). Methods Multicenter, prospective cohort study (COVID-ICU) in 137 hospitals in France, Belgium, and Switzerland. Demographic, clinical, respiratory support, oxygenation failure, and survival data were collected. Oxygenation failure was defined as either intubation or death in the ICU without intubation. Variables independently associated with oxygenation failure and Day-90 mortality were assessed using multivariate logistic regression. Results From February 25 to May 4, 2020, 4754 patients were admitted in ICU. Of these, 1491 patients were not intubated on the day of ICU admission and received standard oxygen therapy (51%), HFNC (38%), or NIV (11%) ( P < 0.001). Oxygenation failure occurred in 739 (50%) patients (678 intubation and 61 death). For standard oxygen, HFNC, and NIV, oxygenation failure rate was 49%, 48%, and 60% ( P < 0.001). By multivariate analysis, HFNC (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.36–0.99, P = 0.013) but not NIV (OR 1.57, 95% CI 0.78–3.21) was associated with a reduction in oxygenation failure). Overall 90-day mortality was 21%. By multivariable analysis, HFNC was not associated with a change in mortality (OR 0.90, 95% CI 0.61–1.33), while NIV was associated with increased mortality (OR 2.75, 95% CI 1.79–4.21, P < 0.001). Conclusion In patients with COVID-19, HFNC was associated with a reduction in oxygenation failure without improvement in 90-day mortality, whereas NIV was associated with a higher mortality in these patients. Randomized controlled trials are needed