Head and thorax elevation prevents the rise of intracranial pressure during extracorporeal resuscitation in swine

Aim: Head and thorax elevation during cardiopulmonary resuscitation improves cerebral hemodynamics and ultimate neurological outcome after cardiac arrest. Its effect during extracorporeal cardiopulmonary resuscitation (E-CPR) is unknown. We tested whether this procedure could improve hemodynamics in swine treated by E-CPR. Methods and Results: Pigs were anesthetized and submitted to 15 minutes of untreated ventricular fibrillation followed by E-CPR. Animals randomly remained in flat position (flat group) or underwent head and thorax elevation since E-CPR institution (head-up group). Electric shocks were delivered after 30 minutes until the return of spontaneous circulation (ROSC). They were followed during 120 minutes after ROSC. After 30 minutes of E-CPR, ROSC was achieved in all animals, with no difference regarding blood pressure, heart rate, and extracorporeal membrane of oxygenation flow among groups. The head-up group had an attenuated increase in ICP as compared with the flat group after cardiac arrest (13 ± 1 vs. 26 ± 2 mm Hg at the end of the follow-up, respectively). Cerebral perfusion pressure tended to be higher in the head-up versus flat group despite not achieving statistical difference (66 ± 1 vs 46 ± 1 mm Hg at the end of the follow-up). Carotid blood flow and cerebral oxygen saturation were not significantly different among groups. Conclusion: During E-CPR, head and thorax elevation prevents ICP increase. Whether it could improve the ultimate neurological outcome in this situation deserves further investigation.The study was supported by grants LIVE-RESP and AREG-SHOCK from Agence Nationale pour la Recherche. Y. Levy was supported by ADEREMVeterinari

a planned ancillary analysis of the coVAPid cohort

Funding: This study was supported in part by a grant from the French government through the «Programme Investissement d’Avenir» (I-SITE ULNE) managed by the Agence Nationale de la Recherche (coVAPid project). The funders of the study had no role in the study design, data collection, analysis, or interpreta tion, writing of the report, or decision to submit for publication.BACKGROUND: Patients with SARS-CoV-2 infection are at higher risk for ventilator-associated pneumonia (VAP). No study has evaluated the relationship between VAP and mortality in this population, or compared this relationship between SARS-CoV-2 patients and other populations. The main objective of our study was to determine the relationship between VAP and mortality in SARS-CoV-2 patients. METHODS: Planned ancillary analysis of a multicenter retrospective European cohort. VAP was diagnosed using clinical, radiological and quantitative microbiological criteria. Univariable and multivariable marginal Cox's regression models, with cause-specific hazard for duration of mechanical ventilation and ICU stay, were used to compare outcomes between study groups. Extubation, and ICU discharge alive were considered as events of interest, and mortality as competing event. FINDINGS: Of 1576 included patients, 568 were SARS-CoV-2 pneumonia, 482 influenza pneumonia, and 526 no evidence of viral infection at ICU admission. VAP was associated with significantly higher risk for 28-day mortality in SARS-CoV-2 (adjusted HR 1.70 (95% CI 1.16-2.47), p = 0.006), and influenza groups (1.75 (1.03-3.02), p = 0.045), but not in the no viral infection group (1.07 (0.64-1.78), p = 0.79). VAP was associated with significantly longer duration of mechanical ventilation in the SARS-CoV-2 group, but not in the influenza or no viral infection groups. VAP was associated with significantly longer duration of ICU stay in the 3 study groups. No significant difference was found in heterogeneity of outcomes related to VAP between the 3 groups, suggesting that the impact of VAP on mortality was not different between study groups. INTERPRETATION: VAP was associated with significantly increased 28-day mortality rate in SARS-CoV-2 patients. However, SARS-CoV-2 pneumonia, as compared to influenza pneumonia or no viral infection, did not significantly modify the relationship between VAP and 28-day mortality. CLINICAL TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov, number NCT04359693.publishersversionpublishe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

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/)

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Dysfonctions neurovasculaires et mitochondriales dans un modèle néonatal d'ischémie cérébrale focale

We evaluated Ciclosporine A effect on brain lesions, and afterwards we explored the mitochondrial metabolism. We have studied the ischemic postconditioning neuroprotective effects and the hemodynamic consequences of the reperfusion. We have shown the mitochondrial permeability transition pore was opened during neonatal ischemia. Ciclosporine A increased calcium reuptake into mitochondria, but also improved the mitochondrial respiration. Ciclosporine A limited the inflammatory processes during ischemia. However, CsA did not reduce the volume of brain lesions. In conclusion, we have shown that Cyclophiline D and the mPTP pore were two major elements in neonatal cerebral ischemia. We have also explored the ischemic postconditioning neuroprotective effects. We did not show a decrease in brain lesions. Nevertheless, we have demonstrated that reperfusion was different in neonatal and adult models, because of a gradual and slow reperfusion in the early reperfusion phase, instead of hyperemia. We have highlighted that the reperfusion had the same kinetic profile in both hemispheres, concerning superficial cortical perfusion and deep cerebral perfusion. We concluded that cerebral vasoconstriction was the sign of the cerebral microcirculation dysfunction. The microcirculation was altered in neonatal cerebral ischemia but differently than in adult models. The early collateral recruitment could explain these differencesNos travaux de recherche menés dans l'ischémie cérébrale néonatale ont évalué l'effet de la Ciclosporine A sur la réduction du volume lésionnel, mais aussi sur le fonctionnement du métabolisme mitochondrial. Nous avons également étudié l'effet du postconditionnement ischémique et les conséquences hémodynamiques de la reperfusion. Le pore de perméabilité membranaire mPTP s'ouvre au cours de l'ischémie néonatale. La CsA, inhibiteur de la Cyclophiline D freine l'ouverture du pore mPTP, améliore la capacité de recapture du calcium par la mitochondrie, la respiration mitochondriale, et limite les effets inflammatoires de l'ischémie. Néanmoins, la CsA ne réduit pas le volume des lésions cérébrales. Nous avons pu montrer que la Cyclophiline D et le pore mPTP étaient bien deux acteurs majeurs dans la constitution des lésions induites par la reperfusion dans l'ischémie cérébrale focale néonatale. Le postconditionnement ischémique ne permet pas de réduire les volumes des lésions. Nous avons montré que la reperfusion chez le jeune était progressive et lente, sans hyperhémie comme chez l'adulte. Cette cinétique de reperfusion est identique dans les deux hémisphères, tant pour la perfusion tissulaire corticale que pour la perfusion des régions cérébrales profondes. La vasoconstriction cérébrale chez le jeune traduit le recrutement précoce de la circulation collatérale mais aussi les dysfonctionnements de la microcirculation cérébrale. Au final, ces résultats ouvrent la voie à de nouvelles stratégies thérapeutiques spécifiques au profil particulier de la reperfusion dans le cerveau immatur

Spectres phénotypiques des dysgénésies corticales liées aux mutations des gènes DCX et LIS1

Les lissencéphalies sont des dysgénésies corticales liées à deux gènes principaux : le gène LIS1 et le gène DCX Le gène LIS1 est responsable de lissencéphalies de sévérité radiologique variable, de la pachygyrie à l agyrie diffuse dans les cas les plus graves (ILS 17). Le gène DCX donne classiquement chez la fille des hétérotopies laminaires sous-corticales (HSB) et chez les garçons une agyrie-pachygyrie. La protéine dcx comporte deux domaines majeurs (ndc et cdc). Les objectifs de cette étude sont de préciser les spectres phénotypiques cliniques et radiologiques des patients présentant une mutation du gène DCX (selon le sexe) ou du gène LIS1, puis de rechercher l existence de corrélations avec les génotypes selon le type mutation et la localisation des mutations. Nous avons réalisé une étude rétrospective multicentrique sur une cohorte comportant 81 patients DCX (57 filles et 24 garçons) et 29 patients LIS1. Chez les patientes HSB/DCX, l épilepsie débute vers l âge de 6 ans et demi principalement par des crises tonico-cloniques généralisées ou des crises partielles. Les épilepsies pharmacorésistantes représentent 16% des cas. Le retard mental est souvent modéré (62% des cas) sans déficit moteur associé (81% des cas) Nous n avons pas mis en évidence chez les patientes DCX de corrélation entre les phénotypes cliniques ou radiologiques et les mutations. En revanche, de manière originale, nous avons montré une corrélation avec les anomalies calleuses Les patients LIS1 (ILS 17) présentent des phénotypes cliniques et radiologiques plus sévères que les patient DCX (ILSX): l épilepsie débute précocement (7mois vs 5ans) par des spasmes (40%) et est fortement pharmacorésistante (63% vs 26%), le retard mental est sévère (86% vs 67%), ainsi que les déficits moteurs (67% vs 38%) Nous avons montré que chez les patients ILSX, la localisation des mutations dans la région ndc pourrait être corrélée à des phénotypes sévères. Par contre, chez les patients ILS17, le type et la localisation des mutations ne semblent pas corrélés à la sévérité de la maladie.PARIS13-BU Serge Lebovici (930082101) / SudocSudocFranceF

Dysfonctions neurovasculaires et mitochondriales dans un modèle néonatal d'ischémie cérébrale focale

Nos travaux de recherche menés dans l ischémie cérébrale néonatale ont évalué l effet de la Ciclosporine A sur la réduction du volume lésionnel, mais aussi sur le fonctionnement du métabolisme mitochondrial. Nous avons également étudié l effet du postconditionnement ischémique et les conséquences hémodynamiques de la reperfusion. Le pore de perméabilité membranaire mPTP s ouvre au cours de l ischémie néonatale. La CsA, inhibiteur de la Cyclophiline D freine l ouverture du pore mPTP, améliore la capacité de recapture du calcium par la mitochondrie, la respiration mitochondriale, et limite les effets inflammatoires de l ischémie. Néanmoins, la CsA ne réduit pas le volume des lésions cérébrales. Nous avons pu montrer que la Cyclophiline D et le pore mPTP étaient bien deux acteurs majeurs dans la constitution des lésions induites par la reperfusion dans l ischémie cérébrale focale néonatale. Le postconditionnement ischémique ne permet pas de réduire les volumes des lésions. Nous avons montré que la reperfusion chez le jeune était progressive et lente, sans hyperhémie comme chez l adulte. Cette cinétique de reperfusion est identique dans les deux hémisphères, tant pour la perfusion tissulaire corticale que pour la perfusion des régions cérébrales profondes. La vasoconstriction cérébrale chez le jeune traduit le recrutement précoce de la circulation collatérale mais aussi les dysfonctionnements de la microcirculation cérébrale. Au final, ces résultats ouvrent la voie à de nouvelles stratégies thérapeutiques spécifiques au profil particulier de la reperfusion dans le cerveau immatureWe evaluated Ciclosporine A effect on brain lesions, and afterwards we explored the mitochondrial metabolism. We have studied the ischemic postconditioning neuroprotective effects and the hemodynamic consequences of the reperfusion. We have shown the mitochondrial permeability transition pore was opened during neonatal ischemia. Ciclosporine A increased calcium reuptake into mitochondria, but also improved the mitochondrial respiration. Ciclosporine A limited the inflammatory processes during ischemia. However, CsA did not reduce the volume of brain lesions. In conclusion, we have shown that Cyclophiline D and the mPTP pore were two major elements in neonatal cerebral ischemia. We have also explored the ischemic postconditioning neuroprotective effects. We did not show a decrease in brain lesions. Nevertheless, we have demonstrated that reperfusion was different in neonatal and adult models, because of a gradual and slow reperfusion in the early reperfusion phase, instead of hyperemia. We have highlighted that the reperfusion had the same kinetic profile in both hemispheres, concerning superficial cortical perfusion and deep cerebral perfusion. We concluded that cerebral vasoconstriction was the sign of the cerebral microcirculation dysfunction. The microcirculation was altered in neonatal cerebral ischemia but differently than in adult models. The early collateral recruitment could explain these differencesPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF