Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths

Publisher Copyright: © 2021 The Authors, some rights reserved.Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-alpha and/or IFN-omega are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-alpha and/or IFN-omega (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-beta. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-alpha and/or IFN-omega are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-beta do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases.Peer reviewe

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 risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

SignificanceThere is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged 4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute; The Rockefeller University; the St. Giles Foundation; the NIH (Grants R01AI088364 and R01AI163029); the National Center for Advancing Translational Sciences; NIH Clinical and Translational Science Awards program (Grant UL1 TR001866); a Fast Grant from Emergent Ventures; Mercatus Center at George Mason University; the Yale Center for Mendelian Genomics and the Genome Sequencing Program Coordinating Center funded by the National Human Genome Research Institute (Grants UM1HG006504 and U24HG008956); the Yale High Performance Computing Center (Grant S10OD018521); the Fisher Center for Alzheimer’s Research Foundation; the Meyer Foundation; the JPB Foundation; the French National Research Agency (ANR) under the “Investments for the Future” program (Grant ANR-10-IAHU-01); the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (Grant ANR-10-LABX-62-IBEID); the French Foundation for Medical Research (FRM) (Grant EQU201903007798); the French Agency for Research on AIDS and Viral hepatitis (ANRS) Nord-Sud (Grant ANRS-COV05); the ANR GENVIR (Grant ANR-20-CE93-003), AABIFNCOV (Grant ANR-20-CO11-0001), CNSVIRGEN (Grant ANR-19-CE15-0009-01), and GenMIS-C (Grant ANR-21-COVR-0039) projects; the Square Foundation; Grandir–Fonds de solidarité pour l’Enfance; the Fondation du Souffle; the SCOR Corporate Foundation for Science; The French Ministry of Higher Education, Research, and Innovation (Grant MESRI-COVID-19); Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM; and the University Paris Cité. P. Bastard was supported by the FRM (Award EA20170638020). P. Bastard., J.R., and T.L.V. were supported by the MD-PhD program of the Imagine Institute (with the support of Fondation Bettencourt Schueller). Work at the Neurometabolic Disease lab received funding from Centre for Biomedical Research on Rare Diseases (CIBERER) (Grant ACCI20-767) and the European Union's Horizon 2020 research and innovation program under grant agreement 824110 (EASI Genomics). Work in the Laboratory of Virology and Infectious Disease was supported by the NIH (Grants P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1), a George Mason University Fast Grant, and the G. Harold and Leila Y. Mathers Charitable Foundation. The Infanta Leonor University Hospital supported the research of the Department of Internal Medicine and Allergology. The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (Grant PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (Grant RECOVER WP 6). This work was also partly supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research, NIH (Grants ZIA AI001270 to L.D.N. and 1ZIAAI001265 to H.C.S.). This program is supported by the Agence Nationale de la Recherche (Grant ANR-10-LABX-69-01). K.K.’s group was supported by the Estonian Research Council, through Grants PRG117 and PRG377. R.H. was supported by an Al Jalila Foundation Seed Grant (Grant AJF202019), Dubai, United Arab Emirates, and a COVID-19 research grant (Grant CoV19-0307) from the University of Sharjah, United Arab Emirates. S.G.T. is supported by Investigator and Program Grants awarded by the National Health and Medical Research Council of Australia and a University of New South Wales COVID Rapid Response Initiative Grant. L.I. reports funding from Regione Lombardia, Italy (project “Risposta immune in pazienti con COVID-19 e co-morbidità”). This research was partially supported by the Instituto de Salud Carlos III (Grant COV20/0968). J.R.H. reports funding from Biomedical Advanced Research and Development Authority (Grant HHSO10201600031C). S.O. reports funding from Research Program on Emerging and Re-emerging Infectious Diseases from Japan Agency for Medical Research and Development (Grant JP20fk0108531). G.G. was supported by the ANR Flash COVID-19 program and SARS-CoV-2 Program of the Faculty of Medicine from Sorbonne University iCOVID programs. The 3C Study was conducted under a partnership agreement between INSERM, Victor Segalen Bordeaux 2 University, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also supported by the Caisse Nationale d’Assurance Maladie des Travailleurs Salariés, Direction générale de la Santé, Mutuelle Générale de l’Education Nationale, Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–INSERM Program “Cohortes et collections de données biologiques.” S. Debette was supported by the University of Bordeaux Initiative of Excellence. P.K.G. reports funding from the National Cancer Institute, NIH, under Contract 75N91019D00024, Task Order 75N91021F00001. J.W. is supported by a Research Foundation - Flanders (FWO) Fundamental Clinical Mandate (Grant 1833317N). Sample processing at IrsiCaixa was possible thanks to the crowdfunding initiative YoMeCorono. Work at Vall d’Hebron was also partly supported by research funding from Instituto de Salud Carlos III Grant PI17/00660 cofinanced by the European Regional Development Fund (ERDF/FEDER). C.R.-G. and colleagues from the Canarian Health System Sequencing Hub were supported by the Instituto de Salud Carlos III (Grants COV20_01333 and COV20_01334), the Spanish Ministry for Science and Innovation (RTC-2017-6471-1; AEI/FEDER, European Union), Fundación DISA (Grants OA18/017 and OA20/024), and Cabildo Insular de Tenerife (Grants CGIEU0000219140 and “Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19”). T.H.M. was supported by grants from the Novo Nordisk Foundation (Grants NNF20OC0064890 and NNF21OC0067157). C.M.B. is supported by a Michael Smith Foundation for Health Research Health Professional-Investigator Award. P.Q.H. and L. Hammarström were funded by the European Union’s Horizon 2020 research and innovation program (Antibody Therapy Against Coronavirus consortium, Grant 101003650). Work at Y.-L.L.’s laboratory in the University of Hong Kong (HKU) was supported by the Society for the Relief of Disabled Children. MBBS/PhD study of D.L. in HKU was supported by the Croucher Foundation. J.L.F. was supported in part by the Evaluation-Orientation de la Coopération Scientifique (ECOS) Nord - Coopération Scientifique France-Colombie (ECOS-Nord/Columbian Administrative department of Science, Technology and Innovation [COLCIENCIAS]/Colombian Ministry of National Education [MEN]/Colombian Institute of Educational Credit and Technical Studies Abroad [ICETEX, Grant 806-2018] and Colciencias Contract 713-2016 [Code 111574455633]). A. Klocperk was, in part, supported by Grants NU20-05-00282 and NV18-05-00162 issued by the Czech Health Research Council and Ministry of Health, Czech Republic. L.P. was funded by Program Project COVID-19 OSR-UniSR and Ministero della Salute (Grant COVID-2020-12371617). I.M. is a Senior Clinical Investigator at the Research Foundation–Flanders and is supported by the CSL Behring Chair of Primary Immunodeficiencies (PID); by the Katholieke Universiteit Leuven C1 Grant C16/18/007; by a Flanders Institute for Biotechnology-Grand Challenges - PID grant; by the FWO Grants G0C8517N, G0B5120N, and G0E8420N; and by the Jeffrey Modell Foundation. I.M. has received funding under the European Union’s Horizon 2020 research and innovation program (Grant Agreement 948959). E.A. received funding from the Hellenic Foundation for Research and Innovation (Grant INTERFLU 1574). M. Vidigal received funding from the São Paulo Research Foundation (Grant 2020/09702-1) and JBS SA (Grant 69004). The NH-COVAIR study group consortium was supported by a grant from the Meath Foundation.Peer reviewe

Accidents de la voie publique (incidence des traumatisés graves, pertinence des examens complémentaires)

Introduction : Les AVP représentent un problème de santé publique majeur et sont la 1ere cause de décès chez les moins de 40 ans. Cette étude a pour but de déterminer l'incidence des patients traumatisés graves adressés au SU dans les suites d'un AVP ainsi que d'évaluer la pertinence des examens complémentaires réalisés. Matériel et méthode : étude prospective, monocentrique, réalisée au SU de Nantes du 1er janvier 2012 au 1er avril 2012. Résultats : 337 patients ont été inclus soit une incidence de 37.24 pour 1000 passages aux urgences traumatologiques. 124 patients ont été conscidérés comme traumatisés graves d'après les critères de VITTEL, soit une incidence de 367.9 pour 1000 patients admis au SU pour AVP. 77,4% des traumatisés graves ont bénéficié de radiographies, 16,1% d'une échographie et 21,8% de TDM. Les délais entre l'admission du traumatisé grave et son examen clinique sont en moyenne de 66,7minutes. Les délais entre la demande et l'obtention des résultats des TDM étaient en moyenne de 309 min. Conclusion : L'incidence des traumatisés graves est importante. Une meilleure évaluation de la gravité des patients et une réduction des délais de prise en charge seraient nécessaires pour diminuer la morbi-mortalité traumatique. Des améliorations multidisciplinaires pourraient être envisagées afin d'optimiser la prise en charge de ces patients notamment en prévision de l'ouverture prochaine d'une SAUV au SU de Nantes.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

The need for agronomic indicators to monitor and assess action and to enhance learning loops during cropping system redesign process

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How “fundamental knowledge” supports the cropping system redesign by farmers?

Re-designing cropping systems to move towards agroecology leads farmers to implement practices which involve biological processes, sometimes qualified as “knowledge-intensive”, as they involve the renewal of agronomic principles and numerous interactions between the systems’ components and their regulations. Agronomists have developed an abundance of models, which encapsulate partial knowledge on systems’ functioning, but these appear to be seldom used by farmers. By contrast, several studies recognize the value of exchanging specific and fundamental knowledge with farmers in relation to technical change processes. This paper discusses how fundamental and generic knowledge acquires an agronomic sense and is reinvested in the action of farmers through their technical changes. We performed an inductive case study of step-by-step cropping system re-design situations. We combined individual interviews with farmers re-designing their cropping-system, and facilitated farmers meeting about a shared technical problem. From full transcripts, we identified each new element of knowledge and its reformulation, its relation to action mentioned by farmers. The focus of our analysis concerns the knowledge which made possible to develop action strategies when farmers were facing hindrances in continuing their technical changes. Our findings concern the specific fundamental knowledge actually mobilized, and the processes of its linkage with action through contextualization. We conclude by suggesting that farmers alternate between systematic and systemic thinking about the biological processes at play in their own situation. This has practical implications for agronomists wishing to support such re-design processes, and provides an insight on how farmers’ experiments might be combined to fundamental scientific knowledge on agroecosystems components to enhance cropping system redesign

How “fundamental knowledge” supports the cropping system redesign by farmers?

Re-designing cropping systems to move towards agroecology leads farmers to implement practices which involve biological processes, sometimes qualified as “knowledge-intensive”, as they involve the renewal of agronomic principles and numerous interactions between the systems’ components and their regulations. Agronomists have developed an abundance of models, which encapsulate partial knowledge on systems’ functioning, but these appear to be seldom used by farmers. By contrast, several studies recognize the value of exchanging specific and fundamental knowledge with farmers in relation to technical change processes. This paper discusses how fundamental and generic knowledge acquires an agronomic sense and is reinvested in the action of farmers through their technical changes. We performed an inductive case study of step-by-step cropping system re-design situations. We combined individual interviews with farmers re-designing their cropping-system, and facilitated farmers meeting about a shared technical problem. From full transcripts, we identified each new element of knowledge and its reformulation, its relation to action mentioned by farmers. The focus of our analysis concerns the knowledge which made possible to develop action strategies when farmers were facing hindrances in continuing their technical changes. Our findings concern the specific fundamental knowledge actually mobilized, and the processes of its linkage with action through contextualization. We conclude by suggesting that farmers alternate between systematic and systemic thinking about the biological processes at play in their own situation. This has practical implications for agronomists wishing to support such re-design processes, and provides an insight on how farmers’ experiments might be combined to fundamental scientific knowledge on agroecosystems components to enhance cropping system redesign

Transition towards low-input cropping systems: characterization of actionable knowledge for technical change

In the context of a current need for cropping systems adapted to new economic, social and environmental requirements, some agronomists have focused their research and advice activities on the re-design of cropping systems. Such adaptation requires firstly new knowledge on biological and ecological mechanisms supporting cropping systems less dependent on synthetic inputs, and secondly, tools (models, methods, participatory processes in which farmers have an active participation) for their design and evaluation. However, the new knowledge and tools proposed until now mainly address a de novo design of completely described cropping systems. Thus, questions remain concerning how farmers may benefit from these resources in order to undertake progressive technical changes in their own cropping systems, without necessarily having a clear description of one specifically targeted cropping system. This led us to study the way farmers engaged in such technical changes are managing the available knowledge in the design of their action. To this end, different characteristics of knowledge were analyzed, and used to describe the forms of knowledge mobilized or not by farmers. We proceeded with different types of interaction between farmers and agronomists to bring out the relevant characteristics: we surveyed farmers re-designing their cropping system and advisors helping them in this action, we organized meetings with farmers, supported with a set of information materials previously characterized. Axes of description of knowledge characteristics include forms of quantification, ways in which different time scales are addressed, ways in which it refers to uncertainty and risks, ways it refers to agronomic situations, and to onfield action. Knowledge characteristics were studied with the aim to understand how they influence legitimation and validation for action, and how they allow them to act in their particular situation, which will need further research. With a better understanding of what can be actionable knowledge, we finally aim at making proposals for adapting the knowledge produced to support technical changes

L’activité de re-conception d’un système de culture par l’agriculteur : implications pour la production de connaissances en agronomie

La re-conception des systèmes de culture, souvent considérée comme nécessaire à la transition agroécologique, est l’enjeu de nombreuses recherches en agronomie. Ces recherches portent souvent sur la formulation de systèmes cibles, sur les outils et méthodes de conception, et plus rarement sur la re-conception « en train de se faire » vue comme la transformation par l’agriculteur de son activité. Dans cet article, nous présentons les apports d’une analyse basée sur des entretiens et ateliers avec des agriculteurs et des agronomes, qui vise à comprendre les productions, circulations, et mobilisations de connaissances par ces acteurs. Nous insistons d’abord sur l’évolution des connaissances mobilisées tout au long du changement. Nous approfondissons ensuite le lien entre cette dynamique du changement, les indicateurs utilisés par les agriculteurs et les connaissances fondamentales sur les objets biologiques.The re-design of cropping systems is often seen as a promising form of evolution of these systems for an agroecological transition, and has become the issue of numerous research in Agronomy. These research focuses mainly on the development of possible and satisfactory systems regarding some expected performances, as well as on tools and methods of design and co-design with diverse stakeholders. Less frequent are the studies that analyze what means the re-design as an ongoing process, as a transformation by the farmer of his own activity. In this article, we present contributions from an analysis of these changes in practices, based on interviews and several workshops with farmers and agronomists that accompany them. This analysis aimed in particular at understanding the knowledge generations, circulations, and mobilizations by these actors. We insist on the evolution of knowledge mobilized throughout the change of practice, from which we propose to identify three phases corresponding to specific forms of legitimation of knowledge and specific assessment of the ongoing change by the farmer. Then, we deepen, discussing the implications for agricultural research and development, the link between this dynamic of change and, on the one hand, the indicators used by farmers, whose learning functions are highlighted, and on the other hand, the basic knowledge on biological objects, whose function in building new action strategies is describe