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      Sepsis therapies: learning from 30 years of failure of translational research to propose new leads

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          Abstract

          Sepsis has been identified by the World Health Organization ( WHO) as a global health priority. There has been a tremendous effort to decipher underlying mechanisms responsible for organ failure and death, and to develop new treatments. Despite saving thousands of animals over the last three decades in multiple preclinical studies, no new effective drug has emerged that has clearly improved patient outcomes. In the present review, we analyze the reasons for this failure, focusing on the inclusion of inappropriate patients and the use of irrelevant animal models. We advocate against repeating the same mistakes and propose changes to the research paradigm. We discuss the long‐term consequences of surviving sepsis and, finally, list some putative approaches—both old and new—that could help save lives and improve survivorship.

          Abstract

          This review recapitulates our knowledge on sepsis and its long‐term consequences, the lack of therapeutic advances in the last decades, and proposes new approaches to improve sepsis survival.

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          Most cited references306

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          The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).

          Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.
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            Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study

            Summary Background Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection. It is considered a major cause of health loss, but data for the global burden of sepsis are limited. As a syndrome caused by underlying infection, sepsis is not part of standard Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimates. Accurate estimates are important to inform and monitor health policy interventions, allocation of resources, and clinical treatment initiatives. We estimated the global, regional, and national incidence of sepsis and mortality from this disorder using data from GBD 2017. Methods We used multiple cause-of-death data from 109 million individual death records to calculate mortality related to sepsis among each of the 282 underlying causes of death in GBD 2017. The percentage of sepsis-related deaths by underlying GBD cause in each location worldwide was modelled using mixed-effects linear regression. Sepsis-related mortality for each age group, sex, location, GBD cause, and year (1990–2017) was estimated by applying modelled cause-specific fractions to GBD 2017 cause-of-death estimates. We used data for 8·7 million individual hospital records to calculate in-hospital sepsis-associated case-fatality, stratified by underlying GBD cause. In-hospital sepsis-associated case-fatality was modelled for each location using linear regression, and sepsis incidence was estimated by applying modelled case-fatality to sepsis-related mortality estimates. Findings In 2017, an estimated 48·9 million (95% uncertainty interval [UI] 38·9–62·9) incident cases of sepsis were recorded worldwide and 11·0 million (10·1–12·0) sepsis-related deaths were reported, representing 19·7% (18·2–21·4) of all global deaths. Age-standardised sepsis incidence fell by 37·0% (95% UI 11·8–54·5) and mortality decreased by 52·8% (47·7–57·5) from 1990 to 2017. Sepsis incidence and mortality varied substantially across regions, with the highest burden in sub-Saharan Africa, Oceania, south Asia, east Asia, and southeast Asia. Interpretation Despite declining age-standardised incidence and mortality, sepsis remains a major cause of health loss worldwide and has an especially high health-related burden in sub-Saharan Africa. Funding The Bill & Melinda Gates Foundation, the National Institutes of Health, the University of Pittsburgh, the British Columbia Children's Hospital Foundation, the Wellcome Trust, and the Fleming Fund.
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              Current understanding of the human microbiome

              Our understanding of the link between the human microbiome and disease, including obesity, inflammatory bowel disease, arthritis and autism, is rapidly expanding. Improvements in the throughput and accuracy of DNA sequencing of the genomes of microbial communities associated with human samples, complemented by analysis of transcriptomes, proteomes, metabolomes and immunomes, and mechanistic experiments in model systems, have vastly improved our ability to understand the structure and function of the microbiome in both diseased and healthy states. However, many challenges remain. In this Review, we focus on studies in humans to describe these challenges, and propose strategies that leverage existing knowledge to move rapidly from correlation to causation, and ultimately to translation.
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                Author and article information

                Contributors
                jean-marc.cavaillon@pasteur.fr
                Journal
                EMBO Mol Med
                EMBO Mol Med
                10.1002/(ISSN)1757-4684
                EMMM
                embomm
                EMBO Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1757-4676
                1757-4684
                16 March 2020
                07 April 2020
                : 12
                : 4 ( doiID: 10.1002/emmm.v12.4 )
                : e10128
                Affiliations
                [ 1 ] Experimental Neuropathology Unit Institut Pasteur Paris France
                [ 2 ] Bloomsbury Institute of Intensive Care Medicine University College London London UK
                [ 3 ] Laboratory of Flow Cytometry and Department of Anesthesiology and Intensive Care Medicine Centre of Postgraduate Medical Education Warsaw Poland
                Author notes
                [*] [* ]Corresponding author. Tel: +337 89 57 09 14; E‐mail: jean-marc.cavaillon@ 123456pasteur.fr
                Author information
                https://orcid.org/0000-0001-7721-2106
                https://orcid.org/0000-0001-6233-7758
                Article
                EMMM201810128
                10.15252/emmm.201810128
                7136965
                32176432
                fe332d7d-3874-495e-8742-09cc9da570ed
                © 2020 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 26 November 2018
                : 12 February 2020
                : 17 February 2020
                Page count
                Figures: 6, Tables: 3, Pages: 24, Words: 21713
                Funding
                Funded by: Polish National Science Center
                Award ID: 2013/11/N/NZ6/02581
                Award ID: UMO‐2016/23/D/NZ6/02554
                Funded by: Institut Pasteur , open-funder-registry 10.13039/501100003762;
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                07 April 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.9 mode:remove_FC converted:07.04.2020

                Molecular medicine
                animal models,cytokine storm,personalized medicine,reprogramming,sepsis,immunology,microbiology, virology & host pathogen interaction,molecular biology of disease

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