{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T15:50:53Z","timestamp":1790437853752,"version":"4.1.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T00:00:00Z","timestamp":1642377600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011068","name":"Fondation Saint Luc","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011068","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Critical COVID-19, like septic shock, is related to a dysregulated systemic inflammatory reaction and is associated with a high incidence of thrombosis and microthrombosis. Improving the understanding of the underlying pathophysiology of critical COVID-19 could help in finding new therapeutic targets already explored in the treatment of septic shock. The current study prospectively compared 48 patients with septic shock and 22 patients with critical COVID-19 regarding their clinical characteristics and outcomes, as well as key plasmatic soluble biomarkers of inflammation, coagulation, endothelial activation, platelet activation, and NETosis. Forty-eight patients with matched age, gender, and co-morbidities were used as controls. Critical COVID-19 patients exhibited less organ failure but a prolonged ICU length-of-stay due to a prolonged respiratory failure. Inflammatory reaction of critical COVID-19 was distinguished by very high levels of interleukin (IL)-1\u03b2 and T lymphocyte activation (including IL-7 and CD40L), whereas septic shock displays higher levels of IL-6, IL-8, and a more significant elevation of myeloid response biomarkers, including Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) and IL-1ra. Subsequent inflammation-induced coagulopathy of COVID-19 also differed from sepsis-induced coagulopathy (SIC) and was characterized by a marked increase in soluble tissue factor (TF) but less platelets, antithrombin, and fibrinogen consumption, and less fibrinolysis alteration. In conclusion, COVID-19 inflammation-induced coagulopathy substantially differs from SIC. Modulating TF release and activity should be evaluated in critical COVID-19 patients.<\/jats:p>","DOI":"10.3389\/fmed.2021.780750","type":"journal-article","created":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T05:13:22Z","timestamp":1642396402000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Inflammation-Induced Coagulopathy Substantially Differs Between COVID-19 and Septic Shock: A Prospective Observational Study"],"prefix":"10.3389","volume":"8","author":[{"given":"M\u00e9lanie","family":"Dechamps","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"De Poortere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Gatto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lie","family":"Daumerie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Bouzin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Octave","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Ginion","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentine","family":"Robaux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Pirotton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Bodart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovic","family":"Gerard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Montiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Campion","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damien","family":"Gruson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Astrid","family":"Van Dievoet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Douxfils","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Haguet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure","family":"Morimont","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Derive","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Jolly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc","family":"Bertrand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure","family":"Dumoutier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Castanares-Zapatero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Fran\u00e7ois","family":"Laterre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Horman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Beauloye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2255","DOI":"10.1056\/NEJMra2026131","article-title":"Cytokine storm","volume":"383","author":"Fajgenbaum","year":"2020","journal-title":"N Engl J Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.thromres.2020.04.013","article-title":"Incidence of thrombotic complications in critically ill ICU patients with COVID-19","volume":"191","author":"Klok","year":"2020","journal-title":"Thromb Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1007\/s00134-020-06062-x","article-title":"High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study","volume":"46","author":"Helms","year":"2020","journal-title":"Intens Care Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1056\/NEJMoa2015432","article-title":"Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19","volume":"383","author":"Ackermann","year":"2020","journal-title":"N Engl J Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1016\/j.immuni.2020.05.002","article-title":"Immunology of COVID-19: current State of the Science","volume":"52","author":"Vabret","year":"2020","journal-title":"Immunity."},{"key":"B7","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1016\/j.ijid.2020.04.041","article-title":"Clinical value of immune-inflammatory parameters to assess the severity of coronavirus disease 2019","volume":"95","author":"Zhu","year":"2020","journal-title":"Int J Infect Dis."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1404","DOI":"10.1161\/CIRCRESAHA.120.317703","article-title":"Platelets can associate with SARS-Cov-2 RNA and are hyperactivated in COVID-19","volume":"127","author":"Zaid","year":"2020","journal-title":"Circ Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1016\/S0140-6736(20)30937-5","article-title":"Endothelial cell infection and endotheliitis in COVID-19","volume":"395","author":"Varga","year":"2020","journal-title":"Lancet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1609","DOI":"10.1161\/CIRCULATIONAHA.120.050354","article-title":"Severe COVID-19 is a microvascular disease","volume":"142","author":"Lowenstein","year":"2020","journal-title":"Circulation."},{"key":"B11","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1093\/infdis\/jiaa349","article-title":"Elevated expression of serum endothelial cell adhesion molecules in COVID-19 patients","volume":"222","author":"Tong","year":"2020","journal-title":"J Infect Dis."},{"key":"B12","doi-asserted-by":"publisher","first-page":"2215","DOI":"10.1111\/jth.15016","article-title":"Hypofibrinolytic state and high thrombin generation may play a major role in SARS-COV2 associated thrombosis","volume":"18","author":"Nougier","year":"2020","journal-title":"J Thromb Haemost."},{"key":"B13","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1182\/bloodadvances.2020003308","article-title":"Dissemination of extreme levels of extracellular vesicles: tissue factor activity in patients with severe COVID-19","volume":"5","author":"Guervilly","year":"2021","journal-title":"Blood Adv."},{"key":"B14","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1161\/CIRCULATIONAHA.120.048925","article-title":"Systemic inflammatory response syndrome is a major contributor to COVID-19-associated coagulopathy: insights from a prospective, single-center cohort study","volume":"142","author":"Masi","year":"2020","journal-title":"Circulation."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1760","DOI":"10.1161\/ATVBAHA.120.315595","article-title":"Vascular endothelial damage in the pathogenesis of organ injury in severe COVID-19","volume":"41","author":"Dupont","year":"2021","journal-title":"Arterioscler Thromb Vasc Biol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1580","DOI":"10.1038\/s41598-020-80010-z","article-title":"Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients","volume":"11","author":"Zuo","year":"2021","journal-title":"Sci Rep."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1055\/a-1347-5555","article-title":"Platelets are hyperactivated but show reduced glycoprotein VI reactivity in COVID-19 patients","author":"Leopold","year":"2021","journal-title":"Thromb Haemost."},{"key":"B18","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1038\/nri.2017.105","article-title":"Neutrophil extracellular traps in immunity and disease","volume":"18","author":"Papayannopoulos","year":"2018","journal-title":"Nat Rev Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1182\/blood.2020007008","article-title":"Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome","volume":"136","author":"Middleton","year":"2020","journal-title":"Blood."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1330","DOI":"10.1182\/blood.2020007252","article-title":"Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19","volume":"136","author":"Hottz","year":"2020","journal-title":"Blood."},{"key":"B21","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1097\/CCM.0000000000002255","article-title":"Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016","volume":"45","author":"Rhodes","year":"2017","journal-title":"Crit Care Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"16045","DOI":"10.1038\/nrdp.2016.45","article-title":"Sepsis and septic shock","volume":"2","author":"Hotchkiss","year":"2016","journal-title":"Nat Rev Dis Primers."},{"key":"B23","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1038\/nri3345","article-title":"Thrombosis as an intravascular effector of innate immunity","volume":"13","author":"Engelmann","year":"2013","journal-title":"Nat Rev Immunol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2033","DOI":"10.1182\/blood.2020006000","article-title":"COVID-19 and its implications for thrombosis and anticoagulation","volume":"135","author":"Connors","year":"2020","journal-title":"Blood."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1001\/jama.2020.17052","article-title":"Cytokine levels in critically ill patients with COVID-19 and other conditions","volume":"324","author":"Kox","year":"2020","journal-title":"JAMA."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.602848","article-title":"Parallels in sepsis and COVID-19 conditions: implications for managing severe COVID-19","author":"Olwal","year":"2021","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"2526","DOI":"10.1001\/jama.2012.5669","article-title":"Acute respiratory distress syndrome: the Berlin Definition","volume":"307","author":"Force","year":"2012","journal-title":"JAMA."},{"key":"B28","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA."},{"key":"B29","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1186\/s13613-019-0540-9","article-title":"Formal guidelines: management of acute respiratory distress syndrome","volume":"9","author":"Papazian","year":"2019","journal-title":"Ann Intensive Care."},{"key":"B30","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1097\/00003246-198510000-00009","article-title":"a severity of disease classification system","volume":"13","author":"Knaus","year":"1985","journal-title":"Crit Care Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1649","DOI":"10.1097\/CCM.0b013e31819def97","article-title":"The Sequential Organ Failure Assessment score for predicting outcome in patients with severe sepsis and evidence of hypoperfusion at the time of emergency department presentation","volume":"37","author":"Jones","year":"2009","journal-title":"Crit Care Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"e017046","DOI":"10.1136\/bmjopen-2017-017046","article-title":"New criteria for sepsis-induced coagulopathy (SIC) following the revised sepsis definition: a retrospective analysis of a nationwide survey","volume":"7","author":"Iba","year":"2017","journal-title":"BMJ Open."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1055\/s-0037-1616068","article-title":"Scientific Subcommittee on Disseminated Intravascular Coagulation of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation","volume":"86","author":"Taylor","year":"2001","journal-title":"Thromb Haemost."},{"key":"B34","doi-asserted-by":"publisher","first-page":"256","DOI":"10.7326\/0003-4819-115-4-256","article-title":"Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI), phase II trial","volume":"115","author":"Bovill","year":"1991","journal-title":"Ann Intern Med."},{"key":"B35","unstructured":"R: A Language and Environment for Statistical Computing 2020"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v070.i01","article-title":"missMDA: a package for handling missing values in multivariate data analysis","author":"Josse","year":"2016","journal-title":"J Stat Softw"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1016\/S1473-3099(20)30434-5","article-title":"Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study","volume":"20","author":"Carsana","year":"2020","journal-title":"Lancet Infect Dis."},{"key":"B38","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1111\/jth.15179","article-title":"Vascular neutrophilic inflammation and immunothrombosis distinguish severe COVID-19 from influenza pneumonia","volume":"19","author":"Nicolai","year":"2021","journal-title":"J Thromb Haemost."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20201012","article-title":"Neutrophil extracellular traps infiltrate the lung airway, interstitial, and vascular compartments in severe COVID-19","author":"Radermecker","year":"2020","journal-title":"J Exp Med."},{"key":"B40","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1016\/j.jaci.2010.11.050","article-title":"Interleukins, from 1 to 37, and interferon-\u03b3: receptors, functions, and roles in diseases","volume":"127","author":"Akdis","year":"2011","journal-title":"J Allergy Clin Immunol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1714","DOI":"10.1007\/s00134-020-06202-3","article-title":"Increased mortality in patients with severe SARS-CoV-2 infection admitted within seven days of disease onset","volume":"46","author":"Azoulay","year":"2020","journal-title":"Intensive Care Med."},{"key":"B42","doi-asserted-by":"publisher","first-page":"m1996","DOI":"10.1136\/bmj.m1996","article-title":"Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series","volume":"369","author":"Argenziano","year":"2020","journal-title":"BMJ."},{"key":"B43","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.tcm.2015.12.001","article-title":"Tissue factor as a link between inflammation and coagulation","volume":"26","author":"Witkowski","year":"2016","journal-title":"Trends Cardiovasc Med."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1076029620943300","DOI":"10.1177\/1076029620943300","article-title":"Biomarkers of platelet activation and their prognostic value in patients with sepsis-associated disseminated intravascular coagulopathy","volume":"27","author":"Wegrzyn","year":"2021","journal-title":"Clin Appl Thromb Hemost."},{"key":"B45","doi-asserted-by":"publisher","first-page":"e12525","DOI":"10.1002\/rth2.12525","article-title":"Comparison of the coagulopathies associated with COVID-19 and sepsis","volume":"5","author":"Campbell","year":"2021","journal-title":"Res Pract Thromb Haemost."},{"key":"B46","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.micinf.2016.08.005","article-title":"Increased circulating procoagulant and anticoagulant factors as TF and TFPI according to severity or infecting serotypes in human dengue infection","volume":"19","author":"Leal de Azeredo","year":"2017","journal-title":"Microbes Infect."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1509","DOI":"10.1097\/QAD.0b013e32833ad914","article-title":"Traditional risk factors and D-dimer predict incident cardiovascular disease events in chronic HIV infection","volume":"24","author":"Ford","year":"2010","journal-title":"Aids."},{"key":"B48","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.thromres.2016.11.007","article-title":"Coagulation and sepsis","volume":"149","author":"Levi","year":"2017","journal-title":"Thromb Res."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1076029620987629","DOI":"10.1177\/1076029620987629","article-title":"Systemic coagulopathy in hospitalized patients with coronavirus disease 2019: a systematic review and meta-analysis","volume":"27","author":"Uaprasert","year":"2021","journal-title":"Clin Appl Thromb Hemost."},{"key":"B50","doi-asserted-by":"publisher","first-page":"2689","DOI":"10.4049\/jimmunol.1201719","article-title":"Neutrophil extracellular traps: double-edged swords of innate immunity","volume":"189","author":"Kaplan","year":"2012","journal-title":"J Immunol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"2661","DOI":"10.1172\/JCI61303","article-title":"Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury","volume":"122","author":"Caudrillier","year":"2012","journal-title":"J Clin Invest."},{"key":"B52","doi-asserted-by":"publisher","first-page":"e575","DOI":"10.1016\/S2352-3026(20)30216-7","article-title":"Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study","volume":"7","author":"Goshua","year":"2020","journal-title":"Lancet Haematol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"e3001109","DOI":"10.1371\/journal.pbio.3001109","article-title":"COVID-19 induces a hyperactive phenotype in circulating platelets","volume":"19","author":"Comer","year":"2021","journal-title":"PLoS Biol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"5490","DOI":"10.4049\/jimmunol.181.8.5490","article-title":"T cell responses to whole SARS coronavirus in humans","volume":"181","author":"Li","year":"2008","journal-title":"J Immunol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1038\/35393","article-title":"CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells","volume":"391","author":"Henn","year":"1998","journal-title":"Nature."},{"key":"B56","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1080\/09537104.2020.1852543","article-title":"Over time relationship between platelet reactivity, myocardial injury and mortality in patients with SARS-CoV-2-associated respiratory failure","volume":"32","author":"Campo","year":"2021","journal-title":"Platelets."},{"key":"B57","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1002\/jlb.63.3.373","article-title":"CD40L-CD40 interactions regulate endothelial cell surface tissue factor and thrombomodulin expression","volume":"63","author":"Miller","year":"1998","journal-title":"J Leukoc Biol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1161\/01.CIR.96.2.396","article-title":"Activation of monocyte\/macrophage functions related to acute atheroma complication by ligation of CD40: induction of collagenase, stromelysin, and tissue factor","volume":"96","author":"Mach","year":"1997","journal-title":"Circulation."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.780750\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T05:13:27Z","timestamp":1642396407000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.780750\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,17]]},"references-count":58,"alternative-id":["10.3389\/fmed.2021.780750"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2021.780750","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,17]]},"article-number":"780750"}}