{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T11:45:45Z","timestamp":1792669545647,"version":"4.5.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,7,2]],"date-time":"2020-07-02T00:00:00Z","timestamp":1593648000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,7,2]],"date-time":"2020-07-02T00:00:00Z","timestamp":1593648000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Tofacitinib, a janus kinase inhibitor, is a novel immunosuppressive drug for treatment of rheumatoid arthritis (RA). Septic arthritis (SA) and sepsis caused by<jats:italic>Staphylococcus aureus<\/jats:italic>(<jats:italic>S. aureus<\/jats:italic>), for which RA patients are at risk, are infections with high mortality. The aim of this study was to investigate the effect of tofacitinib on<jats:italic>S. aureus<\/jats:italic>infections using mouse models. In vitro tofacitinib treated mouse splenocytes were stimulated with<jats:italic>S. aureus<\/jats:italic>derived stimuli. Mice pre-treated with tofacitinib were inoculated intravenously with either arthritogenic- or septic doses of<jats:italic>S. aureus<\/jats:italic>. Arthritis severity and mortality were compared between groups. Additionally, pre-treated mice were challenged with staphylococcal toxin TSST-1 to induce shock. Tofacitinib inhibited splenocyte proliferation and IFN-\u03b3 production in response to TSST-1 and dead<jats:italic>S. aureus<\/jats:italic>. In SA, tofacitinib treatment aggravated arthritis with more severe bone erosions. However, in sepsis, treated mice displayed significantly prolonged survival compared to controls. Similarly, in staphylococcal enterotoxin-induced shock tofacitinib pre-treatment, but not late treatment dramatically reduced mortality, which was accompanied by decreased levels of TNF-\u03b1 and IFN-\u03b3. Our findings show that tofacitinib treatment increase susceptibility of SA in mice, but has a positive effect on survival in<jats:italic>S. aureus<\/jats:italic>-induced sepsis and a strong protective effect in toxin-induced shock.<\/jats:p>","DOI":"10.1038\/s41598-020-67928-0","type":"journal-article","created":{"date-parts":[[2020,7,2]],"date-time":"2020-07-02T10:26:17Z","timestamp":1593685577000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Tofacitinib treatment aggravates Staphylococcus aureus septic arthritis, but attenuates sepsis and enterotoxin induced shock in mice"],"prefix":"10.1038","volume":"10","author":[{"given":"Anders","family":"Jarneborn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majd","family":"Mohammad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Engdahl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhicheng","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manli","family":"Na","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abukar","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,2]]},"reference":[{"key":"67928_CR1","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1016\/s1473-3099(05)70295-4","volume":"5","author":"HFL Wertheim","year":"2005","unstructured":"Wertheim, H. F. L. et al. The role of nasal carriage in Staphylococcus aureus infections. Lancet. Infect. Dis 5, 751\u2013762. https:\/\/doi.org\/10.1016\/s1473-3099(05)70295-4 (2005).","journal-title":"Lancet. Infect. Dis"},{"key":"67928_CR2","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/s41579-018-0147-4","volume":"17","author":"NA Turner","year":"2019","unstructured":"Turner, N. A. et al. Methicillin-resistant Staphylococcus aureus: an overview of basic and clinical research. Nat. Rev. Microbiol. 17, 203\u2013218. https:\/\/doi.org\/10.1038\/s41579-018-0147-4 (2019).","journal-title":"Nat. Rev. Microbiol."},{"key":"67928_CR3","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1111\/1469-0691.12144","volume":"19","author":"KB Laupland","year":"2013","unstructured":"Laupland, K. B. Incidence of bloodstream infection: a review of population-based studies. Clin. Microbiol. Infect. 19, 492\u2013500. https:\/\/doi.org\/10.1111\/1469-0691.12144 (2013).","journal-title":"Clin. Microbiol. Infect."},{"key":"67928_CR4","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1128\/CMR.05022-11","volume":"25","author":"SJ van Hal","year":"2012","unstructured":"van Hal, S. J. et al. Predictors of mortality in Staphylococcus aureus bacteremia. Clin. Microbiol. Rev. 25, 362\u2013386. https:\/\/doi.org\/10.1128\/CMR.05022-11 (2012).","journal-title":"Clin. Microbiol. Rev."},{"key":"67928_CR5","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/s0140-6736(97)09522-6","volume":"351","author":"DL Goldenberg","year":"1998","unstructured":"Goldenberg, D. L. Septic arthritis. Lancet 351, 197\u2013202. https:\/\/doi.org\/10.1016\/s0140-6736(97)09522-6 (1998).","journal-title":"Lancet"},{"key":"67928_CR6","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1016\/S0140-6736(09)61595-6","volume":"375","author":"CJ Mathews","year":"2010","unstructured":"Mathews, C. J., Weston, V. C., Jones, A., Field, M. & Coakley, G. Bacterial septic arthritis in adults. Lancet 375, 846\u2013855. https:\/\/doi.org\/10.1016\/S0140-6736(09)61595-6 (2010).","journal-title":"Lancet"},{"key":"67928_CR7","doi-asserted-by":"publisher","first-page":"1810","DOI":"10.1136\/ard.2011.152769","volume":"70","author":"JB Galloway","year":"2011","unstructured":"Galloway, J. B. et al. Risk of septic arthritis in patients with rheumatoid arthritis and the effect of anti-TNF therapy: results from the British Society for Rheumatology Biologics Register. Ann. Rheum. Dis. 70, 1810\u20131814. https:\/\/doi.org\/10.1136\/ard.2011.152769 (2011).","journal-title":"Ann. Rheum. Dis."},{"key":"67928_CR8","doi-asserted-by":"publisher","first-page":"2377","DOI":"10.1056\/NEJMoa1310476","volume":"370","author":"EB Lee","year":"2014","unstructured":"Lee, E. B. et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N. Engl. J. Med. 370, 2377\u20132386. https:\/\/doi.org\/10.1056\/NEJMoa1310476 (2014).","journal-title":"N. Engl. J. Med."},{"key":"67928_CR9","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1056\/NEJMoa1112072","volume":"367","author":"RF van Vollenhoven","year":"2012","unstructured":"van Vollenhoven, R. F. et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N. Engl. J. Med. 367, 508\u2013519. https:\/\/doi.org\/10.1056\/NEJMoa1112072 (2012).","journal-title":"N. Engl. J. Med."},{"key":"67928_CR10","doi-asserted-by":"publisher","first-page":"1537","DOI":"10.1056\/NEJMoa1615975","volume":"377","author":"P Mease","year":"2017","unstructured":"Mease, P. et al. Tofacitinib or adalimumab versus placebo for psoriatic arthritis. N. Engl. J. Med. 377, 1537\u20131550. https:\/\/doi.org\/10.1056\/NEJMoa1615975 (2017).","journal-title":"N. Engl. J. Med."},{"key":"67928_CR11","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.1056\/NEJMoa1606910","volume":"376","author":"WJ Sandborn","year":"2017","unstructured":"Sandborn, W. J. et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 376, 1723\u20131736. https:\/\/doi.org\/10.1056\/NEJMoa1606910 (2017).","journal-title":"N. Engl. J. Med."},{"key":"67928_CR12","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1038\/ni.3691","volume":"18","author":"AV Villarino","year":"2017","unstructured":"Villarino, A. V., Kanno, Y. & O\u2019Shea, J. J. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat. Immunol. 18, 374\u2013384. https:\/\/doi.org\/10.1038\/ni.3691 (2017).","journal-title":"Nat. Immunol."},{"key":"67928_CR13","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/nrrheum.2015.167","volume":"12","author":"DM Schwartz","year":"2016","unstructured":"Schwartz, D. M., Bonelli, M., Gadina, M. & O\u2019Shea, J. J. Type I\/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat. Rev. Rheumatol. 12, 25\u201336. https:\/\/doi.org\/10.1038\/nrrheum.2015.167 (2016).","journal-title":"Nat. Rev. Rheumatol."},{"key":"67928_CR14","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1038\/nrrheum.2017.23","volume":"13","author":"KL Winthrop","year":"2017","unstructured":"Winthrop, K. L. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat. Rev. Rheumatol. 13, 234\u2013243. https:\/\/doi.org\/10.1038\/nrrheum.2017.23 (2017).","journal-title":"Nat. Rev. Rheumatol."},{"key":"67928_CR15","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1080\/00365540600810026","volume":"39","author":"G Jacobsson","year":"2007","unstructured":"Jacobsson, G., Dashti, S., Wahlberg, T. & Andersson, R. The epidemiology of and risk factors for invasive Staphylococcus aureus infections in western Sweden. Scand J Infect Dis 39, 6\u201313. https:\/\/doi.org\/10.1080\/00365540600810026 (2007).","journal-title":"Scand J Infect Dis"},{"key":"67928_CR16","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1016\/j.jinf.2017.03.003","volume":"74","author":"I Joost","year":"2017","unstructured":"Joost, I. et al. Staphylococcus aureus bacteremia in patients with rheumatoid arthritis: data from the prospective INSTINCT cohort. J. Infect. 74, 575\u2013584. https:\/\/doi.org\/10.1016\/j.jinf.2017.03.003 (2017).","journal-title":"J. Infect."},{"key":"67928_CR17","doi-asserted-by":"publisher","first-page":"1596","DOI":"10.1002\/art.1780390921","volume":"39","author":"E Sakiniene","year":"1996","unstructured":"Sakiniene, E., Bremell, T. & Tarkowski, A. Addition of corticosteroids to antibiotic treatment ameliorates the course of experimental Staphylococcus aureus arthritis. Arthritis. Rheum. 39, 1596\u20131605 (1996).","journal-title":"Arthritis. Rheum."},{"key":"67928_CR18","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1093\/infdis\/jir266","volume":"204","author":"Y Fei","year":"2011","unstructured":"Fei, Y. et al. The combination of a tumor necrosis factor inhibitor and antibiotic alleviates staphylococcal arthritis and sepsis in mice. J. Infect. Dis. 204, 348\u2013357. https:\/\/doi.org\/10.1093\/infdis\/jir266 (2011).","journal-title":"J. Infect. Dis."},{"key":"67928_CR19","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD002243.pub3","author":"D Annane","year":"2015","unstructured":"Annane, D. et al. Corticosteroids for treating sepsis. Cochrane Database Syst. Rev. https:\/\/doi.org\/10.1002\/14651858.CD002243.pub3 (2015).","journal-title":"Cochrane Database Syst. Rev."},{"key":"67928_CR20","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1016\/s0140-6736(05)60602-2","volume":"351","author":"E Abraham","year":"1998","unstructured":"Abraham, E. et al. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. Lancet 351, 929\u2013933. https:\/\/doi.org\/10.1016\/s0140-6736(05)60602-2 (1998).","journal-title":"Lancet"},{"key":"67928_CR21","doi-asserted-by":"publisher","first-page":"1431","DOI":"10.1097\/00003246-199609000-00002","volume":"24","author":"J Cohen","year":"1996","unstructured":"Cohen, J. & Carlet, J. INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group. Crit Care Med. 24, 1431\u20131440 (1996).","journal-title":"Crit Care Med."},{"key":"67928_CR22","doi-asserted-by":"publisher","first-page":"1667","DOI":"10.1136\/annrheumdis-2015-207838","volume":"75","author":"A Richter","year":"2016","unstructured":"Richter, A. et al. Impact of treatment with biologic DMARDs on the risk of sepsis or mortality after serious infection in patients with rheumatoid arthritis. Ann. Rheum. Dis. 75, 1667\u20131673. https:\/\/doi.org\/10.1136\/annrheumdis-2015-207838 (2016).","journal-title":"Ann. Rheum. Dis."},{"key":"67928_CR23","doi-asserted-by":"publisher","first-page":"351","DOI":"10.3109\/00365540903510690","volume":"42","author":"M Klak","year":"2010","unstructured":"Klak, M. et al. Tranexamic acid, an inhibitor of plasminogen activation, aggravates staphylococcal septic arthritis and sepsis. Scand. J. Infect. Dis. 42, 351\u2013358. https:\/\/doi.org\/10.3109\/00365540903510690 (2010).","journal-title":"Scand. J. Infect. Dis."},{"key":"67928_CR24","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1093\/infdis\/jiv212","volume":"212","author":"A Ali","year":"2015","unstructured":"Ali, A. et al. CTLA4 immunoglobulin but not anti-tumor necrosis factor therapy promotes staphylococcal septic arthritis in mice. J. Infect. Dis. 212, 1308\u20131316. https:\/\/doi.org\/10.1093\/infdis\/jiv212 (2015).","journal-title":"J. Infect. Dis."},{"key":"67928_CR25","doi-asserted-by":"publisher","first-page":"4234","DOI":"10.4049\/jimmunol.1003668","volume":"186","author":"K Ghoreschi","year":"2011","unstructured":"Ghoreschi, K. et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J. Immunol. 186, 4234\u20134243. https:\/\/doi.org\/10.4049\/jimmunol.1003668 (2011).","journal-title":"J. Immunol."},{"key":"67928_CR26","doi-asserted-by":"crossref","first-page":"5736","DOI":"10.4049\/jimmunol.155.12.5736","volume":"155","author":"YX Zhao","year":"1995","unstructured":"Zhao, Y. X. & Tarkowski, A. Impact of interferon-gamma receptor deficiency on experimental Staphylococcus aureus septicemia and arthritis. J. Immunol. 155, 5736\u20135742 (1995).","journal-title":"J. Immunol."},{"key":"67928_CR27","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1046\/j.1365-2249.1999.00922.x","volume":"117","author":"N Nilsson","year":"1999","unstructured":"Nilsson, N., Bremell, T., Tarkowski, A. & Carlsten, H. Protective role of NK1.1+ cells in experimental Staphylococcus aureus arthritis. Clin. Exp. Immunol. 117, 63\u201369. https:\/\/doi.org\/10.1046\/j.1365-2249.1999.00922.x (1999).","journal-title":"Clin. Exp. Immunol."},{"key":"67928_CR28","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1007\/s00109-010-0628-z","volume":"88","author":"G Pena","year":"2010","unstructured":"Pena, G., Cai, B., Deitch, E. A. & Ulloa, L. JAK2 inhibition prevents innate immune responses and rescues animals from sepsis. J. Mol. Med. (Berl) 88, 851\u2013859. https:\/\/doi.org\/10.1007\/s00109-010-0628-z (2010).","journal-title":"J. Mol. Med. (Berl)"},{"key":"67928_CR29","first-page":"373","volume":"2","author":"M Fang","year":"2005","unstructured":"Fang, M., Dai, H., Yu, G. & Gong, F. Gene delivery of SOCS3 protects mice from lethal endotoxic shock. Cell. Mol. Immunol. 2, 373\u2013377 (2005).","journal-title":"Cell. Mol. Immunol."},{"key":"67928_CR30","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.1128\/IAI.67.3.1521-1525.1999","volume":"67","author":"BG Stiles","year":"1999","unstructured":"Stiles, B. G., Campbell, Y. G., Castle, R. M. & Grove, S. A. Correlation of temperature and toxicity in murine studies of staphylococcal enterotoxins and toxic shock syndrome toxin 1. Infect. Immun. 67, 1521\u20131525 (1999).","journal-title":"Infect. Immun."},{"key":"67928_CR31","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1002\/eji.1830270405","volume":"27","author":"C Blank","year":"1997","unstructured":"Blank, C. et al. Superantigen and endotoxin synergize in the induction of lethal shock. Eur. J. Immunol. 27, 825\u2013833. https:\/\/doi.org\/10.1002\/eji.1830270405 (1997).","journal-title":"Eur. J. Immunol."},{"key":"67928_CR32","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/S0171-2985(11)80362-1","volume":"189","author":"T Miethke","year":"1993","unstructured":"Miethke, T. et al. Superantigen mediated shock: a cytokine release syndrome. Immunobiology 189, 270\u2013284. https:\/\/doi.org\/10.1016\/S0171-2985(11)80362-1 (1993).","journal-title":"Immunobiology"},{"key":"67928_CR33","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/S1473-3099(09)70066-0","volume":"9","author":"E Lappin","year":"2009","unstructured":"Lappin, E. & Ferguson, A. J. Gram-positive toxic shock syndromes. Lancet Infect. Dis. 9, 281\u2013290. https:\/\/doi.org\/10.1016\/S1473-3099(09)70066-0 (2009).","journal-title":"Lancet Infect. Dis."},{"key":"67928_CR34","doi-asserted-by":"publisher","first-page":"R26","DOI":"10.1186\/cc7731","volume":"13","author":"J Monserrat","year":"2009","unstructured":"Monserrat, J. et al. Clinical relevance of the severe abnormalities of the T cell compartment in septic shock patients. Crit. Care 13, R26. https:\/\/doi.org\/10.1186\/cc7731 (2009).","journal-title":"Crit. Care"},{"key":"67928_CR35","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1097\/CCM.0b013e318274645f","volume":"41","author":"S Inoue","year":"2013","unstructured":"Inoue, S. et al. Reduction of immunocompetent T cells followed by prolonged lymphopenia in severe sepsis in the elderly. Crit. Care Med. 41, 810\u2013819. https:\/\/doi.org\/10.1097\/CCM.0b013e318274645f (2013).","journal-title":"Crit. Care Med."},{"key":"67928_CR36","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1093\/intimm\/dxm045","volume":"19","author":"M Nishihara","year":"2007","unstructured":"Nishihara, M. et al. IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state. Int. Immunol. 19, 695\u2013702. https:\/\/doi.org\/10.1093\/intimm\/dxm045 (2007).","journal-title":"Int. Immunol."},{"key":"67928_CR37","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1007\/s00005-016-0415-9","volume":"65","author":"M Prucha","year":"2017","unstructured":"Prucha, M., Zazula, R. & Russwurm, S. Immunotherapy of sepsis: blind alley or call for personalized assessment?. Arch. Immunol. Ther. Exp. (Warsz) 65, 37\u201349. https:\/\/doi.org\/10.1007\/s00005-016-0415-9 (2017).","journal-title":"Arch. Immunol. Ther. Exp. (Warsz)"},{"key":"67928_CR38","doi-asserted-by":"publisher","DOI":"10.1186\/ar606","author":"T Jin","year":"2003","unstructured":"Jin, T., Tarkowski, A., Carmeliet, P. & Bokarewa, M. Urokinase, a constitutive component of the inflamed synovial fluid, induces arthritis. Arthritis Res. Ther. https:\/\/doi.org\/10.1186\/ar606 (2003).","journal-title":"Arthritis Res. Ther."},{"key":"67928_CR39","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1128\/IAI.01520-15","volume":"84","author":"M Na","year":"2016","unstructured":"Na, M. et al. Deficiency of the complement component 3 but not factor B aggravates Staphylococcus aureus septic arthritis in mice. Infect. Immun. 84, 930\u2013939. https:\/\/doi.org\/10.1128\/IAI.01520-15 (2016).","journal-title":"Infect. Immun."},{"key":"67928_CR40","doi-asserted-by":"publisher","first-page":"e0131645","DOI":"10.1371\/journal.pone.0131645","volume":"10","author":"A Ali","year":"2015","unstructured":"Ali, A. et al. IL-1 Receptor antagonist treatment aggravates staphylococcal septic arthritis and sepsis in mice. PLoS ONE 10, e0131645. https:\/\/doi.org\/10.1371\/journal.pone.0131645 (2015).","journal-title":"PLoS ONE"},{"key":"67928_CR41","doi-asserted-by":"publisher","first-page":"e0171222","DOI":"10.1371\/journal.pone.0171222","volume":"12","author":"F Fatima","year":"2017","unstructured":"Fatima, F. et al. Radiological features of experimental staphylococcal septic arthritis by micro computed tomography scan. PLoS ONE 12, e0171222. https:\/\/doi.org\/10.1371\/journal.pone.0171222 (2017).","journal-title":"PLoS ONE"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67928-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67928-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67928-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T09:25:00Z","timestamp":1696325100000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67928-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,2]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["67928"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-67928-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,2]]},"assertion":[{"value":"25 March 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 June 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 July 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"10891"}}