{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T06:10:30Z","timestamp":1776838230877,"version":"3.51.2"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,6,3]],"date-time":"2022-06-03T00:00:00Z","timestamp":1654214400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,6,3]],"date-time":"2022-06-03T00:00:00Z","timestamp":1654214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81700500"],"award-info":[{"award-number":["81700500"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Applied Basic Research Programs of Science, Technology Department of Changzhou city","award":["CJ20160031"],"award-info":[{"award-number":["CJ20160031"]}]},{"DOI":"10.13039\/501100010854","name":"Jiangsu Provincial Commission of Health and Family Planning","doi-asserted-by":"publisher","award":["H201547"],"award-info":[{"award-number":["H201547"]}],"id":[{"id":"10.13039\/501100010854","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Major Scientific and Technological Project of Changzhou City Commission of Health and Family Planning","award":["ZD201612"],"award-info":[{"award-number":["ZD201612"]}]},{"name":"Scientific and Technological Project of Nanjing medical University","award":["2017NJMU042"],"award-info":[{"award-number":["2017NJMU042"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Commun Signal"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Autoimmune hepatitis (AIH) is a chronic, immune-mediated liver dysfunction. The gut microbiota and T follicular helper (Tfh) cells play critical roles in the immunopathogenesis and progression of AIH. We aimed to investigate the effect of gut microbiota combined with prednisone therapy on Tfh cell response in AIH.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Samples from AIH patients and mouse model of experimental autoimmune hepatitis (EAH) were analyzed using real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting, flow cytometry, and hematoxylin\u2013eosin staining to determine the role of gut microbiota on AIH.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p><jats:italic>Lactobacillus<\/jats:italic> significantly increased the levels of <jats:italic>Bacteroides fragilis<\/jats:italic>, <jats:italic>Clostridium<\/jats:italic>, <jats:italic>Clostridium leptum<\/jats:italic>, <jats:italic>Bifidobacterium<\/jats:italic>, and <jats:italic>Lactobacillus<\/jats:italic> and significantly enhanced the suppressive effects of prednisone on the levels of AIH clinical indexes in AIH patients. <jats:italic>Lactobacillus<\/jats:italic> exerts the same prptective effects as prednisone in EAH mice and enhanced the effects of prednisone. <jats:italic>Lactobacillus<\/jats:italic> also reinforced the inhibitory effects of prednisone on the levels of serum IL-21 and the proportions of Tfh cells in peripheral blood mononuclear cells. Mechanistically, prednisone and <jats:italic>Lactobacillus<\/jats:italic> regulated Tfh cell response in EAH mice in an MyD88\/NF-\u03baB pathway-dependent manner.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Our results suggested a therapeutic potential of <jats:italic>Lactobacillus<\/jats:italic> in the prednisone-combined treatment of AIH.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12964-021-00819-7","type":"journal-article","created":{"date-parts":[[2022,6,3]],"date-time":"2022-06-03T12:03:32Z","timestamp":1654257812000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Lactobacillus improves the effects of prednisone on autoimmune hepatitis via gut microbiota-mediated follicular helper T cells"],"prefix":"10.1186","volume":"20","author":[{"given":"Liang","family":"Ma","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liwen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanbo","family":"Ding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8605-0898","authenticated-orcid":false,"given":"Jianping","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,6,3]]},"reference":[{"key":"819_CR1","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1136\/gutjnl-2018-317836","volume":"69","author":"Y Wei","year":"2020","unstructured":"Wei Y, Li Y, Yan LI, Sun C, Miao Q, Wang Q, Xiao X, Lian M, Li B, Chen Y, Zhang J, et al. Alterations of gut microbiome in autoimmune hepatitis. Gut. 2020;69:569\u201377.","journal-title":"Gut"},{"key":"819_CR2","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1146\/annurev-pathol-020117-043534","volume":"13","author":"GJ Webb","year":"2018","unstructured":"Webb GJ, Hirschfield GM, Krawitt EL, Gershwin ME. Cellular and molecular mechanisms of autoimmune hepatitis. Annu Rev Pathol. 2018;13:247\u201392.","journal-title":"Annu Rev Pathol"},{"key":"819_CR3","doi-asserted-by":"publisher","first-page":"18017","DOI":"10.1038\/nrdp.2018.17","volume":"4","author":"G Mieli-Vergani","year":"2018","unstructured":"Mieli-Vergani G, Vergani D, Czaja AJ, Manns MP, Krawitt EL, Vierling JM, Lohse AW, Montano-Loza AJ. Autoimmune hepatitis. Nat Rev Dis Primers. 2018;4:18017.","journal-title":"Nat Rev Dis Primers"},{"key":"819_CR4","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1136\/gut.16.11.876","volume":"16","author":"WH Summerskill","year":"1975","unstructured":"Summerskill WH, Korman MG, Ammon HV, Baggenstoss AH. Prednisone for chronic active liver disease: dose titration, standard dose, and combination with azathioprine compared. Gut. 1975;16:876\u201383.","journal-title":"Gut"},{"key":"819_CR5","doi-asserted-by":"crossref","unstructured":"de Moraes Falc\u00e3o LT, Terrabuio DR, Diniz MA, da Silva Evangelista A, Souza FG, R Cancado EL (2020) Efficacy and safety of chloroquine plus prednisone for the treatment of autoimmune hepatitis in a randomized trial. JGH Open 4:371\u2013377.","DOI":"10.1002\/jgh3.12258"},{"key":"819_CR6","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1590\/s0004-2803.202000000-69","volume":"57","author":"RS Fedrizzi","year":"2020","unstructured":"Fedrizzi RS, Coral GP, Mattos AA, Mattos \u00c2Z, Tovo CV. Evaluation of patients with autoimmune hepatitis in a specialized outpatient clinic in Southern Brazil. Arq Gastroenterol. 2020;57:361\u20135.","journal-title":"Arq Gastroenterol"},{"key":"819_CR7","doi-asserted-by":"publisher","first-page":"163","DOI":"10.3389\/fimmu.2018.00163","volume":"9","author":"U Christen","year":"2018","unstructured":"Christen U, Hintermann E. Autoantibodies in autoimmune hepatitis: can epitopes tell us about the etiology of the disease? Front Immunol. 2018;9:163.","journal-title":"Front Immunol"},{"key":"819_CR8","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1146\/annurev-immunol-031210-101400","volume":"29","author":"S Crotty","year":"2011","unstructured":"Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol. 2011;29:621\u201363.","journal-title":"Annu Rev Immunol"},{"key":"819_CR9","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1126\/science.1175870","volume":"325","author":"RJ Johnston","year":"2009","unstructured":"Johnston RJ, Poholek AC, Ditoro D, Yusuf I, Eto D, Barnett BE, Dent AL, Craft J, Crotty S. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science. 2009;325:1006\u201310.","journal-title":"Science"},{"key":"819_CR10","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1126\/science.1176676","volume":"325","author":"R Nurieva","year":"2009","unstructured":"Nurieva R, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, Wang YH, Dong C. Bcl6 mediates the development of T follicular helper cells. Science. 2009;325:1001\u20135.","journal-title":"Science"},{"key":"819_CR11","doi-asserted-by":"crossref","unstructured":"Liang M, Liwen Z, Juan D, Yun Z, Yanbo D, Jianping C. Dysregulated TFR and TFH cells correlate with B-cell differentiation and antibody production in autoimmune hepatitis. J Cell Mol Med. 2020.","DOI":"10.1111\/jcmm.14997"},{"key":"819_CR12","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1038\/s41575-018-0011-z","volume":"15","author":"A Tripathi","year":"2018","unstructured":"Tripathi A, Debelius J, Brenner DA, Karin M, Loomba R, Schnabl B, Knight R. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol. 2018;15:397\u2013411.","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"819_CR13","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1016\/j.omtn.2020.04.013","volume":"20","author":"Y Wang","year":"2020","unstructured":"Wang Y, Zhang J, Su Y, Wang C, Zhang G, Liu X, Chen Q, Lv M, Chang Y, Peng J, et al. miRNA-98-5p targeting IGF2BP1 induces mesenchymal stem cell apoptosis by modulating PI3K\/Akt and p53 in immune thrombocytopenia. Mol Ther Nucleic Acids. 2020;20:764\u201376.","journal-title":"Mol Ther Nucleic Acids"},{"key":"819_CR14","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1016\/j.bpg.2017.09.013","volume":"31","author":"W Cai","year":"2017","unstructured":"Cai W, Ran Y, Li Y, Wang B, Zhou L. Intestinal microbiome and permeability in patients with autoimmune hepatitis. Best Pract Res Clin Gastroenterol. 2017;31:669\u201373.","journal-title":"Best Pract Res Clin Gastroenterol"},{"key":"819_CR15","doi-asserted-by":"publisher","first-page":"99","DOI":"10.20344\/amp.5477","volume":"28","author":"D Pereira","year":"2015","unstructured":"Pereira D, Ramos E, Branco J. Osteoarthritis. Acta Med Port. 2015;28:99\u2013106.","journal-title":"Acta Med Port"},{"key":"819_CR16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.steroids.2017.06.002","volume":"125","author":"DJ Morris","year":"2017","unstructured":"Morris DJ, Ridlon JM. Glucocorticoids and gut bacteria: \u201cThe GALF Hypothesis\u201d in the metagenomic era. Steroids. 2017;125:1\u201313.","journal-title":"Steroids"},{"key":"819_CR17","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1038\/s41398-018-0240-5","volume":"8","author":"Y Luo","year":"2018","unstructured":"Luo Y, Zeng B, Zeng L, Du X, Li B, Huo R, Liu L, Wang H, Dong M, Pan J, et al. Gut microbiota regulates mouse behaviors through glucocorticoid receptor pathway genes in the hippocampus. Transl Psychiatry. 2018;8:187.","journal-title":"Transl Psychiatry"},{"key":"819_CR18","doi-asserted-by":"publisher","first-page":"1550","DOI":"10.4049\/jimmunol.1501904","volume":"196","author":"KE Block","year":"2016","unstructured":"Block KE, Zheng Z, Dent AL, Kee BL, Huang H. Gut microbiota regulates K\/BxN autoimmune arthritis through follicular helper T but Not Th17 cells. J Immunol. 2016;196:1550\u20137.","journal-title":"J Immunol"},{"key":"819_CR19","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1016\/j.immuni.2016.03.013","volume":"44","author":"F Teng","year":"2016","unstructured":"Teng F, Klinger CN, Felix KM, Bradley CP, Wu E, Tran NL, Umesaki Y, Wu HJ. Gut microbiota drive autoimmune arthritis by promoting differentiation and migration of Peyer\u2019s patch T follicular helper cells. Immunity. 2016;44:875\u201388.","journal-title":"Immunity"},{"key":"819_CR20","doi-asserted-by":"publisher","first-page":"5387","DOI":"10.2147\/IJN.S130485","volume":"12","author":"Z Wang","year":"2017","unstructured":"Wang Z, Xue K, Bai M, Deng Z, Gan J, Zhou G, Qian H, Bao N, Zhao J. Probiotics protect mice from CoCrMo particles-induced osteolysis. Int J Nanomed. 2017;12:5387\u201397.","journal-title":"Int J Nanomed"},{"key":"819_CR21","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1007\/s11596-019-2045-z","volume":"39","author":"XJ Liu","year":"2019","unstructured":"Liu XJ, Yu R, Zou KF. Probiotic mixture VSL#3 alleviates dextran sulfate sodium-induced colitis in mice by downregulating T follicular helper cells. Curr Med Sci. 2019;39:371\u20138.","journal-title":"Curr Med Sci."},{"key":"819_CR22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0199018","volume":"13","author":"S Arai","year":"2018","unstructured":"Arai S, Iwabuchi N, Takahashi S, Xiao JZ, Abe F, Hachimura S. Orally administered heat-killed Lactobacillus paracasei MCC1849 enhances antigen-specific IgA secretion and induces follicular helper T cells in mice. PLoS ONE. 2018;13: e0199018.","journal-title":"PLoS ONE"},{"key":"819_CR23","unstructured":"Ma L, Zhang LW, Zhuang Y, Ding YB, Chen JP. Exploration the significance of Tfh and related molecules on C57BL\/6 mice model of experimental autoimmune hepatitis. J Microbiol Immunol infection = Wei mian yu gan ran za zhi 2019."},{"key":"819_CR24","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/nbt.3192","volume":"33","author":"R Satija","year":"2015","unstructured":"Satija R, Farrell JA, Gennert D, Schier AF, Regev A. Spatial reconstruction of single-cell gene expression data. Nat Biotechnol. 2015;33:495\u2013502.","journal-title":"Nat Biotechnol"},{"key":"819_CR25","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/s41419-020-2252-3","volume":"11","author":"R Wang","year":"2020","unstructured":"Wang R, Ma Y, Zhan S, Zhang G, Cao L, Zhang X, Shi T, Chen W. B7\u2013H3 promotes colorectal cancer angiogenesis through activating the NF-\u03baB pathway to induce VEGFA expression. Cell Death Dis. 2020;11:55.","journal-title":"Cell Death Dis"},{"key":"819_CR26","doi-asserted-by":"publisher","first-page":"2883","DOI":"10.3389\/fimmu.2018.02883","volume":"9","author":"AJ Stagg","year":"2018","unstructured":"Stagg AJ. Intestinal dendritic cells in health and gut inflammation. Front Immunol. 2018;9:2883.","journal-title":"Front Immunol"},{"key":"819_CR27","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1016\/j.carbpol.2018.10.057","volume":"205","author":"R Bo","year":"2019","unstructured":"Bo R, Liu Z, Zhang J, Gu P, Ou N, Sun Y, Hu Y, Liu J, Wang D. Mechanism of Lycium barbarum polysaccharides liposomes on activating murine dendritic cells. Carbohydr Polym. 2019;205:540\u20139.","journal-title":"Carbohydr Polym"},{"key":"819_CR28","doi-asserted-by":"publisher","first-page":"942","DOI":"10.3389\/fimmu.2018.00942","volume":"9","author":"S Stanisavljevi\u0107","year":"2018","unstructured":"Stanisavljevi\u0107 S, Dini\u0107 M, Jevti\u0107 B, \u0110edovi\u0107 N, Mom\u010dilovi\u0107 M, \u0110oki\u0107 J, Goli\u0107 N, Mostarica Stojkovi\u0107 M, Miljkovi\u0107 \u0110. Gut microbiota confers resistance of albino oxford rats to the induction of experimental autoimmune encephalomyelitis. Front Immunol. 2018;9:942.","journal-title":"Front Immunol"},{"key":"819_CR29","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.jaut.2018.09.010","volume":"95","author":"HD Ma","year":"2018","unstructured":"Ma HD, Zhao ZB, Ma WT, Liu QZ, Gao CY, Li L, Wang J, Tsuneyama K, Liu B, Zhang W, Zhou Y, et al. Gut microbiota translocation promotes autoimmune cholangitis. J Autoimmun. 2018;95:47\u201357.","journal-title":"J Autoimmun"},{"key":"819_CR30","doi-asserted-by":"publisher","first-page":"219","DOI":"10.4110\/in.2016.16.4.219","volume":"16","author":"YH Jeon","year":"2016","unstructured":"Jeon YH, Choi YS. Follicular Helper T (Tfh) cells in autoimmune diseases and allograft rejection. Immune network. 2016;16:219\u201332.","journal-title":"Immune network"},{"key":"819_CR31","first-page":"11","volume":"2020","author":"V Azizov","year":"1998","unstructured":"Azizov V, Dietel K, Steffen F, D\u00fcrholz K, Meidenbauer J, Lucas S, Frech M, Omata Y, Tajik N, Knipfer L, Kolenbrander A. Ethanol consumption inhibits T cell responses and the development of autoimmune arthritis. Nat Commun. 1998;2020:11.","journal-title":"Nat Commun"},{"key":"819_CR32","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1084\/jem.20171976","volume":"216","author":"CE Faliti","year":"2019","unstructured":"Faliti CE, Gualtierotti R, Rottoli E, Gerosa M, Perruzza L, Romagnani A, Pellegrini G, De Ponte CB, Rossi RL, Idzko M, Mazza E, et al. P2X7 receptor restrains pathogenic Tfh cell generation in systemic lupus erythematosus. J Exp Med. 2019;216:317\u201336.","journal-title":"J Exp Med"},{"key":"819_CR33","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1016\/j.immuni.2018.12.020","volume":"50","author":"M Martinez-Lopez","year":"2019","unstructured":"Martinez-Lopez M, Iborra S, Conde-Garrosa R, Mastrangelo A, Danne C, Mann ER, Reid DM, Gaboriau-Routhiau V, Chaparro M, Lorenzo MP, Minnerup L, et al. Microbiota sensing by mincle-syk axis in dendritic cells regulates interleukin-17 and -22 production and promotes intestinal barrier integrity. Immunity. 2019;50:446\u201361.","journal-title":"Immunity"},{"key":"819_CR34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0166751","volume":"11","author":"RP Zhou","year":"2016","unstructured":"Zhou RP, Lin SJ, Wan WB, Zuo HL, Yao FF, Ruan HB, Xu J, Song W, Zhou YC, Wen SY, et al. Chlorogenic acid prevents osteoporosis by Shp2\/PI3K\/Akt pathway in ovariectomized rats. PLoS ONE. 2016;11: e0166751.","journal-title":"PLoS ONE"},{"key":"819_CR35","doi-asserted-by":"publisher","first-page":"31982","DOI":"10.1074\/jbc.M109.046383","volume":"284","author":"C Cekic","year":"2009","unstructured":"Cekic C, Casella CR, Eaves CA, Matsuzawa A, Ichijo H, Mitchell TC. Selective activation of the p38 MAPK pathway by synthetic monophosphoryl lipid A. J Biol Chem. 2009;284:31982\u201391.","journal-title":"J Biol Chem"}],"container-title":["Cell Communication and Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12964-021-00819-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12964-021-00819-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12964-021-00819-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T21:47:36Z","timestamp":1675115256000},"score":1,"resource":{"primary":{"URL":"https:\/\/biosignaling.biomedcentral.com\/articles\/10.1186\/s12964-021-00819-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,3]]},"references-count":35,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["819"],"URL":"https:\/\/doi.org\/10.1186\/s12964-021-00819-7","relation":{},"ISSN":["1478-811X"],"issn-type":[{"value":"1478-811X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,3]]},"assertion":[{"value":"14 September 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 December 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 June 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All experimental procedures involving animals have followed the standard ethical guidelines of the Ethical Committee of the First People\u2019s Hospital of Changzhou and the Third Affiliated Hospital of Soochow University. All efforts were made to ensure mere animal suffering and to minimize the number of mice used.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The manuscript has been reviewed and approved by all authors and represents original work that has not been published elsewhere and is not under consideration for publication elsewhere.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no conflict of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"83"}}