{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T01:45:17Z","timestamp":1782438317233,"version":"3.54.5"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Cholestasis is characterized by increased total bile acid (TBA) levels, which are regulated by farnesoid X receptor (FXR)\/FGF15. Patients with primary sclerosing cholangitis (PSC) typically present with inflammatory bowel disease (IBD). Mast cells (MCs) (i) express FXR and (ii) infiltrate the liver during cholestasis promoting liver fibrosis. In bile\u2010duct\u2010ligated (BDL) MC\u2010deficient mice (B6.Cg\u2010<jats:italic toggle=\"yes\">KitW\u2010sh\n                                 <\/jats:italic>\/HNihrJaeBsmJ [<jats:italic toggle=\"yes\">KitW\u2010sh\n                                 <\/jats:italic>]), ductular reaction (DR) and liver fibrosis decrease compared with BDL wild type, and MC injection exacerbates liver damage in normal mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>In this study, we demonstrated that MC\u2010FXR regulates biliary FXR\/FGF15, DR, and hepatic fibrosis and alters intestinal FXR\/FGF15. We found increased MC number and biliary FXR expression in patients with liver injury compared with control. Histamine and FGF19 serum levels and small heterodimer partner expression increase in patients PSC and PSC\u2010IBD compared with healthy controls. MC injection increased liver damage, DR, inflammation, biliary senescence\/senescence\u2010associated secretory phenotype (SASP), fibrosis, and histamine in <jats:italic toggle=\"yes\">KitW\u2010sh\n                                 <\/jats:italic> mice. Inhibition of MC\u2010FXR before injection reduced these parameters. BDL and <jats:italic toggle=\"yes\">KitW\u2010sh\n                                 <\/jats:italic> mice injected with MCs displayed increased TBA content, biliary FXR\/FGF15, and intestinal inflammation, which decreased in BDL <jats:italic toggle=\"yes\">KitW\u2010sh\n                                 <\/jats:italic> and <jats:italic toggle=\"yes\">KitW\u2010sh\n                                 <\/jats:italic> mice injected with MC\u2010FXR. MCs increased ileal FXR\/FGF15 expression in <jats:italic toggle=\"yes\">KitW\u2010sh\n                                 <\/jats:italic> mice that was reduced following FXR inhibition. BDL and multidrug resistance 2\/ATP\u2010binding cassette family 2 member 4 knockout (<jats:italic toggle=\"yes\">Mdr2<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup>) mice, models of PSC, displayed increased intestinal MC infiltration and FXR\/FGF15 expression. These were reduced following MC stabilization with cromolyn sodium in <jats:italic toggle=\"yes\">Mdr2<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup> mice. <jats:italic toggle=\"yes\">In vitro<\/jats:italic>, MC\u2010FXR inhibition decreased biliary proliferation\/SASP\/FGF and hepatic stellate cell activation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our studies demonstrate that MC\u2010FXR plays a key role in liver damage and DR, including TBA regulation through alteration of intestinal and biliary FXR\/FGF15 signaling.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32028","type":"journal-article","created":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T02:23:52Z","timestamp":1624501432000},"page":"2684-2698","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":56,"title":["Mast Cells Regulate Ductular Reaction and Intestinal Inflammation in Cholestasis Through Farnesoid X Receptor Signaling"],"prefix":"10.1097","volume":"74","author":[{"given":"Vik","family":"Meadows","sequence":"first","affiliation":[{"name":"Richard L. Roudebush VA Medical Center,Indiana University School of Medicine,Indianapolis,IN"},{"name":"Division of Gastroenterology and Hepatology,Department of Medicine,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Department of Medicine,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0741-8007","authenticated-orcid":false,"given":"Burcin","family":"Ekser","sequence":"additional","affiliation":[{"name":"Division of Transplant Surgery,Department of Surgery,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantina","family":"Kyritsi","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Department of Medicine,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debjyoti","family":"Kundu","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Department of Medicine,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianhao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Department of Medicine,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixian","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Department of Medicine,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linh","family":"Pham","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Department of Medicine,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Department of Medicine,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Demieville","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology,Texas A&M University College of Medicine,Bryan,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Hargrove","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology,Texas A&M University College of Medicine,Bryan,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon","family":"Glaser","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology,Texas A&M University College of Medicine,Bryan,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6658-3021","authenticated-orcid":false,"given":"Gianfranco","family":"Alpini","sequence":"additional","affiliation":[{"name":"Richard L. Roudebush VA Medical Center,Indiana University School of Medicine,Indianapolis,IN"},{"name":"Division of Gastroenterology and Hepatology,Department of Medicine,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Francis","sequence":"additional","affiliation":[{"name":"Richard L. Roudebush VA Medical Center,Indiana University School of Medicine,Indianapolis,IN"},{"name":"Division of Gastroenterology and Hepatology,Department of Medicine,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,9,9]]},"reference":[{"key":"hep32028-bib-0001-20250824","doi-asserted-by":"crossref","first-page":"165557","DOI":"10.1016\/j.bbadis.2019.165557","article-title":"Downregulation of hepatic stem cell factor by Vivo\u2010Morpholino treatment inhibits mast cell migration and decreases biliary damage\/senescence and liver fibrosis in Mdr2(\u2212\/\u2212) mice","volume":"1865","year":"2019","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"hep32028-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.jhep.2005.06.025","article-title":"Mdr2 (Abcb4)\u2212\/\u2212 mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro\u2010 and antifibrogenic genes","volume":"43","year":"2005","journal-title":"J Hepatol"},{"key":"hep32028-bib-0003-20250824","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1002\/hep.31017","article-title":"Liver injury in patients with cholestatic liver disease treated with obeticholic acid","volume":"71","year":"2020","journal-title":"Hepatology"},{"key":"hep32028-bib-0004-20250824","first-page":"15","article-title":"Bile acid receptor therapeutics effects on chronic liver diseases","volume":"7","year":"2020","journal-title":"Front Med (Lausanne)"},{"key":"hep32028-bib-0005-20250824","first-page":"124","article-title":"Primary sclerosing cholangitis and inflammatory bowel disease comorbidity: an update of the evidence","volume":"32","year":"2019","journal-title":"Ann Gastroenterol"},{"key":"hep32028-bib-0006-20250824","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1111\/liv.14153","article-title":"The gut microbial influence on cholestatic liver disease","volume":"39","year":"2019","journal-title":"Liver Int"},{"key":"hep32028-bib-0007-20250824","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1002\/hep.28704","article-title":"Inhibition of mast cell\u2010secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2(\u2212\/\u2212) mice","volume":"64","year":"2016","journal-title":"Hepatology"},{"key":"hep32028-bib-0008-20250824","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1002\/hep.29898","article-title":"Blocking H1\/H2 histamine receptors inhibits damage\/fibrosis in Mdr2(\u2212\/\u2212) mice and human cholangiocarcinoma tumorigenesis","volume":"68","year":"2018","journal-title":"Hepatology"},{"key":"hep32028-bib-0009-20250824","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/s41374-020-0405-8","article-title":"Biliary damage and liver fibrosis are ameliorated in a novel mouse model lacking l\u2010histidine decarboxylase\/histamine signaling","volume":"100","year":"2020","journal-title":"Lab Invest"},{"key":"hep32028-bib-0010-20250824","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1002\/hep.29079","article-title":"Bile duct ligation\u2010induced biliary hyperplasia, hepatic injury, and fibrosis are reduced in mast cell\u2010deficient Kit(W\u2010sh) mice","volume":"65","year":"2017","journal-title":"Hepatology"},{"key":"hep32028-bib-0011-20250824","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1002\/hep.31497","article-title":"Mast cells induce ductular reaction mimicking liver injury in mice through mast cell\u2013derived transforming growth factor beta1 signaling","volume":"73","year":"2021","journal-title":"Hepatology"},{"key":"hep32028-bib-0012-20250824","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1111\/1751-2980.12378","article-title":"Role of farnesoid X receptor in cholestasis","volume":"17","year":"2016","journal-title":"J Dig Dis"},{"key":"hep32028-bib-0013-20250824","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1194\/jlr.R900012-JLR200","article-title":"Bile acid transporters","volume":"50","year":"2009","journal-title":"J Lipid Res"},{"key":"hep32028-bib-0014-20250824","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1002\/hep.22519","article-title":"Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response","volume":"48","year":"2008","journal-title":"Hepatology"},{"key":"hep32028-bib-0015-20250824","article-title":"Discovery that theonellasterol a marine sponge sterol is a highly selective FXR antagonist that protects against liver injury in cholestasis","volume":"7","year":"2012","journal-title":"PLoS One"},{"key":"hep32028-bib-0016-20250824","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/S0016-5085(03)01068-0","article-title":"Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct\u2010ligated mice","volume":"125","year":"2003","journal-title":"Gastroenterology"},{"key":"hep32028-bib-0017-20250824","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1136\/gutjnl-2016-312975","article-title":"Fibroblast growth factor 15\/19 (FGF15\/19) protects from diet\u2010induced hepatic steatosis: development of an FGF19\u2010based chimeric molecule to promote fatty liver regeneration","volume":"66","year":"2017","journal-title":"Gut"},{"key":"hep32028-bib-0018-20250824","first-page":"357","article-title":"Expression of basic fibroblast growth factor and its receptor by fibroblast, macrophages and mast cells in hypertrophic scar","volume":"9","year":"1999","journal-title":"Eur J Dermatol"},{"key":"hep32028-bib-0019-20250824","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1038\/s41374-018-0101-0","article-title":"Ursodeoxycholate inhibits mast cell activation and reverses biliary injury and fibrosis in Mdr2(\u2212\/\u2212) mice and human primary sclerosing cholangitis","volume":"98","year":"2018","journal-title":"Lab Invest"},{"key":"hep32028-bib-0020-20250824","doi-asserted-by":"crossref","first-page":"82583","DOI":"10.18632\/oncotarget.19773","article-title":"Fibroblast growth factor modulates mast cell recruitment in a murine model of prostate cancer","volume":"8","year":"2017","journal-title":"Oncotarget"},{"key":"hep32028-bib-0021-20250824","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1126\/science.1072891","article-title":"A natural product that lowers cholesterol as an antagonist ligand for FXR","volume":"296","year":"2002","journal-title":"Science"},{"key":"hep32028-bib-0022-20250824","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1111\/j.1478-3231.2003.00876.x","article-title":"Evaluation of differential gene expression by microarray analysis in small and large cholangiocytes isolated from normal mice","volume":"23","year":"2003","journal-title":"Liver Int"},{"key":"hep32028-bib-0023-20250824","doi-asserted-by":"crossref","first-page":"10214","DOI":"10.1074\/jbc.M209323200","article-title":"Guggulsterone is a farnesoid X receptor antagonist in coactivator association assays but acts to enhance transcription of bile salt export pump","volume":"278","year":"2003","journal-title":"J Biol Chem"},{"key":"hep32028-bib-0024-20250824","article-title":"H2 histamine receptor Vivo\u2010Morpholino treatment ameliorates large bile duct damage in mice deficient in ATP binding cassette subfamily B member 4 (Abcb4\u2212\/\u2212) via down\u2010regulation of cAMP\/ERK signaling","year":"2020","journal-title":"Am J Pathol"},{"key":"hep32028-bib-0025-20250824","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1002\/hep.30150","article-title":"Ductular reaction in liver diseases: pathological mechanisms and translational significances","volume":"69","year":"2019","journal-title":"Hepatology"},{"key":"hep32028-bib-0026-20250824","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.3390\/cells8111429","article-title":"Mast cells in liver fibrogenesis","volume":"8","year":"2019","journal-title":"Cells"},{"key":"hep32028-bib-0027-20250824","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.clinre.2019.02.001","article-title":"Mast cell\u2010mediated splanchnic cholestatic inflammation","volume":"43","year":"2019","journal-title":"Clin Res Hepatol Gastroenterol"},{"key":"hep32028-bib-0028-20250824","doi-asserted-by":"crossref","first-page":"172458","DOI":"10.1016\/j.ejphar.2019.172458","article-title":"Mast cell\u2010mediated mechanistic pathways in organ transplantation","volume":"857","year":"2019","journal-title":"Eur J Pharmacol"},{"key":"hep32028-bib-0029-20250824","first-page":"161","article-title":"The role of transforming growth factor beta 1 under diseases of liver","volume":"62","year":"2017","journal-title":"Klin Lab Diagn"},{"key":"hep32028-bib-0030-20250824","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1016\/j.biopha.2017.11.083","article-title":"Obeticholic acid protects mice against lipopolysaccharide\u2010induced liver injury and inflammation","volume":"96","year":"2017","journal-title":"Biomed Pharmacother"},{"key":"hep32028-bib-0031-20250824","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1194\/jlr.M500427-JLR200","article-title":"Fxr\u2212\/\u2212 mice adapt to biliary obstruction by enhanced phase I detoxification and renal elimination of bile acids","volume":"47","year":"2006","journal-title":"J Lipid Res"},{"key":"hep32028-bib-0032-20250824","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.ajpath.2014.10.009","article-title":"The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats","volume":"185","year":"2015","journal-title":"Am J Pathol"},{"key":"hep32028-bib-0033-20250824","doi-asserted-by":"crossref","first-page":"2831","DOI":"10.1172\/JCI117988","article-title":"Mast cells and histamine contribute to bile acid\u2010stimulated secretion in the mouse colon","volume":"95","year":"1995","journal-title":"J Clin Invest"},{"key":"hep32028-bib-0034-20250824","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/0016-5085(91)90024-F","article-title":"Activation of mast cells by bile acids","volume":"101","year":"1991","journal-title":"Gastroenterology"},{"key":"hep32028-bib-0035-20250824","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1096\/fj.201800935RR","article-title":"Bile acids induce visceral hypersensitivity via mucosal mast cell\u2010to\u2010nociceptor signaling that involves the farnesoid X receptor\/nerve growth factor\/transient receptor potential vanilloid 1 axis","volume":"33","year":"2019","journal-title":"FASEB J"},{"key":"hep32028-bib-0036-20250824","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1093\/ecco-jcc\/jjaa021","article-title":"A pilot integrative analysis of colonic gene expression, gut microbiota, and immune infiltration in primary sclerosing cholangitis\u2010inflammatory bowel disease: association of disease with bile acid pathways","volume":"14","year":"2020","journal-title":"J Crohns Colitis"},{"key":"hep32028-bib-0037-20250824","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1194\/jlr.M088070","article-title":"Hydrophilic bile acids prevent liver damage caused by lack of biliary phospholipid in Mdr2(\u2212\/\u2212) mice","volume":"60","year":"2019","journal-title":"J Lipid Res"},{"key":"hep32028-bib-0038-20250824","doi-asserted-by":"crossref","first-page":"13462","DOI":"10.1038\/srep13462","article-title":"Expression of hepatic fibroblast growth factor 19 is enhanced in primary biliary cirrhosis and correlates with severity of the disease","volume":"5","year":"2015","journal-title":"Sci Rep"},{"key":"hep32028-bib-0039-20250824","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1007\/s40495-017-0085-2","article-title":"Role of FXR in liver inflammation during nonalcoholic steatohepatitis","volume":"3","year":"2017","journal-title":"Curr Pharmacol Rep"},{"key":"hep32028-bib-0040-20250824","first-page":"1170","article-title":"Long\u2010term obeticholic acid therapy improves histological endpoints in patients with primary biliary cholangitis","volume":"18","year":"2019","journal-title":"Clin Gastroenterol Hepatol"},{"key":"hep32028-bib-0041-20250824","doi-asserted-by":"crossref","first-page":"9039","DOI":"10.3748\/wjg.v22.i41.9039","article-title":"Emerging role of obeticholic acid in the management of nonalcoholic fatty liver disease","volume":"22","year":"2016","journal-title":"World J Gastroenterol"},{"key":"hep32028-bib-0042-20250824","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1111\/apt.12999","article-title":"The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid","volume":"41","year":"2015","journal-title":"Aliment Pharmacol Ther"},{"key":"hep32028-bib-0043-20250824","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.jhep.2019.10.003","article-title":"The gut\u2010liver axis in liver disease: pathophysiological basis for therapy","volume":"72","year":"2020","journal-title":"J Hepatol"},{"key":"hep32028-bib-0044-20250824","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1172\/JCI76738","article-title":"Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease","volume":"125","year":"2015","journal-title":"J Clin Invest"},{"key":"hep32028-bib-0045-20250824","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1016\/j.jhep.2019.06.017","article-title":"FXR modulates the gut\u2010vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis","volume":"71","year":"2019","journal-title":"J Hepatol"},{"key":"hep32028-bib-0046-20250824","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1111\/jgh.15225","article-title":"Vitamin D receptor is overexpressed in the duodenum of patients with irritable bowel syndrome","volume":"36","year":"2021","journal-title":"J Gastroenterol Hepatol"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.32028","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.32028","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.32028","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,24]],"date-time":"2025-08-24T23:08:41Z","timestamp":1756076921000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.32028"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,9]]},"references-count":46,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.32028","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,9]]},"assertion":[{"value":"2021-01-10","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-06-17","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}