{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T01:44:12Z","timestamp":1778636652468,"version":"3.51.4"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":7,"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":[[2015,10]]},"abstract":"<jats:p>Certain nucleoside\/nucleotide reverse transcriptase (RT) inhibitors (NRTIs) are effective against human immunodeficiency virus type 1 (HIV\u20101) and hepatitis B virus (HBV). However, both viruses often acquire NRTI resistance, making it crucial to develop more\u2010potent agents that offer profound viral suppression. Here, we report that 4\u2032\u2010C\u2010cyano\u20102\u2010amino\u20102\u2032\u2010deoxyadenosine (CAdA) is a novel, highly potent inhibitor of both HBV (half maximal inhibitory concentration [IC<jats:sub>50<\/jats:sub>]\u2009=\u20090.4 nM) and HIV\u20101 (IC<jats:sub>50<\/jats:sub>\u2009=\u20090.4 nM). In contrast, the approved anti\u2010HBV NRTI, entecavir (ETV), potently inhibits HBV (IC<jats:sub>50<\/jats:sub>\u2009=\u20090.7 nM), but is much less active against HIV\u20101 (IC<jats:sub>50<\/jats:sub>\u2009=\u20091,000 nM). Similarly, the highly potent HIV\u20101 inhibitor, 4\u2032\u2010ethynyl\u20102\u2010fluoro\u20102\u2032\u2010deoxyadenosine (EFdA; IC<jats:sub>50<\/jats:sub>\u2009=\u20090.3 nM) is less active against HBV (IC<jats:sub>50<\/jats:sub>\u2009=\u2009160 nM). Southern analysis using Huh\u20107 cells transfected with HBV\u2010containing plasmids demonstrated that CAdA was potent against both wild\u2010type (IC<jats:sub>50<\/jats:sub>\u2009=\u20097.2 nM) and ETV\u2010resistant HBV (IC<jats:sub>50<\/jats:sub>\u2009=\u200969.6 nM for \n\n                              \n                                 \n                              \n                           ), whereas ETV failed to reduce \n\n                              \n                                 \n                              \n                            DNA even at 1 \u03bcM. Once\u2010daily peroral administration of CAdA reduced \n\n                              \n                                 \n                              \n                            viremia (<jats:italic toggle=\"yes\">P<\/jats:italic>\u2009=\u20090.0005) in human\u2010liver\u2010chimeric\/\n\n                              \n                                 \n                              \n                           \u2013infected mice, whereas ETV completely failed to reduce \n\n                              \n                                 \n                              \n                            viremia. None of the mice had significant drug\u2010related body\u2010weight or serum human\u2010albumin concentration changes. Molecular modeling suggests that a shallower HBV\u2010RT hydrophobic pocket at the polymerase active site can better accommodate the slightly shorter 4\u2032\u2010cyano of CAdA\u2010triphosphate (TP), but not the longer 4\u2032\u2010ethynyl of EFdA\u2010TP. In contrast, the deeper HIV\u20101\u2010RT pocket can efficiently accommodate the 4\u2032\u2010substitutions of both NRTIs. The ETV\u2010TP's cyclopentyl ring can bind more efficiently at the shallow HBV\u2010RT binding pocket. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: These data provide insights on the structural and functional associations of HBV\u2010 and HIV\u20101\u2010RTs and show that CAdA may offer new therapeutic options for HBV patients. (H<jats:sc>epatology<\/jats:sc> 2015;62:1024\u20101036)<\/jats:p>","DOI":"10.1002\/hep.27962","type":"journal-article","created":{"date-parts":[[2015,6,29]],"date-time":"2015-06-29T23:11:24Z","timestamp":1435619484000},"page":"1024-1036","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":50,"title":["4\u2032\u2010modified nucleoside analogs: Potent inhibitors active against entecavir\u2010resistant hepatitis B virus"],"prefix":"10.1097","volume":"62","author":[{"given":"Yuki","family":"Takamatsu","sequence":"first","affiliation":[{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch,National Cancer Institute, National Institutes of Health,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuhito","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Virology & Liver Unit,Nagoya City University Graduate School of Medical Sciences,Nagoya,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoru","family":"Kohgo","sequence":"additional","affiliation":[{"name":"Research Institute & Center for Clinical Sciences,National Center for Global Health and Medicine,Tokyo,Japan"},{"name":"Department of Pharmaceutical Sciences,Nihon Pharmaceutical University,Saitama,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuko","family":"Murakami","sequence":"additional","affiliation":[{"name":"Department of Virology & Liver Unit,Nagoya City University Graduate School of Medical Sciences,Nagoya,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamalendra","family":"Singh","sequence":"additional","affiliation":[{"name":"Molecular Microbiology & Immunology, Biochemistry,School of Medicine and Bond Life Sciences Center, University of Missouri,Columbia,MO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debananda","family":"Das","sequence":"additional","affiliation":[{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch,National Cancer Institute, National Institutes of Health,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Venzon","sequence":"additional","affiliation":[{"name":"Biostatistics and Data Management Section,National Cancer Institute, National Institutes of Health,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayuki","family":"Amano","sequence":"additional","affiliation":[{"name":"Departments of Hematology, Rheumatology, and Clinical Immunology & Infectious Disease,Kumamoto University Graduate School of Medical Sciences,Kumamoto,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nobuyo","family":"Higashi\u2010Kuwata","sequence":"additional","affiliation":[{"name":"Research Institute & Center for Clinical Sciences,National Center for Global Health and Medicine,Tokyo,Japan"},{"name":"Departments of Hematology, Rheumatology, and Clinical Immunology & Infectious Disease,Kumamoto University Graduate School of Medical Sciences,Kumamoto,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manabu","family":"Aoki","sequence":"additional","affiliation":[{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch,National Cancer Institute, National Institutes of Health,Bethesda,MD"},{"name":"Departments of Hematology, Rheumatology, and Clinical Immunology & Infectious Disease,Kumamoto University Graduate School of Medical Sciences,Kumamoto,Japan"},{"name":"Department of Medical Technology,Kumamoto Health Science University,Kumamoto,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole S.","family":"Delino","sequence":"additional","affiliation":[{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch,National Cancer Institute, National Institutes of Health,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanae","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Department of Virology & Liver Unit,Nagoya City University Graduate School of Medical Sciences,Nagoya,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoru","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology & Tumor Biology,Nagoya City University Graduate School of Medical Sciences,Nagoya,Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshikazu","family":"Sukenaga","sequence":"additional","affiliation":[{"name":"Research Institute & Center for Clinical Sciences,National Center for Global Health and Medicine,Tokyo,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiro","family":"Haraguchi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences,Nihon Pharmaceutical University,Saitama,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan G.","family":"Sarafianos","sequence":"additional","affiliation":[{"name":"Molecular Microbiology & Immunology, Biochemistry,School of Medicine and Bond Life Sciences Center, University of Missouri,Columbia,MO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Maeda","sequence":"additional","affiliation":[{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch,National Cancer Institute, National Institutes of Health,Bethesda,MD"},{"name":"Research Institute & Center for Clinical Sciences,National Center for Global Health and Medicine,Tokyo,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroaki","family":"Mitsuya","sequence":"additional","affiliation":[{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch,National Cancer Institute, National Institutes of Health,Bethesda,MD"},{"name":"Research Institute & Center for Clinical Sciences,National Center for Global Health and Medicine,Tokyo,Japan"},{"name":"Departments of Hematology, Rheumatology, and Clinical Immunology & Infectious Disease,Kumamoto University Graduate School of Medical Sciences,Kumamoto,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2015,8,25]]},"reference":[{"key":"hep27962-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1093\/epirev\/mxj009","article-title":"Hepatitis B virus infection: epidemiology and vaccination","volume":"28","year":"2006","journal-title":"Epidemiol Rev"},{"key":"hep27962-bib-0002-20241017","first-page":"1","article-title":"Surveillance for acute viral hepatitis\u2014United States, 2007","volume":"58","year":"2009","journal-title":"MMWR Surveill Summ"},{"key":"hep27962-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1086\/653622","article-title":"The prevalence of hepatitis B virus infection in the United States in the era of vaccination","volume":"202","year":"2010","journal-title":"J Infect Dis"},{"key":"hep27962-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1016\/S0140-6736(02)11913-1","article-title":"HIV\u20101, hepatitis B virus, and risk of liver\u2010related mortality in the Multicenter Cohort Study (MACS)","volume":"360","year":"2002","journal-title":"Lancet"},{"key":"hep27962-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1086\/507532","article-title":"Antiretroviral therapy for hepatitis B virus\u2010HIV\u2010coinfected patients: promises and pitfalls","volume":"43","year":"2006","journal-title":"Clin Infect Dis"},{"key":"hep27962-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"2682","DOI":"10.1056\/NEJMoa043470","article-title":"Peginterferon Alfa\u20102a, lamivudine, and the combination for HBeAg\u2010positive chronic hepatitis B","volume":"352","year":"2005","journal-title":"N Engl J Med"},{"key":"hep27962-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1053\/j.gastro.2008.05.031","article-title":"Sustained HBeAg and HBsAg loss after long\u2010term follow\u2010up of HBeAg\u2010positive patients treated with peginterferon alpha\u20102b","volume":"135","year":"2008","journal-title":"Gastroenterology"},{"key":"hep27962-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1128\/AAC.46.8.2525-2532.2002","article-title":"Efficacies of entecavir against lamivudine\u2010resistant hepatitis B virus replication and recombinant polymerases in vitro","volume":"46","year":"2002","journal-title":"Antimicrob Agents Chemother"},{"key":"hep27962-bib-0009-20241017","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1097\/00002030-200109070-00013","article-title":"The safety and efficacy of adefovir dipivoxil in patients with advanced HIV disease: a randomized, placebo\u2010controlled trial","volume":"15","year":"2001","journal-title":"AIDS"},{"key":"hep27962-bib-0010-20241017","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1086\/368314","article-title":"Tenofovir\u2010related nephrotoxicity in human immunodeficiency virus\u2010infected patients: three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus","volume":"36","year":"2003","journal-title":"Clin Infect Dis"},{"key":"hep27962-bib-0011-20241017","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1002\/tcr.20078","article-title":"2\u2032\u2010Deoxy\u20104\u2032\u2010C\u2010ethynyl\u20102\u2010fluoroadenosine, a nucleoside reverse transcriptase inhibitor, is highly potent against all human immunodeficiency viruses type 1 and has low toxicity","volume":"6","year":"2006","journal-title":"Chem Rec"},{"key":"hep27962-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"2701","DOI":"10.1128\/AAC.00277-07","article-title":"Activity against human immunodeficiency virus type 1, intracellular metabolism, and effects on human DNA polymerases of 4\u2032\u2010ethynyl\u20102\u2010fluoro\u20102\u2032\u2010deoxyadenosine","volume":"51","year":"2007","journal-title":"Antimicrob Agents Chemother"},{"key":"hep27962-bib-0013-20241017","doi-asserted-by":"crossref","first-page":"2410","DOI":"10.1016\/j.biocel.2008.04.007","article-title":"2\u2032\u2010Deoxy\u20104\u2032\u2010C\u2010ethynyl\u20102\u2010halo\u2010adenosines active against drug\u2010resistant human immunodeficiency virus type 1 variants","volume":"40","year":"2008","journal-title":"Int J Biochem Cell Biol"},{"key":"hep27962-bib-0014-20241017","doi-asserted-by":"crossref","first-page":"3887","DOI":"10.1128\/AAC.00270-09","article-title":"Potent activity of a nucleoside reverse transcriptase inhibitor, 4\u2032\u2010ethynyl\u20102\u2010fluoro\u20102\u2032\u2010deoxyadenosine, against human immunodeficiency virus type 1 infection in a model using human peripheral blood mononuclear cell\u2010transplanted NOD\/SCID Janus kinase 3 knockout mice","volume":"53","year":"2009","journal-title":"Antimicrob Agents Chemother"},{"key":"hep27962-bib-0015-20241017","doi-asserted-by":"crossref","first-page":"35681","DOI":"10.1074\/jbc.M109.036616","article-title":"Mechanism of inhibition of HIV\u20101 reverse transcriptase by 4\u2032\u2010Ethynyl\u20102\u2010fluoro\u20102\u2032\u2010deoxyadenosine triphosphate, a translocation\u2010defective reverse transcriptase inhibitor","volume":"284","year":"2009","journal-title":"J Biol Chem"},{"key":"hep27962-bib-0016-20241017","doi-asserted-by":"crossref","first-page":"4707","DOI":"10.1128\/AAC.00723-12","article-title":"Response of simian immunodeficiency virus to the novel nucleoside reverse transcriptase inhibitor 4\u2032\u2010ethynyl\u20102\u2010fluoro\u20102\u2032\u2010deoxyadenosine in vitro and in vivo","volume":"56","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"key":"hep27962-bib-0018-20241017","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1081\/NCN-120037508","article-title":"Design, efficient synthesis, and anti\u2010HIV activity of 4\u2032\u2010C\u2010cyano\u2010 and 4\u2032\u2010C\u2010ethynyl\u20102\u2032\u2010deoxy purine nucleosides","volume":"23","year":"2004","journal-title":"Nucleosides Nucleotides Nucleic Acids"},{"key":"hep27962-bib-0019-20241017","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1002\/hep.21345","article-title":"Influence of hepatitis B virus genotypes on the intra\u2010 and extracellular expression of viral DNA and antigens","volume":"44","year":"2006","journal-title":"Hepatology"},{"key":"hep27962-bib-0020-20241017","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1073\/pnas.84.4.1005","article-title":"Production of hepatitis B virus particles in HepG2 cells transfected with cloned hepatitis B virus DNA","volume":"84","year":"1987","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep27962-bib-0021-20241017","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1128\/AAC.46.3.716-723.2002","article-title":"Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors","volume":"46","year":"2002","journal-title":"Antimicrob Agents Chemother"},{"key":"hep27962-bib-0022-20241017","first-page":"2218","article-title":"2,6\u2010Diaminopurinedeoxyriboside as a prodrug of deoxyguanosine in L1210 cells","volume":"47","year":"1987","journal-title":"Cancer Res"},{"key":"hep27962-bib-0023-20241017","doi-asserted-by":"crossref","first-page":"7096","DOI":"10.1073\/pnas.82.20.7096","article-title":"3\u2032\u2010Azido\u20103\u2032\u2010deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T\u2010lymphotropic virus type III\/lymphadenopathy\u2010associated virus in vitro","volume":"82","year":"1985","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep27962-bib-0024-20241017","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/325773a0","article-title":"Strategies for antiviral therapy in AIDS","volume":"325","year":"1987","journal-title":"Nature"},{"key":"hep27962-bib-0025-20241017","doi-asserted-by":"crossref","first-page":"4771","DOI":"10.1128\/JVI.75.10.4771-4779.2001","article-title":"Molecular modeling and biochemical characterization reveal the mechanism of hepatitis B virus polymerase resistance to lamivudine (3TC) and emtricitabine (FTC)","volume":"75","year":"2001","journal-title":"J Virol"},{"key":"hep27962-bib-0026-20241017","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1002\/hep.510270628","article-title":"Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group","volume":"27","year":"1998","journal-title":"Hepatology"},{"key":"hep27962-bib-0027-20241017","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1177\/135965350400900203","article-title":"Comparisons of the HBV and HIV polymerase, and antiviral resistance mutations","volume":"9","year":"2004","journal-title":"Antivir Ther"},{"key":"hep27962-bib-0028-20241017","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1021\/jm00086a013","article-title":"Synthesis and anti\u2010HIV activity of 4\u2032\u2010azido\u2010 and 4\u2032\u2010methoxynucleosides","volume":"35","year":"1992","journal-title":"J Med Chem"},{"key":"hep27962-bib-0029-20241017","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S0040-4039(00)77667-2","article-title":"Synthesis of 4\u2032\u2010cyanothymidine and analogs as potent inhibitors of HIV","volume":"33","year":"1992","journal-title":"Tetrahedron Lett"},{"key":"hep27962-bib-0030-20241017","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1093\/nass\/42.1.127","article-title":"Synthesis of 4\u2032\u2010substituted nucleosides and their biological evaluation","volume":"42","year":"1999","journal-title":"Nucleic Acids Symp Ser"},{"key":"hep27962-bib-0031-20241017","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1128\/AAC.45.5.1539-1546.2001","article-title":"4\u2032\u2010Ethynyl nucleoside analogs: potent inhibitors of multidrug\u2010resistant human immunodeficiency virus variants in vitro","volume":"45","year":"2001","journal-title":"Antimicrob Agents Chemother"},{"key":"hep27962-bib-0032-20241017","doi-asserted-by":"crossref","first-page":"179","DOI":"10.3851\/IMP2697","article-title":"Delayed emergence of HIV\u20101 variants resistant to 4\u2032\u2010ethynyl\u20102\u2010fluoro\u20102\u2032\u2010deoxyadenosine: comparative sequential passage study with lamivudine, tenofovir, emtricitabine and BMS\u2010986001","volume":"19","year":"2014","journal-title":"Antivir Ther"},{"key":"hep27962-bib-0033-20241017","doi-asserted-by":"crossref","first-page":"24533","DOI":"10.1074\/jbc.M114.562694","article-title":"4\u2032\u2010Ethynyl\u20102\u2010fluoro\u20102\u2032\u2010deoxyadenosine (EFdA) inhibits HIV\u20101 reverse transcriptase with multiple mechanisms","volume":"289","year":"2014","journal-title":"J Biol Chem"},{"key":"hep27962-bib-0034-20241017","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1056\/NEJMra0801644","article-title":"Hepatitis B virus infection","volume":"359","year":"2008","journal-title":"N Engl J Med;"},{"key":"hep27962-bib-0035-20241017","first-page":"32080","article-title":"Long\u2010term therapy with clevudine for chronic hepatitis B can be associated with myopathy characterized by depletion of mitochondrial DNA","volume":"49","year":"2009","journal-title":"Hepatology"},{"key":"hep27962-bib-0036-20241017","doi-asserted-by":"crossref","first-page":"3200","DOI":"10.1128\/AAC.42.12.3200","article-title":"In vitro inhibition of hepadnavirus polymerases by the triphosphates of BMS\u2010200475 and lobucavir","volume":"42","year":"1998","journal-title":"Antimicrob Agents Chemother"},{"key":"hep27962-bib-0037-20241017","first-page":"pii","article-title":"Characterization of novel entecavir resistance mutations","year":"2015","journal-title":"J Hepatol"},{"key":"hep27962-bib-0038-20241017","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1128\/AAC.37.10.2247","article-title":"Metabolism and in vitro antiretroviral activities of bis(pivaloyloxymethyl) prodrugs of acyclic nucleoside phosphonates","volume":"37","year":"1993","journal-title":"Antimicrob Agents Chemother"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.27962","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201510000-00010","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T00:31:29Z","timestamp":1729211489000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201510000-00010"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,8,25]]},"references-count":37,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2015]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.27962","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8,25]]},"assertion":[{"value":"2014-12-12","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-06-24","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}