Hepatology最新文献

{"title":"Saroglitazar improves hepatic steatosis and liver enzymes in women with polycystic ovary syndrome and MASLD: A multicenter, double-blind, placebo-controlled study","authors":"Niharika Samala, José González-González, Robert A Jenders, Monika Sarkar, Raymundo Garcia Reza, Fabian Rodas, Mark Kipnes, Efraín Montaño González, Heather G. Huddleston, Taufik Momin, Farheen Shaikh, Deven Parmar, Naga Chalasani","doi":"10.1097/hep.0000000000001862","DOIUrl":"https://doi.org/10.1097/hep.0000000000001862","url":null,"abstract":"Background and Aims: Polycystic ovary syndrome (PCOS) is the leading endocrine disorder in reproductive-age women. Metabolic dysfunction–associated steatotic liver disease (MASLD) is common in women with PCOS, but they are underrepresented in MASLD therapeutic trials. We evaluated the safety and efficacy of saroglitazar, a novel peroxisome proliferator–activated receptors α/γ agonist, for the treatment of hepatic steatosis in women with PCOS and MASLD. Methods: In this multicenter, randomized, double-blind, placebo-controlled phase 2A trial, 60 women (18–45 y) with PCOS and MASLD were randomized 1:1 to either saroglitazar 4 mg or placebo for 24 weeks. The primary endpoint was relative (percent) change in hepatic fat content, measured by MRI proton density fat fraction. Primary analysis was performed in the per-protocol population (saroglitazar: 25; placebo: 23). Results: Participants in the saroglitazar group showed a significant reduction in percent hepatic fat content at 24 weeks from baseline compared to placebo ([least squares mean±SE]: −14.81±5.52 vs. 1.96±5.75, <jats:italic toggle=\"yes\">p</jats:italic> =0.041). When controlled for baseline HbA1c imbalance, the beneficial effect of saroglitazar was more pronounced ([least squares mean±SE]: −18.93±4.83 vs. 6.43±5.04, <jats:italic toggle=\"yes\">p</jats:italic> &lt;0.009). A higher proportion in the saroglitazar group achieved ≥30% reduction in magnetic resonance imaging-proton density fat fraction (36.0% vs. 8.7%; <jats:italic toggle=\"yes\">p</jats:italic> =0.025). Saroglitazar also significantly reduced aminotransferase levels, lipid parameters, and the FibroScan AST score. Adverse events were comparable between the groups, and none were serious. One pregnancy in the saroglitazar arm resulted in uneventful maternal and neonatal outcomes. Conclusions: In women with PCOS and MASLD, saroglitazar significantly improved hepatic steatosis, liver enzymes, lipid profile, and FibroScan AST score. These findings support further evaluation of saroglitazar in larger studies in women with PCOS.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"21 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond the primary endpoint: Learning from \"negative\" AIH trials.","authors":"Silja Steinmann, Ansgar W Lohse","doi":"10.1097/HEP.0000000000001887","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001887","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149178226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Upholding telomeres prevents hepatic stellate cell transdifferentiation and liver fibrogenesis.","authors":"Lihui Wang, Huiwen Li, Long Yang, Jia Li, Jinghao Xia, Haoze Li, Ling Gao, Jun Zhang, Hongyan Wang, Jun Liu, Xiaojing Hong, Junping Shi, Jun-Ping Liu","doi":"10.1097/HEP.0000000000001889","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001889","url":null,"abstract":"<p><strong>Background aims: </strong>Hepatic stellate cells (HSCs) are principal drivers of liver cirrhosis. Whether and how telomere dysfunction affects HSC function remain unclear. This study was undertaken to investigate the role of telomere maintenance in HSCs during fibrogenesis and to evaluate its therapeutic potential by genetic and pharmacological means.</p><p><strong>Approach results: </strong>Liver fibrosis was established in mice treated with carbon tetrachloride (CCl4) or bile duct ligation (BDL), and characterized by tissue and molecular pathology and biochemistry, followed by HSC isolation using flow cytometry. Animals were engineered for HSC-specific overexpression of the telomerase reverse transcriptase (TERT) gene or Acd (encoding the shelterin component TPP1). Alternatively, mice were intraperitoneally injected with telomere dysfunction inhibitor (TELODIN), a D-amino acid octapeptide that stabilizes the telomerase activator TPP1. HSC-specific TERT expression alleviated hepatic fibrosis by suppressing HSC activation, proliferation, and transdifferentiation. Likewise, HSC-specific TPP1 overexpression mitigated hepatic fibrosis by preventing telomere dysfunction and shortening. Pharmacological stabilization of TPP1 by intraperitoneal administration of TELODIN counteracted hepatic fibrogenesis while maintaining HSC quiescence. Mechanistically, TELODIN stabilized TPP1, reduced telomere dysfunction, and decreased HSC transdifferentiation into profibrotic myofibroblasts.</p><p><strong>Conclusions: </strong>Telomere dysfunction mediates HSC transdifferentiation during experimental hepatic fibrogenesis. Targeted interventions - that increase telomerase activity or TPP1 mediated telomerase recruitment and activation - alleviate HSC-mediated fibrosis. Pharmacological administration of TELODIN effectively attenuates experimental liver fibrosis by restoring telomere homeostasis in HSCs.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149178292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cinderella no more: Alpha-1 antitrypsin deficiency-associated liver disease steps into the ballroom.","authors":"Malin Fromme, Fabienne Klebingat, Pavel Strnad","doi":"10.1097/HEP.0000000000001888","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001888","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149178234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autoimmune hepatitis and primary biliary cholangitis are among a subset of autoimmune diseases defined by profound co-prevalence and genetic risk association with the IL12 pathway.","authors":"Priyanka Nakka, Brian D Hobbs, Carlo Sidore, William H Palmer, Dana Murdock, Lauren Gurski, Arielle Glatman Zaretsky, Keran Moll, Adrian I Campos, Amit Joshi, Sheila M Gaynor, Rita Guerreiro, Jack A Kosmicki, Jing Tang, Anthony Marcketta, Antoine Baldassari, Tyler Joseph, Kyoko Watanabe, Sean Yu, Xiaodong Bai, Christopher E Gillies, Joelle Mbatchou, Kathie Sun, Liron Ganel, Veronica Mas Casullo, Stephen DiMartino, Gregory P Geba, Lili Zhang, Wen Zhu, Zongqi Xia, Olle Melander, Naga Chalasani, Bernhard Hemmer, Christiane Gasperi, Friederike Held, Paula Uibel, Marcus Jones, Alan R Shuldiner, Suganthi Balasubramanian, Maya Ghoussaini, Wenzhen Ge, Jeffrey G Reid, John D Overton, William J Salerno, Jonathan Marchini, Michael D Kessler, George D Yancopoulos, Jamie M Orengo, Aris Baras, Luca A Lotta, Gonçalo R Abecasis, Katherine Siminovitch, Manuel A R Ferreira","doi":"10.1097/HEP.0000000000001819","DOIUrl":"10.1097/HEP.0000000000001819","url":null,"abstract":"<p><strong>Background and aims: </strong>Distinct autoimmune diseases can share symptoms and autoantibodies, but the molecular pathways underlying this shared etiology remain poorly understood. We assessed genetic support for IL12 signaling across 27 diseases.</p><p><strong>Approach and results: </strong>We identified a rare variant upstream of IL12A with large risk-increasing effects on autoimmune hepatitis [AIH; per-allele odds ratio (OR)=2.98, p =3×10 -9 ], primary biliary cholangitis (PBC; OR=2.80, p =2×10 -8 ), systemic sclerosis (SSc; OR=2.64, p =2×10 -11 ), Sjogren's disease (SjD; OR=1.94, p =10 -11 ), systemic lupus erythematosus (SLE; OR=1.83, p =5×10 -10 ) and multiple sclerosis (OR=1.79, p =10 -11 ). Lifetime risk for developing at least one of these conditions increased 6-fold in homozygote carriers (OR=5.73, p =0.003). We then evaluated genetic support for all 4 IL12 signaling genes and found that: (i) a non-coding variant downstream of IL12A (linked to lower gene expression) protected against 5 of the 6 diseases; (ii) an intronic variant in IL12RB2 (linked to higher gene expression) increased risk of all 6 diseases; and (iii) heterozygote carriers of rare predicted loss-of-function or missense variants in IL12RB2 had 18% lower odds of SLE (OR=0.82, p =2×10 -5 ). IL23 signaling, which shares ligand and receptor subunits with IL12, was not associated with these conditions. In epidemiologic analyses of co-prevalence, 5 of the 6 diseases strongly co-occurred with each other: AIH, PBC, SSc, SjD and SLE.</p><p><strong>Conclusions: </strong>AIH, PBC, SSc, SjD and SLE represent a distinct subset of autoimmune diseases that share genetic associations with the IL12 pathway, as well as profound co-prevalence, suggesting they may have a shared etiology and may respond to the same targeted therapeutic intervention(s).</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149178263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum: Circular RNA sequencing identifies CircASAP1 as a key regulator in hepatocellular carcinoma metastasis.","authors":"Zhi-Qiang Hu, Shao-Lai Zhou, Jia Li, Zheng-Jun Zhou, Peng-Cheng Wang, Hao-Yang Xin, Li Mao, Chu-Bin Luo, Song-Yang Yu, Xiao-Wu Huang, Ya Cao, Jia Fan, Jian Zhou","doi":"10.1097/HEP.0000000000001845","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001845","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149178260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adjuvant pegylated interferon-alpha after nucleos(t)ide analog withdrawal drives a temporally coordinated expansion of regulatory B cells and contraction of HBV-specific T cells.","authors":"Sandra Phillips, Alice Burton, Helen Cooksley, Jessica Davies, Nicola Harris, Dhruti Devshi, Dimple Zope, Niyati Raj, Kornelija Suveizdyte, Emanuela Falaschetti, Hanna Box, Mariam Habib, Eleni Nastouli, Patrick F L Kennedy, Kaushik Agarwal, Jack Message, Mark Thursz, Shilpa Chokshi, Mala K Maini","doi":"10.1097/HEP.0000000000001839","DOIUrl":"10.1097/HEP.0000000000001839","url":null,"abstract":"<p><strong>Background and aims: </strong>The NUC-B study showed that a 4-month course of pegylated interferon-alpha (PEG-IFNα) enhanced the outcome and reduced hepatic flares following nucleos(t)ide analog (NUC) withdrawal in HBeAg-negative chronic hepatitis B. Here, we investigated differential T- and regulatory B-cell (B REG ) changes before and during these interventions in a substudy of 41 representative patients.</p><p><strong>Approach and results: </strong>Antigen-specific T cells were primarily evaluated using quality-controlled IFN-γ ELISpot with 15 pools of genotype-matched HBV core/small-surface peptides, confirmed by multiparameter flow cytometry. B-cell responses were tested with multiparameter flow cytometry and intracellular IL-10 staining. Broader baseline IFN-γ-producing-HBV-specific T cells correlated with higher sustained off-treatment viral control and reduced flares. PEG-IFNα led to a transient reduction in HBV-specific T cells that persisted for over 1 month after treatment. B REG producing the immunosuppressive cytokine IL-10 expanded more than 5-fold during adjuvant PEG-IFNα. The kinetics of B REG induction correlated with flares in both arms and showed a significant inverse temporal correlation with IFN-γ-producing-HBV-specific T-cell frequencies.</p><p><strong>Conclusions: </strong>Baseline breadth and magnitude of HBV-specific T cells should be evaluated as biomarkers to select patients more likely to have favorable outcomes with NUC withdrawal ±PEG-IFNα. The expansion of B REG provides insights into homeostatic mechanisms induced by PEG-IFNα and withdrawal flares, which could constrain HBV-specific T cells while limiting inflammation.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AASLD EXPO: Liver biopsy","authors":"Elizabeth C. Verna,Douglas G. Adler,Matthew R. Kappus,Elizabeth B. Rand,Elliot B. Tapper,Don C. Rockey","doi":"10.1097/hep.0000000000001828","DOIUrl":"https://doi.org/10.1097/hep.0000000000001828","url":null,"abstract":"Background: Liver biopsy is a foundational tool in hepatology, providing direct histologic assessment of hepatic parenchyma. Although noninvasive approaches have substantially reduced the need for biopsy in practice, it continues to play a critical role in diagnosis, staging, and therapeutic decision-making across a broad spectrum of liver disorders. Methods: This Expert Practice Opinion (EXPO) document was created by a writing group of subject matter experts appointed by the AASLD Practice Guidelines Committee. Writing group members performed a targeted literature review and created expert opinion statements that were unanimously agreed upon. Results: Histopathologic evaluation of the liver is utilized for 3 major indications: (1) to establish a diagnosis, (2) to stage the severity of inflammation and/or fibrosis, and (3) to enhance clinical management of liver disease. Liver biopsy can be performed using a percutaneous, transjugular, or endoscopic ultrasound approach. Percutaneous liver biopsy is used in most patients, though transjugular liver biopsy is often performed in those with ascites or coagulopathy and/or when hepatic venous pressure gradient measurement is desired. Endoscopic ultrasound–guided liver biopsy is particularly attractive when endoscopy to evaluate and treat varices or portal pressure gradient measurement is desired. The different biopsy techniques appear to have similar safety profiles and yield adequate tissue when performed by experts. Liver biopsy has limitations, including sampling variability, interobserver differences in interpretation, and procedural complications. Conclusions: Liver biopsy continues to play an essential role in contemporary hepatology practice. Recent advances include the introduction of endoscopic ultrasound liver biopsy. Evolving applications—including the potential for molecular profiling, use of digital pathology, and assessment of therapeutic response—underscore the continued relevance of tissue-based evaluation in precision hepatology.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"9 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149089451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An international multicenter analysis of the outcome of pediatric first variceal hemorrhage","authors":"Benjamin L. Shneider,Xiaotian Gao,Kexin Guo,Catalina Jaramillo,Jean P. Molleston,Julio Pimenta,Riccardo Superina,Alexandre Ferreira,Alexis J. Gumm,Amal Aqul,Amy G. Feldman,Angelo Di Giorgio,Anita K. Pai,Anja Praprotnik Novak,Antoine Gardin,Carolina Jimenez-Rivera,César Ulises Amaro-Reynoso,Chaitri Desai,Dariia Voroniak,Denise Aldrian,Elizabeth Bannister,Eyal Shteyer,Georg F. Vogel,Giuseppe Indolfi,Hubert P.J. van der Doef,James E. Squires,Jane L. Hartley,JC Gana,Jesus Quintero- Bernabéu,Jordache Taylor,Katherine Sweeny,Kee-Seang Chew,Keith Z. Hazleton,Lee M. Bass,Maria Mercadal-Hally,Marianna Durilova,Matjaž Homan,Mercedes Martinez,Mohit Kehar,Mureo Kasahara,Oleg Godik,Orith Waisbourd-Zinman,Pamela L. Valentino,Pooja R. Spector,Rima Fawaz,Rodrigo Vázquez-Frias,Rustam Yuldashev,Ryuji Komine,Sakil Kulkarni,Samar H. Ibrahim,Sarah Bedoyan,Sara Kathryn Smith,Scott A. Elisofon,Simon Lam,Shinya Yokoyama,Simona Carrera,Songpon Getsuwan,Suporn Treepongkaruna,Sarah Berkenfeld,Thomai Kotsou,Deborah Goldman,Voytek Slowik,Way-Seah Lee,Wikrom Karnsakul,Winita Hardikar,Yael Mozer-Glassberg,Roberto De Franchis,Oanez Ackermann,Tassos Grammatikopoulos","doi":"10.1097/hep.0000000000001881","DOIUrl":"https://doi.org/10.1097/hep.0000000000001881","url":null,"abstract":"Background &amp; Aims: Management of portal hypertension in children including primary prophylaxis of variceal bleeding is controversial due to limited understanding of mortality risk after first variceal hemorrhage (1VH). This international multicenter study was designed to advance understanding of outcomes after pediatric 1VH. Approach &amp; Results: Center-specific characteristics and approaches to portal hypertension were determined at 44 international sites. K-means clustered the centers based upon volume and complexity of approaches [cluster 1 high (n=5), cluster 2 low (n=21), cluster 3 intermediate (n=18]). Clinical features and outcomes after 1VH were available from 345 subjects. Factors associated with overall survival (OS) and survival with native liver (SNL) were estimated by Kaplan-Meier survival curves, log rank tests, univariable and multivariable Cox regression models. OS and SNL were high in portal vein thrombosis and noncirrhotic diseases and significantly higher than biliary atresia and cirrhotic diseases ( p &lt;.001). Diminished SNL was observed in decompensated disease [diuretics (i.e. ascites) or hospitalization at 1VH], biliary atresia with poor bile flow, cirrhotic disease, after sclerotherapy or no endoscopic intervention. Diminished OS was noted in those with cirrhosis or requiring sclerotherapy. 6-week mortality was determined and compared among clusters using average treatment effect under the Rubin causal model. Overall 6-week mortality was 4.1%, 1.4% in nonhospitalized subjects and was significantly higher in cluster 2 versus 1 centers ( P =.010). Conclusions: Immediate mortality after 1VH in children is low compared to adults. Outcomes after 1VH are diagnosis-specific and worse in decompensated disease and after sclerotherapy. Center-specific factors may influence immediate outcomes after 1VH.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"21 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149092044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering the post-transcriptional code in tumor progression: CPEB3 links genetic variation to alternative polyadenylation in hepatocellular carcinoma","authors":"Kai Wang,Mulong Du","doi":"10.1097/hep.0000000000001882","DOIUrl":"https://doi.org/10.1097/hep.0000000000001882","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"36 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149089448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}