Hepatology最新文献

{"title":"International trends in biliary tract cancer-related mortality, 2000–2022: An observational study of the World Health Organization mortality database","authors":"Quynh Thi Vu, Yoshito Nishimura, Ko Harada, Hiroki Ito, Tsukasa Higashionna, Akinari Maruo, Keisaku Harada, Tatsuaki Takeda, Hirofumi Hamano, Yoshito Zamami, Hideharu Hagiya, Toshihiro Koyama","doi":"10.1097/hep.0000000000001200","DOIUrl":"https://doi.org/10.1097/hep.0000000000001200","url":null,"abstract":"Background & Aims: Biliary tract cancers (BTCs), including intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), gallbladder cancer (GBC), and ampullary cancer, exhibit poor prognosis. This study examined temporal trends in mortality due to BTCs and their major subtypes at international, regional, and national levels. Approach & Results: This observational study used the World Health Organization mortality database. Locally weighted regression (LOESS) was used to produce a smoothed curve of long-term international and regional BTC and major subtype-related mortality rates in 2000–2022 based on available data from countries. Trends in age-standardised mortality rates (ASRs) during 2013–2022 for individual countries were examined using joinpoint regression analysis. Internationally, LOESS-smoothed ASRs per 100,000 population due to BTCs were 2.8 (95% confidence interval: 2.5–3.1) in 2000, and 2.7 (2.3–3.1) in 2022. LOESS-smoothed BTC-related ASRs were the highest in the Western Pacific region at 4.2 (1.8–6.6) in 2022, compared with those in the European and American regions at 2.6 (2.3–2.9) and 2.2 (1.8–2.6), respectively. Among major subtypes, LOESS-smoothed ASRs due to iCCA increased by 120.0%, those due to GBC decreased by 45.5%, and those due to eCCA remained stable between 2000 and 2022. Disparities in BTC and major subtype-related ASR trends were observed between countries during 2013–2022, with iCCA-associated ASRs showing increasing trends in many countries. Conclusions: Although internationally estimated BTC-associated ASRs showed a stable trend over the last two decades, a large increase in estimated iCCA-associated ASRs necessitates developing effective screening for high-risk individuals and disease management strategies.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"13 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858291","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":"Enhancing HBV-specific T cell responses through a combination of epigenetic modulation and immune checkpoint inhibition","authors":"Melanie Urbanek-Quaing, Yin-Han Chou, Manoj Kumar Gupta, Katja Steppich, Birgit Bremer, Hagen Schmaus, Katja Deterding, Benjamin Maasoumy, Heiner Wedemeyer, Cheng-Jian Xu, Anke R. M. Kraft, Markus Cornberg","doi":"10.1097/hep.0000000000001202","DOIUrl":"https://doi.org/10.1097/hep.0000000000001202","url":null,"abstract":"Objective: Chronic HBV infection (CHB) exhausts HBV-specific T cells, develops epigenetic imprints that impair immune responses, and limits the effectiveness of immune checkpoint inhibitor (ICI) monotherapy, such as αPD-L1. This study aimed to determine whether the DNA methyltransferase inhibitor decitabine (DAC) could reverse these epigenetic imprints and enhance ICI efficacy in restoring HBV-specific T cell responses. Methods: We investigated HBV-specific T cell responses by 10-day <jats:italic toggle=\"yes\">in vitro</jats:italic> stimulation of peripheral blood mononuclear cells (PBMCs) from patients with CHB. PBMCs were stimulated with HBV core-specific overlapping peptide pools and HLA-A*02-restricted peptides, core<jats:sub>18</jats:sub> and pol<jats:sub>455</jats:sub>. The immunomodulatory effect of the DAC/αPD-L1 combination was assessed by flow cytometry, and our analysis included clinical characteristics, <jats:italic toggle=\"yes\">ex vivo</jats:italic> DNA methylation of PBMCs, and IFNγ plasma levels. Results: Treatment with DAC/αPD-L1 enhanced HBV-specific CD4<jats:sup>+</jats:sup> T cell responses in a significant proportion of 53 patients, albeit with some variability. This effect was independent of the HBcrAg levels. <jats:italic toggle=\"yes\">Ex vivo</jats:italic> DNA methylation revealed hypermethylation of key genes, such as <jats:italic toggle=\"yes\">IFNG</jats:italic> among DAC-responders versus non-responders, supported by altered <jats:italic toggle=\"yes\">ex vivo</jats:italic> IFNγ plasma levels. Further analysis of HBV-specific CD8<jats:sup>+</jats:sup> T cell responses in 22 HLA-A*02-positive patients indicated distinct response patterns between core<jats:sub>18</jats:sub> and pol<jats:sub>455</jats:sub> stimulation, with pol<jats:sub>455</jats:sub>-specific CD8<jats:sup>+</jats:sup> T cells showing increased susceptibility to DAC/αPD-L1, surpassing the αPD-L1 monotherapy response. Conclusions: The combination of DAC/αPD-L1 shows promise in improving HBV-specific T cell responses <jats:italic toggle=\"yes\">in vitro</jats:italic>, highlighting the potential of remodeling exhaustion-associated epigenetic signatures to enhance HBV-specific T cell restoration and suggesting a novel immunotherapeutic avenue for CHB.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"100 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858256","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":"Value of HCC surveillance in a landscape of emerging surveillance options: Perspectives of a multi-stakeholder modified delphi panel.","authors":"Amit G Singal, Lisa Quirk, Justin Boike, Victoria Chernyak, Ziding Feng, Giamarqo Giamarqo, Fasiha Kanwal, George N Ioannou, Sarah Manes, Jorge A Marrero, Neil Mehta, Anjana Pillai, Nicholas J Shaheen, Aasma Shaukat, Claude B Sirlin, Elizabeth Verna, Sachin Wani, Andrea Wilson Woods, Ju Dong Yang, Neehar D Parikh","doi":"10.1097/HEP.0000000000001203","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001203","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) surveillance is recommended by liver professional societies but lacks broad acceptance by several primary care and cancer societies due to limitations in the existing data. We convened a diverse multidisciplinary group of cancer screening experts to evaluate current and future paradigms of HCC prevention and early detection using a rigorous Delphi panel approach. The experts had high agreement on twenty-one statements about primary prevention, HCC surveillance benefits, HCC surveillance harms, and the evaluation of emerging surveillance modalities. The experts agreed that current data have methodologic limitations as well as unclear generalizability to Western populations. Although a randomized clinical trial of surveillance versus no surveillance is unlikely feasible, they concurred that alternative designs such as a comparison of two surveillance modalities could provide indirect evidence of surveillance efficacy. The panel acknowledged the presence of surveillance harms, but concurred the overall value of surveillance appears high, particularly given a greater emphasis on benefits over harms by both patients and clinicians. The experts underscored the importance of a framework of measuring both benefits and harms when evaluating emerging surveillance strategies. The panel acknowledged performance metrics of emerging methods may differ from other cancer screening programs given differences in populations, including higher risk of cancer development and competing risk of morality, and differences in diagnostic workflow in patients at risk of HCC. These data provide insights into the perceived value of HCC surveillance in an era of emerging blood- and imaging-based surveillance strategies.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851802","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":"Lhx2 specifically expressed in hepatic stellate cells promotes liver regeneration and inhibits liver fibrosis","authors":"Jiawang Tao, Zichao Wu, Yanran Liang, Jiongliang Wang, Miaoxiu Tang, Sunan Huang, Fan Jiang, Guangqi Zhou, Lin Guo, Shengxian Yuan, Yinxiong Li, Jie Wang","doi":"10.1097/hep.0000000000001201","DOIUrl":"https://doi.org/10.1097/hep.0000000000001201","url":null,"abstract":"Background and Aims: Promoting liver regeneration while inhibiting fibrogenesis represented an attractive strategy for treating liver diseases, with hepatic stellate cells (HSCs) being crucial to both processes. This study aimed to identify specific targets in HSCs that simultaneously facilitated regeneration and suppressed fibrosis, and elucidated their molecular mechanisms. Approach and Results: Through comparing acute and chronic liver injury mouse models induced by CCl<jats:sub>4</jats:sub> injections, we revealed that HSCs exhibited dual functionality, expressing pro-regenerative and pro-fibrogenic genes following injury. Analyzing RNA-seq data from primary HSCs of these models, along with publicly available single-cell RNA-seq data of HSCs, we identified transcription factor Lhx2, specifically expressed in HSCs, emerged as a potential regulator of the dual functions. Notably, Lhx2 showed significantly higher expression in HSCs from healthy liver tissue compared to fibrotic liver, in both mouse and human models. Lhx2 knockdown impaired liver function recovery and cellular proliferation after acute liver injury. Consistent changes were observed in mice with HSC-specific Lhx2 overexpression. Additionally, Lhx2 overexpression not only promoted hepatocyte proliferation but also exhibited an anti-fibrogenic function after chronic injury. Mechanistically, Lhx2 suppressed multiple functions of activated HSCs, including fibrogenesis, proliferation and migration, and up-regulated SMAD6 to block TGF-β signaling pathway. Moreover, Lhx2 was an upstream regulator of various pro-regenerative factors, especially HGF, which is crucial for liver regeneration. Conclusions: We demonstrated that Lhx2 had pro-regenerative and anti-fibrogenic functions, and elucidated its regulatory mechanism. The study provided a potential target with dual effects for treating liver diseases.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"25 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848849","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":"Reply: A positive step toward cost-effective and accessible HCC detection awaits further validation","authors":"Hashem B. El-Serag, Qingchun Jin, Tayob Nabihah","doi":"10.1097/hep.0000000000001207","DOIUrl":"https://doi.org/10.1097/hep.0000000000001207","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"31 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848988","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":"Interleukin 8-CXCR2 mediated neutrophil extracellular trap (NET) formation in biliary atresia associated with NET-Induced stellate cell activation.","authors":"Yuhuan Luo, Lisa Fraser, Julia Jezykowski, Nitika A Gupta, Alexander G Miethke, Sarah A Taylor, Estella M Alonso, Simon Horslen, Rohit Kohli, Jean P Molleston, Binita M Kamath, Stephen L Guthery, Kathleen M Loomes, John C Magee, Phillip Rosenthal, Pamela Valentino, Ronald J Sokol, Cara L Mack","doi":"10.1097/HEP.0000000000001195","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001195","url":null,"abstract":"<p><strong>Background aims: </strong>Biliary atresia (BA) entails an inflammatory sclerosing lesion of the biliary tree, with prominent fibrosis in infancy. Previous studies revealed neutrophil-activating IL-8 and neutrophil extracellular traps (NETs) positively correlated with bilirubin and risk of liver transplant. The aims of this study were to determine the mechanism of NET formation (NETosis) in BA and if NETs induce stellate cell activation.</p><p><strong>Approach: </strong>BA and other liver disease control plasma and tissue were obtained at diagnosis and transplant. Elastase, NETs, & IL-8 were quantified by ELISA for plasma and by immunohistochemistry (IHC) for liver tissue. FACS analysis of neutrophils co-cultured with BA or control plasma measured BA-specific NETosis. Stellate cell activation from co-culture studies of stellate cells with NETs was measured by RT-qPCR, ELISA and FACS.</p><p><strong>Results: </strong>Liver neutrophils, NETs and plasma elastase, NETs and IL-8 were significantly increased in BA at diagnosis and transplant. Normal neutrophils co-cultured with BA plasma had increased NETosis and activation of CXCR2, an IL-8 receptor; CXCR2 inhibition decreased NET production. IHC identified increased NET expression of pro-fibrogenic tissue factor and IL-17. NETs co-cultured with stellate cells resulted in stellate cell activation, based on increased ACTA2 & COL1A1 mRNA, collagen protein and cell surface expression of actin, collagen1A and PDGFRβ.</p><p><strong>Conclusions: </strong>BA patients have persistent IL-8-CXCR2-mediated NETosis that correlates with biomarkers of injury and fibrosis and NETs induce stellate cell activation, suggesting a role for NETs in the immunopathogenesis of disease. Future investigations should focus on therapeutic agents that inhibit NETs in BA.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851801","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":"Reply: Can plasma FSTL-1 levels serve as a reliable biomarker for advanced fibrosis?","authors":"Yongquan Chi, Xiaolong Qi, Jianhua Rao","doi":"10.1097/hep.0000000000001208","DOIUrl":"https://doi.org/10.1097/hep.0000000000001208","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"7 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848851","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":"Validation and expansion of Baveno VII criteria for cACLD and CSPH based on liver stiffness and platelet count: Correlation with risk of hepatic decompensation and death","authors":"Philip Vutien, Abbey Barnard Giustini, Nicole J. Kim, Andrew M. Moon, Chun-Nan Hsu, Catherine Mezzacappa, Joleen A. Borgerding, Kay M. Johnson, Trang VoPham, Kristin Berry, Lauren A. Beste, David E. Kaplan, Tamar H. Taddei, George N. Ioannou","doi":"10.1097/hep.0000000000001183","DOIUrl":"https://doi.org/10.1097/hep.0000000000001183","url":null,"abstract":"Background and Aims: Recently proposed “Rule-of-Five” criteria define compensated advanced chronic liver disease (cACLD) and clinically significant portal hypertension (CSPH) using liver stiffness (LS) and platelet count. We aimed to validate these criteria by determining whether they are associated with risk of adverse outcomes. Methods and Results: Patients without prior hepatic decompensation or hepatocellular carcinoma (HCC) who underwent LS and platelet measurements (n=17,076), were categorized as follows: no cACLD (LS 2.5-9.9 kPa); probable cACLD (LS 10-14.9 kPa); certain cACLD-no CSPH (LS 15-19.9 kPa and platelets ≥110,000/µL or LS 20-24.9 kPa and platelets ≥150,000/µL); probable CSPH (LS 15-19.9 kPa and platelets &lt;110,000/µL or LS 20-24.9 and platelets &lt;150,000/µL); and certain CSPH (LS ≥25 Kpa), which we further sub-divided into 25-49.9 kPa and 50-75 kPa. During a median follow-up of 2.82 years, each increase in “Rule-of-Five” category was associated linearly with higher risks of death (hazard ratio [HR] 1.22, 95% CI 1.18-1.25) and decompensation (HR 1.52, 95% CI 1.46-1.58). Compared to patients with LS 25-49.9 kPa, those with LS 50-75 kPa (“critical” CSPH) had approximately double the risk of decompensation (11.24 vs. 4.20 per 100 patient-years) and death (9.85 vs. 6.98 per 100 patient-years). Conclusions: The Baveno VII “Rule-of-Five” criteria provide a valid system for stratifying risks of death and hepatic decompensation and should be used routinely in patients with chronic liver disease. Among patients with CSPH (LS ≥25 kPa), the subgroup with LS 50-75 kPa (“critical” CSPH) has approximately double the risk of death and hepatic decompensation than LS 25-49.9 kPa.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"17 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841125","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":"Diagnostic accuracy of 2D-SWE ultrasound for liver fibrosis assessment in MASLD: A multi-level random effects model meta-analysis","authors":"Madalina-Gabriela Taru, Dan-Corneliu Leucuta, Monica Lupsor-Platon, Laura Turco, Silvia Ferri, Ahmed Hashim, Olga Hilda Orasan, Bogdan Procopet, Horia Stefanescu, Maria Cristina Morelli, Fabio Piscaglia, Federico Ravaioli","doi":"10.1097/hep.0000000000001190","DOIUrl":"https://doi.org/10.1097/hep.0000000000001190","url":null,"abstract":"Background &amp; Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) imposes significant healthcare burdens. Early detection of advanced fibrosis and cirrhosis in MASLD is essential due to their unfavourable outcomes. This multi-level random-effects meta-analysis aimed to provide the best evidence for the diagnostic accuracy of two-dimensional shear wave elastography (2D-SWE) in detecting liver fibrosis in biopsy-proven MASLD. Approach &amp; Results: Systematic search in PubMed/MEDLINE, Embase, Scopus, Web of Science, LILACS, and Cochrane Library electronic databases for full-text articles published in any language up to the 26<jats:sup>th</jats:sup> of February 2024. Included studies reported liver stiffness measurement (LSM) by 2D-SWE and used histological diagnosis as gold standard. A linear mixed-effects multiple thresholds model was employed, and summary estimates for sensitivity (Se), specificity (Sp), and summary area under the curve (sAUC) were computed. 20 observational studies (SuperSonic Imagine, General Electric Healthcare, Canon Medical Systems) fulfilled the inclusion criteria, comprising 2223 participants with biopsy-proven MASLD. The prevalence of mild fibrosis (F1), significant fibrosis (F2), advanced fibrosis (F3), and cirrhosis (F4) was 30.0%, 18.5%, 17.9%, and 10.9%, respectively. The sAUCs [95%CI] in detecting ≥F1, ≥F2, ≥F3, and F4 for all ultrasound machines considered together were 0.82 [0.16-0.98], 0.82 [0.76-0.88], 0.86 [0.77-0.93], and 0.89 [0.80-0.95], respectively. The optimal cut-off values were 6.432 kPa for ≥F1, 8.174 kPa for ≥F2, 9.418 kPa for ≥F3, and 11.548 kPa for F4, respectively. Conclusions: Our meta-analysis identified optimised cut-offs for fibrosis staging by 2D-SWE in etiology-specific chronic liver diseases (MASLD), with excellent diagnostic performance, underscoring the potential for standardising cut-off values.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"23 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841082","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":"Letter to the editor: The race against time in genetic testing for PALF","authors":"Fernanda Monge Urrea, Joseph Valamparampil, Robert Hegarty","doi":"10.1097/hep.0000000000001194","DOIUrl":"https://doi.org/10.1097/hep.0000000000001194","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"8 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841083","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}