Clinical and Molecular Hepatology最新文献

{"title":"RNAi-mediated HBV antigen shutdown enhances the antiviral immune effects of PEGIFNα via T and B cell crosstalk remodeling.","authors":"Wenjing Zai, Kongying Hu, Mengying He, Ziyang Song, Pan Gao, Chen Luo, Minxiang Xie, Asha Ashuo, Min Yang, Jieliang Chen, Zhenghong Yuan","doi":"10.3350/cmh.2026.0385","DOIUrl":"https://doi.org/10.3350/cmh.2026.0385","url":null,"abstract":"<p><strong>Backgrounds/aims: </strong>PEGylated interferon-α (PEGIFNα) shows promise in treating chronic hepatitis B (CHB), yet patient response remains suboptimal. While suppressing hepatitis B virus (HBV) antigens by RNA interference (RNAi) could enhance PEGIFNα efficacy in CHB patients, the underlying immunological mechanisms remain obscure.</p><p><strong>Methods: </strong>Using our newly established extracellular humanized IFNAR (IFNAR-hEC) mouse model of chronic HBV infection, we evaluated the efficacy of a GalNac-conjugated siRNA (GalNac-siHBV) alone or in combination with PEGIFNα. Phenotypic and functional characteristics of immune cells were assessed by flow cytometry, ELISpot, and single-cell RNA sequencing (scRNA-seq).</p><p><strong>Results: </strong>High circulating HBsAg reduced antiviral effects and immune responsiveness of PEGIFNα. Combined PEGIFNα and RNAi therapy synergistically and durably suppressed HBsAg (~4log10 IU/mL, vs PBS) and achieved HBsAg seroconversion in ~30% of mice, outperforming either monotherapy. Mechanistically, PEGIFNα enhanced global T and B cell function, whereas combined therapy further amplified HBV-specific T and B cell responses. scRNA-seq analysis indicated that combined therapy attenuated inhibitory B cell-B cell interactions, strengthened MHC-I-mediated T cell crosstalk, and enhanced MHC-II signaling networks across B cells and hepatocytes/Cd8+ T cells, collectively improving the lymphocyte functionality and facilitating HBsAg seroconversion. Reinforcing MHC-I/II signaling with agonistic antibodies (α4-1BB, αCD40) or IL-2-Fc further potentiated antiviral immune responses of combinational regimen.</p><p><strong>Conclusions: </strong>Combined RNAi and PEGIFNα therapy exerts synergistic antiviral effects by relieving HBV antigen-induced immune tolerance and orchestrating a functional T cell-B cell crosstalk network centered on MHC-I/II signaling. Enhancing antigen presentation pathways represents a promising adjunctive strategy to improve functional cure rate of CHB.</p>","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":""},"PeriodicalIF":21.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929100","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":"Hepatocyte Plasticity in Liver Health and Disease: Zonation, Regeneration, Lineage Conversion, and Hepatic Malignancy.","authors":"Xuan Wang, Yunfang Wang, Shuyong Wang","doi":"10.3350/cmh.2026.0630","DOIUrl":"https://doi.org/10.3350/cmh.2026.0630","url":null,"abstract":"<p><p>Hepatocytes are highly specialized epithelial cells that maintain liver metabolic homeostasis, yet they also display remarkable plasticity in response to physiological demands, injury, disease, and oncogenic stress. In this review, we propose hepatocyte plasticity as an integrative framework that links homeostatic metabolic zonation, injury‑ and disease‑induced zonal remodeling and regeneration, hepatobiliary lineage conversion, and zonally biased malignant transformation. We first delineate homeostatic liver zonation as the baseline spatial architecture that constrains, rather than itself constitutes, hepatocyte plasticity, whereas dynamic re-zonation and state conversion represent plastic responses to perturbation. We further propose a conceptual framework that categorizes these plastic responses into four distinct yet interconnected modalities: transient adaptive state transitions, partial lineage conversion, transdifferentiation, and malignant lineage switching. We delineate the multiscale regulatory mechanisms underpinning each category, and critically assess the translational gaps between murine models and human disease. We further explore the therapeutic duality of this plasticity, evaluating emerging approaches that seek either to exploit its regenerative potential for liver repair and disease regression, or to counteract its pathological roles in cancer progression. By integrating these insights, this review establishes a comprehensive framework for understanding hepatocyte plasticity as a central determinant of liver pathobiology and highlights its translational potential for precision therapeutics in liver disease and cancer.</p>","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":""},"PeriodicalIF":21.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929190","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":"Steatotic liver disease spectrum: From MASLD to MetALD and beyond - Clinical outcomes and precision medicine frontiers.","authors":"Won Kim","doi":"10.3350/cmh.2026.1072","DOIUrl":"10.3350/cmh.2026.1072","url":null,"abstract":"","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":"32 Suppl","pages":"e2026.1072"},"PeriodicalIF":21.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Steatotic liver disease: non-invasive assessment and biomarkers across metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatotic liver disease with moderate alcohol consumption and alcohol-associated liver disease.","authors":"Monica Tincopa, Rohit Loomba","doi":"10.3350/cmh.2026.0415","DOIUrl":"10.3350/cmh.2026.0415","url":null,"abstract":"<p><p>Steatotic liver disease (SLD) is a leading cause of chronic liver disease worldwide impacting more than 30% of the adult population. With the rise of obesity, metabolic syndrome and alcohol use disorder, the prevalence of the two main subtypes of SLD - metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) - continues to increase. There has concurrently been an acknowledgement of a third subtype of SLD-metabolic dysfunction-associated steatotic liver disease with moderate alcohol consumption (MetALD)- wherein an individual has both components of metabolic dysfunction and regular alcohol intake. The public health significance of the SLD epidemic is substantial given risk for progression to cirrhosis, end-stage liver disease and development of hepatocellular carcinoma. Individuals with stage two fibrosis or above and those with active inflammation with hepatocyte injury are at highest risk for adverse liver-related outcomes and overall mortality. Current screening and risk stratification recommendations highlight the importance of identifying individuals at highest risk of clinical outcomes using non-invasive testing (NIT) as these individuals would benefit from liver-directed pharmacotherapy. Importantly, the performance of NITs can vary substantially based on NIT selected, cut points applied and patient population evaluated. The evidence base for NIT performance is strongest in MASLD with comparatively limited data in ALD and emerging data in MetALD. This review discusses NIT diagnostic performance in SLD and their role in chronic disease management.</p>","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":"e2026.0415"},"PeriodicalIF":21.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precision pathophysiology in steatotic liver disease.","authors":"Wonseok Lee, Da Kyung Hwang, Hyun Young Kim, David A Brenner","doi":"10.3350/cmh.2026.0490","DOIUrl":"10.3350/cmh.2026.0490","url":null,"abstract":"<p><p>Steatotic liver disease (SLD) comprises metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-associated liver disease (MetALD), and alcohol-associated liver disease (ALD), which represent subclasses of liver disorders with overlapping etiologies. MASLD is defined as SLD with cardiometabolic dysfunction, whereas MetALD refers to MASLD with moderate alcohol consumption (140-350 g/week in females and 210-420 g/week in males). Despite being classified as distinct entities, MASLD and MetALD exhibit substantial phenotypic overlap, underscoring the need to delineate their pathological and molecular features and to develop models that capture the synergistic effects of alcohol and metabolic stress. Recent advances in multi-omic technologies have enabled integrated single-cell profiling of genetic, epigenetic, spatial, and proteomic features, providing high-resolution insights into cellular heterogeneity and disease mechanisms. In this review, we examine the pathophysiological landscape of SLD, highlight key distinctions between MASLD and MetALD, and discuss experimental models, including human liver spheroids. These approaches provide deeper insights into disease classification and accelerate the development of targeted therapies.</p>","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":"e2026.0490"},"PeriodicalIF":21.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alcohol-aware risk stratification and subtype-specific care pathways across metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction and alcohol-associated liver disease, and alcohol-associated liver disease.","authors":"Hyo Young Lee, Eileen Laurel Yoon, Dae Won Jun","doi":"10.3350/cmh.2026.0659","DOIUrl":"10.3350/cmh.2026.0659","url":null,"abstract":"<p><p>Accurate classification and risk stratification across metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-associated liver disease (MetALD), and alcohol-associated liver disease (ALD) depend critically on the assessment of alcohol exposure. However, current clinical practice relies largely on self-reported alcohol intake, which may underestimate drinking quantity, pattern, and prior heavy exposure and consequently lead to subtype misclassification. This review focuses on an alcohol-aware approach to steatotic liver disease (SLD) phenotyping and clinical management. We discuss the complementary role of structured alcohol assessment and objective biomarkers, particularly phosphatidylethanol, while emphasizing biological, analytical, and host factors that limit interpretation of a single biomarker value. We further examine how active or recent alcohol exposure modifies the interpretation of commonly used risk-stratification tools, particularly FIB-4 and liver stiffness measurement, and when repeat assessment after alcohol reduction or abstinence may be appropriate. Finally, we propose practical subtype-specific care pathways integrating alcohol exposure, non-invasive fibrosis assessment, and longitudinal reassessment across MASLD, MetALD, and ALD. An alcohol-aware approach may reduce subtype misclassification and enable more appropriate referral, monitoring, and therapeutic decision-making across the SLD spectrum.</p>","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":"e2026.0659"},"PeriodicalIF":21.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic and genomic insights across the steatotic liver disease spectrum.","authors":"Jake P Mann, Karn Wijarnpreecha, Vitchapong Prasitsumrit, Eric Trépo, Elizabeth K Speliotes, Vincent L Chen","doi":"10.3350/cmh.2026.0477","DOIUrl":"10.3350/cmh.2026.0477","url":null,"abstract":"<p><p>Chronic liver disease is a rapidly growing cause of morbidity and mortality worldwide, and this increase is largely driven by steatotic liver disease (SLD) comprising metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), and MASLD and increased alcohol intake (MetALD). Hepatic steatosis and fibrosis are highly heritable and genetic variation has also been associated with the risk of hepatocellular carcinoma (HCC) and hepatic decompensation. This review summarizes the state of the art of genetics and genomics in SLD, with particular emphasis on potential clinical utility. Variants in/near genes including PNPLA3, TM6SF2, and HSD17B13 have been associated with cirrhosis and HCC in both MASLD and ALD, while others such as those in GCKR, TRIB1, and GPAM have been consistently associated with greater risk of hepatic steatosis in MASLD with much weaker effects if any on cirrhosis and HCC. While data on MetALD genetics are limited, we believe that the genetic risk factors for liver steatosis, cirrhosis, and HCC will be similar in MetALD compared to MASLD and ALD based on the largely shared genetic risk factors for MASLD and ALD. Finally, we discuss future directions in SLD genetics, notably genetically-defined disease subtypes, gene-environment interactions and their implications for therapy, and the utility of genetics in clinical risk stratification. Genetic studies have provided insight into important disease processes in SLD and may have an upcoming role in clinical care.</p>","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":"e2026.0477"},"PeriodicalIF":21.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148344125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictive modeling and clinical decision tools for risk stratification in steatotic liver disease.","authors":"Jeanette Girard, Elliot B Tapper, Vincent L Chen","doi":"10.3350/cmh.2026.0204","DOIUrl":"10.3350/cmh.2026.0204","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of hepatic decompensation and liver-related death, but most patients with MASLD do not develop these liver-related complications. Risk prediction and care pathways are crucial to identify which patients with MASLD are highest risk and link them to appropriate care. Risk prediction is usually done with blood-based algorithms such as Fibrosis-4, AST-platelet ratio index, and more recent scores such as steatosis-associated fibrosis estimator and LiverRisk Score. Second-line tests include enhanced liver fibrosis and imaging-based tests such as vibration-controlled transient elastography, shear wave elastography, or magnetic resonance elastography. We propose a consensus risk stratification care pathway that can be adapted for different clinical settings. We also discuss key needs to improve upon the state of the art: improving diagnosis/prognostic accuracy, especially of blood-based models, optimizing calibration, and ensuring interpretability of predictive models. Finally, we discuss recent advances in clinical decision support systems including best practice advisories, dashboards, and dynamic guidelines. We highlight factors critical to clinical decision support systems, including integration with existing systems and clinician workflows, minimizing additional burden to clinicians, provision of decision support and recommendations at the time/place of decision-making, and continuous evaluation and local user involvement.</p>","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":"e2026.0204"},"PeriodicalIF":21.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Global epidemiological patterns and disease burden of metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction and alcohol-associated liver disease, and alcohol-associated liver disease.","authors":"Pojsakorn Danpanichkul, Matheus Souza, Primrose Tothanarungroj, Aijaz Ahmed, Donghee Kim","doi":"10.3350/cmh.2026.0444","DOIUrl":"10.3350/cmh.2026.0444","url":null,"abstract":"<p><p>The 2023 multisociety Delphi consensus redefined the nomenclature for steatotic liver disease (SLD) by replacing nonalcoholic fatty liver disease with metabolic dysfunction-associated steatotic liver disease (MASLD) and introducing metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-associated liver disease (ALD). This revised framework is expected to enhance epidemiological surveillance, phenotyping of SLD, and public health interpretation. This review summarizes contemporary literature on the global epidemiology, disease burden, and comparative outcomes of MASLD, MetALD, and ALD. MASLD remains the most prevalent SLD subtype, affecting approximately 30-40% of adults worldwide, with a rising burden over time. MASLD rapidly increases in regions with lower sociodemographic indices. MetALD affects an estimated 2-8% of adults and represents an important overlap phenotype, although its prevalence is likely underestimated due to frequent underreporting of alcohol intake. ALD has a lower prevalence but contributes disproportionately to higher liver-related morbidity and mortality and is reported to have a marked regional variation linked to patterns of alcohol consumption. SLD has emerged as a major global epidemic, with MASLD imposing the greatest population burden and MetALD/ALD disproportionately contributing to severe liver-related outcomes. Across SLD phenotypes, cardiovascular disease is a major cause of death in non-cirrhotic disease, while liver-related outcomes show a gradient associated with alcohol exposure. Significant epidemiologic limitations include heterogeneity in the steatosis assessment methods, limited availability of cardiometabolic criteria, and reliance on self-reported alcohol consumption. Mitigating this growing burden of SLD requires public health policies that incorporate metabolic risk prevention, regulation of alcohol consumption, and early risk stratification.</p>","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":"e2026.0444"},"PeriodicalIF":21.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiovascular and hepatic outcomes: prognostic differences across MASLD-MetALD-ALD continuum.","authors":"Han Ah Lee, Gi-Ae Kim, Won Kim","doi":"10.3350/cmh.2026.0367","DOIUrl":"10.3350/cmh.2026.0367","url":null,"abstract":"<p><p>A paradigm shift in fatty liver disease nomenclature has introduced steatotic liver disease (SLD) as an umbrella term, encompassing metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-related liver disease (MetALD), and alcohol-associated liver disease (ALD). These SLD subtypes exist along a dynamic continuum shaped by the synergistic interplay of metabolic dysfunction and alcohol exposure. Accumulating evidence indicates that SLD exhibits distinct outcome-based clusters reflecting heterogeneity in pathogenic drivers and clinical trajectories. Cardiometabolic clusters, most prominently observed in MASLD, are characterized by systemic metabolic dysfunction and confer increased risks of cardiovascular disease (CVD). In contrast, liver-specific clusters demonstrate progressive fibrosis and cirrhosis, hepatic decompensation, and hepatocellular carcinoma. In large-scale cohorts, CVD accounts for 40-50% of deaths in MASLD, while liver-related mortality predominates in ALD (>60%). The relative dominance of cardiometabolic versus liver-specific clusters shifts progressively across the MASLD-MetALD-ALD spectrum. While CVD remains a major driver of mortality, particularly in MASLD, hepatic outcomes increase stepwise with advancing fibrosis and greater alcohol exposure. Advanced fibrosis is the predominant shared determinant amplifying both CVD and hepatic risks across subtypes. This review synthesizes cardiovascular and hepatic outcome patterns across the MASLD-MetALD-ALD spectrum, highlighting the prognostic reorientation across the continuum, in which hepatic outcomes rise stepwise with alcohol exposure while cardiovascular risk remains an important but less subtype-differentiated burden. These findings advocate outcome-oriented risk stratification integrating noninvasive fibrosis assessment, alcohol biomarkers (phosphatidylethanol), and cardiovascular risk calculators within the cardiovascular-kidney-metabolic framework. Understanding SLD as a modifiable continuum enables individualized management to optimize multisystem outcomes.</p>","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":"e2026.0367"},"PeriodicalIF":21.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147866973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}