Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Chronic hepatitis D is a kind of severe viral hepatitis caused by co-infection with hepatitis D virus (HDV) and hepatitis B virus (HBV) or infection with HDV on the ground of HBV infection. Patients with hepatitis D who are infected with HBV often have faster disease progression and a worse prognosis. However, the public and clinicians have always paid little attention to chronic hepatitis D. Coupled with the limitations of detection methods and the absence of a screening system, the HDV screening rate in various regions of the world is at a low level. Consequently, the enthusiasm for screening, diagnosis, and treatment has been further reduced by the inadequate effectiveness of previous treatment methods. In recent years, progress has been made in the research and development of anti-HDV drugs, and a variety of drugs have already entered the clinical trial stage, and some have already been approved for commercialization in specific parts of the world. In this context, the world is also actively exploring effective ways to increase the HDV screening rate. The reflex test model can effectively raise the HDV screening rate and serve as a reference for HDV screening in other countries and regions, as demonstrated by studies conducted in the United Kingdom, France, and Spain, among others. This article will review the detection methods, screening, diagnosis, and treatment current status, as well as the progress in drug research and development, in order to help clinical physicians understand chronic HDV diagnosis and treatment.

Hepatitis C is the first chronic viral infection that can be cured, and it has taken only 30 years from the discovery of the hepatitis C virus genome to the ability to eliminate the public health threat posed by hepatitis C virus. In the past ten years, the etiological detection of hepatitis C has experienced the development from sensitive and quantitative to rapid, convenient, automatic and point of care testing. With the continuous introduction of direct antiviral drugs, all types of hepatitis C patients, including special populations, can be safely and effectively cured by short courses of all-oral drugs. Progress in the diagnosis and treatment of hepatitis C is an important basis for eliminating the public health threat of hepatitis C. China has published the Planning of prevent and treatment for viral hepatitis in China (2017-2020). We look forward to achieving WHO's goal of eliminating viral hepatitis as a public health threat at an early date through effective screening, diagnosis and treatment.

In December 2019, National Medical Products Administration of China issued Guidelines for Clinical Trials of Drugs for Treatment of Nonalcoholic Steatohepatitis (Interim), which mainly targeted at adult patients with nonalcoholic steatohepatitis with significant liver fibrosis and compensated liver cirrhosis (F2-F4). This article introduces related considerations from the aspects of clinical trial endpoint, overall clinical trial design, specific research and development stages, and safety. With reference to related guidelines of the United States and the European Union, this article attempts to explore the association between clinical trial and clinical practice.

Objective:To investigate the early diagnostic value of red blood cell distribution width(RDW)in elderly patients with acute ischemic stroke(AIS), and to explore whether RDW can be used as an independent predictor of AIS.Methods:This retrospective study included elderly AIS patients who were hospitalized within the first 24 hours after the onset of symptoms from November 2018 to October 2019 as the AIS group, and elderly patients with various conditions that masqueraded as a stroke who were admitted to hospital during the same period were included as the control group.The demographic data, vascular risk factors, and baseline RDW levels were recorded, and the receiver operating characteristic(ROC)curve was used to evaluate the diagnostic value of RDW for AIS.Results:The median level of RDW in the AIS group was significantly higher than that in the control group(13.0% vs.12.4%, P<0.001). The area under the curve of RDW was 0.758(95% CI: 0.685-0.823). At the cut-off value was 12.7%, and its sensitivity and specificity were 73.2% and 75.3%, respectively.Multivariate Logistric regression analysis showed that after adjusting for covariates, the risk of AIS is 5.342-fold for each 1% increase in RDW( OR: 5.342, 95% CI: 2.520-11.324, P<0.001). Conclusions:The increased level of RDW is related to the risk of AIS, and it is an independent predictor of AIS.Thus, it may be used as a preliminary screening index for the diagnosis of AIS.

Objective: To explore the correlation between the level of anti-mitochondrial antibody (AMA) and clinical indicators of first visited primary biliary cholangitis (PBC) patients with positive AMA. Methods: From January 2013 to December 2016, the clinical data of 1 323 patients with positive AMA and/or AMA-M2 detected for the first time were collected through the Information System of Peking University People′s Hospital. Among them, 183 were detected by indirect immunofluorescence assay, 431 were measured by immunoblotting, and 709 were determined by enzyme-linked immunosorbent assay (ELISA). Patients were divided into undiagnosed PBC group (non-PBC group, 973 cases) and newly diagnosed PBC group (new-PBC group, 350 cases including 268 cases of non-liver cirrhosis and 82 cases of liver cirrhosis); among 709 cases detected by ELISA, there were 567 cases in the non-PBC group and 142 cases in the new-PBC group (115 cases of non-liver cirrhosis PBC group and 27 cases of liver cirrhosis PBC group). Among 183 cases determined by indirect immunofluorescence assay, there were 118 cases in the non-PBC group and 65 cases in the new-PBC group. Among them 69 cases with low AMA titer (1∶40—1∶80) (53 cases of non-PBC group and 16 cases of new-PBC group), 95 cases with medium titer (1∶160—1∶320) (59 cases of non-PBC group and 36 cases of new-PBC group) and 19 cases with high titer (≥1∶640) (six cases of non-PBC group and 13 cases of new-PBC group). AMA levels among groups were compared, and its correlation with clinical serology and cirrhosis indicators of PBC including immunoglobulin (Ig)G, IgM, platelet, alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltranspeptadase (GGT), alkaline phosphatase (ALP), serum total protein, serum albumin, total bilirubin (TBil), total cholesterol (TC), and aspartate aminotransferase to platelet ratio index (APRI) and fibrosis (Fib-4) was analysed. Mann-Whitney U test, Kruskal-Wallis test, and linear regression analysis were performed for statistical analysis. Results: By ELISA method, the median titer of AMA-M2 of 709 patients was 53 RU/mL, the serum AMA and AMA-M2 levels of new-PBC group were both higher than those of non-PBC group (1∶320 vs. 1∶80, 180 RU/mL vs. 47 RU/mL), and the differences were statistically significant (χ² = 14.111, Z = -7.531, both P < 0.01). In non-PBC group, the AMA-M2 value was positively correlated with age, serum IgG, IgM, AST, GGT, ALP, serum total protein and TC, all of which were statistically significant (Rho = 0.114, 0.108, 0.337, 0.089, 0.197, 0.086, 0.121 and 0.073, all P<0.05). In new-PBC group, AMA-M2 value was positively correlated with age, IgM, serum total protein and TC, however was negatively correlated with platelet count, all of which were statistically significant (Rho = 0.218, 0.483, 0.230, 0.161, and -0.183, all P<0.05). The median values of serum AMA and AMA-M2 of PBC without liver cirrhosis group were both tended to be lower than those of PBC with liver cirrhosis (1∶160 vs. 1∶320; 174 RU/mL vs. 495 RU/mL), however the differences were not statistically significant (both P>0.05). AMA-M2 value of patients in PBC with liver cirrhosis group was positively correlated with IgM level (r = 0.38, P = 0.039), but was not correlated with APRI and Fib-4 (all P > 0.05). The median of AMA value of 183 patients who underwent indirect immunofluorescence test was 1∶160. In non-PBC group, the IgM levels of patients with low, medium and high AMA titers gradually increased (the median levels were 1.2, 1.7 and 1.8 g/L, respectively); in new-PBC group, the levels of IgM, GGT and ALP of patients with low, medium and high AMA titers gradually increased (median IgM levels were 1.5, 3.7 and 4.1 g/L, respectively; GGT levels were 144, 182 and 317 U/L, respectively; and ALP levels were 137, 168 and 221 U/L, respectively), and the differences were statistically significant (χ² =6.260, 7.081, 8.030, 15.226, all P<0.05). In non-PBC group, the median level of serum AMA-M2 of men was lower than that of women (41 RU/L vs. 50 RU/L), and the difference was statistically significant (Z = -2.945, P = 0.003). In new-PBC group, the median level of serum AMA-M2 of men tended to be lower than that of women (113 RU/mL vs. 206 RU/mL), but the difference was not statistically significant (P=0.257). Conclusion Serum AMA level is correlated with many clinical parameters and may be related with the disease severity in patients with PBC.

Hepatitis C infection is a serious public health threat, and the World Health Organization has recommended the elimination of public health threats from viral hepatitis, including hepatitis C, by 2030. Many countries and regions are actively exploring strategies and models to eliminate the public health threat of hepatitis C. It is estimated that there are at least 7.6 million cases of chronic hepatitis C in China, with both diagnosis and treatment rates far away to 2030 target. China's government, social organizations and doctors at different levels are also actively exploring the mode of eliminating the public health threat of hepatitis C in China, including the main mode supported by national standards, government-led mode, social institution undertaking and government-supported mode, medical alliance mode, screening in high-prevalence areas and services contracted with family doctors. China can have a lessons learning from international and ourselves experience, particularly as "Test and treat all based on needs and demand" strategy in Covid-19 control, finally achieve eliminate the public health threat of hepatitis C as soon as possible.

The key points from the updated guideline of prevention and treatment for hepatitis C (2019 version) is compared with the previous hepatitis C guideline.A new terminology and the World Health Organization's goal of eliminating viral hepatitis as a public-health threat by 2030 are stressed.In the prevention section,the screening for hepatitis C virus infection in high-risk population is the primary means of prevention,emphasizing that treatment,is prevention.In the aspect of treatment,pangenotypic interferon-free scheme are initial recommendations.In addition,it also introduces our country independent research and development on direct-acting antiviral agents,and antiviral therapy schedule for many special populations,including decompensated liver cirrhosis,chronic kidney disease,children and adolescents combined with chronic kidney injury,HBV infection-before and after liver transplantation,treatment failure,and acute hepatitis C.A simplified on-treatment monitoring schedule,especially genotype 3 prevalent in Southwest part of our country is introduced.

Objective To assess the efficacy and safety of 100 mg or 200 mg yimitasvir phosphate combined with sofosbuvir in patients with non-cirrhotic chronic hepatitis C virus ( HCV) genotype 1 infection who were treatment-na?ve or had a virologic failure to prior interferon-based treatment.Methods A multicenter, randomized, open-label, phase 2 clinical trial was conducted.The patients were randomly assigned to yimitasvir phosphate 100 mg+sofosbuvir 400 mg group (Group 100 mg) and yimitasvir phosphate 200 mg+sofosbuvir 400 mg group ( Group 200 mg) in a 1∶1 ratio with the stratified factors of " treatment-naive" or"treatment-experienced" for 12 weeks and followed up for 24 weeks after the end of treatment.During the clinical trial, HCV RNA was tested in all patients.Resistance of virus in patients who didn′t achieved sustained virological response (SVR) was monitored.Safety and tolerability were assessed by monitoring adverse events , physical examination , laboratory examination, electrocardiogram, and vital signs during the study.The primary end point was SVR12 after the end of therapy.Descriptive statistics were used for categorical variables and eight descriptive statistics were used for continuous variables.Descriptive statistics were used and summarized according to HCV genotypes and treatment groups.Safety data were presented using descriptive statistics and summarized according to treatment groups.Results A total of 174 subjects were screened from July 31, 2017 to September 26, 2018.One hundred and twenty-nine patients were successfully enrolled and received treatment , and 127 completed the study.There were 64 patients and 65 patients assigned to Group 100 mg and Group 200 mg, respectively.Among the 129 patients who underwent randomization and were treated , 18.6% were treatment-experienced and: 100%were HCV genotype 1b infection.The total SVR rate was 98.4%(127／129), with 98.4%(63／64, 95%confidence interval [CI]: 91.60%-99.96%) in the Group 100 mg, and 98.50%(64／65, 95%CI: 91.72%-99.96%) in the Group 200 mg.There was no significant difference between the two groups (χ2 ＝0.000 2, P＝0.989 2).The SVR rates in treatment-naive group and treatment-experienced group were 98.10%(95%CI: 93.29%-99.77%) and 100.00%(24／24, 95%CI: 85.75%-100.00%), respectively.Virological failure during treatment ( including breakthrough , rebound and poor efficacy) and relapse after treatment did not occur during the trial.By Sanger sequencing , 11.6%(15／129) patients had baseline NS5A Y93H／Y or Y93H resistance-associated substitutions ( RAS), 1.6%( 2／129) patients had baseline NS5A L31M RAS.No mutation was observed in NS5B S282 at baseline.There was no S282 mutation in HCV NS5B.A total of 100 (77.5%) subjects had adverse events.No adverse events ≥Grade 3 or severe adverse events related to the study treatment.No patient prematurely discontinued study treatment owing to an adverse event.No life-threatening adverse event was reported.Conclusion Twelve weeks of yimitasvir phosphate 100 mg or 200 mg combined with sofosbuvir 400 mg daily is a highly effective and safe regimen for patients without cirrhosis with HCV genotype 1b infection who had not been treated previously or had a virologic failure to prior interferon-based treatment.

Objective: To investigate the incidence and related independent risk factors of depression in treatment-naïve Han ethnic Chinese patients with chronic hepatitis C. Methods: Nine hundred and ninety-seven Han Chinese patients with confirmed chronic HCV infection were enrolled. Beck’s depression inventory scale was used to assess depression score. Patients were divided into two groups according to the score: score≥17, depression group (16.85%, 168/997); score <17, no depression group (83.15%, 829/997). Multivariate logistic regression was used to analyze independent risk factors related with the onset of depression in patients with chronic hepatitis C. Results: There was a statistically significant difference between the two groups in terms of gender distribution, marital status, education level, income level and smoking status (P < 0.05). Independent risk factors were female [odds ratio (OR) = 3.85; 95% CI: 2.28-6.50, P = 0.001], decompensated cirrhosis [OR = 2.31; 95% CI: 1.20-4.48, P = 0.013], unmarried [OR = 2.01; 95% CI: 1.12-3.60, P = 0.019], separated [OR = 17.39; 95% CI: 1.64-184.47, P = 0.018], divorced [OR = 3.82; 95% CI: 1.36-10.74, P = 0.011], without higher education [OR = 2.04; 95% CI: 1.22-3.42, P = 0.007], low income [OR = 3.94; 95% CI: 1.38-11.28, P = 0.011], middle income [OR = 2.96; 95% CI: 1.02-8.62, P = 0.047], uninterrupted smoking [OR = 3.67; 95% CI: 2.13-6.31, P = 0.001], and previously smoked [OR = 3.33, 95% CI: 1.66-6.68, P = 0.001]. Conclusion The incidence of depression in patients with chronic hepatitis C is relatively high. The independent risk factors related with depression include female, unmarried, separated, and divorced, without higher education, low and middle-income level, smoking and disease progression to decompensated cirrhosis, but no significant correlation between hepatitis C virus genotypes and viral load.