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BackgroundHepatitis B virus (HBV) infection is common with major clinical consequences. In Asian Americans, the HBsAg carrier rate ranges from 2% to 16% which approximates the rates from their countries of origin. Similarly, HBV is the most important cause of cirrhosis, hepatocellular carcinoma (HCC) and liver related deaths in HBsAg positive Asians worldwide.AimTo generate recommendations for the management of Asian Americans infected with HBV.MethodsThese guidelines are based on relevant data derived from medical reports on HBV from Asian countries as well as from studies in the HBsAg positive Asian Americans. The guidelines herein differ from other recommendations in the treatment of both HBeAg positive and negative chronic hepatitis B (CHB), in the approach to HCC surveillance, and in the management of HBV in pregnant women.ResultsAsian American patients, HBeAg positive or negative, with HBV DNA levels >2000 IU/mL (>104 copies/mL) and ALT values above normal are candidates for anti-viral therapy. HBeAg negative patients with HBV DNA >2000 IU/mL and normal ALT levels but who have either serum albumin

Importance: Standard care for preventing mother-to-child transmission (MTCT) of hepatitis B virus (HBV) in highly viremic mothers consists of maternal antiviral prophylaxis beginning at gestational week 28 combined with an HBV vaccine series and HBV immune globulin (HBIG) at birth. However, HBIG is unavailable in some resource-limited areas., Objective: To determine whether initiating tenofovir disoproxil fumarate (TDF) at gestational week 16 combined with HBV vaccinations for infants is noninferior to the standard care of TDF at gestational week 28 combined with HBV vaccinations and HBIG for infants in preventing MTCT in mothers with HBV and high levels of viremia., Design, Setting, and Participants: An unblinded, 2-group, randomized, noninferiority clinical trial was conducted in 7 tertiary care hospitals in China. A total of 280 pregnant individuals (who all identified as women) with HBV DNA levels greater than 200 000 IU/mL were enrolled between June 4, 2018, and February 8, 2021. The final follow-up occurred on March 1, 2022., Interventions: Pregnant individuals were randomly assigned to receive either TDF starting at gestational week 16 with HBV vaccinations for the infant or TDF starting at gestational week 28 with HBV vaccinations and HBIG administered to the infant., Main Outcomes and Measures: The primary outcome was the MTCT rate, defined as detectable HBV DNA greater than 20 IU/mL or hepatitis B surface antigen positivity in infants at age 28 weeks. Noninferiority was established if the MTCT rate in the experimental group did not increase by more than an absolute difference of 3% compared with the standard care group, as measured by the upper limit of the 2-sided 90% CI., Results: Among 280 pregnant individuals who enrolled in the trial (mean age, 28 years; mean gestational age at enrollment, 16 weeks), 265 (95%) completed the study. Among all live-born infants, using the last observation carried forward, the MTCT rate was 0.76% (1/131) in the experimental group and 0% (0/142) in the standard care group. In the per-protocol analysis, the MTCT rate was 0% (0/124) in the experimental group and 0% (0/141) in the standard care group. The between-group difference was 0.76% (upper limit of the 2-sided 90% CI, 1.74%) in all live-born infants and 0% (upper limit of the 2-sided 90% CI, 1.43%) in the per-protocol analysis. Both comparisons met the criterion for noninferiority. Rates of congenital defects and malformations were 2.3% (3/131) in the experimental group and 6.3% (9/142) in the standard care group (difference, 4% [2-sided 95% CI, -8.8% to 0.7%])., Conclusions and Relevance: Among pregnant women with HBV and high levels of viremia, TDF beginning at gestational week 16 combined with HBV vaccination for infants was noninferior to the standard care of TDF beginning at gestational week 28 combined with HBIG and HBV vaccination for infants. These results support beginning TDF at gestational week 16 combined with infant HBV vaccine to prevent MTCT of HBV in geographic areas where HBIG is not available., Trial Registration: ClinicalTrials.gov Identifier: NCT03476083.

Postpartum elevation of alanine aminotransferase (ALT) in mothers with chronic hepatitis B (CHB) presents a significant clinical challenge. However, the existing literature demonstrates inconsistencies regarding its incidence and predictors in mothers infected with the hepatitis B virus (HBV). Recent advancements in antiviral prophylaxis against mother-to-child transmission of HBV and postpartum cessation of antiviral therapy further complicate this issue. Our literature review, spanning PubMed, and two Chinese-language databases (CNKI and Wanfang) from 1 January 2000 to 31 December 2023 aimed to consolidate and analyse available data on the frequency and severity of postpartum ALT flares, identify risk factors, and propose a management algorithm. Data from 23 eligible studies involving 8,077 pregnant women revealed an overall incidence of postpartum ALT elevation: 25.7% for mild cases, 4.4% for moderate cases, and 1.7% for severe cases. In the subgroup of mothers who were HBeAg-positive and on antiviral prophylaxis for preventing mother-to-child transmission, postpartum intermediate and severe ALT elevations were reported with pooled rates of 5.9% and 0.8%, respectively. Importantly, none resulted in mortality or necessitated liver transplantation. Identified risk factors for postpartum ALT flares in mothers with CHB included HBV DNA levels, ALT levels during pregnancy, postpartum cessation of antiviral treatment, and HBeAg status. By leveraging this evidence and recent data on predictors of intermediate or severe postpartum ALT flares, we propose a risk-stratified algorithm for managing postpartum ALT elevation and selecting therapy in mothers with CHB, tailoring different approaches for treatment-naive vs treatment-experienced populations. These recommendations aim to provide guidance for clinical decision-making and enhance patient outcomes., Competing Interests: C.Q.P. received institutional research grants from Gilead Sciences and Wuxi Hisky Medical Technologies Co., Ltd. Other authors have no financial interests to be disclosed., (© The Author(s) 2024. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University.)

Introduction: This systematic scoping review aimed to synthesize existing research findings on the clinical manifestations in patients with nonalcoholic fatty liver disease (NAFLD) and sarcopenia., Methods: Adhering to scoping review guidelines, we comprehensively searched five databases for literature on sarcopenia's clinical manifestations in NAFLD patients from December 2013 to December 2023, meticulously compiling and synthesizing the findings., Results: A total of 312 articles were identified, with 9 studies included in the final review. Of these, 90% were cross-sectional investigations, with 70% from Asian cohorts. Comparative analysis between patients solely afflicted with NAFLD and those additionally experiencing sarcopenia revealed discernible trends. Individuals with both conditions tended to be older, have a higher body mass index, and show a higher prevalence among females, underscoring the influence of unhealthy lifestyles and obesity. Furthermore, comorbidities like metabolic syndrome, hypertension, and diabetes have been implicated in sarcopenia manifestation among NAFLD patients. Nonetheless, the lack of standardized diagnostic criteria and patterns poses an ongoing clinical challenge for this subgroup., Conclusions: Our review highlights distinct clinical characteristics evident in NAFLD patients with sarcopenia. However, comprehensive investigations remain scarce, impeding accurate early detection and intervention. Future research should prioritize bridging these gaps and fostering enhanced clinical management strategies., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Objective: International guidelines recommend maternal tenofovir disoproxil fumarate (TDF) therapy accompanied by infant immunoprophylaxis to prevent hepatitis B virus (HBV) mother-to-child transmission (MTCT) in highly viremic mothers. However, pooled analyses for tenofovir alafenamide (TAF) effects and comparisons between the 2 regimens are lacking., Design: In this meta-analysis, pairs of independent reviewers performed multiple database searches from inception to 31 March 2024 and extracted data from cohort studies and randomized controlled trials (RCTs) in highly viremic mothers. The outcomes of interest were the reduction of MTCT and safety in the TDF-treated, TAF-treated, and control groups., Results: We included 31 studies with 2588 highly viremic mothers receiving TDF, 280 receiving TAF, and 1600 receiving no treatment. Compared to the control, TDF therapy reduced the MTCT rate in infants aged 6-12 months (risk ratio: 0.10, 95% confidence interval [CI] .07-.16). Pairwise meta-analysis between TAF and TDF revealed similar effects on reducing MTCT (risk ratio: 1.09, 95% confidence interval .16-7.61). Network meta-analysis showed equal efficacy of the 2 regimens in reducing MTCT (risk ratio: 1.09, 95% CI .15-7.65). The surface under the cumulative ranking curve revealed TDF as the best regimen compared with TAF (probability ranking: .77 vs .72), while receiving a placebo during pregnancy had the lowest efficacy (probability ranking 0.01). There were no safety concerns for mothers and infants in all regimens., Conclusions: Compared to placebo or no treatment, maternal TDF and TAF prophylaxis are equally effective and without safety concerns in reducing MTCT in highly viremic mothers., Competing Interests: Potential conflicts of interest . C. Q. P. received an institutional research grant from Gilead Sciences. A. S. Y. serves as a speaker for Gilead Sciences, Inc. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: In two phase 3 studies, tenofovir alafenamide (TAF) showed non-inferior efficacy versus tenofovir disoproxil fumarate (TDF), with more favourable renal and bone safety in patients with chronic hepatitis B (CHB)., Aims: Here, we report the studies' final 8-year results., Methods: CHB patients (hepatitis B e antigen [HBeAg]-negative and HBeAg-positive) were randomised (2:1) to double-blind TAF 25 mg/day or TDF 300 mg/day for up to 3 years, followed by open-label (OL) TAF through year 8. Virological, biochemical, serological and fibrosis responses, and safety, including bone and renal parameters, were evaluated. Resistance to TAF was assessed annually by deep sequencing of polymerase/reverse transcriptase and by phenotyping., Results: Among 1298 patients randomised to double-blind TAF (n = 866) or double-blind TDF (n = 432), 775 in the TAF group and 382 in the TDF group received OL TAF, including 180 and 202 who switched from TDF to TAF at year 2 (TDF2y → TAF6y) or year 3 (TDF3y → TAF5y), respectively. At year 8, among patients in the TAF8y, TDF2y → TAF6y and TDF3y → TAF5y groups, 69%, 66% and 73% (missing-equals-failure analysis) and 95%, 94% and 97% (missing-equals-excluded) of patients, respectively, achieved HBV DNA <29 IU/mL. Estimated glomerular filtration rate (Cockcroft-Gault method; eGFR CG ) and hip/spine bone mineral density (BMD) remained stable in patients receiving double-blind/OL TAF, with only small declines at year 8. Decreases in eGFR CG and hip/spine BMD observed during double-blind TDF improved after switching to OL TAF. No patients developed resistance to TAF., Conclusion: Long-term TAF treatment exhibited favourable safety and tolerability with high rates of viral suppression and no development of resistance., Clinicaltrials: gov numbers NCT01940341 and NCT01940471., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Achieving a sustained virologic response (SVR) through direct-acting antivirals for hepatitis C virus (HCV) infection significantly reduces the long-term risk of hepatocellular carcinoma (HCC), particularly in patients with advanced fibrosis (F3) or cirrhosis (F4). However, despite this improvement, the risks associated with HCC and the optimal surveillance strategies for patients who have achieved SVR remain topics of debate. This controversy is compounded by challenges in reliably staging liver fibrosis non-invasively, especially at advanced fibrosis (F3), and the unclear cost-effectiveness, modality, frequency, and duration of HCC surveillance in individuals with SVR but without cirrhosis. These factors contribute to significant variations in surveillance guidelines recommended by different professional societies. Therefore, there is a pressing need for an optimal surveillance strategy that is both simplified and cost-effective to facilitate wider adoption by clinicians. This review article evaluates the existing data, addresses ongoing controversies, and aims to provide new perspectives on HCC surveillance strategies for patients who have achieved SVR from HCV., Competing Interests: All authors have completed the ICMJE uniform disclosure form and have no other conflicts of interest to declare. C.Q.P. received institutional research grants from Gilead Sciences and Wuxi Hisky Medical Technologies Co., Ltd. Table 1.Recommendations from international guidelines on HCC surveillance after DAA therapyPre-DAA assessmentAASLDEASLAPASLF0–F2N/AN/AUS+tumor markersa every 6 months for 2 years, followed by annually indefinitelyF3NoUS±AFP every 6 months indefinitelyUS+tumor markersa every 6 months indefinitelyF4US±AFP every 6 months indefinitelyUS±AFP every 6 months indefinitelyUS+tumor markersa every 6 months indefinitelyAASLD = American Association for the Study of Liver Diseases, EASL = European Association for the Study of Liver, APASL = Asian Pacific Association for the Study of Liver, SVR = sustained virologic response, DAA = direct acting antiviral agents,  TE = transient elastography, FIB-4 = Fibrosis-4 index, US = ultrasound, N/A = not available, AFP = alpha-fetoprotein, AFP-L3 = lens culinaris agglutinin-reactive AFP isoform, DCP = des gamma carboxy-prothrombin.aTumor markers: AFP, AFL-L3, DCP., (© The Author(s) 2024. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University.)

Aim: To develop and validate a model for predicting diabetic retinopathy (DR) in patients with type 2 diabetes., Methods: All risk factors with statistical significance in the DR prediction model were scored by their weights. Model performance was evaluated by the area under the receiver operating characteristic (ROC) curve, Kaplan-Meier curve, calibration curve and decision curve analysis. The prediction model was externally validated using a validation cohort from a Chinese hospital., Results: In this meta-analysis, 21 cohorts involving 184,737 patients with type 2 diabetes were examined. Sex, smoking, diabetes mellitus (DM) duration, albuminuria, glycated haemoglobin (HbA1c), systolic blood pressure (SBP) and TG were identified to be statistically significant. Thus, they were all included in the model and scored according to their weights (maximum score: 35.0). The model was validated using an external cohort with median follow-up time of 32 months. At a critical value of 16.0, the AUC value, sensitivity and specificity of the validation cohort are 0.772 ((95% confidence interval (95%CI): 0.740-0.803), p  < .01), 0.715 and 0.775, respectively. The calibration curve lied close to the ideal diagonal line. Furthermore, the decision curve analysis demonstrated that the model had notably higher net benefits. The external validation results proved the reliability of the risk prediction model., Conclusions: The simple DR prediction model developed has good overall calibration and discrimination performance. It can be used as a simple tool to detect patients at high risk of DR.

Competing Interests: C.Q.P. received institutional research grants from Gilead Sciences and Wuxi Hisky Medical Technologies Co., Ltd. The other authors have no conflicts of interest to disclose.

Background and Aim: To identify individuals with metabolic dysfunction-associated steatohepatitis (MASH) or "at-risk" MASH among patients with metabolic dysfunction-associated steatotic liver disease (MASLD), three noninvasive models are available with satisfactory efficiency, which include magnetic resonance imaging [MRI]- AST (MAST), FibroScan-AST (FAST score), and magnetic resonance elastography [MRE] plus FIB-4 (MEFIB). We aimed to evaluate the most accurate approach for diagnosing MASH or "at-risk" MASH., Methods: We included 108 biopsy-proven MASLD patients who underwent simultaneous assessment of MRE, MRI proton density fat fraction (MRI-PDFF), and FibroScan scans. Compared with the histological diagnosis, we analyzed the AUC of each model and assessed the accuracy., Results: Our study cohort consisted of 64.8% of MASH and 25.9% of "at-risk" MASH. When analyzing the performance of each model for the diagnostic accuracy of MASH, we found that the AUC [95% CI] of MAST was comparable to FAST (0.803 [0.719-0.886] vs 0.799 [0.707-0.891], P = 0.930) and better than MEFIB (0.671 [0.571-0.772], P = 0.005). Similar findings were observed in the "at-risk" MASH patients. The AUCs [95% CI] for MAST, FAST, and MEFIB were 0.810 [0.719-0.900], 0.782 [0.689-0.874], and 0.729 [0.619-0.838], respectively. The models of MAST and FAST had comparable AUCs (P = 0.347), which were statistically significantly higher than that of MEFIB (P = 0.041). Additionally, the cutoffs for diagnosis of MASH were lower than "at-risk" MASH., Conclusion: MAST and FAST performed better than MEFIB in diagnosing "at-risk" MASH and MASH using lower cutoff values. Our findings provided evidence for selecting the most accurate noninvasive model to identify patients with MASH or at-risk MASH., (© 2024 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most prevalent chronic liver condition worldwide. Current liver enzyme-based screening methods have limitations that may missed diagnoses and treatment delays. Regarding Chen et al , the risk of developing MAFLD remains elevated even when alanine aminotransferase levels fall within the normal range. Therefore, there is an urgent need for advanced diagnostic techniques and updated algorithms to enhance the accuracy of MAFLD diagnosis and enable early intervention. This paper proposes two potential screening methods for identifying individuals who may be at risk of developing MAFLD: Lowering these thresholds and promoting the use of noninvasive liver fibrosis scores., Competing Interests: Conflict-of-interest statement: Calvin Q Pan received institutional research grants from Gilead Sciences, Inc. and Wuxi Hisky Medical Technologies Co., Ltd. Ming-Hua Zheng has received honoraria for lectures from AstraZeneca, Hisky Medical Technologies and Novo Nordisk, consulting fees from Boehringer Ingelheim. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Serological detection of hepatitis B virus markers plays a vital role in the diagnosis, treatment, prognosis, and therapeutic surveillance of hepatitis B. To compare the diagnostic performance of Autolumo A2000Plus and Abbott Architect i2000 systems in the detection of hepatitis B infection markers. A total of 6 HBV seroconversion panels and 743 participants were enrolled in this study, including 383 HBV-infected patients and 360 healthy adults. Clinical diagnostic information, laboratory results, and HBV genotyping were collected to evaluate the diagnostic performance of the A2000Plus and i2000 systems in detecting HBV infection markers. The results showed that the total percent agreement of HBV markers was all >90 % in both detection systems among the six seroconversion panels and 743 serum samples from the population. The χ2 values of the Chi-square test among hepatitis B virus serological markers in both analyzers were between 550.7 and 743.0, p  < 0.0001. HBV marker consistency test results show perfect consistency between the two analyzers, with Kappa values ranging from 0.854 to 1.000. For specific samples, including Hepatitis B patients with Genotype C, chronic hepatitis B, hepatitis B-related cirrhosis, and hepatocellular carcinoma, spearman correlation analysis showed HBsAg correlation coefficients ranging from 0.8532 to 0.9745, p  < 0.001 in both analyzers. In conclusion, Autolumo A2000Plus diagnostic performance in consistency and correlation is comparable to Abbott Architect i2000 when detecting markers of hepatitis B infection. The Autolumo A2000Plus system can be used as a reliable instrument for HBV marker detection., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Objective: This study aimed to analyze the clinical efficacy of the Jianpi Shengxue tablet for treating renal anemia., Methods: A total of 200 patients with renal anemia from December 2020 to December 2022 were enrolled and randomly divided into two groups. Patients in the control group were treated with polysaccharide-iron complex, and those in the experimental group were administered Jianpi Shengxue tablet. After 8 weeks of continuous treatment, the therapeutic outcomes regarding anemia were compared between the two groups., Results: After treatment, the red blood cell (RBC) count, hematocrit (HCT), reticulocyte percentage (RET), ferritin (SF), serum iron (SI), transferrin saturation (TSAT), and serum albumin (ALB) all increased (P<0.01), and the clinical symptom score and total iron binding capacity decreased (P<0.01) in the experimental group. Moreover, the improvements in RBC, HCT, RET, SF, SI, TAST, ALB, and clinical symptoms (fatigue, anorexia, dull skin complexion, numbness of hands and feet) in the experimental group were significantly greater than those in the control group (P<0.05). The total effective rate for treating renal anemia was significantly higher in the experimental group than in the control group (P<0.01)., Conclusion: The Jianpi Shengxue tablet demonstrates efficacy in treating renal anemia, leading to significant improvements in the laboratory examination results and clinical symptoms of patients with renal anemia., (© 2024. Huazhong University of Science and Technology.)

Background & Aims: Hepatic recompensation may be achieved in patients with decompensated cirrhosis due to chronic hepatitis B (CHB) upon effective suppression of viral replication by nucleos(t)ide analogues (NAs). However, the optimal timing and predictors of recompensation and the subsequent clinical course of patients with CHB with vs. without recompensation are not well-defined., Methods: This study was a retrospective extension of a multi-centre prospective cohort, focusing on patients with CHB and decompensated cirrhosis treated with entecavir. We followed patients beyond treatment week 120 until a second decompensation event or June 2023. We identified the optimal timing and predictors of recompensation by week 120, evaluated durability of recompensation in patients fulfilling recompensation criteria by week 120 and examined late recompensation in those who did not fulfil it by week 120., Results: At treatment week 24, serum albumin ≥34 g/L predicted recompensation by week 120. The Brec-PAS model offered good predictive ability for recompensation by week 120. Of the 283 patients who finished 120 weeks of therapy, 175 were followed beyond week 120 (median follow-up: 240 weeks). Among the 106 patients achieving recompensation by week 120, 92 (86.8%) maintained recompensation for another 120 (72-168) weeks. Among the 69 patients without recompensation by week 120, 40.6% attained late recompensation during the subsequent 120 (72-168) weeks. Additionally, hepatocellular carcinoma incidence was lower in the recompensated group (5.0% vs. 16.13%, p  = 0.002)., Conclusions: A serum albumin ≥34 g/L at treatment week 24 predicted recompensation by week 120. Recompensation achieved by week 120 of NA treatment is maintained in >80% of patients in the long term. Some patients may achieve recompensation only after >120 weeks of NA treatment. The incidence of hepatocellular carcinoma was reduced but not completely abolished after recompensation., Impact and Implications: Our research provides a meaningful contribution to understanding the long-term prognosis of recompensation in patients with chronic hepatitis B and decompensated cirrhosis, as well as to evaluating the predictive value of serum albumin levels, offering a comprehensive view of clinical outcomes after recompensation. The significance of early biomarkers in guiding therapeutic decisions is highlighted, shedding light on the continued benefits and possible risks after recompensation. This enhances the capability for more precise prognostic evaluations and informed therapeutic strategies. For healthcare providers, these insights afford a detailed perspective on patient monitoring and intervention planning, underscoring the need for ongoing assessment past the initial recompensation phase., (© 2024 The Authors.)

Background: Accompanied by the growing prevalence of nonalcoholic fatty liver disease (NAFLD), the coexistence of chronic hepatitis B (CHB) and NAFLD has increased. In the context of CHB, there is limited understanding of the factors that influence the development of NASH., Methods: We enrolled CHB combined NAFLD patients who had liver biopsy and divided them to NASH vs. non-NASH groups. A whole transcriptome chip was used to examine the expression profiles of long noncoding RNAs (lncRNAs) and mRNA in biopsied liver tissues. The function analysis of HIGD1A were performed. We knocked down or overexpressed HIGD1A in HepG2.2.15 cells by transient transfection of siRNA-HIGD1A or pcDNA-HIGD1A. In vivo investigations were conducted using hepatitis B virus (HBV) transgenic mice., Results: In 65 patients with CHB and NAFLD, 28 were patients with NASH, and 37 were those without NASH. After screening 582 differentially expressed mRNAs, GO analysis revealed differentially expressed mRNAs acting on nicotinamide adenine dinucleotide phosphate (NADPH), which influenced redox enzyme activity. KEGG analysis also shown that they were involved in the NAFLD signaling pathway. The function analysis revealed that HIGD1A was associated with the mitochondrion. Then, both in vivo and in vitro CHB model, HIGD1A was significantly higher in the NASH group than in the non-NASH group. HIGD1A knockdown impaired mitochondrial transmembrane potential and induced cell apoptosis in HepG2.2.15 cells added oleic acid and palmitate. On the contrary, hepatic HIGD1A overexpression ameliorated free fatty acids-induced apoptosis and oxidative stress. Furthermore, HIGD1A reduced reactive oxygen species (ROS) level by increasing glutathione (GSH) expression, but Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/Acetyl-CoA carboxylase (ACC) pathway was not involved., Conclusion: Both in vivo and in vitro CHB model, an upward trend of HIGD1A was observed in the NASH-related inflammatory response. HIGDIA played a protective role in cells against oxidative stress. Our data suggested that HIGD1A may be a positive regulator of NASH within the CHB context.

Introduction: The results from 2 phase 3 studies, through 2 years, in chronic hepatitis B infection showed tenofovir alafenamide (TAF) had similar efficacy to tenofovir disoproxil fumarate (TDF) with superior renal and bone safety. We report updated results through 5 years., Methods: Patients with HBeAg-negative or HBeAg-positive chronic hepatitis B infection with or without compensated cirrhosis were randomized (2:1) to TAF 25 mg or TDF 300 mg once daily in double-blind (DB) fashion for up to 3 years, followed by open-label (OL) TAF up to 8 years. Efficacy (antiviral, biochemical, and serologic), resistance (deep sequencing of polymerase/reverse transcriptase and phenotyping), and safety, including renal and bone parameters, were evaluated by pooled analyses., Results: Of 1,298 randomized and treated patients, 866 receiving TAF (DB and OL) and 432 receiving TDF with rollover to OL TAF at year 2 (n = 180; TDF→TAF3y) or year 3 (n = 202; TDF→TAF2y) were included. Fifty (4%) TDF patients who discontinued during DB were excluded. At year 5, 85%, 83%, and 90% achieved HBV DNA <29 IU/mL (missing = failure) in the TAF, TDF→TAF3y, and TDF→TAF2y groups, respectively; no patient developed TAF or TDF resistance. Median estimated glomerular filtration rate (by using Cockcroft-Gault) declined <2.5 mL/min, and mean declines of <1% in hip and spine bone mineral density were seen at year 5 in the TAF group; patients in the TDF→TAF groups had improvements in these parameters at year 5 after switching to OL TAF., Discussion: Long-term TAF treatment resulted in high rates of viral suppression, no resistance, and favorable renal and bone safety., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background: Patients with chronic hepatitis B (CHB) who switch from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) show changes in lipid profiles., Aim: To evaluate how these changes affect cardiovascular risk., Methods: This pooled analysis, based on two large prospective studies, evaluated fasting lipid profiles of patients with CHB who were treated with TAF 25 mg/day or TDF 300 mg/day for 96 weeks. Patients who fulfilled the American College of Cardiology criteria (age 40-79 years, high-density lipoprotein [HDL] 20-100 mg/dL, total cholesterol [TC] 130-320 mg/dL and systolic blood pressure 90-200 mmHg) required to assess 10-year atherosclerotic cardiovascular disease (ASCVD) risk with baseline lipid data and at least one post-baseline measurement were included in the ASCVD-risk population. The 10-year ASCVD risk was calculated for patients in this population, and changes from baseline to Week 96 were assessed using intermediate- (≥7.5%) and high-risk (≥20%) cut-offs., Results: Among 1632 patients, 620 (38%) met the criteria for the ASCVD-risk population. At Week 96, fasting levels of all lipids, except TC:HDL ratio, were lower with TDF than TAF. No significant increase was observed in overall ASCVD risk or in any ASCVD-risk categories during the 96-week treatment period compared with baseline. A similar proportion of patients in the TAF and TDF treatment groups (1.3% and 2.3%, respectively; p = 0.34) reported cardiovascular events., Conclusion: Despite on-treatment differences in lipid profiles with TAF and TDF, predicted cardiovascular risk and clinical events were similar for both groups after 96 weeks., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Although current guidelines didn't support the routine use of furosemide in oliguric acute kidney injury (AKI) management, some patients may benefit from furosemide administration at an early stage. We aimed to develop an explainable machine learning (ML) model to differentiate between furosemide-responsive (FR) and furosemide-unresponsive (FU) oliguric AKI., Methods: From Medical Information Mart for Intensive Care-IV (MIMIC-IV) and eICU Collaborative Research Database (eICU-CRD), oliguric AKI patients with urine output (UO) < 0.5 ml/kg/h for the first 6 h after ICU admission and furosemide infusion ≥ 40 mg in the following 6 h were retrospectively selected. The MIMIC-IV cohort was used in training a XGBoost model to predict UO > 0.65 ml/kg/h during 6-24 h succeeding the initial 6 h for assessing oliguria, and it was validated in the eICU-CRD cohort. We compared the predictive performance of the XGBoost model with the traditional logistic regression and other ML models., Results: 6897 patients were included in the MIMIC-IV training cohort, with 2235 patients in the eICU-CRD validation cohort. The XGBoost model showed an AUC of 0.97 (95% CI: 0.96-0.98) for differentiating FR and FU oliguric AKI. It outperformed the logistic regression and other ML models in correctly predicting furosemide diuretic response, achieved 92.43% sensitivity (95% CI: 90.88-93.73%) and 95.12% specificity (95% CI: 93.51-96.3%)., Conclusion: A boosted ensemble algorithm can be used to accurately differentiate between patients who would and would not respond to furosemide in oliguric AKI. By making the model explainable, clinicians would be able to better understand the reasoning behind the prediction outcome and make individualized treatment.

Background: The majority of HBeAg-positive mothers with chronic hepatitis B have high levels of viremia and inactive disease with normal alanine aminotransferase (ALT) during pregnancy. In addition, postpartum disease activation and ALT flare have been reported in the range of 15 - 35%. However, the current International Association Guidelines have not provided clear recommendations and a risk-stratified monitoring schedule. Furthermore, data are lacking on the definition of normal ALT in the postpartum period in mothers with chronic hepatitis B. The clinical features and ALT flare patterns in HBeAg-positive mothers versus HBeAg-negative mothers are not fully explored. Thus, we design a cohort study to investigate the aforementioned area and generate data to assist healthcare providers in better managing mothers with hepatitis B. We aim to assess the frequency of postpartum ALT flares and predictors for such events., Method: This study is a single-center and prospective cohort study (n = 360) that consists of two groups of patients including HBsAg-positive mothers (n = 120) and healthy mothers without HBV infection (n = 240). In HBeAg-positive mothers, antiviral therapy during late pregnancy is permitted to prevent Mother-to-child transmission (MTCT) but discontinued at delivery if there is no further indication for the treatment. Mothers are enrolled at the gestational weeks of 12-24. After delivery, both mothers and their infants will be followed up until postpartum week 24. Clinical and laboratory data are collected every 4 weeks during the study except there are no follow-up visits at the postpartum weeks 16 and 20. The primary objective is the proportion of patients with postpartum ALT flares. The secondary objectives are independent risk factors during pregnancy for predicting postpartum ALT flares and the normal range of postpartum ALT levels in healthy mothers., Discussion: The current study focuses on the incidence of postpartum ALT flares in mothers with chronic hepatitis B including subgroup analysis based on HBeAg status. The data will have several clinical implications, such as providing evidence for an appropriate monitoring schedule in CHB mothers after delivery. Further analyses on predictors of such events may assist clinicians in identifying mothers who might develop severe postpartum ALT flares. The data generated from healthy mothers have the potential to identify the patterns of ALT changes during pregnancy and postpartum, so we can gain a better understanding of the normal range of ALT in this subpopulation., Trial Registration Number at the Chinese Clinical Trial Registry: ChiCTR2200061130., (© 2023. The Author(s).)

Pyrrolizidine alkaloids induced hepatic sinusoidal obstruction syndrome (PA-HSOS) often occurs after consuming herbs or a dietary supplement containing the plant Tu-San-Qi. Limited data exists to identify patients with fatal outcomes for early interventions. We aimed to analyze the predictors for 3-month survival. We retrospectively enrolled PA-HSOS patients in 5 hospitals and extracted data from the onset of PA-HSOS to 36 months. Outcome measurements were 3-month and 36-month survival rates, baseline prognostic predictors for survival, and the effects of anticoagulant therapy. Among 49 enrollees, the median age was 60 and 49% male. At the onset of PA-HSOS, patients with Child-Turcotte-Pugh (CTP) class of A, B, or C were 8.2% (4/49), 42.8% (21/49) and 49.0% (24/49), respectively. None of them received a transjugular intrahepatic portosystemic shunt or a liver transplant. The 3-month and 36-month survival rates were 86% and 76%, respectively. Compared to the CTP class A or B, class C at baseline independently predicted lower survival rates at both 3 and 36 months. However, anticoagulation therapy treatment within the first 3 months independently predicted significantly higher survival rates at both time points. CTP class C and anticoagulant therapy were the independent predictors for short-term and long-term survival. Anticoagulant therapy could decrease mortality rate of CTP class C patients. The greatest benefit of anticoagulant evaluated by 3-month survival rate was in patients with CTP class C compared with those without treatment (93% vs 40%, P = .009). There were no bleeding complications reported in patients treated with the anticoagulant., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Competing Interests: CWS has received speaker fees from GILEAD Sciences and Abbott. CP received research funding and is a speaker for Gilead. PCM supervises a doctoral student with funding support from GSK. SH has received funding from Gilead for HCV Micro-elimination programs. HR has received research funding and speaker’s honoraria from Gilead Sciences, AbbVie and Pfizer and is a board member of the CDA foundation. SW has received research funding from Gilead Sciences, and honoraria from Prime Inc, and is on the Board of Directors for the Hepatitis B Foundation, World Hepatitis Alliance, and serves in the patient advisory group and HBV special interest group for the AASLD. FR has received consulting fees from Sanofi Pasteur. GD has received consulting fees and speaker fees from Gilead Sciences, has participated on Data Safety Monitoring Board/Advisory Board for janssen, Glaxo Smith Kline, Arbutus, Aligos, Vir and has roles in the National Medical Research Council Singapore and the World Health Organisation Pediatric Working Group on Viral Hepatitis. Please refer to the accompanying ICMJE disclosure forms for further details.

Alcohol-related liver disease (ALD) from excessive alcohol intake has a unique gut microbiota profile. The disease progression-free survival in ALD patients has been associated with the degree of gut dysbiosis. The vicious cycles between gut dysbiosis and the disease progression in ALD including: an increase of acetaldehyde production and bile acid secretion, impaired gut barrier, enrichment of circulating microbiota, toxicities of microbiota metabolites, a cascade of pro-inflammatory chemokines or cytokines, and augmentation in the generation of reactive oxygen species. The aforementioned pathophysiology process plays an important role in different disease stages with a spectrum of alcohol hepatitis, ALD cirrhosis, neurological dysfunction, and hepatocellular carcinoma. This review aims to illustrate the pathophysiology of gut microbiota and clarify the gut-brain crosstalk in ALD, which may provide the opportunity of identifying target points for future therapeutic intervention in ALD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhu, Wang, Pan and Xing.)

Hepatitis D virus (HDV) infection occurs as a coinfection with hepatitis B and increases the risk of hepatocellular carcinoma, decompensated cirrhosis, and mortality compared to hepatitis B virus (HBV) monoinfection. Reliable estimates of the prevalence of HDV infection and disease burden are essential to formulate strategies to find coinfected individuals more effectively and efficiently. The global prevalence of HBV infections was estimated to be 262,240,000 in 2021. Only 1,994,000 of the HBV infections were newly diagnosed in 2021, with more than half of the new diagnoses made in China. Our initial estimates indicated a much lower prevalence of HDV antibody (anti-HDV) and HDV RNA positivity than previously reported in published studies. Accurate estimates of HDV prevalence are needed. The most effective method to generate estimates of the prevalence of anti-HDV and HDV RNA positivity and to find undiagnosed individuals at the national level is to implement double reflex testing. This requires anti-HDV testing of all hepatitis B surface antigen-positive individuals and HDV RNA testing of all anti-HDV-positive individuals. This strategy is manageable for healthcare systems since the number of newly diagnosed HBV cases is low. At the global level, a comprehensive HDV screening strategy would require only 1,994,000 HDV antibody tests and less than 89,000 HDV PCR tests. Double reflex testing is the preferred strategy in countries with a low prevalence of HBV and those with a high prevalence of both HBV and HDV. For example, in the European Union and North America only 35,000 and 22,000 cases, respectively, will require anti-HDV testing annually., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To analyze the occurrence of recompensation conditions in patients with chronic hepatitis B virus-related decompensated cirrhosis after entecavir antiviral therapy. Methods: Patients with hepatitis B virus-related decompensated cirrhosis with ascites as the initial manifestation were prospectively enrolled. Patients who received entecavir treatment for 120 weeks and were followed up every 24 weeks (including clinical endpoint events, hematological and imaging indicators, and others) were calculated for recompensation rates according to the Baveno VII criteria. Measurement data were compared using the Student t -test or Mann-Whitney U test between groups. Categorical data were compared by the χ (2) test or Fisher's exact probability method between groups. Results: 283 of the 320 enrolled cases completed the 120-week follow-up, and 92.2% (261/283) achieved a virological response (HBV DNA 20 IU/ml). Child-Pugh and MELD scores were significantly improved after treatment (8.33 ± 1.90 vs. 5.77 ± 1.37, t = 12.70, P < 0.001; 13.37 ± 4.44 vs. 10.45 ± 4.58, t = 5.963, P < 0.001). During the 120-week follow-up period, 14 cases died, two received liver transplants, 19 developed hepatocellular cancer, 11 developed gastroesophageal variceal bleeding, and four developed hepatic encephalopathy. 60.4% (171/283) (no decompensation events occurred for 12 months) and 56.2% (159/283) (no decompensation events occurred for 12 months and improved liver function) of the patients had achieved clinical recompensation within 120 weeks. Patients with baseline MELD scores > 15 after active antiviral therapy achieved higher recompensation than patients with baseline MELD scores ≤15 [50/74 (67.6%) vs. 109/209 (52.2%), χ (2) = 5.275, P = 0.029]. Conclusion: Antiviral therapy can significantly improve the prognosis of patients with hepatitis B virus-related decompensated cirrhosis. The majority of patients (56.2%) had achieved recompensation. Patients with severe disease did not have a lower probability of recompensation at baseline than other patients.

Background & Aims: Antiviral therapy may attenuate the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We aimed to explore how tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) affect HCC risk in patients with CHB., Methods: The REACH-B, aMAP, and mPAGE-B models were utilized to assess HCC risk in patients with CHB from two global randomized-controlled trials evaluating the impact of TAF vs. TDF treatment. Standard incidence ratios (SIRs) were calculated using data from the REACH-B model as a ratio of observed HCC cases in the TAF- or TDF-treated patients vs. predicted HCC cases for untreated historical controls. Proportions of treated patients shifting aMAP and mPAGE-B risk categories between baseline and Week 240 were calculated., Results: Of the 1,632 patients (TAF, n = 1,093; TDF, n = 539) followed for up to 300 weeks, 22 HCC cases developed. Those receiving TAF had an SIR that was lower compared to the SIR of individuals receiving TDF: 0.32 ( p <0.001) vs. 0.56 ( p  = 0.06). In the general study population, individuals without cirrhosis at baseline had an SIR that was lower compared to the SIR of individuals with cirrhosis at baseline: 0.37 ( p <0.001) vs. 0.58 ( p  = 0.15). Of the patients at low risk of HCC at baseline, the majority (97%) remained low risk by mPAGE-B and aMAP scoring at Week 240. Among those at medium or high risk at baseline, substantial portions shifted to a lower risk category by Week 240 (mPAGE-B: 22% and 42%; aMAP: 39% and 63%, respectively)., Conclusions: This evaluation provides evidence that treatment with TAF or TDF can reduce HCC risk in patients with CHB, particularly in patients without cirrhosis., Impact and Implications: Despite the substantial impact of HCC on long-term outcomes of patients with CHB, the differential risk of HCC development among those receiving treatment with TAF vs. TDF has not been well elucidated. Using three validated risk prediction models, we found that TAF is at least as effective as TDF in reducing HCC risk in patients with CHB. While TDF is well-studied in the context of HCC risk reduction, our novel findings underscore the effectiveness of TAF as a treatment option for patients with CHB., Clinical Trial Numbers: NCT01940341; NCT02836249; NCT01940471; NCT02836236., Competing Interests: AJH: There are no financial disclosures for this author. CP: Has served as a speaker for Gilead and received research grants from Gilead. DRS: There are no financial disclosures for this author. EG: Member of scientific advisory boards for AbbVie, Abbott Diagnostics, Aligos, Arbutus, Arrowhead, Assembly, Avalia, Clear B Therapeutics, Dicerna, Enanta, Gilead Sciences, GSK, Intellia, Janssen, Merck, Novartis, Genentech-Roche, Vaccitech, Ventorx, Vir Bio and Virion Therapeutics. FA: Gilead Sciences employee and stock ownership. HJ: Received grants from: AbbVie, Gilead Sciences, GSK, Janssen, Roche, Vir Biotechnology Inc. Is a consultant for: Aligos, Antios, Arbutus, Eiger, Gilead Sciences, GSK, Janssen, Merck, Roche, VBI Vaccines, Vir Biotechnology Inc., Viroclinics. HC: Has served as an advisor for Aligos, Arbutus, Hepion, Janssen, Gilead, GSK, Roche, Vaccitech, Vir Biotechnology, Virion Therapeutic, and as a speaker for Gilead, Roche, and Mylan. HW: Employee and stockholder for Gilead. JF: Employee and stockholder for Gilead. JK: Consultant for Abbvie, Abbott, Gilead Sciences, Roche and Sysmex. On speaker’s bureaus for Abbvie, Bristol-Myers Squibb, Gilead Sciences, and Fujirebio. JH: Has received consulting fee from AbbVie, Arbutus, Bristol Myers Squibb, Gilead Sciences, Johnson & Johnson, Roche and received grants from Bristol Myers Squibb and Johnson & Johnson. KA: Aligos, Assembly, Bluejay, BMS, BI, DrugFarm, Gilead, GSK, Janssen, Merck, Roche, Sobi. LJY: Employee of Gilead Sciences and own stock in Gilead Sciences. MB: Has served as an advisor for Abbvie, Arbutus, Assembly, Janssen, Gilead, GSK, Roche, and as a speaker for Gilead and Abbvie. MBr: Speakers Bureau for AbbVie and Gilead. Advisory for AbbVie, Gilead, Janssen, Roche, EISAI-MSD. NI: There are no financial disclosures for this author. QN: Has served as a consultant for BMS, GSK, MSD, and Novartis. SHA: Has acted as advisors and investigator for Gilead, Janssen, AbbVie, Roche, Assembly Biosciences, Arbutus, Brii, Vaccitech, GSK, Inovio, Aligos, Vir Biotechnology, SL Vaxigen, GeneOne Life Science, GreenCross, Yuhan, Samil and Ildong. SF: Has received research support from Gilead. Consultant for Abbvie, Assembly Bio, Janssen, and Gilead. Teacher and speaking for Abbvie and Gilead. SGL: Speakers bureau for Gilead, Janssen, Roche, Sysmex. Advisory board for Gilead, Abbott, Roche, GSK, Janssen, Sysmex, Springbank, Arbutus, Assembly, Grifols, Eisai. Research support from Gilead, Abbott, Roche, Sysmex, Fibronostics, Merck. TTC: There are no financial disclosures for this author. WLC: Member of Advisory Board for Gilead, AbbVie, BMS, Roche, and PharmaEssentia. Speaker for Gilead, AbbVie, BMS, Roche, PharmaEssentia. WKS: Received speaker’s fees from Mylan and AstraZeneca, is an advisory board member of Abbott, is an advisory board member and received speaker’s fees from AbbVie, and is an advisory board member, received speaker’s fees and research funding from Gilead Sciences. YSL: Advisor/consultant/speaker for AbbVie, Assembly Biosciences, Bayer Healthcare, GlaxoSmithKline, Gilead Sciences, Janssen, Olix Pharmaceuticals, Roche, Vaccitech, and Vir Biotechnology; and received grant/research support from Gilead Sciences. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Background: Previous studies have indicated that nitric oxide synthase 2 ( NOS2 ) genetic variations are involved in delayed fracture healing and fracture non-union. Whether these genetic variants associate with the development of osteomyelitis (OM) remains unclear. Here, we analyzed the potential relationships between NOS2 genetic variations and the risk of developing post-traumatic OM (PTOM) in a Chinese Han population., Methods: Altogether 704 participants, including 336 PTOM patients and 368 healthy controls, were genotyped of rs2297514 and rs2248814 of the NOS2 gene using the SNaPshot genotyping method., Results: Outcomes showed that the frequency of allele C of rs2297514 in the patient group was significantly lower than that in the control group (48.7% vs . 54.5%, P = 0.029, OR = 0.792, 95% CI 0.642 - 0.976). In addition, significant associations were found between rs2297514 and susceptibility to PTOM by the recessive model ( P = 0.007, OR = 0.633, 95% CI 0.453 - 0.884), and the homozygous model ( P = 0.039, OR = 0.648, 95% CI 0.429 - 0.979). Moreover, patients with the CC genotype of rs2297514 had lower inflammatory biomarkers levels than the TT genotype, especially for the C-reactive protein (CRP) level (median: 4.1 mg/L vs . 8.9 mg/L, P = 0.027). However, no significant relationship was noted between rs2248814 and the risk of developing PTOM., Conclusion: In this Chinese cohort, rs2297514 is correlated with a decreased risk of PTOM development, with genotype CC as a protective factor., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Song, Zhang, Lin, Hu, Pan, Jiang and Hu.)

Background: The 2016 World Health Assembly endorsed the elimination of hepatitis B virus (HBV) infections by 2030. However, the HBV prevalence in Western countries, where the historical prevalence is low and highly impacted by immigration trends, remains uncertain making planning difficult. We aimed to develop a more accurate estimate of HBV prevalence and identify key immigrant populations that need to be screened, vaccinated, and treated to achieve the elimination targets., Methods: US immigration data from 1900 forward and country-specific modeled prevalence by age and sex were used to estimate immigrated HBV infections entering the US, new infections in the US, mortality (all-cause and liver-related), and disease burden through 2030., Findings: Using a dynamic Markov model, we estimated 1.8 million (95% uncertainty interval: 1.3-2.6 million) HBV infections in 2020 in all ages, higher than the NHANES national serosurvey. Infections between ages 30-74 accounted for 82% of all cases. Furthermore, HBV infections were concentrated among immigrants. New decompensated cirrhosis, hepatocellular carcinoma, and liver related deaths are expected to increase by 20%, 31% and 25% respectively from 2019 to 2030 at current diagnosis and treatment rate., Interpretation: National serosurveys can underestimate total infections due to under-sampling in immigrant populations. To meet the WHO elimination targets, culturally appropriate screening and linkage to care programs in the immigrant populations are needed in the US. In their absence, there will be significant increases in the burden of HBV and the US will fail to meet the elimination targets by 2030., Funding: This analysis was funded by a research grant from Gilead Sciences (IN-US-988-5786) and made possible by grants from John C Martin Foundation (2019-G024), ZeShan Foundation (2021-0101-1-CDA-HEP-10), and EndHep2030 who supported country analyses., Competing Interests: Calvin Q. Pan: Consultant – Gilead, AbbVie; Advisory Board – Gilead, BMS, AbbVie; Research – Gilead, Merck. Homie Razavi: Employee – CDA Foundation, Advisory Board – Gilead, AbbVie, VBI Vaccine, Merck, Jansson, Roche; Research – Gilead, AbbVie, Assembly Biosciences, Intercept, Pfizer. Devin Razavi-Shearer, Ivane Gamkrelidze, Kathryn Razavi-Shearer, Sarah Blach, Chris Estes, Ellen Mooneyhan: Employee – CDA Foundation., (© 2023 The Author(s).)

Prevention of mother-to-child transmission of hepatitis B virus (HBV) infection is a cornerstone of efforts to support progress towards elimination of viral hepatitis. Current guidelines recommend maternal screening, antiviral therapy during the third trimester of high-risk pregnancies, universal and timely HBV birth dose vaccination, and post-exposure prophylaxis with hepatitis B immunoglobulin for selected neonates. However, serological and molecular diagnostic testing, treatment and HBV vaccination are not consistently deployed, particularly in many high endemicity settings, and models predict that global targets for reduction in paediatric incidence will not be met by 2030. In this article, we briefly summarise the evidence for current practice and use this as a basis to discuss areas in which prevention of mother-to-child transmission can potentially be enhanced. By reducing health inequities, enhancing pragmatic use of resources, filling data gaps, developing advocacy and education, and seeking consistent investment from multilateral agencies, significant advances can be made to further reduce vertical transmission events, with wide health, societal and economic benefits., Competing Interests: CWS has received speaker fees from GILEAD Sciences and Abbott. CP received research funding and is a speaker for Gilead. PCM supervises a doctoral student with funding support from GSK. SH has received funding from Gilead for HCV Micro-elimination programs. HR has received research funding and speaker’s honoraria from Gilead Sciences, AbbVie and Pfizer and is a board member of the CDA foundation. SW has received research funding from Gilead Sciences, and honoraria from Prime Inc, and is on the Board of Directors for the Hepatitis B Foundation, World Hepatitis Alliance, and serves in the patient advisory group and HBV special interest group for the AASLD. FR has received consulting fees from Sanofi Pasteur. GD has received consulting fees and speaker fees from Gilead Sciences, has participated on Data Safety Monitoring Board/Advisory Board for janssen, Glaxo Smith Kline, Arbutus, Aligos, Vir and has roles in the National Medical Research Council Singapore and the World Health Organisation Pediatric Working Group on Viral Hepatitis. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Background: Plant cell culture technology is a potential way to produce polyphenols, however, this way is still trapped in the dilemma of low content and yield. Elicitation is regarded as one of the most effective ways to improve the output of the secondary metabolites, and therefore has attracted extensive attention. Methods: Five elicitors including 5-aminolevulinic acid (5-ALA), salicylic acid (SA), methyl jasmonate (MeJA), sodium nitroprusside (SNP) and Rhizopus Oryzae Elicitor (ROE) were used to improve the content and yield of polyphenols in the cultured Cyclocarya paliurus (C. paliurus) cells, and a co-induction technology of 5-ALA and SA was developed as a result. Meanwhile, the integrated analysis of transcriptome and metabolome was adopted to interpret the stimulation mechanism of co-induction with 5-ALA and SA. Results: Under the co-induction of 50 μM 5-ALA and SA, the content and yield of total polyphenols of the cultured cells reached 8.0 mg/g and 147.12 mg/L, respectively. The yields of cyanidin-3-O-galactoside, procyanidin B1 and catechin reached 28.83, 4.33 and 2.88 times that of the control group, respectively. It was found that expressions of TFs such as CpERF105, CpMYB10 and CpWRKY28 increased significantly, while CpMYB44 and CpTGA2 decreased. These great changes might further make the expression of CpF3'H (flavonoid 3'-monooxygenase), CpFLS (flavonol synthase), CpLAR (leucoanthocyanidin reductase), CpANS (anthocyanidin synthase) and Cp4CL (4-coumarate coenzyme A ligase) increase while CpANR (anthocyanidin reductase) and CpF3'5'H (flavonoid 3', 5'-hydroxylase) reduce, ultimately enhancing the polyphenols accumulation Conclusion: The co-induction of 5-ALA and SA can significantly promote polyphenol biosynthesis in the cultured C. paliurus cells by regulating the expression of key transcription factors and structural genes associated with polyphenol synthesis, and thus has a promising application., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ling, Wang, Pan, Tang, Yuan, Zhang, Chen, Peng and Yin.)

(1) Background: Glioblastoma multiforme (GBM) is the most common and malignant intracranial tumor in adults. At present, temozolomide (TMZ) is recognized as the preferred chemotherapeutic drug for GBM, but some patients have low sensitivity to TMZ or chemotherapy resistance to TMZ. Our previous study found that GBM patients with EGFRvIII (+) have low sensitivity to TMZ. However, the reasons and possible mechanisms of the chemoradiotherapy resistance in GBM patients with EGFRvIII (+) are not clear. (2) Methods: In this study, tissue samples of patients with GBM, GBM cell lines, glioma stem cell lines, and NSG mice were used to explore the causes and possible mechanisms of low sensitivity to TMZ in patients with EGFRvIII (+)-GBM. (3) Results: The study found that EGFRvIII promoted the proneural-mesenchymal transition of GBM and reduced its sensitivity to TMZ, and EGFRvIII regulated of the expression of ALDH1A3. (4) Conclusions: EGFRvIII activated the NF-κB pathway and further regulated the expression of ALDH1A3 to promote the proneural-mesenchymal transition of GBM and reduce its sensitivity to TMZ, which will provide an experimental basis for the selection of clinical drugs for GBM patients with EGFRvIII (+).

Rho GTPases regulate cell morphogenesis and motility under the tight control of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). However, the underlying mechanism(s) that coordinate their spatiotemporal activities, whether separately or together, remain unclear. We show that a prometastatic RhoGAP, ARHGAP8/BPGAP1, binds to inactive Rac1 and localizes to lamellipodia. BPGAP1 recruits the RacGEF Vav1 under epidermal growth factor (EGF) stimulation and activates Rac1, leading to polarized cell motility, spreading, invadopodium formation, and cell extravasation and promotes cancer cell migration. Importantly, BPGAP1 down-regulates local RhoA activity, which influences Rac1 binding to BPGAP1 and its subsequent activation by Vav1. Our results highlight the importance of BPGAP1 in recruiting Vav1 and Rac1 to promote Rac1 activation for cell motility. BPGAP1 also serves to control the timing of Rac1 activation with RhoA inactivation via its RhoGAP activity. BPGAP1, therefore, acts as a dual-function scaffold that recruits Vav1 to activate Rac1 while inactivating RhoA to synchronize both Rho and Rac signaling in cell motility. As epidermal growth factor receptor (EGFR), Vav1, RhoA, Rac1, and BPGAP1 are all associated with cancer metastasis, BPGAP1 could provide a crucial checkpoint for the EGFR-BPGAP1-Vav1-Rac1-RhoA signaling axis for cancer intervention.

Background and Aims: Decompensated cirrhotic patients with hepatitis C (HCV) are often under-represented in clinical trials. We aimed to evaluate pooled data on the efficacy and safety of sofosbuvir (SOF)-based regimens in these patients., Methods: We conducted a systemic review and meta-analysis by searching multiple databases for studies published from October 2010 to October 2020. Outcomes of interest were sustained virologic response (SVR) and safety of SOF-based regimens in decompensated HCV patients. Two reviewers independently performed the study selection and data extraction., Results: We included 33 studies that enrolled 5,302 HCV patients. The pooled SVR rate in decompensated patients with SOF-based regimens was 85.1% (95% CI: 82.8-87.3). Patients on SOF/velpatasvir±ribavirin achieved a significantly higher SVR (91.0%, 95% CI: 87.7-93.9) than that of SOF/ledipasvir±ribavirin [(86.3%, 95% CI: 84.6-87.8); p =0.004)], or on SOF/daclatasvir±ribavirin (82.4%, 95% CI: 78.2-86.2%; p <0.001). Adding ribavirin to SOF-based regimens (pooled SVR 84.9%, 95% CI: 81.7-87.9) did not significantly increase the SVR [(83.8% (95% CI: 76.8-89.8%; p =0.76)] in decompensated patients, which was also true in subgroup analyses for each regimen within the same treatment duration. However, adding ribavirin significantly increased the frequency of adverse events from 52.9% (95% CI: 28.0-77.1) to 89.2% (95% CI: 68.1-99.9) and frequency of severe events. The pooled incidence of hepatocellular carcinoma and case-fatality of decompensated patients were 3.1% (95% CI: 1.5-5.0) and 4.6% (95% CI: 3.1-6.3), respectively. The overall heterogeneity was high. There was no publication bias., Conclusions: The analysis found that 12 weeks of SOF/velpatasvir without ribavirin is the preferred therapy, with a significantly higher SVR compared with other SOF-based regimens in decompensated HCV patients., Competing Interests: CQP is a speaker and consultant for Gilead Sciences. He also received a research grant from Gilead Sciences and Assembly Biosciences. The other authors have no conflict of interests related to this publication., (© 2023 Authors.)

Background: Mother-to-child transmission (MTCT) of hepatitis B virus may occur in highly viremic mothers despite the infants receiving appropriate immunoprophylaxis. We aimed to review tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) data for preventing MTCT., Methods and Data Selection: We performed a systematic review between January 1, 2015 and December 31, 2021 on PUBMED, EMBASE, Cochrane, CNKI, and Wanfang databases. Data was extracted from randomized controlled trials or cohort studies in English or Chinese. The outcomes of interest included the efficacy and safety of TDF versus TAF or TDF/TAF versus placebo for preventing MTCT (PROSPERO registration: CRD42021256656)., Results: Data from forty-three studies (13 randomized controlled trials, 30 nonrandomized studies) were included in the review. All infants in the studies received appropriate immunoprophylaxis. Among 3656 highly viremic mothers treated with TDF, hepatitis B virus DNA suppression to the levels <200,000 IU/mL at delivery was achieved in 34% to 100% of mothers. MTCT rates were 0 to 5% and 2 to 83% in mothers treated with TDF and in those who received no treatment, respectively. Congenital malformation rates were 0 to 2.1% in the TDF groups, which did not differ from the nontreated groups. Similar findings were reported in 4 studies that enrolled 326 mothers for maternal TAF therapy, resulting in 0% of MTCT and 0% infant malformation. All studies observed that TDF or TAF maternal therapy reduced MTCT rates significantly without safety concerns when compared with untreated groups, except for 1 RCT that failed the therapeutic endpoint., Conclusions: TDF is well established for preventing MTCT in highly viremic mothers, whereas TAF may become an option as data emerges., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The prevalence of non-alcoholic fatty liver disease (NAFLD) in non-lean patients is significantly increased, and obesity significantly increases the risk of cirrhosis and HCC in NAFLD patients. However, whether there is a difference in clinical manifestations of NAFLD between overweight and obesity remains unclear. The objective of this study was to assess the clinical and histological features of NAFLD among a non-lean population., Methods: Current study enrolled consecutive non-lean (body mass index [BMI] &gt;23 kg/m2) patients with NAFLD and available liver biopsy results. Patients were stratified by BMI into two groups for the comparison of their clinical and histological variables, which included the overweight (BMI 23∼&lt;28 kg/m2) and the obese (BMI ≥28 kg/m2). Risk factors for moderate to severe fibrosis (stage &gt;1) were also analyzed through the logistic regression model., Results: Among 184 non-lean patients with metabolic-associated fatty liver disease enrolled, 65 and 119 were overweight and obese, respectively. Patients in the obesity group had a significantly lower level of gamma-glutamyl transpeptidase, higher levels of platelet, glucose, prothrombin time, and more common of moderate to severe inflammatory activity when compared to those in the overweight group. However, a significant low frequency of moderate to severe fibrosis was found in the obesity group versus the overweight group (19.33% vs. 40.00%, p = 0.002). Binary logistics regression analysis of fibrosis found that aspartate transaminase (AST), BMI, alanine transaminase (ALT), and cholesterol (CHOL) were independent predictors for moderate to severe fibrosis in non-lean patients with NAFLD. Compared with the traditional fibrosis-4 (AUC = 0.77) and aminotransferase to platelet ratio index (AUC = 0.79) indexes, the combined index based on AST, BMI, ALT, and CHOL was more accurate in predicting moderate to severe fibrosis in non-lean patients with NAFLD (AUC = 0.87)., Conclusions: Clinical and histological features differed between obesity and overweight patients with NAFLD. When compared to the traditional serum markers, the combination index including AST, BMI, ALT, and CHOL provided a better model to predict moderate to severe fibrosis in non-lean patients with NAFLD., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Human oligodendroglioma presents as a heterogeneous disease, primarily characterized by the isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion. Therapy development for this tumor is hindered by incomplete knowledge of somatic driving alterations and suboptimal disease classification. We herein aim to identify intrinsic molecular subtypes through integrated analysis of transcriptome, genome and methylome., Methods: 137 oligodendroglioma patients from the Cancer Genome Atlas (TCGA) dataset were collected for unsupervised clustering analysis of immune gene expression profiles and comparative analysis of genome and methylome. Two independent datasets containing 218 patients were used for validation., Findings: We identified and independently validated two reproducible subtypes associated with distinct molecular characteristics and clinical outcomes. The proliferative subtype, named Oligo1, was characterized by more tumors of CNS WHO grade 3, as well as worse prognosis compared to the Oligo2 subtype. Besides the clinicopathologic features, Oligo1 exhibited enrichment of cell proliferation, regulation of cell cycle and Wnt signaling pathways, and significantly altered genes, such as EGFR, NOTCH1 and MET. In contrast, Oligo2, with favorable outcome, presented increased activation of immune response and metabolic process. Higher T cell/APC co-inhibition and inhibitory checkpoint levels were observed in Oligo2 tumors. Finally, multivariable analysis revealed our classification was an independent prognostic factor in oligodendrogliomas, and the robustness of these molecular subgroups was verified in the validation cohorts., Interpretation: This study provides further insights into patient stratification as well as presents opportunities for therapeutic development in human oligodendrogliomas., Funding: The funders are listed in the Acknowledgement., Competing Interests: Declaration of interests The authors have no conflicts of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Antiviral therapy improves the clinical outcomes of patients with chronic hepatitis B (CHB), including those with cirrhosis. In the present study, we validated the Baveno VII definition of recompensation and explored the criteria for stable improvement of liver function tests in entecavir-treated patients with CHB-related decompensated cirrhosis., Methods: In this multicentre prospective study, patients with decompensated (ascites) CHB-related cirrhosis were enrolled and treated with entecavir for 120 weeks. Patients were followed up for clinical events, viral and biochemical tests, and ultrasonography every 6 months. The recompensation rate per Baveno VII criteria was calculated. Multivariate regression models were used to identify the predictors of recompensation. Finally, the criteria for stable improvement of liver function tests were explored., Results: Of the 320 recruited patients, 283 completed the 120-week study, with 261/283 (92.2%) achieving HBV DNA levels <20 IU/ml and 171/283 (60.4%) achieving resolution of ascites, encephalopathy, and absence of recurrent variceal bleeding for at least 12 months. We identified model for end-stage liver disease <10 and/or liver function tests within Child-Pugh Class A (albumin >35 g/L, international normalised ratio <1.50 and total bilirubin <34 μmol/L) as the criteria for stable improvement of liver function tests. Accordingly, 56.2% (159/283) of patients fulfilled the Baveno VII definition of recompensation with a stable improvement of liver function tests defined by the current study., Conclusions: Our study defined the criteria for a stable improvement of liver function tests required by the Baveno VII definition of recompensation in patients with CHB-related decompensated cirrhosis on antiviral therapy. The criteria derived from this multicentre prospective study warrant further validation in patients with cirrhosis of other aetiologies., Lay Summary: Decompensation of cirrhosis marks the point at which the liver is no longer able to function normally (and symptoms become apparent). Recently the idea of recompensation was proposed for individuals who may experience an improvement in liver function if the underlying cause of their liver disease is addressed (e.g. antivirals for viral cirrhosis). Herein, we show that over 50% of patients with hepatitis B-related decompensated cirrhosis treated with antivirals could recompensate and we propose laboratory criteria which could be used to define recompensation., Competing Interests: Conflict of interest J.J. received research grants, consulting fees, or speaker honoraria from BMS, Gilead, and GSK. Y.N., X.X., H.Y. and W.X. received speaker honoraria from BMS, Gilead, and GSK. Calvin Q. Pan received research grants and speaker honoraria from Gilead. Other authors have nothing to be disclosed. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Hepatitis C (HCV)-induced decompensated cirrhosis warrants liver transplantation (LT) as the only ultimate solution. These patients experience liver deterioration, while on the transplant waitlist. However, debate remains over the optimal timing for treating HCV relative to before or after LT., Methods: We performed a literature search between 1/2011 and 1/2022 on PubMed and OVID Medline. Data were extracted from direct antiviral agent (DAA) studies in English. The outcomes of interest included sustained virological response (SVR) rates from various cohorts as well as long- and short-term outcomes in the LT settings., Results: After screening, 54 studies were eligible and included into the review. In aligning with the EASL and AASLD guidelines and suggestions, many studies supported DAA therapy before LT in patients with Model for End-stage Liver Disease (MELD) scores < 18 and DAA therapy post-LT in MELD scores > 20 through SVR rates, long-term survival factors, liver deterioration, and incidences of severe adverse events. However, uncertainty still lies in the guideline recommendations and unsettled issues remain for various patient cohorts that may benefit from opposing the guideline cutoffs. Based on the recent studies on predictors of treatment outcomes in decompensated patients and the impact of DAA on the waiting list for LT, we proposed an algorithm to manage patients with MELD scores between 18 and 20., Conclusion: DAA therapy for decompensated patients must be personalized with consideration of different factors, particularly among those with MELD scores between the two cutoff-values proposed by the current associational guidelines., (© 2022. Asian Pacific Association for the Study of the Liver.)

Background: Data that assess maternal and infant outcomes in hepatitis C virus (HCV)-infected mothers are limited., Aim: To investigate the frequency of complications and the associated risk factors., Methods: We performed a cohort study to compare pregnancy and fetal outcomes of HCV-viremic mothers with those of healthy mothers. Risk factors were analyzed with logistic regression., Results: Among 112 consecutive HCV antibody-positive mothers screened, we enrolled 79 viremic mothers. We randomly selected 115 healthy mothers from the birth registry as the control. Compared to healthy mothers, HCV mothers had a significantly higher frequency of anemia [2.6% (3/115) vs 19.0% (15/79), P < 0.001] during pregnancy, medical conditions that required caesarian section [27.8% (32/115) vs 48.1% (38/79), P = 0.004], and nuchal cords [9.6% (11/115) vs 34.2% (27/79), P < 0.001]. In addition, the mean neonatal weight in the HCV group was significantly lower (3278.3 ± 462.0 vs 3105.1 ± 459.4 gms; P = 0.006), and the mean head circumference was smaller (33.3 ± 0.6 vs 33.1 ± 0.7 cm; P = 0.03). In a multivariate model, HCV-infected mothers were more likely to suffer anemia [adjusted odds ratio (OR): 18.1, 95% confidence interval (CI): 4.3-76.6], require caesarian sections (adjusted OR: 2.6, 95%CI: 1.4-4.9), and have nuchal cords (adjusted OR: 5.6, 95%CI: 2.4-13.0). Their neonates were also more likely to have smaller head circumferences (adjusted OR: 2.1, 95%CI: 1.1-4.3) and lower birth weights than the average (≤ 3250 gms) with an adjusted OR of 2.2 (95%CI: 1.2-4.0). The vertical transmission rate was 1% in HCV-infected mothers., Conclusion: Maternal HCV infections may associate with pregnancy and obstetric complications. We demonstrated a previously unreported association between maternal HCV viremia and a smaller neonatal head circumference, suggesting fetal growth restriction., Competing Interests: Conflict-of-interest statement: Dr. Pan received grants from Gilead. He also serves as a speaker for Gilead and Abbvie. Other authors have nothing to be disclosed., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Real-world data are limited on tenofovir alafenamide (TAF). We aimed to study TAF real-world outcomes with other first-line regimens for chronic hepatitis B (CHB). We enrolled patients with CHB from 10 centers retrospectively and followed them for 36 months prospectively. We analyzed switching patterns of antiviral therapy and treatment outcomes of TAF, tenofovir disoproxil fumarate (TDF), and entecavir therapy. For efficacy and safety, we analyzed a subset of patients with complete data at 24 months after switching to TAF or remaining on TDF or entecavir. Among 1037 enrollees, 889 patients were analyzed. The mean age was 52%, and 72% were hepatitis B e antigen-negative. After enrollment, shifts in therapies were mostly in reduced use of TDF from 63% to 30% due to switching to TAF. Clinical parameters were compared at enrollment or initiation to measures at 24 months for patients remaining on TAF (187), TDF (229), or entecavir (181). At 24 months, a significantly higher portion of patients on TAF achieved hepatitis B virus (HBV) DNA ≤ 20 IU/ml (93% vs. 86%; p = 0.012) and normalized alanine aminotransferase (ALT) (66% vs. 56%; p = 0.031) with stable estimated glomerular filtration rates (eGFRs). However, a higher percentage of the patient with eGFR < 60 ml/mi/1.7 m 2 was observed in the TDF-treated group (9% vs. 4%; p = 0.010). In patients who remained on entecavir or TDF for 24 months, ALT and HBV-DNA results did not differ significantly from baseline. Treatment of CHB in the United States has significantly shifted from TDF to TAF. Our data suggest that switching from TDF or entecavir to TAF may result in increased frequency of ALT normalization and potential clearance of viremia at the 24-month time point., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Increased interferon (IFN)-gamma inducible protein-10 (IP-10) level has been shown to be associated with sustained virologic responses (SVRs) to pegylated interferon-alpha 2a/ribavirin-based therapy in patients with chronic hepatitis C (CHC). We investigated the relationship between IP-10 and treatment response in patients with CHC treated with direct-acting antiviral agents (DAAs) therapy., Methods: We measured the dynamic changes of IP-10 in samples from 90 patients with CHC. The serum IP-10 levels, intrahepatic expressions of IP-10 mRNA, and protein were determined, respectively. For the in vitro experiments, the expression changes of IP-10 in hepatitis C virus (HCV)-replicating Huh-7 cells with or without non-structural protein 5A (NS5A) inhibitor were analyzed using real-time reverse transcription-polymerase chain reaction and Western blotting., Results: Patients with chronic hepatitis C had increased baseline IP-10 levels, intrahepatic IP-10 mRNA, and protein expression. After initiating DAAs therapy, serum IP-10 levels decreased gradually in patients who achieved cure, whereas in patients who failed the therapy, IP-10 levels did not change significantly or recovered from the initial decline. Multivariate logistic regression analysis confirmed that baseline IP-10 level ≤ 450 pg/ml and decline >30% at 12 weeks independently predicted the SVR in patients with CHC who received DAAs. In vitro , the expression of IP-10 mRNA and protein in HCV-replicating Huh-7 cells increased significantly. However, such activities were downregulated by NS5A inhibitor, followed by the reduction of HCV RNA levels and a decline in IP-10 levels., Conclusion: IP-10 interfered with HCV replication in hepatocytes and the dynamic decline in IP-10 levels during DAA treatment predicted the SVR in patients with CHC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Hu, Zhang, Luo, Ma, Lu, Liang, Xu, Zhao and Pan.)