Faculty Bibliography

UbiA prenyltransferase domain containing 1 (Ubiad1) has the potential to affect cholesterol and phospholipid levels in different cell types. We previously identified Ubiad1 as a candidate gene for regulating subcutaneous fat pad weight in a mouse genome-wide association study. Here we evaluated the relationship between Ubiad1 and obesity-related traits in cohorts of humans and mice, and in Ubiad1^+/- mice fed a high-fat diet. In both humans and mice, adipose tissue Ubiad1 mRNA expression correlated negatively with adiposity and positively with mitochondria-related genes. To determine the role of Ubiad1 in high-fat diet-induced obesity, we disrupted the Ubiad1 gene in mice. Deletion of Ubiad1 was embryonically lethal in C57BL/6 N mice, preventing analysis of adult Ubiad1^-/- mice. Thus, male and female Ubiad1^+/+ and Ubiad1^+/- mice were fed high-fat diet for 10 weeks, with no difference in weight gain and adipose tissue organ weights observed between the genotypes. Analysis of liver mRNA expression revealed that Ubiad1 heterozygosis (Ubiad1^+/-) altered several pathways involved in lipid metabolism. Detailed lipid quantification with HPLC-qTOF/MS showed increased levels of hepatic ceramides in female Ubiad1^+/- mice, whereas phosphatidylglycerols, phosohatidylinositol and lysophosphatidylethanolamines were reduced in male Ubiad1^+/- mice. Our findings reveal sex-specific effects of Ubiad1 expression on hepatic lipid metabolism.

Published studies on tenofovir alafenamide (TAF) therapy for preventing vertical transmission of hepatitis B virus (HBV) have primarily enrolled mothers with viremic levels of approximately 7 log₁₀ IU/mL. This study aimed to evaluate the efficacy and safety of TAF therapy in preventing mother-to-child transmission (MTCT) in mothers with exceptionally high viral loads, defined as HBV DNA levels > 2,000,000 IU/mL. Hepatitis B e antigen (HBeAg)-positive mothers with HBV DNA levels > 2,000,000 IU/mL were prospectively enrolled from four hospitals and initiated on TAF therapy between gestational weeks 26 and 28, continuing until delivery. All infants received immunoprophylaxis and were followed up to 28 weeks postpartum. The primary endpoints were the MTCT rate and the occurrence of congenital abnormalities in infants. Secondary outcomes included maternal HBV suppression at delivery and the safety of both mothers and infants. Among 137 mothers screened, 120 were enrolled in TAF therapy, and 121 infants completed the study. At delivery, 93.3% (112/120) of mothers achieved HBV DNA levels < 200,000 IU/mL. At birth, 0.8% (1/121) of infants had a congenital malformation, and 9.9% (12/121) tested positive for HBsAg. The vertical transmission rate was 2% (2/121, intention-to-treat) at 28 weeks of age. No severe adverse effects were reported in mothers or infants. On-treatment and postpartum alanine aminotransferase (ALT) flares after TAF cessation occurred in 7.5% (9/120) and 41.1% (46/112) of mothers, respectively, alongside viral rebound after cessation. Infant physical development remained within normal ranges based on national reference standards. In summary, approximately 2% of mothers on TAF therapy during late pregnancy experienced MTCT, despite proper immunoprophylaxis for their infants. Extending the treatment duration beyond 12 weeks for mothers with extremely high viral loads is recommended to improve MTCT prevention. No safety concerns were observed for either mothers or infants. Trial Registration: ClinicalTrials.gov identifier: NCT04237376.

BACKGROUND AND AIMS/OBJECTIVE:The year 2023 marked the 10-year anniversary of the launch of direct-acting antivirals (DAAs) for the treatment of the hepatitis C virus (HCV). HCV treatment trends by country, region, and globally are important to monitor progress toward the World Health Organization's 2030 elimination targets. Additionally, the historical patterns can help predict the treatment uptake for future therapies for other liver diseases. METHODS:The number of people living with HCV (PLHCV) treated between 2014-2023 across 119 countries was estimated using national HCV registries, reported DAA sales data, pharmaceutical companies' reports, and estimates provided by national experts. For the countries with no available data, the average estimate of the corresponding Global Burden of Disease region was used. RESULTS:An estimated 13,816,000 (95% uncertainty intervals (UI): 13,221,000-16,415,000) PLHCV were treated, of whom 12,748,000 (12,226,000-15,231,000) were treated with DAAs, of which 11,081,000 (10,542,000-13,338,000) were sofosbuvir-based DAA regimens. Country-level data accounted for 97% of these estimates. In high-income countries, there was a 41% drop in treatment from its peak, and reimbursement was a large predictor of treatment. In low- and middle-income countries, price played an important role in expanding treatment access through the public and private markets, and treatment continues to increase slowly after a sharp drop at the end of the Egyptian national program. CONCLUSIONS:In the last 10 years, 21% of all HCV infections were treated with DAAs. Regional and temporal variations highlight the importance of active screening strategies. Without program enhancements, the number of treated PLHCV stalled in every country/region which may not reflect a lower prevalence but may instead reflect the diminishing returns of the existing strategies. IMPACT AND IMPLICATIONS/UNASSIGNED:Long-term hepatitis C virus (HCV) infection can lead to cirrhosis and liver cancer. Since 2014, these infections can be effectively treated with 8-12 weeks of oral therapies. In 2015, the World Health Organization (WHO) established targets to eliminate HCV by 2030, which included treatment targets for member countries. The current study examines HCV treatment patterns across 119 countries and regions from 2014 to 2023 to assess the impact of national programs. This study can assist physicians and policymakers in understanding treatment patterns within similar regions or income groups and in utilizing historical data to refine their strategies in the future.

BACKGROUND & AIMS/OBJECTIVE:The health-related quality of life (HRQoL) during pregnancy has not been well-lidated in mothers with chronic hepatitis B (CHB). We aim to compare patient-reported outcomes (PROs) in CHB mothers with those of healthy mothers during pregnancy. METHODS:Between 4/16/2023 and 7/31/2023, we invited consecutive CHB and healthy mothers to complete the self-administered 36-item Short Form Survey (SF-36) and the Chronic Liver Disease Questionnaire (CLDQ) for PRO assessment. Pairwise comparisons of PRO scores between groups were performed using chi-square tests. Covariates for worse PROs were further analyzed by the multiple linear regression model to identify the independent predictors RESULTS: Among 257 participants (CHB: healthy control was 100:157), the mean (SD) age was 29.6 (3.4), and the majority completed the PRO assessment at the gestational weeks of 16-24. When compared to healthy mothers, CHB mothers had a significant impairment of PROs in the CLDQ domain of worry (6.97±0.16 vs 5.83±0.99, p<0.05) and the SF-36 domain of social functioning (95.33±10.00 vs 91.67±16.37, p<0.05). The subgroup analyses in CHB mothers showed HBV DNA >200,000 IU/mL associated with significantly worse PROs. The multivariate analyses identified CHB infection, severe nausea or vomiting, poor living conditions, and spousal negative attitude as independent predictors of HRQoL impairment. CONCLUSION/CONCLUSIONS:This study suggests that CHB infection during pregnancy negatively impacted HRQoL, particularly in worry and social functioning domains. CHB infection was an independent predictor for PRO impairments. Further integration of monitoring and intervention on HRQoL impairment should be considered when managing CHB mothers during pregnancy.

IMPORTANCE/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED:ClinicalTrials.gov Identifier: NCT03476083.

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.

INTRODUCTION/BACKGROUND: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.

Hepatitis E virus (HEV) poses a serious threat to both public health and animal food safety, thereby highlighting the demands for rapid, sensitive, and easy-to-use detection. This study aimed to develop a One-Pot assay using CRISPR/Cas13a for detecting HEV RNA, suitable for point-of-care testing (POCT) in resource-limited settings. CRISPR/Cas13a combined with reverse transcription polymerase chain reaction (RT-PCR) and reverse transcription recombinase-aided amplification (RT-RAA) was applied to a One-Pot assay device. Additionally, a large cohort of HEV-infected patient (154) and animal (104) specimens was utilized for validation. The RT-PCR/RT-RAA + CRISPR/Cas13a assays for HEV RNA detection (genotypes: HEV-1, HEV-3, and HEV-4) were established, optimized, and validated, achieving a limit of detection (LoD) of 1 copy/μL and 100% specificity. In the application validation for HEV infection, the positive rates of the RT-PCR + CRISPR and RT-RAA + CRISPR assays were 98.6% and 89.6% for patients, and 96.6% and 88.8% for animals, respectively, which were superior to those of RT-qPCR. Furthermore, sample rapid lysis, reagent lyophilization, and the One-Pot device were integrated to construct a One-Pot assay with an LoD of 10² copies/μL. Despite slight decreases in sensitivity, the One-Pot assay significantly reduces the assay time to 35 min, making it easy to perform, minimizing contamination, and meeting the requirements for screening. We developed a One-Pot assay of HEV RNA using the CRISPR/Cas13a which effectively realizes a POCT test and maximizes the impetus for POCT implementation and shows potential as a valuable tool for detecting and monitoring HEV infection.

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/OBJECTIVE: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:and hip/spine BMD observed during double-blind TDF improved after switching to OL TAF. No patients developed resistance to TAF. CONCLUSION/CONCLUSIONS:Long-term TAF treatment exhibited favourable safety and tolerability with high rates of viral suppression and no development of resistance. CLINICALTRIALS/RESULTS:gov numbers NCT01940341 and NCT01940471.