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.

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.

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.

OBJECTIVE/UNASSIGNED:This study aimed to identify distinct intestinal microbiota associated with hepatocellular carcinoma (HCC) and to construct a predictive model for HCC. METHODS/UNASSIGNED:A case-control study was conducted including patients with chronic hepatitis B (CHB), liver cirrhosis (LC), HCC, and healthy controls (HC). Fecal 16S rDNA sequences were analyzed using bioinformatics approaches. Specific intestinal microbiota were identified through stratified analysis, and a predictive model was subsequently constructed. RESULTS/UNASSIGNED:were increased irrespective of liver disease stage. By combining microbiota profiles with clinical indicators, we developed a predictive nomogram that achieved an AUC of 0.865 in the training cohort and 0.848 in the external validation cohort. CONCLUSION/UNASSIGNED:Intestinal microbiota were associated not only with liver disease stage but also with the occurrence of HCC itself. Characteristic microbiota may serve as effective biomarkers for predicting HCC.

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.

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.

OBJECTIVE:International guidelines recommend maternal tenofovir disoproxil fumarate (TDF) therapy accompanied by infant immunoprophylaxis to prevent HBV mother-to-child transmission (MTCT) in highly viremic mothers. However, pooled analyses for tenofovir alafenamide (TAF) effects and comparisons between the two regimens are lacking. DESIGN/METHODS:In this meta-analysis, pairs of independent reviewers performed multiple database searches from inception to March 31, 2024, and extracted data from cohort studies and 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 2,588 highly viremic mothers receiving TDF, 280 receiving TAF, and 1,600 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 0.07-0.16). Pairwise meta-analysis between TAF and TDF revealed similar effects on reducing MTCT (risk ratio: 1.09, 95% confidence interval 0.16-7.61). Network meta-analysis showed the equal efficacy of the two regimens in reducing MTCT (risk ratio: 1.09, 95% confidence interval 0.15-7.65). The surface under the cumulative ranking curve revealed TDF as the best regimen compared with TAF (probability ranking: 0.77 vs. 0.72), 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. CONCLUSION/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.