Optimization of Mother-to-Child Hepatitis B Virus Prevention Program: Integration of Maternal Screening and Infant Post-Vaccination Serologic Testing.

BACKGROUND: Evaluation of the impact of a hepatitis B virus (HBV) prevention program that incorporates maternal antiviral prophylaxis on mother-to-child transmission (MTCT) is limited using real-world data. METHODS: We analyzed data on maternal HBV screening, neonatal immunization, and post-vaccination serologic testing (PVST) for hepatitis B surface antigen (HBsAg) among at-risk infants born to HBV carrier mothers from the National Immunization Information System during 2008-2022. Through linkage with the National Health Insurance Database, information on maternal antiviral therapy was obtained. Multivariate logistic regression was performed to explore MTCT risk in relation to infant-mother characteristics and prevention strategies. RESULTS: In total, 2 460 218 deliveries with maternal HBV status were screened. Between 2008 and 2022, the annual HBsAg and hepatitis B e antigen (HBeAg) seropositivity rates among native pregnant women decreased from 12.2% to 2.6% and from 2.7% to 0.4%, respectively (P for both trends < .0001). Among the 22 859 at-risk infants who underwent PVST, the MTCT rates differed between infants born to HBsAg-positive/HBeAg-negative and HBeAg-positive mothers (0.75% and 6.33%, respectively; P < .001). MTCT risk increased with maternal HBeAg positivity (odds ratio [OR], 9.29; 95% confidence interval [CI], 6.79-12.73) and decreased with maternal antiviral prophylaxis (OR, 0.28; 95% CI, .16-.49). For infants with maternal HBeAg positivity, MTCT risk was associated with mothers born in the immunization era (OR, 1.40; 95% CI, 1.17-1.67). CONCLUSIONS: MTCT was related to maternal HBeAg positivity and effectively prevented by maternal prophylaxis in the immunized population. At-risk infants born to maternal vaccinated cohorts might possibly pose further risk.

Topographical metal burden correlates with brain atrophy and clinical severity in Wilson's disease.

BACKGROUND: Quantitative susceptibility mapping (QSM) is a post-processing technique that creates brain susceptibility maps reflecting metal burden through tissue magnetic susceptibility. We assessed topographic differences in magnetic susceptibility between participants with and without Wilson's disease (WD), correlating these findings with clinical severity, brain volume, and biofluid copper and iron indices. METHODS: A total of 43 patients with WD and 20 unaffected controls, were recruited. QSM images were derived from a 3T MRI scanner. Clinical severity was defined using the minimal Unified Wilson's Disease Rating Scale (M-UWDRS) and Montreal Cognitive Assessment scoring. Differences in magnetic susceptibilities between groups were evaluated using general linear regression models, adjusting for age and sex. Correlations between the susceptibilities and clinical scores were analyzed using Spearman's method. RESULTS: In age- and sex-adjusted analyses, magnetic susceptibility values were increased in WD patients compared with controls, including caudate nucleus, putamen, globus pallidus, and substantia nigra (all p < 0.01). Putaminal susceptibility was greater with an initial neuropsychiatric presentation (n = 25) than with initial hepatic dysfunction (n = 18; p = 0.04). Susceptibility changes correlated negatively with regional brain volume in almost all topographic regions. Serum ferritin, but not serum copper or ceruloplasmin, correlated positively with magnetic susceptibility level in the caudate nucleus (p = 0.04), putamen (p = 0.04) and the hippocampus (p = 0.03). The dominance of magnetic susceptibility in cortical over subcortical regions correlated with M-UWDRS scores (p < 0.01). CONCLUSION: The magnetic susceptibility changes could serve as a surrogate marker for patients with WD.

Predictors of Functional Cure of Chronic Hepatitis B Virus Infection: A Long-Term Follow-Up Study.

BACKGROUND & AIMS: A functional cure is an essential endpoint in the management of patients with chronic hepatitis B virus (HBV) infection. We evaluated the cumulative probability and predictors of functional cure in patients with chronic HBV infection after hepatitis B e antigen (HBeAg) seroconversion. METHODS: We retrospectively analyzed 413 (249 males and 164 females) initially HBeAg-positive chronic HBV-infected patients who were followed up for a mean of 26.36 ± 0.53 years. All underwent HBeAg seroconversion during follow-up. A functional cure was defined as durable HBsAg and HBV DNA loss without antiviral treatment for more than 24 weeks. RESULTS: After 10,888 person-years of follow-up, the cumulative probability of functional cure was 14.53% (n = 60). There were 24 (40%) subjects with functional cure after antiviral therapy. The annual functional cure rate was 0.55% per person-year, and increased to 0.96% per person-year after HBeAg seroconversion. In subjects with functional cure, the HBsAg and HBV DNA titers after HBeAg seroconversion were positively correlated with the time to functional cure (P < .001 and < .001, respectively). Multivariate Cox proportional hazards analysis of the cohort revealed that HBeAg seroconversion at <18 years of age, high-genetic-barrier nucleos(t)ide analogue(s) therapy before HBeAg seroconversion, and a serum HBsAg titer <1000 IU/mL at 18 months after HBeAg seroconversion were significant predictors of functional cure (P < .001, .001, and .001, respectively). CONCLUSIONS: In a cohort of chronic HBV-infected patients with long-term follow-up, HBeAg seroconversion in childhood, high-genetic-barrier nucleos(t)ide analogue(s) therapy, and low HBsAg titers after HBeAg seroconversion were significant predictors of functional cure.

Novel PLEC variants associated with infantile cholestasis.

Plectin is a cytoskeletal linker of intermediate filaments, encoded by the PLEC gene. Recently, plectin mutations have been identified in a pair of siblings with progressive familial intrahepatic cholestasis. Here, we reported two unrelated infants with plectinopathy causing cholestatic jaundice with novel variants in the PLEC gene. Trio exome sequencing identified compound heterozygous variants in the PLEC gene for each patient: c.71-11768C>T and c.4331G>T (p.Arg1444Leu) in Patient 1, and c.592C>T (p.Arg198Trp) and c.4322G>A (p.Arg1441His) in Patient 2. Immunofluorescence staining of liver samples from both patients revealed scattered signals of plectin in the cytoplasm of hepatocytes and reduced colocalization of plectin and cytokeratin 8. This study not only underscores the involvement of plectin in cholestasis but also highlights the utility of exome sequencing as a powerful diagnostic tool in identifying genetic underpinnings of infantile cholestasis.

Survey of hepatitis B virus infection status after 35 years of universal vaccination implementation in Taiwan.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) vaccination programs in Taiwan are one of the earliest programs in the world and have largely reduced the prevalence of HBV infection. We aimed to demonstrate the vaccination efficacy after 35 years and identify gaps toward HBV elimination. METHODS: A total of 4717 individuals aged 1-60 years were recruited from four administrative regions based on the proportion of population distribution. Serum levels of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) levels were assessed. HBV viral load, genotypes and HBsAg 'ɑ' determinant variants were evaluated if indicated. RESULTS: After 35 years of vaccination, the overall seropositivity rates for HBsAg and anti-HBc in Taiwan were 4.05% and 21.3%, respectively. The vaccinated birth cohorts exhibited significantly lower seropositivity rates for both markers compared to the unvaccinated birth cohorts (HBsAg: 0.64% vs. 9.78%; anti-HBc: 2.1% vs. 53.55%, respectively; p < 0.0001). Maternal transmission was identified as the main route of HBV infection in breakthrough cases. Additionally, increased prevalences of genotype C and HBsAg escape mutants were observed. CONCLUSION: The 35-year universal HBV vaccination program effectively reduced the burden of HBV infection, but complete eradication of HBV infection has not yet been achieved. In addition to immunization, comprehensive screening and antiviral therapy for infected individuals, especially for pregnant women, are crucial strategies to eliminate HBV.

Tenofovir alafenamide or tenofovir disoproxil fumarate in pregnancy to prevent HBV transmission: Maternal ALT trajectory and infant outcomes.

BACKGROUND: The use of antiviral agents, specifically tenofovir disoproxil fumarate (TDF), in pregnant women to prevent mother-to-child HBV transmission is a key step towards hepatitis elimination. However, data on using tenofovir alafenamide (TAF) is insufficient. The frequent occurrence of postpartum ALT flares may impact the clinical implementation. METHODS: The maternal and infant outcomes were compared in multi-centre trials of high viral load HBsAg/HBeAg+ pregnant women receiving TAF or TDF from the third trimester until 2 weeks postpartum with intensive follow-ups. To explore the dynamic pre- and postpartum changes in ALT levels, we used a group-based trajectory model for analysing data of 332 women from three prospective studies. RESULTS: After treatment, the maternal HBV DNA levels significantly decreased from baseline to delivery: 7.87 ± 0.59 to 3.99 ± 1.07 Log10 IU/mL TAF (n = 78) and 8.30 ± 0.36 to 4.47 ± 0.86 Log10 IU/mL (TDF, n = 53), with viral load reductions of 3.87 versus 3.83 Log10 IU/mL. The HBsAg-positive rates among 12-month-old infants were 1.28% (1/78) versus 1.82% (1/55) respectively (p = 1.00). Of the TAF or TDF-treated mothers, 25.64% versus 16.98% experienced ALT > 2X ULN, and 11.54% versus 1.89% received extended antiviral treatment. Our model revealed four distinct ALT patterns: stable ALT (87.2%), moderate (8.0%) or marked (2.4%) postpartum flares, or prepartum elevations (2.4%). CONCLUSIONS: TAF effectively reduces mother-to-child HBV transmission, but prophylaxis failure still occurred in few cases. Postpartum ALT flares are common in women receiving TAF or TDF during pregnancy. Approximately 12.8% of mothers may require extended postpartum antiviral treatment. CLINICAL TRIAL NUMBER: NCT03695029 (ClinicalTrials.gov).

Update on the diagnosis and management of neonatal intrahepatic cholestasis caused by citrin deficiency: Expert review on behalf of the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Citrin deficiency is an autosomal recessive metabolic liver disease caused by mutations in the SLC25A13 gene. The disease typically presents with cholestasis, elevated liver enzymes, hyperammonemia, hypercitrullinemia, and fatty liver in young infants, resulting in a phenotype known as "neonatal intrahepatic cholestasis caused by citrin deficiency" (NICCD). The diagnosis relies on clinical manifestation, biochemical evidence of hypercitrullinemia, and identifying mutations in the SLC25A13 gene. Several common mutations have been found in patients of East Asian background. The mainstay treatment is nutritional therapy in early infancy utilizing a lactose-free and medium-chain triglyceride formula. This approach leads to the majority of patients recovering liver function by 1 year of age. Some patients may remain asymptomatic or undiagnosed, but a small proportion of cases can progress to cirrhosis and liver failure, necessitating liver transplantation. Recently, advancements in newborn screening methods have improved the age of diagnosis. Early diagnosis and timely management improve patient outcomes. Further studies are needed to elucidate the long-term follow-up of NICCD patients into adolescence and adulthood.

The Influencing Factors of Implementation in Emergency Medical Service Systems - A Scoping Review.

OBJECTIVES: Emergency medical services (EMS) provide health care in situations with limited time and resources. Challenges arise when introducing novel medications, treatments, or technologies or modifying existing practices in these settings. Effective implementation strategies are pivotal for their success. This study aims to identify and categorize potential facilitators and barriers in the implementation of prehospital EMS through a review of relevant research articles. METHODS: We searched PubMed and EMbase to identify studies published before December 2023, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for our search strategy and scoping review. We included original articles written in English that report on the factors that influence the implementation in prehospital settings. We extracted and categorized the factors into different themes. RESULTS: Out of the 371 retrieved papers, we selected 19 (5%) for inclusion in this review. We extracted 46 influencing factors from the selected articles and categorized them into ten themes: (1) Outer system, (2) Inner system, (3) Practitioner characteristics, (4) Resources, (5) Communication and collaboration, (6) Patient factors, (7) Intervention characteristics, (8) De-implementation of prior practices, (9) Logistical issues, and (10) Quality improvement. CONCLUSIONS: This study examined the literature on EMS implementation factors and proposed a 10-theme EMS model framework. Key factors include training/education, equipment/tools, communication with hospitals, and practitioners' attitudes.

Uncovering Reflections of Preclinical Medical Students from Clinical Shadowing: A Thematic Analysis.

PURPOSE: Clinical shadowing(CS) offers preclinical medical students the opportunity to observe certified physicians in practice. Analyzing the content of students' reflective writings(RWs) to understand core competencies they perceived during CS, as well as stages of their reflections, can offer valuable insights for course design and instructor guidance. This study aimed to address this matter by employing a thematic analysis of students' RWs to explore the learning outcomes derived from CS. MATERIALS AND METHODS: The dataset of the thematic analysis comprised de-identified RWs from preclinical medical students who participated in the clinical shadowing program during the first semester of the 2019 academic year at National Taiwan University College of Medicine. Two researchers independently extracted and categorized pertinent content from the texts of RWs, aligning them with the six core competencies of ACGME and mapping them to the stages of Kolb's learning cycle. Additionally, correlation with shadowing specialties and fields was investigated. RESULTS: In total, 155 RWs were analyzed. Patient care emerged as the most frequently reflected competency(30%), followed by systems-based practice(23%), and medical knowledge(21%). The shadowing specialties and fields had an impact on the core competencies students perceived. In terms of Kolb's learning stages, concrete experience(66%) predominated in RWs, while abstract conceptualization(19%) and reflective observation(14%) were less prevalent. For each competency, concrete experience was the prevailing stage, with active experimentation being the least dominant one. Students exhibited varying proportions of reflections at different stages for each core competency. CONCLUSIONS: Clinical shadowing experiences enable preclinical medical students to explore required clinical core competencies, with emphases depending on the shadowing specialties and fields. Currently, most reflections are concentrated at Kolb's concrete experience stage. This study offers valuable insights for designing future CS programs and improving faculty development, aimed at helping students achieve deeper and more comprehensive reflective learning in relation to core competencies, and even professional identity.

Identifying group metacognition associated with medical students' teamwork satisfaction in an online small group tutorial context.

BACKGROUND: Collaborative learning is an essential pedagogy in medical education, within which small group learning constitutes an integral component. Online small group teaching has been widely applied and blended with in-person sessions in the aftermath of the Covid-19 pandemic. This study examined whether group metacognition was associated with teamwork satisfaction in an online small group teaching curriculum for medical students. METHODS: We enrolled medical students of the 2nd and 4th years during the 2021 fall semester after they participated in 3 consecutive sessions of online small group tutorials (SGTs), which have been implemented in our medical school for more than 20 years. The students completed a group metacognitive scale (GMS) and a teamwork satisfaction scale (TSS) after the sessions. We analyzed whether group metacognition in 4 dimensions (knowledge of cognition, planning, evaluating, and monitoring) could be connected with medical students' teamwork satisfaction using partial least squares-structural equation modeling (PLS-SEM). RESULTS: A total of 263 medical students participated in this study. Both GMS and TSS exhibited good reliability and validity. Three of the 4 dimensions of group metacognition (cognition, planning, and evaluating) positively correlated with teamwork satisfaction (path coefficients 0.311, 0.279, and 0.21; p = 0.002, 0.002, and 0.043, respectively) following the online SGT curriculum, whereas the monitoring dimension did not (path coefficient 0.087; p = 0.357). The model achieved an adjusted R square of 0.683. CONCLUSION: We discovered that group metacognition correlated positively with better teamwork satisfaction, supporting the importance of group metacognitive competency for online collaborative learning.

Early predictors of intestinal complications in pediatric-onset Crohn's disease: A long-term cohort study in Taiwan.

PURPOSE: Identifying reliable prognostic factors for pediatric-onset Crohn's disease (CD) is important for guiding early treatment. This study aimed to evaluate the validity of various clinical parameters for predicting long-term intestinal complications in pediatric-onset CD patients with CD in Taiwan. METHODS: This was a single-center, retrospective study. Patients diagnosed with CD under 18 years of age at our hospital between January 1999 and December 2021 were enrolled. The baseline clinical variables and the Pediatric Crohn's Disease Activity Index (PCDAI) were obtained. Patients were categorized into low-, medium-, or high-risk groups based on the 2020 European Crohn's and Colitis Organization and European Society for Pediatric Gastroenterology Hepatology and Nutrition (ECCO-ESPGHAN) guidelines. The primary endpoint was the occurrence of new intestinal complications. RESULTS: Among 53 enrolled patients (33 males and 20 females), 8 patients (33.96%) developed intestinal complications during the follow-up period (median 6.42 years, 3.17-9.75 years). Patients in the initial ECCO-ESPGHAN medium- or high-risk group had a 4.71-fold higher risk of intestinal complications than those in the low-risk group [hazard ratio = 4.71, p = 0.023] after adjusting for PCDAI in the multivariate Cox proportional hazard analysis. The other clinical variables did not reach statistical significance in predicting intestinal complications. The positive and negative predictive values of the ECCO-ESPGHAN stratification method for intestinal complications were 48.15% and 80.77%, respectively. CONCLUSIONS: ECCO-ESPGHAN risk stratification is an effective early predictor of long-term intestinal complications in the Taiwanese population and may be used in clinical practice to guide early advanced therapy.

Clinical experience of infantile hepatic hemangioma.

PURPOSE: To describe the clinical presentation, treatment preference, and relevant complications of infantile hepatic hemangioma (IHH) in propranolol era. METHODS: The National Taiwan University Hospital integrated Medical Database (NTUH-iMD) was used to enroll twenty-one cases of IHH diagnosed from 2006 to 2020. Medical charts were retrospectively reviewed. RESULTS: In nine patients (42.9%), IHH was found incidentally, and in seven patients (33%), it was detected during postnatal self-paid ultrasonography. Focal disease was determined in 17 patients, multifocal disease in 1 patient, and diffuse disease in 3 patients. Patients with diffuse disease had a lower hemoglobulin level than patients with focal IHH (9.38 vs. 12.6 mg/dL, p = 0.045). Two patients had Kasabach-Merritt phenomenon (KMP), one had hypothyroidism, and one had both. All patients with KMP had focal hepatic hemangiomas. Among the 17 patients with focal IHH, nine were prescribed propranolol, one was treated by surgical resection of the tumor, and the others had expectant management. All patients with multifocal and diffuse IHH were administered propranolol. One infant (7.7%) treated with propranolol had bradycardia initially but it subsided after dose adjustment. CONCLUSIONS: Most IHH is found incidentally or detected during postnatal ultrasonography screening. Patients with large focal lesions should also be screened for associated complications. Propranolol is the drug of choice and a safe therapeutic option for IHH, especially for focal tumors >5 cm as well as multifocal and diffuse lesions.

Characterization of Hepatitis B Virus in Tenofovir-Treated and Untreated Chronically Infected Mothers and Their Immunoprophylaxis Failure Infants.

BACKGROUND: Maternal tenofovir disoproxil fumarate (TDF) therapy during late pregnancy can reduce mother-to-infant transmission of hepatitis B virus (HBV). We investigated HBV mutations associated with maternal TDF therapy and their role in infant immunonophylaxis failure (IPF). METHODS: Serum samples from untreated (n = 89) and TDF-treated (n = 68), highly viremic, chronically infected mothers and their infants were analyzed for HBV DNA by nested polymerase chain reaction (PCR) and direct sequencing. RESULTS: At delivery, compared with untreated mothers, TDF-treated mothers had a lower HBV DNA titer and a higher frequency of basal core promoter (BCP) gene mutations, but they had similar frequencies in pre-S/S and pre-core/core mutations. The 14 mothers harboring surface "a" determinant mutants did not transmit the mutants to their immunized infants. Such mutants were found in 3 of 13 IPF infants; the 13 mothers had wild-type hepatitis B surface antigen (HBsAg). In univariable analysis, maternal HBV DNA titer (odds ratio [OR]: 1.54; 95% confidence intervals [CI]: 1.02-2.33; P = .039), genotype C (OR: 4.18; 95% CI: 1.28-13.62; P = .018) and pre-S1 wild-type sequence (OR: 6.33; 95% CI: 1.85-21.68; P = .003) at delivery were associated with infant IPF. Multivariable analyses showed that maternal genotype C (OR: 3.71; 95% CI: 1.11-12.36; P = .033) and pre-S1 wild-type (OR: 6.34; 95% CI: 1.79-22.44; P = .004) were associated with infant IPF independently of maternal viremia. CONCLUSIONS: Along with high maternal HBV DNA titer at delivery, maternal genotype C and pre-S1 wild-type sequence were potential risk factors for infant IPF, although BCP mutations were not. The offspring of pregnant women harboring "a" determinant mutants as major strains seemed to be protected by immunoprophylaxis. CLINICAL TRIALS REGISTRATION: NCT01312012.

Baseline Hepatitis B Virus Surface Antigen Titers in Childhood Predict the Risk of Advanced Liver Fibrosis in Adulthood.

BACKGROUND & AIMS: Hepatitis B virus (HBV) surface antigen (HBsAg) is a marker of both HBV covalently closed circular DNA and integrated HBV genome, whereas the HBV core-related antigen (HBcrAg) indicates the transcriptional activity of covalently closed circular DNA. This study examined the relationship between HBsAg and HBcrAg titers in childhood and advanced fibrosis in adulthood. METHODS: We recruited 214 initially hepatitis B e antigen-positive chronic HBV-infected patients who were followed for a total of 6371 person-years. None of the patients were co-infected with hepatitis C or D virus. Serum HBsAg and HBcrAg titers were assessed at 10 and 15 years of age. Transient elastography was performed at a mean final age of 38.21 years to identify advanced fibrosis. RESULTS: Patients with advanced fibrosis in adulthood had a higher rate of genotype C HBV infection and a higher HBsAg titer at 10 and 15 years of age (P = .003, P = .03, and P = .005, respectively). The HBcrAg titer was not correlated with advanced fibrosis (P > .05). Receiver operating characteristic curve analysis showed that HBsAg cutoffs of >4.23 and >4.44 log10 IU/mL at 10 and 15 years of age, respectively, best predicted advanced fibrosis in the fourth decade of life (P = .001 and P < .001, respectively). In a multivariate analysis, both an HBsAg titer >4.44 log10 IU/mL at 15 years of age and HBV genotype C were predictors of advanced fibrosis (odds ratios, 15.43 and 4.77; P = .01 and P = .02, respectively). CONCLUSIONS: HBsAg titers in childhood predict the progression to liver fibrosis in adulthood.

Combining Panel-Based Next-Generation Sequencing and Exome Sequencing for Genetic Liver Diseases.

OBJECTIVES: To determine how advanced genetic analysis methods may help in clinical diagnosis. STUDY DESIGN: We report a combined genetic diagnosis approach for patients with clinical suspicion of genetic liver diseases in a tertiary referral center, using tools either tier 1: Sanger sequencing on SLC2SA13, ATP8B1, ABCB11, ABCB4, and JAG1 genes, tier 2: panel-based next generation sequencing (NGS), or tier 3: whole-exome sequencing (WES) analysis. RESULTS: In a total of 374 patients undergoing genetic analysis, 175 patients received tier 1 Sanger sequencing based on phenotypic suspicion, and pathogenic variants were identified in 38 patients (21.7%). Tier 2 included 216 patients (39 of tier 1-negative patients) who received panel-based NGS, and pathogenic variants were identified in 60 (27.8%). In tier 3, 41 patients received WES analysis, and 20 (48.8%) obtained genetic diagnosis. Pathogenic variants were detected in 6 of 19 (31.6%) who tested negative in tier 2, and a greater detection rate in 14 of 22 (63.6%) patients with deteriorating/multiorgan disease receiving one-step WES (P = .041). The overall disease spectrum is comprised of 35 genetic defects; 90% of genes belong to the functional categories of small molecule metabolism, ciliopathy, bile duct development, and membrane transport. Only 13 (37%) genetic diseases were detected in more than 2 families. A hypothetical approach using a small panel-based NGS can serve as the first tier with diagnostic yield of 27.8% (98/352). CONCLUSIONS: NGS based genetic test using a combined panel-WES approach is efficient for the diagnosis of the highly diverse genetic liver diseases.

The prognosis of citrin deficiency differs between early-identified newborn and later-onset symptomatic infants.

BACKGROUND: The prognosis for patients with citrin deficiency is not always benign. This study examined the differences between patients identified early by newborn screening and patients identified later with cholestasis/hepatitis. MATERIALS AND METHODS: This retrospective study included 42 patients with genetically confirmed SLC25A13 mutations who were born between May 1996 and August 2019. Fifteen patients were identified during newborn screening (NBS group) and 27 patients were identified through the onset of cholestasis/hepatitis in infancy (clinical group). RESULTS: Overall, 90% of the patients presented with cholestasis, among whom 86% (31/36) recovered at a median age of 174 days. Compared with patients in the clinical group, patients in the NBS group were significantly younger at diagnosis and at cholestasis-free achievement; they also had significantly lower levels of peak direct bilirubin and liver enzymes. At the median follow-up age of 11.8 years, 21% of the patients had dyslipidemia, whereas 36% of the patients had failure to thrive. The overall mortality rate was 2.4%. Variant c.851_854del was the most frequent, constituting 44% of the mutant alleles. CONCLUSION: Patients identified early by NBS had a better prognosis, demonstrating the importance of a timely diagnosis of NICCD and the need for careful follow-up. IMPACT: Some cases of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) are not benign. Compared with patients identified later based on the presence of cholestasis/hepatitis, patients identified early by newborn screening have less severe cholestasis and are cholestasis-free at a significantly younger age. A timely diagnosis is needed, along with follow-up examinations that assess metabolic profile and body weight, to improve the long-term prognosis of NICCD patients.

A Pilot Study of Biliary Atresia Newborn Screening Using Dried Blood Spot Matrix Metalloproteinase-7.

OBJECTIVES: Timely diagnosis is a critical challenge and is associated with improved survival of biliary atresia (BA) patients. We aimed to measure matrix metalloproteinase-7 (MMP-7) levels in BA patients within 3 days of birth using the dried blood spot (DBS) method and evaluate its potential as a screening tool. METHODS: The study enrolled 132 patients, including 25 patients diagnosed with BA and 107 non-BA patients with other congenital or perinatal conditions from the National Taiwan University Children Hospital. The stored DBS samples collected from 48 to 72 hours of life were retrieved from newborn screening centers. MMP-7 on the DBS was quantified using a sensitive sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: The MMP-7 levels of BA patients on the DBS were significantly higher than those of non-BA patients (19.2 ± 10.4 vs 5.6 ± 2.7 ng/mL, P value < 0.0001). MMP-7 levels in non-BA patients, including 5 patients with hepatobiliary structural anomaly, 9 patients with intrahepatic cholestasis, and 93 patients with other perinatal diseases, were 11.6 ± 4.2 ng/mL, 6.9 ± 3.0 ng/mL, and 5.2 ± 2.1 ng/mL, respectively. The DBS MMP-7 level showed good accuracy for identifying BA, with an area under the curve of 93.7% [95% confidence interval (CI): 87.7%-99.7%]. The MMP-7 cutoff at 8.0 ng/mL showed a sensitivity of 92.0% (95% CI: 75.0%-98.6%) and specificity of 92.5% (95% CI: 85.9%-96.1%) for detecting BA from other congenital or perinatal diseases. CONCLUSIONS: MMP-7 DBS analysis can be used to distinguish BA from other conditions as early as 3 days of age.

The effects of job characteristics on physicians' orientation toward lifelong learning.

With the rapidly growing body of medical knowledge, physicians must engage in lifelong learning. Physicians' orientation toward lifelong learning is of crucial importance. This study aimed to explore the effects of job characteristics on physicians' lifelong learning. A multicenter study collecting data from physicians from three medical centers in Taiwan was performed. A total of 321 physicians were surveyed with the Chinese version of the Job Content Questionnaire (C-JCQ) and the revised Jefferson Scale of Physician Lifelong Learning (JeffSPLL) to assess their job characteristics (i.e., job demands, job control, social support) and orientation toward lifelong learning. Exploratory factor analysis was employed to validate both questionnaires. Hierarchical regression was utilized to explore the relationship of job characteristics and predictors with physicians' lifelong learning. The results revealed that job demands (ß = 0.10), job control (ß = 0.19), social support from supervisors (ß = 0.16), the interaction of job demands × job control (ß = - 0.11) and the interaction of job demands × social support from colleagues (ß = 0.13) were significantly (p < .05, p < .001) related to lifelong learning. Moreover, physicians in the active group (high demand, high control) possessed a stronger orientation toward lifelong learning (mean = 3.57) than those in the low-strain group (mean = 3.42), high-strain group (mean = 3.39) and passive group (mean = 3.20). In conclusion, examining physicians' job demands, job control and social support helps us to understand their orientation toward lifelong learning and may provide insight to improve educational strategies.

SLCO1B1 and SLCO1B3 genetic mutations in Taiwanese patients with Rotor syndrome.

Rotor syndrome is a rare, benign, inherited disorder that is commonly associated with mild hyperbilirubinemia. It is caused by bi-allelic pathological variants in both SLCO1B1 and SLCO1B3 genes, causing defective OATP1B1 and OATP1B3 in the sinusoidal membrane and interrupted bilirubin uptake of the hepatocytes. We report five Taiwanese pediatric and adult patients aged 5-32 years presenting with conjugated hyperbilirubinemia, and were found to have genetic variants of SLCO1B1 and SLCO1B3. Two also had history of prolonged neonatal jaundice. Genetic analysis using panel-based next generation sequencing revealed three patients with homozygous mutations c.1738C>T (p.R580∗) in SLCO1B1 and a transposon LINE-1 insertion in SLCO1B3, one patient with homozygous mutations for another haplotype, c.757C>T (p.R253∗) in SLCO1B1 and c.1747+1G>A in SLCO1B3. Another patient had heterozygous c.1738C>T (p.R580∗) in SLCO1B1 linked with a LINE-1 insertion in SLCO1B3, and heterozygous c.757C>T (p.R253∗) in SLCO1B1 linked with c.1747+1G>A in SLCO1B3. In conclusion, we present the first time of genetic diagnosis of Rotor syndrome in Taiwan. Advanced genetic testing has enhanced the diagnosis of rare diseases with mild symptoms.

Universal Infant Hepatitis B Virus (HBV) Vaccination for 35 Years: Moving Toward the Eradication of HBV.

A universal hepatitis B virus (HBV) vaccination program has been implemented in Taiwan since 1984. A total of 1611 individuals in Taipei were enrolled to monitor long-term efficacy. The prevalences of hepatitis B surface antigen (HBsAg) and hepatitis B core antibody in the vaccinated birth cohort were lower than in those born before 1984 (0.4% vs 7.7%, and 2.2% vs 50.8%, respectively; P < .0001). Three vaccine-failure carriers all were born to HBsAg-carrier mothers, probably due to no antiviral intervention during pregnancy. Occult HBV infection was rare in the postvaccination era. High vaccination coverage, comprehensive HBV screening, and antiviral agents for pregnant mothers will be essential to eliminate HBV transmission.