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Background and Aims: Hepatitis B virus (HBV) infection continues to threaten millions of lives across the globe, despite universal vaccination efforts. Current guidelines for screening, vaccination, and treatment are complex and have left too many people undiagnosed or improperly managed. Antiviral therapy has been shown to significantly reduce the incidence of liver-related complications, including liver cancer. However, the complexity of existing guidelines can make it difficult to identify which patients to target for treatment, and recommendations that are difficult to implement in real-world settings pose a barrier to eligible patients to receive therapy and contribute to health disparities in HBV care. The goal of this global expert panel was to gain consensus on a streamlined approach to HBV care to facilitate implementation of HBV intervention and treatment, especially in the primary care setting. Methods: A group of 8 liver and infectious disease specialists attended a meeting in January 2021 with the objective of gaining consensus on a streamlined algorithm for HBV care that would encourage implementation of HBV intervention and treatment. Results: We have created a comprehensive perspective highlighting screening optimization, diagnostic workup, treatment, and monitoring. This treatment algorithm is designed to provide a streamlined visual pathway for risk stratification and management of patients with HBV that can be adapted in various care settings. Conclusion: Simplification of guidelines will be critical to achieving health equity to address this public health threat and achieve HBV elimination.

Background and Aims: Type 1 hepatorenal syndrome (HRS) is a rapid deterioration in kidney function in patients with cirrhosis. Data on efficacy of vasoconstrictors for type 1 HRS have shown mixed results. Methods: Literature searched for randomized controlled trials comparing pharmacological therapy for HRS vs placebo or another drug for HRS. Primary outcome was HRS reversal (serum creatinine

Abstract 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

Abstract The Chinese Government has promulgated the “Belt and Road Initiative” (BRI) to increase trade flows and integrate goods markets between China and BRI countries. The validity of purchasing power parity (PPP) implies well‐integrated goods markets, a precondition for further economic convergence, and the next stage of economic integration in factor, service, and financial markets. Our study aims to examine the validity of the PPP and the extent of goods market integration between China and selected BRI countries in Africa. Since the functional form of the cointegrating relationship may not be exact or linear, we adopt the nonparametric rank tests for analysis without prior knowledge and specification of the functional form. We also address the rank problems that occur in multivariate rank tests. Our empirical results provide strong evidence of an unrestricted PPP relationship with reasonably strong evidence of nonlinearity in the data. We also find that some African BRI countries have experienced goods market integration with China during the second‐half period only. This indicates that the introduction of the BRI in 2013 and China's active involvement in African economic development through BRI projects are leading to enhanced goods market integration between China and Africa. The results indicate favorable prospects of closer economic cooperation in the factor, service, and financial markets to build a free trade area or common markets with BRI countries in Africa.

Abstract Antibiotics are indispensable to infection management. However, use of antibiotics can cause gut microbiota dysbiosis, which has been linked to cognitive impairment by disrupting communication between the gut microbiota and the brain. We conducted a systematic review and meta-analysis on the effects of long-term antibiotic use on cognitive outcomes. We have searched PubMed, Web of Science, Embase, Cochrane Library and Scopus for English publications before March 2023 following the PRISMA guidelines. Screening, data extraction, and quality assessment were performed in duplicate. 960 articles were screened and 16 studies which evaluated the effect of any antibiotic compared to no antibiotics or placebo were included. Case-reports, in vitro and animal studies were excluded. We found that antibiotic use was associated with worse cognitive outcomes with a pooled effect estimate of − 0.11 (95% CI − 0.15, − 0.07, Z = 5.45; P

The aim of this review is to explore the potential of new regenerative medicine approaches in the treatment of cholestatic liver fibrosis. Cholestatic liver diseases, such as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and biliary atresia (BA), due to the accumulation of bile, often progress to liver fibrosis, cirrhosis, and liver failure. When the disease becomes severe enough to require liver transplantation. Deeply understanding the disease’s progression and fibrosis formation is crucial for better diagnosis and treatment. Current liver fibrosis treatments mainly target the root causes and no direct treatment method in fibrosis itself. Recent advances in regenerative medicine offer a potential approach that may help find the ways to target fibrosis directly, offering hope for improved outcomes. We also summarize, analyze, and discuss the current state and benefits of regenerative medicine therapies such as mesenchymal stem cell (MSC) therapy, induced pluripotent stem cells (iPSCs), and organoid technology, which may help the treatment of cholestatic liver diseases. Focusing on the latest research may reveal new targets and enhance therapeutic efficacy, potentially leading to more effective management and even curative strategies for cholestatic liver diseases.

Abstract Hirschsprung disease is characterized by the absence of enteric neurons caused by the defects of enteric neural crest cells, leading to intestinal obstruction. Here, using induced pluripotent stem cell-based models of Hirschsprung and single-cell transcriptomic analysis, we identify a gene set of 118 genes commonly dysregulated in all patient enteric neural crest cells, and suggest HDAC1 may be a key regulator of these genes. Furthermore, upregulation of RNA splicing mediators and enhanced alternative splicing events are associated with severe form of Hirschsprung. In particular, the higher inclusion rate of exon 9 in PTBP1 and the perturbed expression of a PTBP1-target, PKM, are significantly enriched in these patient cells, and associated with the defective oxidative phosphorylation and impaired neurogenesis. Hedgehog-induced oxidative phosphorylation significantly enhances the survival and differentiation capacity of patient cells. In sum, we define various factors associated with Hirschsprung pathogenesis and demonstrate the implications of oxidative phosphorylation in enteric neural crest development and HSCR pathogenesis.

Abstract Background In addition to high vaccination levels, COVID-19 control requires uptake and continued adherence to personal hygiene and social distancing behaviors. It is unclear whether residents of a city with successive experience in worldwide pandemics such as SARS, would quickly adopt and maintain preventive behaviors. Methods A population-based, longitudinal telephone survey was conducted between in first local wave of the COVID-19 pandemic (April 2020) and third local wave (December 2020) (n = 403). The study examined factors associated with personal hygiene and social distancing behavior fatigue, as measured by reduced adherence. Results Over 9 months, face mask use increased (96.5–100%, p

Genetic mutations are critical factors leading to congenital surgical diseases and can be identified through genomic analysis. Early and accurate identification of genetic mutations underlying these conditions is vital for clinical diagnosis and effective treatment. In recent years, artificial intelligence (AI) has been widely applied for analyzing genomic data in various clinical settings, including congenital surgical diseases. This review paper summarizes current state-of-the-art AI-based approaches used in genomic analysis and highlighted some successful applications that deepen our understanding of the etiology of several congenital surgical diseases. We focus on the AI methods designed for the detection of different variant types and the prioritization of deleterious variants located in different genomic regions, aiming to uncover susceptibility genomic mutations contributed to congenital surgical disorders.

Abstract Background Assessing motor function is a simple way to track cognitive impairment. We analysed the associations between cognitive and motor function and assessed the predictive value of two motor function measuring tools for cognitive impairment in older adults with multimorbidity in primary care settings. Methods We conducted a prospective cohort study with a 1 year follow-up. Patients aged ≥60 years with ≥2 morbidities were recruited from four primary care clinics. Motor function was assessed using handgrip strength and a sarcopenia screening scale (SARC-F). Cognitive function was measured using the Hong Kong Montreal Cognitive Assessment (HK-MoCA). We defined cognitive impairment as an HK-MoCA score

Abstract Although the main route of infection for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the respiratory tract, liver injury is also commonly seen in many patients, as evidenced by deranged parenchymal liver enzymes. Furthermore, the severity of liver damage has been shown to correlate with higher mortality. Overall, the mechanism behind the liver injury remains unclear. We showed in this study that intra-hepatic bile duct cells could be grown using a human liver organoid platform. The cholangiocytes were not only susceptible to SARS-CoV-2 infection, they also supported efficient viral replication. We also showed that SARS-CoV-2 replication was much higher than SARS-CoV. Our findings suggested direct cytopathic viral damage being a mechanism for SARS-CoV-2 liver injury.

Abstract Traditional carrier screening has been utilized for the detection of carriers of genetic disorders. Since a comprehensive assessment of the carrier frequencies of recessive conditions in the Southern Chinese population is not yet available, we performed a secondary analysis on the spectrum and carrier status for 315 genes causing autosomal recessive disorders in 1543 Southern Chinese individuals with next-generation sequencing data, 1116 with exome sequencing and 427 with genome sequencing data. Our data revealed that 1 in 2 people (47.8% of the population) was a carrier for one or more recessive conditions, and 1 in 12 individuals (8.30% of the population) was a carrier for treatable inherited conditions. In alignment with current American College of Obstetricians and Gynecologists (ACOG) pan-ethnic carrier recommendations, 1 in 26 individuals were identified as carriers of cystic fibrosis, thalassemia, and spinal muscular atrophy in the Southern Chinese population. When the >1% expanded carrier screening rate recommendation by ACOG was used, 11 diseases were found to meet the criteria in the Southern Chinese population. Approximately 1 in 3 individuals (35.5% of the population) were carriers of these 11 conditions. If the 1 in 200 carrier frequency threshold is used, and additional seven genes would meet the criteria, and 2 in 5 individuals (38.7% of the population) would be detected as a carrier. This study provides a comprehensive catalogue of the carrier spectrum and frequency in the Southern Chinese population and can serve as a reference for careful evaluation of the conditions to be included in expanded carrier screening for Southern Chinese people.

Background: We explored the feasibility of creating BA-like organoids by treating human liver organoids with Polyinosinic:Polycytidylic acid (Poly I:C). Methods: Organoids were developed from the liver parenchyma collected during Kasai portoenterostomy (BA) and surgery for other liver disorders (non-BA). The non-BA organoids were co-cultured with poly I:C (40 µg/mL). The organoid morphology from both samples was compared on day 17. RNA-sequencing was performed to examine the transcriptomic differences. Results: Non-BA liver organoids developed into well-expanded spherical organoids with a single-cell layer of epithelial cells and a single vacuole inside. After poly I:C treatment, the majority of these organoids developed into an aberrant morphology with a high index of similarity to BA organoids which are multi-vacuoled and/or unexpanded. RNA-sequencing analysis revealed that 19 inflammatory genes were commonly expressed in both groups. Conditional cluster analysis revealed several genes (SOCS6, SOCS6.1, ARAF, CAMK2G, GNA1C, ITGA2, PRKACA, PTEN) that are involved in immune-mediated signaling pathway had a distinct pattern of expression in the poly I:C treated organoids. This resembled the expression pattern in BA organoids (p < 0.05). Conclusions: Poly I:C treated human liver organoids exhibit morphology and genetic signature highly compatible to organoids developed from BA liver samples. They are potential research materials to study immune-mediated inflammation in BA.

Background Choledochal cysts (CC) are congenital bile duct anomalies with 6–30% risk for developing bile duct cancer. However, the molecular mechanisms underlying cancer risk of CC are unknown. We sought to identify the gene expression changes underlying the cancer risk of CC patients. Methods Liver organoids (n = 51) were generated from liver/bile duct biopsies of CC (n = 7; type I) and hepatoblastoma (n = 5; HB: non-tumor & tumor) for RNA sequencing. Bioinformatics analysis was conducted to identify differentially expressed cancer-related genes in CC and controls. We compared CC with non-cancerous and cancerous controls, normal adjacent non-tumor region of hepatoblastoma (HB) liver as non-cancerous control and tumor region as non-CC cancer control (HB-tumor). Reverse transcription real-time quantitative PCR (RT-qPCR) verification and immunohistochemistry of selected genes was conducted in additional CC and HB liver biopsies. Findings HB non-tumor and HB tumor organoids displayed distinct gene expression profiles. Expression profiling separated CC organoids into two clusters, one overlapping with HB non-tumor and the other one with HB tumor organoids. Genes selected based on their log2FoldChange values for RT-qPCR verification in 31 CC and 11 HB non-tumor liver tissues revealed significantly elevated expression of FGFR2 in 7 and CEBPB in 2 CC liver tissues (CC vs HB: 4.082 vs. 0.7671, pInterpretation The study identified dysregulated genes related to cancer pathways in CC patients suggesting cancer risk. The findings suggest that the elevated expression of FGFR2 and CEBPB in liver may contribute to cancer development in CC patients.

BackgroundBiliary atresia (BA) is an infantile fibro-obstructive cholestatic disease with poor prognosis. An early diagnosis and timely Kasai portoenterostomy (KPE) improve clinical outcomes. Aggregation of amyloid-beta (Aβ) around hepatic bile ducts has been discovered as a factor for BA pathogenesis, yet whether plasma Aβ levels correlate with hepatic dysfunctions and could be a biomarker for BA remains unknown.MethodPlasma samples of 11 BA and 24 controls were collected for liver function test, Aβ40 and Aβ42 measurement by enzyme-linked immunosorbent assay (ELISA). Pearson's chi-squared test or Mann–Whitney U test was performed to assess differences between groups. Correlation between Aβ42/Aβ40 and liver function parameters was performed using Pearson analysis. The area under the receiver-operative characteristic (ROC) curve (area under curve; AUC) was measured to evaluate the diagnostic power of Aβ42/Aβ40 for BA. Diagnostic enhancement was further evaluated by binary regression ROC analysis of Aβ42/Aβ40 combined with other hepatic function parameters.ResultsPlasma Aβ42/Aβ40 was elevated in BA patients. Aβ42 displayed a weak positive correlation with γ-glutamyl transpeptidase (GGT) (Pearson’s correlation = 0.349), while there was no correlation for Aβ40 with hepatic functions. Aβ42/Aβ40 was moderately correlated with GGT, total bile acid (TBA), direct bilirubin (DBIL) (Pearson’s correlation = 0.533, 0.475, 0.480), and weakly correlated with total bilirubin (TBIL) (Pearson’s correlation = 0.337). Aβ42/Aβ40 showed an acceptable predictive power for cholestasis [AUC = 0.746 (95% CI: 0.552–0.941), p

Tetralogy of Fallot (TOF) is the most common cyanotic heart defect, yet the underlying genetic mechanisms remain poorly understood. Here, we performed whole-genome sequencing analysis on 146 nonsyndromic TOF parent-offspring trios of Chinese ethnicity. Comparison of de novo variants and recessive genotypes of this data set with data from a European cohort identified both overlapping and potentially novel gene loci and revealed differential functional enrichment between cohorts. To assess the impact of these mutations on early cardiac development, we integrated single-cell and spatial transcriptomics of early human heart development with our genetic findings. We discovered that the candidate gene expression was enriched in the myogenic progenitors of the cardiac outflow tract. Moreover, subsets of the candidate genes were found in specific gene coexpression modules along the cardiomyocyte differentiation trajectory. These integrative functional analyses help dissect the pathogenesis of TOF, revealing cellular hotspots in early heart development resulting in cardiac malformations.

ObjectivesTo assess impacts of early detection and prompt antiretroviral therapy (ART) on the latest epidemiologic situation to inform intervention strategy.MethodsWe analysed data from two clinical cohorts in Hong Kong where sexual transmission accounted for the majority of HIV infections. The two cohorts comprised patients newly diagnosed in 2007-2008 and 2016-2018 respectively. Secular trend and differences between men who have sex with men (MSM) and heterosexual patients were examined. Predictors of late presentation (defined as CD4 ≤350 or AIDS-defining illness within 3 months of diagnosis) and prolonged interval between diagnosis and ART initiation were assessed by multivariable regressions.ResultsThere were 1,136 newly diagnosed HIV patients with 644 in the first and 492 in the second cohort, a majority (91.7%) presented with sexually acquired infection. There were less MSM in the first than the second cohort (50.3%% vs 87.8%, χ2 = 117.05, pConclusionsThere was remarkable improvement in acceleration of ART initiation. Clinical implementation of accelerated ART recommendations has been effective for both MSM and heterosexuals. Late presentation was more marked among heterosexuals and remained a problem. The continued phenomenon of late presentation could offset the epidemiologic gains from accelerated ART initiation.

Organoids as three-dimension (3D) cellular organizations partially mimic the physiological functions and micro-architecture of native tissues and organs, holding great potential for clinical applications. Advances in the identification of essential factors including physical cues and biochemical signals for controlling organoid development have contributed to the success of growing liver organoids from liver tissue and stem/progenitor cells. However, to recapitulate the physiological properties and the architecture of a native liver, one has to generate liver organoids that contain all the major liver cell types in correct proportions and relative 3D locations as found in a native liver. Recent advances in stem-cell-, biomaterial- and engineering-based approaches have been incorporated into conventional organoid culture methods to facilitate the development of a more sophisticated liver organoid culture resembling a near to native mini-liver in a dish. However, a comprehensive review on the recent advancement in the bioengineering liver organoid is still lacking. Here, we review the current liver organoid systems, focusing on the construction of the liver organoid system with various cell sources, the roles of growth factors for engineering liver organoids, as well as the recent advances in the bioengineering liver organoid disease models and their biomedical applications.

Vaccination is an effective way in providing protection against COVID-19 infection and severe outcomes. However, vaccine resistance and hesitancy are a great concern among vulnerable populations including older adults who live alone or only with an older partner. This study examined their vaccination status and reasons and associated factors of vaccine resistance and hesitancy. A cross-sectional study was conducted among older adults living alone or only with an older partner in communities in Hong Kong. Participants were interviewed between October 2021 and February 2022. Logistic regression analyses were employed to examine factors associated with vaccine resistance and hesitancy. Of the 2109 included participants, the mean age was 79.3 years (SD 7.6), 1460 (69.2%) were female, 1334 (63.3%) lived alone, and 1621 (76.9%) were receiving social security support. The vaccine uptake, non-uptake (i.e., resistance), and hesitancy rates were 50.1%, 34.4%, and 15.5%, respectively. The top four reasons for vaccine resistance and hesitancy were “Not feeling in good health” (27%), “Worry about vaccine side effects” (18%), “Feeling no need” (10%), and “Lack of recommendation from doctors” (9%). Vaccine resistance and hesitancy was significantly associated with older age, living alone, more chronic conditions, fewer types of social media use, and lower self-rated health status. Similar associations can be observed in their separate analysis for vaccine resistance and vaccine hesitancy, and ever hospital admission over the past 6 months was additionally related to vaccine hesitancy. Older people who live alone or only with an older partner had a low vaccination rate. Poor health or worry about vaccine side effects were the most common reasons for their vaccine resistance and hesitancy. Actions are greatly needed to improve the uptake rate among this vulnerable population, especially those who were older, have poorer health, and use less social media.