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BackgroundPatients with chronic hepatitis B (CHB) with indeterminate phase make up a diverse cohort with likely different outcomes.ObjectiveWe compared the hepatocellular carcinoma (HCC) risk in indeterminate CHB with different baseline types and by phase transition.DesignThis was a retrospective cohort study of 1986 (94.2% Asian) patients with indeterminate CHB from nine countries/regions. Patients were classified according to baseline hepatitis B e-antigen (HBeAg), alanine aminotransferase (ALT) and HBV DNA. The cumulative HCC incidence was compared.ResultsBased on the 2018 American Association for the Study of Liver Disease guidance, most indeterminate patients were HBeAg negative (84.9%). The 20-year HCC incidence was highest in type 1 (HBeAg positive, ALT<1×upper limit of normal (ULN), HBV DNA 20 000–106 IU/mL, 36.2%) and lowest in type 8 (HBeAg negative, ALT 1–2×ULN, HBV DNA<2000 IU/mL, 1.9%). The 20-year HCC incidence of those who remained indeterminate was 4.7%. Cumulative HCC incidence rates were high in patients with indeterminate CHB who transitioned to immune tolerant (15 years: 16.5%) or immune active (20 years: 13.7%) phase but low for those who transitioned to immune inactive phase (20 years: 2.5%). In multivariable analysis, compared with type 8, higher HCC risk was seen with HBeAg-positive type 1 (adjusted HR (aHR)=40.1, p<0.001), type 2 (ALT 1–2×ULN, HBV DNA≥20 000 IU/mL, aHR=25.1, p<0.001), HBeAg-negative type 9 (ALT>2×ULN, HBV DNA<2000 IU/mL, aHR=4.6, p=0.032) and type 10 (ALT<1×ULN, HBV DNA<2000 IU/mL but with moderate to severe inflammation/fibrosis, aHR=7.3, p=0.033). Similar directions in HCC risks were found in analyses based on the 2017 European Association for the Study of the Liver guideline.ConclusionSeveral types of indeterminate CHB had high HCC risk. These data support the potential expansion of treatment criteria for higher risk types of indeterminate CHB.

Background/Aims: Given the increase in prevalence of metabolic diseases, we investigated their long-term impacts on the outcomes of chronic hepatitis B (CHB) patients receiving nucleos(t)ide analogue (NA) treatment.Methods: We analyzed data from CHB patients for whom initiated NA treatment from 30 centers. We balanced patient characteristics with and without metabolic disease (diabetes, obesity, dyslipidemia, and hypertension) via propensity-score matching (PSM) to evaluate adverse outcomes.Results: The study included 4,500 patients. PSM yielded 909 pairs of patients with balanced characteristics. When stratified by the number of metabolic diseases, only patients with ≥2 metabolic diseases had an increased cumulative incidence of cirrhosis and overall death. However, when stratified by the presence of diabetes (regardless of the presence or number of other metabolic diseases), patients with diabetes (versus those without) had a significantly higher cumulative incidence of all outcomes: cirrhosis (P=0.009), hepatocellular carcinoma (HCC, P=0.023), and overall, liver-related, and non-liver-related death (P<0.001, P=0.026 and P<0.001, respectively). Having ≥2 metabolic diseases was associated with cirrhosis, overall death, and non-liver-related death but not HCC or liver-related death, while diabetes was significantly associated with a higher risk of all outcomes: cirrhosis (hazard ratio [HR]=3.75, P=0.004), HCC (HR=2.02, P=0.020), and overall, liver-related, and non-liver-related death (HR=2.53, P<0.001; HR=2.65, P=0.016; HR=2.38, P<0.001).Conclusions: Having two or more metabolic diseases was associated with a higher risk of cirrhosis, overall death, and non-liver-related death, but having diabetes as a single metabolic disease was significantly associated with all adverse outcomes including cirrhosis, HCC, and overall, liver-related, and non-liver-related death.

Given the rise of metabolic diseases, we investigated their long-term impact in chronic hepatitis B (CHB) patients receiving nucleos(t)ide analogue (NA).BackgroundGiven the rise of metabolic diseases, we investigated their long-term impact in chronic hepatitis B (CHB) patients receiving nucleos(t)ide analogue (NA).We analyzed data from CHB patients who initiated NAs from 30 centers (7 countries/regions). We balanced patient characteristics with and without metabolic disease (diabetes, obesity, dyslipidemia, and hypertension) via propensity-score matching (PSM) to evaluate adverse liver events and motality.MethodsWe analyzed data from CHB patients who initiated NAs from 30 centers (7 countries/regions). We balanced patient characteristics with and without metabolic disease (diabetes, obesity, dyslipidemia, and hypertension) via propensity-score matching (PSM) to evaluate adverse liver events and motality.The study included 4,500 CHB patients (54.6% with ≥1 metabolic disease). PSM yielded 909 pairs of patients with balanced characteristics. When stratified by the number of metabolic disease, only patients with ≥2 metabolic diseases had increased cumulative incidence of cirrhosis and overall death (but not HCC or cause-specific death). However, when stratified by the presence of diabetes (regardless of the presence or number of other metabolic diseases), patients with diabetes (vs. those without) had significantly higher cumulative incidence of all outcomes: cirrhosis (P=0.009), HCC (P=0.023), overall, liver-related and non-liver-related death (P<0.001, P=0.026 and P<0.001, respectively). On Cox regression analysis, having ≥2 metabolic diseases was associated with cirrhosis, overall death and non-liver-related death but not HCC and liver-related death, while diabetes was significantly associated with higher risk of all outcomes: cirrhosis (HR=3.75, P=0.004), HCC (HR=2.02, P=0.020), overall, liver-related and non-liver-related death (HR=2.53, P<0.001; HR=2.65, P=0.016; HR=2.38, P<0.001).ResultsThe study included 4,500 CHB patients (54.6% with ≥1 metabolic disease). PSM yielded 909 pairs of patients with balanced characteristics. When stratified by the number of metabolic disease, only patients with ≥2 metabolic diseases had increased cumulative incidence of cirrhosis and overall death (but not HCC or cause-specific death). However, when stratified by the presence of diabetes (regardless of the presence or number of other metabolic diseases), patients with diabetes (vs. those without) had significantly higher cumulative incidence of all outcomes: cirrhosis (P=0.009), HCC (P=0.023), overall, liver-related and non-liver-related death (P<0.001, P=0.026 and P<0.001, respectively). On Cox regression analysis, having ≥2 metabolic diseases was associated with cirrhosis, overall death and non-liver-related death but not HCC and liver-related death, while diabetes was significantly associated with higher risk of all outcomes: cirrhosis (HR=3.75, P=0.004), HCC (HR=2.02, P=0.020), overall, liver-related and non-liver-related death (HR=2.53, P<0.001; HR=2.65, P=0.016; HR=2.38, P<0.001).Having ≥2 metabolic diseases was associated with significantly higher risk of cirrhosis, overall death and non-liver-related death, but having diabetes as a single metabolic disease was significantly associated with all adverse outcomes including cirrhosis, HCC, overall, liver-related and non-liver-related death.ConclusionHaving ≥2 metabolic diseases was associated with significantly higher risk of cirrhosis, overall death and non-liver-related death, but having diabetes as a single metabolic disease was significantly associated with all adverse outcomes including cirrhosis, HCC, overall, liver-related and non-liver-related death.

Background/Aims: Given the increase in prevalence of metabolic diseases, we investigated their long-term impacts on the outcomes of chronic hepatitis B (CHB) patients receiving nucleos(t)ide analogue (NA) treatment. Methods: We analyzed data from CHB patients for whom initiated NA treatment from 30 centers. We balanced patient characteristics with and without metabolic disease (diabetes, obesity, dyslipidemia, and hypertension) via propensity-score matching (PSM) to evaluate adverse outcomes. Results: The study included 4,500 patients. PSM yielded 909 pairs of patients with balanced characteristics. When stratified by the number of metabolic diseases, only patients with ≥2 metabolic diseases had an increased cumulative incidence of cirrhosis and overall death. However, when stratified by the presence of diabetes (regardless of the presence or number of other metabolic diseases), patients with diabetes (versus those without) had a significantly higher cumulative incidence of all outcomes: cirrhosis (P=0.009), hepatocellular carcinoma (HCC, P=0.023), and overall, liver-related, and non-liver-related death (P<0.001, P=0.026 and P<0.001, respectively). Having ≥2 metabolic diseases was associated with cirrhosis, overall death, and non-liver-related death but not HCC or liver-related death, while diabetes was significantly associated with a higher risk of all outcomes: cirrhosis (hazard ratio [HR]=3.75, P=0.004), HCC (HR=2.02, P=0.020), and overall, liver-related, and non-liver-related death (HR=2.53, P<0.001; HR=2.65, P=0.016; HR=2.38, P<0.001). Conclusions: Having two or more metabolic diseases was associated with a higher risk of cirrhosis, overall death, and non-liver-related death, but having diabetes as a single metabolic disease was significantly associated with all adverse outcomes including cirrhosis, HCC, and overall, liver-related, and non-liver-related death. (Clin Mol Hepatol 2025;31:1003-1017)

Cell polarization, the spatial self-organization of key molecules asymmetrically at distinct poles, is critical for cell growth, differentiation, and migration in diverse cell types. Previous studies have largely focused on a few network architectures that can achieve polarity and explored how they explain observed behavior. Here, we computationally explored the full space of one- and two-node signaling network architectures in an unbiased manner using coarse-grained representations, in order to elucidate the core design principles of cell polarity. We found three minimal motifs – positive feedback, mutual inhibition, and presence of a self-enhancing inhibitor - that can self-organize polarity and compared their robustness to variations in component concentrations, diffusion constants, and regulation strengths. Combining these motifs into more complex networks allowed for polarity over a wider range of parameters. Robust polarity is in fact best achieved by combining positive feedback with mutual inhibition, as has been observed in many well-studied biological polarity pathways. Such topologies, likely the result of an evolutionary process, can also serve as blueprints for synthetic biologists.

Children born very preterm are exposed to repeated neonatal procedures that induce pain and stress during hospitalization in the neonatal intensive care unit (NICU). The COMT Val158Met genotype is involved with pain sensitivity, and early life stress is implicated in altered expression of methylation of the serotonin transporter. We examined: (1) whether methylation of the serotonin transporter gene (SLC6A4) promoter differs between very preterm children and full-term controls at school age, (2) relationships with child behavior problems, and (3) whether the extent of neonatal pain exposure interacts with the COMT Val158Met genotype to predict SLC6A4 methylation at 7 years in the very preterm children. We examined the associations between the COMT genotypes, neonatal pain exposure (adjusted for neonatal clinical confounders), SLC6A4 methylation and behavior problems. Very preterm children had significantly higher methylation at 7/10 CpG sites in the SLC6A4 promoter compared to full-term controls at 7 years. Neonatal pain (adjusted for clinical confounders) was significantly associated with total child behavior problems on the Child Behavior Checklist (CBCL) questionnaire (adjusted for concurrent stressors and 5HTTLPR genotype) (p = 0.035). CBCL Total Problems was significantly associated with greater SLC6A4 methylation in very preterm children (p = 0.01). Neonatal pain (adjusted for clinical confounders) and COMT Met/Met genotype were associated with SLC6A4 promoter methylation in very preterm children at 7 years (p = 0.001). These findings provide evidence that both genetic predisposition and early environment need to be considered in understanding susceptibility for developing behavioral problems in this vulnerable population.

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