BACKGROUND & AIMS:The long-term benefit of antiviral treatment with nucleos(t)ide analogues (NAs) for non-cirrhotic patients with chronic hepatitis B (CHB) without significant alanine aminotransferase (ALT) elevation remains debatable. We investigated the impact of NA treatment on the long-term risk of hepatocellular carcinoma (HCC) and cirrhosis in these patients. METHODS:This retrospective multicenter study included 3734 non-cirrhotic patients with CHB with ALT <2 × the upper limit of normal (ULN). To balance baseline characteristics between treated and untreated patients, inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) were applied. The risk of HCC and cirrhosis development was compared between the treated and untreated patients. RESULTS:Of all patients, 37.8% received NA treatment. After IPTW, treated patients had a significantly lower 5-year cumulative incidence of HCC (0.9% vs 4.4%; P < .001) and cirrhosis (4.0% vs 8.9%; P < .001) than untreated patients. In multivariate Cox analyses, NA therapy was associated with a significantly lower risk of developing HCC (adjusted hazard ratio [aHR], 0.14; 95% confidence interval [CI], 0.05-0.37; P < .001) and cirrhosis (aHR, 0.30; 95% CI, 0.18-0.50; P < .001) in the IPTW cohort. The findings were consistent in the subgroup of patients with ALT 1 to 2 × ULN but not in those with ALT ≤1 × ULN. Similar results were obtained in the PSM cohort. CONCLUSIONS:NA therapy reduced the risk of HCC and cirrhosis in non-cirrhotic CHB patients with mildly elevated ALT levels (1-2 × ULN). These findings support the expansion of antiviral treatment criteria for the early treatment of these patients.

Background The association between serum HBV DNA levels and liver fibrosis in patients with chronic hepatitis B (CHB) remains controversial. We investigated this association in non-cirrhotic CHB patients. Methods A total of 5,880 non-cirrhotic treatment-naïve CHB patients with ALT ≤2 × ULN were retrospectively included. Liver fibrosis was evaluated using FIB-4, APRI, LSM, or liver histology. Results The CHB patients had a median age of 38.0 years and 57.6% were male. There was a non-linear, parabolic association between serum HBV DNA loads and non-invasive fibrosis tests (APRI, FIB-4, and LSM). Patients with moderate serum HBV DNA levels (around 6 log10 IU/mL) had the highest APRI, FIB-4, and LSM values. After adjustment, the non-linear relationship between serum HBV DNA loads and non-invasive liver fibrosis indicators remained significant, especially in HBeAg-positive patients. Patients with moderate serum HBV DNA levels (around 6 log10 IU/mL) had the highest proportion of significant liver fibrosis as determined by APRI, FIB-4, LSM, and liver biopsy. Conclusions A non-linear association was observed between serum HBV DNA levels and liver fibrosis in non-cirrhotic, treatment-naïve CHB patients with ALT ≤2 × ULN, with moderate HBV DNA levels (around 6 log₁₀ IU/mL) associated with a higher risk of fibrosis.

Conventional targeted therapies for inflammatory bowel disease (IBD) often rely on unstable biological recognition elements. While molecularly imprinted polymers (MIP) offer robust synthetic alternatives, their utility is limited by an "always-on" binding state: even weak non-specific adsorption can significantly compromise their target-binding capacity. We convert static MIP into reactive oxygen species (ROS)-activated therapeutic actuators by conjugating mannose to transferrin-imprinted MIP via a ROS-cleavable linker. The saccharide acts dually as a therapeutic agent and a protective cloak. It sterically blocks non-specific binding during intestinal transit. At inflammatory sites, elevated ROS levels (higher than in healthy tissue) trigger simultaneous mannose release and activation of high-affinity targeting. This enables precise MIP anchoring to the inflamed epithelium for physical barrier formation and localized microbiome modulation. In murine colitis models, this achieved mucosal healing, mitigated inflammation, and microbiota rebalancing using a mannose equivalent dose of 27.2 mg/kg/d, benchmarking against free mannose and non-responsive MIP controls. This work establishes a generalizable paradigm for targeted recognition and drug delivery in complex physiological environments, paving the way for intelligent, disease-responsive nanomedicines.

ABSTRACTThe exclusion of cirrhosis is important in chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT). We aimed to optimise the performance of the aspartate aminotransferase to platelet ratio index (APRI) and fibrosis score based on four factors (FIB‐4) to exclude cirrhosis in these patients. Five hundred and eighty four patients with normal ALT who underwent liver biopsy were included in the study. The patients were divided into derivation and external validation sets. A grid search method was used to identify new cut‐offs with a negative predictive value (NPV) of > 95% and a sensitivity of > 90% for detecting cirrhosis. The proportion of patients with cirrhosis in the derivation and validation sets was 19.4% and 7.5%, respectively. The conventional cut‐offs of APRI (77.6%) and FIB‐4 (41.8%) had high rates of cirrhosis misclassification. A new APRI cut‐off of 0.21 had a sensitivity of 97.0% and an NPV of 95.6%, and only two (3.0%) patients with cirrhosis were misclassified in the derivation set. Using a new FIB‐4 cut‐off of 0.53, with a sensitivity of 98.5% and NPV of 96.2%, only one (1.5%) patient with cirrhosis was misclassified. External validation showed similar results. Using the new cut‐offs of APRI and FIB‐4, cirrhosis could be completely excluded for HBeAg‐positive patients or those aged > 40 years. The conventional cut‐offs had high misclassification rates for cirrhosis. The new cut‐offs of APRI (≤ 0.21) and FIB‐4 (≤ 0.53) could be used to exclude cirrhosis in CHB patients with normal ALT levels with a low misclassification rate.

The clinical significance of the coexistence of hepatitis B e antigen (HBeAg) and antibodies against HBeAg (anti-HBe) in patients with chronic hepatitis B (CHB) remains unclear. This study investigated the clinical features and phase transition of patients with coexisting HBeAg/anti-HBe. A total of 840 treatment-naïve HBeAg-positive CHB patients from two medical centres were included. Cox regression analysis was used to analyze factors associated with HBeAg clearance and seroconversion. Eighty-six patients (10.2%) had coexisting HBeAg/anti-HBe. Patients with anti-HBe were older (39.0 vs. 34.0 years, p=0.016) and had a higher FIB-4 values (1.5 vs. 1.0, p<0.001) than those without anti-HBe. The proportions of HBeAg clearance (41.9% vs. 16.2%, p<0.001) and HBeAg seroconversion (37.2% vs. 11.4%, p<0.001) were significantly higher in patients with coexisting HBeAg/anti-HBe than in those without anti-HBe during the follow-up period. Surprisingly, 39.5% of patients with anti-HBe transitioned to HBeAg-positive and anti-HBe-negative status. A total of 4.7% of patients with HBeAg and anti-HBe coexistence transitioned to HBeAg-negative and anti-HBe-negative status. Patients with anti-HBe had higher cumulative HBeAg clearance and seroconversion rates than those without anti-HBe (p<0.001). HBeAg/anti-HBe coexistence was associated with higher HBeAg clearance (HR 2.960, 95%CI 1.828-4.791, p<0.001) and HBeAg seroconversion (HR 4.018, 95% CI 2.372-6.805, p<0.001). Patients with coexisting HBeAg and anti-HBe had a higher likelihood of HBeAg clearance and seroconversion. Close follow-up is needed to monitor the phase transitions in patients with coexistence of HBeAg and anti-HBe patients.

BACKGROUND:Whether patients with chronic hepatitis B (CHB) with normal alanine aminotransferase (ALT) levels should receive antiviral therapy remains controversial. We compared the efficacy of nucleos(t)ide analogs (NAs) among CHB patients with different baseline ALT levels. METHODS:A total of 1,204 treatment-naïve CHB patients with detectable hepatitis B virus (HBV) DNA levels who initiated first-line NAs treatment were retrospectively included from three hospitals and followed up for 96 weeks. Virological response (VR) and HBeAg serological responses were compared among patients with different baseline ALT levels. RESULTS:Of the total patients, 682 (56.6%) were HBeAg-positive at baseline. In patients with normal ALT levels, 44.9% and 69.4% of HBeAg-positive patients achieved VR at weeks 48 and 96, respectively, whereas VR rates were 91.2% and 91.9% in HBeAg-negative patients, respectively. In the multivariate Cox regression analysis, baseline ALT ≤ 1×upper limit of normal (ULN) and ALT 1-2×ULN were not associated with VR compared to ALT > 2×ULN. However, the cumulative incidence of HBeAg clearance and seroconversion was significantly lower in patients with ALT ≤ 1×ULN than in those with ALT > 2×ULN (both P < 0.001). Baseline ALT ≤ 1×ULN was associated with a significantly lower chance of achieving HBeAg clearance (HR = 0.314, 95% CI: 0.163-0.607, P = 0.001) and HBeAg seroconversion (HR = 0.280, 95% CI: 0.127-0.615, P = 0.002). CONCLUSIONS:CHB patients with normal ALT levels had comparable VR rates but significantly lower rates of HBeAg clearance and seroconversion during first-line NA therapy than patients with elevated ALT levels.

Quantitative hepatitis B serum antigen (HBsAg) level <100 IU/mL has been proposed as one of the key criteria for partial cure for chronic hepatitis B (CHB) and as an important threshold for stopping nucleos(t)ide analogues (NAs) with a finite therapeutic strategy. We investigated the incidence and associated factors of HBsAg<100 IU/mL in hepatitis B e antigen (HBeAg)-negative CHB patients initiating NAs therapy. A total of 996 HBeAg-negative CHB patients with baseline HBsAg>100 IU/mL initiating first-line NAs treatment from five hospitals in China were retrospectively included. Cumulative incidence and associated factors of HBsAg<100 IU/mL were assessed using Kaplan-Meier and Cox regression analyses, respectively. During a median follow-up of 28.8 months, 69 patients (6.9%) achieved HBsAg<100 IU/mL, with a 5-year cumulative incidence of 13.97% (95%CI: 10.42%-17.38%). Among them, 94.2% (65/69) achieved both HBsAg<100 IU/mL and undetectable HBV DNA, with a 5-year incidence of 13.15% (95%CI: 9.66%-16.50%). Baseline HBsAg<1,000 IU/mL (aHR=19.66, 95%CI: 8.84-43.71, P < 0.001) and HBV DNA<10,000 IU/mL (aHR=2.47, 95%CI: 1.48-4.13, P = 0.001) were independently associated with a high chance of achieving HBsAg<100 IU/mL. Patients with both baseline HBsAg<1,000 IU/mL and HBV DNA<10,000 IU/mL had a 5-year incidence of 58.73% for achieving HBsAg<100 IU/mL, whereas the 5-year incidence was only 3.91% in patients with HBsAg≥1,000 IU/mL and HBV DNA≥10,000 IU/mL. Few HBeAg-negative CHB patients achieved HBsAg<100 IU/mL with NAs treatment. A combination of baseline HBsAg and HBV DNA levels can help identify HBeAg-negative CHB patients who are more likely to achieve HBsAg <100 IU/mL with NAs and may benefit from a finite therapeutic strategy.

BACKGROUND:A substantial proportion of chronic hepatitis B (CHB) patients with indeterminate phase have significant liver injury, yet only a small proportion of these patients receive liver biopsy. We compared the clinical characteristics of indeterminate CHB patients with and without liver biopsy. METHODS:A total of 2928 untreated CHB patients with indeterminate phases were retrospectively included. The indeterminate phase was identified and classified based on the AASLD 2018 guidance. RESULTS:The median age of patients was 39.0 years and male accounted for 65.0%. A total of 288 (9.8%) CHB patients with the indeterminate phase underwent liver biopsy. Patients with liver biopsy were older (42.0 vs. 39.0 years, p < 0.001) and had higher HBV DNA (3.4 log10IU/mL vs. 2.7 log10IU/mL, p < 0.001), APRI (0.42 vs. 0.36, p < 0.001), FIB-4 (1.18 vs. 0.99, p < 0.001), and liver stiffness values (9.9 vs. 6.6 kPa, p < 0.001), whereas lower platelets (169.0 × 109/L vs. 192.0 × 109/L, p < 0.001) than those without liver biopsy. Patients with PLT< 150.0 × 109/L (OR 1.587, 95% CI 1.207-2.085, p < 0.001) and high HBV DNA (OR 1.458, 95% CI 1.298-1.637, p < 0.001) were more likely to receive liver biopsy in the indeterminate phase. CONCLUSION:Only 9.8% of indeterminate CHB patients underwent liver biopsy in our cohort. These patients exhibited higher values on noninvasive fibrosis tests. Hepatic histologic findings from biopsied patients should be interpreted with caution and should not be generalized to all patients in the indeterminate phase.

Chimeric antigen receptor (CAR) T-cell therapy is one of the most effective approaches in cancer immunotherapy. However, shortcomings such as loss of target antigens and poor infiltration remain in the treatment of solid tumors. Herein, we propose an approach to glycoengineer T cells based on glycan covalent targeting chimera (gcTAC), to enhance immunotherapy by modulating the glycan recognition behavior of T cells. We select hydrazide-modified phenylboronic acid (PBA) as gcTAC. The hydrazide group can covalently couple with the aldehyde group generated by the oxidation of galactose/N-acetylgalactosamine on the surface of T cells, while the PBA at the other end can specifically bind to sialic acids (Sia) of tumor cells, thereby enhancing the killing effect of T cells. At the same time, T cells covalently bound to tumor cells surfaces act as a blockade of Sia sites, which can disrupt the recognition between Siglec on natural killer (NK) cells and Sia on tumor cells, further enhancing the immune-killing effect of combined T-NK cell therapy. Our approach represents a novel concept to promote immune killing through cascading interventions in T-tumor and tumor-NK intercellular glycan recognition, thus providing a solution to the problem of immune escape in cancer therapy.

Introduction and Objectives: Seroclearance of hepatitis B e antigen (HBeAg) is an important treatment goal for patients with chronic hepatitis B (CHB). This study developed a nomogram for predicting HBeAg seroclearance in CHB patients treated with nucleos(t)ide analogues (NAs).Patients and Methods: Five hundred and sixty-nine CHB patients treated with NAs from two institutions between July 2016 to November 2021 were retrospectively included. One institution served as the training set (n = 374) and the other as the external validation set (n = 195). A predictive nomogram was established based on cox regression analysis.Results: The overall HBeAg seroclearance rates were 27.3 and 21.5 % after the median follow-up of 100.2 weeks and 65.1 weeks in the training set and validation set, respectively. In the training set, baseline aspartate aminotransferase, gamma-glutamyl transpeptidase, HBeAg, and hepatitis B core antibody levels were independently associated with HBeAg seroclearance and were used to establish the HBEAg SeroClearance (ESC)-nomogram. The calibration curve revealed that the ESC-nomogram had a good agreement with actual observation. The ESC-nomogram showed relatively high accuracy for predicting 48 weeks, 96 weeks, and 144 weeks of HBeAg seroclearance in the training set (AUCs: 0.782, 0.734 and 0.671) and validation set (AUCs: 0.699, 0.718 and 0.689). The patients with high ESC-nomogram scores (>= 79.51) had significantly higher cumulative incidence of HBeAg seroclearance and seroconversion than patients with low scores (< 79.51) in both sets (P < 0.01).Conclusions: The novel ESC-nomogram showed good performance for predicting antiviral efficacy in HBeAgpositive CHB patients with NAs treatment.(c) 2023 Fundacion Clinica Medica Sur, A.C. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Background The clinical significance of gastrointestinal (GI) symptoms in patients with severe fever and thrombocytopenia syndrome (SFTS) is poorly characterized. This study aimed to determine the prevalence and effect of GI symptoms on the prognosis of patients with SFTS. Methods This was a retrospective multi-center cohort study that included hospitalized patients with SFTS from three institutions between October 2010 and August 2022. The risk factors for mortality and intensive care unit (ICU) admission were identified by Cox and logistic regression analyses, respectively. Kaplan-Meier curves were used to analyze the cumulative mortality risk. Results Among 304 patients, the median age was 62.0 years and 51.0% of the patients were male. A total of 202 patients (66.4%) had at least one GI symptom on admission. Diarrhea (69.8%) and nausea (57.4%) were the most common symptoms. Patients with GI symptoms had lower male proportion (46.0% vs. 60.8%, P = 0.015), higher aspartate aminotransferase (177.5 U/L vs. 118.0 U/L, P = 0.010) and lactic dehydrogenase (771.0 U/L vs. 666.5 U/L, P = 0.017) levels than that of patients without GI symptoms. However, there was no significant difference in mortality rates (23.8% vs. 21.6%, P = 0.668) and ICU admission (14.4% vs. 12.7%, P = 0.701) between SFTS patients with and without GI symptoms. Multivariate analysis suggested that GI symptoms at admission were not associated with mortality and ICU admission. Conclusions GI symptoms are common in patients with SFTS. However, the presence of GI symptoms was not an independent risk factor for poor prognosis.

Concerns have been raised regarding changes in lipid profiles among patients with chronic hepatitis B (CHB) during tenofovir alafenamide fumarate (TAF) treatment. We aimed to evaluate the effect of TAF treatment on the lipid profiles of patients with CHB. A total of 430 patients with CHB from three hospitals were retrospectively included, including 158 patients treated with TAF and 272 patients treated with tenofovir disoproxil fumarate (TDF). In this multicenter cohort, the cumulative incidence of dyslipidemia was notably higher in the TAF group than in the TDF group (P < 0.001). After TAF treatment, a significant elevation was observed in triglyceride (TG) levels (from 0.83 mmol/L to 1.02 mmol/L, P < 0.001) and total cholesterol (TC) levels (from 4.16 mmol/L to 4.32 mmol/L, P < 0.001). Similar changes in TG and TC levels were observed in the TAF group after propensity score matching (PSM). The TG levels (from 0.83 mmol/L to 1.04 mmol/L, P < 0.001) and TC levels (from 4.16 mmol/L to 4.38 mmol/L, P < 0.001) were both increased significantly compared to the baseline levels in the PSM cohort of patients treated with TAF. TAF treatment was independently associated with elevated TG levels (HR = 2.800, 95