Chronic liver disease (CLD)-related thrombocytopenia can limit the feasibility of invasive procedures. Recombinant human thrombopoietin (rhTPO) has demonstrated a favorable safety profile without hepatotoxicity. We evaluated the efficacy and safety of rhTPO in patients with CLD-related thrombocytopenia who were undergoing elective invasive procedures. In this multicenter, randomized (2:1), double-blind, placebo-controlled phase III trial, 120 adult Chinese patients with CLD-related thrombocytopenia (platelet count < 50 × 109/L) received rhTPO (n = 80) or placebo (n = 40) once daily for up to 5 or 7 days. The primary endpoint was the proportion of patients with sustained platelet counts ≥ 50 × 109/L from 24 h before invasive procedure to 7 days post-procedure, without requiring emergency bleeding management. The primary endpoint was achieved by 85.0% of patients in the rhTPO group versus 12.5% in the placebo group (p < 0.0001). Preoperatively, platelet counts ≥ 50 × 109/L were achieved in 92.5% and 20.0% of patients in the rhTPO and placebo groups, respectively (p < 0.0001). Platelet transfusion was avoided in 92.5% of rhTPO-treated patients versus 25.0% of placebo-treated patients (p < 0.0001). The median duration of platelet counts ≥ 50 × 109/L was significantly longer with rhTPO than with placebo (21.0 vs. 3.0 days, p = 0.0007). Treatment-related treatment-emergent adverse events (TEAEs) occurred in 12.5% of patients in both the rhTPO and placebo groups. No treatment-related serious adverse events were reported. Overall, rhTPO was effective and well tolerated in patients with CLD-related thrombocytopenia and may represent a viable therapeutic option for those undergoing elective invasive procedures. Trial Registration: www.chinadrugtrials.org.cn: number CTR20230919.

End-stage liver disease (ESLD) is characterized by a dramatic deterioration of liver function, frequently accompanied by systemic inflammatory storms and multiple organ failures. Central to the onset and progression of ESLD, systemic inflammation arises from complex interactions among various inflammatory signaling molecules and immune cells within and beyond the liver. As key inflammatory modulatory molecules, bioactive oxylipins have been increasingly recognized for their complex molecular mechanisms implicated in various diseases. This review aims to summarize recent findings regarding the molecular and immunological mechanisms through which oxylipins contribute to the development of liver injury and failure, with emphasis on both substantial intrahepatic and extrahepatic immune and inflammatory dysregulation associated with ESLD. Furthermore, this review discusses the translational potential of targeting oxylipins for clinical diagnosis, prognosis, and therapeutic intervention in ESLD.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) risk prediction models established in patients with chronic hepatitis B receiving nucleos(t)ide analogue (NA) rarely include viral factors because of mediocre predictability of traditional viral markers. Here, we investigate the role of serum hepatitis B virus (HBV) RNA, a novel biomarker, in predicting HCC risk in NA-treated patients. METHODS: A total of 1374 NA-treated patients were enrolled from 2 prospective chronic hepatitis B cohorts. Serum HBV RNA was detected at baseline, year 1, 2 and 3 of treatment. Cox proportional- hazard model was used to investigate the association of HBV RNA kinetics with HCC risk. RESULTS: After a median follow-up of 5.4 years, 76 patients developed HCC. HBV RNA declines at year 1 (adjusted hazard ratio, 0.70; P = .009) and 2 (adjusted hazard ratio, 0.71; P = .016) were independently associated with HCC risk. Patients with less HBV RNA decline at year 1 (<= 0.4 log10 copies/mL) or 2 (<= 0.6 log10 copies/mL) had 2.22- and 2.09-folds higher HCC risk, respectively, than those with more declines. When incorporating these early on-treatment HBV RNA declines into existing HCC risk scores, including PAGE-B (age, sex, and platelets), modified PAGE-B (mPAGE-B) (age, sex, platelets, and albumin), and aMAP (age, sex, platelets, and albumin-bilirubin score) score, they could enhance their predictive performance (ie, C-index 0.814 vs 0.78 [model (PAGE-B D year-1 HBV RNA decline) vs PAGE-B score based on baseline parameters]). CONCLUSIONS: Serum HBV RNA declines at year 1 and 2 were significantly associated with on-treatment HCC risk. Incorporating early on-treatment HBV RNA declines into HCC risk prediction models can be useful tools to guide appropriate surveillance strategies in NA-treated patients.

We report a case of an adult male with a history of recurrent cough and chest pain for five years. Mycobacterium arosiense was identified in his alveolar lavage fluid, and whole-exome sequencing revealed heterozygosity for CD209 in this patient. After 17 months of combined antibiotic therapy, the patient recovered completely.

Objective Glucocorticoids are vital in treating COVID-19, but standard dosage for noncritical patients remain controversial. To determine the optimal glucocorticoid dosage for noncritical COVID-19 patients, we analyzed factors influencing dosage and developed a predictive model. Methods We retrospectively analyzed 273 noncritical COVID-19 pneumonia patients underwent pulmonary CT and treated with glucocorticoids in a tertiary hospital (12/2022–01/2023). Patients were divided into low and high glucocorticoid dosage groups based on a daily 40mg methylprednisolone or equivalent. Artificial intelligence (AI)-based deep learning was utilized to assess pulmonary CT images for accurate lesion area, which then analyzed through multivariable logistic regression to explore their correlation with glucocorticoid dosage. A predictive model was developed and validated for dosage prediction. Results The primary analysis included 243 patients, with 168 in the training set and 75 in the validation set. High-dose treatment was administered to 139 patients (82.7%) and low-dose to 29 patients (17.3%) in the training cohort. A predictive model incorporating normally inflated ratio, ground-glass opacity (GGO) ratio, and consolidation ratio accurately predicted selection of high- or low-dose, in both training (AUC=0.803) and validation cohorts (AUC=0.836), respectively. In 30 patients with post-CT adjusted dosages, the predicted dosages highly matched with the actual adjusted dosages. Conclusion Glucocorticoid dosages for noncritical COVID-19 pneumonia treatment are influenced by pulmonary CT features. Our predictive model can predict glucocorticoid dosage, however, should be validated by larger, prospective studies.

BACKGROUND AND AIMS:Acute-on-chronic liver failure (ACLF) is driven by systemic inflammation and immune dysregulation. This study aims to characterize the immune landscape in ACLF and identify potential therapeutic targets. APPROACH AND RESULTS:We employed single-cell RNA sequencing, vision spatial sequencing, bulk RNA sequencing, and bioinformatics analysis to profile immune cells in ACLF livers compared to acute liver failure, decompensated cirrhosis, and controls. ACLF livers exhibited a distinct immune signature with increased neutrophils, particularly CCL4 + subsets, which drive unresolved inflammation by recruiting additional neutrophils and inflammatory CD14 + S100A9 + monocytes. Resident KCs were reduced, and monocytes differentiated into TREM2 + macrophages with an M1-like pro-inflammatory phenotype, exacerbating inflammation. Additionally, lymphoid cells showed significant dysfunction, with reduced NK cells and relatively expanded T cells exhibiting diminished cytotoxicity or pro-inflammatory cytokine production. Cell-cell communication analysis identified the ANXA1-FPR1 axis as a key interaction between T cells and myeloid cells, serving as a negative feedback mechanism to dampen inflammation. Plasma and hepatic ANXA1 levels were elevated in ACLF patients, correlating with disease severity. In the preclinical model, the ANXA1 peptide Ac2-26 improved liver function, reduced inflammation, and promoted macrophage polarization from M1 to M2. In vitro, Ac2-26 inhibited CCL4-mediated monocyte chemotaxis and M1 polarization, effects partially blocked by the FPR1 inhibitor Randialic acid B. Mechanically, Ac2-26 activated AMPK and inhibited mTOR signaling. CONCLUSIONS:Our findings provide a comprehensive immune profile in ACLF and highlight ANXA1 as a potential therapeutic target for resolving immune dysregulation and improving outcomes in ACLF.

Aims Acute-on-chronic liver failure (ACLF) frequently develops in patients with compensated liver disease. We aimed to characterize the epidemiological features and mortality rates of ACLF in this population and their changes over time.Methods We performed a meta-analysis of cohort studies on patients with ACLF and compensated liver disease to evaluate pooled baseline characteristics and mortality rates. Literature searches were conducted using EMBASE, PubMed, and the Cochrane Library, covering the period from January 1, 2012, to December 31, 2023. Following Freeman-Tukey double arcsine transformation, pooled estimates of mortality rates and etiological distributions were derived using a random-effects model. Subgroup analyses were performed according to country and period (pre- and post-2014).Results Twenty-four studies involving 4,398 patients were included. The mean age was 48.7 years and 80.4% (3017/3824) were men, after excluding one study based on veterans. The mean Model for End-Stage Liver Disease score was 24.0. Viral hepatitis (42.2%, 2070/4398) and alcohol-related liver disease (ALD) (35.6%, 1328/4283) were the major etiologies of underlying chronic liver disease. Flare-ups of viral hepatitis (24.6%, 788/2263) and alcohol consumption (33.1%, 675/2263) were the predominant acute precipitants. The etiologies of ACLF and types of acute precipitants showed significant regional variation. The pooled 28-day mortality rate among patients with ACLF was 38.6% (1200/3225, 95% confidence interval [CI] 31.5%-45.8%), and the 90-day mortality rate was 45.8% (1625/3565, 95% CI 40.3%-51.4%). Temporal analyses demonstrated a decline in virus-related ACLF, from 42.4% (1012/1761) in the pre-2014 period to 28.2% (490/1169) post-2014, and an increase in ALD-related ACLF, from 31.7% (439/1761) to 48.2% (469/1169).Conclusion The number of patients with ACLF and compensated liver disease remained high, with no improvement over time. The rising prevalence of ALD-related ACLF over the past decade underscores the need for effective therapies for ACLF and preventive strategies for patients with ALD who are at high risk for ACLF.

Donafenib, a deuterium-modified sorafenib derivative, has improved survival outcomes in patients with advanced hepatocellular carcinoma (HCC). This study aimed to investigate the treatment-related adverse events and their associations with overall survival (OS) and time to progression (TTP) in patients with advanced HCC treated with donafenib. In this retrospective analysis, data from 334 patients with unresectable or metastatic HCC who had a Child–Pugh liver function score ≤ 7 and had not received prior systemic treatment were collected from the ZGDH3 study. Donafenib (0.2 g) was administered orally twice daily until either intolerable toxicity or disease progression occurred. The associations between adverse events (AEs) and OS/TTP were analyzed using the Kaplan–Meier method, and statistical significance was tested using the log-rank test. A stratified Cox proportional hazards model was used to estimate hazard ratios (HR) and 95

Background and Aims:Epidemiological data on bacterial infections in cirrhosis in China remain limited. Therefore, we aimed to conduct a multicenter study to investigate the characteristics and outcomes of patients with cirrhosis and bacterial infections in China. Methods:We retrospectively enrolled 1,438 hospitalized adult patients with cirrhosis and bacterial or fungal infections from 24 hospitals across China between January 2018 and September 2024. Data on demographics, clinical features, microbiology, treatment, and outcomes were collected. Results:A total of 1,783 infection episodes were recorded, including 1,668 first infections and 115 second infections. Most infections were community-acquired (86.6%). Pneumonia was the most common infection type (26.7%), followed by spontaneous bacterial peritonitis (19.5%) and spontaneous bacteremia (14.1%). Among 754 pathogens isolated from 620 patients, Klebsiella pneumoniae (20.1%) was nearly as common as Escherichia coli (21.7%). Multidrug-resistant (MDR) organisms accounted for 41.0% of all isolates, with extended-spectrum β-lactamase-producing Escherichia coli being the most prevalent MDR strain (8.9% of patients). Adherence to empirical antibiotic treatment guidelines from the European Association for the Study of the Liver was significantly lower in this cohort compared to the global study (21.5% vs. 61.2%, P < 0.001), accompanied by a lower clinical resolution rate (63.5% vs. 79.8%, P < 0.001). Conclusions:The clinical and microbiological characteristics of bacterial infections in patients with cirrhosis in China differ substantially from those reported in other regions. These findings highlight the need for region-specific management and prevention strategies, particularly in light of the changing microbiological landscape, high MDR prevalence, and suboptimal antibiotic practices.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is now considered to be among the most prevalent chronic liver diseases worldwide. Its comprehensive management encompasses multiple stages, including risk assessment, early detection, stratified intervention, and long-term follow-up. Among these, improving diagnostic accuracy and optimizing individualized therapeutic strategies remain key challenges in both research and clinical practice. In recent years, artificial intelligence and smart devices have developed rapidly and have gradually been applied in the medical field, offering novel tools and pathways for MASLD risk stratification, non-invasive diagnosis, therapeutic evaluation, and patient self-management. This review summarizes the current applications of artificial intelligence and smart devices in MASLD care, highlights their benefits and limitations, and discusses future directions to support precision diagnosis and treatment strategies.

BACKGROUND:Acute-on-chronic liver failure (ACLF) is characterised by intense systemic inflammation and high short-term mortality, yet effective targeted therapies are lacking. OBJECTIVE:To explore monocyte heterogeneity in HBV-related ACLF (HBV-ACLF) to identify specific subsets and associated therapeutic targets. DESIGN:Peripheral blood mononuclear cells from healthy controls (n=4), patients with acute decompensation (n=5), and patients with ACLF (n=9) underwent single-cell RNA sequencing (scRNA-seq). Findings were integrated with hepatic scRNA-seq, bulk transcriptomics, multiplex immunohistochemistry and in vitro functional assays. The in vivo roles of candidate targets were validated in two murine ACLF models. RESULTS:We identified a distinct RETN+ monocyte subset that was expanded in the circulation and liver of patients with HBV-ACLF. These RETN+ monocytes displayed a transcriptional programme enriched for anti-inflammatory and pro-resolving signatures, including MS1-B-like features. Interleukin-6 promoted the expansion of RETN+ monocyte via the JAK/STAT3/RUNX1 signalling axis. In murine ACLF models, neutralisation of Resistin exacerbated liver injury, increased systemic cytokine levels and augmented hepatocyte apoptosis. Conversely, administration of recombinant Resistin mitigated liver damage, diminished levels of inflammatory cytokines and improved survival. Mechanistically, Resistin activated PI3K/AKT signalling in hepatocytes, preserved the Bcl-2/Bax balance and suppressed intrinsic apoptosis. Clinically, plasma Resistin levels in HBV-ACLF patients inversely correlated with systemic inflammatory markers, liver injury, ACLF severity scores (Model for End-Stage Liver Disease, Chronic Liver Failure Consortium ACLF score) and short-term mortality. CONCLUSIONS:RETN+ monocytes constitute a distinct immunoregulatory subset enriched in HBV-ACLF, and their product, Resistin, exerts significant hepatoprotective and anti-inflammatory effects. These findings highlight RETN+ monocytes and Resistin as promising immunotherapeutic targets for HBV-ACLF.

Background: Both entecavir and tenofovir are frequently prescribed for HBV-ACLF, however, their comparative efficacy were not fully clarified. The study aimed to compare the survival, virological and liver function response between patients with entecavir and tenofovir and its analogs. Methods: We retrospectively analyzed 534 patients with HBV-ACLF who were given either entecavir (n= 115) or tenofovir and its analogs (n= 102) in a single medical center in China. The primary endpoints were 28-day and 90-day liver-transplantation-free mortality. Secondary outcomes were changes of serum HBV-DNA and MELD scores. Results: Over 90-day follow-up, 20.9% died in patients with entecavir, and 11.8% in those with tenofovir and its analogs. The cumulative liver-transplantation-free survival rates were similar between the two groups ( 18.2% and 22.2% for 28-day and 90-day mortality in entecavir group; 5.1% and 12.2% for 28-day and 90-day mortality in tenofovir group, respectively, P= 0.003, and 0.060, respectively). In the multivariate Cox proportional hazard analysis adjusting age, cirrhosis, hepatic encephalopathy, ascites, MELD scores, serum HBV-DNA levels and sex, the types of antivirals was not associated to the 90-day mortality (HR: 0.691, 95% CI: 0.337 to 1.42, P=0.314)(entecavir as the reference). The main findings were consistent with that after PSM or by competing risk model. Beside, the decline of serum HBV-DNA levels and improvement of MELD scores were also comparable between the two groups. Conclusion: There was no significant difference in the efficacy of entecavir and tenofovir and analogs in treating patients with HBV-ACLF. There findings suggest both entecavir and tenofovir and its analogs can serve as first-line antivirals for HBV-ACLF.

BACKGROUND AND AIMS:Acute-on-chronic liver failure (ACLF) is a highly dynamic syndrome. The objective of this study was to delineate the clinical course of patients with HBV-ACLF and to develop a model to estimate the temporal evolution of disease severity. METHODS:We enrolled eligible patients from 2 large, multicenter prospective cohorts. The ACLF grade, organ failures, and outcomes were assessed at multiple time points (days 1/4/7/14/21/28). Probabilities for ACLF transitions between these disease states and to death within 28 days were calculated using a multi-state model that used baseline information and updated ACLF status. The model was validated in independent patients. RESULTS:Among all the 445 patients with HBV-ACLF, 76 represented disease progression, 195 had a stable or fluctuating course, 8 with improvement, and the remaining 166 with resolution within 28-day follow-up. New coagulation (63.64%) or renal failure (45.45%) was frequently observed during early progression. Patients with disease progression had a higher incidence of new episodes of ascites [10 (13.16%) vs. 22 (5.96%), p = 0.027] and HE [13(17.11%) vs. 21 (5.69%), p = 0.001], and a significant increase in white blood cell count. The multi-state model represented dynamic areas under the receiver operating characteristic curves ranging from 0.71 to 0.84 for predicting all ACLF states and death at 4, 7, 14, 21, and 28 days post-enrollment and from 0.73 to 0.94 for predicting death alone, performing better than traditional prognostic scores. CONCLUSIONS:HBV-ACLF is a highly dynamic syndrome with reversibility. The multi-state model is a tool to estimate the temporal evolution of disease severity, which may inform clinical decisions on treatment.

Acute-on-chronic liver failure (ACLF) and decompensated cirrhosis (DC) are life-threatening syndromes that can develop at the end-stage of chronic hepatitis B virus (HBV) infection. Both ACLF and DC are complicated by hepatic and extrahepatic pathogeneses. To better understand the compartment-specific metabolic modulations related to their pathogenesis, HBV-DC, HBV-ACLF patients, and controls (30 each) were analyzed by metabolomics using portal (Port), hepatic vein (Hep), and peripheral (Peri) serum. Compartment ratios of metabolites (RatioHep/Port, RatioPeri/Hep, and RatioPort/Peri) were calculated. The liver tissues (10 per group) were analyzed using transcriptomics and metabolomics. An additional 75 patients with ACLF, 20 with DC, and 20 with liver cirrhosis (LC) were used to confirm oxlipid dysregulation. Both multi-omics datasets suggest suppressed energy, amino acid, and pyrimidine metabolism in the ACLF/DC liver. The serum metabolomic variations were contributed primarily by disease rather than sampling compartments, as both HBV-ACLF and HBV-DC patients demonstrated abnormal profiles of amino acids and peptides, indoles, purines, steroids, and benzimidazoles. In ACLF/DC patients, impaired hepatic metabolism resulted in a highly correlated hepatic and portal vein serum metabolome and release of inflammatory lipids and heme metabolites from the liver. HBV-ACLF showed higher RatioPeri/Hep of extrahepatic inflammatory oxlipids, while HBV-DC patients showed higher RatioPort/Peri of gut microbial metabolites. An inflammatory oxlipid outburst was confirmed in the early stages of HBV-ACLF. The inflammatory effects of the selected oxlipids were confirmed in monocytes. These findings support a synergy between liver-specific mechanisms and systemic inflammation in ACLF/DC development, and that pro-inflammatory oxlipids are metabolic signatures of early HBV-ACLF.

Background The model for end-stage liver disease (MELD) score is widely used for the prognostication in end-stage liver disease but has limited performance in acute-on-chronic liver failure (ACLF). In this study, we identified additional predictive parameters and reformed the MELD score to predict ACLF more accurately.Methods A meta-analysis was performed on relevant studies to identify the predictive factors of 28-day/90-day outcomes of ACLF, which were validated in two large prospective cohorts. A prognostic score was developed by incorporating predictive parameters into the MELD score. The model was evaluated with a focus on discrimination and calibration.Results The meta-analysis incorporated 32 cohort studies with a total of 13 939 patients, of which 13 risk factors were identified, and 3 risk factors (age, neutrophil count and hepatic encephalopathy (HE) grade) besides MELD score were validated in 751 patients with ACLF derived from two prospective cohorts. A new model (Chinese Acute-on-Chronic Liver Failure Consortium (CATCH-LIFE)-MELD score) was developed as follows: 0.028×age+0.3×HE grade+0.039×neutrophil count+0.079×MELD score. CATCH-LIFE-MELD score achieved a concordance index of 0.791/0.788 for 28-day/90-day outcomes, which is superior to other traditional scores. Other discrimination indices, including net reclassification improvement, integrated discrimination improvement and probability density function, and calibration including Nagelkerke’s R2 and Brier scores confirmed its superiority. Moreover, the accuracy of CATCH-LIFE-MELD score remained stable. It was highest in patients with or without hepatitis B virus infection, cirrhosis, liver failure or under the Chinese Group on the Study of Severe Hepatitis B (COSSH) criteria or European Association for the Study of the Liver (EASL) criteria. All results were substantiated by an evaluation using an external cohort.Conclusions CATCH-LIFE-MELD score, a modified MELD score exhibited improved accuracy in predicting the short-term prognosis of ACLF than other traditional scores.

BackgroundChronic hepatitis B (CHB) imposes substantial economic and social burdens globally. The management of CHB involves intricate monitoring and adherence challenges, particularly in regions like China, where a high prevalence of CHB intersects with health care resource limitations. This study explores the potential of ChatGPT-3.5, an emerging artificial intelligence (AI) assistant, to address these complexities. With notable capabilities in medical education and practice, ChatGPT-3.5’s role is examined in managing CHB, particularly in regions with distinct health care landscapes. ObjectiveThis study aimed to uncover insights into ChatGPT-3.5’s potential and limitations in delivering personalized medical consultation assistance for CHB patients across diverse linguistic contexts. MethodsQuestions sourced from published guidelines, online CHB communities, and search engines in English and Chinese were refined, translated, and compiled into 96 inquiries. Subsequently, these questions were presented to both ChatGPT-3.5 and ChatGPT-4.0 in independent dialogues. The responses were then evaluated by senior physicians, focusing on informativeness, emotional management, consistency across repeated inquiries, and cautionary statements regarding medical advice. Additionally, a true-or-false questionnaire was employed to further discern the variance in information accuracy for closed questions between ChatGPT-3.5 and ChatGPT-4.0. ResultsOver half of the responses (228/370, 61.6%) from ChatGPT-3.5 were considered comprehensive. In contrast, ChatGPT-4.0 exhibited a higher percentage at 74.5% (172/222; P<.001). Notably, superior performance was evident in English, particularly in terms of informativeness and consistency across repeated queries. However, deficiencies were identified in emotional management guidance, with only 3.2% (6/186) in ChatGPT-3.5 and 8.1% (15/154) in ChatGPT-4.0 (P=.04). ChatGPT-3.5 included a disclaimer in 10.8% (24/222) of responses, while ChatGPT-4.0 included a disclaimer in 13.1% (29/222) of responses (P=.46). When responding to true-or-false questions, ChatGPT-4.0 achieved an accuracy rate of 93.3% (168/180), significantly surpassing ChatGPT-3.5’s accuracy rate of 65.0% (117/180) (P<.001). ConclusionsIn this study, ChatGPT demonstrated basic capabilities as a medical consultation assistant for CHB management. The choice of working language for ChatGPT-3.5 was considered a potential factor influencing its performance, particularly in the use of terminology and colloquial language, and this potentially affects its applicability within specific target populations. However, as an updated model, ChatGPT-4.0 exhibits improved information processing capabilities, overcoming the language impact on information accuracy. This suggests that the implications of model advancement on applications need to be considered when selecting large language models as medical consultation assistants. Given that both models performed inadequately in emotional guidance management, this study highlights the importance of providing specific language training and emotional management strategies when deploying ChatGPT for medical purposes. Furthermore, the tendency of these models to use disclaimers in conversations should be further investigated to understand the impact on patients’ experiences in practical applications.