Mingqin Lu

Acute liver failure (ALF) is characterized by a rapid deterioration of liver function in a very short period of time, with a variety of etiological factors and complex pathogenic mechanisms, for which there are no effective therapeutic options. Recent studies have demonstrated that endotoxin-tolerant dendritic cells (ETDC) possess anti-inflammatory properties, typically established in response to repeated lipopolysaccharide (LPS) stimulation. However, living cells are extremely unstable in vivo , so we fabricated exosome mimics (EM), which have higher yields and are simpler and more convenient to handle than conventional exosome properties. Polyvinylpyrrolidone-stabilised iridium nanoparticles (Ir NPs-PVP) have been reported as enzyme mimics with peroxidase- and catalase-like activities and have been shown to be effective in scavenging reactive oxygen species at the cellular level. The aim of this paper is to investigate the palliative effect of ETDC-derived mimetic vesicles loaded with PVP-IrNPs on ALF. The results showed that the combination of ETDC-derived mimetic vesicles and Ir NPs-PVP had anti-inflammatory and antioxidant effects, which effectively alleviated the damage induced by ALF, and is expected to be a novel therapeutic agent for the clinical treatment of ALF.

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 × 10 ⁹ /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 × 10 ⁹ /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 × 10 ⁹ /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 × 10 ⁹ /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.

INTRODUCTION: Nosocomial infections (NIs) in cirrhosis are associated with high mortality but could be preventable. Logistic regression (LR) models have failed to identify high-risk patients. We aimed to develop machine learning (ML) models to predict NI. METHODS: The CLEARED consortium consists of prospectively enrolled cirrhosis inpatients from >120 centers. Using day-of-admission clinical data, 3 ML approaches (random forest [RF], extreme gradient boosting, and neural networks [NNs]) were used to predict NI. Data were split 80:20 for training and testing stratified by the outcome. Models were compared using area under the receiver operating characteristic curve (AUC). RESULTS: In total, 8,263 patients (55.90 ± 13.34 years; 64.1% men) from 127 centers in 37 countries were included. NI developed in 869 (10.5%), a median of 6 (4–11) days of postadmission. Major NIs were respiratory (29.6%) and urinary tract infection (15.7%), and spontaneous bacterial peritonitis (13.5%). NIs occurred more frequently in patients from low/low-middle income countries and those with severe liver disease, alcohol etiology, and admission infections. NIs were associated with inpatient mortality (31.9% vs 8.1%, P < 0.001) and liver transplantation (4.8% vs 1.9%, P < 0.001). Although the RF model (AUC 0.69) showed good calibration (Brier score 0.09), outperforming extreme gradient boosting, neural network, and LR models (AUC 0.66 for all; LR comparison P = 0.043), no model achieved AUC ≥0.80 for clinical utility. At 10% predicted probability threshold, the RF model demonstrated only 75.4% sensitivity, 52.9% specificity, and 15.9% positive predictive value (PPV). DISCUSSION: NIs cannot be accurately predicted from day-of-admission data using ML models, even in a large, prospective, global cirrhosis cohort. Every hospitalized patient with cirrhosis should receive protocolized infection control measures.

Background: HBV infection continues to pose a significant global health challenge, particularly in patients with normal alanine aminotransferase (ALT) level. The increasing prevalence of Metabolic dysfunction-associated steatotic liver disease (MASLD) among individuals with chronic hepatitis B (CHB) also presents new complications in management. The study aimed to investigate the relationship between MASLD and HBV DNA clearance in CHB patients with normal ALT.Methods: 403 patients with ALT levels below the normal threshold who underwent liver biopsy at our institution and subsequently received antiviral therapy with NAs were retrospectively examined. Among these, 177 patients were diagnosed with MASLD. Further single cell data analysis was conducted on GSE192740 and GSE182159.Results: CHB patients concurrent with MASLD had a higher probability of achieving HBV DNA clearance. The proportion of CD8+Teff-GZMH cells was increased in the MASLD group. The interactions among CD8+ Trm-CD69 cells and other T cell subtypes were enhanced, especially within the active CCL-CCR pathways. An elevated proportion of Monocyte-THBS1 was also observed.Conclusions: CD8+ Trm-CD69 T cells may be activated by Monocyte-THBS1 cells, thereby stimulating the immune system via the CCL-CCR signaling axis. This activation facilitates the recruitment of immune cells and enhances the clearance of hepatitis B virus (HBV).

HBV infection is a global health issue. Given the severity of decompensated cirrhosis, selecting the most appropriate first-line antiviral medication is crucial for optimizing treatment outcomes and providing the best possible disease control. This retrospective real-world study aimed to evaluate the comparative effectiveness and safety profiles of tenofovir alafenamide (TAF) versus tenofovir disoproxil fumarate (TDF) in patients with hepatitis B virus (HBV)-related decompensated cirrhosis. We hypothesised that TAF is non-inferior to TDF for virologic response and superior for renal safety, with corresponding statistical tests to assess non-inferiority and superiority. Patients receiving TAF or TDF were categorized into respective groups based on their treatment regimen. The study spanned 48 weeks, during which the impact on HBV replication, liver enzyme levels, and renal function was assessed. Propensity score matching (PSM) was utilized to minimize disparities between TAF and TDF cohorts. After 48-week treatment, the percentage of patients with detectable HBV DNA significantly decreased from 27.9 to 13.1% (p = 0.044). HBeAg positivity remained stable, increasing slightly from 27.9 to 31.15% (p = 0.887). Mean ALT levels decreased slightly from 26 U/L to 25 U/L, with 85.25% of patients achieving normal ALT levels by week 48. TAF was well-tolerated with no significant impact on renal function, as indicated by stable serum creatinine and eGFR levels (eGFR decline ≥ 25% occurred in 5.2%). After PSM (propensity score matching), both groups showed virologic suppression, but TAF demonstrated superior renal safety: serum creatinine remained stable in TAF (P = 0.921) versus a trend toward increase in TDF (P = 0.831); eGFR significantly declined in TDF (103.58 → 99.05 mL/min/1.73 m²) but remained stable in TAF (101.88 → 101.86 mL/min/1.73 m²); clinically relevant eGFR decline (≥ 25%) was lower with TAF (5.2% vs. 10.5% in TDF). TAF also showed a higher rate of ALT normalization (71.1% → 81.6%, P < 0.05) compared to stable rates in TDF (84%). For liver fibrosis markers, APRI scores decreased non-significantly in TAF (P = 0.365) but increased in TDF (P = 0.763), while FIB-4 scores slightly decreased in TAF (P = 0.527) versus a non-significant increase in TDF. Child-Pugh scores remained minimally changed in both groups. TAF appears to offer similar virologic response rates to TDF, with potentially superior renal safety. This study provides valuable insights into the management of HBV-related decompensated cirrhosis, advocating for TAF’s consideration in treatment protocols. All procedures were performed in accordance with the guidelines of the institutional ethics committee and adhered to the tenets of the Declaration of Helsinki. This study was approved by the Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University, China, which also waived the need for informed consent (approval number: KY2024-101). The registration date is April 24, 2024.

Liver cancer poses a significant global health challenge. Smoking and alcohol consumption are major risk factors for liver cancer. We analyzed data from the Global Burden of Disease (GBD) Study 2021. First, numbers and age-standardized rates of deaths and disability-adjusted life years (DALYs) were assessed globally and by sub-types in 2021. Furthermore, the temporal trend of the disease burden was explored by the linear regression model from 1990 to 2019. Based on the EAPC values, we conducted a hierarchical cluster analysis to categorize the 54 GBD regions into four groups. To explore potential associations between the EAPCs and socioeconomic factors, we employed the Spearman correlation analysis to evaluate the correlation between EAPCs and ASRs, as well as Human Development Index (HDI) scores. Finally, frontier analysis was used to visually demonstrate the potential for burden reduction in each country or region based on their development levels. All analyses were conducted using R software. From 1990 to 2021, the burden of liver cancer attributed to alcohol consumption increased significantly, whereas age-standardized rates (ASRs) remained relatively stable compared to those associated with smoking.In 2021, the number of deaths and disability-adjusted life years (DALYs) due to smoking-related liver cancer were 53,054 (95% uncertainty interval [UI]: 18,268–88,111) and 1,482,896 (95% UI: 505,000–2,478,906), respectively. The corresponding age-standardized rates (ASRs) were 0.61 per 100,000 population (95% UI: 0.21–1.01) for mortality and 16.9 per 100,000 (95% UI: 5.76–28.26) for DALYs. The estimated annual percentage changes (EAPCs) for these ASRs were − 0.84 (95% confidence interval [CI]: -0.96 to -0.73) for mortality and − 1.12 (95% CI: -1.24 to -1.01) for DALYs.Conversely, in 2021, deaths and DALYs attributable to alcohol-related liver cancer totaled 93,807 (95% UI: 77,476–113,542) and 2,385,090 (95% UI: 1,949,109–2,911,783), respectively. The corresponding ASRs were 1.08 per 100,000 (95% UI: 0.89–1.30) for mortality and 27.2 per 100,000 (95% UI: 22.25–33.1) for DALYs. The EAPCs were 0.26 (95% CI: 0.19–0.32) for mortality and 0.04 (95% CI: -0.03 to 0.10) for DALYs. Males, middle-aged, and older adults were high-risk populations, and middle socio-demographic index (SDI) regions were high-risk areas. The Western Pacific had the highest ASDR for smoking-related liver cancer, while East Asia recorded the highest ASDAR. For alcohol-related liver cancer, the Commonwealth High-Income region exhibited the highest ASDR, whereas Australasia had the highest ASDAR. Andean Latin America had the lowest ASRs for both smoking- and alcohol-related liver cancer. Notably, Mongolia had the highest ASRs for liver cancer attributed to both smoking and alcohol consumption, with values hundreds of times greater than those in the country with the lowest burden, Morocco. Although the ASRs of smoking-related liver cancer have continued to decline, the absolute number of cases remains high, and the burden of alcohol-related liver cancer continues to rise. Consequently, the overall disease burden associated with smoking and alcohol consumption remains significant, highlighting the urgent need for more effective risk factor control strategies. Furthermore, the establishment of accurate and efficient screening systems, as well as specialized cancer treatment centers, is imperative—particularly for high-risk populations, such as middle-aged and elderly men, and for high-risk regions classified as High and Middle SDI areas.

Background: Positive blood cultures for Klebsiella pneumoniae liver abscess (KPLA) are associated with an increased risk of extrahepatic organ infections and severe complications such as septicemia and septic shock, leading to higher mortality rates. This study aimed to investigate the clinical characteristics of patients with blood culture-positive KPLA and identify potential predictive indicators. Methods: We performed a retrospective analysis of clinical data from 263 KPLA patients diagnosed at our hospital between January 2019 and December 2023. The objective was to compare clinical characteristics between patients with positive and negative blood cultures and explore factors influencing blood culture positivity. Patients were divided into a blood culture-positive group (study group) and a blood culture-negative group (control group). We compared baseline characteristics, laboratory parameters, ultrasound findings, and complications. Logistic regression identified risk factors, and receiver operating characteristic (ROC) curves assessed the predictive value of inflammatory markers. Results: The study group exhibited higher ICU admission rates, longer hospital stays, and elevated qSOFA scores (≥ 2, 15.1 vs 2.6, P=0.003) along with a greater prevalence of diabetes and biliary diseases. Key laboratory values, including glucose, creatinine, procalcitonin (PCT), and C-reactive protein (CRP), were significantly higher, while albumin and platelet levels were lower (P < 0.05). Complications such as pleural effusion (35.1 vs 12.8, P< 0.001), ascites (15.1 vs 2.6, P=0.003), pulmonary infections (27.6 vs 7.7, P< 0.001), and extrahepatic abscesses (15.7 vs 5.1, P=0.018) were notably more common. Diabetes was identified as an independent risk factor for blood culture-positive KPLA. Among inflammatory markers, PCT showed the highest predictive value for blood culture positivity (AUC=0.683; cutoff=4.97 ng/mL; sensitivity=70.3%; specificity=62.8%). Conclusion: Patients with underlying diabetes mellitus are more prone to developing blood culture-positive KPLA. PCT demonstrates better predictive performance for blood culture-positive KPLA, and patients with PCT levels ≥ 4.97 ng/mL have a higher likelihood of positive blood culture results.

Objective: To analyze the clinical features of elderly patients with blood culture-positive bacterial liver abscess (BLA) and improve diagnostic and treatment strategies.Methods: Elderly BLA patients admitted to our hospital from December 2018 to December 2023 were included in the study. Diagnostic tests included routine blood analysis, biochemistry, C-reactive protein (CRP), procalcitonin (PCT), imaging, and cultures of blood or pus. Treatments involved anti-infective therapy, ultrasound-guided abscess drainage, and supportive care.Results: (1) Elderly patients with blood culture-positive BLA had higher rates of prolonged hospital stays (≥2 weeks), ICU admission, biliary system diseases, hepatitis B infection, maximum body temperature ≥ 39°C, and qSOFA scores ≥2 compared to controls (p < 0.05)0. (2) Laboratory findings showed higher levels of total bilirubin (≥34.2 μmol/L), ALT (≥50 U/L), serum creatinine (≥80 μmol/L), PCT (≥5 ng/mL), and lower platelet counts (≤100 × 10⁹/L) in the research group (p < 0.05). ESBL-positive cases and liver abscesses ≤5 cm were more common in the research group (p < 0.05). (3) Complications such as pleural effusion, ascites, pulmonary infections, and extrahepatic abscesses were significantly more frequent in the blood culture-positive group (p < 0.05). (4) Microbiological analysis indicated that Klebsiella pneumoniae was the leading pathogen (87.93%), followed by Escherichia coli. For ESBL-positive infections, E. coli was dominant (75.76%), especially in patients with biliary diseases (75.56%). (5) Logistic regression identified prolonged hospital stay, hepatitis B infection, biliary system diseases, temperature ≥ 39°C, PCT ≥5, and abscess size ≤5 cm as independent risk factors for blood culture-positive BLA. (6) The combined diagnostic indicator showed good predictive ability (AUC = 0.840, sensitivity 76.6%, specificity 72.2%).Conclusion: Elderly patients with biliary diseases, hepatitis B, high PCT levels (≥5 ng/mL), small abscesses (≤5 cm), and fever (≥39°C) are at higher risk for blood culture-positive BLA. Klebsiella pneumoniae remains the predominant pathogen (87.93%), highlighting the need for prompt empirical antibiotic therapy. The combined diagnostic model offers reliable predictive value for this condition. We developed a predictive model aimed at assisting clinicians in identifying high-risk patients prone to bloodstream infections secondary to BLA. This model provides valuable guidance for clinicians in formulating more rational and individualized treatment strategies.

Background and aims: Traditional observational studies have yielded inconsistent findings regarding the association between COVID-19 and HBV/HIV infections, as well as the protective effects of antiviral therapy against severe COVID-19. This study aimed to investigate the potential links between the current use of antiviral therapy and the rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and symptoms of infection in patients with SARS-CoV-2 and HBV/HIV.Methods: Using a questionnaire-based survey, we recorded whether participants had been infected with SARS-CoV-2, and the symptoms and severity of COVID-19 after the illness.Results: Among 756 participants, chi-square tests showed a higher incidence of COVID-19 in the HBV infection group (75.6%, p = 0.047) and the HIV infection group (77.6%, p = 0.036). These two groups exhibited fewer symptoms than the control group (p < 0.001). The differences in the prevalence of most symptoms were also significant.Conclusion: Our findings suggest that patients with HBV or HIV infection have a higher risk of contracting SARS-CoV-2 than the general population; however, antiviral treatment relieves the symptoms of COVID-19.

Objective: Endotoxin tolerance (ET) has been demonstrated to attenuate the inflammatory response in murine models of sepsis. This study seeks to elucidate the underlying mechanisms by which ET modulates inflammation in sepsis, with a particular focus on macrophage autophagy. Methods: An in vivo sepsis model was generated using cecal ligation and perforation, while an in vitro model of inflammatory injury was induced via lipopolysaccharide (LPS) administration. ET was established through pretreatment with low-dose LPS. Subsequent analyses were conducted to assess the presence of the NLRP3 inflammasome, autophagic flux, and the expression levels of TRIM26. Results: Heightened inflammation was observed in the TNF-α levels and various organs of the sepsis group; conversely, inflammation was reduced in the group receiving ET treatment. Upon stimulation with LPS, primary mouse peritoneal macrophages exhibited activation of the NLRP3 inflammasome and autophagy, accumulation of mitochondrial reactive oxygen species, compromised membrane potential, resulting in cell apoptosis, and decreased expression of TRIM26. ET was found to enhance autophagy, suppress the activation of NLRP3 inflammasomes, and upregulate the expression of TRIM26. Interestingly, modulation of autophagy levels either reversed or intensified the protective effects of ET on macrophages in vitro . Knockdown of TRIM26 using small interfering RNA (siRNA) resulted in increased NLRP3 inflammasome activation and accumulation of P62. Conclusion: We reveal that ET restores the autophagic flux in macrophages, inhibit NLRP3 inflammasome activation, and mitigate inflammatory damage in septic mice, potentially through the regulation of TRIM26.