Background:Sepsis accounts for a significant proportion of global deaths and has limited treatment options. Cancer patients are at a higher risk of sepsis and experience worse outcomes, highlighting the complex interplay between sepsis and cancer on immune cell function and clinical prognosis. Methods:Between July and December 2023, we prospectively enrolled 30 sepsis patients and 10 healthy controls, categorizing the patients into sepsis with non-cancer and sepsis with cancer based on established clinical diagnostics. Multi-color flow cytometry was used to monitor changes in the expression of surface molecules of monocyte and neutrophil subsets, phagocytic activity and cytokine-producing capacity. Results:Compared with sepsis with non-cancer, the sepsis with cancer group demonstrated elevated 28-day mortality rates, increased CD177+ activated band neutrophil and HLA-DRlowCCR2low classical monocyte, and attenuated phagocytic activity of immature neutrophil and monocyte. Further, HLA-DRlowCCR2low classical monocytes and CD177+ myelocytes may serve as immunological predictors of adverse outcomes in sepsis. The HLA-DRlowCCR2low classical monocyte and CD177+ myelocytes exhibit significant correlations with internal environment and coagulation markers. Conclusion:In septic patients, particularly those patients with cancer, attenuated phagocytic activity of immature neutrophil (myelocytes, metamyelocytes, band neutrophils) and monocyte, and HLA-DRlowCCR2low classical monocyte and CD177+ myelocytes may serve as immunological predictors of poor prognosis.

Early identification of significant liver pathology is crucial for timely antiviral intervention in individuals with chronic hepatitis B (CHB) infection. Current non-invasive methods show limited accuracy in detecting occult liver damage, particularly in those with normal ALT. This study evaluated serum N-glycan profiles for diagnosing significant liver pathology in treatment-naïve CHB patients across clinical phases. This cross-sectional study analyzed 626 treatment-naïve CHB patients confirmed by liver biopsy, classified according to 2025 EASL guidelines. Serum N-glycan profiles were determined using DNA sequencer-assisted fluorophore-assisted carbohydrate electrophoresis. Significant liver pathology was defined as inflammation grade ≥ G2 and/or fibrosis stage ≥ S2 (per Scheuer scoring system). Multivariate logistic regression models were developed and compared with traditional non-invasive markers. Among 626 CHB patients, 66.0

We aimed to assess the risk of portal vein thrombosis (PVT) in patients with hepatitis B-related cirrhosis (HBC) using artificial neural networks (ANN). PVT can exacerbate portal hypertension and lead to complications, increasing the risk of mortality. Unfortunately, accurate prediction models for PVT in hepatitis B cirrhosis patients are currently insufficient. To address this gap, we conducted a study at Beijing Ditan Hospital, affiliated with Capital Medical University, involving 986 hospitalized patients. The patients were randomly divided into a training set (685 cases) and a validation set (301 cases) using a 3:1 ratio. Through univariate analysis, we determined independent factors that influence the occurrence of PVT, which were then utilized to develop an ANN model. The performance of the ANN model was assessed using various indicators, such as the area under the receiver operating characteristic curve (AUC) and concordance index (C-index). In the training group, PVT developed within three years in 19.0% of patients, and within five years in 23.7% of patients. Similarly, in the validation group, PVT developed within three years in 16.7% of patients, and within five years in 24.0% of patients. The ANN model incorporated nine independent risk factors, including age, presence of ascites, manifestation of hepatic encephalopathy (HE), occurrence of gastrointestinal varices with bleeding, Child-Pugh classification, alanine transaminase (ALT) levels, albumin (ALB) levels, neutrophil-to-lymphocyte ratio (NLR), and platelet count (PLT). Importantly, the AUC of the ANN model was significantly higher at 0.9718 compared to existing models such as MELD and CTP (all p<0.001). Our ANN model effectively classified patients into high ,medium, and low risk groups for PVT development over a span of 3 and 5 years. These findings were further validated in an independent cohort.

Yu Hao School of Graduate, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, 150006, People’s Republic of ChinaCorrespondence: Yu Hao, School of Graduate, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, 150006, People’s Republic of China, Email tg2605330019@163.com

Background Familial hypercholesterolemia (FH) is a common inherited metabolic disease that causes premature atherosclerosis, cardiovascular disease, and even death at a young age. Approximately 95% of FH-causing genetic variants that have been identified are in the LDLR gene. However, only 10% of the FH population worldwide has been diagnosed and adequately treated, due to the existence of numerous unidentified variants, uncertainties in the pathogenicity scoring of many variants, and a substantial number of individuals lacking access to genetic testing.Objective The aim of this study was to identify a novel variant in the LDLR gene that causes FH in a Chinese family, thereby expanding the spectrum of FH-causing variants.Methods Patients were recruited from Beijing Anzhen Hospital, Capital Medical University. FH diagnosis was made according to the Dutch Lipid Clinical Network (DLCN) criteria. Whole-exome sequencing (WES) was conducted to identify the FH-causing variant in the proband, and amplicon sequencing was used to verify the variant in his family members.Results A three-generation Chinese family was recruited, and two FH patients were clinically diagnosed, both without known FH-causing variants. These two FH patients and another possible patient carried a novel variant, NC_000019.9(NM_000527.5):c.89_92dup (NP_000518.1:p.Phe32Argfs*21), in the ligand-binding domain of the low-density lipoprotein (LDL) receptor that led to a frameshift. The FH adults in the family showed severe clinical symptoms and statin therapy resistance.Conclusion This study identified a novel pathogenic LDLR variant, c.89_92dup, associated with severe FH clinical manifestations and statin therapy resistance.

BACKGROUND:Neurocognitive impairment, including minimal hepatic encephalopathy (MHE) and overt hepatic encephalopathy, is one of the most common complications of all types of primary liver diseases, such as hepatitis B, biliary cholangitis, and autoimmune hepatitis. The EncephalApp Stroop test is a smartphone application-based test that is time-saving for MHE screening. However, neurocognitive impairment is different between alcoholic cirrhosis patients and nonalcoholic cirrhosis patients, so the cutoff value for MHE diagnosis might be inflated. AIM:To validate the Stroop test in nonalcoholic cirrhosis patients. METHODS:This external validation was performed at the National Center for Infectious Diseases (Beijing). Liver cirrhosis patients aged between 18 and 65 years who voluntarily enrolled in the study and provided signed informed consent were included. The Psychometric Hepatic Encephalopathy Score (PHES) test was used as the standard diagnostic criterion for MHE. The EncephalApp Stroop test was then performed on the iPad, including two sessions of tests ("off" and "on") to measure patients' ability to differentiate between numbers and letters. We assessed the performance of the EncephalApp Stroop test in terms of the area under the curve (AUC), sensitivity, specificity, positive predictive value, and negative predictive value, with the PHES as the standard criterion. RESULTS:A total of 160 nonalcoholic cirrhosis patients were included in this validation study, including 87 (54.4%) patients without MHE and 73 (45.6%) patients with MHE. Taking the PHES as the gold standard, the EncephalApp Stroop test performed well for nonalcoholic liver cirrhosis patients in terms of "off" time [AUC: 0.85, 95% confidence interval (CI): 0.79-0.91] and "on + off" time (AUC: 0.85, 95%CI: 0.80-0.91); however, total runs of "off" session (AUC: 0.61, 95%CI: 0.52-0.69), total runs of "on" session (AUC: 0.57, 95%CI: 0.48-0.65), and "on - off" time (AUC: 0.54, 95%CI: 0.44-0.63) were comparatively low. The optimal cutoff points were "off" time > 101.93 seconds and "on + off" time > 205.86 seconds, with sensitivities of 0.84 and 0.90, specificities of 0.77 and 0.71, positive predictive values of 0.75 and 0.72, and false-positive values of 0.85 and 0.89, respectively. CONCLUSION:Our results suggest that different cutoffs should be used for the EncephalApp Stroop tool for MHE screening between alcoholic and nonalcoholic living patients, which is a critical check before generalization to screen for neurocognitive impairment among the whole population of chronic liver diseases.

ETHNOPHARMACOLOGICAL RELEVANCE:Polygonum multiflorum Radix (PMR) is the dried root tuber of Polygonum multiflorum Thunb., which has been used in the clinic for a variety of pharmacological activities. However, Polygonum multiflorum Radix-induced liver injury (PMR-ILI) has been reported in recent years, which has limited its clinical use to some extent. The occurrence of PMR-ILI is not universal, so finding the different metabolic characteristics between PMR-ILI and Polygonum multiflorum Radix-tolerance group (PMR-T) is very important for the PMR rational clinical application and PMR-ILI early clinical diagnosis.METHODS:In this study, 6 clinical plasma samples of PMR-ILI and 13 PMR-T were collected and analyzed by high-resolution liquid chromatography-mass spectrometry. Firstly, the differential metabolites of the two groups were screened by conventional screening methods such as multivariate statistical analysis. Secondly, the characteristic metabolites with greater contribution, correlation with liver injury and high sensitivity were screened by correlation analysis with clinical liver injury indicators, random forest analysis, and receiver operating characteristic curve (ROC).RESULTS:After multivariate statistical analysis and screening analysis, 29 differential metabolites were identified. Compared with PMR-T group, the metabolism of glycerol and phospholipid, glutamine and glutamate, phenylalanine, sphingolipid and tryptophan in PMR-ILI group were disturbed. After correlation analysis with liver injury indexes and random forest screening, 8 potential biomarkers closely related to clinical liver injury were obtained. Finally, 3 potential biomarkers with high expression in PMR-ILI, hypoxanthine, LysoPC(P-16:0/0:0) and taurochenodesoxycholic acid, were screened out through the analysis of ROC, which can provide a basis for the early clinical diagnosis.CONCLUSION:Based on the analysis of the PMR-ILI and PMR-T plasma samples by LC-MS, three biomarkers of clinical liver injury of Polygonum multiflorum Radix were selected: hypoxanthine, LysoPC(P-16:0/0:0) and taurochenodeoxycholic acid.

The pathogenesis of liver fibrosis in nonalcoholic fatty liver disease (NAFLD) remains unclear and the effective treatments have not been explored yet. The activation of hepatic stellate cells (HSCs) is considered as the most critical factor in the progression of liver fibrosis and cirrhosis. Autophagy has recently been identified as a new mechanism to regulate HSC activation. Here, we found that liver macrophages were polarized toward type 2 (M2) during the progression of nonalcoholic steatohepatitis (NASH) and liver fibrosis in both patients and NAFLD mice. Using the methionine–choline-deficient (MCD) diet NAFLD murine model and the in vitro cell culture system, we identified that the M2 macrophages promoted HSC autophagy by secreting prostaglandin E2 (PGE2) and binding its receptor EP4 on the surface of HSCs, which consequently enhanced HSC activation, extracellular matrix deposition, and liver fibrosis. Mechanistically, PGE2/EP4 signals enhanced HSC autophagy through the Erk pathway. A specific PGE2/EP4 antagonist E7046 significantly inhibited M2 macrophage-mediated HSC autophagy and improved liver fibrosis and histopathology in NAFLD mice. Our study provides novel mechanistic insights into the regulation of HSC activation and liver fibrosis. Our findings suggest that the PGE2/EP4 pathway is a promising therapeutic target to prevent NASH progression into cirrhosis.

The fundamental basis for the pathogenesis of sepsis is an inflammatory imbalance, which is considered to be the main target for treatment. Taurine is an intracellular free amino acid that has anti-inflammatory and antioxidant effects. To investigate the protective mechanism of taurine in sepsis, we used in vitro and in vivo experiments to explore the effects of taurine on neutrophil and monocyte immune function. Metabolomic analysis showed large amounts of taurine in neutrophils and monocytes and a dramatic decrease in taurine levels after LPS exposure. Taurine supplementation decreased the expressions of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) in LPS-challenged neutrophils and monocytes and reduced the formation of neutrophil extracellular traps by restricting reactive oxygen species. Moreover, taurine protected septic mice from death, improved tissue injuries in the lung, liver, and kidney by reducing neutrophil infiltration and TNF-α production. Our data indicate that a supplement with taurine might be a promising therapeutic strategy for sepsis to reduce hyper inflammation and improve multi-organ dysfunctions.

Objectives: Transmitted drug resistance (TDR) is a critical ongoing public health challenge in HIV/AIDS therapy. We explore the prevalence of TDR, its patterns, its associated risk factors, and predicted drug sensitivity in Beijing between 2015 and 2018. Methods: Retrospective data on TDR from 3265 antiretroviral therapy (ART)-naive patients were collected at Beijing Ditan Hospital from 1 August 2014 to 31 July 2018. TDR was defined according to the Stanford Drug Resistance Mutations Database. TDR prevalence, pattern, risk factors, and predicted drug sensitivity were analysed. Results: The overall prevalence of HIV-1 TDR was 6.68% (218 of 3265), including 0.77%, 3.64%, and 2.36% resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs), and protease inhibitors, respectively. The thymidine analogue mutations (TAMs) M41L/LM (4, 0.12%) and non-TAMs mutations M184V/MV/MI (8; 0.24%) were the primary NRTI-associated resistance mutations. K103N/KN (NNRTI associated) and M46L/I/IMV/IM/ML (protease inhibitor associated) were the other major resistance mutations. Patients 40-59 years old who had the CRF08_BC subtype were identified as having higher risk for drug resistance mutation. Conclusions: The prevalence of TDR among ART-naive individuals with HIV-1 in Beijing was at a moderate level. Long-time and continuous surveillance of HIV TDR is necessary step in the therapy of ART-naive patients. (c) 2022 The Author(s). Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Background Acute-on-chronic liver failure (ACLF) is a clinical syndrome characterized by acute deterioration of liver function and high short-term mortality. Clusterin, with biological functions similar to small heat shock proteins, can protect cells from apoptosis induced by various stressors. The aim of this study was to detect the level of serum clusterin in hepatitis B virus- (HBV-) related ACLF and to assess the predictive value of clusterin for the short-term prognosis of HBV-ACLF. Methods We detected serum clusterin by ELISA in 108 HBV-ACLF patients, 63 HBV-non-ACLF patients, and 44 normal controls. Results Serum clusterin was markedly lower in HBV-ACLF patients (median, 51.09 μg/mL) than in HBV-non-ACLF patients (median, 188.56 μg/mL) and normal controls (median, 213.45 μg/mL; all P < 0.05). Nonsurviving HBV-ACLF patients who died within 90 days had much lower clusterin levels than did surviving patients, especially those who died within 28 days (nonsurvival group vs. survival group: 39.82 ± 19.34 vs. 72.26 ± 43.52, P < 0.001; survival time ≤ 28 vs. survival time > 28: median 28.39 vs. 43.22, P = 0.013). The results showed that for identifying HBV-ACLF, the sensitivity of clusterin (93.7%) was similar to the sensitivities of the international normalized ratio (INR; 94.4%) and total bilirubin (TBIL; 94.8%), but its specificity (90.7%) was higher than that of prothrombin activity (PTA; 65.8%) and TBIL (69.8%) and was similar to INR (88.9%). As the concentration of clusterin increased, the mortality of HBV-ACLF patients decreased significantly from 59.3% to 7.0%. Clusterin had better ability for predicting the prognosis of HBV-ACLF patients than did the model for end-stage liver disease (MELD) score and the chronic liver failure consortium (CLIF-C) ACLF score (MELD vs. clusterin: P = 0.012; CLIF-C ACLF vs. clusterin: P = 0.031). Conclusion Serum clusterin is a potential biomarker for HBV-ACLF which can be used to assess clinical severity and the short-term prognosis of patients with this disease and may help clinicians identify HBV-ACLF with greater specificity and improved prognostic accuracy than existing prognostic markers.