Early screening and antiviral therapy for significant liver inflammation in chronic hepatitis B (CHB) remain significant barriers as the key to disease reversal. The aim of this study was to develop a machine learning predictive model based on clinically available hematological indicators to assess liver inflammation in patients with CHB. This multicentre retrospective study comprised patients with untreated CHB who underwent hepatic puncture biopsy from 2014 to 2022. The best features were screened by the Gini index and Lasso. The machine learning model with the highest diagnostic performance for apparent liver inflammation was selected by comprehensive evaluation of parameters such as area under the receiver operating characteristic curve (AUROC) and decision curve analysis. This study included a total of 1,592 patients with chronic hepatitis B (CHB). Four indicators were ultimately selected: aspartate transaminase (AST), gamma-glutamyl transpeptidase (GGT), alpha-fetoprotein (AFP), and albumin-globulin ratio (AGR), which were used to construct the AAAG model. The model’s AUROC value ranged from 0.79 to 0.84, particularly in female patients, where the AUROC value reached 0.85 to 0.88. Additionally, a publicly available online tool was developed for assessing liver inflammation. A simple, non-invasive tool with good diagnostic value for assessing significant liver inflammation in patients with chronic hepatitis B for early screening was developed and validated.

BACKGROUND Noninvasive assessment of liver fibrosis is essential for the management of chronic hepatitis B (CHB), but existing tools have important limitations. Liver biopsy is invasive and unsuitable for repeated use, while commonly used serum indices show variable performance across populations and elastography is not universally available. We hypothesized that a laboratory-based machine-learning model using routinely available tests could provide consistent discrimination across independent clinical settings. AIM To develop and externally validate a laboratory-based machine-learning model for identifying significant liver fibrosis in CHB. METHODS This multicenter cohort study included adults with CHB who underwent liver biopsy in two tertiary hospitals as a development cohort and one independent tertiary hospital as an external validation cohort. A population-based cohort from the National Health and Nutrition Examination Survey was used for exploratory evaluation with surrogate fibrosis labels. After rule-based harmonization, a stacking ensemble model was trained using routine laboratory variables and evaluated using discrimination, calibration, and decision curve analyses. RESULTS The model demonstrated good discrimination in the development cohort [area under the curve (AUC) = 0.853] and in the biopsy-confirmed external cohort (0.838), with acceptable calibration in both. Compared with aspartate aminotransferase to platelet ratio index and fibrosis-4 (FIB-4), the model showed comparable discrimination and similar net clinical benefit across clinically relevant thresholds. Within the FIB-4 indeterminate zone, the model achieved an AUC of 0.821 and reclassified 69.8% of patients into lower- or higher-risk categories with a gradient in observed fibrosis prevalence. In the population-based cohort with aspartate aminotransferase to platelet ratio index/FIB-4-based surrogate labeling, the model preserved risk ranking (AUC 0.817). CONCLUSION A routine laboratory-based machine-learning model provides stable discrimination for significant fibrosis in CHB across clinical settings, with explainability supported by feature attribution analysis.

Understanding and enhancing vaccine‐induced immune responses in the elderly population is critical, as they face elevated risks of severe COVID‐19. This work systematically delineates age‐associated alterations in innate and adaptive immunity and their impact on responses to SARS‐CoV‐2 inactivated vaccination. Compared to young mice, aged mice exhibited polarized bystander Th1 CD4 + T cell populations (31.68 ± 5.62% versus 3.31 ± 0.48%) with distinct transcriptomic signatures, which augmented humoral immunity in aged mice. In human cohorts, post‐vaccination antigen‐specific antibody titers are comparable across different age groups. Stratified analysis based on antibody concentration reveals that high‐responder individuals possess elevated pre‐existing Th1 cells at baseline, which exhibit a modest positive correlation with post‐vaccination antibody titers (r = 0.423, p = 0.001). Therefore, compared to age‐based stratification, baseline Th1 cells serve as a superior predictive biomarker for antibody generation following SARS‐CoV‐2 inactivated vaccination. Collectively, these findings unveil novel mechanisms underlying Th1‐mediated vaccine immunogenicity, offering pivotal insights for developing next‐generation vaccines with optimized protective efficacy.

As immunotherapy gains increasing attention and clinical application, the immune modulation therapy has been widely used in the treatment of infectious and critical diseases. Clinical evidence has been accumulated for application of thymosin alpha 1 (T alpha 1), a classical immune modulator, in related domains. The National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases and other institutions invited multidisciplinary experts to develop this expert consensus on clinical application of T alpha 1 in infectious diseases and critical care medicine. Based on the latest domestic and international research findings and considering relevant factors, including economics, patient preferences and values, tradeoffs, accessibility, fairness and acceptability, the consensus assesses the quality levels of current evidence and forms 10 recommendations on the application of T alpha 1 in treatment of liver diseases, viral infections, bacterial infections and critical illnesses. This consensus aims to enhance understanding of T alpha 1 and improving its standardized application for clinicians.

The presence of significant liver inflammation is an important indication for antiviral therapy in immune-tolerant (IT)phase with chronic hepatitis B(CHB) patients. This study aims to establish a non-invasive model to assess significant liver inflammation in the IT-phase of CHB patients. This multicenter retrospective study included a total of 535 IT-phase CHB patients who underwent liver biopsy, and were randomly divided into a training and a validation set. In the training cohort, the relevant indices were initially screened using univariate analysis. Then the least absolute shrinkage and selection operator and multivariable logistic regression were used to identify the significant independent risk factors and establish a predictive model. A diagnostic nomogram was constructed. Calibration curves, decision curve analysis, and receiver operating characteristic curves were utilized to evaluate the performance of the nomogram. In this study, 37.0% of the patients exhibited significant liver inflammation. Baseline characteristics revealed a median age of 35.0 years, with males accounting for 51.7% of the cohort. Age, Aspartate aminotransferase (AST), Prothrombin (PT), Albumin (ALB) and Hepatitis B virus DNA (HBV DNA) were identified as independent predictors of significant liver inflammation in the immune-tolerant phase, and a nomogram was constructed based on these indicators. The predictive model demonstrated good calibration and discrimination in both the training set and the validation set (aera under the curve (AUC) of 0.741 and 0.740, respectively). The nomogram can accurately identify significant liver inflammation in immune-tolerant phase CHB patients and facilitate the early initiation of antiviral therapy, thereby reducing the need for clinical liver biopsies.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by multilineage immune dysregulation, which subsequently causes inflammation, fibrosis, and even cirrhosis of liver. Due to the limitation of traditional assays, the local hepatic immunopathogenesis of PBC has not been fully characterized. Here, we utilize single-cell RNA sequencing technology to depict the immune cell landscape and decipher the molecular mechanisms of PBC patients. We reveal that cholangiocytes and hepatic stellate cells are involved in liver inflammation and fibrosis. Moreover, Kupffer cells show increased levels of inflammatory factors and decreased scavenger function related genes, while T cells exhibit enhanced levels of inflammatory factors and reduced cytotoxicity related genes. Interestingly, we identify a liver-resident Th1-like population with JAK-STAT activation in the livers of both PBC patients and murine PBC model. Finally, blocking the JAK-STAT pathway alleviates the liver inflammation and eliminates the liver-resident Th1-like cells in the murine PBC model. In conclusion, our comprehensive single-cell transcriptome profiling expands the understanding of pathological mechanisms of PBC and provides potential targets for the treatment of PBC in patients. Primary biliary cholangitis is a chronic autoimmune disease critically linked to immunological dysregulation but the local immune-pathogenesis is poorly understood. Here the authors present single cell transcriptomic characterisation of primary biliary cholangitis and implicates Th1 like cells in a murine model.

Ecological studies suggested a link between air pollution and severe COVID-19 outcomes, while studies accounting for individual-level characteristics are limited. In the present study, we aimed to investigate the impact of short-term ambient air pollution exposure on disease severity among a cohort of 569 laboratory confirmed COVID-19 patients admitted to designated hospitals in Zhejiang province, China, from January 17 to March 3, 2020, and elucidate the possible biological processes involved using transcriptomics. Compared with mild cases, severe cases had higher proportion of medical conditions as well as unfavorable results in most of the laboratory tests, and manifested higher air pollution exposure levels. Higher exposure to air pollutants was associated with increased risk of severe COVID-19 with odds ratio (OR) of 1.89 (95% confidence interval (CI): 1.01, 3.53), 2.35 (95% CI: 1.20, 4.61), 2.87 (95% CI: 1.68, 4.91), and 2.01 (95% CI: 1.10, 3.69) for PM2.5, PM10, NO2 and CO, respectively. OR for NO2 remained significant in two-pollutant models after adjusting for other pollutants. Transcriptional analysis showed 884 differentially expressed genes which mainly were enriched in virus clearance related biological processes between patients with high and low NO2 exposure levels, indicating that compromised immune response might be a potential underlying mechanistic pathway. These findings highlight the impact of short-term air pollution exposure, particularly for NO2, on COVID-19 severity, and emphasize the significance in mitigating the COVID-19 burden of commitments to improve air quality.

The early and accurate identification of predictive biomarkers for antiviral treatment efficacy remains a significant clinical challenge, particularly in the management of chronic hepatitis B (CHB). This study aimed to assess whether the plasma metabolome could reliably predict the success of antiviral therapy in CHB patients. We conducted a retrospective analysis on 56 treatment-naive CHB patients at the First Affiliated Hospital of Zhejiang University from December 2013 to March 2016. Patients who underwent a 48-week treatment regimen of entecavir (ETV) and interferon-alpha (IFN-α) were randomly assigned to either a discovery cohort (n=29) or a validation cohort (n=27). Based on the outcome of the treatment, patients were classified as HBeAg seroconversion group (High responders, Hrp) or the non-remission group (Low responder, Lrp). Our methodology involved an untargeted analysis of the amine/phenol and carboxylic acid submetabolomes in the CHB patients under treatment, utilizing chemical isotope labeling (CIL) techniques with liquid chromatography-mass spectrometry (LC-MS). Several metabolites were identified as having significant diagnostic potential for distinguishing Hrp from Lrp, with areas under the receiver operating characteristic curve (AUC) exceeding those typical clinical indicators. Notably, four metabolites, namely 2-methyl-3-ketovaleric acid, 2-ketohexanoic acid, 6-oxo-1,4,5,6-tetrahydronicotinic acid, and α-ketoisovaleric acid, demonstrated exceptionally high sensitivity and specificity in both cohorts, nearing 100%. In contrast, the clinical indicators, including HBcAb, log(HBsAg), and HBeAb, demonstrated lower and inconsistent sensitivity and specificity between the discovery and validation cohorts. Using HBcAb as a marker, the sensitivity was 87.5% with 76.9% specificity in the discovery cohort; however, the sensitivity dropped to 46.7% with 91.7% specificity in the validation cohort. Using log(HBsAg), the sensitivity was 84.6% with 69.2% specificity in the discovery cohort, compared to 85.7% sensitivity and 83.3% specificity in the validation cohort. For HBeAb, the separation of Hrp and Lrp had a sensitivity of 87.5% with 69.2% specificity in the discovery cohort, while the validation cohort showed 86.7% sensitivity and 91.7% specificity.

肝衰竭是多种因素引起的严重肝脏损害,导致合成、解毒、代谢和生物转化功能严重障碍或失代偿,出现以黄疸、凝血功能障碍、肝肾综合征、肝性脑病、腹水等为主要表现的一组临床症候群.我国引起肝衰竭的主要病因是肝炎病毒(尤其是HBV),其次是药物及肝毒性物质(如酒精、化学制剂等).儿童肝衰竭还可见于遗传代谢性疾病.

Background and Aims:A functional cure, or hepatitis B virus (HBV) surface antigen (HBsAg) loss, is difficult to achieve in patients with hepatitis B virus e antigen (HBeAg)-positive chronic hepatitis B. The HBV vaccine and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been reported to help reduce HBsAg levels and promote HBsAg loss. In this prospective randomized trial, we evaluated HBsAg loss in patients receiving pegylated interferon-α2b (PEGIFN-α2b) and tenofovir disoproxil fumarate (TDF), with and without GM-CSF and HBV vaccination.Methods:A total of 287 patients with HBeAg positive chronic hepatitis B and seroconversion after nucleot(s)ide analog treatment were assigned randomly to three treatment groups for 48 weeks, TDF alone (control), PEGIFN-α2b + TDF, and PEGIFN-α2b + TDF + GM-CSF + HBV vaccine. The primary endpoints were the proportions of patients with HBsAg loss and seroconversion at 48 and 72 weeks.Results:The cumulative HBsAg loss rates in the control, PEGIFN-α2b + TDF, and PEGIFN-α2b + TDF + GM-CSF + HBV vaccine groups at week 48 were 0.0%, 28.3%, and 41.1%, respectively. The cumulative HBsAg seroconversion rates in these groups at week 48 were 0.0%, 21.7%, and 33.9%, respectively. Multivariate regression analysis showed that GM-CSF use plus HBV vaccination was significantly associated with HBsAg loss (p=0.017) and seroconversion (p=0.030).Conclusions:In patients with HBeAg-positive chronic hepatitis B and seroconversion after nucleot(s)ide analog treatment, immunomodulatory/antiviral treatment regimens effectively improved HBsAg loss, and the regimen including GM-CSF and HBV vaccination was most effective.

目的:评估索磷布韦/维帕他韦/伏西瑞韦(Sofosbuvir/Velpatasvir/Voxilaprevir，SOF/VEL/VOX)再治疗直接抗病毒药物(Direct acting antivirals，DAAs)治疗失败的不同基因型慢性丙型肝炎(Chronic hepatitis C，CHC)的有效性和安全性。方法:回顾性分析2022年1至10月16家医疗机构中DAAs治疗失败的21例CHC患者接受12周SOF/VEL/VOX抗病毒治疗的临床资料。分析患者基线、治疗4周、12周和治疗结束后12周的HCV RNA水平，以及基线和治疗结束后12周的血常规、肝肾功能等指标。收集患者治疗和随访期间的不良事件。采用SPSS 25.0对数据进行统计分析。结果:所有患者治疗4周、12周及治疗结束后12周均实现了病毒学应答。治疗结束后12周，丙氨酸转氨酶、天冬氨酸转氨酶和APRI均较治疗前下降( Z＝－3.940、－3.680和－3.889， P值均<0.001)，丙氨酸转氨酶复常率为95.2%(20/21)。2例(9.5%，2/21)患者出现胃肠道反应，包括腹痛、腹泻，恶心和呕吐。1例(4.8%，1/21)患者出现头痛，1例(4.8%，1/21)患者出现疲劳，未发生因不良反应引起的严重不良事件、死亡或中止治疗的情况。 结论:SOF/VEL/VOX对CHC患者是一种有效且安全的再治疗方案，对于DAAs治疗失败的不同基因型患者具有良好的病毒学应答率，耐受性良好。

Objectives: This study aimed to investigate the differences between elderly patients hospitalized with COVID-19 or influenza A H1N1 virus infections. Methods: We contrasted two absolute groups of patients (age =60 years) infected with either COVID-19 (n = 222) or influenza A H1N1 virus infections (n = 96). Propensity score matching was used to reduce the imbalance between the two matched groups. The clinical features, imaging presentations, therapies, and prognosis data were compared between the two groups. Results: The patients with influenza showed higher proportions of cough, expectoration, fatigue, and shortness of breath. Higher counts of lymphocytes, hemoglobin, and creatine kinase and lower counts of white blood cells, neutrophils, blood urea nitrogen, and C-reactive protein were found in the patients with COVID-19. Regarding the imaging characteristics, bilateral pneumonia was the most abnormal pattern in the two groups of patients. The incidence of acute respiratory distress syndrome or death was lower among the patients with COVID-19. Conclusion: The clinical manifestations of patients with COVID-19 are more concealed than those of patients with influenza. Fewer symptoms of sputum production, fatigue, and shortness of breath, combined with lower counts of white blood cells, neutrophils, and C-reactive protein are the possible predictive factors of COVID-19 among elderly patients. (c) 2022 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

AIM: Influenza infection poses a severe threat to pregnant mothers, and antiviral treatment is recommended. However, the safety of neuraminidase-inhibitor antiviral medications during pregnancy has not been well described. METHODS: A systematic review and meta-analysis were performed to evaluate the adverse neonatal outcomes associated with exposure to neuraminidase inhibitors during pregnancy. The PubMed, Embase, and Cochrane Library databases were searched to identify potential studies for inclusion. RESULTS: Nine cohort studies that estimated adverse neonatal outcomes associated with exposure to neuraminidase-inhibitor medication during pregnancy were included. Exposure to a neuraminidase inhibitor during pregnancy was not associated with an increased risk of congenital malformation (odds ratio [OR] 0.9, 95% confidence interval [CI] 0.72–1.12, P = 0.341), low Apgar score (OR 0.96, 95% CI 0.77–1.2, P = 0.733), or preterm birth (OR 0.99, 95% CI 0.89–1.09, P = 0.771) compared with no exposure. However, exposure to a neuraminidase inhibitor was associated with a reduced risk of low birth weight (OR 0.79, 95% CI 0.68–0.92, P = 0.002) and giving birth to a small-for-gestational-age infant (OR 0.78, 95% CI 0.69–0.88, P < 0.001). Further analyses limited to oseltamivir exposure were consistent with the overall results. CONCLUSION: Exposure to neuraminidase-inhibitor medication during pregnancy does not appear to be associated with adverse neonatal outcomes. We recommend further studies to investigate this association, which will help clinicians determine whether to prescribe a neuraminidase inhibitor during pregnancy.

病例1,男,21岁,餐厅职工,因"头痛伴间断低热1周"于2021年6月17日入新疆维吾尔自治区人民医院. 患者于入院1周前受凉后出现头痛,呈头部胀痛不适,主要于夜间出现,持续数小时不缓解,伴午后及夜间低热,体温波动在37. 5℃左右,伴乏力、恶心,偶伴右下肢关节疼痛不适,就诊于当地医院,诊断考虑脑膜炎,给予积极对症治疗后体温未见下降,入院前3天出现胡言乱语、答非所问,故转至我院. 病程中患者饮食睡眠差,大小便正常,体重无明显变化. 既往有屠宰场工作经历,家中养羊,平素与家畜有密切接触史. 体格检查:T 37. 4 ℃,Bp 101/55 mmHg,P 80次/分,R 20次/分. 神志清楚,语言明晰,精神差,发育正力型,双侧瞳孔等大同圆,对光反射灵敏.

Hepatitis B surface antigen (HBsAg) loss or seroconversion is an ideal treatment endpoint for patients with chronic hepatitis B but is rarely achievable in  hepatitis B e-antigen (HBeAg)-positive patients using existing treatment strategies. In this study, the effect of pegylated interferon (peg-IFN) alfa-2b plus tenofovir disoproxil fumarate (TDF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and hepatitis B vaccine was evaluated. This randomized controlled trial was conducted at nine liver centers in Chinese university hospitals from May 2018 to July 2020. Patients (n = 303) enrolled were randomly administered peg-IFN-α-2b combined with TDF, GM-CSF, and hepatitis B vaccine (experimental group); peg-IFN-α-2b plus TDF (control group 2); or interferon-α-2b alone (control group 1). The primary efficacy endpoint was HBsAg seroconversion at 48 weeks and the secondary endpoint included safety. No differences in baseline HBsAg levels were observed among the groups. The primary endpoint was achieved in three (3.0%), one (1.03%), and one (1.19%) patient in the experimental group, control group 2, and control group 1, respectively. The incidence of HBsAg seroconversion at week 48 was not significantly different among the three groups (p = 0.629). However, the decrease in serum levels of HBsAg at week 48 was significantly higher in the experimental and control group 2 compared with that in control group 1 (p = 0.008 and 0.006, respectively). No significant difference between the experimental and control group 2 was observed (p = 0.619). Adverse events were not significantly different among the groups except for the lower incidence of neutropenia in the experimental group. Peg-IFN-α-2b combined with TDF, GM-CSF, and hepatitis B vaccine is not superior to peg-IFN-α-2b combined with TDF in HBeAg-positive naïve patients. Clinical Trials Registration: ChiCTR1800016173.

Background. Hundreds of millions of people worldwide suffer from chronic hepatitis B (CHB), making it one of the most serious public health problems. CHB can lead to serious acute-on-chronic liver failure (ACLF). Since ACLF has a high mortality rate, predicting the risk of ACLF is a critical issue in clinical practice. Methods. To investigate the occurrence of ACLF in CHB, we used high-throughput RNA sequencing to detect the expression of a novel endogenous noncoding RNA (circRNA) in healthy controls (HC) as well as CHB and ACLF patients. Differentially expressed circRNAs were selected and analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway analyses, circRNA-miRNA coexpression networks, and statistical analyses. Results. A total of 21,101 circRNAs were identified in HC, CHB, and ACLF subjects. Compared with the HCs, 4 circRNAs were upregulated and 14 circRNAs were downregulated in ACLF subjects, with a consistent trend in all three groups. GO analysis revealed that regulation of lymphocyte activation and macrophage tolerance induction were the most important biological processes in ACLF progression. KEGG pathway analysis revealed that primary immunodeficiency and NOD-like receptor signaling pathways were the most enriched terms. The circRNA-miRNA coexpression network and statistical analyses showed that circRNA_07734, circRNA_08533, and circRNA_16083 were the most important circRNAs in the process of ACLF. Conclusions. Immune dysfunction and deficiency may play a key role in the development of ACLF, especially circRNA_07734, circRNA_08533, and circRNA_16083.

Background Although individuals infected with HIV for the first time manifest a series of acute syndromes, most patients show mild or no symptoms, which complicates the initial clinical diagnosis. Early diagnosis is important for effective prevention and management of patients. Metagenomic next-generation sequencing technology (mNGS) can rapidly detect a wide range of pathogenic microorganisms, even in atypical cases. However, to date, few studies have reported the application of mNGS to diagnose acute HIV infection with aseptic meningitis. Case Presentation A 38-year-old man was admitted to the Department of Infectious Diseases due to repeated fever, headache, and scattered rashes on his limbs. Routine blood analysis revealed elevated absolute lymphocytes and monocytes. Moreover, monocytes were found to be significantly increased following a lumbar puncture and cerebrospinal fluid detection. mNGS results revealed the presence of the human immunodeficiency virus (HIV-1), with HIV RNA of 910 copies/mL in his cerebrospinal fluid. The HIV antigen/antibody test was negative. According to a study by Fie Big et al, a clear diagnosis of acute HIV infection at Fiebig stage I. The patient’s condition improved after treatment, and he was prescribed antiretroviral therapy (ART) after discharge. Conclusion Aseptic meningitis is easily misdiagnosed during the initial stages of acute HIV infection. mNGS can be used to identify the pathogen early, rapidly, and accurately, thereby improving the treatment of acute HIV infections.