Liver inflammation activity in patients with autoimmune hepatitis with normal alanine aminotransferase and immunoglobulin G levels.

Background and aims: Normal serum transaminases and immunoglobulin G (IgG) levels are surrogate markers for hepatic histologic disease activity in autoimmune hepatitis (AIH). This study aimed to evaluate liver inflammation in patients with AIH with normal serum alanine aminotransferase (ALT) and IgG levels. Methods: Two hundred and five AIH patients who underwent liver biopsy in four medical centers were included. Logistic regression analysis was used to identify risk factors associated with advanced inflammation. Results: One hundred and thirty-one (63.9 %) AIH patients had advanced liver inflammation, and 108 (52.7 %) patients had advanced liver fibrosis. 60.0 % of patients with normal ALT and 51.7 % of patients with normal ALT and IgG had advanced inflammation. However, 76.7 % and 35.0 % of patients with or without advanced fibrosis with normal ALT had advanced inflammation, while the corresponding proportions of advanced inflammation were 78.6 % and 26.7 % in patients with normal ALT and IgG, respectively. Moreover, 81.0 % and 44.8 % of patients with and without cirrhosis with normal ALT had advanced inflammation, while the corresponding proportions were 83.3 % and 29.4 % in patients with normal ALT and IgG, respectively. Red cell distribution width (OR = 1.325, 95%CI 1.045-1.681, P = 0.020) and PT (OR = 1.514, 95%CI 1.138-2.014, P = 0.004) were independent factors associated with advanced inflammation. Conclusions: High proportion of advanced inflammation was found in AIH patients with normal ALT and IgG levels despite without advanced fibrosis. Although using non-invasive methods may contribute to rule out liver fibrosis in AIH patients with normal ALT and IgG levels, liver biopsy is encouraged to assess liver inflammation.

Histological features of chronic hepatitis B patients with normal alanine aminotransferase according to different criteria.

BACKGROUND: The upper limits of normal (ULNs) for alanine aminotransferase (ALT) are different among international guidelines for chronic hepatitis B (CHB). We aimed to investigate the proportion of significant histological disease in Asian patients with CHB with detectable hepatitis B virus (HBV) DNA under diverse ALT ULNs. METHODS: Consecutive patients with CHB and detectable HBV DNA who underwent liver biopsy were retrospectively included from four tertiary hospitals. Above grade 2 inflammation and stage 2 fibrosis were defined as significant inflammation and significant fibrosis, respectively. Significant histological disease was defined as above grade 2 inflammation or stage 2 fibrosis. RESULTS: Among the 414 patients with detectable HBV DNA and normal ALT, the proportion of those with significant histological disease was lower (59.7%) according to the ULN for ALT at 30/19 U/L (male/female), while the corresponding proportions were 66.7% and 62.3% according to the ULNs of 40 U/L and 35/25 U/L (male/female), respectively. In patients with detectable HBV DNA and normal ALT levels without significant fibrosis, the proportions of significant inflammation were comparable among different ULNs of ALT at 40 U/L (30.7%), 35/25 U/L (27.3%) and 30/19 U/L (25.0%). The proportion of significant histological disease was significantly lower in patients with normal ALT for 2 determinations at least 6 months apart compared to patients with normal ALT once. CONCLUSIONS: Although a more stringent ALT ULN may reduce the risk of the presence of significant histological disease in patients with detectable HBV DNA, the rates of significant histological disease remain high. Persistently normal ALT levels are more important for excluding patients with CHB with a high probability of significant histological disease.

Metabolic and immune-related gene signatures: Predictive stratification and prognostic implications in gastric cancer.

BACKGROUND: Gastric cancer, marked by its heterogeneous nature, showcases various molecular subtypes and clinical trajectories. This research delves into the significance of metabolic and immune-driven pathways in gastric cancer, constructing a prognostic signature derived from differentially expressed metabolic and immune-correlated genes (DE-MIGs). METHODS: Metabolic and immune-associated gene were sourced from the GeneCards database. Differential expression analysis on the TCGA-STAD dataset was executed using the limma package, unveiling 51 DE-MIGs that underwent functional enrichment scrutiny. The LASSO Cox regression methodology guided the creation of the prognostic signature, and individual patient risk scores were determined. Assessment tools like CIBERSORT, ESTIMATE and ssGSEA were deployed to study the immune microenvironment, while mutation profiles, genomic stability, resistance to chemotherapy and immunotherapy responsiveness were scrutinized across distinct signature categorizations. RESULTS: Among the identified DE-MIGs, 26 were significantly tied to the overall survival of gastric cancer patients. The developed prognostic signature proficiently differentiated patients into high-risk and low-risk cohorts, with the latter showing markedly better outcomes. The study underscored the centrality of the immune microenvironment in influencing gastric cancer outcomes. Key pathways such as TGF-Beta, TP53 and NRF2 dominated the high-risk group, whereas the LRTK-RAS and WNT pathways characterized the low-risk group. Interestingly, the low-risk segment also manifested a heightened tumor mutation burden and enhanced susceptibility to immunotherapy. CONCLUSIONS: Our findings introduce a pivotal prognostic signature, rooted in DE-MIGs, that effectively segregates gastric cancer patients into distinct risk-based segments. Insights into the influential role of the immune microenvironment in gastric cancer progression pave the way for more refined therapeutic interventions.

A novel web-based online nomogram to predict advanced liver fibrosis in patients with autoimmune hepatitis-primary biliary cholangitis overlap syndrome.

Background: Patients with autoimmune hepatitis-primary biliary cholangitis (AIH-PBC) overlap syndrome have a worse prognosis compared to AIH or PBC alone and accurately predicting the severity and dynamically monitoring the progression of disease are therefore essential. We aimed to develop a nomogram-based model to predict advanced liver fibrosis in patients with AIH-PBC overlap syndrome. Methods: A total of 121 patients with AIH-PBC overlap syndrome were retrospectively included and randomly assigned to a development set and a validation set. Backward stepwise regression's best model with the lowest AIC was employed to create a nomogram. Diagnose accuracy was evaluated using the area under the receiver operator characteristic curve (AUROC), calibration analysis, and decision curve analysis (DCA) and was compared with aspartate aminotransferase-to-platelet ratio (APRI) and fibrosis index based on four factors-4 (FIB-4) score. Results: The median age of patients was 53.0 years (IQR: 46.0-63.0), and female patients accounted for 95.0 %. Platelets, globulin, total bilirubin, and prothrombin time were associated with advanced fibrosis (≥S3) and used to construct an AIH-PBC overlap syndrome fibrosis (APOSF)-nomogram (available online at https://ndth-zzy.shinyapps.io/APOSF-nomogram/). The AUROCs of APOSF-nomogram were 0.845 (95 % CI: 0.754-0.936) and 0.843 (95 % CI: 0.705-0.982) in development set and validation set respectively, which was significantly better than APRI and FIB-4. Calibration revealed that the estimated risk fits well with biopsy-proven observation. DCA outperformed APRI and FIB4 in terms of net benefit, demonstrating clinical utility. Conclusion: This novel non-invasive web-based online APOSF-nomogram provided a convenient tool for identifying advanced fibrosis in patients with AIH-PBC overlap syndrome. Further prospective, multicenter studies with large sample size are necessary to validate the applicability of APOSF-nomogram.

Develop and validate a novel online AIHI-nomogram to predict severe liver inflammation in patients with autoimmune hepatitis.

INTRODUCTION AND OBJECTIVES: Assessment of liver inflammation plays a vital role in the management of patients with autoimmune hepatitis (AIH). We aimed to establish and validate a nomogram to predict severe liver inflammation in AIH patients. PATIENTS AND METHODS: AIH patients who underwent liver biopsy were included and randomly divided into a training set and a validation set. Independent predictors of severe liver inflammation were selected by the least absolute shrinkage and selection operator regression from the training set and used to conduct a nomogram. Receiver characteristic curves (ROC), calibration curves, and decision curve analysis (DCA) were adopted to evaluate the performance of nomogram. RESULTS: Of the 213 patients, female patients accounted for 83.1% and the median age was 53.0 years. The albumin, gamma-glutamyl transpeptidase, total bilirubin, red cell distribution width, prothrombin time, and platelets were independent predictors of severe inflammation. An online AIHI-nomogram was established and was available at https://ndth-zzy.shinyapps.io/AIHI-nomogram/. The calibration curve revealed that the AIHI-nomogram had a good agreement with actual observation in the training and validation sets. The area under the ROCs of AIHI-nomogram were 0.795 in the training set and 0.759 in the validation set, showing significantly better performance than alanine aminotransferase and immunoglobulin G in the training and validation sets, as well in AIH patients with normal ALT in the training set. DCA indicated that the AIHI-nomogram was clinically useful. CONCLUSIONS: This novel AIHI-nomogram provided an excellent prediction of severe liver inflammation in AIH patients and could be used for the better management of AIH.

An easy-to-use AIHF-nomogram to predict advanced liver fibrosis in patients with autoimmune hepatitis.

Background: The evaluation of liver fibrosis is essential in the management of patients with autoimmune hepatitis (AIH). We aimed to establish and validate an easy-to-use nomogram to identify AIH patients with advanced liver fibrosis. Methods: AIH patients who underwent liver biopsies were included and randomly divided into a training set and a validation set. The least absolute shrinkage and selection operator (LASSO) regression was used to select independent predictors of advanced liver fibrosis from the training set, which were utilized to establish a nomogram. The performance of the nomogram was evaluated using the receiver characteristic curve (ROC), calibration curve, and decision curve analysis (DCA). Results: The median age of 235 patients with AIH was 54 years old, with 83.0% of them being female. Six independent factors associated with advanced fibrosis, including sex, age, red cell distribution width, platelets, alkaline phosphatase, and prothrombin time, were combined to construct a predictive AIH fibrosis (AIHF)-nomogram. The AIHF-nomogram showed good agreement with real observations in the training and validation sets, according to the calibration curve. The AIHF-nomogram performed significantly better than the fibrosis-4 and aminotransferase-to-platelet ratio scores in the training and validation sets, with an area under the ROCs for predicting advanced fibrosis of 0.804 in the training set and 0.781 in the validation set. DCA indicated that the AIHFI-nomogram was clinically useful. The nomogram will be available at http://ndth-zzy.shinyapps.io/AIHF-nomogram/as a web-based calculator. Conclusions: The novel, easy-to-use web-based AIHF-nomogram model provides an insightful and applicable tool to identify AIH patients with advanced liver fibrosis.

Significant histological disease of patients with chronic hepatitis B virus infection in the grey zone.

BACKGROUND: Many patients with chronic hepatitis B (CHB) do not meet the definitions of the traditional natural phases and are classified as being in the grey zone (GZ). AIMS: To investigate liver histology, and to establish a management strategy for patients with CHB in the GZ. METHODS: This study included 1043 patients with CHB who underwent liver biopsy. Phases of natural history were determined according to the AASLD 2018 hepatitis B guidance. CHB patients in the GZ were divided into HBeAg-positive, normal ALT and HBV DNA ≤106  IU/ml (GZ-A); HBeAg-positive, elevated ALT and HBV DNA ≤2 × 104  IU/ml (GZ-B); HBeAg-negative, normal ALT and HBV DNA ≥2 × 103  IU/ml (GZ-C) and HBeAg-negative, elevated ALT and HBV DNA ≤2 × 103  IU/ml (GZ-D). Significant histological disease was defined as liver inflammation ≥G2 and/or liver fibrosis ≥S2. RESULTS: Two hundred and forty two (23.2%) patients were in the GZ. Approximately 72.7% had significant histological disease. HBeAg-positive GZ CHB patients had a higher proportion of significant histological disease than HBeAg-negative GZ patients (91.1% vs. 68.5%, p = 0.002). GZ-D (42.6%) was the dominant category, followed by GZ-C (38.8%), GZ-A (10.3%) and GZ-B (8.3%). The highest proportion of significant histological disease was observed patients in GZ-B (100.0%), followed by GZ-A (84.0%), GZ-D (69.9%) and GZ-C (67.0%). Prothrombin time (PT) was an independent risk factor of significant histological disease in the HBeAg-negative GZ. CONCLUSIONS: Over 70% of GZ CHB patients had significant histological disease. We recommend antiviral treatment for HBeAg-positive and HBeAg-negative GZ CHB patients with high PT.

Integrating network pharmacology and an experimental validation strategy elucidates the protective effect and mechanism of callicarpa nudiflora against neuroinflammation.

Abnormal activation of microglia promotes neuroinflammation (NI) in Alzheimer's disease (AD). Callicarpa nudiflora Hook et Arn. (CN) is a traditional Chinese herb with a wide range of clinical applications and definite anti-inflammatory effects. However, the anti-inflammatory action and mechanism of NI are not known. The purpose of this research was to survey whether CN could inhibit lipopolysaccharide (LPS)-induced inflammatory activation in BV-2 microglia. This study used a network pharmacology and pharmacophore model-based approach to explore the molecular mechanism of CN anti-NI by combining molecular docking and experimental validation. First, we screened the key active components and targets of CN anti-NI by network pharmacology. Then, the common structural features of these functional molecules in the treatment of neuroinflammation were predicted by 3D-QSAR pharmacodynamic modeling. Finally, the molecular mechanism of the active ingredient 5-hydroxy-3,7,4'-trimethoxyflavone (THF) against neuroinflammation was validated by molecular docking and in vitro experiments. In conclusion, this study established the structure-activity relationships of the active components of CN anti-NI and provided new insights into the pharmacological mechanisms of CN anti-NI at an integrative level.

[A new labdane-type diterpenoids from Callicarpa nudiflora].

The purpose of the research is to study the bioactive constituents of Callicarpa nudiflora. From the 65% ethanol extract of C. nudiflora leaves, ten compounds were isolated by macroporous adsorption resin, Sephadex LH-20, ODS, silica gel, and preparative HPLC. These compounds were identified as callicapene M6(1), sterebin A(2), isomartynoside(3), crenatoside(4), luteolin-7-O-neohesperidoside(5), apigenin-7-O-ß-D-neohesperidoside(6), isoacteoside(7), acteoside(8),(7R)-campneoside I(9), and(7S)-campneoside I(10) on the basis of NMR, HR-ESI-MS, and optical rotation data. Compound 1 was obtained as a new compound. Compounds 2 and 4 were isolated from the genus Callicarpa for the first time. Compounds 9 and 10 were isolated from C. nudiflora for the first time.

Sliding mode control with system constraints for aircraft engines.

This paper proposes a constraint-tolerant design with sliding mode strategy to improve the stability of aircraft engine control. To handle the difficulties associated with the high-frequency switching laws, merely attenuating the chattering is far from satisfactory. System constraints on input, output, and input rate should be addressed in the design process. For a sort of uncertain nonlinear systems subjected to the constraints, sliding mode regulators are designed using Lyapunov analysis. A turbofan engine is adopted for simulation, which shows that the methodology developed in this paper can handle the speed tracking and limit protection problem in a stable fashion, despite the negative influence posed by the system constraints.

Vaccination knowledge, attitude and practice among Chinese travelers who visit travel clinics in Preparation for international travel.

BACKGROUND: Although international travel has become increasingly more common in main land China, few data are available on vaccination knowledge, attitude and practice (KAP) among Chinese travelers. METHOD: In each of 14 International Travel Healthcare Centers (ITHCs) situated in mainland China 200 volunteers were recruited for a cross-sectional investigation by questionnaire on KAP related to travel vaccinations. For the evaluation the study subjects were grouped by demographic data, past travel experience, travel destination, duration of stay abroad, purpose of travel. RESULTS: Among the 2,800 Chinese travelers who participated in the study, 67.1% were aware of national and travel vaccination recommendations. The knowledge about vaccine preventable diseases was low. The most common sources (73.4%) of information were requirements by destination countries obtained in connection with the visa application, Chinese companies employing workers/laborers for assignments overseas, and foreign schools. The overall acceptance rate of recommended vaccines was 68.7%, but yellow fever was accepted by 99.8% of the participants when recommended. Among 81.1% respondents who recalled to have received vaccinations in the past, only 25.9% of them brought the old vaccination records with them to their ITHC consultations. CONCLUSION: The results indicate that increased awareness of the importance of pre-travel vaccination is needed among the travellers in order to improve their KAP.

[Effect of Telbivudine Tablet Combined Jianpi Bushen Recipe on HBV Specific Cytotoxic T Lymphocyte and HBeAg Seroconversion in Patients with HBeAg Positive Chronic Hepatitis B].

OBJECTIVE: To explore the effect of Telbivudine (LDT) Tablet combined with Jianpi Bushen Recipe (JBR) on serum hepatitis B virus (HBV) specific cytotoxic T lymphocyte (CTL) and HBeAg seroconversion in chronic hepatitis B (CHB) patients. METHODS: Totally 90 HBeAg-positive and human leukocyte antigen (HLA)-A2 positive CHB patients were randomly assigned to the treatment group and the control group, 45 cases in each group. Patients in the treatment group took LDT Tablet (600 mg, once per day) combined with JBR granule (twice per day), while those in the control group took LDT Tablet alone. The therapeutic course for all was one year. HBV DNA negative conversion rate, HBeAg seroconversion rate, and level of HBV specific CTL were compared after 1 year treatment; liver function, drug resistance mutations, and adverse reactions were also compared between the two groups. RESULTS: After 1 year treatment, HBV DNA negative conversion rate and HBeAg seroconversion rate were 88.89% (40/45) and 40.00% (18/45) in the treatment group, higher than those of the control group [68.89% (31/45) and 20.00% (9/45)], with statistical difference (P < 0.05). Level of HBV specific CTL in the treatment group was 0.78% +/- 0.09% after treatment, higher than that of the control group after 1 year treatment (0.54% +/- 0.11%) and that before treatment (0.36% +/- 0.07%), with statistical difference (P < 0.01). Level of HBV specific CTL in 27 patients with HBeAg seroconversion was 0.81% 0.10%, higher than that of 63 patients without HBeAg seroconversion (0.60% +/- 0.09%), with statistical difference (P < 0.01). ALT returned to normal in 44 cases of the treatment group (97.78%), while it was 42 cases (93.33%) of the control group, with no statistical difference between the two groups (P > 0.05). Total bilirubin (TBil) in the two groups all turned to normal. rtM204I variation occurred in 1 case (2.22%) of the treatment group and 2 cases (4.44%) in the control group. No obvious adverse reaction occurred in the two groups. CONCLUSION: LDT Tablet combined with JBR could elevate levels of HBV specific CTL and HBeAg seroconversion in CHB patients.

Hepatitis B surface antigen quantification at hepatitis B e antigen seroconversion predicts virological relapse after the cessation of entecavir treatment in hepatitis B e antigen-positive patients.

OBJECTIVES: To assess off-treatment virological relapse rates and to determine the role of hepatitis B surface antigen (HBsAg) quantification in predicting virological relapse after stopping entecavir (ETV) treatment in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB). METHODS: One hundred and twelve CHB patients for whom ETV was stopped in accordance with the Asian Pacific Association for the Study of the Liver guidelines stopping rules were enrolled. Patient HBsAg and HBV DNA levels were monitored every 4-12 weeks during ETV treatment and after ETV cessation. Post-treatment virological relapse was defined as a serum HBV DNA level of >10 000 copies/ml after stopping ETV treatment. RESULTS: The virological relapse rate at 52 weeks after stopping ETV was 48.2%. The post-treatment virological relapse rate was significantly higher in patients aged >50 years than in those aged <50 years (p < 0.001), and the virological relapse rate was significantly lower in patients with an HBsAg level <2.0 log10 IU /ml than in those with a level ≥ 2.0 log10 IU /ml at ETV cessation (p = 0.005). An HBsAg level of 2.5 log10 IU/ml at HBeAg seroconversion was the optimal cut-off value for predicting post-treatment virological relapse (p < 0.001). In those aged <50 years and with HBsAg ≤ 2.5 log10 IU/ml at HBeAg seroconversion, the relapse rate was only 5%. In patients with HBsAg ≤ 2.5 log10 IU/ml at HBeAg seroconversion, 52.4% achieved HBsAg levels ≤ 2.0 log10 IU/ml at ETV cessation, while in those with HBsAg >2.5 log10 IU/ml at HBeAg seroconversion, only 4.4% achieved this criterion. CONCLUSIONS: HBsAg levels can help guide the timing of cessation of ETV treatment. HBsAg levels of 2.5 log10 IU/ml at HBeAg seroconversion may be a useful marker to predict virological relapse after the cessation of ETV treatment in HBeAg-positive CHB patients.

[Treatment of early and mid-term primary biliary cirrhosis by Qingying Huoxue Decoction Combined ursodeoxycholic acid: a clinical observation].

UNLABELLED: OBJECTIVE To observe the clinical efficacy by Qingying Huoxue Decoction (QHD) combined ursodeoxycholic acid (UDCA) in treating patients with early and mid-term primary biliary cirrhosis (PBC). METHODS Totally 78 patients were randomly assigned to the treatment group and the control group, 39 in each group. All patients received basic treatment and took UDCA (at the daily dose of 13-15 mg/kg). Patients in the treatment group took QHD, one dose per day. The treatment course for all was 6 weeks. Clinical efficacy, gamma-glutamyl transferase (γ-GGT), alkaline phospatase (ALP), TBIL, alanine aminotransferase (ALT), and aspartate transaminase (AST) were observed before and after treatment. RESULTS Totally 21 (53. 8%) patients obtained complete response in the treatment group, with statistical difference when compared with that of the control group (11 cases, 30. 8%). Levels of GGT, ALP, ALT, AST, and TBIL decreased in the two groups after treatment (P < 0.01). Levels of ALP, GGT, and TBIL were obviously lower in the treatment group than in the control group (P < 0.05). CONCLUSIONS: QHD combined UDCA in treating early and mid-term PBC patients was superior to the effect of using UDCA alone. It also could improve patients' liver function.

The efficacy and safety of entecavir in patients with advanced schistosomiasis co-infected with hepatitis B virus.

OBJECTIVE: To evaluate the efficacy and safety of entecavir (ETV) in patients with advanced schistosomiasis and hepatitis B virus (HBV) co-infection. METHODS: Sixty-seven patients with advanced schistosomiasis and HBV co-infection were enrolled in this study. The patients were randomly divided into the ETV treatment group (n=35) and the control group (n=32). The patients in the control group adopted routine supportive therapy for 52 weeks, and those in the ETV treatment group received ETV at a dose of 0.5mg once daily on the basis of routine supportive therapy for 52 weeks. Hepatic fibrosis markers (hyaluronic acid, type III procollagen, type IV collagen, laminin, and fibronectin), Ishak fibrosis score, alanine transaminase (ALT), HBV DNA, and Child-Pugh score were compared between the two groups. The intention to treat (ITT) population was used for the analysis. The measurement data and count data were analyzed by t-test and Chi-square test, respectively. RESULTS: After 52 weeks of treatment, the hepatic fibrosis markers (hyaluronic acid, type III procollagen, type IV collagen, laminin, and fibronectin) were significantly improved in the ETV treatment group compared to the control group (all p<0.05). A ≥1-point improvement in the Ishak fibrosis score was found in 25.7% (9/35) of the ETV group, and the mean change from the baseline in the Ishak fibrosis score was a 0.3-point reduction. The control group showed disease progression in the Ishak fibrosis score. More patients in the ETV group than in the control group had undetectable serum HBV DNA levels (82.9% vs. 3.1%, p<0.05) and ALT normalization (68.6% vs. 18.3%, p<0.05). The ETV treatment group demonstrated an improvement in Child-Pugh score at week 52 (-3.7 vs. 0.3, p<0.05). In addition, no obvious adverse reactions were observed during ETV treatment. CONCLUSION: ETV is safe and effective in patients with advanced schistosomiasis and HBV co-infection.

[The efficacy of antiviral therapy for hepatitis B virus related decompensated cirrhosis].

Not Abstract.

[Separation and identification of two benzotropolones from teapigment].

OBJECTIVE: To study the chemical constituents of teapigment. METHOD: Some constituents were isolated by chromatographic methods and identified by chemical constituents and their structures were elucidated by spectral data. RESULT: From teapigment, two compounds have been isolated and identified as purpurogallin (I) and purpurogallin carboxylic acid (II). CONCLUSION: These compounds were main pigments obtained from teapigment for the first time, and likely to be active compounds of teapigment.