Object:Our objective was to estimate the 5-year cumulative risk of HCC in patients with HBC by utilizing an artificial neural network (ANN).Methods:We conducted this study with 1589 patients hospitalized at Beijing Ditan Hospital of Capital Medical University and People's Liberation Army Fifth Medical Center. The training cohort consisted of 913 subjects from Beijing Ditan Hospital of Capital Medical University, while the validation cohort comprised 676 subjects from People's Liberation Army Fifth Medical Center. Through univariate analysis, we identified factors that independently influenced the occurrence of HCC, which were then used to develop the ANN model. To evaluate the ANN model, we assessed its predictive accuracy, discriminative ability, and clinical net benefit using metrics such as the area under the receiver operating characteristic curve (AUC), concordance index (C-index), calibration curves.Results:In total, we included nine independent risk factors in the development of the ANN model. Remarkably, the AUC of the ANN model was 0.880, significantly outperforming the AUC values of other existing models including mPAGE-B (0.719) (95% CI 0.670-0.768), PAGE-B (0. 710) (95% CI 0.660-0.759), FIB-4 (0.693) (95% CI 0.640-0.745), and Toronto hepatoma risk index (THRI) (0.705) (95% CI 0.654-0.756) (p<0.001 for all). The ANN model effectively stratified patients into low, medium, and high-risk groups based on their 5-year In the training cohort, the positive predictive value (PPV) for low-risk patients was 26.2% (95% CI 25.0-27.4), and the negative predictive value (NPV) was 98.7% (95% CI 95.2-99.7). For high-risk patients, the PPV was 54.7% (95% CI 48.6-60.7), and the NPV was 91.6% (95% CI 89.4-93.4). These findings were validated in the independent validation cohort.Conclusion:The ANNs model has good individualized prediction performance and may be helpful to evaluate the probability of the 5-year risk of HCC in patients with HBC.

BackgroundHepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) has significant morbidity and mortality and is associated with the induction of cytokines/chemokines, which might contribute to the pathogenesis of liver injury. This study aimed to explore the cytokine/chemokine profiles of patients with HBV-ACLF and develop a composite clinical prognostic model.MethodsWe prospectively collected blood samples and the clinical data of 107 patients with HBV-ACLF admitted to the Beijing Ditan Hospital. The concentrations of 40-plex cytokines/chemokines were measured in 86 survivors and 21 non-survivors using the Luminex assay. Discrimination between the cytokine/chemokine profiles in different prognosis groups was analyzed using the multivariate statistical techniques of principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA). An immune-clinical prognostic model was obtained using multivariate logistic regression analysis.ResultsThe PCA and PLS-DA indicated that cytokine/chemokine profiling could clearly distinguish patients with different prognoses. A total of 14 cytokines, namely, IL-1β, IL-6, IL-8, IL-10, TNF-α, IFN-γ, CXCL1, CXCL2, CXCL9, CXCL13, CX3CL1, GM-SCF, CCL21, and CCL23, were significantly correlated with disease prognosis. Multivariate analysis identified CXCL2, IL-8, total bilirubin, and age as independent risk factors that constituted the immune-clinical prognostic model, which showed the strongest predictive value of 0.938 compared with those of the Chronic Liver Failure Consortium (CLIF-C) ACLF (0.785), Model for End-Stage Liver Disease (MELD) (0.669), and MELD-Na (0.723) scores (p < 0.05 for all).ConclusionThe serum cytokine/chemokine profiles correlated with the 90-day prognosis of patients with HBV-ACLF. The proposed composite immune-clinical prognostic model resulted in more accurate prognostic estimates than those of the CLIF-C ACLF, MELD, and MELD-Na scores.

新型冠状病毒肺炎(COVID-19)重症发生发展符合瘟疫"温邪上受,首先犯肺,逆传心包"发病特点和传变规律,属于"变证、坏证"范畴,病情进展迅速,初见疫毒犯肺,继则疫毒闭肺,甚则出现内闭外脱的危重阶段.西医学认为重症涉及病毒损伤、免疫炎症反应、内皮细胞损伤、血栓形成和肾素-血管紧张素-醛固酮系统失调等一系列病理生理变化.关于COVID-19重症治疗,首先是阻抑重症的发生,必要时不拘卫气营血,可以"先证而治";凝练总结了解毒凉血法、通腑泻肺法和健脾化湿法在COVID-19重症治疗中的作用,并结合西医学研究分析了上述3种治法可能的作用机制.

ObjectiveTo investigate the risk factors for the 90-day prognosis of patients with decompensated liver cirrhosis and type I hepatorenal syndrome (HRS). MethodsA retrospective analysis was performed for the clinical data of 299 patients with decompensated liver cirrhosis and type I HRS who were hospitalized in Beijing Ditan Hospital from October 2008 to October 2018, and according to the 90-day prognosis, they were divided into survival group with 135 patients and death group with 164 patients. The t-test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the chi-square test was used for comparison of categorical data between groups. A multivariate binary logistic regression analysis was used to investigate the influencing factors for 90-day prognosis, and the receiver operating characteristic (ROC) curve was plotted for each factor. ResultsThe univariate analysis showed that there were significant differences between the two groups in Model for End-Stage Liver Disease (MELD) score, Child-Turcotte-Pugh (CTP) score, hepatic encephalopathy, serum Na, serum creatinine (Cr), blood urea nitrogen (BUN), uric acid (UA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), albumin (Alb), cholinesterase (CHE), white blood cell count (WBC), neutrophil (NE), neutrophil-to-lymphocyte ratio (NLR), red blood cell count (RBC), red blood cell distribution width (RDW), platelet count (PLT), and international normalized ratio (INR) (P＜0.05). The multivariate logistic regression analysis showed that Na (odds ratio ［OR］=0.918, 95% confidence interval ［CI］: 0.880-0.957, P＜0.05), BUN (OR=1.077, 95% CI: 1.029-1.127, P＜0.05), RDW (OR=1.019, 95% CI: 1.005-1.032, P＜0.05), and INR (OR=3.478, 95% CI: 2.096-5.771, P＜0.05) were independent influencing factors for poor 90-day prognosis in patients with decompensated liver cirrhosis and type I HRS. A predictive model, HRS-D, was established using the four factors above, and the ROC curves were plotted for each factor to calculate the area under the ROC curve (AUC), which showed that HRS-D had an AUC of 0.813 (95% CI: 0.762-0.864), with a sensitivity of 76.50% and a specificity of 72.50% at the diagnostic cut-off value of -1.264. There was a significant difference between HRS-D score and MELD score (Z=3.804, P＜0.001), while there was no significant difference between HRS-D score and CTP score and between CTP score and MELD score (both P＞0.05). ConclusionNa, BUN, RDW, and INR are independent influencing factors for poor 90-day prognosis in patients with decompensated liver cirrhosis and type I HRS, and the predictive model based on these indices can better predict the 90-day prognosis of HRS patients.

Introduction The platelet count/spleen thickness ratio (PC/ST ratio) is associated with the grade of esophagogastric varices (EGV) in cirrhotic patients, but little is known about its relationship with esophagogastric variceal bleeding (EGVB). The aim of this study was to investigate the association between the PC/ST ratio and the risk of EGVB within 1 year in cirrhotic patients. Methods A total of 1,354 patients with cirrhosis who had EGV were enrolled in this cohort study. A logistic regression model was used to determine the association between the PC/ST ratio and the risk of EGVB within 1 year in patients with cirrhosis by adjusting the PC/ST ratio with all the important clinical variables and confounders. Results The quartile values of the PC/ST ratio were 1.01, 1.36, and 1.98, respectively. The PC/ST ratio was an independent risk factor for variceal bleeding in cirrhotic patients with moderate or severe EGV. After adjusting for multiple variables, the relationship was still unchanged. The odds ratios of the first EGVB in these patients were 5.07-fold at non-adjustment and 3.28-fold after multivariate adjustment. The odds ratios of rebleeding in these patients from the lowest to the highest quartile were 2.34-fold at non-adjustment and 2.01-fold after multivariable adjustment. The PC/ST ratio ≤ 1.36 elevated the 1-year risk of first-time variceal bleeding or rebleeding in cirrhotic patients with moderate or severe EGV (All P < 0.05). Conclusion The PC/ST ratio ≤ 1.36 is an independent risk factor for the onset of first bleeding or rebleeding in cirrhotic patients with moderate or severe EGV.

目的:研究解毒凉血方含药血清对TNFα联合ActD诱导肝衰竭肝细胞凋亡的抑制作用及机制.方法:采用人正常肝细胞Chang liver及肿瘤细胞HepG2筛选解毒凉血方含药血清的有效比例.干预组采用有效比例的解毒凉血方含药血清预刺激24 h,然后采用TNFα联合ActD刺激Chang liver模拟急性肝衰竭肝细胞凋亡,流式细胞术检测各组细胞的凋亡率,免疫荧光实验检测凋亡肝细胞TBFβ1的表达及分布,免疫印迹法检测TGFβ1/Smad信号通路中TGFβ1、p-TβRⅡ、Smad7及p-Smad2/3的表达水平.结果:15％(体积比)解毒凉血方含药血清对TNFα联合ActD诱导的肝细胞凋亡具有抑制作用,15％解毒凉血方含药血清组细胞凋亡率显著低于模型组及空白血清组(P<0.01);与模型组及空白血清组比较,15％解毒凉血方含药血清预处理组胞质中TGFβ1、p-TβRⅡ以及Smad2/3磷酸化(p-Smad2/3)均低水平表达,而Smad7表达水平较高(均P<0.05).结论:解毒凉血健脾方含药血清对TNFα联合ActD刺激诱导的急性肝衰竭肝细胞凋亡具有抑制作用,其机制可能与调节TGFβ1/Smad信号通路有关.

目的:评价凉血解毒法治疗乙肝慢加急性肝衰竭(HBV Acute-on-chronic Liver Failure,HBV-ACLF)的治疗效果和安全性.方法:计算机检索2010年1月至2020年5月公开发表的以中医凉血解毒法为干预手段治疗HBV-ACLF的临床随机对照试验.依照纳排标准进行文献筛选、质量风险评估和资料提取,通过RevMan5.3软件进行荟萃分析.结果:最终纳入20项随机对照试验,共1812例患者.Meta分析结果显示凉血解毒法可以改善临床总有效率(OR=2.61,95％CI为1.93～3.52,Z=6.24,P<0.00001);降低临床死亡率(OR=0.39,95％CI为0.29～0.53,Z=6.14,P<0.00001),降低GPT(MD=-20.86,95％CI为-29.91～-11.80,Z=4.51,P<0.00001)、GOT(MD-4.99,95％CI为-8.05～-1.92,Z=3.19,P=0.001)、TBil(MD=-40.47,95％CI为-45.69～-35.25,Z=15.19,P<0.00001)、MELD(MD=1.19,95％CI为0.29～2.09,Z=2.90,P=0.01),提高白蛋白(MD=2.57,95％CI为1.95～3.19,Z=8.13,P<0.00001)、胆碱酯酶(MD=1.15,95％CI为0.37～1.92,Z=2.90,P=0.004)、凝血酶原活性(MD=11.2、46,95％CI为9.32～13.60,Z=10.50,P<0.00001)水平,改善中医证候(MD=-3.65,95％CI为-4.63～-2.67,Z=7.92,P<0.00001),差异有统计学意义.其中4项临床研究报告了应用凉血解毒法治疗HBV-ACLF的不良反应,并显示其不良反应可自行缓解.结论:凉血解毒法可提高HBV-ACLF患者的临床有效率,降低临床死亡率、改善肝功、凝血功能,且不良反应发生率较低.

BACKGROUND:Hepatocellular carcinoma (HCC) is a common malignant tumor with limited treatment options. Conventional antitumor therapy combined with traditional Chinese medicine (TCM) to limit tumor progression has gradually become the focus of complementary and alternative therapies for HCC treatment. The Fuzheng Jiedu Xiaoji formulation (FZJDXJ) alleviates the clinical symptoms of patients and inhibits tumor progression, but its curative effect still requires extensive clinical research and mechanistic analysis.PURPOSE:To explore the effectiveness of FZJDXJ in HCC patients and investigate its biological function and mechanism underlying anticancer therapy.METHODS:This randomized controlled clinical trial enrolled 291 HCC patients receiving transcatheter arterial chemoembolization (TACE) therapy; patients received either FZJDXJ combined with standard treatment, or standard treatment alone, for 48 weeks. Statistical analyses were performed according to survival time at the end of the trial. The main constituents of the FZJDXJ extracts were identified and evaluated using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and molecular docking. The antitumor effects of FZJDXJ and its specific biological mechanism of action were studied.RESULTS:After 48 weeks of treatment, one-year overall survival (OS) and progression-free survival (PFS) were significantly different between the two groups. Co-administration of FZJDXJ and TACE prolonged the OS of HCC patients, especially in BCLC A or B stage. FZJDXJ and TACE treatment effectively extended the PFS of patients, especially in the BCLC B stage. HPLC-MS/MS identified 1619 active constituents of FZJDXJ, including formononetin, chlorogenic acid (CGA), caffeic acid, luteolin, gallic acid, diosgenin, ergosterol endoperoxide, and lupeol, which may function through the AKT/CyclinD1/p21/p27 pathways. Through molecular docking, CGA and gallic acid could effectively combine with Thr308, an important phosphorylation site of AKT1. FZJDXJ inhibited tumor growth in nude mice. In vitro, FZJDXJ-mediated serum inhibited the proliferation, migration, and invasion of liver cancer cells, and promoted cell apoptosis.CONCLUSION:Clinically, FZJDXJ combined with TACE therapy significantly prolonged OS and PFS and reduced the mortality rate of HCC patients. Mechanistically, FZJDXJ effectively inhibited the proliferation and migration of liver cancer cells through the modulation of the AKT/CyclinD1/p21/p27 pathways, and may be a promising TCM drug for anti-HCC therapy.

目的:探讨健脾解毒凉血方治疗肝损伤肠屏障功能障碍的作用靶点.方法:选取C57BL/6雄性小鼠32只,随机分为正常组、模型组、中药组、培菲康组,腹腔注射硫代乙酰胺100 mg/kg造模;中药组予以健脾解毒凉血方灌胃,培菲康组给予培菲康溶液灌胃;16 h后采集小鼠血清、肝组织、小肠组织,观察小鼠肝功能、肠道组织HE染色变化,免疫组织化学染色方法观察小肠闭锁小带蛋白-1表达.结果:模型组、中药组、培菲康组小鼠的ALT、AST均显著高于正常组,模型组、中药组、培菲康组比较差异无统计学意义(P>0.05).小肠组织在光镜和电镜下均可观察到中药组病变轻于模型组和培菲康组,免疫组织化学染色在小肠上皮细胞上可见闭锁小带蛋白-1棕黄色阳性标记,模型组、中药组、培菲康组阳性标记均显著少于正常组,中药组阳性标记显著多于模型组(P<0.05).结论:健脾解毒凉血方治疗硫代乙酰胺诱导急性肝损伤小鼠,可维护肠上皮细胞紧密连接部闭锁小带蛋白-1表达,修复肠屏障功能.

ObjectiveTo investigate the clinical features of chronic liver disease with immune blood diseases and the clinical effect of glucocorticoid therapy. MethodsA retrospective analysis was performed for the clinical data of 17 patients with chronic liver disease and immune blood diseases who were admitted to Beijing Ditan Hospital from January 2008 to December 2019, and according to the type of blood disease, they were divided into autoimmune hemolytic anemia (AIHA) group, immune thrombocytopenia (ITP) group, and Evans syndrome group. After glucocorticoid therapy and related treatment of liver disease, the three groups were compared in terms of clinical data and laboratory markers before and after treatment. The Mann-Whitney U test was used for comparison of continuous data between two groups. ResultsAmong the 17 patients with chronic liver disease, 15 had no viral hepatitis, among whom 9 (52.9%) had autoimmune liver disease. Among these 17 patients, 6 had AIHA, 8 had ITP, and 3 had Evans syndrome. Glucocorticoid therapy was given for 13 patients, among whom12 achieved complete remission or partial remission, resulting in an overall response rate of 92.3%. After treatment, the ITP group had significant reductions in total bilirubin ［35.8 (14.3-58.0) μmol/L vs 165.6 (21.3-374.3) μmol/L, Z=-2.205, P=0027］ and direct bilirubin ［24.9 (7.0-43.3) μmol/L vs 121.9 (11.7-279.9) μmol/L, Z=-2.205, P=0.027］, and the AIHA group had a significant increase in hemoglobin ［94.0 (65.0-99.3) g/L vs 62.2 (42.3-80.5) g/L, Z=-2.242, P=0.025］. ConclusionImmune blood diseases are observed in patients with various types of chronic liver disease, among which autoimmune liver disease with immune blood diseases has a relatively high incidence rate. Glucocorticoid is a safe and effective therapeutic method for the treatment of chronic liver disease with immune blood diseases.

ObjectiveTo investigate the influencing factors for chronic kidney disease (CKD) in patients with hepatitis B cirrhosis within 3 years. MethodsA total of 376 patients with hepatitis B cirrhosis who attended Beijing Ditan Hospital, Capital Medical University, from January 2014 to July 2017 were enrolled and followed up for 3 years, and according to the presence or absence of CKD, they were divided into CKD group with 23 patients and non-CKD group with 353 patients. Related general information and laboratory markers were collected. The t-test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test or the Fisher’s exact test was used for comparison of categorical data between two groups; a stepwise forward Cox regression analysis was used to screen out the independent influencing factors for CKD within 3 years in patients with hepatitis B cirrhosis. The area under the receiver operating characteristic curve (AUC) was used to investigate the value of the influencing factors in predicting CKD in patients with hepatitis B cirrhosis; the Kaplan-Meier method was used for survival analysis, and the log-rank test was used for comparison of the cumulative incidence rate of CKD between the patients with different risks. ResultsThe multivariate Cox regression analysis showed that age (hazard ratio ［HR］=1.078, 95% confidence interval ［CI］: 1.007-1.114, P=0.026), albumin (Alb) (HR=0.923, 95% CI: 0.860-0.989, P=0.024), and estimated glomerular filtration rate (eGFR) (HR=0.977, 95% CI: 0.955-0.999, P=0.037) were independent influencing factors for CKD within 3 years in patients with hepatitis B cirrhosis. Age, Alb, and eGFR had a relatively good value in predicting CKD, with AUCs of 0.701, 0.710, and 0.706, respectively. The Kaplan-Meier survival curve showed that the patients with baseline age ≥55 years, Alb ＜32 g/L, and eGFR ≥60 ml·min-1·1.73 m-2 and ＜76 ml·min-1·1.73 m-2 had a higher risk of CKD (χ2=9647, 13621, and 30.940, all P＜0.05). ConclusionRenal function should be closely monitored for patients with old age and low Alb and eGFR levels.

Acute-on-chronic liver failure(ACLF) is a reversible and complex clinical syndrome caused by various factors in patients with pre-existing chronic liver diseases,with the clinical features of acute liver function decompensation and high short-term mortality rate.ACLF has a complex pathogenesis,rapid progression,and a dangerous prognosis,and early and accurate prediction of prognosis is of vital importance. At present,there is still no ideal therapy for ACLF,and in recent years,integrated traditional Chinese and Western medicine therapy has achieved a certain effect in the treatment of this disease. This article reviews the advances in prognostic evaluation and integrated traditional Chinese and Western medicine therapy for ACLF,in order to provide guidance to prognostic evaluation of ACLF and selection of the regimens of integrated traditional Chinese and Western medicine therapy.

Background To compare the efficacies of transcatheter arterial chemoembolization (TACE) with radiofrequency ablation (RFA) (TACE + RFA) and TACE alone in patients with hepatocellular carcinoma (HCC) and macrovascular invasion (MVI). Methods In total, 664 patients having HCC with MVI were included. Of these patients, 141 were treated with TACE + RFA, 254 with TACE alone, and 269 with supportive therapy (control group). The overall survival (OS) was compared among these groups. Propensity score matching (PSM) was performed for balancing the characteristics of the three groups. Results After one-to-one PSM, the 12-month OS rates were higher in the TACE and TACE + RFA groups than in the control group (p=0.0009 and p=0.0017, respectively). Furthermore, higher 12-month OS rates were observed in the TACE + RFA group than in the TACE group (p=0.0192). The 12-month OS rates of patients were remarkably higher in α-fetoprotein (AFP) < 400 ng/ml, tumor < 3, tumor diameter < 5 cm, or portal vein tumor thrombosis (PVTT) group who were treated with TACE + RFA than in those who were treated with TACE (p=0.0122, p=0.0090, p=0112, and p=0.0071, respectively). Conclusions TACE + RFA provides a superior survival outcome than TACE alone in HCC patients, especially in AFP <400 ng/ml, tumor <3, tumor diameter <5 cm, or PVTT group.

目的 探讨扶正解毒消积方对早中期原发性肝癌患者2年生存情况的影响及可能作用机制.方法 回顾性分析首都医科大学附属北京地坛医院中西医结合中心首次确诊的原发性肝癌且随访满2年(24个月)的早中期患者76例,根据治疗方式的不同分为扶正解毒消积方组55例和西医治疗组21例.比较两组患者2年病死率,治疗前及治疗6、12、18、24个月时中性粒细胞与淋巴细胞比值(NLR).结果 扶正解毒消积方组2年病死率为12.7％,明显低于西医治疗组的33.3％ (P ＜0.05).扶正解毒消积方组在治疗6、12、18个月时NLR水平与治疗前比较差异无统计学意义(P＞0.05),而治疗24个月与治疗前比较明显升高(P＜0.05).西医治疗组在治疗6、12、18、24个月与治疗前比较NLR均明显升高(P＜0.05).扶正解毒消积方组治疗6、12、18、24个月时NLR水平均明显低于同时间西医治疗组(P＜0.05). 结论 扶正解毒消积方能提高早中期原发性肝癌患者两年生存率,调节维持NLR水平可能是其重要作用机制之一.

This study aimed to develop prognostic models for predicting 28- and 90-day mortality rates of hepatitis B virus (HBV)-associated acute-on-chronic liver failure (HBV-ACLF) through artificial neural network (ANN) systems. Six hundred and eight-four cases of consecutive HBV-ACLF patients were retrospectively reviewed. Four hundred and twenty-three cases were used for training and constructing ANN models, and the remaining 261 cases were for validating the established models. Predictors associated with mortality were determined by univariate analysis and were then included in ANN models for predicting prognosis of mortality. The receiver operating characteristic curve analysis was used to evaluate the predictive performance of the ANN models in comparison with various current prognostic models. Variables with statistically significant difference or important clinical characteristics were input in the ANN training process, and eight independent risk factors, including age, hepatic encephalopathy, serum sodium, prothrombin activity, γ-glutamyltransferase, hepatitis B e antigen, alkaline phosphatase and total bilirubin, were eventually used to establish ANN models. For 28-day mortality in the training cohort, the model’s predictive accuracy (AUR 0.948, 95% CI 0.925–0.970) was significantly higher than that of the Model for End-stage Liver Disease (MELD), MELD-sodium (MELD-Na), Chronic Liver Failure-ACLF (CLIF-ACLF), and Child-Turcotte-Pugh (CTP) (all p < 0.001). In the validation cohorts the predictive accuracy of ANN model (AUR 0.748, 95% CI: 0.673–0.822) was significantly higher than that of MELD (p = 0.0099) and insignificantly higher than that of MELD-Na, CTP and CLIF-ACLF (p > 0.05). For 90-day mortality in the training cohort, the model’s predictive accuracy (AUR 0.913, 95% CI 0.887–0.938) was significantly higher than that of MELD, MELD-Na, CTP and CLIF-ACLF (all p < 0.001). In the validation cohorts, the prediction accuracy of the ANN model (AUR 0.754, 95% CI: 0.697–0.812 was significantly higher than that of MELD (p = 0.019) and insignificantly higher than MELD-Na, CTP and CLIF-ACLF (p > 0.05). The established ANN models can more accurately predict short-term mortality risk in patients with HBV- ACLF. The main content has been postered as an abstract at the AASLD Hepatology Conference (https://doi.org/10.1002/hep.30257).