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Objective:To analyze the effect of nucleos(t)ide analog (NAs) antiviral treatment on the clinical features and prognosis of patients with hepatitis B virus-related hepatocellular carcinoma (HBV-HCC).Methods:A retrospective analysis was performed on the data of 450 HBV-HCC patients first diagnosed and treated in the Third Hospital of Hebei Medical University from January 2015 to January 2021, including 193 patients in the continuous NAs treatment group and 257 patients in the NAs treatment after hepatocellular carcinoma (HCC) group. The baseline data of the two groups were balanced by propensity score matching. The relapse-free survival rate of HCC was estimated by Kaplan-Meier method, and the risk factors for HCC recurrence were analyzed by Cox proportional risk models. Spearman correlation analysis was used to explore the association between clinical features of HCC and hepatitis B virus (HBV) DNA load in patients receiving continuous NAs treatment.Results:Before matching, the proportions of liver cirrhosis, body mass index≥25.0 kg/m 2, single tumor, maximum tumor diameter ≤5 cm, Child-Pugh grade A, China liver cancer staging Ⅰ in the continuous NAs treatment group were 93.8%(181/193), 45.1%(87/193), 70.5%(136/193), 82.4%(159/193), 74.6%(144/193) and 74.6%(144/193), respectively. All of them were higher than those in the NAs treatment after HCC group (87.5%(225/257), 44.0%(113/257), 61.1%(157/257), 55.3%(142/257), 63.8%(164/257) and 56.0%(144/257), respectively). The proportions of drinking history and portal vein tumor thrombi in the continuous NAs treatment group were 12.4%(24/193) and 3.1%(6/193), respectively, which were lower than 33.9%(87/257) and 10.5%(27/257) in the NAs treatment after HCC group.The differences were all statistically significant ( χ2=4.86, 7.58, 4.27, 36.63, 8.15, 21.05, 27.21 and 8.88, respectively, all P<0.05). After matching, the median relapse-free survival time of the patients in the continuous NAs treatment group and the NAs treatment after HCC group were 388 days and 277 days, respectively. The five-year cumulative relapse-free survival rates were 50.0% and 37.5%, respectively, with statistically significant difference ( χ2=5.30, P=0.021). Multivariate analysis showed that no antiviral therapy before diagnosis of HCC, multiple tumors, maximum tumor diameter ≥5 cm and palliative treatment were independent risk factors for HBV-HCC recurrence (hazard ratio ( HR)=1.509, 1.491, 0.446 and 1.472, respectively, all P<0.05). After matching, the maximum tumor diameter ( r=0.175, P=0.042), incidence of portal vein tumor thrombi ( r=0.210, P=0.014) and recurrence of HBV-HCC ( r=0.178, P=0.038) in the continuous NAs treatment group were positively correlated with HBV DNA load. Conclusions:Early initiation of NAs antiviral treatment can improve the tumor characteristics when the disease progresses to HBV-HCC, and improve the relapse-free survival rate of HBV-HCC patients. No antiviral therapy before diagnosis of HCC, multiple tumors, maximum tumor diameter ≥5 cm and palliative treatment are independent risk factors for HBV-HCC recurrence.
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Hepatic venous pressure gradient (HVPG) is the "gold standard" for the diagnosis of portal hypertension, which could be applied in the evaluation of liver cirrhosis. Combined use of HVPG with model for end-stage liver disease (MELD) scoring system may more accurately match the donors and recipients undergoing liver transplantation for liver cirrhosis, select the appropriate timing of surgery, and provide guidance for bridging treatment for patients on the waiting list for liver transplantation. Besides, HVPG may also predict clinical prognosis of liver transplant recipients, and provide evidence for early detection and intervention of potential complications. Therefore, the value of HVPG in preoperative evaluation and prognosis prediction of liver transplant recipients was reviewed, aiming to provide guidance for clinical diagnosis and treatment of liver transplant recipients before and after surgery.
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Liver failure is a serious clinical syndrome of liver disease with critical condition and high mortality， and besides liver transplantation， there is still a lack of satisfactory radical treatment methods. The pathogenesis of liver failure is complex and remains unclear， involving a variety of factors that affect the balance of hepatocyte necrosis and regeneration. This article summarizes autophagy as the key pathway for maintaining cell homeostasis and points out that autophagy plays an important protective role in the pathogenesis of liver failure by regulating NLRP3 inflammasome activation， reducing oxidative stress， and inhibiting cell apoptosis. Meanwhile， it is believed that the molecular signaling pathways targeting autophagy， such as exosomes and peroxisome proliferator－activated receptor α， participate in antagonizing the development and progression of liver failure and will become important ideas and directions for molecular targeted therapies for liver failure.
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Objective:To investigate the diagnostic accuracy of serological indicators and evaluate the diagnostic value of a new established combined serological model on identifying the minimal hepatic encephalopathy (MHE) in patients with compensated cirrhosis.Methods:This prospective multicenter study enrolled 263 compensated cirrhotic patients from 23 hospitals in 15 provinces, autonomous regions and municipalities of China between October 2021 and August 2022. Clinical data and laboratory test results were collected, and the model for end-stage liver disease (MELD) score was calculated. Ammonia level was corrected to the upper limit of normal (AMM-ULN) by the baseline blood ammonia measurements/upper limit of the normal reference value. MHE was diagnosed by combined abnormal number connection test-A and abnormal digit symbol test as suggested by Guidelines on the management of hepatic encephalopathy in cirrhosis. The patients were randomly divided (7∶3) into training set ( n=185) and validation set ( n=78) based on caret package of R language. Logistic regression was used to establish a combined model of MHE diagnosis. The diagnostic performance was evaluated by the area under the curve (AUC) of receiver operating characteristic curve, Hosmer-Lemeshow test and calibration curve. The internal verification was carried out by the Bootstrap method ( n=200). AUC comparisons were achieved using the Delong test. Results:In the training set, prevalence of MHE was 37.8% (70/185). There were statistically significant differences in AMM-ULN, albumin, platelet, alkaline phosphatase, international normalized ratio, MELD score and education between non-MHE group and MHE group (all P<0.05). Multivariate Logistic regression analysis showed that AMM-ULN [odds ratio ( OR)=1.78, 95% confidence interval ( CI) 1.05-3.14, P=0.038] and MELD score ( OR=1.11, 95% CI 1.04-1.20, P=0.002) were independent risk factors for MHE, and the AUC for predicting MHE were 0.663, 0.625, respectively. Compared with the use of blood AMM-ULN and MELD score alone, the AUC of the combined model of AMM-ULN, MELD score and education exhibited better predictive performance in determining the presence of MHE was 0.755, the specificity and sensitivity was 85.2% and 55.7%, respectively. Hosmer-Lemeshow test and calibration curve showed that the model had good calibration ( P=0.733). The AUC for internal validation of the combined model for diagnosing MHE was 0.752. In the validation set, the AUC of the combined model for diagnosing MHE was 0.794, and Hosmer-Lemeshow test showed good calibration ( P=0.841). Conclusion:Use of the combined model including AMM-ULN, MELD score and education could improve the predictive efficiency of MHE among patients with compensated cirrhosis.
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Objective:To investigate the diagnostic value of independent and combined subtests of the psychometric hepatic encephalopathy score (PHES) in mild hepatic encephalopathy(MHE) of patients with liver cirrhosis, so as to optimize the PHES.Methods:This was a prospective, multicenter and real-world study which was sponsored by the National Clinical Research Center of Infectious Diseases and the Portal Hypertension Consortium. Twenty-six hospitals from 13 provinces, autonomous regions and municipalities countrywide participated in this study, induding Tianjin Third Central Hospital, the Fourth People′s Hospital of Qinghai Province, the Second Affiliated Hospital of Baotou Medical College, the Third People′s Hospital of Taiyuan, the Fifth Medical Center of PLA General Hospital and so on. From October 2021 to February 2022, outpatients and hospitalized patients with liver cirrhosis and no obvious hepatic encephalopathy were consecutively enrolled. All patients received 5 PHES subjects in the same order: number connection test(NCT)-A, NCT-B, digit symbol test(DST), line tracing test(LTT) and serial dotting test(SDT), and the scores were calculated. The total score of PHES <-4 was taken as the cut-off value for diagnosing MHE. Compare the differences in each subtest between MHE group and non-MHE group. Receiver operating characteristic curve(ROC) and area under the curve(AUC) was performed to assess the diagnostic value of independent and combined subtests in MHE. Mann-Whitney U test and DeLong test were used for statistical analysis. Results:A total of 581 patients with liver cirrhosis were enrolled, 457 were diagnosed as MHE, and the incidence of MHE was 78.7%. The results of NCT-A, NCT-B, SDT, LTT, DST of MHE group were 60.00 s(47.01 s, 88.00 s), 90.45 s(69.32 s, 125.35 s), 74.00 s(57.65 s, 96.60 s), 74.72(60.00, 98.61) and 27.00(20.00, 36.00), respectively. Compared those of non-MHE group(34.00 s(29.15 s, 44.48 s), 50.00 s(40.98 s, 60.77 s), 50.00 s(41.07 s, 63.03 s), 46.23(38.55, 59.42) and 42.00(34.00, 50.75)), the differences were statistically significant( Z=12.37, 12.98, 9.83, 11.56, 10.66; all P<0.001). The AUC(95% confidence interval(95% CI)) of subtests of PHES NCT-B, NCT-A, LTT, DST and SDT alone in MHE diagnosis were 0.880(0.849 to 0.910), 0.862(0.828 to 0.896), 0.838(0.799 to 0.877), 0.812(0.772 to 0.851) and 0.788(0.743 to 0.832), respectively. The combination of 2 PHES subtests significantly increased the diagnostic efficacy. Among them the diagnostic efficacy of the combination of NCT-B and LTT was the best, the AUC(95% CI) was 0.924(0.902 to 0.947), the specificity was 91.9% and the sensitivity was 79.2%, which was better than a single PHES subtest (NCT-A, NCT-B, SDT, LTT and DST) and the combination of NCT-A and DST(AUC was 0.879, 95% CI0.847 to 0.910) which was recommended by guidelines on the management of hepatic encephalopathy in cirrhosis, the differences were statistically significant ( Z=3.78, 3.83, 5.57, 5.51, 5.38, 2.93; all P<0.01). Furthermore, compared between the combination of NCT-B and LTT and the combination of 3 subests of PHES, only the diagnostic efficacy of combination of NCT-B, LTT and SDT (AUC was 0.936, 95% CI 0.916 to 0.956) was better than that of the combination of NCT-B and LTT, the difference was statistically significant( Z=2.32, P=0.020). Conclusion:Based on the diagnostic efficacy and clinical feasibility of PHES subtests and their combinations, the combination of NCT-B and LTT is recommended for the diagnosis of MHE.
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Objective:To investigate the risk factors for anti-tuberculosis drug-induced liver injury (ATB-DILI) in treatment-naive tuberculosis patients, and to provide evidence to avoid the occurrence of ATB-DILI in treatment-naive tuberculosis patients receiving anti-tuberculosis drug treatment.Methods:A retrospective case-control study was carried out in 177 treatment-naive tuberculosis patients admitted to the Third Hospital of Hebei Medical University from January 2014 to December 2019. According to whether developed ATB-DILI during anti-tuberculosis treatment, the patients were divided into non-ATB-DILI group and ATB-DILI group. General basic data of sex, age and body mass index, hepatic biological parameters, prothrombin time, serum ferritin level, basic liver condition and the number of first line hepatotoxic anti-tuberculosis drugs were collected. Mann-Whitney U test and chi-square test were used for statistical analysis, and multi-factor logistic regression analysis was adopted to analyze risk factors for ATB-DILI in treatment-naive tuberculosis patients. Results:The incidence of ATB-DILI was 20.3%(36/177) in the 177 treatment-naive tuberculosis patients. Alanine aminotransferase (ALT), aspartate aminotransferase, incidence of high serum ferritin and the number of first line hepatotoxic anti-tuberculosis drugs were significantly different between non-ATB-DILI group and ATB-DILI group ( Z=-2.13, Z=-2.08, χ2=9.08 and Z=-2.79, respectively, all P<0.050). Multivariate logistic regression analysis showed that chronic viral liver disease (odds ratio ( OR)=9.675, P<0.001), the number of first line hepatotoxic anti-tuberculosis drugs ( OR=4.863, P=0.001), baseline ALT level ( OR=1.016, P=0.011) and high serum ferritin level ( OR=3.336, P=0.018) were the independent risk factors for ATB-DILI. The number of first line hepatotoxic anti-tuberculosis drugs (regression coefficient was 1.582) and baseline ALT level (regression coefficient was 0.016) were both positively correlated with the occurrence of ATB-DILI. Conclusions:Chronic viral liver disease, the number of first line hepatotoxic anti-tuberculosis drugs, higher baseline ALT level and high serum ferritin level are the independent risk factors for ATB-DILI.
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There are complex mechanisms in the development and progression of hepatocellular carcinoma, which have not been fully clarified at present. Zinc finger protein family is the largest transcription factor family in human genome, and more and more evidence has shown that zinc finger proteins play an important role in the development and progression of hepatocellular carcinoma and are expected to become new tumor biomarkers and therapeutic targets for hepatocellular carcinoma. This article reviews the structure and biological functions of zinc finger proteins and their role and regulatory mechanisms in hepatocellular carcinoma.
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Objective@#To explore the risk factors for prognosis in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF), and to establish a prognostic model.@*Methods@#A total of 193 patients diagnosed with HBV-ACLF who were admitted to the Department of Infectious Diseases of the Third Hospital of Hebei Medical University were collected from 1st January 2013 to 1st November 2018 as a derivation cohort. Thirty-five patients diagnosed with HBV-ACLF who were admitted to the Fifth Hospital of Shijiazhuang during the period from 1st July 2017 to 1st November 2018 were collected as a validation cohort. The survival condition of all patients at week 12 of admission was observed. The risk factors associated with short-term prognosis were analyzed by using multivariate logistic regression analysis, and a logistic regression equation prediction model was established and verified. The diagnostic performance of the prognostic model was evaluated using the receiver operating characteristic (ROC) curve, and was compared with model for end-stage liver disease (MELD) scoring system, Child-Turcotte-Pugh (CTP) scoring system, sequential organ failure assessment (SOFA) scoring system and chronic liver failure (CLIF)-SOFA scoring system.@*Results@#Multivariate logistic regression analysis showed that age (odds ratio(OR)=2.133, 95% confidence interval(CI)1.033-4.405), total bilirubin (OR=3.371, 95%CI 1.610-7.060), serum creatinine (OR=4.448, 95%CI 1.697-11.661), hepatic encephalopathy (OR=5.313, 95%CI 2.463-11.461), and ascites (OR=2.959, 95%CI 1.410-6.210) were independent risk factors for predicting the short-term prognosis of patients with HBV-ACLF. The newly established logistic regression model (LRM)=-1.726+ 0.757×age+ 1.215×total bilirubin+ 1.049 2×serum creatinine+ 1.670×hepatic encephalopathy (with=1, without=0) + 1.085×ascites (with=1, without=0). The area under the ROC curve of the LRM for predicting the short-term prognosis of patients with HBV-ACLF was 0.82 (95%CI 0.76-0.88). Furthermore, the areas under the ROC curve of the models of MELD, CTP, SOFA, CLIF-SOFA were 0.67 (95%CI 0.60-0.75), 0.73 (95%CI 0.66-0.80), 0.77 (95%CI 0.70-0.83) and 0.72 (95%CI 0.65-0.80), respectively. The ROC-area under curve of the validation cohort was 0.81 (95%CI 0.65-0.97).@*Conclusions@#Age, total bilirubin, serum creatinine, hepatic encephalopathy, and ascites are independent risk factors for the prognosis of HBV-ACLF. The prognostic model established based on these factors can accurately predict the patients′ short-term prognosis, which is superior to MELD, CTP, SOFA and CLIF-SOFA.
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Objective To validate the predictive value of hepatitis B virus ( HBV )-related hepatocellular carcinoma ( HCC) risk score model D2AS in chronic HBV infection patients without antiviral therapy.Methods A total of 93 patients with chronic HBV infection were selected between January 2015 and July 2017 in the Third Affiliated Hospital of Hebei Medical University.Clinical data including age , gender, medical history, ultrasonography, hepatitis B surface antigen ( HBsAg), hepatitis B surface antibody ( anti-HBs), hepatitis B e antigen ( HBeAg), hepatitis B e antibody ( anti-HBe), hepatitis B core antibody ( anti-HBc), HBV DNA and alanine aminotransferase levels were collected by information center .REACH-B score and D2AS score were used to predict the risk of HCC.Receiver operating characteristic curve (ROC) was used to evaluate the discrimination , and Hosmer-Lemeshow ( H-L) goodness-of-fit test was used to evaluate the calibration of the model.Results REACH-B score and D2 AS score for the 95 chronic HBV infection patients were 9 (8,12) and 0.95 (0.57,2.08), respectively.The area under the curve ( AUC) for REACH-B score and D2 AS score were 0.916 (95% confidence interval [ CI] 0.834-0.998) and 0.784 (95%CI 0.587-0.981), respectively.The difference was not statistically significant ( P ＝0.195).However, for HBeAg-negative patients with chronic HBV infection , the AUC for D2 AS score and REACH-B score were 0.952 (95%CI 0.876-1.000) and 0.913 (95%CI 0.821-1.000), respectively (P＝0.458).The H-L goodness-of-fit test was P＞0.05.Conclusions The D2 AS score can be used for HCC prediction among patients who do not meet antiviral criteria.The predictive value of the D 2AS score for HCC is comparable to the REACH-B score in HBeAg-negative patients with chronic HBV infection.
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Objective To explore the risk factors for prognosis in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF),and to establish a prognostic model.Methods A total of 193 patients diagnosed with HBV-ACLF who were admitted to the Department of Infectious Diseases of the Third Hospital of Hebei Medical University were collected from 1st January 2013 to 1st November 2018 as a derivation cohort.Thirty-five patients diagnosed with HBV-ACLF who were admitted to the Fifth Hospital of Shijiazhuang during the period from 1st July 2017 to 1st November 2018 were collected as a validation cohort.The survival condition of all patients at week 12 of admission was observed.The risk factors associated with short-term prognosis were analyzed by using multivariate logistic regression analysis,and a logistic regression equation prediction model was established and verified.The diagnostic performance of the prognostic model was evaluated using the receiver operating characteristic (ROC) curve,and was compared with model for end-stage liver disease (MELD) scoring system,Child-Turcotte-Pugh (CTP) scoring system,sequential organ failure assessment (SOFA) scoring system and chronic liver failure (CLIF)-SOFA scoring system.Results Multivariate logistic regression analysis showed that age (odds ratio (OR) =2.133,95％ confidence interval (CI) 1.033-4.405),total bilirubin (OR =3.37 1,95％CI 1.610-7.060),serum creatinine (OR =4.448,95％C1 1.697-11.661),hepatic encephalopathy (OR =5.313,95％CI2.463-11.461),and ascites (OR =2.959,95％CI 1.410-6.210) were independent risk factors for predicting the short-term prognosis of patients with HBV-ACLF.The newly established logistic regression model (LRM) =-1.726 + 0.757 × age + 1.215 × total bilirubin + 1.049 2 × serum creatinine + 1.670 × hepatic encephalopathy (with =1,without =0) + 1.085 × ascites (with =1,without =0).The area under the ROC curve of the LRM for predicting the short-term prognosis of patients with HBV-ACLF was 0.82 (95％CI0.76-0.88).Furthermore,the areas under the ROC curve of the models of MELD,CTP,SOFA,CLIF-SOFA were 0.67 (95％CI 0.60-0.75),0.73 (95％CI 0.66-0.80),0.77 (95％CI 0.70-0.83) and 0.72 (95％CI 0.65-0.80),respectively.The ROC-area under curve of the validation cohort was 0.81 (95％CI0.65-0.97).Conclusions Age,total bilirubin,serum creatinine,hepatic encephalopathy,and ascites are independent risk factors for the prognosis of HBV-ACLF.The prognostic model established based on these factors can accurately predict the patients' short-term prognosis,which is superior to M ELD,CTP,SOFA and C LIF-SOFA.
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Objective To assess the efficacy and safety of 100 mg or 200 mg yimitasvir phosphate combined with sofosbuvir in patients with non-cirrhotic chronic hepatitis C virus ( HCV) genotype 1 infection who were treatment-na?ve or had a virologic failure to prior interferon-based treatment.Methods A multicenter, randomized, open-label, phase 2 clinical trial was conducted.The patients were randomly assigned to yimitasvir phosphate 100 mg+sofosbuvir 400 mg group (Group 100 mg) and yimitasvir phosphate 200 mg+sofosbuvir 400 mg group ( Group 200 mg) in a 1∶1 ratio with the stratified factors of " treatment-naive" or"treatment-experienced" for 12 weeks and followed up for 24 weeks after the end of treatment.During the clinical trial, HCV RNA was tested in all patients.Resistance of virus in patients who didn′t achieved sustained virological response (SVR) was monitored.Safety and tolerability were assessed by monitoring adverse events , physical examination , laboratory examination, electrocardiogram, and vital signs during the study.The primary end point was SVR12 after the end of therapy.Descriptive statistics were used for categorical variables and eight descriptive statistics were used for continuous variables.Descriptive statistics were used and summarized according to HCV genotypes and treatment groups.Safety data were presented using descriptive statistics and summarized according to treatment groups.Results A total of 174 subjects were screened from July 31, 2017 to September 26, 2018.One hundred and twenty-nine patients were successfully enrolled and received treatment , and 127 completed the study.There were 64 patients and 65 patients assigned to Group 100 mg and Group 200 mg, respectively.Among the 129 patients who underwent randomization and were treated , 18.6% were treatment-experienced and: 100%were HCV genotype 1b infection.The total SVR rate was 98.4%(127／129), with 98.4%(63／64, 95%confidence interval [CI]: 91.60%-99.96%) in the Group 100 mg, and 98.50%(64／65, 95%CI: 91.72%-99.96%) in the Group 200 mg.There was no significant difference between the two groups (χ2 ＝0.000 2, P＝0.989 2).The SVR rates in treatment-naive group and treatment-experienced group were 98.10%(95%CI: 93.29%-99.77%) and 100.00%(24／24, 95%CI: 85.75%-100.00%), respectively.Virological failure during treatment ( including breakthrough , rebound and poor efficacy) and relapse after treatment did not occur during the trial.By Sanger sequencing , 11.6%(15／129) patients had baseline NS5A Y93H／Y or Y93H resistance-associated substitutions ( RAS), 1.6%( 2／129) patients had baseline NS5A L31M RAS.No mutation was observed in NS5B S282 at baseline.There was no S282 mutation in HCV NS5B.A total of 100 (77.5%) subjects had adverse events.No adverse events ≥Grade 3 or severe adverse events related to the study treatment.No patient prematurely discontinued study treatment owing to an adverse event.No life-threatening adverse event was reported.Conclusion Twelve weeks of yimitasvir phosphate 100 mg or 200 mg combined with sofosbuvir 400 mg daily is a highly effective and safe regimen for patients without cirrhosis with HCV genotype 1b infection who had not been treated previously or had a virologic failure to prior interferon-based treatment.
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A lack of effective drugs and technical means to eradicate hepatitis B virus (HBV) is a bottleneck that limits the ability to fully cure HBV infection. Recently, genome-editing technology based on clustered regularly interspaced short palindromic repeats -associated protein 9 is an emerging technique for editing specific gene loci, which can specifically target HBV covalently closed circular DNA, effectively inhibits HBV DNA replication and regulates HBV functional protein expression, and is expected to become a powerful gene therapy tool for the complete eradication of HBV. Considering this, it has become the focus of attention for scholars at home and abroad that how to use clustered regularly interspaced short palindromic repeats -associated protein 9 to accomplish modification of HBV genomes for complete eradication of HBV. This paper summarizes the latest progress based on the latest research results at home and abroad in the application of clustered regularly interspaced short palindromic repeats -associated protein 9 gene editing technology in anti-HBV infection treatment, and expounds its potential and challenges as a radical cure for HBV infection.
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Objective@#To evaluate the safety and efficacy of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) 25/150/100 mg once daily combined with dasabuvir 250mg, twice daily in non-cirrhotic Chinese adult patients with newly diagnosed and treated chronic HCV genotype 1b infection. @*Methods@#A randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial was conducted in mainland China, Korea, and Taiwan.Safety and efficacy of OBV/PTV/r plus DSV administered for 12 weeks were evaluated in a newly diagnosed and treated (interferon alpha /pegylated interferon alpha) and ribavirin non-cirrhotic adults with chronic HCVgenotype 1b infection. Patients randomly received OBV/PTV/r plus DSV for 12 weeks (Group A), or placebo for 12 weeks (Group B) followed by an open-label phase of OBV/PTV/r plus DSV for 12 weeks. Sustained response (SVR12) rate obtained at 12 weeks and (SVR24) 24 weeks after discontinuation of treatment, and the incidence of adverse events and laboratory abnormalities after double-blind and open-label phase treatment were assessed. @*Results@#A total of 410 cases of Chinese patients were included and randomly assigned to group A and B (with 205 cases in each group) in a 1:1 ratio. The rates of SVR12 and SVR24 were 99% (95% CI: 94.8% - 99.8%) in the newly diagnosed patients in group A (205 patients) and the rates of SVR12 and SVR24 were 100% in treated patients (95% CI: 96.3% - 100%). Different baseline characteristics had no effect on SVR12 and SVR24 rates. Most of the adverse events occurred were mild, asymptomatic, and≥ 3 laboratory abnormalities during treatment were rare, including elevation of alanine aminotransferase (2 cases in double-blind stage A group), aspartate aminotransferase (Double-blind stage A (3 cases) and total bilirubin (1 case in open-label phase B group); however, those mild adverse events could be recovered after drug withdrawal or discontinuation. only1 person discontinued drugs due to adverse events (Group B, open-label phase). @*Conclusion@#The 12 weeks treatment course of OBV/PTV/r combined with DSV produced 99% ~ 100% rates of SVR12 and SVR24 in non-cirrhotic Asian adult patients with newly diagnosed and treated chronic HCV genotype 1b infection, and the tolerance and safety were good.
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Resident standardization training is an essential way in cultivating medical professionals. It is important for subject development and talent reserve. For cultivating high-quality resident physicians with comprehensive theory, independent clinical thinking, great practical ability, and innovative scientific idea, it recourses to both optimizing training scheme and evaluation system with highly specialization and comprehensive quality. In this study, the authors proposed incorporate training patterns includingoptimiz-ing design, innovating training, and standardized assessment based on their recent experience on resident standardization training.
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Objective To investigate the differences of expression and activation of natural killer (NK) cell G2D (NKG2D) in patients with different immune status of chronic hepatitis B virus (HBV) infection, and to explore the significance of NKG2D-mediated immune injury in HBV infection.Methods Fifteen chronic HBV carriers (immune tolerance),15 chronic hepatitis B (CHB, immune activation) patients, 15 HBV-related acute/subacute-on-chronic liver failure (HBV-ACLF, immune over-activation) patients were enro1led in this study from January 2010 to December 2011 in the Third Hospital of Hebei Medical University.The frequencies of NK cells and NKG2D+ NK cells in peripheral blood mononuclear cells (PBMC) were detected by flow cytometry.The NKG2D mRNA expressions were measured by real-time fluorescent quantitative polymerase chain reaction.Localization and hemi-quantitative analysis of NKG2D+ cells in liver tissue were performed by immunohistochemistry staining.Concentrations of serum interferon(IFN)-γ, tumor necrosis factor(TNF)-α, perforin and granzyme B were quantified by enzyme 1inked immunosorbent assay (ELISA).Normally distributed continuous variables were analyzed using one-way analysis of variance (ANOVA), followed by Student-Newman-Keuls q test for evaluating variances between each two groups.For non-normally distributed data or heterogeneity of variance, differences between groups were analyzed using nonparametric Kruskal-Wallis H test, followed by Nemenyi test for pairwise comparisons.Pearson chi-square test was used to analyze categorical variables.Results The percentages of NK cells in PBMC were (13.58±3.24)% in healthy controls, (5.42±2.18)% in chronic HBV carriers, (7.92±2.85)% in HBV-ACLF group and (8.43±2.92)% in CHB group.The percentage of NK cells in PBMCs was lower in each chronic HBV-infected group compared with healthy controls (F=22.04, P<0.05).The frequency of NKG2D+ NK cells in HBV-ACLF group (18.92±5.85)% was the highest, followed by CHB group (12.85±3.39)%, healthy controls (8.45±2.86)%, and chronic HBV carriers (3.36±1.05%), with the statistically significant differences between each two groups (H=46.09, P<0.01).Intrahepatic NKG2D mRNA expression and NKG2D+ cells density were highest in HBV-ACLF group (6.58±1.86 and 30.69±6.67, respectively), followed by CHB group (3.25±0.95 and 17.36±4.13, respectively) and chronic HBV carriers (0.69±0.20 and 3.16±1.24, respectively), with the statistically significant differences between each two groups (H=52.10 and 52.73 respectively, both P<0.01).The similar patterns were observed in serum IFN-γ, TNF-α, perforin and granzyme B concentrations.Conclusions NKG2D expresses variously in patients with different immune status of chronic HBV infection.Activation of NKG2D may take part in the immune pathogenesis of chronic HBV infection.
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Objective@#To investigate the knowledge of nonalcoholic fatty liver disease (NAFLD) among medical staff and general population in Hebei Province, China, understand the degree of awareness of NAFLD among residents, standardize the diagnosis and treatment of NAFLD, improve the correct awareness of NAFLD among general population, promote the establishment of a reasonable lifestyle, and scientifically and effectively control the incidence and mortality rates of NAFLD.@*Methods@#The investigation was performed in 30 hospitals and neighboring schools and communities in Hebei Province, and a questionnaire survey on the knowledge of NAFLD was performed for 1 300 medical workers and 2 000 persons from the general population. EpiData3.1 software was used to input data, and SPSS21.0 was used for statistical analysis. The chi-square test was used for comparison of rates between groups.@*Results@#Of all medical staff, 39.0% knew that liver biopsy was the gold standard for the diagnosis of NAFLD; 63.7% thought liver biopsy had the highest diagnostic value, followed by liver ultrasound (61.0%) and liver CT (48.1%); only 1.2% thought improvement of insulin resistance was the preferred treatment for NAFLD. Among 486 medical workers who had participated in the diagnosis and treatment of NAFLD, only 1.2% thought that the patients had good compliance. Of all persons from the general population, 15.2% thought NAFLD was infectious and 58.6% thought NAFLD might progress to liver cirrhosis or liver cancer. Of all respondents with body mass index ≥28 kg/m2, 17.8% did not know that he/she had obesity, and as high as 55.8% were obese or did not control body weight within the past 1 year. Of all NAFLD patients, 50.5% were complicated by hyperlipidemia, 18.5% were complicated by diabetes, and 29.5% were complicated by hypertension; 43.0% had not received standardized treatment, and among the other 57.0% respondents who received treatment, 79.0% were given non-drug treatment such as reasonable diet and physical exercise. In NAFLD patients who were not improved after treatment, the major cause of failure was that they were not able to stick to healthy living habits. Most NAFLD patients were willing to obtain the knowledge of disease through television, website, and newspaper.@*Conclusion@#Medical staff do not have enough awareness of NAFLD, and some of them cannot perform standardized diagnosis and treatment of NAFLD with reference to clinical guidelines. Therefore, the education on NAFLD should be enhanced for medical staff to guide them to perform accurate screening, diagnosis, evaluation, and treatment of NAFLD. The general population has low awareness of NAFLD and NAFLD patients have poor treatment compliance, which are important causes of increased incidence rate of NAFLD and disease progression. The general population should be educated about NAFLD to help them establish a reasonable lifestyle.
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Chronic HBV infection may not only cause liver damage , but also lead to renal injury . HBV-related kidney injuries mainly include ( 1 ) HBV-associated glomerulonephritis , ( 2 ) hepatorenal syndrome, and (3) kidney injuries caused by long-term nucleos(t)ide analogues therapy.This paper mainly reviews the pathogenesis and therapeutic principle of HBV-related kidney injuries , so as to provide the foundation for clinical management .
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Objective To investigate the mechanism of live combined Bifidobacterium and Lactobacillus tablets in acute liver failure (ALF) treatment.Methods Ten mice were injected intraperitoneally with 3.0 g/kg D-galactosamine to establish the model of ALF and treated with live combined Bifidobacterium and Lactobacillus tablets.Protein levels of Jagged1,Notch1,Notch intracellular domain (NICD),Hes5 and the mRNA expressions of Jagged1,Notch1,Hes5 were measured via Western blot and real time-polymerase chain reaction (PCR),respectively.The protein level of CD68 was detected by immunohistochemical staining method.Meanwhile,serum alanine aminotransferase (ALT),aspartate aminotransferase (AST),interleukin (IL)-10,high mobility group protein B1 (HMGB1) and plasma lipopolysaccharide (LPS) were measured.Moreover,model group and control group were also established with 10 mice each.In vitro,RAW264.7 cells were cultured with normal mice plasma,plasma of ALF mice and plasma of treated mice,respectively.Real time-PCR and Western blot were used to determine the mRNA expressions of Jagged1,Notch1,Hes5 and proteins levels of Jagged1,Notch1,NICD,Hes5.The levels of IL-10,HMGB1 and LPS in the supernatant of RAW264.7 cells were detected as well.The total significant differences among groups were compared by one way ANOVA,and q test was used to evaluate the significance of subgroup differences.Results The levels of serum ALT,AST,HMGB1,IL10,plasma LPS,and the expressions of Jagged1,Notch1,NICD,Hes5,CD68 were higher in ALF model group than control group (all P＜0.01).Compared with the ALF model group,all of these indexes could be improved in mice with live combined Bifidobacterium and Lactobacillus tablets (HMGB1:[82.6±9.7] μg/L vs [101.9±12.4] μg/L,q=6.36,P＜0.01; IL-10.:[3 183±769] pg/mL vs [4 628±842] pg/mL,q=6.79,P＜0.01; plasma LPS:[7.40±0.92] EU/mL vs [11.80±0.89] EU/mL,q=18.81,P＜0.01; Jagged1 mRNA:5.55±0.71 vs 7.63±1.41,q=7.22,P＜0.01;Jagged1 protein:0.56±0.07 vs 0.71±0.07,q=7.20,P＜0.01; Notch1 mRNA:3.66±0.67 vs 7.10±0.66,q=20.06,P＜0.01; Notch1 protein:0.38±0.08 vs 0.66±0.11,q=9.57,P＜0.01;NICD protein:0.47±0.05 vs 0.76±0.07,q=12.68,P＜0.01; Hes5 mRNA:3.94±0.68 vs 7.95± 0.71,q=22.40,P＜0.01; Hes5 protein:1.04±0.12 vs 1.20±0.07,q=5.61,P＜0.01; CD68 protein:5 180±610 vs 7 685 ±417,q=16.38,P＜0.01).And the differences were statistically significant.After RAW264.7 cells cultured with the plasma of ALF model mice,the levels of HMGB1,IL-10 and LPS in the supernatant and the expressions of Jagged1,Notch1,NICD and Hes5 in cells were increased,whereas if RAW264.7 cells were cultured with the plasma of treated mice,indexes mentioned above were significantly decreased (all P＜0.01).Conclusions Live combined Bifidobacterium and Lactobacillus tablet could prevent the occurrence and development of ALF by decreasing the plasma level of LPS,inhibiting the activation of Notch signaling pathway in macrophages and reducing the secretion of HMGB1 and IL-10.
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The activation of NK cell , mediated by natural killer group 2 ( NKG2 ) family receptor , plays an important role in antiviral immune response and disease progression after hepatitis B virus (HBV) infection.To explore the NKG2 receptors-mediated NK cell activation and its mechanism may be of value for anti-HBV targeting immune treatment .This article reviews the recent research progress on the role of NK cells and its NKG2 family receptors in immunity of chronic HBV infection and its mechanisms .
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<p><b>OBJECTIVE</b>To investigate the role of the Notch signaling pathway, and the underlying mechanism, in development of acute liver failure (ALF) in a mouse model.</p><p><b>METHODS</b>For in vivo analysis of the role of Notch signaling in ALF, a mouse model of ALF was generated by intraperitoneal injection of 3.0 g/kg D-galactosamine. Histological specimens were stained by hematoxylin-eosin, and then studied microscopically.Expression level of Jaggedl, Notchl, NICD, and Hes5 was measured by western blotting (for protein) and real time-PCR (for mRNA). The level of CD68 protein was detected by immunohistochemical staining. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), IL-10, high mobility group box 1 (HMGB1) chromatin protein, and lipopolysaccharide (LPS) were measured by standard methods. For in vitro analysis of the molecular mechanism, the RAW264.7 macrophage cell line was cultured with LPS in the absence or presence of the Notch inhibitor DAPT, and the intracellular levels of Notch1, NICD, and Hes5 were measured by western blotting and real time-PCR and the extracellular levels of IL-10 and HMGB1 were detected in the supematant.</p><p><b>RESULTS</b>Compared with unmodeled (normal control) mice, the ALF modeled mice showed higher levels of serum ALT (848.40+/-94.83 U/L vs. 38.99+/-9.63 U/L), AST (911.49+/-67.65 U/L vs. 55.28+/-7.50 U/L), HMGB1 (101.91+/-12.43 µg/L vs. 20.73+/-5.37 µg/L), 1L-10 (4 627.88+/-842.45 pg/mL vs. 1 064.92+/-238.46 pg/mL) and LPS (11.80+/-0.89 EU/mL vs. 0.58+/-0.12 EU/mL), as well as higher expression of Jagged1 (mRNA: 7.63+/-1.41 vs. 1.00+/-0.00; protein: 0.71+/-0.07 vs. 0.34+/-0.07), Notch1 (mRNA: 7.10+/-0.66 vs. 1.00+/-0.00; protein: 0.66+/-0.11 vs. 0.27+/-0.08), NICD (protein: 0.76+/-0.08 vs. 0.27+/-0.08), Hes5 (mRNA: 7.95+/-0.71 vs. 1.00+/-0.00; protein: 1.20+/-0.07 vs. 0.76+/-0.07), and CD68 (protein: 7 685.05+/-417.34 vs. 2 294.01+/-392.93) (all P<0.01). In vitro, LPS increased the extracellular levels of HMGB1 (7.44+/-0.63 vs. 0.21+/-0.05), IL-10 (315.19+/-79.13 vs. 59.19+/-23.30) and the intracellular expression of Notch1 (mRNA: 6.49+/-0.73 vs. 1.00+/-0.00), NICD (protein: 0.65+/-0.10 vs. 0.23+/-0.07), and Hes5 (mRNA: 7.30+/-0.85 vs. 1.00+/-0.00; protein: 0.96+/-0.10 vs. 0.54+/-0.07) (all P<0.01). DAPT treatment led to a decrease above the index serum levels of HMGB1 (6.22+/-0.71) and IL-10 (252.06+/-57.63), and of expression of Notch 1 (mRNA: 3.20+/-0.68), NICD (protein: 0.42+/-0.05), and Hes5 (mRNA: 4.72+/-0.67; protein: 0.84+/-0.09) (P<0.01 or <0.05).</p><p><b>CONCLUSION</b>The Notch signaling pathway may plan an important role in the development of ALF upon activation of the pathway in macrophages by LPS and leading to promoted secretion of HMGB 1 and IL-10, with a greater effect on the former.</p>