BACKGROUND Insulin resistance,lipotoxicity,and mitochondrial dysfunction contribute to the pathogenesis of metabolic dysfunction-associated steatotic liver disease(MASLD).Mitochondrial dysfunction impairs oxidative ph...BACKGROUND Insulin resistance,lipotoxicity,and mitochondrial dysfunction contribute to the pathogenesis of metabolic dysfunction-associated steatotic liver disease(MASLD).Mitochondrial dysfunction impairs oxidative phosphorylation and increases reactive oxygen species production,leading to steatohepatitis and hepatic fibrosis.Artificial intelligence(AI)is a potent tool for disease diagnosis and risk stratification.AIM To investigate mitochondrial DNA polymorphisms in susceptibility to MASLD and establish an AI model for MASLD screening.METHODS Multiplex polymerase chain reaction was performed to comprehensively genotype 82 mitochondrial DNA variants in the screening dataset(n=264).The significant mitochondrial single nucleotide polymorphism was validated in an independent cohort(n=1046)using the Taqman®allelic discrimination assay.Random forest,eXtreme gradient boosting,Naive Bayes,and logistic regression algorithms were employed to construct an AI model for MASLD.RESULTS In the screening dataset,only mt12361A>G was significantly associated with MASLD.mt12361A>G showed borderline significance in MASLD patients with 2-3 cardiometabolic traits compared with controls in the validation dataset(P=0.055).Multivariate regression analysis confirmed that mt12361A>G was an independent risk factor of MASLD[odds ratio(OR)=2.54,95%confidence interval(CI):1.19-5.43,P=0.016].The genetic effect of mt12361A>G was significant in the non-diabetic group but not in the diabetic group.mt12361G carriers had a 2.8-fold higher risk than A carriers in the non-diabetic group(OR=2.80,95%CI:1.22-6.41,P=0.015).By integrating clinical features and mt12361A>G,random forest outperformed other algorithms in detecting MASLD[training area under the receiver operating characteristic curve(AUROC)=1.000,validation AUROC=0.876].CONCLUSION The mt12361A>G variant increased the severity of MASLD in non-diabetic patients.AI supports the screening and management of MASLD in primary care settings.展开更多
BACKGROUND Chronic hepatitis C virus(HCV)infection induces profound alterations in the cytokine and chemokine signatures in peripheral blood.Clearance of HCV by antivirals results in host immune modification,which may...BACKGROUND Chronic hepatitis C virus(HCV)infection induces profound alterations in the cytokine and chemokine signatures in peripheral blood.Clearance of HCV by antivirals results in host immune modification,which may interfere with immune-mediated cancer surveillance.Identifying HCV patients who remain at risk of hepatocellular carcinoma(HCC)following HCV eradication remains an unmet need.We hypothesized that antiviral therapy-induced immune reconstruction may be relevant to HCC development.AIM To investigate the impact of differential dynamics of cytokine expression on the development of HCC following successful antiviral therapy.METHODS One hundred treatment-naïve HCV patients with advanced fibrosis(F3/4)treated with direct-acting antivirals(DAAs)or peginterferon/ribavirin who achieved sustained virologic response[SVR,defined as undetectable HCV RNA throughout 12 wk(SVR12)for the DAA group or 24 wk(SVR24)for the interferon group after completion of antiviral therapy]were enrolled since 2003.The primary endpoint was the development of new-onset HCC.Standard HCC surveillance(abdominal ultrasound andα-fetoprotein)was performed every six months during the followup.Overall,64 serum cytokines were detected by the multiplex immunoassay at baseline and 24 wk after end-of-treatment.RESULTS HCC developed in 12 of the 97 patients over 459 person-years after HCV eradication.In univariate analysis,the Fibrosis-4 index(FIB-4),hemoglobin A1c(HbA1c),the dynamics of tumor necrosis factor-α(TNF-α),and TNF-like weak inducer of apoptosis(TWEAK)after antiviral therapy were significant HCC predictors.The multivariate Cox regression model showed thatΔTNF-α(≤-5.7 pg/mL)was the most important risk factor for HCC(HR=11.54,95%CI:2.27-58.72,P=0.003 in overall cases;HR=9.98,95%CI:1.88-52.87,P=0.007 in the interferon group).An HCC predictive model comprising FIB-4,HbA1c,ΔTNF-α,andΔTWEAK had excellent performance,with 3-,5-,10-,and 13-year areas under the curve of 0.882,0.864,0.903,and 1.000,respectively.The 5-year accumulative risks of HCC were 0%,16.9%,and 40.0%in the low-,intermediate-,and high-risk groups,respectively.CONCLUSION Downregulation of serum TNF-αsignificantly increases the risk of HCC after HCV eradication.A predictive model consisting of cytokine kinetics could ameliorate personalized HCC surveillance strategies for post-SVR HCV patients.展开更多
BACKGROUND Prisoners are at risk of hepatitis C virus(HCV)infection,especially among the people who inject drugs(PWID).We implemented an outreach strategy in combination with universal mass screening and immediate ons...BACKGROUND Prisoners are at risk of hepatitis C virus(HCV)infection,especially among the people who inject drugs(PWID).We implemented an outreach strategy in combination with universal mass screening and immediate onsite treatment with a simplified pan-genotypic direct-acting antivirals(DAA)regimen,12 wk of sofosbuvir/velpatasvir,in a PWID-dominant prison in Taiwan.AIM To implement an outreach strategy in combination with universal mass screening and immediate onsite treatment with a simplified pan-genotypic DAA regimen in a PWID-dominant prison in Taiwan.METHODS HCV-viremic patients were recruited for onsite treatment program for HCV micro-elimination with a pangenotypic DAA regimen,12 wk of sofosbuvir/velpatasvir,from two cohorts in Penghu Prison,either identified by mass screen or in outpatient clinics,in September 2019.Another group of HCV-viremic patients identified sporadically in outpatient clinics before mass screening were enrolled as a control group.The primary endpoint was sustained virological response(SVR12,defined as undetectable HCV ribonucleic acid(RNA)12 wk after end-of-treatment).RESULTS A total of 212 HCV-viremic subjects were recruited for HCV micro-elimination campaign;91 patients treated with sofosbuvir/Ledipasvir or glecaprevir/pibrentasvir before mass screening were enrolled as a control.The HCV microelimination group had significantly lower proportion of diabetes,hypertension,hyperlipidemia,advanced fibrosis and chronic kidney diseases,but higher levels of HCV RNA.The SVR12 rate was comparable between the HCV microelimination and control groups,95.8%(203/212)vs 94.5%(86/91),respectively,in intent-to-treat analysis,and 100%(203/203)vs 98.9%(86/87),respectively,in perprotocol analysis.There was no virological failure,treatment discontinuation,and serious adverse event among sofosbuvir/velpatasvir-treated patients in the HCV micro-elimination group.CONCLUSION Outreach mass screening followed by immediate onsite treatment with a simplified pangenotypic DAA regimen,sofosbuvir/velpatasvir,provides successful strategies toward HCV micro-elimination among prisoners.展开更多
Aim:Despite the high cure rate of interferon-free directly acting antivirals(DAAs)for chronic hepatitis C(CHC)patients,the treatment efficacy for patients with preexisting hepatocellular carcinoma(HCC)remains undefine...Aim:Despite the high cure rate of interferon-free directly acting antivirals(DAAs)for chronic hepatitis C(CHC)patients,the treatment efficacy for patients with preexisting hepatocellular carcinoma(HCC)remains undefined.We aimed in the present study to address the issue by using novel DAAs in treating CHC patients who were adherent to treatment in Taiwan.Methods:CHC patients with or without HCC were consecutively enrolled.The primary objective was sustained virological response(SVR)defined as undetectable HCV RNA throughout 12 weeks of a post-treatment follow-up period(SVR12).Only patients with available SVR12 were enrolled for final analysis.Results:A total of 1237 patients(1113 non-HCC,101 inactive HCC and 23 active HCC)were enrolled.The overall SVR12 rate was 98.9%,and was similar between HCV patients with and without pre-existing HCC(98.4%vs.98.9%,P=0.64).While HCC patients were classified as those who had active or inactive HCC,the SVR12 was also similar between patients with and without active HCC(95.7%vs.99.0%,P=0.34).Among the 101 patients without viable HCC at the time of DAA initiation,eighty-four patients exhibited curative therapy and the other 17 ;patients experienced HCC recurrence before DAAs.Among the 23 patients with viable HCC at the time of DAA treatment,10 patients had received curative therapy for HCC whereas the remaining 13 patients had HCC that was never cured.The SVR12 rates were also similar among the four subpopulations,being 98.8%(83/84),100%(17/17),90%(9/10)and 100%(13/13)respectively.Conclusion:CHC patients with HCC who were adherent to potent DAAs achieved similar SVR12 rate compared to those without HCC and could be effectively treated.展开更多
基金Supported by the“Center of Excellence for Metabolic Associated Fatty Liver Disease,National Sun Yat-sen University,Kaohsiung”,No.NSTC 112-2321-B-001-006The Featured Areas Research Center Program within the Framework of the Higher Education Sprout Project by the Ministry of Education in Taiwan,No.MOHW112-TDU-B-221-124007.
文摘BACKGROUND Insulin resistance,lipotoxicity,and mitochondrial dysfunction contribute to the pathogenesis of metabolic dysfunction-associated steatotic liver disease(MASLD).Mitochondrial dysfunction impairs oxidative phosphorylation and increases reactive oxygen species production,leading to steatohepatitis and hepatic fibrosis.Artificial intelligence(AI)is a potent tool for disease diagnosis and risk stratification.AIM To investigate mitochondrial DNA polymorphisms in susceptibility to MASLD and establish an AI model for MASLD screening.METHODS Multiplex polymerase chain reaction was performed to comprehensively genotype 82 mitochondrial DNA variants in the screening dataset(n=264).The significant mitochondrial single nucleotide polymorphism was validated in an independent cohort(n=1046)using the Taqman®allelic discrimination assay.Random forest,eXtreme gradient boosting,Naive Bayes,and logistic regression algorithms were employed to construct an AI model for MASLD.RESULTS In the screening dataset,only mt12361A>G was significantly associated with MASLD.mt12361A>G showed borderline significance in MASLD patients with 2-3 cardiometabolic traits compared with controls in the validation dataset(P=0.055).Multivariate regression analysis confirmed that mt12361A>G was an independent risk factor of MASLD[odds ratio(OR)=2.54,95%confidence interval(CI):1.19-5.43,P=0.016].The genetic effect of mt12361A>G was significant in the non-diabetic group but not in the diabetic group.mt12361G carriers had a 2.8-fold higher risk than A carriers in the non-diabetic group(OR=2.80,95%CI:1.22-6.41,P=0.015).By integrating clinical features and mt12361A>G,random forest outperformed other algorithms in detecting MASLD[training area under the receiver operating characteristic curve(AUROC)=1.000,validation AUROC=0.876].CONCLUSION The mt12361A>G variant increased the severity of MASLD in non-diabetic patients.AI supports the screening and management of MASLD in primary care settings.
基金Kaohsiung Medical University and Kaohsiung Medical University Hospital(KMU-KMUH Co-Project of Key Research),No.KMU-DK107004.
文摘BACKGROUND Chronic hepatitis C virus(HCV)infection induces profound alterations in the cytokine and chemokine signatures in peripheral blood.Clearance of HCV by antivirals results in host immune modification,which may interfere with immune-mediated cancer surveillance.Identifying HCV patients who remain at risk of hepatocellular carcinoma(HCC)following HCV eradication remains an unmet need.We hypothesized that antiviral therapy-induced immune reconstruction may be relevant to HCC development.AIM To investigate the impact of differential dynamics of cytokine expression on the development of HCC following successful antiviral therapy.METHODS One hundred treatment-naïve HCV patients with advanced fibrosis(F3/4)treated with direct-acting antivirals(DAAs)or peginterferon/ribavirin who achieved sustained virologic response[SVR,defined as undetectable HCV RNA throughout 12 wk(SVR12)for the DAA group or 24 wk(SVR24)for the interferon group after completion of antiviral therapy]were enrolled since 2003.The primary endpoint was the development of new-onset HCC.Standard HCC surveillance(abdominal ultrasound andα-fetoprotein)was performed every six months during the followup.Overall,64 serum cytokines were detected by the multiplex immunoassay at baseline and 24 wk after end-of-treatment.RESULTS HCC developed in 12 of the 97 patients over 459 person-years after HCV eradication.In univariate analysis,the Fibrosis-4 index(FIB-4),hemoglobin A1c(HbA1c),the dynamics of tumor necrosis factor-α(TNF-α),and TNF-like weak inducer of apoptosis(TWEAK)after antiviral therapy were significant HCC predictors.The multivariate Cox regression model showed thatΔTNF-α(≤-5.7 pg/mL)was the most important risk factor for HCC(HR=11.54,95%CI:2.27-58.72,P=0.003 in overall cases;HR=9.98,95%CI:1.88-52.87,P=0.007 in the interferon group).An HCC predictive model comprising FIB-4,HbA1c,ΔTNF-α,andΔTWEAK had excellent performance,with 3-,5-,10-,and 13-year areas under the curve of 0.882,0.864,0.903,and 1.000,respectively.The 5-year accumulative risks of HCC were 0%,16.9%,and 40.0%in the low-,intermediate-,and high-risk groups,respectively.CONCLUSION Downregulation of serum TNF-αsignificantly increases the risk of HCC after HCV eradication.A predictive model consisting of cytokine kinetics could ameliorate personalized HCC surveillance strategies for post-SVR HCV patients.
基金Supported by the Kaohsiung Medical University,No.108-2314-B-037-066 and No.DK107004and the Kaohsiung Medical University Hospital,No.KMUH-108-8R05,No.KMUH-DK109002 and No.KMUH-DK109005-1.
文摘BACKGROUND Prisoners are at risk of hepatitis C virus(HCV)infection,especially among the people who inject drugs(PWID).We implemented an outreach strategy in combination with universal mass screening and immediate onsite treatment with a simplified pan-genotypic direct-acting antivirals(DAA)regimen,12 wk of sofosbuvir/velpatasvir,in a PWID-dominant prison in Taiwan.AIM To implement an outreach strategy in combination with universal mass screening and immediate onsite treatment with a simplified pan-genotypic DAA regimen in a PWID-dominant prison in Taiwan.METHODS HCV-viremic patients were recruited for onsite treatment program for HCV micro-elimination with a pangenotypic DAA regimen,12 wk of sofosbuvir/velpatasvir,from two cohorts in Penghu Prison,either identified by mass screen or in outpatient clinics,in September 2019.Another group of HCV-viremic patients identified sporadically in outpatient clinics before mass screening were enrolled as a control group.The primary endpoint was sustained virological response(SVR12,defined as undetectable HCV ribonucleic acid(RNA)12 wk after end-of-treatment).RESULTS A total of 212 HCV-viremic subjects were recruited for HCV micro-elimination campaign;91 patients treated with sofosbuvir/Ledipasvir or glecaprevir/pibrentasvir before mass screening were enrolled as a control.The HCV microelimination group had significantly lower proportion of diabetes,hypertension,hyperlipidemia,advanced fibrosis and chronic kidney diseases,but higher levels of HCV RNA.The SVR12 rate was comparable between the HCV microelimination and control groups,95.8%(203/212)vs 94.5%(86/91),respectively,in intent-to-treat analysis,and 100%(203/203)vs 98.9%(86/87),respectively,in perprotocol analysis.There was no virological failure,treatment discontinuation,and serious adverse event among sofosbuvir/velpatasvir-treated patients in the HCV micro-elimination group.CONCLUSION Outreach mass screening followed by immediate onsite treatment with a simplified pangenotypic DAA regimen,sofosbuvir/velpatasvir,provides successful strategies toward HCV micro-elimination among prisoners.
文摘Aim:Despite the high cure rate of interferon-free directly acting antivirals(DAAs)for chronic hepatitis C(CHC)patients,the treatment efficacy for patients with preexisting hepatocellular carcinoma(HCC)remains undefined.We aimed in the present study to address the issue by using novel DAAs in treating CHC patients who were adherent to treatment in Taiwan.Methods:CHC patients with or without HCC were consecutively enrolled.The primary objective was sustained virological response(SVR)defined as undetectable HCV RNA throughout 12 weeks of a post-treatment follow-up period(SVR12).Only patients with available SVR12 were enrolled for final analysis.Results:A total of 1237 patients(1113 non-HCC,101 inactive HCC and 23 active HCC)were enrolled.The overall SVR12 rate was 98.9%,and was similar between HCV patients with and without pre-existing HCC(98.4%vs.98.9%,P=0.64).While HCC patients were classified as those who had active or inactive HCC,the SVR12 was also similar between patients with and without active HCC(95.7%vs.99.0%,P=0.34).Among the 101 patients without viable HCC at the time of DAA initiation,eighty-four patients exhibited curative therapy and the other 17 ;patients experienced HCC recurrence before DAAs.Among the 23 patients with viable HCC at the time of DAA treatment,10 patients had received curative therapy for HCC whereas the remaining 13 patients had HCC that was never cured.The SVR12 rates were also similar among the four subpopulations,being 98.8%(83/84),100%(17/17),90%(9/10)and 100%(13/13)respectively.Conclusion:CHC patients with HCC who were adherent to potent DAAs achieved similar SVR12 rate compared to those without HCC and could be effectively treated.
