Machine-learning-based plasma metabolomic profiles for predicting long-term complications of cirrhosis.

BACKGROUND AND AIMS: The complications of liver cirrhosis occur after long asymptomatic stages of progressive fibrosis and are generally diagnosed late. We aimed to develop a plasma metabolomic-based score tool to predict these events. APPROACH AND RESULTS: We enrolled 64,005 UK biobank participants with metabolomic profiles. Participants were randomly divided into the training (n=43,734) and validation cohorts (n=20,271). Liver cirrhosis complications were defined as hospitalization for liver cirrhosis or presentation with HCC. An interpretable machine-learning framework was applied to learn the metabolomic states extracted from 168 circulating metabolites in the training cohort. An integrated nomogram was developed and compared to conventional and genetic risk scores. We created 3 groups: low-risk, middle-risk, and high-risk through selected cutoffs of the nomogram. The predictive performance was validated through the area under a time-dependent receiver operating characteristic curve (time-dependent AUC), calibration curves, and decision curve analysis. The metabolomic state model could accurately predict the 10-year risk of liver cirrhosis complications in the training cohort (time-dependent AUC: 0.84 [95% CI: 0.82-0.86]), and outperform the fibrosis-4 index (time-dependent AUC difference: 0.06 [0.03-0.10]) and polygenic risk score (0.25 [0.21-0.29]). The nomogram, integrating metabolomic state, aspartate aminotransferase, platelet count, waist/hip ratio, and smoking status showed a time-dependent AUC of 0.930 at 3 years, 0.889 at 5 years, and 0.861 at 10 years in the validation cohort, respectively. The HR in the high-risk group was 43.58 (95% CI: 27.08-70.12) compared with the low-risk group. CONCLUSIONS: We developed a metabolomic state-integrated nomogram, which enables risk stratification and personalized administration of liver-related events.

Protein truncating variants in mitochondrial-related nuclear genes and the risk of chronic liver disease.

BACKGROUND: Mitochondrial (MT) dysfunction is a hallmark of liver diseases. However, the effects of functional variants such as protein truncating variants (PTVs) in MT-related genes on the risk of liver diseases have not been extensively explored. METHODS: We extracted 60,928 PTVs across 2466 MT-related nucleus genes using whole-exome sequencing data obtained from 442,603 participants in the UK Biobank. We examined their associations with liver dysfunction that represented by the liver-related biomarkers and the risks of chronic liver diseases and liver-related mortality. RESULTS: 96.10% of the total participants carried at least one PTV. We identified 866 PTVs that were positively associated with liver dysfunction at the threshold of P value < 8.21e - 07. The coding genes of these PTVs were mainly enriched in pathways related to lipid, fatty acid, amino acid, and carbohydrate metabolisms. The 866 PTVs were presented in 1.07% (4721) of participants. Compared with participants who did not carry any of the PTVs, the carriers had a 5.33-fold (95% CI 4.15-6.85), 2.82-fold (1.69-4.72), and 4.41-fold (3.04-6.41) increased risk for fibrosis and cirrhosis of liver, liver cancer, and liver disease-related mortality, respectively. These adverse effects were consistent across subgroups based on age, sex, body mass index, smoking status, and presence of hypertension, diabetes, dyslipidemia, and metabolic syndrome. CONCLUSIONS: Our findings revealed a significant impact of PTVs in MT-related genes on liver disease risk, highlighting the importance of these variants in identifying populations at risk of liver diseases and facilitating early clinical interventions.

Prognostic factors for competing risk in patients with AIDS-related Kaposi's sarcoma: A SEER population-based study.

OBJECTIVES: Despite the improved survival of patients with AIDS and Kaposi's sarcoma (KS), competing events are a non-negligible issue affecting the survival of such patients. In this study, we explored the prognostic factors of KS-specific and non-KS-specific mortality in patients with AIDS-related KS (AIDS-KS), accounting for competing risk. METHODS: We identified 17 103 patients with AIDS-KS aged 18-65 years between 1980 and 2016 from the Surveillance, Epidemiology, and End Results (SEER) 18 registry database. Prognostic factors for KS-specific and non-KS-specific mortality were determined by the Fine and Grey proportional subdistribution hazard model. We built competing risk nomograms and assessed their predictive performance based on the identified prognostic factors. RESULTS: In total, 12 943 (75.68%) patients died, 1965 (15.50%) of whom died from competing events. The KS-specific mortality rate was 14 835 per 100 000 person-years, and the non-KS specific mortality rate was 2719 per 100 000 person-years. Specifically, age >44 years was associated with an 11% decrease in the subdistribution hazard of KS-specific mortality compared with age <43 years but a 50% increase in the subdistribution hazard of non-KS-specific mortality. Being male was associated with a 26% increase in the subdistribution hazard of KS-specific mortality compared with being female but a 32% decrease in the subdistribution hazard of non-KS-specific mortality. Notably, being in the antiretroviral therapy (ART) era consistently showed a decrease in the subdistribution hazard of both KS-specific and non-KS-specific mortality than being in the pre-ART era. CONCLUSIONS: Competing events commonly occurred among patients with AIDS-KS, which deserves further attention to improve the prognosis of these patients.

Changing prevalence of chronic hepatitis B virus infection in China between 1973 and 2021: a systematic literature review and meta-analysis of 3740 studies and 231 million people.

OBJECTIVE: China concentrates a large part of the global burden of HBV infection, playing a pivotal role in achieving the WHO 2030 global hepatitis elimination target. METHODS: We searched for studies reporting HBV surface antigen (HBsAg) seroprevalence in five databases until January 2023. Eligible data were pooled using a generalised linear mixed model with random effects to obtain summary HBsAg seroprevalence. Linear regression was used to estimate annual percentage change (APC) and HBsAg prevalence in 2021. RESULTS: 3740 studies, including 231 million subjects, were meta-analysed. HBsAg seroprevalence for the general population decreased from 9.6% (95% CI 8.4 to 10.9%) in 1973-1984 to 3.0% (95% CI 2.1 to 3.9%) in 2021 (APC=-3.77; p<0.0001). Decreases were more pronounced in children <5 years (APC=-7.72; p<0.0001) and 5-18 years (-7.58; p<0.0001), than in people aged 19-59 years (-2.44; p<0.0001), whereas HBsAg seroprevalence increased in persons ≥60 years (2.84; p=0.0007). Significant decreases were observed in all six major Chinese regions, in both men (APC=-3.90; p<0.0001) and women (-1.82; p<0.0001) and in high-risk populations. An estimated 43.3 million (95% uncertainty interval 30.7-55.9) persons remained infected with HBV in China in 2021 (3.0%), with notable heterogeneity by region (<1.5% in North China to>6% in Taiwan and Hong Kong) and age (0.3%, 1.0%, 4.7% and 5.6% for <5 years, 5-18 years, 19-59 years and ≥60 years, respectively). CONCLUSIONS: China has experienced remarkable decreases in HBV infection over the last four decades, but variations in HBsAg prevalence persist in subpopulations. Ongoing prevention of HBV transmission is needed to meet HBV elimination targets by 2030. TRIAL REGISTRATION NUMBER: PROSPERO (CRD42021284217).

Associations of healthy lifestyle and three latent socioeconomic status patterns with physical multimorbidity among middle-aged and older adults in China.

BACKGROUND: Multimorbidity is an emerging global public health concern. However, complex associations of healthy lifestyle and socioeconomic status (SES) with multimorbidity have not been identified. METHODS: This population-based prospective cohort study used data from four waves of the China Health and Retirement Longitudinal Study (CHARLS) to explore these relationships. Physical multimorbidity was measured using 12 non-communicable diseases. Latent class analysis (LCA) was conducted to determine the optimal SES patterns based on annual per-capita household expenditure, occupation, education level, and health insurance. The healthy lifestyle score (0-5) was constructed comprising information on smoking, drinking, physical activity, sleep, and body shape. RESULTS: Of 17,708 participants in the CHARLS, 7776 were eligible for inclusion in our analysis (13.3% with high SES, 26.1% with medium SES, and 60.6% with low SES). Compared with high SES participants, those with low SES had higher risks of incident physical multimorbidity (OR 1.22, 95% CI 1.05, 1.42), which was competitively mediated by lifestyle (mediation proportion, -10.17%, 95% CI -19.12%, -1.23%). Significant interactions were observed between lifestyle factors and SES in patients with incident diabetes. Participants with low SES and no or one healthy lifestyle factor had a higher risk of incident physical multimorbidity than those with high SES and four to five healthy lifestyle factors (OR 2.19, 95% CI 1.57, 3.04). CONCLUSION: Healthy lifestyles competitively mediate a fractional proportion of socioeconomic inequity in incident physical multimorbidity. Furthermore, healthy lifestyles were associated with lower multimorbidity risk in the SES subgroups, supporting the important role of lifestyle in reducing physical multimorbidity burden.

Global Burden of Nonalcoholic Fatty Liver Disease, 1990 to 2019: Findings From the Global Burden of Disease Study 2019.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver diseases worldwide. We provided a comprehensive description regarding the disease burden of NAFLD in 204 countries and territories. MATERIALS AND METHODS: We reported the deaths and disability-adjusted life years (DALYs) related to NAFLD in the Global Burden of Disease database by sex, age, specific causes, and regions. Estimated annual percentage change was applied to describe the changing trends. RESULTS: Globally, the NAFLD-related deaths and DALYs in 2019 were 0.17 million [95% uncertainty interval (UI): 0.13 to 0.21] and 4.42 million (95% UI: 3.35 to 5.67), increased by 80.2% and 62.9% compared with 1990, respectively. The overall age-standardized rate of mortality and DALYs (ASMR and ASDR) showed a downward trend from 1990 to 2019, the estimated annual percentage change were -0.67 (95% confidence interval: -0.76, -0.57) and -0.82 (95% confidence interval: -0.93, -0.7), respectively. NAFLD-related deaths due to cirrhosis and liver cancer increased by 76.7% and 95.1% between 1990 and 2019. The ASMR and ASDR were the highest in the middle and low sociodemographical index regions in 2019, respectively. Of the 21 Global Burden of Disease regions, Eastern Europe, Central Asia, High-income North America, and Australasia experienced an increase in both ASMR and ASDR. CONCLUSIONS: NAFLD imposes heavy disease burden on humankind worldwide, especially in countries with low-to-middle sociodemographical index level. More potent measures are urgently needed in regions with rising age-standardized rate to forestall the increase of NAFLD disease burden.

Low thyroid function is associated with an increased risk of advanced fibrosis in patients with metabolic dysfunction-associated fatty liver disease.

AIMS: Observational studies showed that low thyroid function may perturb liver function. We aimed to evaluate the association of low thyroid function with both metabolic dysfunction-associated fatty liver disease (MAFLD) and advanced hepatic fibrosis. METHODS: Participants who underwent abdominal ultrasonography and thyroid function test in a Chinese hospital from 2015 to 2021were enrolled. Fibrosis-4 index (FIB-4) > 2.67 and/or non-alcoholic fatty liver disease fibrosis score (NFS) > 0.676 were used to define advanced fibrosis. Descriptive analyses were performed to characterize the epidemiology of MAFLD according to levels of thyroid-stimulating hormone (TSH). The logistic regression model was applied to estimate the association of low thyroid function with MAFLD and advanced fibrosis. RESULTS: A total of 19,946 participants (52.78% males, mean age: 47.31 years, 27.55% MAFLD) were included, among which 14,789 were strict-normal thyroid function, 4,328 were low-normal thyroid function, 829 were subclinical hypothyroidism. TSH levels were significantly higher in MAFLD patients with a FIB-4 > 2.67 and /or NFS > 0.676 than their counterparts. The logistic regression model adjusted for age and sex showed that low-normal thyroid function increased the risk of MAFLD (odds ratio [OR] = 1.09; 95% confidence interval [CI] 1.01-1.18). Multivariable regression model adjusted for age, sex, body mass index, type 2 diabetes, and hypertension showed low-normal thyroid function increased the risk of advanced fibrosis in patients with MAFLD (FIB-4 > 2.67: OR = 1.41, 95% CI 1.02-1.93; NFS > 0.676: OR = 1.72, 95% CI 1.08-2.72). CONCLUSION: Elevated TSH concentrations are associated with advanced hepatic fibrosis, even in the euthyroid state.

The Health Impact of MAFLD, a Novel Disease Cluster of NAFLD, Is Amplified by the Integrated Effect of Fatty Liver Disease-Related Genetic Variants.

BACKGROUND & AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a newly proposed disease category that derived from non-alcoholic fatty liver disease. The impact of MAFLD on health events has not been investigated. METHODS: UK Biobank participants were diagnosed for whether MAFLD presented at baseline. Five genetic variants (PNPLA3 rs738409 C/G, TM6SF2 rs58542926 C/T, GCKR rs1260326 T/C, MBOAT7 rs641738 C/T, and HSD17B13 rs72613567 T/TA) were integrated into a genetic risk score (GRS). Cox proportional hazard model was used to examine the association of MAFLD with incident diseases. RESULTS: A total of 160 979 (38.0%, 95% confidence interval [CI] 37.9%, 38.2%) participants out of 423 252 were diagnosed as MAFLD. Compared with participants without MAFLD, MAFLD cases had multivariate adjusted hazard ratio (HR) for liver cancer of 1.59 (95% CI, 1.28, 1.98), cirrhosis of 2.77 (2.29, 3.36), other liver diseases of 2.09 (1.95, 2.24), cardiovascular diseases of 1.39 (1.34, 1.44), renal diseases of 1.56 (1.48, 1.65), and cancers of 1.07 (1.05, 1.10). The impact of MAFLD, especially on hepatic events, was amplified by high GRS, of which the genetic variations in PNPLA3, TM6SF2, and MBOAT7 play the principal roles. MAFLD case with normal body weight is also associated with an increased risk of hepatic outcomes, but the genetic factor seems do not influence the risk in this subpopulation. CONCLUSIONS: MAFLD is independently associated with an increased risk of both intrahepatic and extrahepatic events. Fatty liver disease related genetic variants amplify the effect of MAFLD on disease outcomes.

Alcohol consumption and hepatocellular carcinoma: novel insights from a prospective cohort study and nonlinear Mendelian randomization analysis.

BACKGROUND: Heavy drinking was well associated with an increased risk of hepatocellular carcinoma (HCC), whereas the effect of low-to-moderate drinking on HCC remains under debate. METHODS: Participants from the UK Biobank with detailed information on alcohol use and free of common diseases were included. Daily pure alcohol intake (g/day) was calculated, and the predominant alcoholic beverage type was assigned for each participant. Additive Cox regression model and nonlinear Mendelian randomization (NLMR) analyses were performed to evaluate the association of alcohol intake with HCC. RESULTS: Of 329,164 participants (52.3% females, mean [SD] age = 56.7 [8.0] years), 201 incident HCC cases were recorded during the median follow-up of 12.6 years. The best-fitted Cox regression model suggested a J-shaped relationship between daily alcohol intake level and HCC risk. However, NLMR analysis did not detect a nonlinear correlation between alcohol use and HCC (nonlinearity P-value: 0.386). The J-shaped correlation pattern was detected only in subjects who mainly drank wine but not in those who mainly drank beer, spirits, or fortified wine. Moderate wine drinking showed a significant alanine transaminase (ALT)- and aspartate aminotransferase-lowering effect compared to that of the nondrinkers. In low-risk populations of HCC including women, people aged < 60 years, subjects with normal ALT levels, and those carrying non-risk genotypes of PNPLA3 rs738409 and TM6SF2 rs58542926, we observed a J-shaped correlation between alcohol use and HCC; however, a positive dose-response correlation was found in their respective counterparts, even in those predominantly drinking wine. CONCLUSIONS: Low-to-moderate drinking may be inversely associated with the risk of HCC in low-risk populations, which may be largely driven by wine drinking. However, those in high-risk populations of HCC, such as men and older people, and those with abnormal ALT levels and carry genetic risk variants, should abstain from drinking alcohol. Given the small HCC case number, further validations with larger case numbers are warranted in future works.

Evolutionary characteristics and immune mutation of hepatitis C virus genotype 1b among intravenous drug users in mainland, China.

China is one of the countries with the heaviest burden of hepatitis C virus (HCV) worldwide, especially subtype 1b. To better control hepatitis C, insights into the characteristics of dynamic spread and genomic mutations are urgently needed. We retrieved sequences of HCV-1b NS5B among intravenous drug users (IDUs) and general people (Non-IDUs) in China from 2000 to 2011 in NCBI. Bayesian phylogenetic and phylogeographic analyses were used to evaluate the transmission dynamics of HCV-1b. Non-synonymous substitutions were detected to illustrate immune adaptation. Evolutionary history demonstrated that HCV-1b effective population size experienced a sharp increase in 1990. HCV-1b sequences among IDUs had a higher estimated evolutionary rate (5.7185 × 10-3  substitutions/site/year) than overall (7.7332 × 10-4 ). 105/136 (77.2%) of HCV-1b sequences clustered into 38 networks. The average non-synonymous HCV-1b immune epitopes among IDUs were 0.211, higher than non-IDUs, especially in the HLA-A*02 molecular recognition region. All of these posed significant challenges for the prevention and treatment of HCV. Heterogeneity and genetic linkages of HCV-1b suggest that evolutionary surveillance of HCV in cities in east-central China and among IDUs could not be neglected.

Environmental risk factors and genetic markers of Kaposi's sarcoma-associated herpesvirus infection among Uygur population in Xinjiang, China.

Kaposi sarcoma-associated herpesvirus (KSHV) is endemic in Xinjiang, China. Determinants of KSHV seropositivity among high-risk groups are not well understood. We seek to identify genetic and environmental predisposing factors for KSHV infection among Uygurs in this endemic region. A cross-sectional study was performed among the Uygur population in Xinjiang, China. KSHV-antibodies were detected using immunofluorescence assay (IFA) and human leukocyte antigen (HLA) alleles were genotyped. Univariate and multivariate logistic regression analyses were applied to explore the environmental and genetic risk factors of KSHV seropositivity. Finally, a total of 721 participants were included. The seroprevalence of KSHV was 24.1% among this population. Sweet-food preference (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.03-3.34), and coronary heart disease (OR 1.91, 95%CI 1.24-2.94) were statistically correlated with KSHV infection. HLA-DQB1*06:09 were found to significantly increase the risk of KSHV infection under all 3 models (ORAllelic = 4.06; ORDominant = 3.27; and ORRecessive = 8.06). Six SNPs (SNP0260, SNP0361, SNP0797, SNP0852, SNP1159, and SNP1375) in the DQB1 and DRB1 region and haploid type GTCTAACTAATC in block 17 were statistically associated with KSHV infection. We demonstrated that genetic variations in HLA-DQB1/DRB1 and environmental risk factors were strongly associated with KSHV infection among this population.

Glucocorticoids enhance the antileukemic activity of FLT3 inhibitors in FLT3-mutant acute myeloid leukemia.

FLT3 is a frequently mutated gene that is highly associated with a poor prognosis in acute myeloid leukemia (AML). Despite initially responding to FLT3 inhibitors, most patients eventually relapse with drug resistance. The mechanism by which resistance arises and the initial response to drug treatment that promotes cell survival is unknown. Recent studies show that a transiently maintained subpopulation of drug-sensitive cells, so-called drug-tolerant "persisters" (DTPs), can survive cytotoxic drug exposure despite lacking resistance-conferring mutations. Using RNA sequencing and drug screening, we find that treatment of FLT3 internal tandem duplication AML cells with quizartinib, a selective FLT3 inhibitor, upregulates inflammatory genes in DTPs and thereby confers susceptibility to anti-inflammatory glucocorticoids (GCs). Mechanistically, the combination of FLT3 inhibitors and GCs enhances cell death of FLT3 mutant, but not wild-type, cells through GC-receptor-dependent upregulation of the proapoptotic protein BIM and proteasomal degradation of the antiapoptotic protein MCL-1. Moreover, the enhanced antileukemic activity by quizartinib and dexamethasone combination has been validated using primary AML patient samples and xenograft mouse models. Collectively, our study indicates that the combination of FLT3 inhibitors and GCs has the potential to eliminate DTPs and therefore prevent minimal residual disease, mutational drug resistance, and relapse in FLT3-mutant AML.

Prevalence and correlates of Kaposi's sarcoma-associated herpesvirus and herpes simplex virus type 2 infections among adults: evidence from the NHANES III data.

BACKGROUND: Kaposi's sarcoma-associated herpes virus (KSHV) prevalence and risk factors exhibit considerable variations across populations in different geographic regions. Determinants and the transmission routes of KSHV infection are uncertain. We seek to identify the possible risk factors and the transmission routes of KSHV infection in non-endemic areas. METHODS: We collected annual cases and seroprevalence of KSHV and herpes simplex virus type 2 (HSV-2) from the NHANES III sampled individuals from the US general population (1988-1994). We included 13,179 and 10,720 individuals with available remaining serum samples of KSHV and HSV-2. Logistic regression was employed to explore potential risk factors for the seropositivity. RESULTS: The seroprevalence was 2.05% for KSHV infection and 31.03% for HSV2 infection among this population. All risk factors of sexual behaviors included were strongly associated with HSV-2 positive, however, only MSM had an approximately fivefold increased risk of KSHV infection (OR = 4.71; 95%CI 1.61 11.30). Mexican Americans (2.51%) and older (chi-squaretrend = - 6.71, P < 0.001) individuals had a higher risk of KSHV infection. After adjustment, individuals with higher level of education and economic status had lower KSHV infection. CONCLUSIONS: In non-endemic areas, KSHV transmission may be related to sexual activity in men, especially in male homosexuals. Higher education level and economic status are protective factors for KSHV infection.

Differential YAP expression in glioma cells induces cell competition and promotes tumorigenesis.

Intratumor heterogeneity associates with cancer progression and may account for a substantial portion of therapeutic resistance. Although extensive studies have focused on the origin of the heterogeneity, biological interactions between heterogeneous malignant cells within a tumor are largely unexplored. Glioblastoma (GBM) is the most aggressive primary brain tumor. Here, we found that the expression of Yes-associated protein (YAP, also known as YAP1) is intratumorally heterogeneous in GBM. In a xenograft mouse model, differential YAP expression in glioma cells promotes tumorigenesis and leads to clonal dominance by cells expressing more YAP. Such clonal dominance also occurs in vitro when cells reach confluence in the two-dimensional culture condition or grow into tumor spheroids. During this process, growth of the dominant cell population is enhanced. In the tumor spheroid, such enhanced growth is accompanied by increased apoptosis in cells expressing less YAP. The cellular interaction during clonal dominance appears to be reminiscent of cell competition. RNA-seq analysis suggests that this interaction induces expression of tumorigenic genes, which may contribute to the enhanced tumor growth. These results suggest that tumorigenesis benefits from competitive interactions between heterogeneous tumor cells.

World-wide Prevalence of Substitutions in HCV Genome Associated With Resistance to Direct-Acting Antiviral Agents.

BACKGROUND & AIMS: The efficacy of direct-acting antiviral agents against hepatitis C virus (HCV) infection can be compromised by substitutions in the HCV genome that occur before treatment (resistance-associated substitutions [RASs]). We performed a meta-analysis to determine the prevalence of RASs and their effects. METHODS: We searched publication databases for studies of HCV RNA substitutions that mediate resistance to direct-acting antiviral agents. Findings from 50 studies of the prevalence of RAS in HCV, from 32 countries, were used in a meta-analysis. We retrieved the HCV RNA sequence from the Los Alamos HCV sequence database to estimate the prevalence of the RASs. The degree of resistance to treatment conferred by each RAS was determined based on fold-change in the 50% effective concentration of the drugs. RESULTS: Our final analysis included data from 49,744 patients with HCV infection and 12,612 HCV sequences. We estimated the prevalence of 56 RASs that encoded amino acids and 114 specific RASs. The average prevalence of RASs was highest in HCV genotype (GT) 6, followed by HCV GT1a, GT2, GT1b, GT3, and GT4. The highest prevalence of RASs observed encoded Q80K in NS3 to NS4A of HCV GT1a, Y93T in NS5A of GT1a, and C316N in NS5B of GT1b. The greatest number of RASs were observed at D168 in NS3 to NS4A, at Y93 in NS5A, and at C316 in NS5B. The prevalence of RASs and mutation burdens were high in Japan, the United States, Germany, Thailand, and the United Kingdom; low in Russia, Brazil, Egypt, and India; and intermediate in China, Canada, Australia, Spain, and France. CONCLUSIONS: In a meta-analysis, we found evidence for 114 RASs in HCV of different genotypes. Patients with HCV infection should be tested for RASs before treatment is selected, especially in regions with a high prevalence of RASs.

Prevalence of transmitted HIV-1 drug resistance among treatment-naive individuals in China, 2000-2016.

Human immunodeficiency virus (HIV) with transmitted drug-resistance (TDR) limits the therapeutic options available for treatment-naive HIV patients. This study aimed to further our understanding of the prevalence and transmission characteristics of HIV with TDR for the application of first-line antiretroviral regimens. A total of 6578 HIV-1 protease/reverse-transcriptase sequences from treatment-naive individuals in China between 2000 and 2016 were obtained from the Los Alamos HIV Sequence Database and were analyzed for TDR. Transmission networks were constructed to determine genetic relationships. The spreading routes of large TDR clusters were identified using a Bayesian phylogeographic framework. TDR mutations were detected in 274 (4.51%) individuals, with 1.40% associated with resistance to nucleoside reverse transcriptase inhibitors, 1.52% to non-nucleoside reverse transcriptase inhibitors, and 1.87% to protease inhibitors. The most frequent mutation was M46L (58, 0.89%), followed by K103N (36, 0.55%), M46I (36, 0.55%), and M184V (26, 0.40%). The prevalence of total TDR initially decreased between 2000 and 2010 (OR = 0.83, 95% CI 0.73-0.95) and then increased thereafter (OR = 1.50, 95% CI 1.13-1.97). The proportion of sequences in a cluster (clustering rate) among HIV isolates with TDR sequences was lower than that of sequences without TDR (40.5% vs. 48.8%, P = 0.023) and increased from 27.3% in 2005-2006 to 63.6% in 2015-2016 (P < 0.001). While most TDR mutations were associated with reduced relative transmission fitness, mutation M46I was associated with higher relative transmission fitness than the wild-type strain. This study identified a low-level prevalence of TDR HIV in China during the last two decades. However, the increasing TDR HIV rate since 2010, the persistent circulation of drug resistance mutations, and the expansion of self-sustaining drug resistance reservoirs may compromise the efficacy of antiretroviral therapy programs.

Non-invasive fibrosis markers are associated with mortality risk in both general populations and non-alcoholic fatty liver disease patients.

AIM: We assessed the correlations between non-invasive fibrosis scores and mortality in both the general population and non-alcoholic fatty liver disease (NAFLD) patients. METHODS: We used data from the US National Health and Nutrition Examination Survey 1988-2014. The NAFLD fibrosis score (NFS), Fibrosis-4 index (FIB-4) score, aspartate aminotransferase to platelet ratio index (APRI) score, and Forns index score were calculated at baseline. The associations of these scores with the risk of mortality were determined using additive Cox proportional hazard models. The area under the receiver operating characteristic curve (AUROC) was used to study the predictive capacity of each scoring system. RESULTS: A total of 44 508 participants were included; among them, 9721 deaths occurred during a mean follow-up of 12.5 years. A "J"-shaped correlation pattern was observed for both the FIB-4 and APRI scores. A "U"-shaped correlation pattern was observed for both the Forns index and NFS. Similar correlation patterns were observed in 1955 NAFLD patients. For overall mortality, the AUROC values of the selected fibrosis scores were comparable between general population and NAFLD patients. The superior predictive capacity was found for FIB-4, with AUROC of 75.03% (95% confidence interval, 70.91% to 79.82%) in general population and 75.32% (95% confidence interval, 69.43% to 80.11%) in NAFLD patients, respectively. CONCLUSIONS: Non-linear associations were shown between the fibrosis scoring systems and mortality risk. These scores could serve as indicators for mortality in people with or without NAFLD.

A prognostic system for epithelial ovarian carcinomas using machine learning.

INTRODUCTION: Integrating additional factors into the International Federation of Gynecology and Obstetrics (FIGO) staging system is needed for accurate patient classification and survival prediction. In this study, we tested machine learning as a novel tool for incorporating additional prognostic parameters into the conventional FIGO staging system for stratifying patients with epithelial ovarian carcinomas and evaluating their survival. MATERIAL AND METHODS: Cancer-specific survival data for epithelial ovarian carcinomas were extracted from the Surveillance, Epidemiology, and End Results (SEER) program. Two datasets were constructed based upon the year of diagnosis. Dataset 1 (39 514 cases) was limited to primary tumor (T), regional lymph nodes (N) and distant metastasis (M). Dataset 2 (25 291 cases) included additional parameters of age at diagnosis (A) and histologic type and grade (H). The Ensemble Algorithm for Clustering Cancer Data (EACCD) was applied to generate prognostic groups with depiction in dendrograms. C-indices provided dendrogram cutoffs and comparisons of prediction accuracy. RESULTS: Dataset 1 was stratified into nine epithelial ovarian carcinoma prognostic groups, contrasting with 10 groups from FIGO methodology. The EACCD grouping had a slightly higher accuracy in survival prediction than FIGO staging (C-index = 0.7391 vs 0.7371, increase in C-index = 0.0020, 95% confidence interval [CI] 0.0012-0.0027, p = 1.8 × 10-7 ). Nevertheless, there remained a strong inter-system association between EACCD and FIGO (rank correlation = 0.9480, p = 6.1 × 10-15 ). Analysis of Dataset 2 demonstrated that A and H could be smoothly integrated with the T, N and M criteria. Survival data were stratified into nine prognostic groups with an even higher prediction accuracy (C-index = 0.7605) than when using only T, N and M. CONCLUSIONS: EACCD was successfully applied to integrate A and H with T, N and M for stratification and survival prediction of epithelial ovarian carcinoma patients. Additional factors could be advantageously incorporated to test the prognostic impact of emerging diagnostic or therapeutic advances.

Lifestyle, multi-omics features, and preclinical dementia among Chinese: The Taizhou Imaging Study.

China has the largest number of patients with dementia in the world. However, dementia in the Chinese population is still poorly understood and under-researched. Given the differences in genetic, demographic, sociocultural, lifestyle, and health profiles among Chinese and other ethnic/racial groups, it is crucial to build appropriate infrastructure for long-term longitudinal studies to advance Chinese cognitive aging and dementia research. We initiated a community-based prospective cohort-the Taizhou Imaging Study (TIS)-to accelerate the understanding of dementia and cerebrovascular diseases in Chinese. This article presents the rationale, aims, study design, and organization of TIS. In addition, we described some examples of the types of studies such a resource might support. The TIS provides a new framework for facilitating Chinese dementia research, encompassing invaluable resources including detailed epidemiological, sociocultural, neuroimaging, and omics data.

The mitochondrial chaperone Prohibitin 1 negatively regulates interleukin-8 in human liver cancers.

Prohibitin 1 (PHB1) is a mitochondrial chaperone whose expression is dysregulated in cancer. In liver cancer, PHB1 acts as a tumor suppressor, but the mechanisms of tumor suppression are incompletely understood. Here we aimed to determine PHB1 target genes to better understand how PHB1 influences liver tumorigenesis. Using RNA-Seq analysis, we found interleukin-8 (IL-8) to be one of the most highly up-regulated genes following PHB1 silencing in HepG2 cells. Induction of IL-8 expression also occurred in multiple liver and nonliver cancer cell lines. We examined samples from 178 patients with hepatocellular carcinoma (HCC) and found that IL-8 mRNA levels were increased, whereas PHB1 mRNA levels were decreased, in the tumors compared with adjacent nontumorous tissues. Notably, HCC patients with high IL-8 expression have significantly reduced survival. An inverse correlation between PHB1 and IL-8 mRNA levels is found in HCCs with reduced PHB1 expression. To understand the molecular basis for these observations, we altered PHB1 levels in liver cancer cells. Overexpression of PHB1 resulted in lowered IL-8 expression and secretion. Silencing PHB1 increased c-Jun N-terminal kinase (JNK) and NF-κB activity, induced nuclear accumulation of c-JUN and p65, and enhanced their binding to the IL-8 promoter containing AP-1 and NF-κB elements. Conditioned medium from PHB1-silenced HepG2 cells increased migration and invasion of parental HepG2 and SK-hep-1 cells, and this was blocked by co-treatment with neutralizing IL-8 antibody. In summary, our findings show that reduced PHB1 expression induces IL-8 transcription by activating NF-κB and AP-1, resulting in enhanced IL-8 expression and release to promote tumorigenesis.