Association between exposure to per- and polyfluoroalkyl substance and liver injury in American adults.

Epidemiological data is scarce regarding the association between exposure to mixtures of per- and polyfluoroalkyl substances (PFASs) and liver injury in the general populace. The current research used data from the National Health and Nutrition Examination Survey (2009-2018). The PFAS exposure levels were defined by the serum concentrations of PFASs with > 70% detection in samples, namely perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorohexane sulfonic acid (PFHxS), perfluorodecanoic acid (PFDeA), and perfluorooctane sulfonic acid (PFOS). Liver injury was assessed from two aspects: first, the degree of liver inflammation was determined based on serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamyltransferase (GGT), and total bilirubin (TBIL) levels; second, the degree of liver fibrosis was determined based on fibrosis-4 (FIB-4) index. We assessed the associations between individual or total PFAS exposure and these outcomes using multivariable linear regression models and logistic regression models, restricted cubic splines, and weighted quantile sum regression. Among the samples of 7484 American adults, the median concentration of PFOS was the highest, followed by PFOA and PFHxS. Using multivariable linear regression, a positive correlation was observed between all PFASs and liver enzymes such as ALT, AST, and TBIL. Additionally, the weighted quantile sum model indicated an overall positive association between the five PFASs and liver injury indicators. For liver function biomarkers and liver fibrosis, PFNA and PFOS were the most heavily weighting chemicals, respectively. Our findings provide new epidemiological evidence indicating a potential association between PFAS exposure and adverse effects on liver injury biomarkers, highlighting the potentially harmful effects of PFAS exposure on liver health.

Healthy Lifestyle Is Associated with Reduced Mortality in Patients with Non-Alcoholic Fatty Liver Disease.

Background and Aims: It is unclear whether a healthy lifestyle impacts mortality in the presence of non-alcoholic fatty liver disease (NAFLD). The present study aimed to examine the joint association of several modifiable lifestyle factors with mortality risk for NAFLD patients. Methods: We collected lifestyle behavior data form the National Health and Nutrition Examination Survey (NHANES) III from 1988 to 1994 and follow-up data form NHANES III-linked mortality data through 2015. We estimated joint association between four healthy lifestyle factors (non-smoking, non-drinking, regular physical activity, a healthy diet) after NAFLD diagnosis and mortality using Cox proportional hazards regression models. Results: During a median of 22.83 years of follow-up, 2932 deaths occurred. The risk of all-cause mortality decreased significantly with the healthy lifestyle scores increasing (p < 0.001). NAFLD patients with a favorable lifestyle (3 or 4 healthy lifestyle factors) reduced 36% of all-cause mortality and 43% of cardiovascular disease (CVD) mortality compared with those with an unfavorable lifestyle (0 or 1 healthy lifestyle factor) (HR, 0.64 [95% CI, 0.50−0.81], 0.57 [95% CI, 0.37−0.88]). Compared with the non-NAFLD group, the number of NAFLD patients required to adhere to a favorable lifestyle to prevent one cardiovascular disease death in 20 years was fewer (77 vs. 125). Conclusions: For the NAFLD patients, adopting a healthy lifestyle could significantly reduce their risk of death.

Optimization of Ultrasound-Assisted Extraction of Polyphenols from Ilex latifolia Using Response Surface Methodology and Evaluation of Their Antioxidant Activity.

The polyphenolic extract of Ilex latifolia (PEIL) exhibits a variety of biological activities. An evaluation of the parameters influencing the ultrasonic extraction process and the assessment of PEIL antioxidant activity are presented herein. Response surface methodology (RSM) was used to optimize the experimental conditions for the polyphenols ultrasonic-assisted extraction (UAE) from the leaves of Ilex latifolia. We identified the following optimal conditions of PEIL: ethanol concentration of 53%, extraction temperature of 60 °C, extraction time of 26 min and liquid−solid ratio of 60 mL/g. Using these parameters, the UAE had a yield of 35.77 ± 0.26 mg GAE/g, similar to the value we predicted using RSM (35.864 mg GAE/g). The antioxidant activity of PEIL was assessed in vitro, using various assays, as well as in vivo. We tested the effects of various doses of PEIL on D-galactose induced aging. Vitamin C (Vc) was used as positive control. After 21 days of administration, we measured superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, malondialdehyde (MDA) levels in mouse serum and liver tissue. The results demonstrated that the PEIL exhibits potent radical scavenging activity against 1,1-diphenyl-2-picrythydrazyl (DPPH∙), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS+), and hydroxyl (∙OH) radicals. The serum concentrations of SOD and GSH-Px were higher, and MDA levels were lower, in the medium- and high-dose PEIL-treated groups than those in the aging group (p < 0.01), and the activity of MDA was lower than those of the model group (p < 0.01). The liver concentrations of SOD and GSH-Px were higher (p < 0.05), and MDA levels were lower, in the medium- and high-dose PEIL-treated groups than those in the aging control group (p < 0.01). These results suggest that optimizing the conditions of UAE using RSM could significantly increase the yield of PEIL extraction. PEIL possesses strong antioxidant activity and use as a medicine or functional food could be further investigated.

Weight Change across Adulthood in Relation to Non-Alcoholic Fatty Liver Disease among Non-Obese Individuals.

BACKGROUND: To investigate the associations of weight change patterns across adulthood with the risk of non-alcoholic fatty liver disease (NAFLD). METHODS: Using data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 cycle, we performed a retrospective cohort study with 2212 non-obese participants aged 36 years old over. Weight change patterns were categorized as "stable non-obese", "early adulthood weight gain", "middle and late adulthood weight gain" and "revert to non-obese" according to the body mass index (BMI) at age 25, 10 years prior and at baseline. Vibration-controlled transient elastography (VCTE) was performed to diagnose NAFLD. Modified Poisson regression was used to quantify the associations of weight change patterns with NAFLD. RESULTS: Compared with participants in the "stable non-obese" group, those who gained weight at early or middle and late adulthood had an increased risk of NAFLD, with an adjusted rate ratio (RR) of 2.19 (95% CI 1.64-2.91) and 1.92 (95% CI 1.40-2.62), respectively. The risk of NAFLD in "revert to the non-obese" group showed no significant difference with the stable non-obese group. If the association of weight change and NAFLD was causal, we estimated that 73.09% (95% CI 55.62-82.93%) of incident NAFLD would be prevented if the total population had a normal BMI across adulthood. CONCLUSIONS: Weight gain to obese at early or middle and late adulthood was associated with an evaluated risk of NAFLD. A large proportion would have been prevented with effective weight intervention.

Hepatitis B virus infection and the risk of cancer among the Chinese population.

The relationship between hepatitis B virus (HBV) and nonhepatocellular cancers remains inconclusive. This large case-control study aimed to assess the associations between HBV infection status and multiple cancers. Cases (n = 50 392) and controls (n = 11 361) were consecutively recruited from 2008 to 2016 at the First Affiliated Hospital of Nanjing Medical University. Multivariable adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression by adjusting age and gender. A meta-analysis based on published studies was also performed to verify the associations. Of these, 12.1% of cases and 5.5% of controls were hepatitis B surface antigen (HBsAg) seropositive. We observed significant associations between HBsAg seropositivity and esophagus cancer (aOR [95% CI] = 1.32 [1.13-1.54]), stomach cancer (1.46 [1.30-1.65]), hepatocellular carcinoma (HCC; 39.11 [35.08-43.59]), intrahepatic and extrahepatic bile duct carcinoma (ICC and ECC; 3.83 [2.58-5.67] and 1.72 [1.28-2.31]), pancreatic cancer (PaC; 1.37 [1.13-1.65]), non-Hodgkin lymphoma (NHL; 1.88 [1.61-2.20]) and leukemia (11.48 [4.05-32.56]). Additionally, compared to participants with HBsAg-/anti-HBs-/anti-HBc-, participants with HBsAg-/anti-HBs-/anti-HBc+, indicating past HBV-infected, had an increased risk of esophagus cancer (aOR [95% CI] = 1.46 [1.24-1.73]), stomach cancer (1.20 [1.04-1.39]), HCC (4.80 [3.95-5.84]) and leukemia (15.62 [2.05-119.17]). Then the overall meta-analysis also verified that HBsAg seropositivity was significantly associated with stomach cancer (OR [95% CI] = 1.23 [1.14-1.33]), ICC (4.05 [2.78-5.90]), ECC (1.73 [1.30-2.30]), PaC (1.26 [1.09-1.46]), NHL (1.95 [1.55-2.44]) and leukemia (1.54 [1.26-1.88]). In conclusion, both our case-control study and meta-analysis confirmed the significant association of HBsAg seropositivity with stomach cancer, ICC, ECC, PaC, NHL and leukemia. Of note, our findings also suggested that the risk of stomach cancer elevated for people whoever exposed to HBV.

Whole exome sequencing reveals the different responsiveness to Enterovirus 71 vaccination in Chinese children.

PURPOSE: To explore the molecular genetic mechanisms underlying different responsiveness to Enterovirus 71 (EV71) vaccine. METHODS: We recruited 10,245 healthy children into a phase 3 clinical trial to evaluate the efficacy of EV71 vaccine in 2012. Fifty subjects from the trial were divided into the potent immune response group (20 subjects) and the ineffective immune response group (30 subjects). Whole-exome sequencing was performed for these 50 samples and we conducted bioinformatics analyses based on online public database. RESULTS: A total of 222,180 germline variants were detected across 50 subjects. Single nucleotide variant (SNV)-based screening of the subjects with potent or ineffective immune response allowed the identification of a potentially detrimental heterozygous missense variant (c.3784C>T) in EEA1. We also retained TRIM59 and ABCA7 genes that contain different loss of function (LoF) variants shared in two cases and involved in the immune response process. Then, we conducted high-resolution typing of 9 classical HLA genes, HLA-DRB1*03:01, HLA-DQA1*05:01 and HLA-DQB1*02:01 alleles were frequently (recurrence ≥5) observed only in ineffective immune responders. CONCLUSIONS: Our study is a meaningful attempt on the comparison of genomic profiles between potent and ineffective immune responders induced by EV71 vaccine, and several candidate potentially detrimental genes were identified.

Identification of risk loci and a polygenic risk score for lung cancer: a large-scale prospective cohort study in Chinese populations.

BACKGROUND: Genetic variation has an important role in the development of non-small-cell lung cancer (NSCLC). However, genetic factors for lung cancer have not been fully identified, especially in Chinese populations, which limits the use of existing polygenic risk scores (PRS) to identify subpopulations at high risk of lung cancer for prevention. We therefore aimed to identify novel loci associated with NSCLC risk, and generate a PRS and evaluate its utility and effectiveness in the prediction of lung cancer risk in Chinese populations. METHODS: To systematically identify genetic variants for NSCLC risk, we newly genotyped 19 546 samples from Chinese NSCLC cases and controls from the Nanjing Medical University Global Screening Array Project and did a meta-analysis of genome-wide association studies (GWASs) of 27 120 individuals with NSCLC and 27 355 without NSCLC (13 327 cases and 13 328 controls of Chinese descent as well as 13 793 cases and 14 027 controls of European descent). We then built a PRS for Chinese populations from all reported single-nucleotide polymorphisms that have been reported to be associated with lung cancer risk at genome-wide significance level. We evaluated the utility and effectiveness of the generated PRS in predicting subpopulations at high-risk of lung cancer in an independent prospective cohort of 95 408 individuals from the China Kadoorie Biobank (CKB) with more than 10 years' follow-up. FINDINGS: We identified 19 susceptibility loci to be significantly associated with NSCLC risk at p≤5·0 × 10-8, including six novel loci. When applied to the CKB cohort, the PRS of the risk loci successfully predicted lung cancer incident cases in a dose-response manner in participants at a high genetic risk (top 10%) than those at a low genetic risk (bottom 10%; adjusted hazard ratio 1·96, 95% CI 1·53-2·51; ptrend=2·02 × 10-9). Specially, we observed consistently separated curves of lung cancer events in individuals at low, intermediate, and high genetic risk, respectively, and PRS was an independent effective risk stratification indicator beyond age and smoking pack-years. INTERPRETATION: We have shown for the first time that GWAS-derived PRS can be effectively used in discriminating subpopulations at high risk of lung cancer, who might benefit from a practically feasible PRS-based lung cancer screening programme for precision prevention in Chinese populations. FUNDING: National Natural Science Foundation of China, the Priority Academic Program for the Development of Jiangsu Higher Education Institutions, National Key R&D Program of China, Science Foundation for Distinguished Young Scholars of Jiangsu, and China's Thousand Talents Program.

Pathogenesis and pathophysiology of heart failure with reduced ejection fraction: translation to human studies.

Heart failure represents the end result of different pathophysiologic processes, which culminate in functional impairment. Regardless of its aetiology, the presentation of heart failure usually involves symptoms of pump failure and congestion, which forms the basis for clinical diagnosis. Pathophysiologic descriptions of heart failure with reduced ejection fraction (HFrEF) are being established. Most commonly, HFrEF is centred on a reactive model where a significant initial insult leads to reduced cardiac output, further triggering a cascade of maladaptive processes. Predisposing factors include myocardial injury of any cause, chronically abnormal loading due to hypertension, valvular disease, or tachyarrhythmias. The pathophysiologic processes behind remodelling in heart failure are complex and reflect systemic neurohormonal activation, peripheral vascular effects and localised changes affecting the cardiac substrate. These abnormalities have been the subject of intense research. Much of the translational successes in HFrEF have come from targeting neurohormonal responses to reduced cardiac output, with blockade of the renin-angiotensin-aldosterone system (RAAS) and beta-adrenergic blockade being particularly fruitful. However, mortality and morbidity associated with heart failure remains high. Although systemic neurohormonal blockade slows disease progression, localised ventricular remodelling still adversely affects contractile function. Novel therapy targeted at improving cardiac contractile mechanics in HFrEF hold the promise of alleviating heart failure at its source, yet so far none has found success. Nevertheless, there are increasing calls for a proximal, 'cardiocentric' approach to therapy. In this review, we examine HFrEF therapy aimed at improving cardiac function with a focus on recent trials and emerging targets.

Associations Between Hepatitis B Virus Infection and Risk of All Cancer Types.

Importance: Hepatitis B virus (HBV) has been identified as a major risk factor for hepatocellular carcinoma. However, the associations between HBV infection and other cancer types are not well understood. Objective: To assess the associations between chronic HBV infection and risk of all cancer types. Design, Setting, and Participants: This population-based study involved 3 cohorts in China. The China Kadoorie Biobank (CKB) prospective cohort study, conducted between June 2004 and July 2008, used a dipstick assay for detection of serum hepatitis B surface antigen (HBsAg) among 496 732 participants to determine the association between HBV infection and risk of all cancer types. Two cohort studies were used to validate the associations by applying more precise serum HBsAg detection assays: the Qidong cohort (37 336 participants enrolled from November 2007 to April 2011) and the Changzhou nested case-control study (17 723 participants enrolled from June 2004 to September 2005). A total of 97 samples of stomach cancer tissues, 10 samples of pancreatic cancer tissues, and 9 samples of lung cancer tissues were included to assess the presence of HBV replication and expression. Statistical analysis was performed from December 2016 to October 2018. Exposures: Serum HBsAg status in the population-based stage and HBV DNA status, the expression of hepatitis B X protein, and hepatitis B core antibody (anti-HBc) in the tissue-based stage. Main Outcomes and Measures: Incidence of all cancer types during follow-up. Results: In the CKB cohort, the mean (SD) age of the 496 732 participants was 51.5 (10.7) years; 59.0% of the participants were women. After 4.4 million person-years of follow-up, participants who were HBsAg seropositive (n = 15 355) had a higher risk of hepatocellular carcinoma (hazard ratio [HR], 15.77; 95% CI, 14.15-17.57), stomach cancer (HR, 1.41; 95% CI, 1.11-1.80), colorectal cancer (HR, 1.42; 95% CI, 1.12-1.81), oral cancer (HR, 1.58; 95% CI, 1.01-2.49), pancreatic cancer (HR, 1.65; 95% CI, 1.03-2.65), and lymphoma (HR, 2.10; 95% CI, 1.34-3.31) when compared with participants who were HBsAg seronegative (n = 481 377). Because of the limitation of sample size, only associations of HBV infection with hepatocellular carcinoma and stomach cancer were validated in the Qidong cohort (hepatocellular carcinoma: HR, 17.51; 95% CI, 13.86-22.11; stomach cancer: HR, 2.02; 95% CI, 1.24-3.29); the Changzhou nested case-control study validated only an association between HBV infection and stomach cancer (odds ratio, 1.76; 95% CI, 1.04-2.98). Moreover, among 22 participants with stomach cancer from the Qidong cohort who were anti-HBc seropositive, 12 samples (54.5%) of cancer tissues were HBV DNA positive, while among 25 participants with stomach cancer who were anti-HBc seronegative, no HBV DNA was detected. The same negative and positive rate was observed in the validation set from Zhejiang Tumor Hospital (19 of 35 samples [54.3%] were HBV DNA positive). Moreover, among the 8 patients with stomach cancer from the Qidong cohort who were anti-HBc seropositive, anti-HBc and hepatitis B X protein were expressed in all of their stomach cancer tissue samples. The same phenomenon was observed in the patients with pancreatic cancer but not in the patients with lung cancer, which was consistent with the population-based results of the CKB cohort. Conclusions and Relevance: This study found that HBV infection was also associated with the risk of nonliver cancer, especially digestive system cancers among adults in China.

HBV mutations in EnhII/BCP/PC region contribute to the prognosis of hepatocellular carcinoma.

BACKGROUND: Accompanied by HBV infection, HBV mutations gradually occur because HBV polymerase appears proofread deficiencies. In our previous study, we have identified that EnhII/BCP/PC mutations and genotype C of HBV DNA were associated with hepatocellular carcinoma (HCC) risk. In this study, we extend our research to explore HCC prognosis associated genotype and mutations in EnhII/BCP/PC regions. METHODS: We designed a case-cohort study of 331 HCC patients to evaluate the effects of the HBV genotypes and mutations on HCC survival. Log-rank test and Cox proportional hazard models were used for the analyses. RESULTS: Results showed that genotype C, which was more frequent in HBV-related HCC (77.4%), presented a negative signal with HCC survival. Interestingly, we detected a significant association between EnhII/BCP/PC mutation nt1753 and HCC prognosis (Log-rank P = 0.034). Subgroup analysis revealed that this risk effect was more pronounced in non-B genotype (P = 0.090 for heterogeneity test). We also detected a borderline multiplicative interaction between genotypes of nt1753 and HBV genotype on HCC survival (P for interaction = 0.069). CONCLUSIONS: These findings indicated that, in Chinese population, nt1753 in EnhII/BCP/PC region might be a novel marker for HCC prognosis.