A cost-effective, machine learning-driven approach for screening arterial functional aging in a large-scale Chinese population.

Introduction: An easily accessible and cost-free machine learning model based on prior probabilities of vascular aging enables an application to pinpoint high-risk populations before physical checks and optimize healthcare investment. Methods: A dataset containing questionnaire responses and physical measurement parameters from 77,134 adults was extracted from the electronic records of the Health Management Center at the Third Xiangya Hospital. The least absolute shrinkage and selection operator and recursive feature elimination-Lightweight Gradient Elevator were employed to select features from a pool of potential covariates. The participants were randomly divided into training (70%) and test cohorts (30%). Four machine learning algorithms were applied to build the screening models for elevated arterial stiffness (EAS), and the performance of models was evaluated by calculating the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy. Results: Fourteen easily accessible features were selected to construct the model, including "systolic blood pressure" (SBP), "age," "waist circumference," "history of hypertension," "sex," "exercise," "awareness of normal blood pressure," "eat fruit," "work intensity," "drink milk," "eat bean products," "smoking," "alcohol consumption," and "Irritableness." The extreme gradient boosting (XGBoost) model outperformed the other three models, achieving AUC values of 0.8722 and 0.8710 in the training and test sets, respectively. The most important five features are SBP, age, waist, history of hypertension, and sex. Conclusion: The XGBoost model ideally assesses the prior probability of the current EAS in the general population. The integration of the model into primary care facilities has the potential to lower medical expenses and enhance the management of arterial aging.

Diet-Derived Circulating Antioxidants and Risk of Stroke: A Mendelian Randomization Study.

BACKGROUND: Oxidative stress is crucial in stroke pathogenesis. Many cohort-based studies suggested that the intake of exogenous antioxidants originated from food may prevent stroke. However, the corresponding randomized controlled trials did not show diet-derived antioxidants have a protective effect on stroke. OBJECTIVES: To examine the association of genetically proxied diet-derived antioxidants with stroke risk using Mendelian randomization. METHODS: We performed a two-sample Mendelian randomization (MR) analysis to evaluate the causal effect of diet-derived antioxidants on stroke risk. For exposure data, we extracted genetic variants as instrumental variables (IVs) that are strongly associated with frequently used diet-derived antioxidants, including vitamin C, vitamin E (α-tocopherol, γ-tocopherol), carotene, retinol, zinc, and selenium, from a large-scale genome-wide association study (GWAS). We obtained IVs' corresponding effect estimates on the risk of total stroke and ischemic stroke from a GWAS meta-analysis with 40,585 cases and 406,111 controls. Finally, we applied five types of Mendelian randomization analysis to obtain preliminary MR results and performed four three kinds of sensitivity analysis to verify them. RESULTS: According to the primary MR estimations and further sensitivity analyses, we established two robust associations after Bonferroni correction: genetically proxied circulating γ-tocopherol was causally associated with total stroke [odds ratio (OR) = 0.68, 95% confidence interval (CI) (0.52-0.88), p = 3.78E - 03] and ischemic stroke [OR = 0.66, 95% CI (0.51-0.86), p = 2.34E - 03]. There was no evidence to support the causal effect of other diet-derived antioxidants on the risk of total stroke and ischemic stroke. CONCLUSION: Our study revealed a protective impact of genetic susceptibility to high circulating γ-tocopherol levels on stroke risk, providing new information on the potential therapeutic targets for primary stroke prevention.

Hepatic leukocyte immunoglobulin-like receptor B4 (LILRB4) attenuates nonalcoholic fatty liver disease via SHP1-TRAF6 pathway.

Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent liver pathology characterized by hepatic steatosis and commonly accompanied by systematic inflammation and metabolic disorder. Despite an accumulating number of studies, no pharmacological strategy is available to treat this condition in the clinic. In this study, we applied extensive gain- and loss-of-function approaches to identify the key immune factor leukocyte immunoglobulin-like receptor B4 (LILRB4) as a negative regulator of NAFLD. The hepatocyte-specific knockout of LILRB4 (LILRB4-HKO) exacerbated high-fat diet-induced insulin resistance, glucose metabolic imbalance, hepatic lipid accumulation, and systematic inflammation in mice, whereas LILRB4 overexpression in hepatocytes showed a completely opposite phenotype relative to that of LILRB4-HKO mice when compared with their corresponding controls. Further investigations of molecular mechanisms demonstrated that LILRB4 recruits SHP1 to inhibit TRAF6 ubiquitination and subsequent inactivation of nuclear factor kappa B and mitogen-activated protein kinase cascades. From a therapeutic perspective, the overexpression of LILRB4 in a genetic model of NAFLD, ob/ob mice, largely reversed the inherent hepatic steatosis, inflammation, and metabolic disorder. CONCLUSION: Targeting hepatic LILRB4 to improve its expression or activation represents a promising strategy for the treatment of NAFLD as well as related liver and metabolic diseases. (Hepatology 2018;67:1303-1319).

Downregulation of the ß1 adrenergic receptor in the myocardium results in insensitivity to metoprolol and reduces blood pressure in spontaneously hypertensive rats.

The ß1­adrenergic receptor (AR) is the primary ß­AR subtype in the heart and is the target of metoprolol (Met), which is commonly used to treat angina and hypertension. Previous studies have revealed a positive correlation between the methylation levels of the adrenoreceptor ß1 gene (Adrb1) promoter in the myocardium with the antihypertensive activity of Met in spontaneously hypertensive rats (SHR), which affects ß1­AR expression in H9C2 cells. The aim of the present study was to investigate the effects of myocardial ß1­AR downregulation using short­hairpin RNA (shRNA) against Adrb1 on the antihypertensive activity of Met in SHR. Recombinant adeno­associated virus type 9 (rAAV9) vectors carrying Adrb1 shRNA (rAAV9­Adrb1) or a negative control sequence (rAAV9­NC) were generated and used to infect rat hearts via the pericardial cavity. The results of reverse transcription­quantitative polymerase chain reaction, immunohistochemistry and western blotting analyses demonstrated that cardiac ß1­AR expression in the rAAV9­Adrb1 group was significantly downregulated when compared with the rAAV9­NC group (P<0.001, P<0.001 and P=0.032, respectively). In addition, a greater reduction in systolic blood pressure (SBP) was observed in the rAAV9­NC group compared with the rAAV9­Adrb1 group following Met treatment (P=0.035). Furthermore, downregulation of myocardial ß1­AR was associated with a significant decrease in SBP (P<0.001). In conclusion, these data suggest that suppression of ß1­AR expression in the myocardium reduces SBP and sensitivity to Met in SHR.