Copula-based exposure risk dynamic simulation of dual heavy metal mixed pollution accidents at the watershed scale.

Most heavy metal exposure and pollution results from multiple industrial activities, including metal processing in refineries, and microelectronics. These issues pose a great threat to human health, ecological balance, and even societal stability. During 2012-2017, China, in particular, faced the challenge of 23 heavy metals accidents, six of which were extraordinarily serious accidents. Accidental environmental pollution is rarely caused by a single heavy metal, but rather by heavy metal mixtures. To address the need for a joint exposure risk assessment for heavy metal mixed pollution accidents at the watershed scale, a Copula-based exposure risk dynamic simulation model was proposed. A coupled hydrodynamic and accidental heavy metal exposure model is constructed for an hourly simulation of the exposure fate of heavy metals from each risk source once accidental leakage has occurred. The Copula analysis was introduced to calculate the dual heavy metal joint exposure probability in real time. This method was applied to an acute Cr6+-Hg2+ joint exposure risk assessment for 43 electroplating plants in nine sub-watersheds within the Dongjiang River downstream basin. The results indicated seven risk sources (i.e., S1, S4, H18, H23, H27-H28, and H34) that presented relatively high exposure risk to their surrounding sub-watersheds. Spatially, the acute exposure risk level was highest in the tributary basin (sub-watershed XW) than in the mainstream (sub-watershed DW2) and the river network (sub-watershed RW) of the lower reaches of the Dongjiang River. This research highlights an effective probabilistic approach for performing a joint exposure risk analysis of heavy metal mixed pollution accidents at the watershed scale.

A Bayesian Network-based risk dynamic simulation model for accidental water pollution discharge of mine tailings ponds at watershed-scale.

Mine tailings ponds that contain heavy metals are sources of potential risk to human security and ecosystem health. China particularly faces challenge of accidental water pollution risk from more than 8869 mine tailings ponds in serve by 2015, some of which are close to residential areas and other important infrastructures within 1 km downstream. To address watershed-scale risk assessment of accidental water pollution from mine tailings ponds, a Bayesian Network-based Risk Dynamic Simulation (BN-RDS) model was proposed to simulate "sources/stressors-receptors-endpoints" risk routes. An accidental water pollution convection-diffusion simulation was coupled to Bayesian Networks to perform the risk dynamic simulation and risk evolution quantification at watershed-scale. This method was applied to the risk assessment of 23 tailings dams in 12 sub-watersheds covering the Guanting Reservoir basin (the major backup drinking water source for Beijing) in Zhangjiakou City, China. The result indicated that ecosystem health and property security were the endpoints at the highest risk in the overall watershed. Spatially, the combined risk distribution map showed the risk was higher in the downstream of the Guanting Reservoir Watershed and in its two tributary basins (the Qingshui River and the Longyang River). This research highlighted a probabilistic approach to accidental water pollution risk assessment of tailings ponds with verifiable and tangible results for risk managers and stakeholders.

Land-use suitability analysis for urban development in Beijing.

Land-use suitability analyses are of considerable use in the planning of mega-cities. An Urban Development Land-use Suitability Mapping (UDLSM) approach has been constructed, based on opportunity and constraint criteria. Two Multi-criteria Evaluation (MCE) methods, the Ideal Point Method (IPM) and Ordered Weighted Averaging (OWA), were used to generate the opportunity map. The protection map was obtained by means of constraint criteria, utilizing the Boolean union operator. A suitability map was then generated by overlaying the opportunity and protection maps. By applying the UDLSM approach to Beijing, its urban development land-use suitability was mapped, and a sensitivity analysis undertaken to examine the robustness of the proposed approach. Indirect validation was achieved by mutual comparisons of suitability maps resulting from the two MCE methods, where the overall agreement of 91% and kappa coefficient of 0.78 indicated that both methods provide very similar spatial land-use suitability distributions. The suitability level decreases from central Beijing to its periphery, and the area classed as suitable amounts to 28% of the total area. Leading attributes of each opportunity factor for suitability were revealed, with 2256 km(2), i.e. 70%, of existing development land being overlaid by suitable areas in Beijing. Conflicting parcels of land were identified by overlaying the resultant map with two previous development blueprints for Beijing. The paper includes several recommendations aimed at improving the long-term urban development plans for Beijing.

Discovery of a Novel Thienopyrimidine Compound as a Urate Transporter 1 and Glucose Transporter 9 Dual Inhibitor with Improved Efficacy and Favorable Druggability.

Gout and hyperuricemia are metabolic diseases characterized with high serum uric acid (SUA) levels that significantly impact human health. Lesinurad, a uricosuric agent, is limited to concurrent use with xanthine oxidase inhibitors (XOIs) in clinical practice due to its restricted efficacy and potential nephrotoxicity. Herein, extensive structural modifications of lesinurad were conducted through scaffold hopping and substituent modification strategies, affording 54 novel derivatives containing pyrimidine-fused cyclic structures. Notably, the thienopyrimidine compound 29 demonstrated a remarkable 2-fold increase in SUA-lowering in vivo activity compared to lesinurad, while exhibiting potent inhibitory activity against the urate transporter 1 (URAT1, IC50 = 2.01 µM) and glucose transporter 9 (GLUT9, IC50 = 18.21 µM). Furthermore, it possessed a lower effective dosage of 0.5 mg/kg, favorable safety profile without any apparent acute toxicity at doses of 1000 mg/kg, and improved pharmacokinetic properties. Overall, we have discovered an efficacious URAT1/GLUT9 dual inhibitor for inhibiting urate reabsorption with favorable pharmacokinetic profiles.

[Tumor necrosis factor alpha-238G/A polymorphism and tuberculosis susceptibility: a meta-analysis].

OBJECTIVE: A comprehensive meta-analysis was performed to investigate the relationship between TNF -238G/A polymorphism and tuberculosis susceptibility. METHODS: Tuberculosis, TB, mycobacteria, polymorphism, variant, mutation, susceptibility, tumor necrosis factor or, TNF, cytokine, and gene were used as key words both in Chinese and English to search all the published related articles in Pubmed, Embase, Web of science, Science Direct, Springer Link, EBSCO, Wanfang and Chinese Journal Full-text Database until October 2011. HWE test was performed in all the comparisons. Heterogeneity across studies was determined, and sensitivity analyses were conducted. RESULTS: Nine case-control studies were included. The meta-analysis indicated that there was no significant association between TNF -238G/A polymorphism and tuberculosis susceptibility (GA + AA vs GG model: OR = 1.00, 95%CI: 0.77 - 1.32; A vs G model: OR = 1.00, 95%CI: 0.77 - 1.30). No significant heterogeneity (Q was 5.04 and 5.82 respectively, P > 0.05) and publication bias (GA + AA vs GG model: Begg test Z = 0.73, Egger test t = 1.94, P > 0.05; A vs G model: Begg test Z = 0.52, Egger test t = 1.72, P > 0.05) were demonstrated. Sensitivity analyses further indicated the reliability of the study (OR were 0.94 - 1.10 respectively, all P > 0.05). CONCLUSION: Our study did not detect any association between TNF -238G/A polymorphism and tuberculosis susceptibility.

Developing Chinese race-specific warfarin dose prediction algorithms.

BACKGROUND: Numerous genotype-guided warfarin dosing algorithms have been developed to individualize warfarin doses, but they can only explain 47-52% of the variability. AIM: This study aimed to develop new warfarin algorithms suitable to predict the stable warfarin dose for the Chinese population and to compare their prediction performance with those of the most commonly used algorithms. METHOD: Multiple linear regression analysis with the warfarin optimal dose (WOD), logarithm (log) WOD, 1/WOD, and [Formula: see text], respectively, as the dependent variables were performed to deduce a new warfarin algorithm (NEW-Warfarin). WOD was the stable dose that maintained the international normalized ratio (INR) within the target range (2.0-3.0). Three major genotype-guided warfarin dosing algorithms were selected and compared against NEW-Warfarin predictive performance using the mean absolute error (MAE). Furthermore, patients were divided into five groups according to warfarin indications [atrial fibrillation (AF), pulmonary embolism (PE), cardiac-related disease (CRD), deep vein thrombosis (DVT), and other diseases (OD)]. Multiple linear regression analyses were also performed for each group. RESULTS: The regression equation with [Formula: see text] as the dependent variable had the highest coefficient of determination (R2 = 0.489). The NEW-Warfarin had the best predictive accuracy compared to the three algorithms selected. Group analysis, according to indications, showed that the R2 of the five groups were PE (0.902) > DVT (0.608) > CRD (0.569) > OD (0.436) > AF (0.424). CONCLUSION: Dosing algorithms based on warfarin indications are more suitable for predicting warfarin doses. Our research provides a novel strategy to develop indication-specific warfarin dosing algorithms to improve the efficacy and safety of warfarin prescribing.

A clinical study of the correlation between metabolic-associated fatty liver disease and coronary plaque pattern.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome (MetS) and has been correlated with coronary atherosclerosis (CAS). Since NAFLD was renamed metabolic-associated fatty liver disease(MAFLD) in 2020, no studies have evaluated the correlation between MAFLD and CAS. The aim of this study was to evaluate the relationship between MAFLD and CAS. A total of 1330 patients underwent continuous coronary computed tomography angiography (CCTA) and abdominal ultrasound as part of a routine physical examination. Ultrasonography was used to assess fatty liver, and CCTA was used to assess coronary artery plaques, degree of stenosis, and diseased blood vessels. Univariate and multivariate logistic regression analyses were performed with plaque type and degree of stenosis as dependent variables and MAFLD and traditional cardiovascular risk factors as independent variables to analyze the correlation between MAFLD and CAS. Among the 1164 patients, 680 (58.4%) were diagnosed with MAFLD through a combination of ultrasound and auxiliary examinations. Compared with the non-MAFLD group, the MAFLD group had more cardiovascular risk factors,and the MAFLD group had more likely to have coronary atherosclerosis, coronary stenosis and multiple coronary artery stenosis.In the univariate logistic regression, MAFLD was significantly correlated with overall plaque, calcified plaques, noncalcified plaques, mixed plaques,and significant stenosis in the coronary arteries.(p < 0.05). After adjusting for cardiovascular risk factors , MAFLD was correlated with noncalcified plaques (1.67; 95% confidence interval (CI) 1.15-2.43; p = 0.007) and mixed plaques (1.54; 95% CI 1.10-2.16; p = 0.011). In this study, MAFLD group had more cardiovascular risk factors, MAFLD was correlated with coronary atherosclerosis,and significant stenosis.Further study found independent associations between MAFLD and noncalcified plaques and mixed plaques, which suggest a clinically relevant link between MAFLD and coronary atherosclerosis.

Association between tumor necrosis factor alpha-238G/a polymorphism and tuberculosis susceptibility: a meta-analysis study.

BACKGROUND: Tumor necrosis factor alpha (TNF-α) plays a key role in the containment of tuberculosis. The relationship between the TNF -238G/A polymorphism and tuberculosis susceptibility remains inconclusive. A comprehensive meta-analysis was made to provide a more precise estimate of the relationship between them. METHODS: Multiple search strategies were used. A fixed effect model was takentook to estimate pooled OR with 95% confidence interval (CI) for the association between the TNF -238G/A polymorphism and tuberculosis susceptibility. The Chi-squared-based Q-test and I-squaredI2 statistic were calculated to examine heterogeneity. Begg's funnel plot and Egger's test were used to assess publication bias. RESULTS: 9 case-control studies were included in this meta-analysis. No significant heterogeneity was demonstrated, and no obvious publication bias was detected among the included studies. The meta-analysis indicated that there was no significant association between the TNF -238G/A polymorphism and tuberculosis susceptibility (GA+AA versus GG model: OR=1.005, 95% CI: 0.765-1.319; A versus G model: OR=1.000, 95% CI: 0.769-1.300). In the subgroup analyses by ethnicity, types of TB and human immunodeficiency virus (HIV) status, no significant association were identified. CONCLUSIONS: The meta-analysis involving 2723 subjects did not detect any association between the TNF -238G/A polymorphism and tuberculosis susceptibility.

Design, synthesis and activity evaluation of novel lesinurad analogues containing thienopyrimidinone or pyridine substructure as human urate transporter 1 inhibitors.

Urate Transporter 1 (URAT1) plays a crucial role in uric acid transport, making it an attractive target for the treatment of gout and hyperuricemia. As a representative URAT1 inhibitor, Lesinurad treat gout by promoting the uric acid excretion. However, its lower in vitro and in vivo activity should be highly attracted attention. Herein, the bioisosterism, molecular hybridization and scaffold hopping strategies were exploited to modify all the structural components of Lesinurad and finally thirty novel compounds bearing thienopyrimidinone or pyridine core were obtained. Most of the compounds displayed certain URAT1 inhibitory activity in vitro. Among them, thienopyrimidinones 6 (IC50 = 7.68 µM), 10 (IC50 = 7.56 µM), 14 (IC50 = 7.31 µM) and 15 (IC50 = 7.90 µM) showed slightly better potency than positive control Lesinurad (IC50 = 9.38 µM). Notably, 10 also displayed inhibitory activity (IC50 = 55.96 µM) against GLUT9. Additionally, in vivo serum uric acid (SUA)-lowering experiments were performed on some representative compounds and it was revealed that all the selected compounds could decrease the SUA level in mice, of which the decrease rate of SUA was 73.29% for the most promising compound 10, significantly greater than that of Lesinurad (26.89%). Meanwhile, the preliminary SARs based on the URAT1 inhibitory activity were discussed in detail, which pointed out the direction for further structural optimization. Overall, the thienopyrimidinone and pyridine are prospective skeletons for the developing novel URAT1 inhibitors with considerable potential for optimization.

Discovery of Novel Bicyclic Imidazolopyridine-Containing Human Urate Transporter 1 Inhibitors as Hypouricemic Drug Candidates with Improved Efficacy and Favorable Druggability.

Lesinurad is a uricosuric agent for the treatment of hyperuricemia associated with gout, which was found lacking in efficacy and safety. Here, scaffold hopping and molecular hybridization were exploited to modify all the structural components of lesinurad, and 36 novel compounds bearing bicyclic imidazolopyridine core were obtained. In a mouse model of acute hyperuricemia, 29 compounds demonstrated increased serum uric acid (SUA)-reducing activity; SUA was treated with 12, 23, and 29 about fourfold lower compared with that of lesinurad. Moreover, 23 exhibited stronger URAT1 inhibition activity (IC50 = 1.36 µM) than lesinurad (IC50 = 5.54 µM). Additionally, 23 showed favorable safety profiles, and no obvious acute toxicity was observed in Kunming mice under a single dose of 1000 mg·kg-1. 23 also achieved excellent pharmacokinetic properties with the oral bioavailability of 59.3%. Overall, all the results indicated that 23 is a promising drug candidate in the treatment of hyperuricemia and gout.

Acceptable Risk Analysis for Abrupt Environmental Pollution Accidents in Zhangjiakou City, China.

Abrupt environmental pollution accidents cause considerable damage worldwide to the ecological environment, human health, and property. The concept of acceptable risk aims to answer whether or not a given environmental pollution risk exceeds a societally determined criterion. This paper presents a case study on acceptable environmental pollution risk conducted through a questionnaire survey carried out between August and October 2014 in five representative districts and two counties of Zhangjiakou City, Hebei Province, China. Here, environmental risk primarily arises from accidental water pollution, accidental air pollution, and tailings dam failure. Based on 870 valid questionnaires, demographic and regional differences in public attitudes towards abrupt environmental pollution risks were analyzed, and risk acceptance impact factors determined. The results showed females, people between 21-40 years of age, people with higher levels of education, public servants, and people with higher income had lower risk tolerance. People with lower perceived risk, low-level risk knowledge, high-level familiarity and satisfaction with environmental management, and without experience of environmental accidents had higher risk tolerance. Multiple logistic regression analysis indicated that public satisfaction with environmental management was the most significant factor in risk acceptance, followed by perceived risk of abrupt air pollution, occupation, perceived risk of tailings dam failure, and sex. These findings should be helpful to local decision-makers concerned with environmental risk management (e.g., selecting target groups for effective risk communication) in the context of abrupt environmental accidents.

Accidental Water Pollution Risk Analysis of Mine Tailings Ponds in Guanting Reservoir Watershed, Zhangjiakou City, China.

Over the past half century, a surprising number of major pollution incidents occurred due to tailings dam failures. Most previous studies of such incidents comprised forensic analyses of environmental impacts after a tailings dam failure, with few considering the combined pollution risk before incidents occur at a watershed-scale. We therefore propose Watershed-scale Tailings-pond Pollution Risk Analysis (WTPRA), designed for multiple mine tailings ponds, stemming from previous watershed-scale accidental pollution risk assessments. Transferred and combined risk is embedded using risk rankings of multiple routes of the "source-pathway-target" in the WTPRA. The previous approach is modified using multi-criteria analysis, dam failure models, and instantaneous water quality models, which are modified for application to multiple tailings ponds. The study area covers the basin of Gutanting Reservoir (the largest backup drinking water source for Beijing) in Zhangjiakou City, where many mine tailings ponds are located. The resultant map shows that risk is higher downstream of Gutanting Reservoir and in its two tributary basins (i.e., Qingshui River and Longyang River). Conversely, risk is lower in the midstream and upstream reaches. The analysis also indicates that the most hazardous mine tailings ponds are located in Chongli and Xuanhua, and that Guanting Reservoir is the most vulnerable receptor. Sensitivity and uncertainty analyses are performed to validate the robustness of the WTPRA method.

Tumor necrosis factor-α gene polymorphisms and risk of oral cancer: evidence from a meta-analysis.

Numerous studies have been conducted regarding association between TNF-α and oral cancer risk, but the results remain controversial. The present meta-analysis is performed to acquire a more precise estimation of relationships. Databases of Pubmed, the Cochrane library and the China National Knowledge Internet (CNKI) were retrieved until August 10, 2013. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated with fixed- or random-effect models. The heterogeneity assumption was assessed by I-squared test. Among the eight included case-control studies, all were focused on TNF-α-308G>A and four also concerned the TNF-α-238G>A polymorphism. It was found that oral cancer risk were significant decreased with the TNF-α-308G>A polymorphism in the additive genetic model (GG vs. AA, OR=0.19, 95% CI: [0.04, 1.00], P=0.05, I2=68.9%) and the dominant genetic model (GG+GA vs. AA, OR=0.22, 95% CI: [0.06, 0.82], P=0.03, I2=52.4%); however, no significant association was observed in allele contrast (G vs. A, OR=0.70, 95% CI: [0.23, 2.16], P=0.54, I2=95.9%) and recessive genetic models (GG vs. GA+AA, OR=0.72, 95% CI: [0.33, 1.57], P=0.41, I2=93.1%). For the TNF-α-238G>A polymorphism, significant associations with oral cancer risk were found in the allele contrast (G vs. A, OR=2.75, 95% CI: [1.25, 6.04], P=0.01, I2=0.0%) and recessive genetic models (GG vs. GA+AA, OR=2.23, 95%CI: [1.18, 4.23], P=0.01, I2=0.0%). Conclusively, this meta-analysis indicates that TNF-α polymorphisms may contribute to the risk of oral cancer. Allele G and the GG+GA genotype of TNF-α- 308G>A may decrease the risk of oral cancer, while allele G and the GG genotype of TNF-α-238G>A may cause an increase.

Tumor necrosis factor alpha -308G>A, -863C>A, -857C>T gene polymorphisms and tuberculosis susceptibility: a meta-analysis.

BACKGROUND/AIMS: A large number of studies have shown that polymorphisms in the tumor necrosis factor-α (TNF-α, TNFA) gene are implicated in susceptibility to tuberculosis (TB). However, the results are inconsistent. We performed this meta-analysis to estimate the association between polymorphisms in the TNFA gene and TB susceptibility. METHODS: Relevant studies published before March 2012 were identified by searching PubMed, ISI web of knowledge, EBSCO and CNKI. The strength of relationship between the TNFA gene and TB susceptibility was assessed using odds ratios (ORs). RESULTS: A total number of twenty-three case-control studies including 3630 cases and 4055 controls were identified referring to three previously chosen single-nucleotide polymorphisms (SNPs): -308G>A, -863C>A and -857C>T. No association was found between -308G>A, -863C>A and TB susceptibility: -308G>A (GG+GA vs. AA): OR 0.85, 95%CI: 0.55-1.30, P=0.44; -863C>A (CC+CA vs. AA): OR 0.93, 95%CI: 0.84-1.81, P=0.83. Increased risk of TB was associated with -857C>T in the dominant genetic model (CC+CT vs. TT: OR 2.13, 95%CI: 1.25-3.63, P=0.01), the heterozygote comparison (CT vs. TT: OR 2.69, 95%CI: 1.44-5.02, P=0.00) and the homozygote comparison (CC vs. TT: OR 2.08, 95%CI: 1.22-3.53, P=0.01) in Asian subjects. CONCLUSION: There is an increased association between TNFA -857C>T polymorphism and TB risk among Asian subjects. No association was found between -308G>A and -863C>A with TB risk. Due to several limitations in the present study, well-designed epidemiological studies with large sample size among different ethnicities should be performed in the future.