Vascular calcification and coagulation disorders are highly prevalent in patients with chronic renal failure (CRF); however, whether a causal relationship between these two exist is not clear. This study investigated the role of the coagulation factor von Willebrand factor (vWF) in the pathogenesis of vascular calcification in CRF. RNA sequencing was used to detect changes in gene expression involved in coagulation cascades in human umbilical vascular endothelial cells (HUVECs) treated with Na2HPO4 and NaH2PO4, reaching a final total phosphate concentration of 3 mM. A rat model of vascular calcification was generated by feeding rats a diet containing 0.5

The triglyceride-glucose (TyG) index is regarded as a surrogate marker of systemic insulin resistance (IR). Studies have substantiated the impact of IR on cardiovascular diseases. Nonetheless, the prognostic value of the TyG index in critical patients with heart failure (HF) with intensive care unit (ICU) admission remains unclear. This study aims to assess the association between the TyG index and all-cause mortality in critically ill patients with HF. Patients with HF requiring ICU admission were identified from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database and subsequently stratified into quartiles based on their TyG index. The primary outcome was 30-day all-cause mortality, and the secondary outcome was 1-year all-cause mortality. The relationship between the TyG index and all-cause mortality in HF patients was analyzed using multivariable Cox proportional hazards models and restricted cubic splines. A total of 1220 patients (62.4% men) were enrolled, with a mean age of 70.6 years. The 30-day and one-year all-cause mortality rate were 15.7% and 34.6%, respectively. Multivariable Cox regression revealed that TyG index was significantly associated with an elevated risk of 30-day all-cause mortality (adjusted HR, 1.360; 95% CI, 1.093-1.694; P = 0.006), but not with one-year mortality (adjusted HR 1.046; 95% CI 0.895-1.222, P = 0.574). Restricted cubic splines showed a progressively increasing risk of 30-day mortality was linearly related to an elevated TyG index. Subgroup analyses indicated a more prominent association between TyG index and 30-day mortality in patients with age ≤ 65, female or BMI > 30 kg/m2. In critically ill patients with HF, the TyG index is significantly associated with short-term all-cause mortality. Our results highlight that the TyG index can be useful in identifying HF patients at high risk of all-cause mortality and require close follow-up after discharge.

Background: Approximately 10-20% of individuals with non-alcoholic fatty liver disease (NAFLD) are lean, and the underlying pathophysiology is not yet understood. This study aims to explore the characteristics and the diagnostic value of triglyceride-glucose index (TyG) in early diagnosis of lean NAFLD. Methods: 99 patients with lean NAFLD and 1891 healthy controls were included in the health examination. The characteristics were compared between groups. Restricted cubic spline was utilized to analyze the relationship between TyG index and the risk of lean NAFLD. Logistic regression and receiver operating curve (ROC) were applied to explore the diagnostic value of TyG index for lean NAFLD. Results: Overall, 99 (4.97%) patients had lean NAFLD. Patients with lean NAFLD have significant abnormal glycolipid metabolism and higher TyG index. Restriction cube spline analysis showed a significant dose-response relationship between the TyG index and risk of lean NAFLD. After adjusting for confounders, the relationship remained and the risk of developing lean NAFLD increased 2.99 times for per unit increase of TyG index (95% CI: 1.94, 4.67, P< 0.001). The areas under the ROC of the TyG index for lean NAFLD detection were 0.851 (0.815 to 0.886). Conclusion: The TyG index is positively associated with the risk of developing lean NAFLD and could be a useful marker for early diagnosis of lean NAFLD.

Dexmedetomidine (Dex) is widely used in the sedation in intensive care units and as an anesthetic adjunct. Considering the anti-inflammatory and antioxidant properties of Dex, we applied in vivo rat model as well as in vitro cardiomyocyte models (embryonic rat cardiomyocytes H9c2 cells and neonatal rat cardiomyocytes, NRCMs) to evaluate the effects of Dex against myocardial ischemia reperfusion (I/R) injury. Transcriptomic sequencing for gene expression in heart tissues from control rats and Dex-treated rats identified that genes related to fatty acid metabolism were significantly regulated by Dex. Among these genes, the elongation of long-chain fatty acids (ELOVL) family member 6 (Elovl6) was most increased upon Dex-treatment. By comparing the effects of Dex on both wild type and Elovl6-knockdown H9c2 cells and NRCMs under oxygen-glucose deprivation/reoxygenation (OGD/R) challenge, we found that Elovl6 knockdown attenuated the protection efficiency of Dex, which was supported by the cytotoxicity endpoints (cell viability and lactate dehydrogenase release) and apoptosis as well as key gene expressions. These results indicate that Dex exhibited the protective function against myocardial I/R injury via fatty acid metabolism pathways and Elovl6 plays a key role in the process, which was further confirmed using palmitate exposure in both cells, as well as in an in vivo rat model. Overall, this study systematically evaluates the protective effects of Dex on the myocardial I/R injury and provides better understanding on the fatty acid metabolism underlying the beneficial effects of Dex.

Revealing the spatial distribution and regional differences of red blood cell distribution width (RDW) reference values in the healthy Chinese population is important for the monitoring, diagnosis and prevention of the top chronic diseases in the disease spectrum in China. Medical indicator data were matched with geographical data and environmental pollution data to predict RDW reference values for the whole region of China using ridge regression analysis, support vector machine and BP neural network. Taylor diagrams and assignment methods were used to select the optimal model, and the spatial distribution was mapped according to the prediction results of the optimal model, and the intervals of RDW reference values for different age groups of healthy people in China were redefined. It was suggested that the reference values of RDW in the young and middle-aged groups in China were divided into low-value areas in the north (12.31,12.80) and high-value areas in the south (12.80,13.18); the reference values of RDW in the elderly group were divided into low-value areas in the north (11.28,12.60) and high-value areas in the south (12.60,13.91).In turn, it can provide a more accurate reference basis in the monitoring, diagnosis and prevention of chronic diseases at the top of the disease spectrum.

ObjectiveObesity, hypertension and diabetes are high prevalent that are often associated with poor outcomes. They have become major global health concern. Little research has been done on the impact of lymphocyte-to-monocyte ratio (LMR) on outcomes in these patients. Thus, we aimed to explore the association between LMR and all-cause mortality in obese hypertensive patients with diabetes and without diabetes.MethodsThe researchers analyzed data from the National Health and Nutrition Examination Survey (2001-2018), which included 4,706 participants. Kaplan-Meier analysis was employed to compare survival rate between different groups. Multivariate Cox proportional hazards regression models with trend tests and restricted cubic splines (RCS) analysis and were used to investigate the relationship between the LMR and all-cause mortality. Subgroup analysis was performed to assess whether there was an interaction between the variables.ResultsThe study included a total of 4706 participants with obese hypertension (48.78% male), of whom 960 cases (20.40%) died during follow-up (median follow-up of 90 months). Kaplan–Meier curves suggested a remarkable decrease in all-cause mortality with increasing LMR value in patients with diabetes and non-diabetes (P for log-rank test < 0.001). Moreover, multivariable Cox models demonstrated that the risk of mortality was considerably higher in the lowest quartile of the LMR and no linear trend was observed (P > 0.05). Furthermore, the RCS analysis indicated a non-linear decline in the risk of death as LMR values increased (P for nonlinearity < 0.001).ConclusionsIncreased LMR is independently related with reduced all-cause mortality in patients with obese hypertension, regardless of whether they have combined diabetes.

BACKGROUND:Currently, the influenza epidemic in China is at a high level and mixed with other respiratory diseases. Current studies focus on regional influenza and the impact of environmental pollutants on time series, and lack of overall studies on the national influenza epidemic and the nonlinear correlation between environmental pollutants and influenza. The unclear spatial and temporal evolution patterns of influenza as well as the unclear correlation effect between environmental pollutants and influenza epidemic have greatly hindered the prevention and treatment of influenza epidemic by relevant departments, resulting in unnecessary economic and human losses.METHOD:This study used Chinese influenza incidence data for 2007-2017 released by the China CDC and air pollutant site monitoring data. Seasonal as well as inter monthly differences in influenza incidence across 31 provinces of China have been clarified through time series. Space-Time Cube model (STC) was used to investigate the spatio-temporal evolution of influenza incidence in 315 Chinese cities during 2007-2017. Then, based on the spatial heterogeneity of influenza incidence in China, Generalized additive model (GAM) was used to identify the correlation effect of environmental pollutants (PM2.5, PM10, CO, SO2, NO2, O3) and influenza incidence.RESULT:The influenza incidence in China had obvious seasonal changes, with frequent outbreaks in winter and spring. The influenza incidence decreased significantly after March, with only sporadic outbreaks occurring in some areas. In the past 11 years, the influenza epidemic had gradually worsened, and the clustering of influenza had gradually expanded, which had become a serious public health problem. The correlation between environmental pollutants and influenza incidence was nonlinear. Generally, PM2.5, CO and NO2 were positively correlated at high concentrations, while PM10 and SO2 were negatively correlated. O3 was not strongly correlated with the influenza incidence.CONCLUSION:The study found that the influenza epidemic in China was in a rapidly rising stage, and several regions had a multi-year outbreak trend and the hot spots continue to expand outward. The association between environmental pollutants and influenza incidence was nonlinear and spatially heterogeneous. Relevant departments should improve the monitoring of influenza epidemic, optimize the allocation of resources, reduce environmental pollution, and strengthen vaccination to effectively prevent the aggravation and spread of influenza epidemic in the high incidence season and areas.

Objective To investigate the role and mechanism of dapagliflozin（Dapa）, a sodium glucose cotransporter 2 inhibitor, in acute liver injury. Methods Eight-week-old C57BL6/J mice were given a single intraperitoneal injection of CCl 4 to induce acute liver injury. The mice were preventively given 5 mg/kg Dapa by gavage 24 h and 2 h before CCl 4 injection, while those in the control group were given an equal volume of solvent gavage. After 24 h, the mice were anesthetized and sacrificed. H＆E staining, plasma biochemistry, RT-q PCR, and Western blotting were used to detect the severity of liver injury and the expressions of macrophage-related genes. Results In the CCl 4 group, hepatic infiltration of inflammatory cells increased, and liver and renal functions significantly deteriorated, which was further aggravated by Dapa. CCl 4 could promote the expressions of M1 macrophages and fibrosis-related genes in the liver, but reduce those of M2 and antioxidant-related genes, and the latter was further inhibited by Dapa. In addition, the protein expression of arginase 1 decreased and that of SGLT2 increased after Dapa intervention, while NF-κB pathway did not change significantly, suggesting that Dapa might directly affect the energy metabolism homeostasis in the liver and aggravate acute liver injury induced by CCl 4 . Conclusion Dapa can exacerbate hepatic and renal damage in acute stage of liver injury, inhibit macrophages M2 polarization, and aggravate oxidative stress and inflammatory injury induced by CCl 4 .

PURPOSE:Vitamin D receptors (VDR) play important roles in cardiovascular, immune, metabolic and other functions. Activation of VDR may help improve endothelial dysfunction, atherosclerosis, vascular calcification, and cardiac hypertrophy. However, the specific target genes and mechanisms of VDR in improving Human Umbilical Vein Endothelial Cell (HUVEC) functions remain unclear. This study aims to investigate the function and mechanism of VDR in HUVECs.METHODS:Endothelial dysfunction cell model was constructed by oxidized low-density lipoprotein (ox-LDL). An animal model of atherosclerosis was established in male homozygous Apoe-/- mice (6 weeks) on a high fat diet for 6 weeks. The relationship between VDR and adrenomedullin (ADM) was studied by bioinformatics analysis, ChIP, and luciferase reporter gene analysis. Endothelial cell function was evaluated by Transwell migration and Tube Formation tests. Ferroptosis was detected by measuring intracellular iron content, levels of oxidative stress markers, and ferroptosis related proteins.RESULTS:Overexpression of VDR in HUVECs inhibits ox-LDL-induced endothelial dysfunction and ferroptosis. VDR binds to the ADM promoter sequence and regulates the transcription of ADM. Inhibition of ADM promotes ox-LDL-induced endothelial dysfunction and ferroptosis. ADM regulates ox-LDL-induced endothelial dysfunction and ferroptosis through the AMPK signaling pathway. Overexpression of VDR in Apoe-/- mice inhibited lipid deposition and plaque area in atherosclerotic mice.CONCLUSION:VDR inhibits ox-LDL-induced endothelial dysfunction and ferroptosis by regulating ADM transcription and acting on AMPK signaling pathway. Overexpression of VDR in Apoe-/- mice reduced lipid deposition and plaque area in the thoracic aorta of atherosclerotic mice.

Background: The prevalence of hypertension and obesity in China has sharply increased in recent decades. We aimed to develop and validate a novel model for predicting the risk of hypertension based on anthropometric indicators relating to obesity in the general population of China. Methods: In this retrospective study, 6196 participants from the China Health and Nutrition Survey (CHNS) during the 2009-2015 waves were included. Risk factors for hypertension were assessed by LASSO regression combined with multivariate logistic regression analysis. A nomogram was developed as a predictive model based on the screening prediction factors. The discrimination and calibration of the model were evaluated by receiver operating curve (ROC) and calibration plots, respectively. Decision curve analysis (DCA) was used to evaluate the clinical application value of the model. Results: A total of 6196 participants were divided into two sets at a ratio of 7:3, using computer-generated random numbers: 4337 individuals were assigned to the training set and 1859 to the validation set. The training set was divided into a hypertension group (n = 1016) and a non-hypertension group (n = 3321) based on the follow-up outcomes for hypertension. Predictive factors of hypertension included age, drinking, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and arm-to-height ratio (AHtR) at baseline as predictors. The area under the ROC curve (AUC) for the training and validation sets was 0.906 (95% CI: 0.897-0.915) and 0.905 (95% CI: 0.887-0.922), respectively. In bootstrap validation, the C-index was 0.905 (95% CI: 0.888-0.921). The model also had good predictive accuracy according to the calibration plot. DCA demonstrated that people would benefit more when the threshold probability was between 5% and 80%. Conclusion: A nomogram model was successfully established to effectively predict the risk of hypertension based on anthropometric indicators. The model could be a feasible tool for hypertension screening in the general population of China.

急性ST段抬高型心肌梗死(STEMI)是严重威胁人类生命健康的心血管疾病,起病凶险且死亡率高.随着经皮冠状动脉内介入(PCI)手术的开展,短期内尽快开通闭塞血管、恢复远端心肌血流灌注,能够显著降低STEMI患者病死率、改善临床预后.然而,相当部分STEMI患者PCI术后出现冠脉内无复流(CNR)现象,极大地阻碍了其临床治疗效果和远期预后改善.目前,CNR的病理机制尚未完全清楚,临床上亦缺乏可靠的预测指标和治疗措施.部分药物和手术操作显示出一定预防和改善PCI术后CNR的疗效,但远期心血管获益尚有待研究.本文就CNR的定义与诊断、相关危险因素、预测评估及防治措施进行回顾,以提高临床对于STEMI患者PCI术后CNR的认知与重视,并对未来研究方向进行展望.

目的:探讨2型糖尿病(T2DM)合并非酒精性脂肪性肝病(NAFLD)老龄小鼠模型的建立方法.方法:18周龄C57BL/6J雄性小鼠随机分为正常对照组与模型组,每组8只.模型组小鼠全程给予高脂饲料(HFD,60％Fat)喂养6周,对照组采用普通饲料喂养.第3周开始,模型组小鼠连续5 d腹腔注射50 mg/kg链脲佐菌素(STZ),对照组给予等体积柠檬酸/柠檬酸钠溶液腹腔注射.注射结束后3 d和1周分别尾尖采血测禁食4 h后血糖,＞11.0 mmol/L即为糖尿病造模成功.监测小鼠体重与一般情况,继续HFD饲喂至第6周造模结束.腹腔麻醉、眼球采血,分离心脏、肝脏及肾脏,进行血浆生化与组织病理检测.结果:6周HFD喂养联合STZ造模后,模型组小鼠肝脏体积增大,H&E染色显示肝细胞内出现脂肪空泡与气球样改变,小叶结构破坏,并伴有炎症细胞浸润增加;心肌与肾皮质中炎症细胞浸润、组织结构紊乱.同时,血浆中谷丙转氨酶、谷草转氨酶及胱抑素C水平升高,提示肝肾功能损伤发生.血浆葡萄糖、总胆固醇、三酰甘油、低密度脂蛋白及高密度脂蛋白胆固醇水平均显著增加.肝脏油红O染色显示脂滴大量蓄积,肝内总胆固醇与三酰甘油含量增加.结论:老龄小鼠中通过HFD喂养联合低剂量STZ多次注射能够诱发糖尿病与肝脂肪变性,从而快速有效地建立T2DM合并NAFLD的老龄小鼠模型.

目的 探究慢性心衰合并SARS-CoV-2感染的高龄老年患者临床特征及预后相关因素.方法 收集2022-12-28～2023-01-31西安交通大学第二附属医院心血管内科收治的慢性心衰合并2019冠状病毒病老年患者.根据年龄分为老年患者组(<80岁)与高龄老年患者组(≥80岁),组间比较两组患者在临床特征、实验室化验与药物治疗方面的差异,Spearman相关性与多元线性回归分析老年慢性心衰合并2019冠状病毒病患者住院天数的影响因素.结果 ① 两组患者性别构成比、基础疾病与ICU重症患者比例相近,高龄老年患者组吸烟、饮酒者比例较低,住院天数延长(P<0.05);相比老年患者组,高龄老年患者外周血淋巴细胞计数更低(P<0.05),谷草转氨酶与胱抑素C水平明显升高(P>0.05;P>0.05),纤维蛋白降解产物更高(P>0.05),钠离子与氯离子水平显著降低(P<0.05;P<0.05).② 高龄老年患者中接受糖皮质激素治疗者更为普遍(51.9％vs 21.2％,P<0.05),乙酰半胱氨酸、雾化治疗比例更高(74.1％vs 48.5％,P<0.05;66.7％vs 27.3％,P<0.05).早期抗病毒药物在两组患者中使用比例均较低;心血管疾病药物方面,高龄老年患者中接受阿司匹林与P2Y12受体拮抗剂治疗比例较低(60.6％vs 37.0％,P>0.05;54.5％vs 22.2％,P<0.05),袢利尿剂使用比例则更高(78.8％vs 96.3％,P<0.05).③Spearman相关性分析显示,年龄、外周血淋巴细胞计数减低、低钠血症与老年心衰合并2019冠状病毒病患者住院时间延长显著相关(r=0.291,P<0.05;r=0.373 P<0.05;r=0.285,P<0.05).④ 线性回归结果显示,女性、淋巴细胞计数减低、接受雾化治疗可能是老年心衰合并2019冠状病毒病患者住院天数延长的危险因素(B=2.719,P<0.05;B=2.885,P<0.05;B=3.115,P<0.05).结论 慢性心衰合并2019冠状病毒病的高龄老年患者入院时淋巴细胞耗竭更为严重,更易出现肝肾功损害与凝血纤溶亢进,常伴乏力纳差与低钠、低氯血症,接受糖皮质激素、祛痰、雾化与袢利尿剂治疗的比例更高,住院天数更长,尤其是淋巴细胞显著耗竭、需要雾化治疗的老年女性患者.

心血管疾病是危害人类生命健康的头号杀手,也是非酒精性脂肪性肝病与肝纤维化病人的首要死因,且肝纤维化是心血管疾病发病的重要危险因素,两者之间存在着复杂的共同致病机制.综述肝纤维化和心血管疾病共病机制研究及其治疗的相关进展.

This study aimed to investigate the geospatial distribution of normal reference values of Interleukin 4 (IL-4) in healthy Chinese adults and to provide a basis for the development of standard references. IL-4 values of 5,221 healthy adults from 64 cities in China were collected and analyzed for a potential correlation with 24 topographical, climatic and soil factors. Seven of these factors were extracted and used to build a back propagation (BP) neural network model that was used to predict IL-4 reference values in healthy individuals from 2,317 observation sites nationwide. The predicted values were tested for normality and geographic distribution by analytic Kriging interpolation to map the geographic distribution of IL-4 reference values in healthy Chinese subjects. The results showed that IL-4 values generally decreased and then increased from the South to the North. We concluded that the BP neural network model applies to this approach, where certain geographical factors determine levels of various biochemical and immunological standards in healthy adults in regions with different topography, climate and soil indices.

The Anti-mullerian hormone (AMH) reference value is an important indicator of ovarian function. The main targets of this were to screen the geographical environmental factors that may influence the distribution of AMH reference values in Chinese females of childbearing age, and to further explore the geographical distribution differences of AMH reference values. We gathered the AMH data of 28,402 healthy Chinese females from 62 cities in China for this study in order to conduct a spearman regression analysis to determine the relationship between the AMH and 30 geography factors. The AMH reference value in different regions was forecasted by using a ridge regression model. The magnitude of influence from the geographical factor on different regions was analysed by geographically weighted regression. Ultimately, We were able to figure out the geographic distribution risk prediction of AMH reference values by utilizing the disjunctive Kriging method. The AMH reference value was significantly correlated with the 16 secondary indexes. The geographical distribution of AMH showed a trend of being higher in Qinghai-Tibet and Southern regions, and lower in the Northwest and Northern regions. This study lays the foundation for future investigations into the mechanism of different influencing factors on the reference value of AMH. It is suggested that such regional variations in AMH reference values be taken into account while diagnosing and treating individuals with reproductive medicine.

目的 探究可能对健康人血尿酸(uric acid,UA)产生影响的地理环境因子并探究全国尺度下 UA参考值的变化趋势.方法 收集全国 565 个位点的 607 905 例健康人的 UA参考值,运用相关分析法分析 25 项地理环境因素与UA参考值的相关性,构建CatBoost模型并应用 SHAP值解释模型,预测全国各县市级的健康人 UA参考值,并采用普通克里金绘制全国健康人的 UA参考值地理分布图.结果 纬度、海拔高度、年平均气温、年平均相对湿度、年降水量、气温年较差、年平均风速、表土粉粒百分率、表土容重、表土石砾含量、表土有机质含量、表土 pH、表土(粘土)阳离子交换量、表土(粉土)阳离子交换量、表土盐基饱和度、表土总可交换量、T-CaCO3、T-CaSO4、表土碱度、表土盐分这 20 项指标与全国健康人UA参考值呈现相关.全国健康人UA参考值的空间分布呈现差异性,表现为高海拔地区较高,沿海地区在相近海拔高度下高于内陆地区,中东部低、西南部高的变化趋势.结论 本研究为后续近一步研究不同影响因子对 UA参考值的作用机制奠定基础.建立 CatBoost模型在不同地区使用 UA 参考值作为高尿酸血症及相关慢性疾病预后因子制定参考标准时提供依据.

Correction for ‘A fluorescent biosensor for cardiac biomarker myoglobin detection based on carbon dots and deoxyribonuclease I-aided target recycling signal amplification’ by Jishun Chen et al., RSC Adv., 2019, 9, 4463–4468, https://doi.org/10.1039/C8RA09459D.

Recently, there have been numerous reports of suspected myocarditis cases following vaccination against Corona Virus Disease 2019 (COVID-19), although the exact mechanism behind it is still unclear [1,2]. Shaw KE and colleagues reported four cases of acute myocarditis that were temporally related to the receiving of COVID-19 vaccine based on their Cardiac Magnetic Resonance (CMR) imaging findings [3]. Among them, two patients with previous COVID-19 infection developed symptoms after the first dose, while the other two patients with no previous COVID-19 infection developed symptoms after the second dose. Therefore, the authors argued that there might be a potential immune-boosting mechanism flowing prior immune exposure or priming.

Background: Blood lipid is an important factor affecting cardiovascular disease in middle-aged and elderly people. At present, the associations between environmental factors and blood lipid level in elderly people has been controversial, and the nonlinear effect of their relationship is lack of research. Methods: This study used data from a national cross-sectional survey of blood lipid levels in 13,354 subjects and data from environmental monitoring sites. Logistic regression was used to measure the relationship between the basic characteristics of the study population and blood lipid levels. After controlling the confounding factors, the nonlinear associations between environmental factors and blood lipid levels of middle-aged and elderly people in different geographical regions were studied by random forest model. Results: The risk of dyslipidemia is significantly higher in middle-aged women, obese people, elderly people, and urban people. Smoking and alcohol consumption increase the risk. The associations between environmental factors and lipid levels of middle-aged and elderly people are nonlinear, the correlation effect between air pollutants and blood lipid level is mainly shown in northern China, and the correlation between meteorological factors and blood lipid level is more obvious in southern China. Conclusions: This study shows that the associations between environmental factors and lipid levels in middle-aged and elderly population are nonlinear and have regional differences. Therefore it should be considered in optimizing the allocation of public health resources and preventing and controlling environmental exposure of middle-aged and elderly population.