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Yu-Qin Yan,1 Yu-Qing Huang,2 Ying-Qing Feng2 1Department of Cardiology, People’s Hospital of Shenzhen Baoan District, Shenzhen, People’s Republic of China; 2Department of Cardiology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of ChinaCorrespondence: Yu-Qin Yan, Department of Cardiology, People’s Hospital of Shenzhen Baoan District, No. 118, Longjing Second Road, Xinan Street, Baoan District, Shenzhen, 518100, People’s Republic of China, Tel/Fax +86-755-27788311, Email graceyuqin@163.comBackground: The Great Chinese Famine, as the famine of 1959– 1961 was often known. Famine exposure during early life was proven to be associated with some kidney diseases but has not been studied with kidney stone. We aimed to investigate the relationship between exposure to the Great Chinese Famine in early life and the incidence of kidney stone in adulthood.Methods: From 1 January 2017 to 31 December 2018, a total of 19,658 eligible adults were recruited in a cross-sectional survey who were born between 1 October 1952 and 30 September 1964 in Guangdong, China. Participants were separated into kidney stone and none-kidney stone groups based on kidney stone status. According to birth data, participants were divided into non-exposed, fetal-exposed, early-, mid-, and late-childhood-exposed groups. Multivariate logistic regression, subgroup analysis and interaction test were used to estimate the odds ratios (ORs) and confidence intervals (CIs) between famine exposure and kidney stone.Results: In total, 19,658 (12,246 female, mean age 59.31 ± 3.68 years) subjects were enrolled, and 3219 (16.38%) participants with kidney stone. The prevalence of kidney in none-, fetal-, early-, mid-, and late-childhood-exposed groups were 645 (14.9%), 437 (15.9%), 676 (16.3%), 743 (17.0%), and 718 (17.6%), respectively (P< 0.001). When compared with the unexposed group, the fully adjusted ORs for kidney stone from fetal-exposed, early-, mid- to late-childhood-exposed groups were 1.37 (95% CI: 1.13, 1.68, P=0.002), 1.98 (95% CI: 1.45, 2.72, P< 0.001), 2.94 (95% CI: 1.96, 4.42, P< 0.001), and 3.48 (95% CI: 2.11, 5.72, P< 0.001), respectively (P for trend< 0.001). Subgroup analyses revealed no interactions between the famine effect on kidney stones and body mass index, gender, smoking status, history of diabetes or hypertension (all P for interaction > 0.05).Conclusion: This study found that exposure to the Great Chinese Famine during early life was independently associated with the increased incidence of kidney stone in adulthood.Keywords: Great Chinese Famine, early life, famine exposure, adulthood, kidney stone

Background Cheese intake has been observed to be associated with obesity, but whether this relationship was causal was still unclear. To evaluate whether cheese intake have an causality effect on obesity and related traits. Methods We performed a two-sample Mendelian randomization (MR) analysis. Summary statistics from published Genome-wide association study (GWAS) associated with obesity and related traits including body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR) were obtained from FinnGen Biobank, IEU OpenGWAS database and UK Biobank. The cheese intake summary dataset was obtained from a UK Biobank database including 451,486 participants. Effect estimates were evaluated using inverse-variance weighted (IVW) method. Other MR analyses, including MR Egger (bootstrap), weighted median and weighted mode methods were performed in sensitivity analyses. Results In the MR analysis, genetically predicted cheese intake were associated with a 60% decreased risk of obesity (95% CI: 0.25, 0.63, P = 9.76E-5), 72% of obesity class 1 (95% CI: 0.16, 0.51, P = 1.75E-5), 74% of obesity class 2 (95% CI: 0.13, 0.55, P = 4.12E-4), 79% of obesity class 3 (95% CI: 0.07, 0.64, P = 6.25E-3) and 52% of overweight (95% CI: 0.33, 0.71, P = 2.39E-4) per 1-standard deviation (SD) increment of cheese intake by IVW. The results also provided strong evidence that cheese intake was causally and negatively associated with BMI (β=-0.60, 95% CI: -0.90, -0.29; P = 0.000), WC (β=-0.28, 95% CI: -0.40, -0.17; P = 2.13E-6), HC (β=-0.27, 95% CI: -0.41, -0.13; P = 2.13E-4) and WHR (β=-0.39, 95% CI: -0.50, -0.27; P = 5.92E-11). Results were robust using other MR methods in sensitivity analyses. Conclusions This two-sample MR analysis found that genetically predicted cheese intake had causal effect on an decreased risk of obesity and related traits. The improvement of dietary behavior may be beneficial to prevent obesity.

MicroRNA-199a-5p (miR-199a-5p) and -3p are enriched in the myocardium, but it is unknown whether miR-199a-5p and -3p are co-expressed in cardiac remodeling and what roles they have in cardiac hypertrophy and fibrosis. We show that miR-199a-5p and -3p are co-upregulated in the mouse and human myocardium with cardiac remodeling and in Ang-II-treated neonatal mouse ventricular cardiomyocytes (NMVCs) and cardiac fibroblasts (CFs). miR-199a-5p and -3p could aggravate cardiac hypertrophy and fibrosis in vivo and in vitro. PPAR gamma coactivator 1 alpha (Ppargc1a) and sirtuin 1 (Sirt1) were identified as target genes to mediate miR-199a-5p in promoting both cardiac hypertrophy and fibrosis. However, miR-199a-3p aggravated cardiac hypertrophy and fibrosis through targeting RB transcriptional corepressor 1 (Rb1) and Smad1, respectively. Serum response factor and nuclear factor κB p65 participated in the upregulation of miR-199a-5p and -3p in Ang-II-treated NMVCs and mouse CFs, and could be conversely elevated by miR-199a-5p and -3p. Together, Ppargc1a and Sirt1, Rb1 and Smad1 mediated the pathological effect of miR-199a-5p and -3p by promoting cardiac hypertrophy and fibrosis, respectively. This study suggests a possible new strategy for cardiac remodeling therapy by inhibiting miR-199a-5p and -3p., Graphical abstract, Transcription factor SRF and NF-κB p65 regulate the co-expression of miR-199a-5p and -3p by positive feedback in the pathological cardiac remodeling. Ppargc1a and Sirt1, Rb1 and Smad1 mediate the pathological role of miR-199a-5p and -3p by promoting cardiac hypertrophy and fibrosis, respectively.

Genomic instability (GIN) is pivotal in regulating tumor drug resistance, which blocked the treatment of triple negative breast cancer (TNBC). Although recent studies implied that non-coding RNA (ncRNA)-mediated autophagy abolishment promoted tumorigenesis by up-regulation of GIN, autophagy was known as a risk factor in tumor drug resistance. However, previous study also pointed that up-regulation of autophagy promoted GIN. Therefore, the relationship between autophagy and GIN is not clear, and more work is needed. And, if an ncRNA is identified to be a co-regulator of autophagy and GIN, it will be a potential therapy target of chemotherapy resistance in TNBC. In our study, we recognized both autophagy-GIN-associated microRNA (mi-26a-5p) by big data analysis, which was prognosis-correlated in breast cancer. Next, we identified the up-stream regulators (long non-coding RNA, lncRNA) and down-stream targets of miR-26a-5p by bioinformatics analysis (online public databases). Finally, we established lncRNA OTUD6B-AS1/miR-26a-5p/MTDH signaling pathway, and verified their functions by cytological, molecular biological and zoological experiments. In general, our study found (1) miR-26a-5p was a protective factor of breast cancer, while OTUD6B-AS1 and MTDH were risk factors; (2) OTUD6B-AS1 was the up-stream regulator of miR-26a-5p verified by luciferase; (3) up-regulation of miR-26a-5p and down-regulation of MTDH promoted cellular cytotoxicity of paclitaxel (PTX) in vitro and in vivo. (4) down-regulation of miR-26a-5p, overexpression of MTDH and OTUD6B-AS1 promoted autophagy and DNA damage; (5) up-regulation of OTUD6B-AS1 and MTDH inhibited DNA damage response (DDR) by inhibiting the phosphorylated activation of RAD51, ATR and ATM.

In this study, the aim is to explore whether frailty status modified the associations of serum 25(OH)D levels with all-cause and cause-specific mortality in the oldest old Chinese population.A total of 1411 participants aged at least 80 years were enrolled in the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Information on serum 25(OH)D level, frailty status, and covariates were examined at baseline. All-cause and cause-specific mortality status were ascertained during the follow-up survey conducted in 2017-2018 by using the ICD-10 codes. Cox proportional hazard models with stratified analyses were performed to evaluate potential associations. Over a median follow-up of 3.2 years, 722 (51.2%) participants were deceased, including 202 deaths due to circulatory diseases, and 520 deaths due to noncirculatory causes. After multivariable adjustment, the lowest quartile of serum 25(OH)D levels (Hazard Ratios (95% Confidence Intervals), 1.85 (1.45-2.36), 1.85 (1.45-2.36), 1.73 (1.31-2.29), respectively) and frailty (Odd Ratios (95% Confidence Intervals), 1.91 (1.60-2.29), 2.67 (1.90-3.74), 1.64 (1.31-2.05)) were associated with significantly higher risk of all-cause mortality, circulatory mortality, and noncirculatory mortality, respectively. In addition, we observed significant interactions among 25(OH)D and frailty on the risk of all-cause and cause-specific mortality (all P-interaction 0.001). Similar results were found in sensitivity analyses by excluding participants who died in the first year of follow-up and using clinical cutoffs of serum 25(OH)D levels.Low serum 25(OH)D levels were associated with higher risk of all-cause and cause-specific mortality among the oldest old of the Chinese population, and the associations were significantly stronger in individuals with frailty.

Background and aims The relationship between lipid variability and stroke among patients with hypertension were inconclusive. We aimed to investigate the association of lipid variability with ischemic stroke in hypertensive patients. Methods and results This retrospective cohort study included 4995 individuals with hypertension between 2013 and 2015, and recorded their status of ischemic stroke until the end of 2018. The variability in total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured using the standard deviation (SD), coefficient of variation (CV), variability independent of the mean (VIM) and average absolute difference between successive values (ASV). Multivariate Cox proportional hazards models with hazard ratios (HRs) and 95% confidence interval (CI) were performed. There were 110 cases of ischemic stroke during a median follow up of 4.2 years. The multivariable adjusted HRs and 95% CIs comparing the highest versus the lowest quartiles of SD of TC, LDL-C, HDL-C and TG were 4.429 (95% CI: 2.292, 8.560), 2.140 (95% CI: 1.264, 3.621), 1.368 (95% CI: 0.793, 2.359) and 1.421 (95% CI: 0.800, 2.525), respectively. High variability in TC and LDL-C were associated with a higher risk for ischemic stroke. Similarly, the results were consistent when calculating variability of TC and LDL-C using CV, ASV and VIM, and in various subgroup analyses. Conclusion Higher variability of TC and LDL-C associated with the risk of ischemic stroke among hypertensive patients. These findings suggest reducing variability of lipid parameters may decrease adverse outcomes.

Little was known about the effect of famine exposure on carotid intima-media thickness (cIMT). The present study aimed to explore the relationship in a Chinese population.Participants were divided into five groups: not exposed to famine, exposed to famine in fetal, early, mid or late childhood. Elevated cIMT was defined as a thickness of0.9 mm measured by carotid ultrasound. Multivariate logistic regression was performed to calculate odds ratio (OR) and confidence interval (CI) between famine exposure and cIMT. A total of 2637 (970 male, mean age 59.1 ± 3.65 years) participants were recruited, and 491 (18.62%) of them had elevated cIMT. When compared with the non-exposure group, the fully adjusted ORs for increased cIMT for exposure in fetal, early, mid to late childhood were 1.321 (95%CI: 0.872, 1.994, P = 0.186), 1.713 (95% CI: 1.188, 2.483, P = 0.004), 2.359 (95% CI: 1.674, 3.357, P 0.001) and 2.485 (95% CI: 1.773, 3.518, P 0.001), respectively. Subgroup analyses showed that the exposure to famine did not interact with body mass index, gender, smoking status, hypertension and diabetes history on its effect on cIMT.Our findings indicated that early-life exposure to the Chinese famine might be associated with an increased risk of increased cIMT in adulthood.

Background The link between total cholesterol (TC) and all-cause and specific mortality has not been elucidated. Herein, we aimed to evaluate the effect of TC levels on all-cause, cardiovascular disease (CVD), and cancer mortality. Methods All data analyzed were obtained from the National Health and Nutrition Examination Survey 1999–2014. The relationship between levels of TC and mortality was determined through Cox proportional hazard regression analysis coupled with multivariable adjustments. Two-piecewise linear regression models and Cox models with penalized splines were applied to explore nonlinear and irregular shape relationships. Kaplan–Meier survival curve and subgroup analyses were conducted. Results The sample studied comprised 14,662 men and 16,025 women, categorized as 25,429 adults aged 18–65 and 5,258 adults over 65 years old. A total of 2,570 deaths were recorded. All-cause, cardiovascular, and cancer mortality showed U-curve associations after adjusting for confounding variables in the restricted cubic spline analysis. Hazard ratios (HRs) of all-cause and cancer mortality were particularly negatively related to TC levels in the lower range Conclusions A nonlinear association of TC level with all-cause, cancer, and CVD mortality in the American population was observed, suggesting that too low or too high serum total cholesterol levels might correlate with adverse outcomes.

Antiepileptic drug zonisamide has been shown to be curative for Parkinson’s disease (PD) through increasing HMG-CoA reductase degradation protein 1 (Hrd1) level and mitigating endoplasmic reticulum (ER) stress. Hrd1 is an ER-transmembrane E3 ubiquitin ligase, which is involved in cardiac dysfunction and cardiac hypertrophy in a mouse model of pressure overload. In this study, we investigated whether zonisamide alleviated cardiac hypertrophy in rats by increasing Hrd1 expression and inhibiting ER stress. The beneficial effects of zonisamide were assessed in two experimental models of cardiac hypertrophy: in rats subjected to abdominal aorta constriction (AAC) and treated with zonisamide (14, 28, 56 mg · kg(−1) · d(−1), i.g.) for 6 weeks as well as in neonatal rat cardiomyocytes (NRCMs) co-treated with Ang II (10 μM) and zonisamide (0.3 μM). Echocardiography analysis revealed that zonsiamide treatment significantly improved cardiac function in AAC rats. We found that zonsiamide treatment significantly attenuated cardiac hypertrophy and fibrosis, and suppressed apoptosis and ER stress in the hearts of AAC rats and in Ang II-treated NRCMs. Importantly, zonisamide markedly increased the expression of Hrd1 in the hearts of AAC rats and in Ang II-treated NRCMs. Furthermore, we demonstrated that zonisamide accelerated ER-associated protein degradation (ERAD) in Ang II-treated NRCMs; knockdown of Hrd1 abrogated the inhibitory effects of zonisamide on ER stress and cardiac hypertrophy. Taken together, our results demonstrate that zonisamide is effective in preserving heart structure and function in the experimental models of pathological cardiac hypertrophy. Zonisamide increases Hrd1 expression, thus preventing cardiac hypertrophy and improving the cardiac function of AAC rats.

Purpose Whether the paradox of high-density lipoprotein cholesterol (HDL-C) and elevated mortality risk extends to hypertensive patients is unclear. We aimed to investigate the association between HDL-C and all-cause and cardiovascular disease mortality in adults with hypertension. Methods In the National Health and Nutrition Examination Surveys, 11,497 hypertensive participants aged ≥18years old and examined at baseline between 1999 and 2014 were followed up until December 2015. We categorized the HDL-C concentration as ≤30, 31-40, 41-50, 51-60 (reference), 61-70, >70 mg/dL and examined their associations with all-cause and cardiovascular mortality, respectively. Multivariate Cox regression was used to calculated hazard ratio (HR) and 95% confidence interval (CI) for mortality risk. Results During follow-up (median: 9.2 ± 3.8 years), 3012 deaths and 713 cardiovascular deaths were observed. In the restrictive cubic curves, associations of HDL-C levels and all-cause and cardiovascular mortality were detected to be U-shaped. After multivariable adjustment, HRs for all-cause mortality were for the lowest HDL-C concentration (≤30 mg/dL) 1.29 (95% CI, 1.07-1.56) and the highest (>70 mg/dL) 1.20 (1.06-1.37), comparing with the reference group. For cardiovascular mortality, HRs were 1.31 (0.83-1.48) and 1.09 (0.83-1.43), respectively. Similar results were obtained in subgroups stratified by age, gender, race, and taking lipid-lowering drugs. The lowest all-cause mortality risk was observed at HDL-C 66 mg/dL (concentration) and 51-60 mg/dL (range). Conclusion Both lower and higher HDL-C concentration appeared to be associated with higher mortality in hypertensive population. Further investigation is warranted to clarify the underlying mechanisms.

Purpose The relationship between thigh circumference and all-cause and cause-specific mortality has not been consistent. We aimed to examine how thigh circumference associates with all-cause, cardiovascular, and cerebrovascular mortality among US adults. Patients and Methods This cohort study included 19,885 US adults who participated in the 1999-2006 National Health and Nutrition Examination Survey (NHANES) with thigh circumference being measured at baseline, and survival status was ascertained until 31 December 2015. We used Cox proportional hazards models to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for mortality according to thigh circumference in quartiles. Kaplan-Meier survival curve and restricted cubic spline regression were performed to evaluate the prospective association. Finally, subgroup analyses by age, gender, body mass index (BMI), and medical history at baseline were conducted. Results During a median follow-up of 11.9 years, 3513 cases of death, 432 death cases due to cardiovascular disease, and 143 death cases due to cerebrovascular disease have occurred. Multivariate Cox regression indicated that every 1cm increase in thigh circumference was related to 4% and 6% decreased risk of all-cause mortality and cardiovascular mortality, respectively. Compared to the reference group, the highest quartile of thigh circumference significantly decreased all-cause mortality by 21% (HR 0.79, 95% CI 0.62-1.00, P

Purpose The associations of high-density lipoprotein cholesterol (HDL-C) with mortality are still unclear. We explored the associations of HDL-C with all-cause and cause-specific mortality in an adult population. Methods Deaths were classified into all-cause, cardiovascular, and cancer mortality. Survival curve, multivariate Cox regression, and subgroup analyses were conducted, and hazard ratio (HR) and 95% confidence interval (CI) were performed. We fitted Cox regression models for all-cause, cardiovascular, and cancer mortality to evaluate their associations with categories of HDL-C (≤30, 31-40, 41-50, 51-60 [reference], 61-70, >70 mg/dL). Results A total of 42,145 (20,415 (48.44%) males, mean age 47.12±19.40 years) subjects were enrolled. At an average follow-up of 97.52±54.03 months, all-cause, cardiovascular, and cancer mortality numbers were 5,061 (12.01), 1,081 (2.56%), and 1,061 (2.52%), respectively. When compared with the reference group (HDL-C: 51-60 mg/dL), a U-shaped association was apparent for all-cause mortality, with elevated risk in participants with the lowest (≤30 mg/dL) (HR=1.33; 95% CI=1.14- 1.56) and highest (>70 mg/dL) (HR=1.14; 95% CI=1.02-1.27) HDL-C concentration. Associations for cardiovascular and cancer mortality were non-linear. An elevated risk for cancer mortality was observed in those with the highest HDL-C concentration (HR=1.06; 95% CI-0.84-1.34) compared with the reference group, although it was not statistically significant. The effect of HDL-C on mortality was adjusted by some traditional risk factors including age, gender, race, or comorbidities. Conclusion A U-shaped association was observed between HDL-C and all-cause mortality among an adult population.

Purpose Little is known about the recent trends of hypertension in southern China. The aim of the study was to investigate the trends of hypertension in Guangdong Province between 2012 and 2019. Methods We conducted two cross-sectional surveys in 2012 and 2019 in southern China, which included 10,970 and 27,483 participants, respectively, aged 35 to 75 years old using a method of stratified, multistage, and cluster sampling. Hypertension was defined as a mean systolic/diastolic blood pressure (SBP/DBP) ≥140/90mmHg, or a self-reported condition, or any pharmacological treatment in the last 2 weeks. In addition, according to the 2017 ACC/AHA guideline for high blood pressure, we estimated the prevalence and control rate of hypertension. Results According to the 2010 Chinese guideline, the age-standardized rate of hypertension prevalence was 34.7% in 2012 and 36.9% in 2019 with a slight increase, while the prevalence of prehypertension was stable (14.5% vs 14.3%). Over the period of our study, 45.6% and 60.7% of hypertensive patients knew their diagnosis in 2012 and 2019, and 40.8% and 51.5% were using antihypertensive medications, respectively. The control rates increased from 15.1% to 23.6%. Hypertension prevalence was 64.5% in 2012 and 63.2% in 2019, and the control rate increased from 3.0% to 4.8% during the study period under the 2017 ACC/AHA guideline. Conclusion Although the past 7 years have seen some progress in hypertension management, the rates of hypertension awareness, treatment, and control in southern Chinese remained regrettably low, and the prevalence rate was still high.

Background Increased left atrium diameter (LAD) is associated with an elevated risk of cardiovascular diseases. The relationship between nutrition status and left atrial enlargement (LAE) is still unclear. The present study aimed to investigate the association of famine exposure in early life with LAE in adulthood. Methods Participants were divided into non-exposed, fetal, early, middle and late childhood exposed groups according to birth data. LAE was defined when LAD was ≥3.9 cm in women and ≥4.1 cm in men, or ≥2.3 cm m-2 by a sex-independent cut-off normalised for body surface area. Multivariate logistic regression was performed to calculate the odds ratio (OR) and confidence interval (CI) between famine exposure and LAE. Results In total, 2522 [905 male, mean (SD) age 59.1 (3.65) years] subjects were enrolled, including 392 (15.5%) LAE subjects. The prevalence of LAE in non-exposed, fetal, early, middle and late childhood exposed groups was 55 (10.8%), 38 (11.2%), 88 (18.1%), 102 (16.7%) and 109 (19.0%), respectively. Compared to the non-exposed group, the ORs for LAE were in fetal (OR = 0.956, 95% CI = 0.605-1.500, P = 0.847), late (OR = 1.748, 95% CI = 1.208-2.555, P = 0.003), middle (OR = 1.647, 95% CI = 1.140-2.403, P = 0.008) and early (OR = 1.630, 95% CI = 1.116-2.399, P = 0.012) childhood exposed groups after adjusting potential cofounders. When stratified by gender, smoking, body mass index, hypertension and diabetes, we found that the effect of famine exposure on LAE was only modified by diabetes (Pinteraction = 0.007). Conclusions Famine exposure during childhood stage might increase the risk of LAE in adults, and this effect interacts with diabetes.

Background The optimal blood pressure (BP) level for diabetic patients remains controversial, while studies provided limited evidence on BP management for individuals with normoglycemia or prediabetes. We aimed to investigate the associations between systolic blood pressure (SBP) and all-cause and cardiovascular (CVD) mortality among US adults with different glycemic profiles. Methods We used data from the 1999-2014 National Health and Nutrition Examination Survey (NHANES, n=40,046) with comprehensive baseline examination and follow-up assessment. Restricted cubic spline analysis was performed to examine dose-response relationship between SBP and mortality risk. Cox regression models were used to estimate hazard ratios of all-cause mortality and CVD mortality for SBP categories. Results U-shaped associations between SBP and all-cause mortality were observed regardless of glucose status. The relationship between SBP and CVD mortality was found to be U-shaped only in normoglycemic participants. The lowest mortality risk of optimal SBP (mmHg) by group was 115-120 (normoglycemia), 120-130 (prediabetes), and 125-135 (diabetes). When compared with the reference group, SBP < 100 mmHg was significantly associated with 49% (HR=1.49, 95% CI: 1.13-1.96), 57% (1.57, 1.07-2.3), and 59% (1.59, 1.12-2.25) higher all-cause mortality risk in people with normoglycemia, prediabetes, and diabetes, respectively. The multivariable-adjusted HRs of all-cause mortality for SBP ≥150 mmHg were 1.51 (1.25-1.82), 1.56 (1.27-1.93), and 1.33 (1.08-1.64), respectively. As for CVD mortality, the multivariable-adjusted HRs were 2.85 (1.29-6.33) for SBP

Purpose Previous studies suggested inconsistent relationship between subscapular skinfold and all-cause, cardiovascular, and cerebrovascular mortality. Therefore, the present study aimed to investigate the associations between subscapular skinfold with all-cause, cardiovascular, and cerebrovascular mortality. Patients and methods Data were collected from the National Health and Nutrition Examination Survey (NHANES, 1999-2006) with follow-up data through 31 December 2015. Participants were categorized by subscapular skinfold quartiles. The hazard ratios (HRs) and 95% confidence intervals (CIs) were evaluated using the multivariate Cox regression model and subgroup analysis. Kaplan-Meier curves were used to present cause-specific mortalities and used Cox cubic regression splines to examine the association of subscapular skinfold with cause-specific mortalities. Results A total of 16,402 subjects (49.61% male) were involved in our study. After a mean follow-up of 141.73 months, there were 3078 (18.77%), 392 (2.39%), and 128 (0.78%) cases of all-cause, cardiovascular, and cerebrovascular mortality, respectively. Participants in the highest quartile of subscapular skinfold (≥24.80mm) versus the lowest ( 0.05). Conclusion Subscapular skinfold showed an inverse association with all-cause and cardiovascular disease mortality in people aged ≥65 years.

Objective The relationship between fasting blood glucose and first ischemic stroke in older adults was unclear, so we explored this association among older patients with hypertension in China. Methods We recruited hypertensive participants with 60 or more of age. Fasting blood glucose concentrations were categorized into quartiles. Hazard ratio (HR) and 95% confidence interval (CI) for ischemic stroke were estimated using multivariate Cox regression analysis and subgroup analysis. Results A total of 3310 (1474 (44.53%) male) patients with mean age of 71.41±7.20 years were included. During the mean follow-up period of 5.5 years, 206 cases of ischemic stroke occurred. After adjusting for potential confounding variables, multivariate adjusted HRs for each standard deviation increment of fasting blood glucose, the risk of ischemic stroke increased by 11% (95% CI: 1.03, 1.21; P= 0.008). In addition, when using the lowest group (Q1) as reference, the multivariate adjusted HRs for first ischemic stroke were 1.76 (95% CI: 1.08, 2.86; P=0.023), 1.73 (95% CI: 1.06, 2.81; P=0.027) and 2.42 (95% CI: 1.49, 3.93; P

BACKGROUND Although many studies have suggested the association between elevated blood pressure and atrial fibrillation (AF), how the relationship between systolic blood pressure (SBP) and AF differ by antihypertensive treatment has been unclear. Therefore, this study aimed to explore the relationship between SBP and AF in hypertensive patients with or without antihypertensive treatment. METHODS This was a cross-sectional study that enrolled 7,808 hypertensive patients aged ≥18 years old in 2013 in Guangdong, China. AF was screened and diagnosed by rest 12-lead electrocardiogram (ECG) or by self-reported. Patients were categorized into 5 groups according to a 10 mmHg increment in SBP. We then performed logistic regression and restricted cubic spline regression to evaluate the relationship between SBP and AF. RESULTS Out of 7,808 participants (women 52.9%, mean age 62.3 years), 78 cases of AF were identified. Both univariate and multivariate logistic regression illustrated that SBP associated with a lower chance of AF in all participants when SBP was treated as a continuous variable (P

Background Mean arterial pressure (MAP) is a predictor of all-cause and cardiovascular disease (CVD) mortality in middle-aged population and elderly, but less evidence has been shown in young adults. Objectives We examined the associations of MAP with all-cause and CVD mortality in young adults aged between 18 and 40 years. Methods Data were from the National Health and Nutrition Examination Survey (1999–2006) and participants were followed up to 31 December 2015. MAP was categorised by quartiles. Multivariable Cox proportional hazards models and Kaplan-Meier survival curves were performed to estimate the association between MAP, all-cause and CVD mortality. Results There were a total of 8356 (4598 women (55.03%)) participants with the mean age of 26.63±7.01 years, of which 265 (3.17%) and 10 (0.12%) cases of all-cause and cardiovascular mortality occurred during a median follow-up duration of 152.96±30.45 months, respectively. There was no significant difference in the survival rate by MAP quartiles (p=0.058). When MAP was treated as a continuous variable, the multivariable adjusted HRs for all-cause and CVD mortality were 1.00 (95% CI 0.96 to 1.04; p=0.910) and 0.94 (95% CI 0.77 to 1.14; p=0.529), respectively. When using the lowest quartile (Q1) as referent, the adjusted HRs for all-cause mortality from Q2 to Q4 were 1.16 (95% CI 0.56 to 2.42), 1.06 (95% CI 0.48 to 2.32) and 0.91 (95% CI 0.37 to 2.24; p for tend was 0.749) after adjusting for potential confounders. Conclusion There was no significant association of MAP with all-cause and CVD mortality in young adults with a relatively short follow-up time.

Objective Although poor sleep health and vitamin D deficiency may be associated with diabetes and hypertension, whether this association shows a trend depending on vitamin D concentration is unclear. Subjects and methods We analyzed data from 10,742 participants (4997 men) from the 2007-2014 National Health and Nutrition Examination Survey. Abnormal sleep pattern (ie, short sleep duration, sleep complaint, and/or sleep disorder), lifestyle factors, serum vitamin D level, and the status of diabetes and hypertension were assessed. Logistic regression was performed to estimate the odds ratio (OR) and 95% confidence interval (CI). Results Serum vitamin D significantly interacted with short sleep duration and abnormal sleep pattern (both p = 0.003) on the association with diabetes in men. Short sleep duration (OR: 1.82, 95% CI = 1.29, 2.57) and abnormal sleep pattern (OR: 1.95, 95% CI = 1.38, 2.77) were associated with diabetes in men with serum vitamin D of >75 nmol/L. Serum vitamin D significantly interacted with sleep complaint on the association with hypertension in men and women (both p 75 nmol/L (OR: 1.28, 95% CI = 0.90, 1.83). Similarly, the magnitude of association between sleep complaint and hypertension in women was stronger when serum vitamin D level was 75 nmol/L (OR: 1.64, 95% CI = 0.98, 2.72). No significant interactions were observed between serum vitamin D level and other sleep variables. Conclusion Abnormal sleep pattern is associated with a high risk of diabetes and hypertension. The relationship between sleep complaint and hypertension may be strong in people with vitamin D deficiency, and this observation should be verified by prospective studies.

Yu-qing Huang,1,* Lin Liu,1,* Cheng Huang,1,* Yu-ling Yu,1 Kenneth Lo,1,2 Jia-yi Huang,1 Chao-lei Chen,1 Ying-ling Zhou,1 Ying-qing Feng1 1Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou 510080, People’s Republic of China; 2Department of Epidemiology, Centre for Global Cardio-Metabolic Health, Brown University, Providence, Rhode Island, NY, USA*These authors contributed equally to this workCorrespondence: Ying-qing Feng; Ying-ling ZhouDepartment of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou 510080, People’s Republic of ChinaTel/ Fax +86-20-83827812Email 651792209@qq.com; drcacocolacai@gmail.comBackground: Among the population without cardiovascular diseases (CVD), it is unclear whether pre-diabetes and/or prehypertension elevated the risk of all-cause and cardiovascular mortality.Methods: All participants without CVD at baseline were recruited from the 1999– 2014 National Health and Nutrition Examination Survey (NHANES), with survival status being updated until 31 December 2015. Cox proportional hazards models and subgroup analyses were performed to estimate hazard ratios (HRs) and 95% confidence interval (CI).Results: There were 23,622 participants (11,233 [47.6%] male) with mean age of 37.2 years. Compared to participants without prehypertension or pre-diabetes, the HRs for all-cause mortality among participants with prehypertension alone, pre-diabetes alone, and combined pre-diabetes and prehypertension were 1.04 (95% CI: 0.88, 1.24), 0.96 (95% CI:0.76, 1.21), and 1.19 (95% CI:0.98, 1.46), respectively. The corresponding HRs for cardiovascular mortality were 1.51 (95% CI: 0.83, 2.77), 1.40 (95% CI: 0.64, 3.06), and 1.70 (95% CI: 0.88, 3.27), respectively. A subgroup analysis showed that participants with combined pre-diabetes and prehypertension had a higher risk of all-cause mortality among younger participants, higher BMI, white population, and people with elevated non-HDLC. Moreover, the association between combined pre-diabetes and prehypertension and cardiovascular death was only significant among people with elevated non-HDLC.Conclusion: Pre-diabetes combined with prehypertension might elevate the risk of all-cause mortality among subjects, particularly for those with elevated body weight, high non-HDLC, younger participants or white population.Keywords: pre-diabetes, prehypertension, cardiovascular disease, CVD, all-cause mortality, cardiovascular mortality

Purpose Pulmonary mucormycosis is a highly lethal invasive fungal infection usually found in immunocompromised patients. We report herein the case of an adult woman who developed pulmonary mucormycosis with possible systemic dissemination after recovering from acute liver failure secondary to acetaminophen overdose. Results Our case developed an invasive pulmonary mucormycosis with probable systemic dissemination. She did not suffer from any immunocompromising disease other than severe acute liver failure. She did not survive the disease, although she received appropriate antifungal treatment. We also performed a systematic review of the literature on pulmonary mucormycosis, with or without dissemination, in immunocompetent patients. We found 16 cases of pulmonary or disseminated mucormycosis in immunocompetent patients. Fifty-seven percent of them died and none occurred after an acute liver failure episode. Conclusion This case report is the first one to present an invasive pulmonary mucormycosis infection after acute liver failure in an adult patient. The clinical course of this disease is highly lethal, even in immunocompetent adults.

Background Despite obesity being a major risk factor for ischaemic stroke (IS), the association between body mass index (BMI) and IS in patients with hypertension remains uncertain. Objective To assess the association between BMI and IS among elderly hypertensive patients in China. Methods and results We recruited 3500 hypertensive patients aged ≥60 between 1 January 2010 and 31 December 2011 in China and ascertained their stroke status until December 2016. Multivariate Cox regression was used to evaluate the association between BMI and IS with interaction tests for exposure and covariates. A total of 3315 subjects (mean age 71.41±7.20 years, 44.5% were men) were included for data analysis. During an average follow-up period of 5.5 years, there were 206 onset cases (6.21%) of IS. When BMI was treated as a continuous variable, it was positively associated with the incidence of new onset IS (HR=1.14; 95% CI: 1.05 to 1.34; p=0.005) after adjusting for potential confounders. Meanwhile, when BMI was treated as a categorical variable, the highest category (≥28 kg/m2) was strongly associated with an increased risk for IS compared with normal BMI category (18.5 to 24 kg/m2) (HR=1.36, 95% CI: 1.09 to 1.80; p Conclusion BMI was significantly associated with IS and was an independent risk of IS in Chinese elderly hypertensive patients.

It is uncertain how serum uric acid (SUA) associated with all-cause mortality among people with normal weight, hence was explored in this study.We enrolled participants from 1999 to 2006 National Health and Nutrition Examination Survey (NHANES) that had mortality status through 31 December 2015. We estimated adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for all-cause mortality using Cox proportional hazard models, and propensity score analyses were performed. We also performed restricted cubic splines to demonstrate the nonlinear relationship, and used subgroup analysis to examine the effect modification.We enrolled 6169 participants (2905 men and 3264 women, mean age 42.3 ± 21.4 years) and 1060 (17.2%) cases of all-cause mortality occurred during the mean follow-up of 11.9 years. When using the lowest quartile of SUA as referent, the multivariable HRs for all-cause mortality increased in not parallel with the quartiles of SUA (HRs were 0.92 (95%CI: 0.68, 1.23), 1.10 (95%CI: 0.82, 1.47), and 1.08 (95%CI: 0.80, 1.45) from the second to the fourth quartiles, respectively. When treating SUA as continuous variable, the HRs for all-cause mortality were 1.07 (95%CI: 1.00, 1.15; P = 0.046), 1.03 (95%CI: 0.94, 1.12; P = 0.518) and 1.15 (95%CI: 1.01, 1.31; P = 0.032) in all population, male and female subjects, respectively. Elevated SUA was associated with all-cause mortality and the propensity scores analysis showed the similar results. Subgroup analysis showed SUA was an independent risk of all-cause mortality in female (HR1.17, 95%CI: 1.05, 1.31, P = 0.005), people aged60 years (HR1.18, 95%CI: 1.03, 1.35, P = 0.018), non-diabetic population (HR1.10, 95%CI: 1.02, 1.18, P = 0.017) and people with eGFR90 (HR1.10, 95%CI: 1.02, 1.19, P = 0.016). Smoothing spline plots suggested the optimal SUA for the lowest risk of all-cause mortality was approximately 4.7 mg/dl.In normal-weight population, SUA was seemed to be a U-shaped relationship with all-cause mortality.

BackgroundTo investigate the association between insulin resistance (IR), quantified by triglyceride glycemic index (TyG index), cardiovascular mortality (CVM), and all-cause mortality (ACM) in hypertension patients.MethodsWe included 8,554 patients with hypertension aged ≥18 years old from the 1999–2014 National Health and Nutrition Examination Surveys (NHANES). The status of CVM and ACM of participants were followed through December 31, 2015. Cox proportional hazards models and Kaplan-Meier survival curves were used to evaluate the relationship between TyG index, CVM, and ACM.ResultsDuring a median of 82 months follow-up, 1,882 mortality cases had occurred, 434 of which were due to cardiovascular disease. The patients with hypertension with TyG ≥ 10 were older, had a higher chance of being smokers, were obese, had higher blood pressure, and had risk or had cardiovascular disease. In Cox proportional hazards models, compared with the patients with TyG P < 0.05).ConclusionsWe demonstrated that the association between ACM and TyG index in elderly patients with hypertension aged ≥60 years was non-linear. However, TyG index was only more than 9.52, hence, the risk for CVM would increase among the whole hypertension group.

Background: Limited studies focused on the association between serum uric acid (SUA) change with ischemic stroke, and their results remain controversial. The present study aimed to investigate the relationship between change in SUA with ischemic stroke among hypertensive patients.Method: This was a retrospective cohort study. We recruited adult hypertensive patients who had two consecutive measurements of SUA levels from 2013 to 2014 and reported no history of stroke. Change in SUA was assessed as SUA concentration measured in 2014 minus SUA concentration in 2013. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The Kaplan–Meier analysis and log-rank test were performed to quantify the difference in cumulative event rate. Additionally, subgroup analysis and interaction tests were conducted to investigate heterogeneity.Results: A total of 4,628 hypertensive patients were included, and 93 cases of ischemic stroke occurred during the mean follow-up time of 3.14 years. Participants were categorized into three groups according to their SUA change tertiles [low (SUA decrease substantially): P = 0.0451], but for the SUA decrease substantially group, the hazard effect was insignificant [HR (95% CI), 1.31 (0.75, 2.28), P = 0.3353]. Age played an interactive role in the relationship between SUA change and ischemic stroke. Younger participants (age < 65 years) tended to have a higher risk of ischemic stroke when SUA increase substantially.Conclusion: SUA increase substantially was significantly correlated with an elevated risk of ischemic stroke among patients with hypertension.

Background: Although many cardiovascular disease studies have focused on the microRNAs of circulating exosomes, the profile and the potential clinical diagnostic value of plasma exosomal long RNAs (exoLRs) are unknown for acute myocardial infarction (AMI).Methods: In this study, the exoLR profile of 10 AMI patients, eight stable coronary artery disease (CAD) patients, and 10 healthy individuals was assessed by RNA sequencing. Bioinformatic approaches were used to investigate the characteristics and potential clinical value of exoLRs.Results: Exosomal mRNAs comprised the majority of total exoLRs. Immune cell types analyzed by CIBERSORT showed that neutrophils and monocytes were significantly enriched in AMI patients, consistent with clinical baseline values. Biological process enrichment analysis and co-expression network analysis demonstrated neutrophil activation processes to be enriched in AMI patients. Furthermore, two exosomal mRNAs, ALPL and CXCR2, were identified as AMI biomarkers that may be useful for evaluation of the acute inflammatory response mediated by neutrophils.Conclusions: ExoLRs were assessed in AMI patients and found to be associated with the acute inflammatory response mediated by neutrophils. Exosomal mRNAs, ALPL and CXCR2, were identified as potentially useful biomarkers for the study of AMI.

Background We aimed to investigate the association between serum uric acid (SUA) and all-cause or cardiovascular mortality among participants with obesity. Method All participants were included from the 1999 to 2014 National Health and Nutrition Examination Survey with follow-up mortality assessment through 31 December 2015. Cox proportional hazards models were built to estimate adjusted HRs and 95% CIs for mortality according to baseline uric acid in quartiles. Obesity was defined as body mass index ≥30 (kg/m2). Generalised additive model (GAM) and two-piecewise linear regression models were performed to explore any non-linearity in associations. Results There were 12 637 adults with obesity eligible for analysis. There were 999 (7.91%) all-cause and 147 (1.16%) cardiovascular mortality occurred during the mean follow-up of 98.11 months. Comparing with the lowest quartile of SUA, the highest SUA group did not have significant association with all-cause (HR 1.08, 95% CI 0.76 to 1.52) and cardiovascular mortality (HR 1.63, 95% CI 0.58 to 4.53) after adjusting for various confounding factors. GAM and two-piecewise linear regression model demonstrated a non-linearly relationship between SUA and all-cause mortality, and the corresponding cut-off point was 6.5 mg/dL. However, there is no significant relationship between uric acid and cardiovascular death on both sides of the cut-off value of 6.1 mg/dL. Conclusions SUA showed a J-shaped relationship with all-cause mortality, but no significant with cardiovascular mortality in adults with obesity.

Background It is uncertain how diastolic blood pressure (DBP) may associate with ischaemic stroke in elder patients with hypertension. We aimed to explore this relationship in a Chinese community. Methods A total of 3315 participants aged ≥60 years with essential hypertension were enrolled between January 2010 and December 2011, and being followed up until 31 December 2016. DBP levels were categorised into five groups ( Results Among the 3315 participants, 44.49% were men and they were 71.4 years old on average. During a median follow-up period of 5.5 years, there were 206 onset cases of ischaemic stroke. The HRs for the first ischaemic stroke in the fully adjusted model were 1.32 (95% CI 0.73 to 2.40) for DBP Conclusions DBP had a non-linear association with the risk of ischaemic stroke among Chinese elderly patients with hypertension. DBP between 70 and 80 mm Hg may be an appropriate indicator for a lower stroke risk.

Background Pulse blood pressure was significantly associated with all-cause mortality in middle-aged and elderly populations, but less evidence was known in young adults. Objective To assess the association of pulse pressure (PP) with all-cause mortality in young adults. Methods This cohort from the 1999–2006 National Health and Nutrition Examination Survey included adults aged 18–40 years. All included participants were followed up until the date of death or 31 December 2015. PP was categorised into three groups: Results After applying the exclusion criteria, 8356 participants (median age 26.63±7.01 years, 4598 women (55.03%)) were included, of which 265 (3.17%) have died during a median follow-up duration of 152.96±30.45 months. When treating PP as a continuous variable, multivariate Cox analysis showed that PP was an independent risk factor for all-cause mortality (HR 1.94, 95% CI 1.02 to 3.69; p=0.0422). When using PP Conclusion Among young adults, higher PP was significantly associated with an increased risk of all-cause mortality, particularly among those without hypertension.

Background Although hyperlipidaemia was a well-known risk factor for ischaemic stroke, the association between triglyceride and first ischaemic stroke remains uncertain. Objectives The present study attempted to explore the relationship between triglyceride and first ischaemic stroke in a Chinese community elderly patients with hypertension. Methods and results This was a retrospective cohort study. We enrolled 3249 consecutive elderly patients with hypertension from a community in China between January 2010 and December 2011. Patients were divided into four groups based on the quartiles of triglyceride. Multivariate Cox regression analysis, subgroup and interaction test were performed to evaluate the relationship between triglyceride and first ischaemic stroke. There were a total of 3249 participants including 1455 male and 1794 female, with a mean age of 71.36±7.18 years. At an average follow-up of 5.5 years, 205 patients were identified to have first ischaemic stroke. After adjustment for potential confounders, using the lowest quartiles of triglyceride as the reference, multivariable HR (95% CI) for first ischaemic stroke increased in parallel with the quartiles of triglyceride (HRs were 1.56 (95% CI 1.07 to 2.51), 1.74 (95% CI 1.07 to 2.84) and 1.85 (95% CI 1.05 to 2.89)) from the second to the fourth quartiles, respectively (p=0.002 for trend). Subgroup and interaction analysis showed that there was no interactive effect on triglyceride and first ischaemic stroke. Conclusion Triglyceride was an independent risk factor for first ischaemic stroke among Chinese elderly patients with hypertension.

Background The prognostic value of serum uric acid (SUA) for incident acute coronary syndrome (ACS) in hypertensive subjects is uncertain. Therefore, the present study examined the association between SUA and incident ACS in a large cohort of Chinese hypertensive adults. Methods This was a retrospective cohort study, which enrolled 5473 Chinese community-dwelling hypertensive patients from 1 January 2012 to 31 December 2012. Study outcomes were ACS events, and patients were followed until 31 December 2016. Cox regression analyses were conducted to determine adjusted HRs and 95% CIs for baseline SUA tertiles (low, middle and high group) and for men and women separately. Results A total of 5473 participants were included in the analysis (median follow-up was 4.5 years). Participants were divided into tertiles based on SUA levels. During follow-up, 9 (0.49%), 14 (0.77%) and 25 (1.37%) patients developed ACS in the lowest, middle and highest tertiles, respectively. When compared with the lowest tertile of SUA, the highest tertile of SUA was associated with ACS risk in all subjects and in men and women separately (HR: 2.62, 95% CI 1.14 to 7.01, p=0.0233; 2.15, 95% CI 1.08 to 6.04, p=0.021, and 3.49, 95% CI 1.25 to 7.74, p=0.017, respectively). Conclusions Higher SUA levels were independently associated with an elevated risk of ACS incidence. The relationship between SUA levels and ACS in hypertensive patients was J-shaped.

The aim of this meta-analysis of longitudinal studies was to obtain a valid and cogent assessment of predictive value of central haemodynamic variables for cardiovascular outcomes and all-cause mortality. We searched for eligible articles using MEDLINE, CINAHL, EMBASE and Web of Science between 1 January 1969 and 31 December 2017. We finally included 24 prospective cohort studies, comprising 146,986 individuals for this analysis. Adjusted pooled hazard ratio of total cardiovascular events was 1.10 (95% confidence interval [CI] 1.04–1.16) for a 10 mmHg increase of central systolic pressure, 1.12 (95% CI 1.05–1.19) for a 10 mmHg increase of central pulse pressure and 1.18 (95% CI 1.09–1.27) for a 10% increase of central augmentation index. Furthermore, pooled hazard ratio of all-cause mortality was 1.22 (95% CI 1.14–1.31) for a 10 mmHg increase of central pulse pressure and 1.19 (95% CI 1.05–1.34) for a 10% increase of central augmentation index. Central haemodynamic variables are independent predictors of cardiovascular disease and all-cause mortality. This finding supports the notion that central pressure components and indices could be suitably implemented in clinical practice.

Purpose: The aim was to explore the association of normal range SBP with cardiovascular and all-cause mortality in older adults without hypertension.Methods: Participants aged ≥ 65 years without hypertension and those had an SBP level between 90 and 129 mmHg were included from the National Health and Nutrition Examination Survey (1999–2014). SBP was categorized into: 90–99, 100–109, 110–119, and 120–129 mmHg. Multivariate Cox regression was performed with hazard ratio (HR) and 95% confidence interval (CI).Results: Of the 1,074 participants, 584 were men (54.38%). Compared with participants with SBP level ranged 110 to 119 mmHg, the HRs for all-cause mortality risk was 1.83 (95% CI: 1.04, 3.23) for SBP level ranged 90 to 99 mm Hg, 0.87 (95% CI: 0.54, 1.41) for SBP level ranged 100 to 109 mmHg, and 1.30 (95% CI: 0.96, 1.75) for SBP level ranged 120 to 129 mmHg (P for trend = 0.448), and the HR for cardiovascular mortality risk was 3.30 (95% CI: 0.87, 12.54) for SBP level ranged 90 to 99 mmHg, 0.35(95% CI: 0.08, 1.56) for SBP level ranged 100 to 109 mmHg, and 1.75 (95% CI: 0.78, 3.94) for SBP level ranged 120 to 129 mm Hg (P for trend = 0.349) after confounders were adjusted.Conclusion: These were a nonlinear association of normal range SBP level with all-cause and cardiovascular death in older adults.