Search

Background Breastfeeding is said to prevent overweight and obesity in childhood but the evidence about its long-term impact on body size into adolescence and adulthood is scarce. We sought to examine the association between feeding types and subsequent physical size at the ages of 3, 6, 12, and 22 years. Methods The Ibaraki Children's Cohort (IBACHIL) Study, which began in 1992, involved a cohort of 4,592 Japanese children from 87 communities of a single prefecture whose parents answered health questionnaires about their child's health and life habits at the age of 3 years. Follow-up questionnaires were distributed to the same cohort when they were 6, 12, and 22 years old. Self-reported height and weight, body mass index (BMI), and overweight status at ages of 3 (n = 4,290), 6 (n = 1,999; proportion of participants analyzed = 47%), 12 (n = 2,227; 52%), and 22 (n = 1,459; 34%) years were compared according to feeding type (breastfeeding, formula feeding, and mixed feeding) during infancy. Results At the age of 3 years, multivariable adjusted-mean weight and prevalence of overweight were less for breastfed children than those formula-fed in both boys (weight: 14.6 kg vs 14.7 kg, P = 0.07, overweight: 6.3% vs 9.3%, P = 0.03) and in girls (14.0 kg vs 14.2 kg, P = 0.01 and 10.4% vs 13.6%, P = 0.06). However, there were no statistically significant differences in weight, BMI, and overweight at the ages of 6, 12, and 22 years according to feeding type. Conclusions Breastfeeding may prevent overweight in childhood, but its impact is not significant in adolescence and adulthood.

Historically, a right bundle branch block has been considered a benign finding in asymptomatic individuals. However, this conclusion is based on a few old studies with small sample sizes. We examined the association between a complete right bundle branch block (CRBBB) and subsequent cardiovascular mortality in the general population in Japan. In this large community-based cohort study, data of 90,022 individuals (mean age, 58.5 ± 10.2 years; 66.2% women) who participated in annual community-based health check-ups were assessed. Subjects were followed up from 1993 to the end of 2016. Cox proportional hazards’ models and log-rank tests were used for the data analysis. CRBBB was documented in 1,344 participants (1.5%). Among all included participants, CRBBB was associated with an increased risk of cardiovascular mortality after adjustment for all potential confounders (hazard ratio [HR] 1.21; 95% confidence interval [CI] 1.06–1.38). The increased risk of cardiovascular mortality was particularly evident in women aged

Aim: The association between atrial fibrillation (AF) and risk of stroke mortality among men and women without traditional cerebrocardiovascular risk factors (TCVRFs) is unclear. This study aimed to determine whether AF was a risk factor for stroke and total cardiovascular disease mortality among individuals without TCVRFs. Methods: A total of 90,629 Japanese subjects from the Ibaraki Prefectural Health Study aged 40–79 years, with and without TCVRFs, were studied from 1993 to 2013. Hazard ratios (HRs) were calculated using the Cox proportional hazard regression model stratified by sex and the presence of TCVRFs. Covariates were age, systolic blood pressure, anti-hypertensive medication use, and serum total cholesterol levels. A standard 12-lead electrocardiogram at rest was used to screen AF. Cause-specific mortality was classified according to the International Classification of Disease code. Results: Compared with participants without AF, multivariable-adjusted hazard ratios (with 95% confidence intervals) for stroke mortality among participants without TCVRFs were 4.3 (1.1–17.8) and 15.0 (5.5–40.8) for men and women with AF, respectively. HRs for total cardiovascular disease mortality were 6.2 (2.8–14.2) for men and 10.7 (4.8–24.1) for women. For participants with TCVRFs, multivariable-adjusted HRs for stroke mortality were 3.1 (2.2–4.6) and 4.3 (2.6–7.3), whereas HRs for total cardiovascular disease mortality were 2.9 (2.2–3.8) and 3.5 (2.4–5.1) for men and women, respectively. Conclusions: AF was found to be an independent risk factor for stroke and total cardiovascular mortality even in individuals without other TCVRFs.

Aim Diabetes mellitus and hypertriglyceridemia may adversely interact with the development of ischemic cardiovascular disease, but epidemiological evidence on this issue is scarce. We hypothesized that the impact of hypertriglyceridemia on ischemic cardiovascular disease (ischemic heart disease and ischemic stroke) would differ according to the presence or absence of diabetes mellitus and tested our a priori hypothesis under a large population-based prospective study. Methods A total of 90,468 men and women aged 40-79 years in 1993 were enrolled in the Ibaraki Prefectural Health Study (IPHS), a community-based cohort study of Japanese. The participants' serum triglyceride levels (mostly nonfasting) were measured every 5 years, and the participants were followed up for mortality from ischemic cardiovascular disease through 2016. Hazard ratios (95% confidence intervals) were calculated according to 5-year updated triglyceride levels (＜100, 100-149, 150-199, 200-299, and ≥ 300 mg/dl). Results During 1,795,877 person-years, there were 3,323 deaths from ischemic cardiovascular diseases (1,968 ischemic heart diseases and 1,355 ischemic strokes). We found no association between triglyceride levels and the risk of mortality from ischemic cardiovascular disease after adjustment for known cardiovascular risk factors. However, when stratified by the presence or absence of diabetes mellitus, excess mortality from ischemic cardiovascular disease appeared among participants with diabetes mellitus with triglyceride levels of ≥ 300 mg/dl. Further adjustment for high-density lipoprotein-cholesterol attenuated the association toward being statistically nonsignificant. Conclusion The impact of high serum triglyceride levels on the risk of ischemic cardiovascular disease mortality was confined to participants with diabetes mellitus.

IMPORTANCE Early identification of individuals at elevated risk of developing chronic kidney disease (CKD) could improve clinical care through enhanced surveillance and better management of underlying health conditions.OBJECTIVE To develop assessment tools to identify individuals at increased risk of CKD, defined by reduced estimated glomerular filtration rate (eGFR).DESIGN, SETTING, AND PARTICIPANTS Individual-level data analysis of 34 multinational cohorts from the CKD Prognosis Consortium including 5 222 711 individuals from 28 countries. Data were collected from April 1970 through January 2017. A 2-stage analysis was performed, with each study first analyzed individually and summarized overall using a weighted average. Because clinical variables were often differentially available by diabetes status, models were developed separately for participants with diabetes and without diabetes. Discrimination and calibration were also tested in 9 external cohorts (n = 2 253 540).EXPOSURES Demographic and clinical factors.MAIN OUTCOMES AND MEASURES Incident eGFR of less than 60 mL/min/1.73 m(2).RESULTS Among 4 441 084 participants without diabetes (mean age, 54 years, 38% women), 660 856 incident cases (14.9%) of reduced eGFR occurred during a mean follow-up of 4.2 years. Of 781 627 participants with diabetes (mean age, 62 years, 13% women), 313 646 incident cases (40%) occurred during a mean follow-up of 3.9 years. Equations for the 5-year risk of reduced eGFR included age, sex, race/ethnicity, eGFR, history of cardiovascular disease, ever smoker, hypertension, body mass index, and albuminuria concentration. For participants with diabetes, the models also included diabetes medications, hemoglobin A(1c), and the interaction between the 2. The risk equations had a median C statistic for the 5-year predicted probability of 0.845 (interquartile range [IQR], 0.789-0.890) in the cohorts without diabetes and 0.801 (IQR, 0.750-0.819) in the cohorts with diabetes. Calibration analysis showed that 9 of 13 study populations (69%) had a slope of observed to predicted risk between 0.80 and 1.25. Discrimination was similar in 18 study populations in 9 external validation cohorts; calibration showed that 16 of 18 (89%) had a slope of observed to predicted risk between 0.80 and 1.25.CONCLUSIONS AND RELEVANCE Equations for predicting risk of incident chronic kidney disease developed from more than 5 million individuals from 34 multinational cohorts demonstrated high discrimination and variable calibration in diverse populations. Further study is needed to determine whether use of these equations to identify individuals at risk of developing chronic kidney disease will improve clinical care and patient outcomes.

Introduction: Those who are considered to be low risk in short term such as 10 year risk actually have high risk of cardiovascular disease for the remaining lifespan at younger age. Absolute risk of Lifetime risk (LTR) is more useful and understandable for lay audience compared with short term risk or relative risk. CKD (Chronic Kidney Disease) is global burden of cardiovascular disease (CVD) and hypertension is damaging complication of CKD for CVD. To date, there have been no reports of LTR with the outcome of CVD death based on CKD in Asian population. Hypothesis: We sought to estimate LTR of CVD death stratified by the status of CKD and hypertension. Methods: We used data from EPOCH-JAPAN (Evidence for Cardiovascular Prevention From Observational Cohorts in Japan) which is designed to pool data from nationwide and regional cohort studies in Japan. Modified Kaplan-Meier approach was used to estimate the remaining lifetime risk of cardiovascular death at each index age starting from 40 years according to CKD stratified by Hypertension. Participants were classified into four groups, which were those without CKD and hypertension (CKD-/HT-), those with CKD but without hypertension (CKD+/HT-), those without CKD but with hypertension (CKD-/HT+), and those with both CKD and hypertension (CKD+/HT+). Results: A total of 44,582 participants from 8 cohorts was included in the analysis. Mean follow-up period was 14.9 years with 662,488 person years and total CVD death was 1,035 in men and 1,160 in women. The LTRs at the index age of 40 years increased in groups with CKD and/or HT as follows: 12.6% (95% confidence interval: 9.4 - 14.5%) in CKD-/HT- group, 20.6% (11.4 - 25.9%) in CKD+/HT- group, 23.2% (19.9 - 25.2%) in CKD-/HT+ group, and 27.9% (21.7 - 32.9%) in CKD+/HT+ group for men; 11.3%(8.9 - 13.2%), 17.4%(13.2 - 20.4%) , 17.8%(15.3 - 19.8%) , and 22.7%(19.5 - 25.2%) for women. Conclusions: We observed that complication of CKD and hypertension are collectively responsible for lifetime risk due to CVD death. Management of blood pressure from an early age is important to reduce CVD mortality in CKD patients.

AIM: Lifetime risk (LTR) indicates the absolute risk of disease during the remainder of an individual's lifetime. We aimed to assess the LTRs for coronary heart disease (CHD) mortality associated with blood pressure (BP) and total cholesterol levels in an Asian population using a meta-analysis of individual participant data because no previous studies have assessed this risk. METHODS: We analyzed data from 105,432 Japanese participants in 13 cohorts. Apart from grade 1 and 2-3 hypertension groups, we defined "normal BP" as systolic/diastolic BP ＜130/＜80 mmHg and "high BP" as 130-139/80-89 mmHg. The sex-specific LTR was estimated while considering the competing risk of death. RESULTS: During the mean follow-up period of 15 years (1,553,735 person-years), 889 CHD deaths were recorded. The 10-year risk of CHD mortality at index age 35 years was ≤ 0.11%, but the corresponding LTR was ≥ 1.84%. The LTR of CHD at index age 35 years steeply increased with an increase in BP of participants with high total cholesterol levels [≥ 5.7 mmol/L (220 mg/dL)]. This risk was 7.73%/5.77% (95% confidence interval: 3.53%-10.28%/3.83%-7.25%) in men/women with grade 2-3 hypertension and high total cholesterol levels. In normal and high BP groups, the absolute differences in LTRs between the low and high total cholesterol groups were ≤ 0.25% in men and ≤ 0.40% in women. CONCLUSIONS: High total cholesterol levels contributed to an elevated LTR of CHD mortality in hypertensive individuals. These findings could help guide high-risk young individuals toward initiating lifestyle changes or treatments. ispartof: JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS vol:28 issue:1 pages:6-24 ispartof: location:Japan status: published

Background:Habitual speed eating is a risk factor of obesity but evidence of this in children is limited. We examined the association between speed-eating habit and subsequent body mass index (BMI) and blood pressure (BP) among Japanese children. Methods and Results:The community-based study comprised 1,490 Japanese boys and girls who were born in 1989, involved in the Ibaraki Children’s Cohort Study at age 3 years, and had returned questionnaires at both ages 6 and 12 years. In a subsample, we measured BP (n=263). Speed-eating habit was categorized into 4 groups: Never, Quit, Newly, and Continuous. Sex-specific mean values of questionnaire-based BMI and measured BPs at age 12 were examined according to speed-eating habit. Children with continuous speed eating had a higher BMI at age 12 than those who had never had a speed-eating habit (20.0 vs. 17.9 kg/m2for boys (P

Background The aim of this study was to examine the attribution of each cardiovascular risk factor in combination with abdominal obesity (AO) on Japanese health expenditures. Methods The health insurance claims of 43,469 National Health Insurance beneficiaries aged 40–75 years in Ibaraki, Japan, from the second cohort of the Ibaraki Prefectural Health Study were followed-up from 2009 through 2013. Multivariable health expenditure ratios (HERs) of diabetes mellitus (DM), high low-density lipoprotein cholesterol (LDL-C), low high-density lipoprotein cholesterol (HDL-C), and hypertension with and without AO were calculated with reference to no risk factors using a Tweedie regression model. Results Without AO, HERs were 1.58 for DM, 1.06 for high LDL-C, 1.27 for low HDL-C, and 1.31 for hypertension (all P, Highlights • The highest population attributable fraction was for hypertension without obesity. • The total population attributable fraction of hypertension was 11.7%. • Hypertension could impose the greatest attribute on Japanese health expenditures.

Low levels of serum high-density lipoprotein cholesterol (HDL-C) have been shown to be associated with increased risk of coronary heart disease (CHD). However, because this is usually observed in the context of other lipid abnormalities, it is not known whether isolated low serum HDL-C levels are an independent risk factor for CHD. We performed a large pooled analysis in Japan using data from nine cohorts with 41,206 participants aged 40-89 years who were free of cardiovascular disease at baseline. We divided participants into three groups: isolated low HDL-C, non-isolated low HDL-C, and normal HDL-C. Cohort-stratified Cox proportional hazards models were used to estimate multivariate-adjusted hazard ratios (HRs) for death due to CHD, ischemic stroke, and intracranial cerebral hemorrhage; during a 12.9-year follow-up, we observed 355, 286, and 138 deaths, respectively, in these groups. Non-isolated low HDL-C was significantly associated with increased risk of CHD compared with normal HDL-C (HR 1.37, 95 % confidence interval (CI) 1.04-1.80); however, isolated low HDL-C was not. Although isolated low HDL-C was significantly associated with decreased risk of CHD (HR 0.51, 95 % CI 0.29-0.89) in women, it was significantly associated with increased risk of intracranial cerebral hemorrhage in all participants (HR 1.62, 95 % CI 1.04-2.53) and in men (HR 2.00, 95 % CI 1.04-3.83). In conclusion, isolated low HDL-C levels are not associated with increased risk of CHD in Japan. CHD risk may, therefore, be more strongly affected by serum total cholesterol levels in this population.

The age-specific impact of atrial fibrillation (AF) on cardiovascular diseases remains unclear. A total of 90,629 participants who were from 40 to 79 years of age in 1993 were followed up until 2013 as part of the Ibaraki Prefectural Health Study. Hazard ratios for mortality stratified by gender and age groups were calculated using Cox's proportional hazards regression models. A total of 22,794 patients (11,329 men and 11,465 women) died during the follow-up period, including 6,684 patients who died of cardiovascular causes (2,951 men and 3,733 women). On multivariable analysis, participants with AF had an increased risk of cardiovascular-related mortality compared with those without AF. Among participants aged 40 to 64 years, the adjusted hazard ratios were 3.2 (95% confidence interval [CI] 2.0 to 5.3) for men and 7.1 (95% CI 3.2 to 16.0) for women; the corresponding adjusted hazard ratios among participants aged 65 to 79 years were 3.0 (95% CI 2.2 to 4.0) for men and 3.7 (95% CI 2.5 to 5.4) for women. No significant difference in hazard ratios between age groups was found for either gender. AF was significantly associated with all-cause mortality in each age and gender group; again, no significant difference in hazard ratios between the age groups was found in terms of AF. AF may be an independent risk factor for cardiovascular and all-cause mortalities regardless of age.

Lifetime risk (LTR) provides an absolute risk assessment during the remainder of one’s life. Few studies have focused on the LTRs of stroke and coronary heart disease (CHD), categorized by fine blood pressure in Asian populations. We aimed to assess it using a large database of a meta-analysis with the individual participant data. The present meta-analysis included 107 737 Japanese (42.4% men; mean age, 55.1 years) from 13 cohorts. During the mean follow-up of 15.2±5.3 years (1 559 136 person-years), 1922 died from stroke and 913 from CHD. We estimated risks after adjusting for competing risk of death other than the outcome of interest. The 10-year risk of stroke and CHD deaths at index age of 35 years was ≤1.9% and ≤0.3%, respectively. The LTRs of stroke death at the index age of 35 years (men/women) were 6.1%/4.8% for optimal, 5.7%/6.3% for normal, and 6.6%/6.0% for high-normal blood pressure groups, and 9.1%/7.9% for grade 1, 14.5%/10.3% for grade 2, and 14.6%/14.3% for grade 3 hypertension groups. The LTRs of CHD death similarly elevated with an increase in blood pressure but were lower (≤7.2%) than those of stroke death. In conclusion, blood pressure was clearly associated with an elevated LTR of stroke or CHD death, although the LTR of CHD death was one-half of that of stroke death in an Asian population. These results would help young people with hypertension to adopt a healthy lifestyle or start antihypertensive therapy early.

Rationale & Objective Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework. Study Design Cross-sectional individual participant-level analyses in a global consortium. Setting & Study Populations 17 CKD and 38 general population and high-risk cohorts. Selection Criteria for Studies Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension. Data Extraction Data were obtained and analyzed between July 2015 and January 2018. Analytical Approach We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses. Results The CKD cohorts (n = 254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n = 1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59 mL/min/1.73 m 2), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30 mg/g). Limitations Variations in study era, health care delivery system, typical diet, and laboratory assays. Conclusions Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD. © 2018. This is the authors’ accepted and refereed manuscript to the article. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ "

Purpose To examine the relationship between body mass index (BMI) and the risk of stage ≥3 chronic kidney disease (CKD) in a general Japanese population. Methods A total of 105 611 participants aged 40–79 years who completed health checkups in Ibaraki Prefecture, Japan, and were free of CKD in 1993 were followed-up through 2006. Stage ≥3 CKD was defined by an estimated glomerular filtration rate

Aims The long-term prognosis of subjects with supraventricular premature complexes (SVPCs) remains unclear in the general population. The aim of this study was to examine the prognostic significance of SVPCs in community-based health checkups. Methods and results We assessed 63 197 individuals (mean age, 58.8 ± 9.9 years; 67.6% women) who participated in annual community-based health checkups in 1993 and were followed until 2008. The primary endpoint was stroke death, cardiovascular death (CVD), or all-cause death during a 14-year mean follow-up, and the secondary endpoint was first atrial fibrillation (AF) event in subjects without self-reported heart diseases or AF at baseline. Compared with subjects without SVPCs, the multivariate-adjusted hazard ratios (HRs) [95% confidence interval (CI)] of stroke death, CVD, and all-cause death in subjects with SVPCs were 1.24 (0.98–1.56) for men and 1.63 (1.30–2.05) for women, 1.22 (1.04–1.44) for men and 1.48 (1.25–1.74) for women, and 1.08 (0.99–1.18) for men and 1.21 (1.09–1.34) for women, respectively. Atrial fibrillation occurred in 386 subjects during the follow-up (1.05/1000 person-years). The presence of SVPCs at baseline was the significant predictor of AF onset [HRs (95% CI): 4.87 (3.61–6.57) for men and 3.87 (2.69–5.57) for women]. Propensity score matched analyses also revealed the presence of SVPCs was significantly associated with increased risks of AF incidence and CVD even after adjusting the potential confounders. Conclusion The presence of SVPCs in 12-lead electrocardiograms was a strong predictor of AF development, and associated with increased risk of CVD in general population.

Aim The levels of lipids, especially triglycerides (TG), and obesity are associated with diabetes mellitus (DM). Although typically measured in fasting individuals, non-fasting lipid measurements play an important role in predicting future DM. This study compared the predictive efficacy of lipid variables according to the fasting status and body mass index (BMI) category. Methods Data were collected for 39,196 nondiabetic men and 87,980 nondiabetic women 40-79years of age who underwent health checkups in Ibaraki-Prefecture, Japan in 1993 and were followed through 2007. The hazard ratios (HRs) for DM in relation to sex, the fasting status and BMI were estimated using a Cox proportional hazards model. Results A total of 8,867 participants, 4,012 men and 4,855 women, developed DM during a mean follow-up of 5.5 years. TG was found to be an independent predictor of incident DM in both fasting and non-fasting men and non-fasting women. The multivariable-adjusted HR for DM according to the TG quartile (Q) 4 vs. Q1 was 1.18 (95% confidence interval (CI): 1.05, 1.34) in the non-fasting men with a normal BMI (18.5-24.9). This trend was also observed in the non-fasting women with a normal BMI. That is, the multivariable-adjusted HRs for DM for TG Q2, Q3 and Q4 compared with Q1 were 1.07 (95% CI: 0.94, 1.23), 1.17 (95%CI: 1.03, 1.34) and 1.48 (95%CI: 1.30, 1.69), respectively. Conclusions The fasting and non-fasting TG levels in men and non-fasting TG levels in women are predictive of future DM among those with a normal BMI. Clinicians must pay attention to those individuals at high risk for DM.

There are limited studies addressing whether proteinuria and estimated glomerular filtration rate (eGFR) are independently associated with cardiovascular disease in Asia. Using data from 7 prospective cohorts recruited between 1980 and 1994 in Japan, we assessed the influence of proteinuria (≥1+ on dipstick) and reduced eGFR on the risk of cardiovascular disease mortality in 39,405 participants (40-89 years) without kidney failure. During a 10.1-year follow-up, 1,927 subjects died from cardiovascular disease. Proteinuria was associated with a 1.75-fold (95% confidence interval (CI): 1.44, 2.11) increased risk of cardiovascular disease mortality after adjustment for potential confounding factors. Additionally, the multivariate-adjusted hazard ratio of cardiovascular disease mortality increased linearly with lower eGFR levels (P(trend) < 0.001): Subjects with eGFR of

Liver cancer a global public health concern and well known for poor prognosis. The association between low total cholesterol level and liver cancer has been reported. However, the association between low low-density lipoprotein (LDL) cholesterol levels and liver cancer is still unclear. The aim of this study was to examine the relationship between LDL cholesterol level and liver cancer mortality. A total of 16,217 persons (5,551 men and 10,666 women) aged 40-79 years in 1993 were followed until 2008. LDL cholesterol levels were divided into four categories (

BACKGROUND Cold temperature has been reported to contribute to cardiovascular mortality, but it is not clear which people are more susceptible to cold temperature. METHODS AND RESULTS The relationship between ambient temperature and mortality was examined in 3,593 subjects from the Ibaraki Prefectural Health Study who died of cardiovascular disease during a mean follow-up period of 9.7±4.0 years. Daily values of meteorological variables were obtained from the Japan Meteorological Agency. Time-stratified case cross-over analysis was used. The multivariate odds ratios (ORs; 95% confidence interval) per 1°C decrease in daily maximum temperature over the day of death and the 2 days prior to this day adjusted for relative humidity were 1.018 (1.003-1.034) for all cardiovascular deaths and 1.025 (1.003-1.048) for stroke deaths. Risk-stratified analysis showed that younger subjects aged

Background Patients with renal impairment are at risk of not only end-stage kidney disease but also cardiovascular disease (CVD). The current definition of CKD stage G3a is eGFR 45–59 ml/min/1.73 m2 and of G3b is 30–44 ml/min/1.73 m2, and subjects in the CKD 3a category are considered to be at lower risk of mortality than are those in CKD 3b. Methods We evaluated the outcome of 97,043 people (33,131 men and 63,912 women) living in Ibaraki Prefecture who underwent annual community-based health checkups beginning in 1993 at age 40–80 years and who were followed for a mean of 17.1 years. Results The number of all-causes deaths was 20,534 (10,375 men and 10,159 women), of which 5,995 (2,695 men and 3,300 women) were deaths due to CVD. Multivariable-adjusted hazard ratio for CVD death in the eGFR 45–49 ml/min/1.73 m2 category was significantly increased (1.82; 95% confidential interval, 1.23–2.69) in non-elderly men, whereas all-cause mortality and CVD mortality in elderly men with eGFR 45–49 ml/min/1.73m2 were non significant. In contrast, both in non-elderly women and in elderly women with eGFR 45–49 ml/min/1.73 m2 showed small, but significant, increases in the risks of all-cause mortality and CVD. Conclusions We demonstrated proportionate increases in mortality with decreasing eGFR in a Japanese CKD population. Like patients in the CKD G3b subgroup, non-elderly men and women with an eGFR of 45–49 ml/min/1.73 m2 (i.e. a part of CKD G3a) are at considerable risk of CVD mortality. Age dependent and eGFR dependent finer risk recognition were required for CVD prevention in clinical practice with regard to CKD patients.

Objective: The aim of this study was to examine the association between BMI and risk of incident hypertension among Japanese men and women who are middle-aged and older. Design: Prospective, population-based cohort study. Patients: A total of 68 205 nonhypertensive adults (18 336 men and 49 869 women) aged 40–79 years who completed health check-ups in the Ibaraki prefecture, Japan, in 1993 were followed up through 2006. To exclude the impact of BMI change during the follow-up period, a time-dependent covariate Cox proportional hazards model was used to compute the hazard ratios of incident hypertension according to BMI categories. Incident hypertension was defined as a SBP of at least 140 mmHg, a diastolic BP of at least 90 mmHg, and/or hypertensive medication use. Results: A total of 30 982 adults (45.4%) developed hypertension (9331 men and 21 651 women) during a mean of 3.9 years of follow-up. Compared with a BMI of less than 19.0, time-dependent covariates adjusted hazard ratios [95% confidence interval (CI)] for hypertension among participants with a BMI of at least 25.0 were 1.42 (1.17–1.73) for men aged 40–59 years, 1.34 (1.19–1.51) for men aged 60–79 years, 1.47 (1.33–1.62) for women aged 40–59 years, and 1.29 (1.18–1.41) for women aged 60–79 years. Conclusion: The baseline BMI is associated with future risk for incident hypertension even after accounting for weight change during the follow-up period. Weight loss may be recommended to nonhypertensive obese adults to prevent the development of hypertension.

Background— It is unclear whether mild hypertensive retinopathy is a risk factor for mortality. This study examined whether mild hypertensive retinopathy could be a risk factor for cardiovascular mortality in subjects with and without hypertension. Methods and Results— In this cohort study, 87 890 individuals (29 917 men and 57 973 women) 40 to 79 years of age in 1993 were followed up until 2008. Retinal photography was classified as normal, grade 1, or grade 2 based on the Keith-Wagener-Barker system. Risk ratios for all-cause and cause-specific mortality for each classification were calculated with Cox proportional hazards regression models. Covariates included age, systolic blood pressure, antihypertensive medication use, and other cardiovascular risk factors. Multivariable hazard ratios for total cardiovascular disease mortality were 1.24 (95% confidence interval [CI], 1.12–1.38) and 1.23 (95% CI, 1.03–1.47) for grades 1 and 2 among men and 1.12 (95% CI, 1.01–1.24) and 1.44 (95% CI, 1.24–1.68) for grades 1 and 2 among women, respectively. Hazard ratios for total stroke mortality were 1.31 (95% CI, 1.13–1.53) and 1.38 (95% CI, 1.08–1.77) for grades 1 and 2 among men and 1.30 (95% CI, 1.12–1.50) and 1.70 (95% CI, 1.36–2.11) for grades 1 and 2 among women, respectively. For both hypertensive and normotensive subjects of each sex, multivariable hazard ratios for all-cause mortality, total cardiovascular mortality, and total stroke mortality were significantly higher for grade 1 or 2 compared with normal. Conclusions— Mild hypertensive retinopathy is a risk factor for cardiovascular mortality independently of cardiovascular risk factors among men and women with and without hypertension.

Background The effect of very high or extremely high levels of high-density lipoprotein cholesterol (HDL-C) on cardiovascular disease (CVD) is not well described. Although a few recent studies have reported the adverse effects of extremely high levels of HDL-C on CVD events, these did not show a statistically significant association between extremely high levels of HDL-C and cause-specific CVD mortality. In addition, Asian populations have not been studied. Objective We examine the impact of extremely high levels of HDL-C on cause-specific CVD mortality using pooled data of Japanese cohort studies. Methods We performed a large-scale pooled analysis of 9 Japanese cohorts including 43,407 participants aged 40–89 years, dividing the participants into 5 groups by HDL-C levels, including extremely high levels of HDL-C ≥2.33 mmol/L (≥90 mg/dL). We estimated the adjusted hazard ratio of each HDL-C category for all-cause death and cause-specific deaths compared with HDL-C 1.04–1.55 mmol/L (40–59 mg/dL) using a cohort-stratified Cox proportional hazards model. Results During a 12.1-year follow-up, 4995 all-cause deaths and 1280 deaths due to overall CVD were identified. Extremely high levels of HDL-C were significantly associated with increased risk of atherosclerotic CVD mortality (hazard ratio = 2.37, 95% confidence interval: 1.37–4.09 for total) and increased risk for coronary heart disease and ischemic stroke. In addition, the risk for extremely high HDL-C was more evident among current drinkers. Conclusion We showed extremely high levels of HDL-C had an adverse effect on atherosclerotic CVD mortality in a pooled analysis of Japanese cohorts.

Background This retrospective cohort study examined the sex- and age-specific impact of hypertension on medical expenditures. Methods In 2006, we analyzed the medical expenditure records of 42 426 Japanese National Health Insurance beneficiaries (16 169 men, 26 257 women) who lived in Ibaraki, Japan, were aged 40 to 69 years, and underwent health checkups in 2002. Blood pressure was classified into 4 categories according to the criteria outlined in the seventh report of the Joint National Committee. Results The difference in median total expenditure between the hypertension categories and the normotension category was 119 585 yen (140 360 yen vs 20 775 yen) for men aged 40 to 54 years, 126 160 yen (204 070 yen vs 77 910 yen) for men aged 55 to 69 years, 125 495 yen (158 025 yen vs 32 530 yen) for women aged 40 to 54 years, and 122 370 yen (208 700 yen vs 86 330 yen) for women aged 55 to 69 years. The median total and outpatient medical expenditures markedly differed between patients with stage 1 hypertension and stage 2 hypertension (which included people on antihypertensive medication) in both sexes and all age subgroups. The median total and outpatient medical expenditures were higher among women than among men in all blood pressure categories. Conclusions The impact of hypertension on medical expenditures was similar in all age groups. Therefore, from the perspective of medical economics, prevention of the onset of hypertension seems equally important for all age subgroups.

OBJECTIVE To investigate the age-specific relationship between body mass index (BMI) and risk of diabetes in a Japanese general population. PARTICIPANTS AND METHODS A cohort of Japanese men (N=19,926) and women (N=41,489) (aged 40-79 years) who under went community-based health checkups in 1993 and were free of diabetes was followed up by annual examinations with measurement of blood glucose concentrations until the end of 2006. Incident diabetes mellitus was defined as a blood glucose concentration of 126 mg/dL or greater under fasting conditions, 200 mg/dL or greater under nonfasting conditions, or diabetic medication use at baseline. Hazard ratios (HRs) for diabetes according to BMI were estimated using a Cox proportional hazard model. The model was adjusted for possible confounding variables. RESULTS A total of 4429 participants (7.2%) developed diabetes (2065 men and 2364 women) during a mean follow-up of 5.5 years. Compared with those with a BMI of less than 25.0, the multivariate HRs for diabetes among participants with a BMI of 30.0 or greater were 1.40 (95% confidence interval [CI], 0.89-2.20) for men aged 40 to 59 years and 1.26 (95% CI, 0.81-1.96) for men aged 60 to 79 years ( P= .002 for interaction). The HRs were 2.50 (95% CI, 2.01-3.11) for women aged 40 to 59 years and 1.80 (95% CI, 1.41-2.30) for women aged 60 to 79 years ( P =.04 for interaction). CONCLUSION The effect of obesity on the risk of diabetes is greater for middle-aged than for older adults.

Noda H, Iso H, Irie F, Sairenchi T, Ohtaka E, Ohta H (Osaka University, Osaka, Japan; Harvard School of Public Health, Cambridge, MA, USA; Ibaraki Prefectural Office, Ibaraki; Dokkyo Medical University School of Medicine, Tochigi; Ibaraki Health Service Association, Ibaraki; Japan). Gender difference of association between LDL cholesterol concentrations and mortality from coronary heart disease amongst Japanese: the Ibaraki Prefectural Health Study. J Intern Med 2010; 267:576–587. Objective. The aim of this study was to examine whether LDL cholesterol raises the risk of coronary heart disease in a dose–response fashion in a population with low LDL-cholesterol levels. Design. Population-based prospective cohort study in Japan. Subjects and main outcome measures. A total of 30 802 men and 60 417 women, aged 40 to 79 years with no history of stroke or coronary heart disease, completed a baseline risk factor survey in 1993. Systematic mortality surveillance was performed through 2003 and 539 coronary heart disease deaths were identified. Results. The mean values for LDL-cholesterol were 110.5 mg dL−1 (2.86 mmol L−1) for men and 123.9 mg dL−1 (3.20 mmol L−1) for women. Men with LDL-cholesterol ≥140 mg dL−1 (≥3.62 mmol L−1) had two-fold higher age-adjusted risk of mortality from coronary heart disease than did those with LDL-cholesterol

Background— Few studies have examined the association between low levels of low-density lipoprotein (LDL) cholesterol and risk of intraparenchymal hemorrhage. Methods and Results— A total of 30 802 men and 60 417 women, 40 to 79 years of age with no history of stroke or coronary heart disease, completed a baseline risk factor survey in 1993 under the auspices of the Ibaraki Prefectural Health Study. Systematic mortality surveillance was performed through 2003, and 264 intraparenchymal hemorrhage deaths were identified. LDL cholesterol levels were calculated with the Friedewald formula. Persons with LDL cholesterol ≥140 mg/dL had half the sex- and age-adjusted risk of death due to intraparenchymal hemorrhage of those with LDL cholesterol Conclusions— Low LDL cholesterol levels are associated with elevated risk of death due to intraparenchymal hemorrhage.

Background: The impact of being overweight, as a component of the metabolic syndrome (MetS), for cardiovascular disease (CVD) mortality was investigated and compared with the predictive value of MetS by 2 different definitions. Methods and Results: A 12-year prospective study of 30,774 Japanese men and 60,383 women aged 40-79 years was conducted. The multivariate hazard ratio (HR; 95% confidence interval) of total CVD mortality for overweight subjects with ≥2 additional risk factors with reference to subjects with 0 of 4 MetS components was 1.83 (1.41-2.38) for men and 1.90 (1.45-2.49) for women, and for non-overweight subjects with ≥2 additional risk factors 1.75 (1.38-2.24) and 1.97 (1.52-2.55), respectively. The proportion of excess CVD deaths in the latter group was 1.5-fold higher than that in the former group. Multivariate HRs of coronary heart disease and total CVD mortality for MetS by the modified criteria of the American Heart Association/National Heart, Lung, and Blood Institute were 1.62 (1.31-2.00) and 1.23 (1.09-1.39), respectively, for men and 1.32 (1.05-1.65) and 1.12 (1.00-1.25), respectively, for women. The respective HRs for MetS by the International Diabetic Federation definition did not reach statistical significance, except for coronary heart disease in men. Conclusions: Non-overweight individuals with metabolic risk factors, as well as overweight individuals with such factors, should be targeted to reduce the CVD burden in the general population. (Circ J 2009; 73: 1635-1642)

Background: Because of the increasing number of mothers who continue to work after childbirth, participation in childcare has diversified. However, the impact of the main caregiver on children’s habits has not been determined. We sought to examine the effect of caregiver differences on childhood habituation of between-meal eating and body mass index (BMI). Methods: The Ibaraki Children’s Cohort Study involved 4592 Japanese children whose parents answered health questionnaires at age 3. Follow-up questionnaires were distributed to parents when children were 6 and 12 years old and to study subjects directly when they were 22 years old. We compared prevalence of between-meal eating and overweight as well as mean BMI at ages 6, 12, and 22 years, by their main daytime caregiver at age 3. Results: Compared to children cared for by mothers, those cared for by grandparents had a higher prevalence of between-meal eating before dinner for boys and girls at ages 6 and 12 years. At age 22 years, boys cared for by grandparents had a higher prevalence of overweight than those cared for by mothers (18.5% versus 11.2%, P = 0.037), but no such difference was noted in girls. However, both boys and girls cared for by grandparents had higher mean BMI over time than those cared for by mothers (coefficient = 0.47 kg/m2 for boys and coefficient = 0.35 kg/m2 for girls). Conclusions: Being cared for by grandparents at age 3 was associated with subsequent between-meal eating habits, being overweight, and increased mean BMI from childhood to adulthood.

Chronic kidney disease (CKD) is a potential independent risk factor for atrial fibrillation (AF). It remains unclear whether anemia is synergistically associated with increased risk of AF onset in subjects with CKD. We evaluated the association of kidney function, hemoglobin (Hb), and their combination with new-onset AF in a population-based cohort study. We conducted a 15-year prospective cohort study of 132,250 Japanese subjects aged 40 to 79 years who participated in annual health checkups from 1993. Kaplan-Meier survival analysis was used to compare freedom from new-onset AF between groups classified by estimated glomerular filtration rate grade, Hb grade, and their combination. Cox proportional hazard model analysis was used to estimate hazard ratios (HRs) for new-onset AF. During a 13.8-year mean follow-up period, 1,232 (0.93%) subjects with new-onset AF were identified. Lower estimated glomerular filtration rate and lower Hb grades were significantly associated with a higher incidence of new-onset AF. Multivariate HRs and 95% confidence intervals (CIs) of new-onset AF were 1.38 (1.21 to 1.56) for mild CKD group, 2.56 (2.09 to 3.13) for CKD group, and 1.50 (1.24 to 1.83) for anemia group. Borderline Hb level was not significantly associated with increased risk for new-onset AF (HR 1.07, CI 0.91 to 1.25, p = 0.4284). In the model with interaction term between CKD and anemia, the risk was significantly higher (p = 0.0343 for the interaction) than that predicted by each factor independently. In conclusion, decreased kidney function and lower Hb level are associated with increased risk for new-onset AF, especially when both are present.

Purpose The relationship between duration of cigarette smoking and the risk of oropharyngeal cancer has not been studied in the general Japanese population. Thus, the aim of the present study was to examine the relationship between the duration of cigarette smoking and the risk of oropharyngeal cancer mortality in the Japanese population. Methods In this large cohort study, 32,989 men and 63,894 women, ages 40–79 years, who completed health check-ups in Ibaraki Prefecture, Japan, in 1993 were followed through 2008. Oropharyngeal cancer mortality was identified by death certificates. Smoking habits were divided into five categories, and years of cigarette smoking and pack-year classifications were divided into four categories. Hazard ratios and 95% confidence intervals for oropharyngeal cancer mortality were calculated by use of the Cox proportional hazards regression models. Results During the follow-up period, deaths from oropharyngeal cancer occurred in 38 of 32,989 men and 31 of 63,894 women. The multivariate hazard ratios for oropharyngeal cancer mortality were significantly greater for those subjects currently smoking for 40 years or longer (hazard ratio: 4.22, 95% confidence interval: 1.23–14.51), and they were greater with longer years of cigarette smoking among men ( P for trend = .027). Conclusions Smoking duration can be a risk factor for oropharyngeal cancer mortality in the Japanese population.

Volume 69, no. 2, p. 143-148, 2016. Page 143, Title should appear as shown below.An Epidemiological Investigation of a Nosocomial Outbreak of Multidrug-Resistant Acinetobacter baumannii in a Critical Care Center in Japan, 2011-2012.

We appreciate the interest of Triantafyllou et al and Cheung et al in our recent article on retinopathy and cardiovascular mortality.1 They pointed out several issues with the article. Triantafyllou et al discussed 3 major points. First, they stated that grade 1 retinopathy did not possess a predictive role for cardiovascular mortality in normotensive individuals. However, the probability value for the trend showed significance in nonhypertensive men and women (Table 3); in addition, the multivariable (including blood pressure levels and antihypertensive medication use) adjusted hazard ratio for grade 1 retinopathy was significantly higher in all (ie, nonhypertensive and hypertensive) men and women (Table 2). These results appear to suggest the predictive role of grade 1 retinopathy. Second, the lack of information on antihypertensive drugs during the follow-up period, especially in nonhypertensive subjects, was pointed out. We excluded subjects who used antihypertensive drugs …

Background: In spite of the importance of a multifactorial approach to preventing cardiovascular disease in smokers, most information on the combined adverse effects of smoking and hypertension or high serum cholesterol on cardiovascular disease has been derived from Western populations, and coronary heart disease was often used as the only endpoint. Therefore, the present large-scale pooled analysis attempted to provide reliable information on the adverse effects of the coexistence of smoking and hypertension or high serum cholesterol on the risk of mortality from coronary heart disease and stroke in both, individuals and the entire population in Japan. Methods: A total of 27,385 male and 39,207 female participants aged 40–89 years were enrolled from 10 well-qualified Japanese cohort studies with a mean follow-up of 10.1 years. Hazard ratios and their corresponding 95% confidence intervals in smokers who had hypertension or high serum cholesterol were estimated for men and women separately using a Cox proportional hazards regression model that included age, body mass index, cohort and either serum total cholesterol or systolic blood pressure as covariates. Fractions of deaths attributable to the coexistence of these risk factors were also calculated. Results: The multivariate-adjusted hazard ratios in male and female current smokers with hypertension, compared with those with neither factor were 2.57 (95% confidence intervals, 1.51–4.38) and 6.14 (3.49–10.79) for coronary heart disease, and 3.28 (1.89–5.71) and 1.61 (0.81–3.18) for cerebral infarction, respectively. The fractions of deaths attributable to the coexistence of current smoking and hypertension in men and women were 24.6 and 9.6% for coronary heart disease and 28.1 and 2.0% for cerebral infarction, respectively. Smokers with high serum cholesterol were broadly comparable to hypertensive smokers only with respect to coronary mortality risk; the hazard ratios, compared with those with neither factor were 4.19 (2.33–7.53) for men and 3.90 (1.57–9.67) for women. The fraction of coronary deaths attributable to the coexistence of current smoking and high serum cholesterol was 6.3% in men and 2.2% in women. There was no interaction between smoking habit and blood pressure or serum total cholesterol for these two subtypes in both men and women. Conclusions: Particular attention should be given to smokers who have concomitant hypertension or high serum cholesterol for preventing deaths due to cardiovascular disease. From a public health perspective in Japan, priority should be given to hypertensive smokers, since this group makes a large contribution to the burden of both coronary and cerebral infarction deaths.

High blood pressure (BP) has been well established as a leading risk factor for both cardiovascular disease and mortality in general. However, the effect of long-term exposure to elevated BP on mortality risks in Asian populations remains unclear. The purpose of this study was to investigate the effects of time-averaged BP levels over 5 years on subsequent cardiovascular disease mortalities in a Japanese population. A total of 46 484 adults (14 771 men and 31 713 women) aged 40–79 years, who had no history of stroke or heart disease and who underwent health checkups in Ibaraki prefecture, Japan, in 1993 and 1998 were followed up through 2005. Hazard ratios (HRs) for mortality were estimated using a Cox proportional hazard model. Multivariate HRs (95% confidence interval) associated with a 10 mm Hg increase in systolic BP were measured in 1993 and 1998, and their averages were 1.11 (1.05–1.16), 1.13 (1.07–1.18) and 1.17 (1.10–1.27), respectively. Multivariate HRs for a 10 mm Hg increase in time-averaged systolic BP were 1.12 (1.03–1.21) in men and 1.24 (1.13–1.35) in women. The subgroup analysis of antihypertensive use showed that multivariate HRs for time-averaged systolic BP were 1.20 (1.11–1.29) in sustained non-users and 1.17 (1.04–1.32) in sustained users. Similar results were also obtained for diastolic BP. In conclusion, long-term exposure to elevated BP substantially associates with excess risk for cardiovascular disease mortality among Japanese subjects, irrespective of antihypertensive medication use. Thus, appropriate management of BP is important in both users and non-users of antihypertensive medication.

Aim: The aim of this study was to examine whether non-high-density lipoprotein cholesterol (non-HDL-cholesterol) raises the risk of coronary heart disease in a dose-response fashion in a non-obese population with low total cholesterol levels and high HDL-cholesterol levels, such as Japanese.Methods: A total of 30,802 men and 60,417 women, aged 40 to 79 years with no history of stroke or coronary heart disease, completed a baseline risk factor survey in 1993 under the auspices of the Ibaraki Prefectural Health Study. Systematic mortality surveillance through 2003 identified 539 coronary heart disease deaths.Results: The mean values for non-HDL-cholesterol were 140 mg/dL for men and 151 mg/dL for women. The corresponding mean values were 193 mg/dL and 208 mg/dL total cholesterol and 52 mg/dL and 57 mg/dL HDL-cholesterol, respectively. Men with non-HDL-cholesterol ≥180 mg/dL had a two-fold higher age-adjusted risk of mortality from coronary heart disease than did those with non-HDL-cholesterol

We thank Dr Drinka for his interest in our study1 and the opportunity to clarify several issues. Dr Drinka presented one possible causal pathway that might link reduced low-density lipoprotein (LDL) cholesterol with the development of arteriolosclerosis and increased risk of intraparenchymal hemorrhage. This hypothesis asserts that distal lipohyalin degeneration (destruction: arteriolosclerosis) may be protected against by proximal atheromatous degeneration (plaque formation: atherosclerosis) through the flow restriction and consequent lower blood pressure in the distal penetrating artery. The lower risk of intraparenchymal hemorrhage associated with higher LDL cholesterol levels may be explained in part by his flow restriction hypothesis. Although we consider the proposed causal pathway to be plausible, we do not consider this explanation to be the major one involving low LDL cholesterol for the following reasons. First, if it were true that atheromatous degeneration prevents the development of arteriolosclerosis, increased risk of intraparenchymal hemorrhage should be observed at levels of LDL cholesterol at which the risk of coronary heart disease decreases. However, in our study the increased risk of death from intraparenchymal hemorrhage was observed at a level of LDL cholesterol 100 mg/dL, whereas death from coronary heart disease plateaued in this range. Second, low high-density lipoprotein cholesterol and high triglycerides, which may lead to atheromatous degeneration, were not associated with reduced death from intraparenchymal hemorrhage. Our finding supports Konishi’s osmotic fragility hypothesis2 that very low levels of serum cholesterol in the intimal cell membranes of intracerebral arteries contribute to plasma insudation into the intima because of reduced osmotic resistance, which leads to the destruction of smooth muscle cells in the media and increased risk of intraparenchymal hemorrhage.3 This hypothesis was also supported by a community-based pathology study.4 An in vivo study suggested the hypothesis, showing that low sarcolemmal cholesterol content in neonatal cardiomyocytes enhanced sarcolemmal fluidity and anoxial-induced cell damage.5 Moreover, other in vivo studies showed that cellular cholesterol depletion may induce apoptosis. 6 Further studies are necessary to explore pathological mechanisms.

Wei Zheng and colleagues quantify the burden of tobacco-smoking-related deaths for adults in Asia. Please see later in the article for the Editors' Summary, Background Tobacco smoking is a major risk factor for many diseases. We sought to quantify the burden of tobacco-smoking-related deaths in Asia, in parts of which men's smoking prevalence is among the world's highest. Methods and Findings We performed pooled analyses of data from 1,049,929 participants in 21 cohorts in Asia to quantify the risks of total and cause-specific mortality associated with tobacco smoking using adjusted hazard ratios and their 95% confidence intervals. We then estimated smoking-related deaths among adults aged ≥45 y in 2004 in Bangladesh, India, mainland China, Japan, Republic of Korea, Singapore, and Taiwan—accounting for ∼71% of Asia's total population. An approximately 1.44-fold (95% CI = 1.37–1.51) and 1.48-fold (1.38–1.58) elevated risk of death from any cause was found in male and female ever-smokers, respectively. In 2004, active tobacco smoking accounted for approximately 15.8% (95% CI = 14.3%–17.2%) and 3.3% (2.6%–4.0%) of deaths, respectively, in men and women aged ≥45 y in the seven countries/regions combined, with a total number of estimated deaths of ∼1,575,500 (95% CI = 1,398,000–1,744,700). Among men, approximately 11.4%, 30.5%, and 19.8% of deaths due to cardiovascular diseases, cancer, and respiratory diseases, respectively, were attributable to tobacco smoking. Corresponding proportions for East Asian women were 3.7%, 4.6%, and 1.7%, respectively. The strongest association with tobacco smoking was found for lung cancer: a 3- to 4-fold elevated risk, accounting for 60.5% and 16.7% of lung cancer deaths, respectively, in Asian men and East Asian women aged ≥45 y. Conclusions Tobacco smoking is associated with a substantially elevated risk of mortality, accounting for approximately 2 million deaths in adults aged ≥45 y throughout Asia in 2004. It is likely that smoking-related deaths in Asia will continue to rise over the next few decades if no effective smoking control programs are implemented. Please see later in the article for the Editors' Summary, Editors' Summary Background Every year, more than 5 million smokers die from tobacco-related diseases. Tobacco smoking is a major risk factor for cardiovascular disease (conditions that affect the heart and the circulation), respiratory disease (conditions that affect breathing), lung cancer, and several other types of cancer. All told, tobacco smoking kills up to half its users. The ongoing global “epidemic” of tobacco smoking and tobacco-related diseases initially affected people living in the US and other Western countries, where the prevalence of smoking (the proportion of the population that smokes) in men began to rise in the early 1900s, peaking in the 1960s. A similar epidemic occurred in women about 40 years later. Smoking-related deaths began to increase in the second half of the 20th century, and by the 1990s, tobacco smoking accounted for a third of all deaths and about half of cancer deaths among men in the US and other Western countries. More recently, increased awareness of the risks of smoking and the introduction of various tobacco control measures has led to a steady decline in tobacco use and in smoking-related diseases in many developed countries. Why Was This Study Done? Unfortunately, less well-developed tobacco control programs, inadequate public awareness of smoking risks, and tobacco company marketing have recently led to sharp increases in the prevalence of smoking in many low- and middle-income countries, particularly in Asia. More than 50% of men in many Asian countries are now smokers, about twice the prevalence in many Western countries, and more women in some Asian countries are smoking than previously. More than half of the world's billion smokers now live in Asia. However, little is known about the burden of tobacco-related mortality (deaths) in this region. In this study, the researchers quantify the risk of total and cause-specific mortality associated with tobacco use among adults aged 45 years or older by undertaking a pooled statistical analysis of data collected from 21 Asian cohorts (groups) about their smoking history and health. What Did the Researchers Do and Find? For their study, the researchers used data from more than 1 million participants enrolled in studies undertaken in Bangladesh, India, mainland China, Japan, the Republic of Korea, Singapore, and Taiwan (which together account for 71% of Asia's total population). Smoking prevalences among male and female participants were 65.1% and 7.1%, respectively. Compared with never-smokers, ever-smokers had a higher risk of death from any cause in pooled analyses of all the cohorts (adjusted hazard ratios [HRs] of 1.44 and 1.48 for men and women, respectively; an adjusted HR indicates how often an event occurs in one group compared to another group after adjustment for other characteristics that affect an individual's risk of the event). Compared with never smoking, ever smoking was associated with a higher risk of death due to cardiovascular disease, cancer (particularly lung cancer), and respiratory disease among Asian men and among East Asian women. Moreover, the researchers estimate that, in the countries included in this study, tobacco smoking accounted for 15.8% of all deaths among men and 3.3% of deaths among women in 2004—a total of about 1.5 million deaths, which scales up to 2 million deaths for the population of the whole of Asia. Notably, in 2004, tobacco smoking accounted for 60.5% of lung-cancer deaths among Asian men and 16.7% of lung-cancer deaths among East Asian women. What Do These Findings Mean? These findings provide strong evidence that tobacco smoking is associated with a substantially raised risk of death among adults aged 45 years or older throughout Asia. The association between smoking and mortality risk in Asia reported here is weaker than that previously reported for Western countries, possibly because widespread tobacco smoking started several decades later in most Asian countries than in Europe and North America and the deleterious effects of smoking take some years to become evident. The researchers note that certain limitations of their analysis are likely to affect the accuracy of its findings. For example, because no data were available to estimate the impact of secondhand smoke, the estimate of deaths attributable to smoking is likely to be an underestimate. However, the finding that nearly 45% of the global deaths from active tobacco smoking occur in Asia highlights the urgent need to implement comprehensive tobacco control programs in Asia to reduce the burden of tobacco-related disease. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001631. The World Health Organization provides information about the dangers of tobacco (in several languages) and about the WHO Framework Convention on Tobacco Control, an international instrument for tobacco control that came into force in February 2005 and requires parties to implement a set of core tobacco control provisions including legislation to ban tobacco advertising and to increase tobacco taxes; its 2013 report on the global tobacco epidemic is available The US Centers for Disease Control and Prevention provides detailed information about all aspects of smoking and tobacco use The UK National Health Services Choices website provides information about the health risks associated with smoking MedlinePlus has links to further information about the dangers of smoking (in English and Spanish) SmokeFree, a website provided by the UK National Health Service, offers advice on quitting smoking and includes personal stories from people who have stopped smoking Smokefree.gov, from the US National Cancer Institute, offers online tools and resources to help people quit smoking

Proteinuria, high serum creatinine, and reduced glomerular filtration rate (GFR) have been associated with increased mortality from cardiovascular disease (CVD) and all causes. However, the combined effect of proteinuria with serum creatinine and GFR on CVD or all-cause mortality has not been well investigated. We conducted a 10-year prospective cohort study of 30,764 men and 60,668 women aged 40-79 years who participated in annual health checkups in 1993. The Cox proportional hazards model was used to estimate the relative risk (RR) after adjusting for age, smoking, and other cardiovascular risk factors. The multivariable RR (95% confidence interval (CI)) of CVD death for positive vs negative proteinuria was 1.38 (1.05-1.79) among men and 2.15 (1.64-2.81) among women. The respective RR for the highest vs lowest creatinine groups (or = 1.3 vsor = 0.8 mg/dl for men andor = 1.1 vsor = 0.6 mg/dl for women) was 1.56 (1.19-2.04) among men and 2.15 (1.58-2.93) among women. The respective RR for GFR60 vsr = 100 ml/min/1.73 m2 was 1.65 (1.25-2.18) among men and 1.81 (1.39-2.36) among women. For individuals with proteinuria combined by hypercreatininemia or reduced GFR, the risk of CVD death was two-fold higher in men and 4-6-fold higher in women compared to those without proteinuria and with normal creatinine level or GFR. Similar associations were observed for stroke, coronary heart disease, and all-cause mortality. Proteinuria, and hypercreatininemia or reduced GFR and their combination were significant predictors of CVD and all-cause mortality.