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To investigate the association between stage 1 hypertension, defined as systolic blood pressure (BP) of 130-139 mmHg or diastolic BP of 80-89 mmHg, in the first and second trimesters and the risk of adverse pregnancy outcomes.We analyzed 79,249 singleton pregnancies from a nationwide birth cohort study. BP in the first and second trimesters was classified into normal, elevated, stage1 hypertension, and stage 2 hypertension. We examined the risk of adverse pregnancy outcomes in each group using multivariable logistic regression analysis. We also investigated the influence of BP changes between the first and second trimesters on adverse pregnancy outcomes.Overall preterm birth (PTB 37 weeks), early PTB (34 weeks), and small for gestational age (SGA).Stage 1 hypertension in the first trimester was associated with increased risks of overall PTB (aOR, 1.23; 95 %CI, 1.08-1.39), early PTB (aOR, 1.38; 95 %CI, 1.07-1.79), and SGA (aOR, 1.19; 95 %CI, 1.04-1.36) compared to normal BP. These risks were more evident in the second trimester; overall PTB (aOR, 1.87; 95 %CI, 1.64-2.14), early PTB (aOR, 2.21; 95 %CI, 1.69-2.87), and SGA (aOR, 1.38; 95 %CI, 1.18-1.62). The risk of PTB was higher among women with an upward BP trajectory between the first and second trimesters.Stage 1 hypertension in the first and second trimesters was associated with increased risks of overall PTB, early PTB, and SGA. Monitoring the BP trajectory for stage 1 hypertension may be useful for identifying high-risk groups.

Aims Reports on the association between height and aortic disease have been modest, and there are only a few studies investigating the association between height and mortality from specific aortic disease types or by sex. Methods We conducted the Japan Collaborative Cohort Study, a prospective study of 99,067 Japanese (41,730 men and 57,337 women) aged 40-79 years old. Height was self-reported, and the participants were followed up from 1988-1989 to the end of 2009. Sex-specific hazard ratios (95% confidence intervals) of mortality from aortic disease type according to sex-specific quartiles of height were analyzed using the Cox proportional hazards model. Results During the median follow-up period of 19.1 years, the numbers of deaths due to aortic aneurysm, thoracic aortic aneurysm, abdominal aortic aneurysm, and aortic dissection were 87, 29, 48, and 56 among men and 35, 17, 15, and 65 among women, respectively. The sex-specific multivariate hazard ratios (95% confidence intervals) and p for trend for the highest versus lowest quartiles of height were 1.10 (0.66-1.83), p=0.58 among men and 1.54 (0.85-2.79), p=0.06 among women for total aortic disease; 1.85 (0.80-4.28), p=0.16 among men and 5.67 (0.90-35.77), p=0.08 among women for abdominal aortic aneurysm; and 1.13 (0.48-2.64), p=0.65 among men and 1.70 (0.82-3.50), p=0.04 among women for aortic dissection. The positive association was observed for both sexes, albeit more prominent among women. No association was found between height and mortality from thoracic aortic aneurysms. Conclusions As per our findings, we were able to determine that height was positively associated with mortality from abdominal aortic aneurysm in the Japanese population.

AIM Reports have shown that physical activity is inversely associated with heart failure risk, but evidence in Asian populations is lacking. We sought to examine the impacts of walking and sports participation on heart failure mortality among a Japanese population. METHODS We involved 36,223 Japanese men and 50,615 women (aged 40-79 years) who completed a self-administered questionnaire between 1988 and 1990. We divided participants into four categories of walking (＜0.5, 0.5, 0.6-1.0, and ≥ 1 h/day) and sports participation (＜1, 1-2, 3-4, and ≥ 5 h/week) and examined associations with activity and heart failure mortality through 2009. RESULTS We found inverse associations between physical activity and heart failure mortality. The multivariable hazard ratios (95% confidence intervals) for the highest category of walking time compared with the second-lowest category were 0.76 (0.59-0.99) in men and 0.78 (0.61-0.99) in women, while the ratios for the highest category of sports participation time compared with the second-lowest category were 0.62 (0.41-0.93) in men and 1.09 (0.73-1.65) in women. The lower hazard ratios in the highest categories of walking and sports participation time in men became no longer statistically significant after excluding heart failure deaths for the first 5, 10, and 15 years for walking time and 10 and 15 years for sports participation. However, in women, the low hazard ratios for the highest category ≥ 1.0 h/day of walking time did not change materially. CONCLUSIONS Physical activity was associated with a lower risk of mortality from heart failure in this Japanese community-based population. The attenuated and nonsignificant association of walking and sports participation with the risk in men after exclusion of first 5-15 years heart failure death was probably due to changes in physical activity and death certificate diagnosis during the follow-up and reverse causation. However, the persistent inverse association between walking and the risk in women suggests a beneficial preventive effect on heart failure.

Aim We aimed to examine the impact of high-risk levels of cardiovascular risk factors on the incidence of cardiovascular disease (CVD) in overweight and non-overweight individuals without treatment for the risk factors. Methods A total of 8,051 individuals aged 40-74 years without a history of CVD and/or without treatment for hypertension, diabetes, hyperlipidemia, and kidney disease at baseline in 1995-2000 were followed up for a median of 14.1 years. We classified the participants into three risk categories (low-, intermediate-, and high-risk groups) on the basis of individual risk factors (blood pressure, serum glucose, low-density lipoprotein cholesterol [LDL-C], and urinary protein) according to the guidelines of Japanese clinical societies. The high-risk group (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg, fasting serum glucose ≥ 130 mg/dL or non-fasting serum glucose ≥ 180 mg/dL, LDL-C ≥ 180 mg/dL, proteinuria ≥ 2+) needed to refer to physicians or start treatment immediately. Overweight was defined as a body mass index of ≥ 25 kg/m2. Results Compared with those in the non-overweight low-risk group, the hazard ratios (HRs) (95% confidence intervals, population-attributable fractions [PAFs]) of CVD in the high-risk categories of blood pressure were 2.0 (1.4-2.9, 7.0%) in the non-overweight high-risk group and 2.9 (1.9-4.3, 6.8%) in the overweight high-risk group. The corresponding HRs (95% confidence intervals, PAFs) of serum glucose were 2.0 (1.2-3.4, 2.5%) and 2.2 (1.1-4.3, 1.5%) in the non-overweight and overweight high-risk groups, respectively. Such associations were not observed for the high-risk group of LDL-C and proteinuria. Conclusions The present long-term observational study implies that targeting persons with non-treated severe hypertension and diabetes is prioritized to prevent CVD regardless of overweight status.

This study aimed to investigate the association between retinal microvascular abnormalities and the risk of incident stroke and its subtypes in the general Japanese population.A total of 12 965 residents aged 40-74 years without a history of stroke and/or coronary heart disease underwent retinal photography during the annual health checkups of four Japanese communities between 1990 and 1999. Retinal microvascular abnormalities, such as the presence or absence of generalized arteriolar narrowing, focal arteriolar narrowing, arteriovenous nicking, enhanced arteriolar light reflex, and retinal hemorrhages were graded using standard protocols.During a median follow-up of 20 years, 817 patients were diagnosed with incident stroke. Retinal microvascular abnormalities were positively associated with the risk of total stroke; after adjustment for age, sex, community, SBP, antihypertensive medication use, and other cardiovascular risk factors, the multivariable hazard ratio [95% confidence interval (CI)] was 1.68 (1.42-1.98), 1.67 (1.34-2.07), 1.41 (1.17-1.72), 1.54 (1.26-1.87), and 1.57 (1.19-2.07) for generalized arteriolar narrowing, focal arteriolar narrowing, arteriovenous nicking, enhanced arteriolar light reflex, and retinal hemorrhages, respectively. Similar positive associations were observed for the risk of stroke subtypes, except for subarachnoid hemorrhage, for which no association was observed. Furthermore, the positive associations were similar in participants with and without hypertension.Retinal microvascular abnormalities were positively associated with the risk of incident stroke in the general Japanese population. Routine retinal photography could provide positive clinical insights into stroke risk stratification independent of blood pressure, antihypertensive medication use, and other risk factors.

Aim Seaweed contains soluble dietary fibers, potassium, and flavonoids and was recently reported to be inversely associated with the risk of coronary heart disease and mortality from stroke. However, epidemiological evidence on this issue has remained scarce. Methods At the baseline survey of four Japanese communities between 1984 and 2000, we enrolled 6,169 men and women aged 40-79 years who had no history of cardiovascular disease. We assessed their seaweed intake using the data from a 24 h dietary recall survey and categorized the intake into four groups (0, 1-5.5, 5.5-15, and ≥ 15 g/day). We used sex-specific Cox proportional hazards models to examine the association between seaweed intake and risk of cardiovascular disease (stroke, stroke subtypes, and coronary heart disease). Results During the 130,248 person-year follow-up, 523 cases of cardiovascular disease occurred: 369 cases of stroke and 154 cases of coronary heart disease. Seaweed intake levels were inversely associated with the risk of total stroke and cerebral infarction among men but not among women. Adjustment for cardiovascular risk factors did not change the associations: the hazard ratios (95% confidence intervals; P for trend) for the highest versus lowest categories of seaweed intake were 0.63 (0.42-0.94; 0.01) for total stroke and 0.59 (0.36-0.97; 0.03) for cerebral infarction. No associations were observed between seaweed intake and risks of intraparenchymal hemorrhage, subarachnoid hemorrhage, or coronary heart disease among men or women. Conclusions We found an inverse association between seaweed intake and risk of total stroke, especially that from cerebral infarction, among Japanese men.

Background: The association between overweight and chronic musculoskeletal pain may vary by anatomical site and be modified by hypertension status. This study examined the associations between overweight and low back and knee pains and their effect modification by hypertension status. Methods: We conducted a community-based cross-sectional study involving 2,845 adults (1,080 men and 1,765 women) aged 40–89 years. Chronic knee pain (CKP) and low back pain (CLBP) lasting more than 3 months were categorized into more or less severe pain. Odds ratios (ORs) and 95% confidence intervals (CIs) of the association between overweight and more or less severe CKP and CLBP were determined using logistic regression and stratified by hypertension status. Adjustment variables were age, sex, area, hypertension, smoking and drinking status, inactivity, job category, mental stress, depression, and overall CKP or CLBP. Results: Overall, 288 (10.1%) and 631 (22.2%) adults had more and less severe CKP, respectively, and 284 (10.0%) and 830 (29.2%) had more and less severe CLBP, respectively. Overweight was associated with overall CKP and more or less severe CKP, regardless of hypertension status. Overweight was not associated with overall CLBP; its association was more pronounced for more severe CLBP. The association between overweight and more severe CLBP was evident among non-hypertensives (multivariable OR 1.72; 95% CI, 1.09–2.71); however, that between overweight and less severe CLBP was not evident (multivariable OR 1.07; 95% CI, 0.73–1.56). Conclusions: As hypertension may attenuate the association between overweight and CLBP, we should consider hypertension status for proper management of CLBP among overweight individuals.

Background and purpose An effect of dietary carotenes on risk of cardiovascular disease (CVD) is uncertain. We aimed to investigate whether the association between dietary carotenes intake and risk of CVD mortality will persist after controlling for the intakes of potential cardioprotective dietary factors that correlate with dietary alpha- and/or beta-carotenes. Methods and results We followed up a total of 58,646 Japanese between 1988 and 1990 and 2009. We used a food frequency questionnaire (FFQ) to determine the dietary intakes of carotenes, and estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) of CVD mortality in relation to carotene intake by the proportional hazard regression developed by David Cox. During 965,970 person-years of follow-up (median 19.3 years), we identified 3388 total CVD deaths. After adjusting for demographic and lifestyle factors, dietary intakes of alpha-carotene were significantly associated with the reduced risk of mortality from coronary heart disease (CHD); adjusted HR (95% CI) in the highest versus lowest quintiles of intake was 0.75 (0.58–0.96; P-trend = 0.02) and dietary intakes of beta-carotene were significantly associated with the reduced risk of mortality from CVD, CHD, and other CVD; adjusted HRs (95% CIs) were 0.88 (0.79–0.98; P-trend = 0.04), 0.78 (0.61–0.99; P-trend = 0.01), and 0.81 (0.67–0.98; P-trend = 0.04), respectively. However, after further adjusting for the dietary intakes of potassium, calcium, vitamins C, E, or K, these associations disappeared. Conclusions —Dietary alpha- and beta-carotene intakes were not associated with risk of CVD mortality after controlling for intakes of other potential cardioprotective nutrients.

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

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

Purpose To investigate whether and how unhealthy sleep habits (i.e., the frequency of difficulty falling or staying asleep, and the frequency of waking up tired) and the duration of sleep are related to the prevalence of dry eye disease (DED) in a general population. Methods This study included a total of 106,282 subjects aged 40–74 years who participated in a baseline survey of the Japan Public Health Center-based Prospective Study for the Next Generation. DED was defined as the presence of clinically diagnosed DED or severe symptoms. Multivariable-adjusted logistic regression models were used to assess the relationships of various components of sleep status with DED. Results Higher frequencies of having difficulty falling or staying asleep, and waking up tired were significantly related to increased DED in both sexes (Ptrend Conclusions Sleep deprivation and poor sleep quality were significantly related to DED in a Japanese population.

Although a positive link between hypertension and intraocular pressure (IOP) has been suggested, the individual effects of systolic and diastolic blood pressure (SBP and DBP, respectively) on IOP remain unclear, particularly among Japanese populations. Here, we conducted a large-scale, cross-sectional study to determine individual and combined effects of SBP/DBP and hypertension on IOP. In total, 6783 Japanese people aged over 40 years underwent systemic and ophthalmological examinations, including measurements of blood pressure and IOP, conducted using non-contact tonometers. After adjusting for a priori known confounding factors, SBP and DBP levels were found to be positively correlated with IOP levels. The multivariable-adjusted odds ratio when comparing the hypertensive and normotensive groups for the prevalence of ocular hypertension was 1.88 (95% confidence interval, 1.14–3.08). When analysing the combined effects of SBP and DBP on ocular hypertension, SBP elevation had a greater effect on ocular hypertension than DBP increase. In conclusion, SBP and DBP levels and the prevalence of systemic hypertension were found to be positively associated with IOP levels and the prevalence of ocular hypertension in an ophthalmologically healthy Japanese population. Our findings suggest that systemic blood pressure control may be key for controlling IOP.

Background: The health risks associated with moderate alcohol consumption continue to be debated. Small amounts of alcohol might lower the risk of some health outcomes but increase the risk of others, suggesting that the overall risk depends, in part, on background disease rates, which vary by region, age, sex, and year. Methods: For this analysis, we constructed burden-weighted dose-response relative risk curves across 22 health outcomes to estimate the theoretical minimum risk exposure level (TMREL) and non-drinker equivalence (NDE), the consumption level at which the health risk is equivalent to that of a non-drinker, using disease rates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020 for 21 regions, including 204 countries and territories, by 5-year age group, sex, and year for individuals aged 15-95 years and older from 1990 to 2020. Based on the NDE, we quantified the population consuming harmful amounts of alcohol. Findings: The burden-weighted relative risk curves for alcohol use varied by region and age. Among individuals aged 15-39 years in 2020, the TMREL varied between 0 (95% uncertainty interval 0-0) and 0·603 (0·400-1·00) standard drinks per day, and the NDE varied between 0·002 (0-0) and 1·75 (0·698-4·30) standard drinks per day. Among individuals aged 40 years and older, the burden-weighted relative risk curve was J-shaped for all regions, with a 2020 TMREL that ranged from 0·114 (0-0·403) to 1·87 (0·500-3·30) standard drinks per day and an NDE that ranged between 0·193 (0-0·900) and 6·94 (3·40-8·30) standard drinks per day. Among individuals consuming harmful amounts of alcohol in 2020, 59·1% (54·3-65·4) were aged 15-39 years and 76·9% (73·0-81·3) were male. Interpretation: There is strong evidence to support recommendations on alcohol consumption varying by age and location. Stronger interventions, particularly those tailored towards younger individuals, are needed to reduce the substantial global health loss attributable to alcohol. Research reported in this publication was supported by the Bill & Melinda Gates Foundation. S Afzal acknowledges the support for intellectual contributions to this manuscript by the Department of Community Medicine and Epidemiology at King Edward Medical University, Lahore, Pakistan. T Bärnighausen was supported by the Alexander von Humboldt Foundation through the Alexander von Humboldt Professor award, funded by the German Federal Ministry of Education and Research. L Belo acknowledges support from FCT in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of UCIBIO and the project LA/P/0140/2020 of i4HB. D Bennett is supported by the UK Medical Research Council Population Health Research Unit at the University of Oxford (Oxford, UK). M Carvalho acknowledges support from FCT in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of UCIBIO and the project LA/P/0140/2020 of i4HB. L Castro-de-Araujo was funded by the Medical Research Council (UK), Grant no. MR/T03355X/1 and by the National Institute of Mental Health Grant no. R01MH128911. FJ Elgar is supported by the Canada Research Chairs program. F Greaves acknowledges support from the NIHR Applied Research Collaboration for NW London. V K Gupta acknowledges funding support from the National Health and Medical Research Council (NHMRC), Australia. VB Gupta acknowledges funding support from the National Health and Medical Research Council (NHMRC), Australia. C Herteliu is partially supported by a grant from the Romanian National Authority for Scientific Research and Innovation, CNDS-UEFISCDI, project number PN-III-P4-ID-PCCF-2016-0084. C Herteliu is partially supported by a grant from the Romanian Ministry of Research Innovation and Digitalization, MCID, project number ID-585-CTR-42-PFE-2021. S Hussain was supported by the Operational Programme Research, Development and Education –Project, Postdoc2MUNI “(No. CZ.02.2.69/0.0/0.0/18_053/0016952). S M S Islam is funded by the National Health and Medical Research Council and received funding from the National Heart Foundation of Australia. The Serbian part of this GBD-related contribution has been co-financed through Grant OI 175 014 of the Ministry of Education Science and Technological Development of the Republic of Serbia. M Kivimaki was supported by the Wellcome Trust (221854/Z/20/Z), the UK Medical Research Council (MR/S011676/1), the US National Institute on Aging (R01AG056477), and the Academy of Finland (350426). K Krishan is supported by the UGC Centre of Advanced Study (Phase II), awarded to the Department of Anthropology, Panjab University, Chandigarh, India. B Lacey acknowledges support from the UK Biobank, funded largely by the UK Medical Research Council and Wellcome. S Lorkowski acknowledges institutional support from the Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig (Germany; German Federal Ministry of Education and Research; grant agreement number 01EA1808A). G Lucchetti received a productivity scholarship from the Brazilian National Council for Scientific and Technological Development — CNPq (Level 1D). J McGrath was supported by the Danish National Research Foundation (Niels Bohr Professor). J McGrath is employed by the Queensland Centre for Mental Health Research (Australia), which receives support from the Queensland Health Department. C Parry acknowleges the South African Medical Research Council. A Peden is supported by a National Health and Medical Research Council Emerging Leadership Fellowship (Grant ID: APP2009306). M R Phillips was supported in part by the Global Alliance for Chronic Diseases - National Natural Science Foundation of China (NSFC. No. 81761128031). M Pinheiro acknowledges FCT for funding through program DL 57/2016 – Norma transitória. A Rahman acknowledges the support from the Data Science Research Unit in Charles Sturt University (Bathurst, NSW, Australia). U Saeed would like to acknowledge the International Center of Medical Sciences Research (ICMSR), Islamabad, Pakistan. A M Samy acknowledges support from Ain Shams University (Cairo, Egypt) and the Egyptian Fulbright Mission Program. N Senthil Kumar acknowledges the DBT, New Delhi sponsored Advanced State Level Biotech Hub (BT/NER/143/SP44475/2021), Mizoram University (Aizawl, Mizoram, India) for facilitating this work. F Sha is supported by the Shenzhen Science and Technology Program (Grant No. KQTD20190929172835662). A Shetty acknowledges Kasturba Medical College (Mangalore, India) and Manipal Academy of Higher Education (Manipal, India) for all the academic support. R Shrestha acknowledges a career development award from the National Institutes of Health (K01DA051346). D Silva was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brazil (CAPES)-Finance Code 001 and is supported in part by CNPq - Brazil (309589/2021-5). D Sleet acknowledges partial support from Veritas Management Group, Inc and The Bizzell Group, LLC. S Trias-Llimós acknowledges research funding from the Juan de la Cierva-Formación program of the Spanish Ministry of Science and Innovation (FJC-2019-039314-I). Sí

ObjectiveTo examine whether the relationship between smoking cessation and risk of cardiovascular disease (CVD) was modified by weight gain.MethodsA total of 69 910 participants (29 650 men and 46 260 women) aged 45–74 years were grouped into six groups by smoking status in the first and 5-year surveys: sustained smokers, recent quitters according to postcessation weight gain (no weight gain, 0.1–5.0 kg, >5.0 kg), long-term quitters and never smokers. Quitting smoking within and longer than 5 years were defined as recent and long-term quitters, respectively. We used Cox proportional hazard models to estimate the HR for incident CVD, coronary heart disease (CHD) and stroke.ResultsWe identified 4023 CVDs (889 CHDs and 3217 strokes) during a median of 14.8 years of follow-up. Compared with sustained smokers, the multivariable HR (95% CI) for CVD was 0.66 (0.52 to 0.83) for recent quitters without weight gain, 0.71 (0.55 to 0.90) for recent quitters with weight gain of 0.1–5.0 kg, 0.70 (0.44 to 1.10) for recent quitters with weight gain of >5.0 kg, 0.56 (0.49 to 0.64) for long-term quitters, and 0.60 (0.55 to 0.66) for never smokers. The analysis restricted to men showed a similar association. Prespecified analysis by age suggested that recent quitters overall had a lower HR for CVD among those aged ConclusionsPostcessation weight gain did not attenuate the protective association between smoking cessation and risk of CVD.

Aims Patients with chronic kidney disease (CKD) have a higher burden of cardiovascular morbidity and mortality than the general population. Endothelial dysfunction has been suggested to play a role in both glomerular filtration rate loss and cardiovascular damage. Thus, the present study aimed to evaluate the relationship between endothelial dysfunction and the prevalence of CKD in the general Japanese population. Methods We conducted a cross-sectional study of 1042 men and women aged 30-81 years in two communities under the Circulatory Risk in Communities Study between 2013 and 2017. Endothelial function was evaluated by percent change of brachial artery flow-mediated dilation (%FMD) before and after the cuff inflation. Results Among the total 1042 participants, there were 62 cases of CKD (~6%). The multivariable odds ratios (ORs) (95% confidence intervals [CIs]) of CKD according to quartiles of %FMD were 2.02 (0.68-5.99), 3.56 (1.27-9.94), and 3.14 (1.10-8.93) for the third to lowest quartile compared with the highest %FMD quartile; p for trend=0.02. The respective multivariable ORs (95% CIs) of CKD in subjects without antihypertensive medication use (39 cases among 886 subjects) were 1.83 (0.46-7.33), 3.41 (0.92-12.61), and 4.60 (1.22-17.31); p for trend=0.01, and that for one-point decrement in %FMD was 1.16 (1.00-1.35); p for interaction with the status of antihypertensive medication use was 0.12. Conclusions Our cross-sectional study suggested the relationship between endothelial dysfunction and the higher prevalence of CKD in the general Japanese population.

Background Acute ischemic stroke (AIS) is a serious cause of mortality and disability. AIS is a serious cause of mortality and disability. Early diagnosis of atherosclerosis, which is the major cause of AIS, allows therapeutic intervention before the onset, leading to prevention of AIS. Methods Serological identification by cDNA expression cDNA libraries and the protein array method were used for the screening of antigens recognized by serum IgG antibodies in patients with atherosclerosis. Recombinant proteins or synthetic peptides derived from candidate antigens were used as antigens to compare serum IgG levels between healthy donors (HDs) and patients with atherosclerosis-related disease using the amplified luminescent proximity homogeneous assay-linked immunosorbent assay. Results The first screening using the protein array method identified death-inducer obliterator 1 (DIDO1), forkhead box J2 (FOXJ2), and cleavage and polyadenylation specificity factor (CPSF2) as the target antigens of serum IgG antibodies in patients with AIS. Then, we prepared various antigens including glutathione S-transferase-fused DIDO1 protein as well as peptides of the amino acids 297–311 of DIDO1, 426–440 of FOXJ2, and 607–621 of CPSF2 to examine serum antibody levels. Compared with HDs, a significant increase in antibody levels of the DIDO1 protein and peptide in patients with AIS, transient ischemic attack (TIA), and chronic kidney disease (CKD) but not in those with acute myocardial infarction and diabetes mellitus (DM). Serum anti-FOXJ2 antibody levels were elevated in most patients with atherosclerosis-related diseases, whereas serum anti-CPSF2 antibody levels were associated with AIS, TIA, and DM. Receiver operating characteristic curves showed that serum DIDO1 antibody levels were highly associated with CKD, and correlation analysis revealed that serum anti-FOXJ2 antibody levels were associated with hypertension. A prospective case–control study on ischemic stroke verified that the serum antibody levels of the DIDO1 protein and DIDO1, FOXJ2, and CPSF2 peptides showed significantly higher odds ratios with a risk of AIS in patients with the highest quartile than in those with the lowest quartile, indicating that these antibody markers are useful as risk factors for AIS. Conclusions Serum antibody levels of DIDO1, FOXJ2, and CPSF2 are useful in predicting the onset of atherosclerosis-related AIS caused by kidney failure, hypertension, and DM, respectively.

Aim The fact that low concentrations of high-density lipoprotein cholesterol are associated with the risk of cardiovascular disease is well known, but high-density lipoprotein metabolism has not been fully understood. Apolipoprotein A2 (ApoA2) is the second-most dominant apolipoprotein of high-density lipoprotein. We tested the hypothesis that ApoA2 isoforms are inversely associated with myocardial infarction. Methods We measured the plasma levels of three ApoA2 isoforms (ApoA2-ATQ/ATQ, ApoA2-ATQ/AT, ApoA2-AT/AT) in nested case-control study samples of 1:2 from the Japan Public Health-Center-based Study (JPHC Study): 106 myocardial infarction incidence cases and 212 controls. Results ApoA2-AT/AT was inversely associated with risk of myocardial infarction, in a matched model (OR, 2.78; 95% CI, 1.26-6.09 for lowest compared with the highest quartile), but its association was attenuated after adjustment for smoking only (OR=2.13; 95% CI, 0.91-4.97) or drinking only (OR=2.07; 0.91-4.74), and the multivariable OR was 1.20 (95% CI, 0.41-3.57). Neither ApoA2-ATQ/ATQ nor ApoA2-ATQ/AT was associated with the risk of myocardial infarction. Conclusions Our nested case-control study did not show a significant association of ApoA2 isoforms with a risk of myocardial infarction.

Background and aims The impact of weight changes in middle age on the incidence of cardiovascular disease has not been well elucidated. We investigated whether a 5-year weight change was associated with risk of stroke and coronary heart disease (CHD) in middle-aged individuals. Methods We analyzed data of 74,928 participants aged 40–69 years who provided responses to the baseline and 5-year follow-up questionnaires in the Japan Public Health Center–based Prospective Study. Weight change was calculated by subtracting self-reported weight at baseline from that at 5-year follow-up. Stroke and CHD events were confirmed by reviewing hospital records. Results During 997,406 person-years of follow-up, we documented 3,975 stroke and 914 CHD events. The multivariable HRs of stroke for losing ≥5 kg compared to stable weight (change ≤2 kg) was 1.17 (95% CI, 1.01–1.37) in men versus 1.33 (1.13–1.57) for losing ≥5 kg and 1.61 (1.36–1.92) for gaining ≥5 kg in women (U-shaped association). These associations did not change after the exclusion of early events. The multivariable HR of CHD for gaining ≥5 kg was 1.22 (0.95–1.58) in men. After exclusion of early events within another 5 years, that positive association became stronger [multivariable HR 1.34 (1.00–1.82)]. Conclusions Weight gain during middle age was associated with an increased risk of stroke in women and an increased risk of CHD in men. Weight loss was associated with an increased risk of stroke in both men and women.

Aims: Reports on an association between body mass index and aortic disease, which remains controversial. This study investigated the association between body mass index and mortality from aortic disease. Methods: We conducted the Japan Collaborative Cohort Study, a prospective study of 103,972 Japanese men and women aged 40–79 years. Body mass index was calculated on the basis of self-reported height and weight, and the participants were followed up from 1988–89 through 2009. Sex-specific hazard ratios (95% confidence intervals) of mortality from aortic disease according to quintiles of body mass index were analyzed using the Cox proportional hazards model. Results: During the median 18.8 years of follow-up, we documented 139 deaths due to aortic aneurysm (including 51 thoracic and 74 abdominal aortic aneurysms) and 134 deaths due to aortic dissection. We observed positive associations of body mass index with mortality from aortic aneurysm among men: the multivariable hazard ratios (95% confidence intervals) for highest versus lowest quintiles of body mass index were 4.48 (2.10–9.58), P for trend < 0.0001 for aortic aneurysm; 6.52 (1.33–32.02), P = 0.005 for thoracic aortic aneurysm; 3.81 (1.39–10.49), P = 0.01 for abdominal aortic aneurysm; and 2.71 (1.59–4.62), P = 0.001 for total aortic disease. No association was found for aortic dissection. Among ever-smokers (men ≥ 90%) but not never-smokers (women ≥ 84%), an association between body mass index and aortic disease mortality was observed regardless of sex, which may explain the sex difference (P for sex-interaction = 0.046). Conclusions: We found a positive association between body mass index and mortality from aortic aneurysm among Japanese men and smokers.

This study determined the validity of claims-based definitions for identifying the incidence of total and site-specific cancers in a population-based cohort study.Claims data were obtained for 21 946 participants aged 40-74 years enrolled in the Japan Public Health Center-based Prospective Study for the Next Generation. We defined total and site-specific cancer incidence using combinations of codes from claims data, including diagnosis and procedure codes for cancer therapy. Data from the cancer registry were used as the gold standard to evaluate validity.Among 21 946 participants, 454 total, 89 stomach, 67 colorectal, 51 lung, 39 breast and 99 prostate invasive cancer cases were newly diagnosed in the cancer registry. For invasive cancer, the sensitivity and specificity of the definition that combined codes for diagnosis and procedures for cancer therapy were 87.0% and 99.4% for total, 88.8% and 99.9% for stomach, 80.6% and 99.9% for colorectal, 86.3% and 99.9% for lung, 100% and 99.9% for breast and 91.9% and 99.9% for prostate cancer, respectively. Furthermore, for invasive and/or in situ cancer, the sensitivity and specificity of the definition were 84.5% and 99.5% for total, 66.7% and 99.9% for colorectal and 100% and 99.9% for breast cancer.Our findings suggest that claims-based definitions using diagnosis and procedure codes generally have high validity for total, stomach, lung, breast and prostate cancer incidence, but may underestimate colorectal cancer incidence.

This population-based cross-sectional study was performed to determine the mean corneal endothelial cell density (ECD), coefficient of variation (CV), and hexagonality (HEX), and their associations with myopia in Japanese adults living in Chikusei city. Of 7109 participants with available data, 5713 (2331 male and 3382 female) participants were eligible for analysis. After assessing the relationship between participant characteristics and spherical equivalent refraction (SER), the association of SER with the abnormal value of ECD (

Background: The frequency of laughter has been associated with cardiovascular disease and related biomarkers, but no previous studies have examined association between laughter and changes in blood pressure levels. We sought to identify temporal relationships between frequency of laughter in daily life and systolic and diastolic blood pressure changes in participants from 2010 through 2014. Methods: Participants were 554 men and 887 women aged 40–74 years who answered self-administered questionnaire quantifying frequency of laughter at baseline. We measured participant blood pressure levels twice using automated sphygmomanometers for each year from 2010 to 2014. The associations between laughter and changes in blood pressure over time were analyzed using linear mixed-effect models. Results: There was no significant difference in blood pressure according to frequency of laughter at baseline in either sex. Men with frequency of laughter 1 to 3 per month or almost never had significantly increased systolic and diastolic blood pressure levels over the 4-year period (time-dependent difference: 0.96 mm Hg (95% confidence interval [CI], −0.2 to 1.8; P = 0.05). Changes in blood pressure associated with infrequent laughter (ie, 1 to 3 per month or almost never) were evident in men without antihypertensive medication use over 4 years (0.94 mm Hg; 95% CI, −0.2 to 2.0; P = 0.09) and men who were current drinkers at baseline (1.29 mm Hg; 95% CI, −0.1 to 2.3; P = 0.04). No significant difference was found between frequency of laughter and systolic (0.23 mm Hg; 95% CI, −1.0 to 1.5; P = 0.72) and diastolic (−0.07 mm Hg; 95% CI, −0.8 to 0.7; P = 0.86) blood pressure changes in women. Conclusions: Infrequent laughter was associated with long-term blood pressure increment among middle-aged men.

Supplemental Digital Content is available in the text., Background and Purpose: The effect of green tea and coffee consumption on mortality among cardiovascular diseases survivors is unknown. We examined the association between green tea and coffee consumption and mortality among persons with and without stroke or myocardial infarction (MI). Methods: In the Japan Collaborative Cohort Study, 46 213 participants (478 stroke survivors, 1214 MI survivors, and 44 521 persons without a history of stroke or MI), aged 40 to 79 years at baseline (1988–1990), completed a lifestyle, diet, and medical history questionnaire and were followed up regarding mortality until 2009. The Cox proportional hazard model was used to calculate the multivariable hazard ratios with 95% CIs of all-cause mortality after adjusting for potential confounding factors. Results: During the 18.5-year median follow-up period, 9253 cases were documented. Green tea consumption was inversely associated with all-cause mortality among stroke or MI survivors; the multivariable hazard ratios (95% CIs) for stroke survivors were 0.73 (0.42–1.27) for 1 to 6 cups/wk, 0.65 (0.36–1.15) for 1 to 2 cups/d, 0.56 (0.34–0.92) for 3 to 4 cups/d, 0.52 (0.31–0.86) for 5 to 6 cups/d, and 0.38 (0.20–0.71) for ≥7 cups/d, compared with nondrinkers. A similar inverse association was observed for MI survivors, but not evident for those without a history of stroke or MI. Coffee consumption was inversely associated with all-cause mortality in persons without a history of stroke or MI; the multivariable hazard ratios (95% CIs) were 0.86 (0.82–0.91) for 1 to 6 cups/wk, 0.86 (0.80–0.92) for 1 cup/d, and 0.82 (0.77–0.89) for ≥2 cups/d, compared with nondrinkers. The corresponding hazard ratios (95% CIs) for MI survivors were 0.69 (0.53–0.91), 0.78 (0.55–1.10), and 0.61 (0.41–0.90). No such association was observed for stroke survivors. Conclusions: Green tea consumption can be beneficial in improving the prognosis for stroke or MI survivors, whereas coffee consumption can also be so for persons without a history of stroke or MI as well as MI survivors.

We sought to examine the prospective associations of specific fruit consumption, in particular flavonoid-rich fruit (FRF) consumption, with the risk of stroke and subtypes of stroke in a Japanese population. A study followed a total of 39,843 men and 47,334 women aged 44-76 years, and free of cardiovascular disease, diabetes, and cancer at baseline since 1995 and 1998 to the end of 2009 and 2012, respectively. Data on total and specific FRF consumption for each participant were obtained using a self-administrated food frequency questionnaire. The hazard ratios (HRs) of stroke in relation to total and specific FRF consumption were estimated through Cox proportional hazards regression models. During a median follow-up of 13.1 years, 4092 incident stroke cases (2557 cerebral infarctions and 1516 hemorrhagic strokes) were documented. After adjustment for age, body mass index, study area, lifestyles, dietary factors, and other risk factors, it was found that total FRF consumption was associated with a significantly lower risk of stroke in women (HR= 0.70; 95% CI, 0.58-0.84), while the association in men was not significant (HR= 0.93; 95% CI, 0.79-1.09). As for specific FRFs, consumptions of citrus fruits, strawberries, and grapes were found associated with a lower stroke risk in women. Higher consumptions of FRFs, in particular citrus fruits, strawberries, and grapes, were associated with a lower risk of developing stroke in Japanese women.

To clarify how low BMI and weight loss were associated with risk of chronic obstructive pulmonary disease (COPD) mortality, in a large prospective cohort of the general population across Japan, the Japan Collaborative Cohort Study, conducted between 1988 and 2009. A total of 45,837 male residents were observed for a median period of 19.1 years. Self-administered questionnaires, collecting information on BMI, weight loss since the age of 20, lifestyles, history of diseases, as well as records of COPD mortality, were analysed at 2019. During follow-up, 268 participants died from COPD. The multivariate-adjusted hazard ratio (95% confidence interval) of COPD mortality associated with a 1-SD increment of body mass index (BMI) was 0.48 (0.41–0.57), while for weight change from age of 20 (+ 2.0 kg) it was 0.63 (0.59–0.68). These associations were persistently observed after stratifications with smoking status, excluding those having airway symptoms in the baseline survey, and excluding early COPD deaths within 5, 10 and 15 years. Our study suggests that BMI and weight change since the age of 20 could be markers for COPD prognosis, indicated by risk of COPD mortality.

Purpose This study compared working cancer survivors’ self-rated health status (SRHS), physical functional capacity, depressive symptoms, and happiness to those of cancer-free workers. Methods A nationwide general population-based cross-sectional study on a sample of Japanese was conducted. Prevalence of deteriorated SRHS, restricted physical functional capacity, depressive symptoms, and perceived happiness were compared between working cancer survivors and cancer-free workers with multivariable logistic regression analysis adjusted for age and sociodemographic and health-related backgrounds. Results Of the 28,311 male and 26,068 female workers, 977 (3.5%) and 1267 (4.9%) were cancer survivors, respectively. Working cancer survivors reported deteriorated SRHS more frequently than cancer-free workers: 21.3% vs. 13.8%, multivariable-adjusted odds ratio (95% confidence interval), 1.64 (1.39–1.95) for men, 23.8% vs. 17.5%, 1.34 (1.16–1.54) for women. Restricted physical functional capacity was reported more frequently in working cancer survivors than cancer-free workers: 6.8% vs. 2.6%, 1.76 (1.34–2.32) for men, 4.9% vs. 2.0%, 2.06 (1.56–2.71) for women. No significant difference was found for depressive symptoms: 21.6% vs. 22.9% in men, 30.0% vs. 28.5% in women. Working cancer survivors felt happiness more frequently than cancer-free survivors in men (77.3% vs. 71.7%, 1.21 (1.01–1.45)) but not in women (76.1% vs. 74.9%). Conclusions Working cancer survivors had worse SRHS and more restricted physical functional capacity than cancer-free workers. In men, working cancer survivors felt happiness more frequently than cancer-free workers. Implications for Cancer Survivors Continuous support to improve cancer survivors’ SRHS and physical functional capacity would be necessary even while they are working.

Background Despite the hypoglycemic and antioxidant effects of manganese, only one recent Chinese study has investigated the association between dietary manganese intake and type 2 diabetes. Methods We recruited 19,862 Japanese men and women in the Japan Collaborative Cohort Study. The participants completed a food frequency questionnaire at the baseline survey (1988 = 1990) and a diabetes history at both baseline and 5-year surveys. We calculated the odds ratios (95 % CIs) of the 5-year cumulative incidence of self-reported physician-diagnosed type 2 diabetes according to quartiles of dietary manganese intake. Results Within the 5-year period, we confirmed 530 new cases of type 2 diabetes (263 in men and 267 in women) with a 5-year cumulative incidence of 2.7 % (3.6 % in men and 2.1 % in women). Higher manganese intake was inversely associated with the women’s but not the men’s cumulative risk of type 2 diabetes over the 5-year period. In a full model adjusted for the participants’ characteristics, diabetes risk factors and a wide range of dietary variables, the multivariable odds ratios (95 %CIs) of type 2 diabetes across the increasing quartiles of manganese intake (Q1 to Q4) were 1.00, 0.97 (0.65, 1.43), 1.04 (0.67, 1.61) and 1.10 (0.64, 1.92), p-trend = 0.66 among men and 1.00, 0.74 (0.51, 1.06), 0.62 (0.41, 0.94) and 0.53 (0.31, 0.88), p-trend = 0.01 among women. The association was observed mainly for those with low iron intake in women, particularly premenopausal women. Conclusion Strong inverse associations between dietary manganese intake and risk of type 2 diabetes were observed in women but not men.

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.

Seaweeds contain minerals, vitamins, soluble dietary fibers, and flavonoids, which are regarded as preventive agents against lifestyle-related diseases. Seaweeds are consumed commonly in East Asian countries including Japan. Thus, intake of seaweeds might contribute to Japanese longevity via prevention of lifestyle-related diseases. Recently, two large Japanese cohort studies have reported the association of seaweed intake with reduced risk of cardiovascular diseases. On the other hand, seaweeds also contain iodine and heavy metals such as arsenic species, which are considered to have adverse effects on health. We here reviewed studies of the association between seaweed intake and mortality from or incidence of cancer and cardiovascular diseases, and their risk factors such as blood pressure or serum lipids. We also summarized the adverse effects of iodine and arsenic species in seaweeds. Although seaweeds have not been widely consumed in Western countries, dietary diversification and an increased proportion of immigrants from East Asia may increase seaweed consumption in those countries. Further epidemiological studies including observational and interventional studies are necessary to clarify the effects of seaweeds on disease and health.

Background Few studies examining the impact for women of employment status on health have considered domestic duties and responsibilities as well as household socioeconomic conditions. Moreover, to our knowledge, no studies have explored the influence of work-family conflict on the association between employment status and health. This research aimed to investigate the cross-sectional associations between employment status (regular employee, non-regular employee, or self-employed) with self-rated health among Japanese middle-aged working women. Methods Self-report data were obtained from 21,450 working women aged 40-59 years enrolled in the Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT Study) in 2011-2016. Multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for poor self-rated health ('poor' or 'not very good') by employment status. Sub-group analyses by household income and marital status, as well as mediation analysis for work-family conflict, were also conducted. Results Adjusted ORs for the poor self-rated health of non-regular employees and self-employed workers were 0.90 (95% CI, 0.83-0.98) and 0.84 (95% CI, 0.75-0.94), respectively, compared with regular employees. The identified association of non-regular employment was explained by work-family conflict. Subgroup analysis indicated no statistically significant modifying effects by household income and marital status. Conclusion Among middle-aged working Japanese women, employment status was associated with self-rated health; non-regular employees and self-employed workers were less likely to report poor self-rated health, compared with regular employees. Lowered OR of poor self-rated health among non-regular employees may be explained by their reduced work-family conflict.

The association of fermented soy products, separately from total soy products, with cardiovascular disease (CVD) and total cancer has not been reported. We examined this association in a population-based prospective cohort study in Japan. We studied 79,648 participants (42,788 women; 36,860 men) aged 45–74 years without a history of cancer, myocardial infarction, or stroke. Participants completed a food frequency questionnaire (1995–1998) and were followed to 2009–2012. Cox proportional hazards regression analysis was used to calculate the hazard ratios (HR) and 95% confidence intervals (CI) of incidence of CVD and total cancer according to quartiles of total soy products, nonfermented soy products, fermented soy products, miso soup, natto, total isoflavones from soy products, isoflavones from nonfermented soy products, and isoflavones from fermented soy products. In women, we observed a significant inverse association between fermented soy product intake and the risk of CVD (multivariate HR in the highest compared with the lowest quartile of fermented soy product intake: 0.80; 95% CI: 0.68, 0.95; P for trend = 0.010), and also found significant inverse associations for natto and isoflavones among fermented soy products. In site-specific analysis, we observed a similar, significant inverse association between fermented soy product intake and the risk of stroke in women. We found no significant association between any soy product and risk of CVD in men or total cancer in both sexes. Intake of fermented soy products such as natto was inversely associated with the risk of CVD in women.

Objective The burden of death from pneumonia is expected to increase with the aging of the population, as has been observed in Japan. Depressive tendency, a common psychosocial sign, may be a risk factor for pneumonia due to its possible association with some immune dysfunction. This study aimed to clarify the association between depressive tendency and the risk of death from pneumonia. Methods A population-based cohort that consisted of 75,174 Japanese men and women was followed for a median of 19.1 years. Four psychological and behavioral symptoms (depressive symptoms) were used to evaluate depressive tendency. Results A total of 1,329 deaths from pneumonia were observed. Depressive symptoms were positively and dose-dependently associated with the risk of death from pneumonia (p

Although the association between fruit consumption and CHD risk has been well studied, few studies have focused on flavonoid-rich fruits (FRF), in particular strawberries and grapes. We aimed to verify the association of total and specific FRF consumption with risk of CHD by a large prospective cohort study. A total of 87 177 men and women aged 44–75 years who were free of CVD and cancer at study baseline were eligible for the present analysis. FRF consumption was assessed using a FFQ. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) of CHD in relation to FRF consumption with adjustment for potential risk factors and confounders. During a mean follow-up of 13·2 years, we identified 1156 incident CHD cases. After full adjustment for covariates including demographics, lifestyles and dietary factors, the HR were 0·93 (95 % CI 0·77, 1·11), 0·91 (95 % CI 0·75, 1·11), 0·84 (95 % CI 0·67, 1·04) and 0·78 (95 % CI 0·62, 0·99) for the second, third, fourth and fifth quintiles compared with the lowest quintile of FRF consumption. Regarding specific fruits, we observed a significant inverse association for citrus fruit consumption and a borderline inverse association for strawberry consumption, while no association was observed for apple/pear or grape consumption. Although the associations appeared to be stronger in women, they were not significantly modified by sex. Higher consumption of FRF, in particular, citrus fruits, may be associated with a lower risk of developing CHD.

Aim A positive association between non-high-density lipoprotein cholesterol (non-HDL-C) and coronary heart disease (CHD) has been established; however, associations between non-HDL-C and stroke subtypes have not been determined. Methods We conducted a prospective study of 30,554 individuals aged 40-69 yrs with no history of cardiovascular disease (CVD) in Japan. Sex-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for the incidence of stroke subtypes and CHD were estimated according to quintiles of non-HDL-C, using Cox proportional hazard models adjusted for other established risk factors. Results We identified 1,705 stroke and 296 CHD events over a median 15 yrs of follow-up. The fractional polynomials analysis revealed a U-shaped association between non-HDL-C and stroke risk in men. When analyzed for stroke subtypes, the data revealed an inverse relationship between non-HDL-C and intracerebral hemorrhage (ICH), primarily with lobar ICH, and a positive association between non-HDL-C and large-artery occlusive infarction in men [adjusted HR 0.55 (95% CI, 0.35-0.87) and 2.05 (95% CI, 1.07-3.93) for the highest and lowest quintile of non-HDL-C, respectively]. The lowest risk of ICH in women was observed in the fourth quintile, and the lowest risk of embolic infarction was observed in the third quintile. In contrast, non-HDL-C was positively associated with CHD in both sexes. Conclusions In Japanese men, lower non-HDL-C levels were associated with a decreased risk of large-artery occlusive infarction and an increased risk of ICH, particularly lobar ICH.

Although a meta-analysis previously suggested a positive relationship between diabetes and intraocular pressure (IOP), the interrelationships among diabetes, IOP, and other ocular biometric parameters remain unclear. The present study investigated the relationships of diabetes, haemoglobin A1c (HbA1c), and serum glucose with IOP and ocular hypertension (IOP > 21 mmHg) in non-glaucomatous Japanese adults living in Chikusei City. Diabetes was defined as a self-reported history of diabetes, the use of antidiabetic medication, or HbA1c levels ≥6.5%. Among 6,786 enrolled participants aged 40 years and above, 734 were classified as diabetic (10.8%). After adjusting for several confounders, the IOP values were significantly higher in participants with diabetes than in those without diabetes (14.4 ± 0.1 vs. 13.9 ± 0.1 mmHg, P

Background. Recently, chronic hepatitis E has been reported in solid organ transplant (SOT) recipients in European countries. Previously, we clarified the prevalence of hepatitis E virus (HEV) infection in Japanese liver transplant recipients and identified 2 chronic hepatitis E patients infected by blood transfusion. However, the rate of HEV infection in recipients of SOTs other than liver in Japan remains unclear, so we conducted a nationwide survey to clarify the prevalence of chronic HEV infection in Japanese heart and kidney transplant recipients. Methods. A total of 99 heart and 2526 kidney transplant recipients in 17 hospitals in Japan were examined for the presence of the IgG class of anti-HEV antibodies as well as for serum HEV RNA. Results. The prevalence of anti-HEV IgG among heart and kidney transplant recipients was 7.07% (7/99) and 4.08% (103/2526), respectively. One heart transplant patient (1.01%) and 11 kidney transplant patients (0.44%) were found to be positive for HEV RNA. The HEV isolates from all viremic patients were typed as genotype 3. Four patients developed chronic hepatitis E after transplantation. Three patients were treated with ribavirin; their liver enzymes normalized, and HEV RNA became negative immediately. Sustained virologic response was achieved in all cases. Conclusions. This is the first nationwide survey of HEV infection in Japanese heart and kidney transplant recipients. The prevalence of anti-HEV IgG and HEV RNA in heart and kidney transplant recipients in Japan was lower than that in European countries. Of note, 42% of viremic transplant patients developed chronic hepatitis.

Background Few studies have investigated the effects of Okinawan vegetable consumption on the risk of incident stroke and coronary heart disease. This study aimed to examine associations of vegetable, fruit, and Okinawan vegetable consumption with risk of incident stroke and coronary heart disease in the Japanese population of Okinawa. Methods The study design was a prospective cohort study. During 1995-1998, a validated food frequency questionnaire was administered in two study areas to 16,498 participants aged 45-74 years. In 217,467 person-years of follow-up until the end of 2012, a total of 839 stroke cases and 197 coronary heart disease cases were identified. Results No statistically significant association between total Okinawan vegetable consumption and risk of stroke and coronary heart disease was obtained: the multivariable adjusted hazard ratios for the highest versus lowest tertile of consumption were 1.09 (95% confidence interval, 0.93-1.29; P for trend = 0.289) in model 2. Total vegetable and fruit and specific Okinawan vegetable consumption were also not statistically significantly associated with risk of cardiovascular outcomes. Conclusions This study demonstrated that consumption of total vegetable and fruit, total Okinawan vegetables, and specific Okinawan vegetables in Japanese residents of Okinawa was not associated with risk of incident stroke and coronary heart disease.

Purpose This population-based, cross-sectional study was performed to assess the influence of life-style modalities, including physical activity, sedentary behaviors, and visual display terminal (VDT) use, on the prevalence of dry eye disease (DED). Methods The study included a total of 102,582 participants aged 40–74 years, from the Japan Public Health Center-based Prospective Study for the Next Generation, a large nationwide prospective ongoing Japanese cohort study. Logistic regression analyses were used to investigate the relationship of total and leisure-time physical activity, duration of sedentary behaviors, and VDT use (hours/day) with DED. Results Among 47,346 men and 55,236 women, 25,234 (8315 males and 16,919 females) cases of DED were documented. Total physical activity was significantly related to decreased DED in both sexes; for the highest vs. lowest total physical activity quartiles, the multivariable-adjusted odds ratios (ORs) for DED were 0.90 (95% confidence interval [CI], 0.84–0.97; Ptrend Conclusions Physical inactivity, prolonged sedentary behaviors, and use of VDT were related to increased susceptibility to DED among middle-aged to older Japanese adults.

The association of chocolate consumption with risk of gestational diabetes has not been examined. We aimed to investigate the prospective association between chocolate consumption and risk of gestational diabetes in a large birth cohort in Japan. A total of 97 454 pregnant women with a median gestational age of 12 weeks were recruited from January 2011 to March 2014. Data on demographic information, disease history, socio-economic status, lifestyle and dietary habits were obtained at the study enrolment. Dietary intake during the past 12 months before study enrolment was assessed through a semi-quantitative FFQ. The logistic regression was used to obtain the OR of gestational diabetes in relation to chocolate consumption. Among 84 948 women eligible for the analysis, 1904 cases of gestational diabetes (2·2 %) were identified during the period of pregnancy. After controlling for potential confounding factors including age, smoking status, drinking status, education level, occupation, pre-pregnant BMI, depression, previous history of macrosomia babies, parity, physical activity and dietary factors, women in the highest quartile of chocolate consumption, compared with those in the lowest quartile, had a significantly lower risk of developing gestational diabetes (OR 0·78, 95 % CI 0·67, 0·90; P for trend = 0·002). Stratified analyses suggested that the association was not significantly modified by pre-pregnancy BMI, age, parity, smoking status or drinking status. The present prospective cohort study provided evidence that chocolate consumption was associated with a significant lower risk of gestational diabetes in Japanese women.

Background The minerals, vitamins, soluble dietary fibers, and flavonoids of seaweed are protective for preventing cardiovascular diseases. However, the association between seaweed intake and risk of cardiovascular disease has not been established. Objectives We examined the dietary intake of seaweed and its impact upon stroke and ischemic heart disease risk among a Japanese study population. Methods We surveyed 40,707 men and 45,406 women from 2 large cohorts (age range: 40-69 y). Seaweed intake was determined by FFQ at baseline (1990-1994). Incidences of stroke and ischemic heart disease were ascertained until the end of 2009 (Cohort I) or 2012 (Cohort II). Sex-specific cardiovascular disease HRs (95% CIs) were estimated using Cox proportional hazard models after stratification by area and adjustment for cardiovascular disease risk and dietary factors. Results During 1,493,232 person-years of follow-up, 4777 strokes (2863 ischemic stroke, 1361 intraparenchymal hemorrhages, and 531 subarachnoid hemorrhages) and 1204 ischemic heart disease cases were identified. Among men, significant multivariable HRs (95% CIs) for almost daily consumption compared with almost no consumption of seaweed were seen in ischemic heart disease [0.76 (0.58, 0.99); P-trend = 0.04] and total cardiovascular diseases [0.88 (0.78, 1.00); P-trend = 0.08]. Among women, such inverse associations were 0.56 (0.36, 0.85; P-trend = 0.006) for ischemic heart disease and 0.89 (0.76, 1.05; P-trend = 0.10) for total cardiovascular diseases. No significant associations were observed between seaweed intake and risk of total stroke or stroke types among either men or women. Conclusions Seaweed intake was inversely associated with risk of ischemic heart disease.

The prospective association between secondhand smoke (SHS) and the risk of incident cardiovascular disease (CVD) remains unclear. This study was the first to examine the association between SHS and risks of ischemic heart disease (IHD), stroke, and total CVD in a large cohort in Asia. The study followed 24,232 never-smoking women aged 40-59 from around Japan (Akita, Iwate, Nagano, Niigata, Ibaraki, Kochi, Nagasaki, and Okinawa prefectures). Their husbands were classified into never, former, and current smokers. After adjustment for age, body mass index, alcohol consumption, histories of hypertension and diabetes mellitus, medication use for hyperlipidemia, menopausal status, and public health center areas, the hazard ratios (HRs) of CVD according to husbands' smoking status were estimated by Cox proportional hazards models. During the 440,360 person-years follow-up, 846 women had total CVDs (103 IHDs, 744 strokes). The proportional hazard assumption was not assured during the total follow-up from 1990 to 2012, but so was then the follow-up ofand ≥ 10 person-years were examined separately. The multivariable HRs (95% confidence intervals) associated with husbands' current versus non-current smoking was 2.02 (1.19-3.45) for IHD, 1.18 (0.98-1.42) for stroke, and 1.25 (1.05-1.49) for total CVD in the follow-up of ≥10 person-years. The SHS from husbands may raise the risk of IHD among middle-aged never-smoking women.

Circadian misalignments have been linked to adverse cardiometabolic outcomes. However, the association between irregular daily routine and the risk of cardiovascular disease (CVD) remains unknown. We examined this association in a prospective study in Japan. The study included 78,115 Japanese participants aged 45-74 years. The self-reported daily routine was evaluated using the question, 'Is your daily routine or activity schedule regular?' The response (yes/no) was obtained as a binary variable. Cox proportional hazard regression analysis was used to estimate the hazard ratios and 95% confidence intervals for the association between an irregular daily routine and CVD incidence risk. Among the participants, 23.7% reported an irregular daily routine. During the mean follow-up period of 13.3 years, we observed 4641 CVD events. An irregular daily routine was significantly associated with increased risks of CVD and total stroke in women, but not in men. This positive association between an irregular daily routine and the risk of CVD was weak in the high vegetable and fruit consuming population. An irregular daily routine is positively associated with the risk of incident CVD, especially in women. These associations may be weak in populations that consume a diet rich in vegetables and fruits.

We evaluated the association between total soy, soy product (natto, miso and tofu) and isoflavone intake and incident disabling dementia in a Japanese population.We conducted a population-based prospective study in 18,991 men and 22,456 women. Intake of soy products and isoflavone was calculated using a validated food frequency questionnaire when participants were 45-74 years old (1995 and 1998). Incident disabling dementia was defined by the daily living disability status related to dementia in the long-term care insurance program of Japan from 2006 to 2016. Multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) of disabling dementia were calculated by quintiles of total soy, individual soy product and isoflavone intake, using Cox proportional hazard regression models.Total soy product intake was not associated with disabling dementia risk in both men and women. By individual soy products, natto intake was marginally inversely associated with disabling dementia in women (trend P = 0.050). When we stratified by age, this inverse association was clearer in women aged under 60 years (multivariate HR for the highest versus lowest quintile was 0.78, 95% CI 0.59-1.04, trend P = 0.020 for those aged under 60 years and 0.90, 95% CI 0.77-1.05, trend P = 0.23 for those aged 60 years and older, respectively). Any soy product or isoflavone intake was not associated with disabling dementia risk in men.Although total soy product intake was not associated with disabling dementia risk, natto intake may contribute to reducing the risk of disabling dementia in women, especially in those aged under 60 years.

Background Regularly updated data on stroke and its pathological types, including data on their incidence, prevalence, mortality, disability, risk factors, and epidemiological trends, are important for evidence-based stroke care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) aims to provide a standardised and comprehensive measurement of these metrics at global, regional, and national levels. Methods We applied GBD 2019 analytical tools to calculate stroke incidence, prevalence, mortality, disability-adjusted life-years (DALYs), and the population attributable fraction (PAF) of DALYs (with corresponding 95% uncertainty intervals [UIs]) associated with 19 risk factors, for 204 countries and territories from 1990 to 2019. These estimates were provided for ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and all strokes combined, and stratified by sex, age group, and World Bank country income level. Findings In 2019, there were 12·2 million (95% UI 11·0–13·6) incident cases of stroke, 101 million (93·2–111) prevalent cases of stroke, 143 million (133–153) DALYs due to stroke, and 6·55 million (6·00–7·02) deaths from stroke. Globally, stroke remained the second-leading cause of death (11·6% [10·8–12·2] of total deaths) and the third-leading cause of death and disability combined (5·7% [5·1–6·2] of total DALYs) in 2019. From 1990 to 2019, the absolute number of incident strokes increased by 70·0% (67·0–73·0), prevalent strokes increased by 85·0% (83·0–88·0), deaths from stroke increased by 43·0% (31·0–55·0), and DALYs due to stroke increased by 32·0% (22·0–42·0). During the same period, age-standardised rates of stroke incidence decreased by 17·0% (15·0–18·0), mortality decreased by 36·0% (31·0–42·0), prevalence decreased by 6·0% (5·0–7·0), and DALYs decreased by 36·0% (31·0–42·0). However, among people younger than 70 years, prevalence rates increased by 22·0% (21·0–24·0) and incidence rates increased by 15·0% (12·0–18·0). In 2019, the age-standardised stroke-related mortality rate was 3·6 (3·5–3·8) times higher in the World Bank low-income group than in the World Bank high-income group, and the age-standardised stroke-related DALY rate was 3·7 (3·5–3·9) times higher in the low-income group than the high-income group. Ischaemic stroke constituted 62·4% of all incident strokes in 2019 (7·63 million [6·57–8·96]), while intracerebral haemorrhage constituted 27·9% (3·41 million [2·97–3·91]) and subarachnoid haemorrhage constituted 9·7% (1·18 million [1·01–1·39]). In 2019, the five leading risk factors for stroke were high systolic blood pressure (contributing to 79·6 million [67·7–90·8] DALYs or 55·5% [48·2–62·0] of total stroke DALYs), high body-mass index (34·9 million [22·3–48·6] DALYs or 24·3% [15·7–33·2]), high fasting plasma glucose (28·9 million [19·8–41·5] DALYs or 20·2% [13·8–29·1]), ambient particulate matter pollution (28·7 million [23·4–33·4] DALYs or 20·1% [16·6–23·0]), and smoking (25·3 million [22·6–28·2] DALYs or 17·6% [16·4–19·0]). Interpretation The annual number of strokes and deaths due to stroke increased substantially from 1990 to 2019, despite substantial reductions in age-standardised rates, particularly among people older than 70 years. The highest age-standardised stroke-related mortality and DALY rates were in the World Bank low-income group. The fastest-growing risk factor for stroke between 1990 and 2019 was high body-mass index. Without urgent implementation of effective primary prevention strategies, the stroke burden will probably continue to grow across the world, particularly in low-income countries. Funding Bill & Melinda Gates Foundation.

Several studies have shown that smoking is a significant risk factor for pneumonia, but it is uncertain to what extent smoking cessation reduces the risk. This study aimed to investigate whether and to what extent smoking cessation is associated with reduced risk of mortality from pneumonia in a Japanese, prospective, community-based cohort. We examined 94,972 individuals (mean age, 57 years; women, 57%) who provided valid responses to a lifestyle questionnaire including questions about smoking. We used years of smoking cessation at baseline to divide former smokers into 5 groups: 0-1 year, 2-4 years, 5-9 years, 10-14 years, and 15 years or more. The endpoint was the underlying cause of death from pneumonia. During the median 19-year follow-up of 94,972 study participants, 1806 died from pneumonia. Multivariable hazard ratios (95% confidence intervals) compared with the current smokers were 1.02 (0.72-1.45) for 0-1 year of smoking cessation at baseline, 0.92 (0.70-1.22) for 2-4 years, 0.95 (0.74-1.21) for 5-9 years, 0.71 (0.53-0.96) for 10-14 years, 0.63 (0.48-0.83) for 15 years or more, and 0.50 (0.36-0.70) for never-smokers. Although smoking increases the risk of pneumonia mortality, the present study showed that the risk of pneumonia mortality decreased with years of smoking cessation, eventually improving to levels similar to those of non-smokers for 10 years or more. Continued smoking cessation may be effective in preventing pneumonia deaths.

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.

Atherosclerosis has been considered as the main cause of morbidity, mortality, and disability worldwide. The first screening for antigen markers was conducted using the serological identification of antigens by recombinant cDNA expression cloning, which has identified adaptor-related protein complex 3 subunit delta 1 (AP3D1) as an antigen recognized by serum IgG antibodies of patients with atherosclerosis. Serum antibody levels were examined using the amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) using a recombinant protein as an antigen. It was determined that the serum antibody levels against AP3D1 were higher in patients with acute ischemic stroke, transient ischemic attack , diabetes mellitus (DM), cardiovascular disease , chronic kidney disease (CKD), esophageal squamous cell carcinoma (ESCC), and colorectal carcinoma than those in the healthy donors. The area under the curve values of DM, nephrosclerosis type of CKD, and ESCC calculated using receiver operating characteristic curve analysis were higher than that of other diseases. Correlation analysis showed that the anti-AP3D1 antibody levels were highly associated with maximum intima-media thickness, which indicates that this marker reflected the development of atherosclerosis. The results of the Japan Public Health Center-based Prospective Study indicated that this antibody marker is deemed useful as risk factors for AIS.

Background: Given the projected trends in population ageing and population growth, the number of people with dementia is expected to increase. In addition, strong evidence has emerged supporting the importance of potentially modifiable risk factors for dementia. Characterising the distribution and magnitude of anticipated growth is crucial for public health planning and resource prioritisation. This study aimed to improve on previous forecasts of dementia prevalence by producing country-level estimates and incorporating information on selected risk factors. Methods: We forecasted the prevalence of dementia attributable to the three dementia risk factors included in the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 (high body-mass index, high fasting plasma glucose, and smoking) from 2019 to 2050, using relative risks and forecasted risk factor prevalence to predict GBD risk-attributable prevalence in 2050 globally and by world region and country. Using linear regression models with education included as an additional predictor, we then forecasted the prevalence of dementia not attributable to GBD risks. To assess the relative contribution of future trends in GBD risk factors, education, population growth, and population ageing, we did a decomposition analysis. Findings: We estimated that the number of people with dementia would increase from 57·4 (95% uncertainty interval 50·4-65·1) million cases globally in 2019 to 152·8 (130·8-175·9) million cases in 2050. Despite large increases in the projected number of people living with dementia, age-standardised both-sex prevalence remained stable between 2019 and 2050 (global percentage change of 0·1% [-7·5 to 10·8]). We estimated that there were more women with dementia than men with dementia globally in 2019 (female-to-male ratio of 1·69 [1·64-1·73]), and we expect this pattern to continue to 2050 (female-to-male ratio of 1·67 [1·52-1·85]). There was geographical heterogeneity in the projected increases across countries and regions, with the smallest percentage changes in the number of projected dementia cases in high-income Asia Pacific (53% [41-67]) and western Europe (74% [58-90]), and the largest in north Africa and the Middle East (367% [329-403]) and eastern sub-Saharan Africa (357% [323-395]). Projected increases in cases could largely be attributed to population growth and population ageing, although their relative importance varied by world region, with population growth contributing most to the increases in sub-Saharan Africa and population ageing contributing most to the increases in east Asia. Interpretation: Growth in the number of individuals living with dementia underscores the need for public health planning efforts and policy to address the needs of this group. Country-level estimates can be used to inform national planning efforts and decisions. Multifaceted approaches, including scaling up interventions to address modifiable risk factors and investing in research on biological mechanisms, will be key in addressing the expected increases in the number of individuals affected by dementia. F Carvalho and E F Fernandes acknowledge support from the University of Porto (UID/MULTI/04378/2019 and UID/QUI/50006/2019 with funding from FCT/MCTES through national funds). L F S Castro-de-Araujo acknowledges support from the Medical Research Council (London; grant number MC_PC_MR/T03355X/1). V M Costa acknowledges her grant (SFRH/BHD/110001/2015), received by Portuguese national funds through Fundação para a Ciência e Tecnologia (FCT), IP, under the Norma Transitória (DL57/2016/CP1334/CT0006). A Douiri acknowledges support from the NIHR Applied Research Collaboration (ARC) South London at King’s College Hospital NHS Foundation Trust and the Royal College of Physicians, as well as the support from the NIHR Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. N Ghith acknowledges her salary as a postdoc is covered by a grant to her research group provided by Novo Nordisk Foundation. V K Gupta and V B Gupta acknowledge funding support from National Health and Medical Research Council (NHMRC), Australia. S Haque acknowledges support from Jazan University, Saudi Arabia, for providing access to the Saudi Digital Library for this study. C Herteliu is partially supported by a grant of the Romanian National Authority for Scientific Research and Innovation (CNDS-UEFISCDI, project number PN-III-P4-ID-PCCF-2016-0084). Y J Kim was supported by the Research Management Centre, Xiamen University, Malaysia (No. XMUMRF/2020-C6/ITCM/0004). M Kivimäki was supported by the MRC (S011676) and the Wellcome Trust (221854/Z/20/Z). M Kumar acknowledges support from Fogarty International Center (K43 TW010716-04). S Lorkowski acknowledges institutional support from the Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig (Germany; German Federal Ministry of Education and Research, grant agreement number 01EA1808A). S Mondello was supported by the Italian Ministry of Health (GR-2013-02354960). A Raggi acknowledges support from a grant from the Italian Ministry of Health (Ricerca Corrente, Fondazione Istituto Neurologico C. Besta, Linea – Outcome Research: dagli Indicatori alle Raccomandazioni Cliniche). D A S Silva acknowledges support from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brasil (CAPES; Finance Code 001 / CAPES-PRINT). J P Silva acknowledges support from the Applied Molecular Biosciences Unit (UCIBIO; grant number UIDB/04378/2020), supported through Portuguese national funds via FCT/MCTES. Sí