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Previous evidence suggests the association of lower educational attainment and depressive symptoms with tooth loss. The hypothesis of this study was that these factors may exacerbate the effect on tooth loss beyond the sum of their individual effects. We aimed to clarify the independent and interactive effects of educational attainment and depressive symptoms on the number of missing teeth among community residents. Cross-sectional data of 9,647 individuals were collected from the general Japanese population. Dental examination was conducted by dentists. Educational attainment was categorized into 3 levels based on the number of educational years: ≤9, >9 to ≤12, and >12 y. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess depressive symptoms; a total score of ≥16 and/or the use of medications for depression indicate the presence of depressive symptoms. In the multivariate analysis with adjustment for conventional risk factors, educational attainment was identified as a determinant of the number of missing teeth (>9 to ≤12 y of education: coefficient = 0.199, 95% confidence interval [CI], 0.135 to 0.263, P < 0.001; ≤9 y of education: coefficient = 0.318, 95% CI, 0.231 to 0.405, P < 0.001: reference, >12 y of education). An analysis that included interaction terms revealed that the relationship between "≤9 y of education" and the number of missing teeth differed depending on the depressive symptoms, indicating a positive interactive association (coefficient for interaction = 0.198; 95% CI, 0.033 to 0.364, P for interaction = 0.019: reference, >12 y of education). Our study suggests the presence of a significant association between educational attainment and tooth loss, as well as a partial interactive association between "≤9 y of education" and "depressive symptoms" in the general Japanese population. [ABSTRACT FROM AUTHOR]

Background: Diaphragm thickness is a potential marker of sarcopenia in addition to muscle mass and strength at extremities. We aimed to clarify the descriptive epidemiology and prognostic significance of diaphragm thickness in the general population., Methods: The study participants were 3324 community residents (mean age: 61.4 ± 12.8 years) who participated in a longitudinal cohort study. Clinical parameters were obtained during the follow-up survey of the study population. Diaphragm thickness was measured from B-mode ultrasound images obtained in a supine position. Clinical and physical factors independently associated with diaphragm thickness were assessed by a linear regression model and a causal mediation analysis. All-cause mortality was determined by reviewing residential registry records. Prognostic significance of diaphragm thickness for all-cause mortality was examined using a Cox proportional hazard model analysis., Results: Diaphragm thickness was greater in men than women (end-expiration, β = 0.161, p < 0.001; end-inspiration, β = 0.156, p < 0.001) and associated with waist circumference (end-expiration, β = 0.259, p < 0.001; end-inspiration, β = 0.128, p < 0.001). Handgrip strength, smoking habit, insulin resistance and exercise habit were not associated with diaphragm thickness. Skeletal muscle mass index showed apparent association with diaphragm thickness, though this association was not observed after adjusting for waist circumference. Over a mean follow-up of 1686 days (15 358 person-years), there were 56 cases of all-cause mortality. Weak handgrip strength (hazard ratio = 0.95, p = 0.044) and low forced vital capacity (hazard ratio = 0.57, p = 0.045) were associated with all-cause mortality, though none of the diaphragm thickness parameters showed a significant association (thickness at end-expiration, p = 0.722; thickness at end-inspiration, p = 0.277; thickening fraction, p = 0.219)., Conclusions: Waist circumference but not parameters of sarcopenia was independently associated with diaphragm thickness. Diaphragm thickness was not associated with all-cause mortality. Diaphragm thickness may not be a marker of systemic sarcopenia., (© 2025 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Backgrounds: Locomotive syndrome is a condition in which a person is at risk of requiring nursing care due to musculoskeletal disorders. The 25-question Geriatric Locomotive Function Scale (GLFS-25) was developed to determine the severity of locomotive syndrome. In this study, we aimed to determine the prognostic significance of the GLFS-25 for all-cause mortality., Methods: The study participants consisted of 3,447 community residents aged ≥65 years. All-cause mortality was determined using residential registry records. Skeletal muscle mass assessed via bioimpedance methods was considered in the analysis as a confounding factor., Results: During a mean follow-up period of 3,236 days (30,566 person-years), 288 cases of all-cause mortality occurred. When participants were categorized by the GLFS-25 score [grade 1: <7 points (n = 1,948); grade 2: ≥7 to <16 points (n = 894); grade 3: ≥16 points (n = 605)], their survival probability decreased linearly with increasing grade (log-rank test P = 0.014). In a Cox proportional hazards model adjusted for confounding factors, including low skeletal muscle mass, GLFS-25 grade 3 was identified as an independent risk factor for all-cause mortality (hazard ratio: 1.60; P = 0.007) in the subpopulation aged ≥70 years but not in the overall population (P = 0.062). The hazard ratio for all-cause mortality with GLFS-25 grade 3 and low skeletal muscle mass combined was 2.66 (P < 0.001)., Conclusion: The GLFS-25 is independently associated with all-cause mortality in older adults. Using this questionnaire to assess locomotive syndrome could be useful for identifying individuals at risk., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Nocturnal urination frequency is associated with sleep blood pressure (BP). However, it was uncertain to what extent the sleep BP increases within individuals with each increase in the number of nocturnal urination. We calculated intraindividual differences in sleep BP between nights with different urination frequencies to clarify their relationship. We enrolled 2418 community residents (mean age, 61.1 years). Participants wore a cuff on the upper arm when sleeping that automatically measured BP at fixed times during a 1-week period. The frequency of nocturnal urination was recorded in a sleep diary by the study participants. Sleep systolic BP increased with increased nocturnal urination frequency (0 time vs. 1 time, Δ2.1 mmHg, P < 0.001; 1 time vs. 2 times, Δ1.8 mmHg, P < 0.001; 2 times vs. ≥3 times, Δ1.4 mmHg, P = 0.012), and a similar association was observed for sleep diastolic BP. These associations were independent of age, the use of antihypertensive drugs reduced renal function, and the presence of sleep-disordered breathing. Sleep BP in participants who experienced nocturnal urination 0, 1, and 2 times during the 1-week measurement period showed a linear increase with the frequency of urination (0 time vs. 2 times: systolic BP, Δ4.7 mmHg; diastolic BP, Δ3.1 mmHg; P < 0.001). There was an intraindividual correlation between nocturnal urination frequency and sleep BP. These correlations were independent of baseline BP and participants' clinical backgrounds. Nocturnal urination frequency may be an indicator of individuals who require detailed ambulatory BP measurement., Competing Interests: Compliance with ethical standards. Conflict of interest: The Department of Respiratory Care and Sleep Control Medicine at Kyoto University is funded by endowments from Philips Respironics, Fukuda Denshi, Fukuda Lifetec-Keiji, and ResMed to Kyoto University. The Department of Sleep Medicine and Respiratory Care, Division of Sleep Medicine, Nihon University of Medicine is funded by endowments from Philips Respironics, Fukuda Denshi, Fukuda Lifetec-Tokyo, and ResMed to Nihon University., (© 2025. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Background: Although sex differences in the prevalence of sleep disordered breathing (SDB) is recognized, whether a sex difference exists among obese individuals with SDB with or without comorbidities has not been well investigated. This study aimed to explore the relationships of sex differences among SDB, obesity, and metabolic comorbidities., Methods: This study evaluated 7713 community participants with nocturnal oximetry ≥2 nights. SDB was assessed by the 3% oxygen desaturation index corrected for sleep duration obtained by wrist actigraphy (Acti-ODI3%), and moderate-to-severe SDB was defined as Acti-ODI3% levels ≥15/h. Obesity was defined as body mass index ≥25 kg/m 2 ., Results: The prevalence of moderate-to-severe SDB was 21.6%/0% among those with obesity/without obesity in women under 40 years old. The adjusted odds ratios for moderate-to-severe SDB in those with both diabetes/metabolic syndrome and obesity compared to others were 86.4 (95%CI 24.2-308.8)/40.4 (95%CI 15.0-108.8) in pre-menopausal women. The association among SDB, obesity, and metabolic comorbidities showed significant interactions between pre-menopausal women and men or post-menopausal women., Conclusions: Sex differences exist among the prevalence of SDB and the relationships among SDB, obesity, and metabolic comorbidities. Especially, pre-menopausal women are more vulnerable to the consequences of obesity. SDB prevalence may be impacted by the coexistence of obesity and diabetes or metabolic syndrome in pre-menopausal women., Competing Interests: Conflicts of interest Takeshi Matsumoto, Takuma Minami, Osamu Kanai, Kiminobu Tanizawa, Tomoko Wakamura, Naoko Komenami, Kazuya Setoh, Takahisa Kawaguchi, Satoshi Morita, Yoshimitsu Takahashi, and Toyohiro Hirai have nothing to disclosure. Hironobu Sunadome and Naomi Takahashi reports grants from Philips Japan, grants from ResMed, grants from Fukuda Denshi, grants from Fukuda Lifetec Keiji, outside the submitted work. Kimihiko Murase reports grants from Philips Japan, grants from Teijin Pharma, grants from Fukuda Denshi, grants from Fukuda Lifetec Keiji, outside the submitted work. Yasuharu Tabara reports grants from the Ministry of Education, Culture, Sports, Science & Technology in Japan, grants from Japan Science and Technology Agency, grants from Mitsubishi Foundation, grants from Daiwa Securities Health Foundation, and grants from Sumitomo Foundation, outside the submitted work. Satoshi Hamada reports grants from Teijin Pharma, outside the submitted work. Takeo Nakayama reports grants from Special Health Check-up Research Group from the Ministry of Health, Labor and Welfare of Japan, personal fees from Pfizer Japan Inc., personal fees from MSD K.K., personal fees from Ohtsuka Pharmaceutical co., personal fees from Dainippon Sumitomo Pharmaceutical co., personal fees from Ono Pharmaceutical co., personal fees from Chugai Pharmaceutical co., personal fees from Dentsu co., personal fees from Takeda Pharmaceutical co., personal fees from Novo Nordisk Pharma. co., personal fees from Janssen Pharmaceutical K.K., personal fees from Boehringer Ingelheim International GmbH, personal fees from Nikkei Business Publications, Inc., personal fees from Eli Lilly Japan K.K., personal fees from Novartis Pharma K.K., personal fees from Baxter, personal fees from Alexion Pharma, personal fees from Mitsubishi Tanabe Pharma Corporation, grants for the collaborative study from HANSHIN Dispensing Holding Co. Ltd., grants from Nakagawa Pharmacy Co., Ltd., grants from Konica Minolta, Inc., donations for the department from Nakamura hospital, donations from Japan Medical Data Center Toyota, donations from Tsusho All Life Co., outside the submitted work. Susumu Sato reports grants from Philips Japan, ResMed, Fukuda Denshi, Fukuda Lifetec Keiji, Fuji Film corporation and Nippon Boehringer Ingelheim, outside the submitted work. Fumihiko Matsuda reports grants from Kyoto University, grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan, grants from the Center of Innovation Program, grants from Japan Science and Technology Agency, from the Practical Research Project for Rare/Intractable Diseases, during the conduct of the study. Kazuo Chin reports grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology, grants from the Intractable Respiratory Diseases and Pulmonary Hypertension Research Group, the Ministry of Health, Labor and Welfare, Japan, grants from the Japan Vascular Disease Research Foundation, grants from Health, Labour and Welfare Sciences Research Grants, Research on Region Medical, during the conduct of the study; grants and personal fees from Philips Japan, grants and personal fees from Teijin Pharma, grants and personal fees from Fukuda Denshi, grants and personal fees from Fukuda Lifetec Keiji, grants from KYORIN Pharmaceutical Co., Ltd, grants from Nippon Boehringer Ingelheim Co., Ltd, grants and personal fees from GlaxoSmithKline, personal fees from MSD, personal fees from Resmed, personal fees from Astellas Pharma, personal fees from Eisai Co., Ltd., outside the submitted work., (Copyright © 2024. Published by Elsevier B.V.)

Background: Nocturnal blood pressure (BP) is associated with cardiovascular disease independently of awake BP. However, nocturnal BP measured using an ambulatory monitoring device has limited reproducibility because it is a single-day measurement. We investigated the association between sleep BP measured on multiple days using a timer-equipped home BP monitor and cardiovascular diseases in a general population., Methods: The study population comprised 5814 community residents. Participants were required to sleep with wrapping cuffs on their upper arm and BP was measured automatically at 0 : 00, 2 : 00, and 4 : 00. Actigraph was used to determine BP measured during sleep. Participants were also measured home morning and evening BP manually using the same device., Results: During the 7.3-year mean follow-up period, we observed 117 cases of cardiovascular diseases. The association between sleep BP (per 10 mmHg hazard ratio = 1.31, P  < 0.001) and cardiovascular events remained significant (hazard ratio = 1.22, P  = 0.036) even after adjusting for office BP and confounding factors, such as sleep-disordered breathing. Individuals with sleep-only hypertension ( n  = 1047; hazard ratio = 2.23, P  = 0.005) had a significant cardiovascular risk. Daytime-only hypertension ( n  = 264; hazard ratio = 3.57, P  = 0.001) and combined sleep and daytime hypertension ( n  = 1216; hazard ratio = 3.69, P  < 0.001) was associated with cardiovascular events to the same extent. Sleep BP dipping was not identified as a significant determinant of cardiovascular events., Conclusion: Sleep BP measured using a home BP monitor was independently associated with the incidence of cardiovascular disease in a general population., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer., Competing Interests: Declaration of interests H.H. and I.C.H. received funding from Alzheimer’s Research UK and the Dunhill Medical Trust Foundation. M.A.P. reported receiving grants and personal and travel fees from Roche, Novartis, Merck, and Biogen outside the submitted work. M. Scholz receives funding from Pfizer Inc. for a project not related to this research. C.D. serves as a consultant of Novartis Pharmaceuticals. B.F. has received educational speaking fees from Medice. N.J. and P.M.T. are MPIs of a research grant from Biogen Inc. for work unrelated to the contents of this manuscript. D.J.W. received funding from the Stroke Foundation/British Heart Foundation. D.J.S. has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda, and Vistagen. H.H. received funding from MRC, Wellcome Trust, and NIHR UCLH BRC. H.J.G. has received travel grants and speaker’s honoraria from Fresenius Medical Care, Neuraxpharm, and Janssen Cilag as well as research funding from Fresenius Medical Care., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The seasonal influenza vaccine remains one of the vital recommended infection control measures for the elderly with chronic illnesses. We investigated the immunogenicity of a single dose of influenza vaccine in 123 seronegative participants and classified them into four distinct groups, determined by the promptness of vaccine response, the longevity of humoral immunity, and the likelihood of exhibiting cross-reactivity. Subsequently, we used transcriptional profiling and differential gene expression analysis to identify potential genes directly associated with the robust response to the vaccine. The group of exemplary vaccine responders differentially expressed 16 genes, namely: MZB1, MYDGF, TXNDC5, TXNDC11, HSP90B1, FKBP11, PDIA5, PRDX4, CD38, SDC1, TNFRSF17, TNFRSF13B, PAX5, POU2AF1, IRF4, and XBP1. Our findings point out a list of expressed proteins that are related to B cell proliferation, unfolded protein response, and cellular haemostasis, as well as a linkage of these expressions to the survival of long-lived plasma cells.

An East Asian-specific variant on aldehyde dehydrogenase 2 ( ALDH2 rs671, G>A) is the major genetic determinant of alcohol consumption. We performed an rs671 genotype-stratified genome-wide association study meta-analysis of alcohol consumption in 175,672 Japanese individuals to explore gene-gene interactions with rs671 behind drinking behavior. The analysis identified three genome-wide significant loci ( GCKR , KLB , and ADH1B ) in wild-type homozygotes and six ( GCKR , ADH1B , ALDH1B1 , ALDH1A1 , ALDH2 , and GOT2 ) in heterozygotes, with five showing genome-wide significant interaction with rs671. Genetic correlation analyses revealed ancestry-specific genetic architecture in heterozygotes. Of the discovered loci, four ( GCKR , ADH1B , ALDH1A1 , and ALDH2 ) were suggested to interact with rs671 in the risk of esophageal cancer, a representative alcohol-related disease. Our results identify the genotype-specific genetic architecture of alcohol consumption and reveal its potential impact on alcohol-related disease risk.

Background & Aims: Levels of circulating amino acids (AAs) have been suggested to be associated with cardiovascular diseases (CVDs). This study aimed to develop a plasma-free amino acid (PFAA)-based CVD risk-prediction model in a general population., Methods: The study participants consisted of 9220 community residents (mean age, 53.2 years; standard deviation, 13.3 years). Circulating levels of 19 PFAAs were measured via high-performance liquid chromatography/electrospray ionization mass spectrometry. The incidence of CVDs was determined by reviewing participants' clinical records. The prediction model was developed using the Cox proportional hazards model with the brute force variable selection and then cross-validated., Results: During the 8.5-year follow-up, 220 CVD events were observed. Six AAs (alanine, citrulline, glycine, histidine, serine, and tyrosine) were identified as components of the prediction model, of which the C-index was 0.72. The association between the fourth quartile of the risk score calculated using the prediction model and the CVD events was independent of conventional risk factors (adjusted hazard ratio [HR], 1.9; 95 % confidence interval, 1.1-3.3). When examining crude relationships between conventional risk factors and the PFAA-based risk score by subgroup analyses, the association was significant for most subpopulations, men [crude HR = 6.4 (2.0-20.2)] and women [crude HR = 4.9 (2.6-9.3)], and individuals with [crude HR = 4.7 (2.5-8.9)] and without [crude HR = 7.2 (2.7-18.9)] lifestyle-related diseases, but not for older (≥70 years) participants [crude HR = 3.3 (0.8-13.5)]. The risk score successfully identified at-risk individuals [HR = 2.1 (1.2-3.5)] from participants who were classified as low risk by a conventional CVD risk score., Conclusions: The PFAA-based risk score predicted CVD events independently of conventional risk factors., Competing Interests: Conflict of interest Plasma amino acid levels were measured by Ajinomoto Co., Inc. The Center for Genomic Medicine received research funding, and YT and FM received consultation fees from Ajinomoto Co., Inc. MT, HY, KN, AI, and YK are employees of Ajinomoto Co., Inc. This does not alter the authors’ adherence to all of the journal policies. No other potential conflicts of interest in relation to this article are declared., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: This study aimed to clarify the relationships among tooth loss, periodontal condition, and subclinical atherosclerosis from the aspect of intensity, extent, and duration of inflammation., Methods: This cross-sectional study included 9,778 people from the Nagahama Study, a large-scale, general population-based study conducted in Japan. The number of teeth and periodontal status, including the attachment level (AL) and pocket depth (PD) of representative teeth from six regions, were evaluated by dentists. The maximum intima-media thickness (IMT) of the common carotid artery was used as an index of atherosclerosis., Results: In the multivariate analysis adjusted for conventional risk factors, a large number of missing teeth (＜9 remaining teeth), which related to long-lasting inflammation indicative of the highest stage of periodontitis, was identified as an independent determinant of IMT in a general population (coefficient: 0.042; 95% confidence interval [CI]: 0.016 to 0.068). The presence of two or more regions with an AL ≥4 mm, which is indicative of the progressing, long-lasting stages of periodontal inflammation, was also independently associated with IMT (coefficient: 0.016; 95% CI: 0.004 to 0.028). On the contrary, PD, a measure of the early and reversible phases of periodontal inflammation, and loss of AL in the group without tooth loss were not significantly associated with IMT, because of the limited degree of accumulated periodontitis., Conclusion: The present results suggest that the association between periodontitis and atherosclerosis depends on the inflammation intensity, extent, and duration.

Sleep-disordered breathing (SDB) is often accompanied by noncommunicable diseases (NCDs), including gout. However, the association between serum uric acid (sUA) levels and NCDs is complicated in patients with SDB. We aimed to clarify this issue utilizing large-scale epidemiological data. This community-based study included 9850 inhabitants. SDB and its severity were assessed by a 3% oxygen desaturation index (3% ODI) corrected for sleep duration using wrist actigraphy. The associations between sUA and moderate to severe SDB (MS-SDB) and sUA and NCDs in patients with MS-SDB were analyzed. A total of 7895 subjects were eligible. In females, the prevalence of MS-SDB increased according to an elevation in sUA levels even after adjusting for confounders, and sUA ≥ 5 mg/dL was the threshold. These were not found in males. There was a positive interaction between sUA ≥ 5 mg/dL and female sex for MS-SDB. In females with MS-SDB, the prevalence of diabetes mellitus (DM) increased according to an elevation in sUA levels, and those with sUA ≥ 5 mg/dL showed a higher prevalence of DM than their counterparts. There is a clear correlation between sUA levels and the severity of SDB, and elevated sUA poses a risk for DM in females with MS-SDB.

Objectives: Masked hypertension, which is characterized by out-of-office hypertension but normal office blood pressure, is a risk factor for cardiovascular disease. However, the factors that contribute to masked hypertension are unclear. We aimed to determine the involvement of sleep-related characteristics in masked hypertension., Methods: The study included 3844 normotensive (systolic/diastolic blood pressure < 140/90 mmHg) community residents with no antihypertensive drug use at baseline (mean age 54.3 years). Home morning and evening blood pressure, oxygen desaturation during sleep (pulse oximetry), and sleep efficiency (actigraphy) were measured for 1 week. The number of nocturnal urinations during this period was obtained using a sleep diary., Results: Masked hypertension (mean morning and evening blood pressure ≥135/85 mmHg) was detected in 11.7% of study participants, and 79.0% of the participants with masked hypertension had sleep hypertension (≥120/70 mmHg). Multinominal logistic regression analysis identified different factors involved in masked hypertension with and without sleep hypertension; factors for masked hypertension with sleep hypertension included the frequency of at least 3% oxygen desaturation (coefficient = 0.038, P  = 0.001), nocturia (coefficient = 0.607, P  < 0.001), and carotid intima-media thickness (coefficient = 3.592, P  < 0.001). Only carotid intima-media thickness and measurement season were associated with masked hypertension without sleep hypertension. Low sleep efficiency was associated with isolated sleep hypertension but not masked hypertension., Conclusion: Sleep-related factors associated with masked hypertension differed depending on the presence of sleep hypertension. Sleep-disordered breathing and nocturnal urination frequency may help identify individuals who need home blood pressure monitoring., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Cross-sectional relationships between nocturia and sleep problems have been well evaluated but the risk association for each incidence is scarcely reported. This analysis included 8076 participants of the Nagahama study in Japan (median age 57, 31.0% male) and associations between nocturia and self-reported, sleep-related problems (poor sleep) were evaluated cross-sectionally. Causal effects on each new-onset case were analyzed longitudinally after 5 years. Three models were applied: univariable analysis, adjustment for basic variables (i.e., demographic and lifestyle variables) and full adjustment for basic and clinical variables. The overall prevalences of poor sleep and nocturia were 18.6% and 15.5%, while poor sleep was positively associated with nocturia (OR = 1.85, p < 0.001) and vice versa (OR = 1.90, p < 0.001). Among 6579 good sleep participants, 18.5% developed poor sleep. Baseline nocturia was positively associated with this incident poor sleep (OR = 1.49, p < 0.001, full adjustment). Among 6824 non-nocturia participants, the nocturia incidence was 11.3%. Baseline poor sleep was positively associated with this incident nocturia (OR = 1.26, p = 0.026); such associations were significant only in women (OR = 1.44, p = 0.004) and under-50-year-old groups (OR = 2.82, p < 0.001), after full adjustment. Nocturia and poor sleep associate with each other. Baseline nocturia can induce new-onset poor sleep while baseline poor sleep may induce new-onset nocturia only in women., (© 2023. The Author(s).)

Recently an association between blood glucose dysregulation and sleep disruption was suggested. The association between sleep disordered breathing, most of which is due to obstructive sleep apnea (OSA) in the general population, and diabetic severity, as well as the impact of antidiabetic treatment, remains unclear. This study aimed to investigate these associations as well as age and sex differences. This cross-sectional study evaluated 7,680 community participants as the main cohort (population-based cohort). OSA was assessed by the 3% oxygen desaturation index from pulse oximetry, which was corrected for sleep duration obtained by wrist actigraphy. For arguing the limitations for using pulse oximetry, 597 hospitalised patients, who were assessed by the apnea-hypopnea index from attended polysomnography, were also evaluated as the validation cohort (hospital-based cohort). Moderate-to-severe OSA was more prevalent as haemoglobin A1c (HbA1c) levels increased (<5.6%/5.6%-<6.5%/6.5%-<7.5%/≥7.5%, respectively) in both cohorts (p < 0.001), but only in those without antidiabetic treatment. The HbA1c level was an independent factor for moderate-to-severe OSA (population-based cohort, odds ratio [OR] 1.26, 95% confidence interval [CI] 1.10-1.45; hospital-based cohort, OR 1.69, 95% CI 1.22-2.33, per 1% increase). These associations were more prominent in the middle-aged (aged <60 years) than in the elderly (aged ≥60 years) and in women than in men in both cohorts. The prevalence of moderate-to-severe OSA in patients with antidiabetic treatment in the hospital-based cohort was ≥75% regardless of HbA1c levels. In conclusion, an association between the prevalence of OSA and HbA1c level even within or over the normal range was found only in patients without antidiabetic treatment and was more prominent in the middle-aged and in women., (© 2022 European Sleep Research Society.)

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets., (© 2023. The Author(s).)

Background: The influenza vaccine administrated every year is a recommended infection control procedure for individuals above the age of six months. However, the effectiveness of repeated annual vaccination is still an active research topic. Therefore, we investigated the vaccine immunogenicity in two independent groups: previously vaccinated versus non-vaccinated individuals at three time points; prior vaccination, one week and three months post vaccination. The assessment enabled us to evaluate the elicited immune responses and the durability of the induced protection in both groups., Research Design and Methods: A research study was conducted to assess the immunogenicity of a single dose of Trivalent Inactivated Influenza Vaccine (A/H1N1, A/H3N2, and B) in 278 healthy adults aged between 32 and 66 years. Almost half of the participants, 140 (50·36%), received influenza vaccination at least once precursor to past influenza seasons. One blood sample was taken prior to vaccination for complete blood analysis and baseline immunogenicity assessment. The selected study participants received a single vaccine dose on the first day, and then followed up for three months. Two blood samples were taken after one week and three months post vaccination, respectively, for vaccine immunogenicity assessment., Results: Before vaccination, the seroprotection, defined as a hemagglutination-inhibiting titer of =>1:40, was detected for the three vaccine virus strains in 20 previously vaccinated participants (14·29%) [8·95%, 21·2%]. We compared the overall vaccine response for the three virus strains using a normalized response score calculated from linearly transformed titer measurements; the score before vaccination was 84% higher in the previously vaccinated group and the mean difference between the two groups was statistically significant. Three months post-vaccination, we didn't find a significant difference in vaccine responses; the number of fully seroprotected individuals became 48 (34·29%) [26·48%, 42·77%] in the previously vaccinated group and 59 (42·75%) [34·37%, 51·45%] in the non-vaccinated group. The calculated response score was almost equal in both groups and the mean difference was no longer statistically significant., Conclusion: Our findings suggest that a single dose of influenza vaccine is equally protective after three months for annually vaccinated adults and first-time vaccine receivers.

Background: We aimed to determine if skeletal muscle mass is a predictor of all-cause mortality and if muscle mass plays a role in the association between body mass index (BMI) and all-cause mortality in community residents., Methods: The study population consists of 3582 elderly (age ≥65 years) adults. The skeletal muscle mass index (SMI) was measured between 2013 and 2016. Men with SMI <7.0 kg/m 2 and women with SMI <5.7 kg/m 2 were considered to have low SMI. All-cause mortality was determined by reviewing residential registry records (follow-up duration: 2564 ± 373 days)., Results: The mortality rate of the low SMI group was significantly higher than that of the normal SMI group in men (191.3 vs. 93.0 per 10 000 person-years, P < 0.001), but not in women (P = 0.191). In Cox proportional hazard analysis adjusted for possible covariates, the group differences remained significant (hazard ratio = 1.82, P = 0.011). The results were similar when individuals who died within 1 year of follow-up were excluded from the analysis (P = 0.015). Cubic splines revealed that SMI <6.9 kg/m 2 is a risk factor of all-cause mortality in men. BMI was found to be significantly associated with all-cause mortality in men (P = 0.010), but not in women (P = 0.288); however, the association disappeared after adjustment for SMI (P = 0.163)., Conclusion: SMI <6.9 kg/m 2 is a risk factor of all-cause mortality in men but not in women. SMI underlies the relationship between BMI and all-cause mortality. Geriatr Gerontol Int 2022; 22: 956-960., (© 2022 Japan Geriatrics Society.)

There is disparity between the sexes in cardiovascular diseases including heart failure (HF). This study aimed to investigate the effect of periodontal disease (PD) on plasma B-type natriuretic peptide (BNP) concentration across sex, age, and menopausal status, as well as the interaction effect of PD and diabetes mellitus (DM) on BNP. This large-scale prospective cohort study enrolled 7539 individuals with no myocardial infarctions or angina pectoris at baseline from the general Japanese population. The association between baseline number of missing teeth (MT) and the longitudinal changes in BNP over 5 years (ΔBNP) was evaluated according to sex and menopausal status. Among 7539 participants, 3190 were postmenopausal women with a mean age ± standard deviation of 61.1 ± 7.6 at baseline. Multivariate analysis revealed a positive association between MT and ΔBNP among postmenopausal women even after adjusting for covariates, including traditional HF risk factors (coefficient, 0.210; 95% confidence interval [CI], 0.107 to 0.312; P < 0.001), but not in men aged > 50. Including an interaction term (MT × DM) in the multivariate model revealed a positive interaction between MT and DM in ΔBNP among postmenopausal women (coefficient for interaction, 1.365; 95% CI, 0.902 to 1.827; P for interaction < 0.001). In conclusion, our study showed a positive association between MT and ΔBNP, as well as a positive effect of the interactive association between MT and DM, among postmenopausal women. Our results suggest a sex difference of an adverse effect of PD on initial myocardial wall stress in the ventricles., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: We aimed to develop models to predict new-onset overactive bladder in 5 years using a large prospective cohort of the general population., Methods: This is a secondary analysis of a longitudinal cohort study in Japan. The baseline characteristics were measured between 2008 and 2010, with follow-ups every 5 years. We included subjects without overactive bladder at baseline and with follow-up data 5 years later. Overactive bladder was assessed using the overactive bladder symptom score. Baseline characteristics (demographics, health behaviors, comorbidities, and overactive bladder symptom scores) and blood test data were included as predictors. We developed two competing prediction models for each sex based on logistic regression with penalized likelihood (LASSO). We chose the best model separately for men and women after evaluating models' performance in terms of discrimination and calibration using an internal validation via 200 bootstrap resamples and a temporal validation., Results: We analyzed 7218 participants (male: 2238, female: 4980). The median age was 60 and 55 years, and the number of new-onset overactive bladder was 223 (10.0%) and 288 (5.8%) per 5 years in males and females, respectively. The in-sample estimates for C-statistic, calibration intercept, and slope for the best performing models were 0.77 (95% confidence interval 0.74-0.80), 0.28 and 1.15 for males, and 0.77 (95% confidence interval 0.74-0.80), 0.20 and 1.08 for females. Internal and temporal validation gave broadly similar estimates of performance, indicating low optimism., Conclusion: We developed risk prediction models for new-onset overactive bladder among men and women with good predictive ability., (© 2022 The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Urological Association.)

Study Objectives: Since subjective sleep duration (SSD) is considered to be longer than objective sleep duration (OSD), results of SSD minus OSD (SSD-OSD) might always be thought to be positive. Some recent reports showed different results, but exact results have not been obtained. The difference between SSD and OSD may change according to OSD. We investigated this difference and its association with sleep-disordered breathing (SDB) or nonrestorative sleep., Methods: This cross-sectional study evaluated 6,908 community residents in Nagahama, Japan. SSD was determined by self-administered questionnaire. OSD was measured by wrist actigraphy and sleep diary. SDB was assessed according to the 3% oxygen desaturation index adjusted for OSD., Results: Worthy of notice was that SSD was shorter than OSD for those with SSD longer than 6.98 hours in all participants, 7.36 hours in males, and 6.80 hours in females. However, SSD was longer than OSD (mean ± SD: 6.49 ± 1.07 vs 6.01 ± 0.96; P < .001) overall, as SSD is considered to be longer than OSD. In patients with SDB, the difference between SSD-OSD was greater when OSD was s horter. The difference also depended on SDB severity. The degree of positivity between OSD and SSD was a significant factor in nonrestorative sleep (odds ratio: 2.691; P < .001)., Conclusions: When OSD was slightly less than 7 (6.98) hours, participants reported or perceived SSD > OSD. When OSD was > 6.98 hours, participants reported or perceived SSD < OSD. Patients with SDB reported longer SSD than OSD according to severity of SDB. Evaluating SSD, OSD, and their differences may be useful for managing sleep disturbances, including nonrestorative sleep., Citation: Takahashi N, Matsumoto T, Nakatsuka Y, et al. Differences between subjective and objective sleep duration according to actual sleep duration and sleep-disordered breathing: the Nagahama Study. J Clin Sleep Med . 2022;18(3):851-859., (© 2022 American Academy of Sleep Medicine.)

Rationale: Although sleep-disordered breathing (SDB) may increase urinary albumin excretion (UAE) by raising nocturnal blood pressure (BP) in addition to diurnal BP, the correlation has not been investigated in a general population. Objectives: To evaluate the relationships among UAE, SDB, and BP during sleep in a large population cohort. Methods: Among 9,850 community residents, UAE was assessed by the urinary albumin-to-creatinine ratio (UACR) in spot urine. Sleep duration and SDB were evaluated by a wearable actigraph and pulse oximeter, respectively. We calculated the actigraphy-modified 3% oxygen desaturation index (Acti-3%ODI) by correcting the time measured by pulse oximetry according to sleep duration obtained by actigraphy. Furthermore, participants were instructed to measure morning and sleep BP at home by a timer-equipped oscillometric device. Results: Measurements of sleep parameters, UAE, and office BP were obtained in 6,568 participants. The multivariate analysis that included confounders showed a significant association of Acti-3%ODI with UACR (β = 0.06, P  < 0.001). Furthermore, a positive interaction between office systolic BP (SBP) and Acti-3%ODI for UACR was found (β = 0.06, P  < 0.001). Among the 6,568 persons enrolled in the analysis, 5,313 completed measurements of BP at home. In this cohort, the association of Acti-3%ODI with UACR remained significant (β = 0.06, P  < 0.001) even after morning and sleep SBP were included in the analysis. Furthermore, a mediation analysis revealed that 28.3% (95% confidence interval, 14.9-41.7%; P  < 0.001) of the association of Acti-3%ODI with UACR was explained by the mediation of morning and sleep SBP metrics. Conclusions: SDB and office SBP were independently and synergistically associated with UAE, which is considered a risk factor for chronic kidney disease and cardiovascular events. SDB may raise UAE not only by increasing BP but also by involving other pathologic pathways.

Objective: An association between the Moyamoya disease susceptible gene ring finger protein 213 (RNF213) variant and ischemic stroke and coronary artery disease has been suggested in case-control studies. We aimed to investigate the possible association between the RNF213 variant and the incidence of cardiovascular disease in a general population., Methods: The study participants consisted of 9153 Japanese community residents without history of cardiovascular disease. The clinical parameters employed in this analysis were observed at baseline between 2008 and 2010. The RNF213 p.R4859K variant was determined by TaqMan probe assay and then confirmed by Sanger sequencing., Results: During 8.52 years follow-up period, we observed 214 incident cases of cardiovascular diseases (99 total stroke cases, 119 major adverse cardiac event cases, including 4 cases of both). The incidence rate was higher for the variant allele carriers (120 cases; incidence rate, 71.0 per 10 000 person-years) than for the homozygotes of the wild-type allele (26.9), and the group differences achieved statistical significance (P = 0.009). Although the RNF213 variant was also associated with systolic blood pressure (dominant model: coefficient of 8.19 mmHg; P < 0.001), the Cox regression analysis adjusted for major covariates including systolic blood pressure identified the RNF213 variant as an independent determinant for cardiovascular disease (hazard ratio of 3.41, P = 0.002) and major adverse cardiac event (hazard ratio of 3.80, P = 0.010) but not with total stroke (P = 0.102)., Conclusion: The Moyamoya disease susceptible RNF213 variant was associated with blood pressure and the incidence of cardiovascular disease in a Japanese general population., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Circulating levels of inflammatory proteins have to be prognostic markers of all-cause mortality. α1-Antitrypsin (AAT) is a major inflammatory plasma protein, but its association with all-cause mortality is unclear. We aimed to evaluate the prognostic significance of AAT levels for all-cause mortality. Study participants comprised 9682 community residents (53.5 ± 13.3 years old). During the 9.8-year follow-up period, 313 participants died from any cause. The mortality rate increased linearly with AAT quintiles (Q1, 18.2; Q2, 24.7; Q3, 23.8; Q4, 31.9; Q5, 64.6 per 10,000 person-years). There were significant correlations between AAT and high-sensitivity C-reactive protein (hsCRP) levels (correlation coefficient, 0.331; P < 0.001). However, the Cox model analysis, when adjusted for possible covariates including hsCRP, identified the fifth AAT quintile as a risk factor for all-cause death (hazard ratio, 2.12 [95% confidence interval, 1.41-3.18]; P < 0.001). An analysis of participants older than 50 years (hazard ratio, 1.98, P < 0.001) yielded similar results. The hazard ratio increased proportionately in combination with high AAT and high hsCRP levels, and the highest hazard ratio reached 4.51 (95% confidence interval, 3.14-6.54, P < 0.001). High AAT levels were determined to be an independent risk factor for mortality in the general population., (© 2021. The Author(s).)

Faster pulse wave velocity (PWV) is known to be associated with the incidence of cardiovascular diseases (CVD). The aim of this study was to clarify the hypothesis that PWV may be associated with future CVD events even when its time-dependent changes were adjusted. We also investigated a prognostic significance of cardio-ankle vascular index, another index of arterial stiffness. Study participants included 8850 community residents. The repeated measures of the clinical parameters at 5.0 years after the baseline were available for 7249 of the participants. PWV was calculated using the arterial waveforms measured at the brachia and ankles (baPWV). The cardio-ankle vascular index was calculated by estimated pulse transit time from aortic valve to tibial artery. During the 8.53 years follow-up period, we observed 215 cases of CVD. The incidence rate increased linearly with baPWV quartiles (per 10 000 person-years: Q1, 2.7; Q2, 12.6; Q3, 22.5; Q4, 76.2), and the highest quartile was identified as an independent determinant of incident CVD by conventional Cox proportional hazard analysis adjusted for known risk factors [hazard ratio (HR), 4.00; p = .007]. Per unit HR of baPWV (HR, 1.15; p < .001) remained significant in the time-dependent Cox regression analysis including baPWV and other clinical values measured at 5-year after the baseline as time-varying variables (HR, 1.14; p < .001). The cardio-ankle vascular index was also associated with CVD with similar manner though the associations were less clear than that of baPWV. baPWV is a good risk marker for the incidence of CVD., (© 2021 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10 -8 ), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.

Human immune systems are very complex, and the basis for individual differences in immune phenotypes is largely unclear. One reason is that the phenotype of the immune system is so complex that it is very difficult to describe its features and quantify differences between samples. To identify the genetic factors that cause individual differences in whole lymphocyte profiles and their changes after vaccination without having to rely on biological assumptions, we performed a genome-wide association study (GWAS), using cytometry data. Here, we applied computational analysis to the cytometry data of 301 people before receiving an influenza vaccine, and 1, 7, and 90 days after the vaccination to extract the feature statistics of the lymphocyte profiles in a nonparametric and data-driven manner. We analyzed two types of cytometry data: measurements of six markers for B cell classification and seven markers for T cell classification. The coordinate values calculated by this method can be treated as feature statistics of the lymphocyte profile. Next, we examined the genetic basis of individual differences in human immune phenotypes with a GWAS for the feature statistics, and we newly identified seven significant and 36 suggestive single-nucleotide polymorphisms associated with the individual differences in lymphocyte profiles and their change after vaccination. This study provides a new workflow for performing combined analyses of cytometry data and other types of genomics data.

Background: An accurate prediction model could identify high-risk subjects of incident Overactive bladder (OAB) among the general population and enable early prevention which may save on the related medical costs. However, no efficient model has been developed for predicting incident OAB. In this study, we will develop a model for predicting the onset of OAB at 5-year in the general population setting., Methods: Data will be obtained from the Nagahama Cohort Project, a longitudinal, general population cohort study. The baseline characteristics were measured between Nov 28, 2008 and Nov 28, 2010, and follow-up was performed every 5 years. From the total of 9,764 participants (male: 3,208, female: 6,556) at baseline, we will exclude participants who could not attend the follow-up assessment and those who were defined as having OAB at baseline. The outcome will be incident OAB defined using the Overactive Bladder Symptom Score (OABSS) at follow-up assessment. Baseline questionnaires (demographic, health behavior, comorbidities and OABSS) and blood test data will be included as predictors. We will develop a logistic regression model utilizing shrinkage methods (LASSO penalization method). Model performance will be evaluated by discrimination and calibration. Net benefit will be evaluated by decision curve analysis. We will perform an internal validation and a temporal validation of the model. We will develop a web-based application to visualize the prediction model and facilitate its use in clinical practice., Discussion: This will be the first study to develop a model to predict the incidence of OAB.

Study Objectives: It is well known that a family history of diabetes (FHD) is a definitive risk factor for type 2 diabetes. It has not been known whether sleep-disordered breathing (SDB) increases the prevalence of diabetes in those with an FHD., Methods: We assessed SDB severity in 7,477 study participants by oximetry corrected by objective sleep duration determined by wrist actigraphy. Glycated hemoglobin ≥6.5% and/or current medication for diabetes indicated the presence of diabetes. In addition to the overall prevalence, the prevalence of recent-onset diabetes during the nearly 5 years before the SDB measurements were made was investigated., Results: Of the 7,477 participants (mean age: 57.9; range: 34.2-80.7; SD: 12.1 years; 67.7% females), 1,569 had an FHD. The prevalence of diabetes in FHD participants with moderate-to-severe SDB (MS-SDB) was higher than in those without SDB (MS-SDB vs without SDB: all, 29.3% vs 3.3% [P < .001]; females, 32.6% vs 1.9% [P < .001]; males, 26.2% vs 11.7% [P = .037]). However, multivariate analysis showed that MS-SDB was significantly associated with a higher prevalence of diabetes only in FHD-positive females (odds ratio [95% confidence interval]: females, 7.43 [3.16-17.45]; males, 0.92 [0.37-2.31]). Among the FHD-positive participants, the prevalence of recent-onset diabetes was higher in those with MS-SDB than those without SDB, but only in females (MS-SDB vs without SDB: 21.4% vs 1.1%; P < 0.001)., Conclusions: MS-SDB was associated with diabetes risk in females with an FHD, and future studies are needed on whether treatment of SDB in females with an FHD would prevent the onset of diabetes., (© 2021 American Academy of Sleep Medicine.)

Aim: To evaluate the relationship between nocturia and medical history of nocturnal enuresis: two conditions where diurnal urination rhythm is disturbed., Methods: The Nagahama study is a longitudinal population-based health survey involving people aged 30-75 years in Nagahama city, Japan. Our analysis included 5,402 participants who completed enuresis and International Prostate Symptom Score questionnaires. Associations between nocturnal enuresis and nocturia were evaluated cross-sectionally and longitudinally with three models: (1) univariate analysis; (2) adjusted for basic characteristics (e.g., age, sex, body mass index, activity, alcohol, and smoking); and (3) adjusted for basic and clinical variables (e.g., hyperglycemia, hyperlipidemia, hypertension, renal insufficiency, insomnia, obstructive sleep apnea, and mental health)., Results: In total, 1,613 participants (29.9%) had a medical history of enuresis. The mean night-time frequency was 0.73 at baseline and 0.85 at the 5-year follow-up. The cross-sectional analysis showed participants with a medical history of enuresis had night-time frequency more often than those without this history (0.84 vs. 0.68, p < .0001). Significant differences were observed in Models 2 (p < .0001) and 3 (p < .0001). The longitudinal analysis showed nocturia progression was significantly related to a history of enuresis, with odds ratios of 1.32 (p < .0001) in Model 1, 1.21 (p < .01) in Model 2, and 1.22 (p < .01) in Model 3., Conclusions: Medical history of enuresis during school age was significantly related to nocturia in adulthood in the cross-sectional analysis, and to progression to nocturia in the longitudinal analysis. These two conditions may possess a common causative association., (© 2020 Wiley Periodicals LLC.)

Aims: Sleep-disordered breathing (SDB) is a well-known risk factor for cardiovascular outcomes. Studies of patients with SDB have identified frequent night-time urination as a manifestation related to SDB. We aimed to clarify whether night-time frequency of urination is independently associated with SDB in a general population. We also investigated whether night-time frequency of urination can help presumptive diagnose SDB., Methods: Study participants consisted of 7151 community residents. Oxygen saturation during sleep was measured for four nights using a pulse oximeter. SDB was defined as ≥15 events per hour in which oxygen desaturation exceeded or equal to 3% during an actigraphy-determined sleep period. Night-time frequency of urination was recorded for one week using a sleep diary., Results: Significant positive correlations were evident between night-time frequency of urination and SDB (none, 5.8%; once/night, 14.1%; twice/night, 20.1%; thrice/night, 28.7%; >thrice/night, 44.1%, P < 0.001). This association was independent of possible covariates, including sleep duration (adjusted odds ratio: once/night = 1.50, twice/night = 2.15, thrice/night = 3.07, >thrice/night = 3.73, P < 0.001). Other factors significantly associated with SDB were age, sex, obesity, observation of sleep apnea, and short sleep duration. The area under the curve of the risk score for SDB consisting of these conventional six items (0.834) significantly improved (0.842, P = 0.001) when night-time frequency of urination was considered as a risk score item., Conclusion: Night-time frequency of urination was associated with SDB. Our findings suggest that the urination frequency should be considered a manifestation of SDB even in a general population., (Copyright © 2020 Elsevier B.V. All rights reserved.)

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

Background: High sleep blood pressure (BP) has been suggested to be an independent risk factor for cardiovascular outcomes. To assess the applicability of sleep BP measured using a timer-equipped home device, we investigated the association between home device-measured sleep BP and large artery stiffness., Methods: We performed a cross-sectional analysis of a dataset from the Nagahama study (N = 5916), a general population-based cohort study. Home morning BP and sleep BP were measured using a timer-equipped cuff-oscillometric device (HEM-7080IC). Office BP, carotid intima--media thickness (IMT), and brachial--ankle pulse wave velocity (baPWV) were measured at the follow-up investigation of the Nagahama study., Results: Sleep hypertension (SBP ≥120 mmHg and/or DBP ≥70 mmHg) was associated with the arterial parameters (IMT: β = 0.051, baPWV: β = 0.141, both P < 0.001) independently of morning hypertension (IMT: β = 0.093, baPWV: β = 0.216, both P < 0.001) irrespective of antihypertensive medication status. Individuals exhibiting isolated sleep hypertension (N = 801) had thicker IMT (0.69 ± 0.14 vs. 0.64 ± 0.13 mm, P = 0.017) and faster baPWV (1,299 ± 197 vs. 1,183 ± 178 cm/s, P < 0.001) than normotensives. A sleep SBP at least 110 mmHg and a sleep DBP at least 65 mmHg were identified as the lower threshold BP values for the association with arterial parameters., Conclusion: Sleep BP measurement using a home device may be a simple way to assess cardiovascular risks overlooked by office and home morning BP measurements.

Purpose: Nocturia has been reported as a risk factor for mortality. However, evidence is limited and has a high risk of bias. We evaluated the association between nocturia and mortality using longitudinal data from the general Japanese population., Materials and Methods: Data were obtained from the Nagahama Cohort Project, a longitudinal, general population cohort study. Nocturia was measured using the International Prostate Symptom Score. Mortality data were obtained from the Basic Resident Register in Nagahama City. We used Cox proportional hazard models and time-varying covariates at baseline and 5-year followup to analyze the association between nocturia and mortality., Results: We analyzed 9,762 participants (median age 56.8 years, male 32.8%). The prevalence rates of nocturnal voiding at 0, 1, 2 and 3 or more times were 44.3%, 39.1%, 11.7% and 4.9%, respectively. A total of 263 participants died. Followup assessment was performed 3,224 (SD 537) days after baseline. According to multivariable Cox proportional hazard regressions, mortality increased dose dependently with the nocturnal voiding frequency as HR 1.46 for 1 time (95% CI 1.02-2.09), HR 1.85 for 2 times (95% CI 1.23-2.77) and HR 2.06 (95% CI 1.28-3.32) for 3 or more times in comparison with 0 times (p for trend=0.00084). In the time varying Cox proportional hazard regression the association was still significant (p for trend=0.0017)., Conclusions: According to this longitudinal study with a low incidence of missing data and high representation of the general population, nocturia is associated with mortality.

It is well known that the prevalence of sleep disordered breathing (SDB) is increased in patients with obesity or metabolic comorbidities. However, the way in which the prevalence of SDB increases in relation to comorbidities according to the severity of obesity remains unclear.This cross-sectional study evaluated 7713 community participants using nocturnal oximetry ≥2 nights. SDB was assessed by the 3% oxygen desaturation index corrected for sleep duration obtained by wrist actigraphy (acti-ODI3%). SDB severity was defined by acti-ODI3%. Obesity was defined as body mass index ≥25 kg·m -2 The prevalence of SDB was 41.0% (95% CI 39.9-42.1%), 46.9% (45.8-48.0%), 10.1% (9.5-10.8%) and 2.0% (1.7-2.3%) in normal, mild, moderate and severe SDB, respectively, with notable sex differences evident (males>post-menopausal females>premenopausal females). Comorbidities such as hypertension, diabetes and metabolic syndrome were independently associated with the prevalence of moderate-to-severe SDB, and coincidence of any one of these with obesity was associated with a higher probability of moderate-to-severe SDB (hypertension OR 8.2, 95% CI 6.6-10.2; diabetes OR 7.8, 95% CI 5.6-10.9; metabolic syndrome OR 6.7, 95% CI 5.2-8.6). Dyslipidaemia in addition to obesity was not additively associated with the prevalence of moderate-to-severe SDB. The number of antihypertensive drugs was associated with SDB (p for trend <0.001). Proportion of a high cumulative percentage of sleep time with oxygen saturation measured by pulse oximetry <90% increased, even among moderate-to-severe SDB with increases in obesity.Metabolic comorbidities contribute to SDB regardless of the degree of obesity. We should recognise the extremely high prevalence of moderate-to-severe SDB in patients with obesity and metabolic comorbidities., Competing Interests: Conflict of interest: T. Matsumoto has nothing to disclose. K. Murase reports grants from Philips-Respironics, Teijin Pharma, Fukuda Denshi, Fukuda Lifetec Keiji, ResMed and Japan Society for the Promotion of Science, outside the submitted work. Conflict of interest: Y. Tabara reports grants from Japan Agency for Medical Research and Development (AMED) and The Ministry of Education, Culture, Sports, Science and Technology in Japan, during the conduct of the study. Conflict of interest: T. Minami reports personal fees from Teijin Zaitakuiryou, outside the submitted work. Conflict of interest: O. Kanai has nothing to disclose. Conflict of interest: H. Takeyama reports grants from Philips-Respironics, ResMed, Fukuda Denshi, Fukuda Lifetec Keiji and Teijin Pharma, outside the submitted work. Conflict of interest: N. Takahashi reports grants from Philips-Respironics, ResMed, Fukuda Denshi and Fukuda Lifetec Keiji, outside the submitted work. Conflict of interest: S. Hamada reports grants from Teijin Pharma, outside the submitted work. Conflict of interest: K. Tanizawa has nothing to disclose. Conflict of interest: T. Wakamura has nothing to disclose. Conflict of interest: N. Komenami has nothing to disclose. Conflict of interest: K. Setoh has nothing to disclose. Conflict of interest: T. Kawaguchi has nothing to disclose. Conflict of interest: T. Tsutsumi has nothing to disclose. Conflict of interest: S. Morita has nothing to disclose. Conflict of interest: Y. Takahashi has nothing to disclose. Conflict of interest: T. Nakayama has nothing to disclose. Conflict of interest: T. Hirai has nothing to disclose. Conflict of interest: F. Matsuda reports grants from Kyoto University, the Ministry of Education, Culture, Sports, Science and Technology in Japan, Japan Agency for Medical Research and Development (AMED) and The Takeda Medical Research Foundation, during the conduct of the study. Conflict of interest: K. Chin reports grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology, grants from the Intractable Respiratory Diseases and Pulmonary Hypertension Research Group, the Ministry of Health, Labour and Welfare, Japan, grants from the Research Foundation for Healthy Aging, grants from Health, Labour and Welfare Sciences Research Grants, Research on Region Medical, grants from the Center of Innovation Program, and the Global University Project from Japan Science and Technology Agency, Japan Agency for Medical Research and Development, during the conduct of the study; grants and personal fees from Philips-Respironics, Teijin Pharma, Fukuda Denshi, Fukuda Lifetec Keiji, GlaxoSmithKline and Resmed, grants from KYORIN Pharmaceutical Co., Ltd and Nippon Boehringer Ingelheim Co., Ltd, personal fees from MSD, Astellas Pharma and Eisai Co., Ltd, outside the submitted work., (Copyright ©ERS 2020.)

Backgrounds: Sarcopenia in older adults is a risk factor for age-related morbidity and mortality. This study aimed to clarify the diagnostic significance of the revised diagnostic algorithm for sarcopenia from Asian Working Group for Sarcopenia by comparing physical and clinical characteristics of individuals diagnosed with sarcopenia by the initial and revised algorithms., Methods: Study participants were 2061 older community residents. Skeletal muscle mass was measured by bioimpedance analysis. Handgrip strength and physical function required for the diagnosis of sarcopenia were measured by conventional methods. Carotid intima-media thickness was used as a marker of atherosclerosis in a large artery., Results: Using the initial algorithm, 60 of the participants were diagnosed with sarcopenia, but based on the revised algorithm, 89 had sarcopenia and 21 severe sarcopenia. The higher frequency of sarcopenia was attributed to changes in the cut-off values for slow gait speed and the addition of the 5-time chair-stand test as part of the assessment of physical performance. Physical characteristics of individuals diagnosed with sarcopenia by either algorithm did not differ markedly, but those with severe sarcopenia had significantly poorer physical performance even with a muscle mass similar to those with sarcopenia. There was a linear correlation between the severity of sarcopenia and carotid intima-media thickness (no sarcopenia: 0.94 ± 0.31, sarcopenia: 1.04 ± 0.41, and severe sarcopenia: 1.07 ± 0.55 mm, P = 0.003)., Conclusion: The revised diagnostic algorithm was superior to the initial version at identifying individuals with sarcopenia and severe sarcopenia with a worse cardiovascular profile., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Although alkaline phosphatase (ALP) activity is relatively low in carriers of recessive type hypophosphatasia (HPP), most are asymptomatic and therefore do not undergo medical evaluations. We analyzed the association of ALP-encoding ALPL variants with serum ALP and bone traits in the general Japanese population. Study participants (n = 9671) were from the Nagahama Study, which was a longitudinal cohort study of an apparently healthy general Japanese population. ALPL variants were analyzed by whole-genome sequencing or TaqMan probe assays using DNA extracted from peripheral blood samples. The speed of sound in calcaneal bone was assessed by quantitative ultrasound (QUS) and used as surrogate measures of bone mineral density. We identified 13 ALPL variants. Minor allele frequencies of three variants were higher than expected. Variant c.529G > A has been reported as a possible pathogenic variant for adult type HPP. Variants c.979C > T and c.1559delT are reported as pathogenic variants for perinatal severe HPP or infantile HPP. The allele frequencies of c.529G > A, c.979C > T, and c.1559delT were 0.0107, 0.0040, and 0.0014, respectively. Serum ALP activity was significantly lower and differed among the three variants (P < 0.001), as well as between individuals with and without any of the three variants (P < 0.001). Serum ALP activity was inversely associated with QUS values, although no direct association was observed between the ALPL variants and QUS values. An association between serum ALP activity and QUS was confirmed; however, we failed to detect an association between ALPL variants and bone traits in the general Japanese population.

Accumulation of advanced glycation end products (AGEs) has been linked with cognitive decline as a risk factor based on the analysis in small populations. We investigated the association between skin autofluorescence of AGEs and global cognitive function in a Japanese older (≥60 years) population (n = 4,041). The AGEs quartiles were inversely associated with the Revised Hasegawa's Dementia Scale score (Q1: reference, Q2: β= -0.011, p = 0.537, Q3: β= -0.043, p = 0.016, Q4: β= -0.064, p < 0.001) independent of major risk factors. Accumulation of AGEs was associated with lower cognitive performance in older adults.

Nocturia in older adults has been reported to be a risk factor for cardiovascular outcomes, and the stiffening of large arteries might be an underlying mechanism. To clarify the possible association between nocturia and arterial stiffness, we analyzed a dataset from the Japanese general population. Study participants consisted of 5928 community residents (mean age: 60.0 ± 11.8 years). The frequency of nocturnal urination was recorded for 1 week using a sleep diary. Arterial stiffness was assessed by brachial-to-ankle pulse wave velocity (baPWV). Sleep blood pressure was measured automatically at 0000, 0200, and 0400 hours by wearing a cuff on the upper arm during sleep. The mean baPWV was 1278 ± 227 cm/s. The frequency of nocturnal urination showed a linear positive association with baPWV (P < 0.001). The association between a sleep diary-based nocturnal urination frequency > 1.5 times/night (corresponding to a ≥ 2 times/night frequency obtained by the questionnaire) and baPWV remained significant after adjusting for major covariates, including office blood pressure (β = 0.051, P < 0.001) and sleep blood pressure (β = 0.040, P < 0.001). This association was more prominent in men (β = 0.069, P < 0.001) than in women (β = 0.023, P = 0.013), particularly in older (β = 0.068, P = 0.006) compared with younger (β = 0.029, P = 0.270) men. Frequent nocturnal urination was independently associated with baPWV in older men. Nocturia may be a marker for cardiovascular disease risks that cannot be assessed by conventional risk factors such as blood pressure.

Background: Nocturia is a risk factor for poor quality of life and increased mortality. This study was aimed to clarifying dietary habits, eating behaviors, and sleep characteristics associated with nocturia to identify modifiable lifestyle factors for nocturia., Methods: This cross-sectional study included 5683 community residents (64.5 ± 7.7 years old). The frequency of nocturnal urination was recorded for 1 week using a sleep diary. The frequency of food intake, unfavorable eating behaviors, and sleep characteristics that may have influence on salt intake and wasting were obtained using a structured questionnaire., Results: The frequency of nocturnal urination was increased with age (β = .312, P < .001). Other basic factors associated with the frequency were the male sex (β = .090), hypertension (β = .038), sleep apnea (β = .030), B-type natriuretic peptide level (β = .089), and spot urine sodium excretion (β = -.058). Dietary factors independently associated with nocturnal urination frequency were coffee (≥1 time/day: β = -.059, P < .001) and green vegetable consumption (≥1 time/week: β = -.042, P = .001), whereas habitual intake of dairy products, miso soup, and alcohol were not associated with urination frequency. Later bedtime was inversely associated with nocturnal urination frequency independent of sleep duration (before 23:00: β = -.096; before 24:00: β = -.225; after midnight: β = -.240; all P < .001)., Conclusion: Coffee and green vegetable consumption and later bedtime but not sleep duration are lifestyle factors associated with nocturnal urination frequency., (© 2019 Wiley Periodicals, Inc.)

Aim: Nocturia is a common phenomenon in older individuals, and is associated with poor quality of life. Nocturia is a multifactorial disorder, wherein the frailty of skeletal muscles, particularly muscle weakness in the lower trunk and hip regions, might be a risk factor in women. We analyzed a dataset of the general Japanese population to clarify the hypothesis., Methods: Study participants included 1207 older women (mean age 67.4 ± 5.2 years). The frequency of nocturnal urination was assessed using a sleep diary for 1 week, and associations with lower muscle strength, skeletal muscle index, sarcopenia and physical performance (one-leg standing time and Timed Up and Go test) were investigated., Results: The frequency of nocturnal urination more than one voiding per night was 28.1%; this frequency was inversely associated with hip abduction strength quartiles (Q1: 37.0, Q2: 30.5, Q3: 25.1 and Q4: 19.9%, P < 0.001). When a sleep diary-based nocturnal urination frequency >1.5 times/night (corresponding to a ≥2 times/night frequency obtained by questionnaire) was considered as nocturia, logistic regression analysis adjusted for major covariates identified hip abduction strength as an independent inverse determinant of nocturia (odds ratio 0.75, 95% CI 0.52-0.90, P = 0.002). In contrast, no significant association was observed with knee extension (P = 0.322) and hip flexion (P = 0.603) strengths. Physical performance, skeletal muscle index and sarcopenia did not show significant associations with nocturia., Conclusions: Weak hip abduction strength might be a factor associated with nocturnal urination frequency in older women. Geriatr Gerontol Int 2019; 19: 1010-1016., (© 2019 Japan Geriatrics Society.)

The sodium-to-potassium ratio (Na/K) of a urine sample is a simple index of salt loading. To practically use Na/K, we aimed to determine whether the Na/K value affects blood pressure (BP) at any age, irrespective of urinary Na and K levels. We analyzed a dataset of the general population (the Nagahama study), including baseline and second-visit measurements performed 5 years after the baseline. Spot urine samples were used for Na/K assessments. A total of 18,505 observations were analyzed using a linear mixed model, including the measurement term as a random effect. Urinary Na/K values showed a positive association with BP. When the highest quartile of Na/K was further divided by the urinary Na/creatinine (Cre) and K/Cre levels, the high-Na/Cre (3.58) and high-K/Cre (0.75) (Na/K = 4.80) groups, as well as the low Na/Cre (1.23) and low-K/Cre (0.26) (Na/K = 4.87) groups, exhibited similar effects on systolic BP (6.82 mmHg [95% CI: 5.72-7.92] and 6.63 mmHg [95% CI: 5.35-7.91], respectively). A similar association was observed in other Na/K quartiles. The positive association of Na/K and Na/Cre with BP was steeper in the older groups, while the inverse association of K/Cre was predominant in the younger population. The results of the multivariate analysis identified interaction terms between age and Na/K, Na/Cre and K/Cre as significant determinants for SBP. The positive association of urinary Na/K with BP was independent of the urinary Na and K levels. The association between Na/K and BP may not be uniform across ages by decade.

Objectives: We aimed to analyze associations of sleep disturbance, including sleep disordered breathing, sleep fragmentation, and sleep efficiency, with abnormal nocturnal blood pressure (BP) profiles that may be risk factors for adverse cardiovascular outcomes., Methods: The study included 5854 community residents with 20,725 multi-day measurements. Sleep fragmentation and efficiency were evaluated using a wrist-worn activity monitor. Sleep disordered breathing was assessed using the 3% oxygen desaturation index corrected for actigraphy-determined sleep duration. A timer-equipped standard cuff-oscillometric device was used for home and sleep BP monitoring., Results: Mean nocturnal systolic BP (SBP) change was -8.6 ± 9.7% (-11.1 ± 12.6 mmHg), and inter-day correlation coefficient of the nocturnal SBP change was 0.443. Results of a linear mixed model analysis using daily measured values identified lower sleep efficiency (coefficient = -0.130, p < 0.001) as a determinant for decreased nocturnal SBP dipping beyond the interday variations of these parameters. Number of nocturnal urinations was another strong determinant (coefficient = 1.191, p < 0.001), although the association of sleep efficiency was independent of nocturnal urination, awake SBP, and sleep disordered breathing (coefficient = -0.102, p < 0.001). Sleep efficiency was also independently associated with sleep SBP level (coefficient = -0.138, p < 0.001). Estimated differences in nocturnal SBP dipping and sleep SBP level as a function of the degree of sleep efficiency (less than 80%) reached 1.63% (1.09-2.17%) and 2.16 mmHg (1.49-2.82%), respectively., Conclusion: More attention should be paid to sleep efficiency as a factor in maintaining circadian BP rhythm., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The accumulation of advanced glycation end product (AGE) might exert deleterious effects on musculoskeletal properties. Our study aims to clarify this possible association in a large general population., Methods: This study investigated a general population of 9,203 patients (mean age, 57.8 years). Skeletal muscle mass was measured by bioelectrical impedance analysis, whereas accumulation of AGEs was assessed by skin autofluorescence (SAF-AGE). The muscle strength of upper and lower limbs and usual gait speed were measured in a portion of older (≥60 years of age) participants (n = 1,934). The speed of sound (SOS) in the calcaneal bone was assessed via a quantitative ultrasound technique., Results: In the total population, the frequency of low skeletal muscle mass linearly increased with the SAF-AGE quartiles (Q1: 14.2%, Q2: 16.1%, Q3: 21.1%, Q4: 24.8%; p < .001), and this association was independent of covariates including glycemic traits (Q4: odds ratio [OR] = 1.48, p < .001). The association between the highest SAF-AGE quartile and low skeletal muscle mass remained significant in the older subpopulation (OR = 1.85, p = .002). A similar but weak association was observed for low SOS (Q1: 8.9%, Q2: 8.3%, Q3: 10.4%, Q4: 12.2%; p < .001). Similar inverse associations were also observed with grip strength (OR = 1.98, p = .003), hip flexion strength (OR = 1.50, p = .012), and hip abduction strength (OR = 1.78, p = .001), but not with usual gait speed., Conclusion: Accumulation of AGEs might be a deleterious factor for musculoskeletal properties., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)