Publications by authors named "Takahisa Kawaguchi"

123 Publications

The association between the Moyamoya disease susceptible gene RNF213 variant and incident cardiovascular disease in a general population: the Nagahama study.

J Hypertens 2021 Dec;39(12):2521-2526

Department of Medical Ethics and Medical Genetics, Kyoto University School of Public Health, Sakyo-ku, Kyoto.

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.
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http://dx.doi.org/10.1097/HJH.0000000000002964DOI Listing
December 2021

Differences between subjective and objective sleep duration according to actual sleep duration and sleep-disordered breathing: the Nagahama Study.

J Clin Sleep Med 2021 Oct 26. Epub 2021 Oct 26.

Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

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 (NRS).

Methods: This cross-sectional study evaluated 6908 community residents in Nagahama city, 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 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 <0.001) overall, as SSD is considered to be longer than OSD. In patients with SDB, the difference between SSD-OSD was greater when OSD was horter. The difference also depended on SDB severity. The degree of positivity between OSD and SSD was a significant factor in NRS (odds ratio: 2.691, P <0.001).

Conclusions: When OSD was slightly <7 (6.98) hours, participants reported or perceived SSD>OSD. When OSD was >6.98 hours, participants reported or perceived SSD
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http://dx.doi.org/10.5664/jcsm.9732DOI Listing
October 2021

Association Between Tooth Loss and Longitudinal Changes in B-Type Natriuretic Peptide Over 5 Years in Postmenopausal Women: The Nagahama Study.

Curr Probl Cardiol 2021 Sep 25:100997. Epub 2021 Sep 25.

Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.

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.
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http://dx.doi.org/10.1016/j.cpcardiol.2021.100997DOI Listing
September 2021

Association between serum α1-antitrypsin levels and all-cause mortality in the general population: the Nagahama study.

Sci Rep 2021 08 26;11(1):17241. Epub 2021 Aug 26.

Graduate School of Public Health, Shizuoka Graduate University of Public Health, Aoi-ku, Shizuoka, 420-0881, Japan.

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.
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http://dx.doi.org/10.1038/s41598-021-96833-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390682PMC
August 2021

Association of Sleep Disordered Breathing and Blood Pressure with Albuminuria: The Nagahama Study.

Ann Am Thorac Soc 2021 Aug 4. Epub 2021 Aug 4.

Graduate School of Medicine, Kyoto University, Respiratory Care and Sleep Control Medicine, Kyoto, Japan;

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 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. Further, 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 completed 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) Further, 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. Further, 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 as a risk factor for chronic kidney disease and cardiovascular events. SDB may raise UAE not only by increasing BP but involving other pathologic pathways.
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http://dx.doi.org/10.1513/AnnalsATS.202105-528OCDOI Listing
August 2021

Impacts of lipid-related metabolites, adiposity, and genetic background on blood eosinophil counts: the Nagahama study.

Sci Rep 2021 07 28;11(1):15373. Epub 2021 Jul 28.

Department of Respiratory Medicine, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Blood eosinophil count is a useful measure in asthma or COPD management. Recent epidemiological studies revealed that body mass index (BMI) is positively associated with eosinophil counts. However, few studies focused on the role of adiposity and fatty acid-related metabolites on eosinophil counts, including the effect of genetic polymorphism. In this community-based study involving 8265 participants (30-74 year old) from Nagahama city, we investigated the relationship between eosinophil counts and serum levels of fatty acid-related metabolites. The role of MDC1, a gene that is related to eosinophil counts in our previous study and encodes a protein that is thought to be involved in the repair of deoxyribonucleic acid damage, was also examined taking into account its interaction with adiposity. Serum levels of linoleic acid (LA) and β-hydroxybutyric acid (BHB) were negatively associated with eosinophil counts after adjustment with various confounders; however, there were positive interactions between serum LA and BMI and between serum BHB and BMI/body fat percentages in terms of eosinophil counts. In never-smokers, there was positive interaction for eosinophil counts between the CC genotype of MDC1 rs4713354 and BMI/body fat percentages. In conclusion, both serum LA and BHB have negative impacts on eosinophil counts, while adiposity shows robust positive effects on eosinophil counts, partly via genetic background in never-smokers.
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http://dx.doi.org/10.1038/s41598-021-94835-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319143PMC
July 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

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), 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.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Brachial-ankle pulse wave velocity and cardio-ankle vascular index are associated with future cardiovascular events in a general population: The Nagahama Study.

J Clin Hypertens (Greenwich) 2021 07 26;23(7):1390-1398. Epub 2021 May 26.

Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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.
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http://dx.doi.org/10.1111/jch.14294DOI Listing
July 2021

Pre-emptive Short-term Nicotinamide Mononucleotide Treatment in a Mouse Model of Diabetic Nephropathy.

J Am Soc Nephrol 2021 06 1;32(6):1355-1370. Epub 2021 Apr 1.

Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.

Background: The activation of NAD-dependent deacetylase, Sirt1, by the administration of nicotinamide mononucleotide (NMN) ameliorates various aging-related diseases.

Methods: Diabetic mice were treated with NMN transiently for 2 weeks and observed for effects on diabetic nephropathy (DN).

Results: At 14 weeks after the treatment period, NMN attenuated the increases in urinary albumin excretion in mice without ameliorating hemoglobin A1c levels. Short-term NMN treatment mitigated mesangium expansion and foot process effacement, while ameliorating decreased Sirt1 expression and increased claudin-1 expression in the kidneys of mice. This treatment also improved the decrease in the expression of H3K9me2 and DNMT1. Short-term NMN treatment also increased kidney concentrations of NAD and the expression of Sirt1 and nicotinamide phosphoribosyltransferase (Nampt), and it maintained nicotinamide mononucleotide adenyltransferase1 (Nmnat1) expression in the kidneys. In addition, survival rates improved after NMN treatment.

Conclusions: Short-term NMN treatment in early-stage DN has remote renal protective effects through the upregulation of Sirt1 and activation of the NAD salvage pathway, both of which indicate NMN legacy effects on DN.
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http://dx.doi.org/10.1681/ASN.2020081188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259649PMC
June 2021

Genome wide association study of HTLV-1-associated myelopathy/tropical spastic paraparesis in the Japanese population.

Proc Natl Acad Sci U S A 2021 03;118(11)

Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Sakyo-ku, 606-8507 Kyoto, Japan;

HTLV-1-associated myelopathy (HAM/TSP) is a chronic and progressive inflammatory disease of the central nervous system. The aim of our study was to identify genetic determinants related to the onset of HAM/TSP in the Japanese population. We conducted a genome-wide association study comprising 753 HAM/TSP patients and 899 asymptomatic HTLV-1 carriers. We also performed comprehensive genotyping of , , , , , and genes using next-generation sequencing technology for 651 HAM/TSP patients and 804 carriers. A strong association was observed in class I ( = 1.54 × 10) and class II ( = 1.21 × 10) loci with HAM/TSP. Association analysis using genotyping results showed that * ( = 2.61 × 10), * ( = 4.97 × 10), * ( = 1.15 × 10) and * ( = 2.30 × 10) were associated with disease risk, while * ( = 3.03 × 10), * ( = 1.06 × 10) and * ( = 1.78 × 10) worked protectively. Logistic regression analysis identified amino acid position 7 in the G-BETA domain of HLA-DRB1 as strongly associated with HAM/TSP ( = 9.52 × 10); individuals homozygous for leucine had an associated increased risk of HAM/TSP (odds ratio, 9.57), and proline was protective (odds ratio, 0.65). Both associations were independent of the known risk associated with proviral load. DRB1-GB-7-Leu was not significantly associated with proviral load. We have identified DRB1-GB-7-Leu as a genetic risk factor for HAM/TSP development independent of proviral load. This suggests that the amino acid residue may serve as a specific marker to identify the risk of HAM/TSP even without knowledge of proviral load. In light of its allele frequency worldwide, this biomarker will likely prove useful in HTLV-1 endemic areas across the globe.
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http://dx.doi.org/10.1073/pnas.2004199118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980450PMC
March 2021

Diabetic condition induces hypertrophy and vacuolization in glomerular parietal epithelial cells.

Sci Rep 2021 01 15;11(1):1515. Epub 2021 Jan 15.

Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Diabetic nephropathy (DN) is accompanied by characteristic changes in the glomerulus, but little is known about the effect of diabetes on parietal epithelial cells (PECs). In this study, a descriptive analysis of PECs was undertaken in diabetic db/db mice and in diabetic patients. PEC hypertrophy was significantly more prominent in diabetic mice than in nondiabetic mice, and this was evident even at the early stage. Additionally, the number of vacuoles in PECs was markedly increased in diabetic mice, suggesting the presence of cellular injury in PECs in DN. Although rare, binuclear cells were observed in mice with early diabetes. In cultured PECs, a high glucose condition, compared with normal glucose condition, induced cellular hypertrophy and apoptosis. Flow cytometry showed that some PECs in the G0 phase reentered the cell cycle but got arrested in the S phase. Finally, in human diabetic subjects, hypertrophy and vacuolization were observed in the PECs. Our data showed that PECs undergo substantial changes in DN and may participate in rearrangement for differentiation into podocytes.
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http://dx.doi.org/10.1038/s41598-021-81027-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810998PMC
January 2021

Gastroesophageal reflux disease is a risk factor for sputum production in the general population: the Nagahama study.

Respir Res 2021 Jan 6;22(1). Epub 2021 Jan 6.

Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54, Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: Chronic sputum production in the general population is historically associated with clinical indices including male sex and smoking history. However, its relationship with gastroesophageal reflux disease (GERD), which may prove an underlying factor in sputum production, is unclear. We aimed to clarify factors associated with sputum production in the general population in cross-sectional and longitudinal manners.

Methods: In the Nagahama study, a community-based cohort study, 9804 subjects were recruited between 2008 and 2010 (baseline assessment), 8293 of whom were followed from 2013 to 2015 (follow-up assessment). This study contained a self-completed questionnaire which included medical history, assessment of sputum production, and a frequency scale for symptoms of GERD. A Frequency Scale for Symptoms of Gastroesophageal Reflux Disease score of ≥ 8 was defined as GERD. In addition to the frequency of sputum production at each assessment, frequency of persistent sputum production defined as sputum production at both assessments was examined.

Results: Frequency of sputum production was 32.0% at baseline and 34.5% at follow-up. Multivariable analysis demonstrated that sputum production at baseline was significantly associated with GERD [odds ratio (OR), 1.92; 95% confidence interval (CI) 1.73-2.13] and post-nasal drip (PND) (OR, 2.40; 95% CI 2.15-2.68), independent of other known factors such as older age, male sex and smoking history. These associations between sputum production and GERD or PND were also observed at follow-up. In longitudinal analysis, 19.4% had persistent sputum production and 12.3% had transient sputum production, i.e., at baseline only. Multivariable analysis for risk of persistence of sputum production revealed that persistent sputum production was associated with GERD and PND, in addition to the known risk factors listed above. The proportion of subjects with GERD at both assessments was highest among subjects with persistent sputum production.

Conclusions: Cross-sectional and longitudinal analysis demonstrated an association in the general population between sputum production and GERD, as well as PND, independent of known risk factors. The presence of GERD should be assessed in patients complaining of sputum production.
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http://dx.doi.org/10.1186/s12931-020-01601-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788913PMC
January 2021

Genome-wide association study of individual differences of human lymphocyte profiles using large-scale cytometry data.

J Hum Genet 2021 Jun 23;66(6):557-567. Epub 2020 Nov 23.

Department of Statistical Genetics, Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

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.
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http://dx.doi.org/10.1038/s10038-020-00874-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144016PMC
June 2021

Medical history of nocturnal enuresis during school age is an independent risk factor for nocturia in adults: The Nagahama study.

Neurourol Urodyn 2021 01 29;40(1):326-333. Epub 2020 Oct 29.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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.
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http://dx.doi.org/10.1002/nau.24562DOI Listing
January 2021

Night-time frequency of urination as a manifestation of sleep-disordered breathing: the Nagahama study.

Sleep Med 2021 01 12;77:288-294. Epub 2020 Sep 12.

Department of Respiratory Care and Sleep Control Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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.
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http://dx.doi.org/10.1016/j.sleep.2020.09.007DOI Listing
January 2021

Impact of sleep-disordered breathing on glucose metabolism among individuals with a family history of diabetes: the Nagahama study.

J Clin Sleep Med 2021 02;17(2):129-140

Department of Respiratory Care and Sleep Control Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

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.
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http://dx.doi.org/10.5664/jcsm.8796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853232PMC
February 2021

Home device-monitored sleep blood pressure reflects large artery stiffness: the Nagahama study.

J Hypertens 2020 12;38(12):2459-2464

Center for Gnomic Medicine, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto.

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.
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http://dx.doi.org/10.1097/HJH.0000000000002576DOI Listing
December 2020

Descriptive epidemiology of high frequency component based on heart rate variability from 10-second ECG data and daily physical activity among community adult residents: the Nagahama Study.

Biosci Trends 2020 Sep 4;14(4):241-247. Epub 2020 Jul 4.

Department of Health Informatics, Kyoto University School of Public Health, Kyoto, Japan.

Characteristics of high frequency (HF) component based on heart rate variability (HRV) in a large general population remain unclear, particularly on the relationship with daily physical activity. We aimed to characterize the distribution of HF component and examine the association with daily physical activity among community residents. We performed spectral analysis of HRV from 10-second ECG recordings among 9135 residents aged 30 to 74 years in Nagahama City, Japan. HF components were log-transformed to consider the distribution. Simple correlations between HF and age were determined. Age-adjusted mean values of HF component were calculated for each questionnaire item related to daily physical activity. Multiple regression analysis was performed to examine the effect of daily physical activity on HF component value. Mean values of logarithmically-transformed HF component (lnHF) were higher in women than in men (p < 0.001). lnHF was inversely associated with age (r = -0.40, -0.49 for men, women, respectively). Adjusted mean lnHF for physically active people was significantly higher than that in inactive people (p < 0.001). HF components from 10-second ECG recordings were moderately and negatively correlated with age in both sexes, and positively correlated with daily physical activity in the general adult population. Maintaining the level of daily physical activity, especially to exercise regularly could keep the parasympathetic function high.
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http://dx.doi.org/10.5582/bst.2020.03146DOI Listing
September 2020

Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer.

Nat Commun 2020 06 24;11(1):3175. Epub 2020 Jun 24.

Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, 464-8681, Japan.

Pancreatic cancer is the fourth leading cause of cancer-related deaths in Japan. To identify risk loci, we perform a meta-analysis of three genome-wide association studies comprising 2,039 pancreatic cancer patients and 32,592 controls in the Japanese population. Here, we identify 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P < 5.0 × 10), of which 16p12.3 has not been reported in the Western population. The lead single nucleotide polymorphism (SNP) at 16p12.3 is rs78193826 (odds ratio = 1.46, 95% confidence interval = 1.29-1.66, P = 4.28 × 10), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant. Associations between selected GP2 gene variants and pancreatic cancer are replicated in 10,822 additional cases and controls of East Asian origin. Functional analyses using cell lines provide supporting evidence of the effect of rs78193826 on KRAS activity. These findings suggest that GP2 gene variants are probably associated with pancreatic cancer susceptibility in populations of East Asian ancestry.
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http://dx.doi.org/10.1038/s41467-020-16711-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314803PMC
June 2020

Identification of type 2 diabetes loci in 433,540 East Asian individuals.

Nature 2020 06 6;582(7811):240-245. Epub 2020 May 6.

Vanderbilt Genetics Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D); however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.
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http://dx.doi.org/10.1038/s41586-020-2263-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292783PMC
June 2020

Sleep disordered breathing and metabolic comorbidities across sex and menopausal status in East Asians: the Nagahama Study.

Eur Respir J 2020 08 20;56(2). Epub 2020 Aug 20.

Dept of Respiratory Care and Sleep Control Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

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·mThe 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.
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http://dx.doi.org/10.1183/13993003.02251-2019DOI Listing
August 2020

Comparison of diagnostic significance of the initial versus revised diagnostic algorithm for sarcopenia from the Asian Working Group for Sarcopenia.

Arch Gerontol Geriatr 2020 Jul - Aug;89:104071. Epub 2020 Apr 25.

Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan.

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.
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http://dx.doi.org/10.1016/j.archger.2020.104071DOI Listing
November 2020

Correlates of autonomic nervous system function in a general population with special reference to HbA: The Nagahama study.

Diabetes Res Clin Pract 2020 May 31;163:108126. Epub 2020 Mar 31.

Department of Health Informatics, School of Public Health, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address:

Aims: As the glucose tolerance of patients with diabetes worsens, autonomic nervous system (ANS) function decreases. Only a few studies, using plasma glucose, have reported on this relationship in large general populations that include people with wide range of glycemia. This study aimed to examine correlates of ANS function with special reference to HbA which is more stable than plasma glucose among community residents.

Methods: Spectral analysis was performed to assess heart rate variability (HRV) using 1-minute electrocardiogram RR interval data recordings from 7690 residents aged 35-79 years in Nagahama City, Japan. HRV parameters were log-transformed. Multiple regression analysis was performed using potential correlates.

Results: lnLF decreased with age (regression coefficient, -0.025; P < 0.001), BMI (-0.010; P = 0.035), and HbA (-0.068; P = 0.036). lnHF decreased with age (-0.029; P < 0.001), BMI (-0.032; P < 0.001), and HbA (-0.173; P < 0.001). lnLF/HF increased with age (0.003; P = 0.002), BMI (0.023; P < 0.001), and HbA (0.105; P < 0.001). Women showed lower lnLF and lnLF/HF than men. Sleep quality assessed by the Pittsburgh Sleep Quality Index, smoking and drinking had almost no relation.

Conclusions: Although the associations were weak, age, BMI and HbA were inversely correlated with parasympathetic activity, while positively correlated with sympathetic activity among general residents.
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http://dx.doi.org/10.1016/j.diabres.2020.108126DOI Listing
May 2020

Advanced Glycation End Product Accumulation is Associated with Lower Cognitive Performance in an Older General Population: The Nagahama Study.

J Alzheimers Dis 2020 ;74(3):741-746

Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Sakyo-ku Kyoto, Japan.

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.
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http://dx.doi.org/10.3233/JAD-190878DOI Listing
April 2021

Association of ALPL variants with serum alkaline phosphatase and bone traits in the general Japanese population: The Nagahama Study.

J Hum Genet 2020 Mar 20;65(3):337-343. Epub 2019 Dec 20.

Department of Medical Ethics and Medical Genetics, Kyoto University School of Public Health, Sakyo-ku, Kyoto, Japan.

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.
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http://dx.doi.org/10.1038/s10038-019-0712-3DOI Listing
March 2020

Lifestyle habits associated with nocturnal urination frequency: The Nagahama study.

Neurourol Urodyn 2019 11 4;38(8):2359-2367. Epub 2019 Sep 4.

Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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.
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http://dx.doi.org/10.1002/nau.24156DOI Listing
November 2019

Association of weak hip abduction strength with nocturia in older women: The Nagahama study.

Geriatr Gerontol Int 2019 Oct 1;19(10):1010-1016. Epub 2019 Sep 1.

Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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.
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http://dx.doi.org/10.1111/ggi.13761DOI Listing
October 2019
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