論文 - 杉山　大典

Reliability of urinary charged metabolite concentrations in a large-scale cohort study using capillary electrophoresis-mass spectrometry

Ishibashi Y., Harada S., Takeuchi A., Iida M., Kurihara A., Kato S., Kuwabara K., Hirata A., Shibuki T., Okamura T., Sugiyama D., Sato A., Amano K., Hirayama A., Sugimoto M., Soga T., Tomita M., Takebayashi T.

Scientific Reports （Scientific Reports）  11 （ 1 ）  2021年12月

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Currently, large-scale cohort studies for metabolome analysis have been launched globally. However, only a few studies have evaluated the reliability of urinary metabolome analysis. This study aimed to establish the reliability of urinary metabolomic profiling in cohort studies. In the Tsuruoka Metabolomics Cohort Study, 123 charged metabolites were identified and routinely quantified using capillary electrophoresis-mass spectrometry (CE-MS). We evaluated approximately 750 quality control (QC) samples and 6,720 participants’ spot urine samples. We calculated inter- and intra-batch coefficients of variation in the QC and participant samples and technical intraclass correlation coefficients (ICC). A correlation of metabolite concentrations between spot and 24-h urine samples obtained from 32 sub-cohort participants was also evaluated. The coefficient of variation (CV) was less than 20% for 87 metabolites (70.7%) and 20–30% for 19 metabolites (15.4%) in the QC samples. There was less than 20% inter-batch CV for 106 metabolites (86.2%). Most urinary metabolites would have reliability for measurement. The 96 metabolites (78.0%) was above 0.75 for the estimated ICC, and those might be useful for epidemiological analysis. Among individuals, the Pearson correlation coefficient of 24-h and spot urine was more than 70% for 59 of the 99 metabolites. These results show that the profiling of charged metabolites using CE-MS in morning spot human urine is suitable for epidemiological metabolomics studies.

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Experimental study on the efficacy of a hybrid artificial nerve: The hot dog method

Tamura R., Hashikawa K., Sakakibara S., Osaki T., Kitano D., Maruguchi H., Nomura T., Sugiyama D., Terashi H.

International Journal of Artificial Organs （International Journal of Artificial Organs）  44 （ 10 ） 711 - 717 2021年10月

ISSN  03913988

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Introduction: We hypothesized that hybrid artificial nerves might overcome the limitations of a nerve conduit by isolating nerve fascicles from autologous nerves. Nerve sacrifice during harvest, a drawback of conventional autologous nerve transplantation, may be reduced by the hot dog method. The hot dog method (based on the morphology of hybrid artificial nerves) adds nerve conduits to autologous nerve fascicles. Methods: Forty-eight rats with a 10-mm sciatic nerve defect were divided into six groups (n = 8 per group) according to the neural reconstruction method: autologous nerve transplantation, the hot dog method, nerve conduit, nerve fascicle transplantation, sham control, and nerve fascicle isolation were classified as Groups I, II, III, IV, V, and VI, respectively. The sciatic nerve function was assessed in these groups, a histological evaluation was performed, and statistical analyses were conducted based on these data. Results: Group III (nerve conduit) and Group IV (nerve fascicle transplantation) showed the lowest functional and axonal regenerative effects, followed by Group II (hot dog method) and Group I (autologous nerve transplantation). Group VI (nerve fascicle isolation) tended to achieve better recovery in motor function and axonal regeneration than Group I (autologous nerve transplantation). Conclusions: The hot dog method is simple, safe, and easy to execute. This method can serve as a new neural reconstruction method that uses artificial nerves.

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Prevalence of anti-dense fine speckled 70 antibodies in healthy individuals and patients with antinuclear antibody-associated autoimmune rheumatic diseases in Japan

Hayashi N., Uto K., Imanishi A., Sugiyama D., Morinobu A., Saegusa J.

Medicine （Medicine）  100 （ 9 ）  2021年03月

ISSN  00257974

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ABSTRACT: Previous studies from various countries have reported anti-dense fine speckled pattern (DFS)70 antibody prevalence but few studies have been from Asia. We investigated the prevalence of anti-DFS70 autoantibodies in a Japanese cohort of healthy individuals (HI) and patients with antinuclear antibody-associated autoimmune rheumatic diseases (AARD).Enzyme-linked immunosorbent assay and indirect immunofluorescence were performed using samples from 250 HI and 276 AARD patients.The overall anti-DFS70 antibody prevalence in HI was 16.4%, with 12.8% for males and 20.0% for females (sex difference; P = .12). In AARD patients, the anti-DFS70 antibody prevalence in systemic lupus erythematosus, mixed connective tissue disease, systemic sclerosis, dermatomyositis and polymyositis (DM/PM), Sjögren syndrome, and rheumatoid arthritis (RA) was 22.1%, 14.3%, 14.3%, 3.0%, 21.3%, and 18.1%, respectively (no significant difference between AARD patients except DM/PM and HI). The prevalence of isolated anti-DFS70 antibody in HI and all AARD patients excluding RA was 14.8% (37/250) and 4.4% (9/204), respectively (P  < .01 vs HI). Among anti-DFS70 antibody-positive cases, 63.4% (26/41) were DFS pattern by IIF and 23.5% (8/34) were HI and AARD patients excluding RA, respectively.The anti-DFS70 antibody prevalence in HI and AARD patients in Japan was similar. Furthermore, the anti-DFS70 antibody prevalence in HI and AARD in Japan is higher than in HI and AARD in regions other than Asia. This makes AARD differential diagnosis by antinuclear antibody screening difficult.

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The effect of soy isoflavones on arterial stiffness: a systematic review and meta-analysis of randomized controlled trials

Man B., Cui C., Zhang X., Sugiyama D., Barinas-Mitchell E., Sekikawa A.

European Journal of Nutrition （European Journal of Nutrition）  60 （ 2 ） 603 - 614 2021年03月

ISSN  14366207

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Purpose: Some but not all randomized controlled trials (RCTs) of soy isoflavones showed their beneficial effect on arterial stiffness, a predictor of cardiovascular events, dementia, and all-cause mortality, independent of traditional risk factors. To test the hypothesis that supplementation of soy isoflavones reduces arterial stiffness, we performed a systematic review and meta-analysis of RCTs of soy isoflavones on arterial stiffness. Methods: The protocol of this systematic review was registered with PROSPERO (CRD42019126128) and written in accordance with PRISMA. The PubMed, Embase, and clinicaltrials.gov databases were searched using the following criteria: human subjects, soy isoflavones as intervention, and arterial stiffness as primary outcome. A random-effects meta-analysis was used to pool estimates across studies. Standardized mean difference (SMD) was used to synthesize quantitative results. Results: Among 998 articles retrieved, 8 articles met our criteria. Duration of intervention was relatively short (maximum of 12 weeks). Outcome measurements extracted were pulse wave velocity (PWV), systemic arterial compliance (SAC), augmentation index (AI), and cardio-ankle vascular index (CAVI). Soy isoflavones reduced arterial stiffness compared to placebo (standardized mean difference − 0.33, 95% confidence interval − 0.47, − 0.19). Subgroup analyses showed no difference between treatment effects for intervention duration (< 6 weeks vs. ≥ 6 weeks) or gender (women only vs. men only vs. combined). Sensitivity analysis showed no difference in the effect of soy isoflavones between PWV, CAVI, SAC, and AI. Conclusion: Supplementation of soy isoflavones reduced arterial stiffness. Longer duration trials with larger number of participants are warranted.

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Charged metabolite biomarkers of food intake assessed via plasma metabolomics in a population-based observational study in Japan

Shibutami E., Ishii R., Harada S., Kurihara A., Kuwabara K., Kato S., Iida M., Akiyama M., Sugiyama D., Hirayama A., Sato A., Amano K., Sugimoto M., Soga T., Tomita M., Takebayashi T.

PLoS ONE （PLoS ONE）  16 （ 2 February ）  2021年02月

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Food intake biomarkers can be critical tools that can be used to objectively assess dietary exposure for both epidemiological and clinical nutrition studies. While an accurate estimation of food intake is essential to unravel associations between the intake and specific health conditions, random and systematic errors affect self-reported assessments. This study aimed to clarify how habitual food intake influences the circulating plasma metabolome in a free-living Japanese regional population and to identify potential food intake biomarkers. To achieve this aim, we conducted a cross-sectional analysis as part of a large cohort study. From a baseline survey of the Tsuruoka Metabolome Cohort Study, 7, 012 eligible male and female participants aged 40-69 years were chosen for this study. All data on patients' health status and dietary intake were assessed via a food frequency questionnaire, and plasma samples were obtained during an annual physical examination. Ninety-four charged plasma metabolites were measured using capillary electrophoresis mass spectrometry, by a non-targeted approach. Statistical analysis was performed using partial-least-square regression. A total of 21 plasma metabolites were likely to be associated with long-term food intake of nine food groups. In particular, the influential compounds in each food group were hydroxyproline for meat, trimethylamine- N-oxide for fish, choline for eggs, galactarate for dairy, cystine and betaine for soy products, threonate and galactarate for carotenoid-rich vegetables, proline betaine for fruits, quinate and trigonelline for coffee, and pipecolate for alcohol, and these were considered as prominent food intake markers in Japanese eating habits. A set of circulating plasma metabolites was identified as potential food intake biomarkers in the Japanese community-dwelling population. These results will open the way for the application of new reliable dietary assessment tools not by self-reported measurements but through objective quantification of biofluids.

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Validity assessment of self-reported medication use for hypertension, diabetes, and dyslipidemia in a pharmacoepidemiologic study by comparison with health insurance claims

Matsumoto M., Harada S., Iida M., Kato S., Sata M., Hirata A., Kuwabara K., Takeuchi A., Sugiyama D., Okamura T., Takebayashi T.

Journal of Epidemiology （Journal of Epidemiology）  31 （ 9 ） 495 - 502 2021年

ISSN  09175040

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Background: Although self-reported questionnaires are widely employed in epidemiologic studies, their validity has not been sufficiently assessed. The aim of this study was to evaluate the validity of a self-reported questionnaire on medication use by comparison with health insurance claims and to identify individual determinants of discordance in the Tsuruoka Metabolomics Cohort Study. Methods: Participants were 2,472 community-dwellers aged 37 to 78 years from the Tsuruoka Metabolomics Cohort Study. Information on lifestyle and medications was collected through a questionnaire. Sensitivity and specificity were determined using health insurance claims from November 2014 to March 2016, which were used as a standard. Potential determinants of discordance were assessed using multivariable logistic regression. Results: The self-reported questionnaire on medication use showed high validity. Sensitivity and specificity were 0.95 (95% CI, 0.93–0.96) and 0.97 (95% CI, 0.96–0.98) for antihypertensive medications, 0.94 (95% CI, 0.91–0.97) and 0.98 (95% CI, 0.98–0.99) for diabetes medications, and 0.84 (95% CI, 0.82–0.87) and 0.98 (95% CI, 0.97–0.99) for dyslipidemia medications, respectively. Males without high education and those who currently smoke cigarettes were found to be associated with discordant reporting which affected sensitivity, especially those with medication use for dyslipidemia. Conclusions: In this population-based cohort study, we found that the self-reported questionnaire on medication use was a valid measure to capture regular medication users. Sensitivity for dyslipidemia medications was lower than those for the other medications. Type of medication, sex, education years, and smoking status influenced discordance, which affected sensitivity in self-reporting.

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Association of the estimated coronary artery incidence risk according to the japan atherosclerosis society guidelines 2017 with cardio-ankle vascular index

Sata M., Okamura T., Harada S., Sugiyama D., Kuwabara K., Hirata A., Takeuchi A., Iida M., Kato S., Matsumoto M., Kurihara A., Takebayashi T.

Journal of Atherosclerosis and Thrombosis （Journal of Atherosclerosis and Thrombosis）  28 （ 12 ） 1266 - 1274 2021年

ISSN  13403478

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Aims: The categories in the comprehensive lipid and risk management guidelines were proposed by the Japan Atherosclerosis Society (JAS Guidelines 2017), which adopted the estimated 10 year absolute risk of coronary artery disease (CAD) incidence in the Suita score. We examined whether those categories were concordant with the degree of arterial stiffness. Methods: In 2014, the cardio-ankle vascular index (CAVI), an arterial stiffness parameter, was measured in 1,972 Japanese participants aged 35–74 years in Tsuruoka City, Yamagata Prefecture, Japan. We examined the mean CAVI and the proportion and odds ratios (ORs) of CAVI ≥ 9.0 on the basis of the following three management classifications using the analysis of variance and logistic regression: “Category I (Low risk),” “Category II (Middle risk),” and “Category III (High risk).” Results: The mean CAVI and proportion of CAVI ≥ 9.0 were 8.6 and 34.8% among males and 8.1 and 18.3% among females, respectively. The mean CAVI and proportion of CAVI ≥ 9.0 were associated with an estimated 10 year absolute risk for CAD among males and females, excluding High risk for females. These results were similar to the management classification by the guideline: the multivariable-adjusted ORs (95% confidence intervals) of CAVI ≥ 9.0 among Category II and Category III compared with those among Category I were 2.96 (1.61–5.43) and 7.33 (4.03–13.3) for males and 3.99 (2.55–6.24) and 3.34 (2.16–5.16) for females, respectively. Conclusions: The risk stratification, which was proposed in the JAS Guidelines 2017, is concordant with the arterial stiffness parameter.

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A combination of blood pressure and total cholesterol increases the lifetime risk of coronary heart disease mortality: EPOCH–JAPAN

Satoh M., Ohkubo T., Asayama K., Murakami Y., Sugiyama D., Waki T., Tanaka-Mizuno S., Yamada M., Saitoh S., Sakata K., Irie F., Sairenchi T., Ishikawa S., Kiyama M., Okayama A., Miura K., Imai Y., Ueshima H., Okamura T.

Journal of Atherosclerosis and Thrombosis （Journal of Atherosclerosis and Thrombosis）  28 （ 1 ） 6 - 24 2021年

ISSN  13403478

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

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Electrocardiographic left atrial abnormality and b-type natriuretic peptide in a general Japanese population: NIPPON DATA2010

Shoji S., Kohsaka S., Sawano M., Okamura T., Hirata A., Sugiyama D., Ohkubo T., Nakamura Y., Watanabe M., Kadota A., Ueshima H., Okayama A., Miura K.

Journal of Atherosclerosis and Thrombosis （Journal of Atherosclerosis and Thrombosis）  28 （ 1 ） 34 - 43 2021年

ISSN  13403478

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Aims: P-wave terminal force in lead V1 (PTFV1) is an electrocardiogram marker of increased left atrial pressure and may be a noninvasive and early detectable marker for future cardiovascular events in the general population compared to serum B-type natriuretic peptide (BNP) concentration. The clinical significance of PTFV1 in the contemporary general population is an area of unmet need. We aimed to demonstrate the correlation between PTFV1 and BNP concentrations in a contemporary representative Japanese population. Methods: Among 2,898 adult men and women from 300 randomly selected districts throughout Japan (NIPPON DATA2010), we analyzed 2,556 participants without cardiovascular disease (stroke, myocardial infarction, and atrial fibrillation). Elevated BNP was defined as a value of ≥ 20 pg/mL based on the definition from the Japanese Circulation Society guidelines. Results: In total, 125 (4.9%) participants had PTFV1. Participants with PTFV1 were older with a higher prevalence of hypertension, major electrocardiographic findings, and elevated BNP concentrations (13.5 [6.9, 22.8] versus 7.8 [4.4, 14.5] pg/mL; P＜0.001). After adjustment for confounders, PTFV1 was correlated with elevated BNP (odds ratio, 1.66; 95% confidence interval, 1.05–2.62; P= 0.030). This correlation was consistent among various subgroups and was particularly evident in those aged ＜65 years or those without a history of hypertension. Conclusions: In the contemporary general population cohort, PTFV1 was independently related to high BNP concentration. PTFV1 may be an alternative marker to BNP in identifying individuals at a higher risk of future cardiovascular events in the East Asian population.

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Estimated 24 h urinary sodium-to-potassium ratio is related to renal function decline: A 6-year cohort study of japanese urban residents

Hattori H., Hirata A., Kubo S., Nishida Y., Nozawa M., Kawamura K., Hirata T., Kubota Y., Sata M., Kuwabara K., Higashiyama A., Kadota A., Sugiyama D., Miyamatsu N., Miyamoto Y., Okamura T.

International Journal of Environmental Research and Public Health （International Journal of Environmental Research and Public Health）  17 （ 16 ） 1 - 12 2020年08月

ISSN  16617827

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The effect of the sodium-to-potassium ratio (Na/K) on renal function within the clinically normal range of renal function are limited. We investigated the effects of an estimated 24 h urinary Na/K (e24hUNa/K) on a 6-year renal function decline among 927 urban Japanese community dwellers with no history of cardiovascular diseases and medication for hypertension, diabetes, or dyslipidemia. We partitioned the subjects into quartiles according to the e24hUNa/K. The estimated glomerular filtration rate (eGFR) was calculated using the chronic kidney disease epidemiology collaboration (CKD/EPI) formula and renal function decline was defined as an absolute value at or above the third quartile of the eGFR decline rate. A multivariable logistic regression model was used for estimation. Compared with the first quartile of the e24hUNa/K, multivariable-adjusted odds ratios (ORs) for eGFR decline in the second, third, and fourth quartiles were 0.96 (95% confidence interval: 0.61–1.51), 1.06 (0.67–1.66), and 1.65 (1.06–2.57), respectively. These results were similar when the simple spot urine Na/K ratio was used in place of the e24hUNa/K. Apparently healthy urban residents with an almost within normal range mean baseline eGFR and high e24hUNa/K ratios had an increased risk for a future decline in renal function. Reducing the Na/K ratio may be important in the prevention of chronic kidney disease in its early stage.

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US detection of medial meniscus extrusion can predict the risk of developing radiographic knee osteoarthritis: a 5-year cohort study

Chiba D., Sasaki E., Ota S., Maeda S., Sugiyama D., Nakaji S., Ishibashi Y.

European Radiology （European Radiology）  30 （ 7 ） 3996 - 4004 2020年07月

ISSN  09387994

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Objectives: To clarify the relationship between the baseline value of medial meniscus extrusion (MME) and the radiographic change of knee osteoarthritis (KOA) through a 5-year follow-up. Methods: Overall, 472 participants and 944 knees were eligible. MME (mm) was measured at the baseline, and KOA was radiographically evaluated at both baseline and 5-year follow-up by Kellgren-Lawrence grade (KLG). Radiographic KOA (ROA) was defined as the knee showing KLG ≥ 2. Incident ROA (iROA) was defined if the baseline KLG of 0–1 increased to KLG ≥ 2 in 5 years. Progressive ROA (pROA) was defined if the baseline KLG of 2–3 worsened to a higher grade in 5 years. Receiver operating characteristic (ROC) curve and generalized estimating equations were used for analysis. Results: Of 574 non-ROA knees at the baseline, 43 knees (7.5%) developed iROA; of 370 ROA knees, 47 knees (12.7%) developed pROA. Based on the ROC curves, 4 mm was the optimal cutoff to detect the risk of iROA (area under curve [AUC] 0.639 [right knee]; AUC 0.641 [left knee]) and that of pROA (AUC 0.750 [right knee]; AUC 0.863 [left knee]). Multiple regression analysis showed that the 4-mm cutoff of MME was significantly associated with both the prevalence of iROA (regression coefficient [B] 1.909; p ≤ 0.001; adjusted odds ratio [aOR] 6.746) and that of pROA (B 1.791; p ≤ 0.001; aOR 5.993). Conclusions: On ultrasonography, the participants with more extruded medial meniscus showed a higher prevalence of both iROA and pROA. Ultrasonography could identify patients who had a risk of developing KOA. Key Points: • Through a 5-year follow-up, the current cohort study was conducted to clarify the relationship between the baseline value of medial meniscus extrusion (MME) and the radiographic change of knee osteoarthritis (KOA). • More extruded medial meniscus evaluated by ultrasonography was associated with the development of radiographic KOA. • Ultrasonography could identify the patients who had a risk of developing KOA, and the 4-mm cutoff of MME was optimal to detect this risk.

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Hypercholesterolemia and lifetime risk of coronary heart disease in the general japanese population: Results from the suita cohort study

Sugiyama D., Turin T.C., Yeasmin F., Rumana N., Watanabe M., Higashiyama A., Takegami M., Kokubo Y., Okamura T., Miyamoto Y.

Journal of Atherosclerosis and Thrombosis （Journal of Atherosclerosis and Thrombosis）  27 （ 1 ） 60 - 70 2020年

ISSN  13403478

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Lifetime risk (LTR) is a measure of disease burden, which presents the probability of occurrence of a specific disease in the remaining lifetime of a group of people for a given index age. This measure is useful for presenting the risk dynamics of a disease at the population level, which constitutes important public health information toward prevention. To date, there have been no studies investigating the LTR for coronary heart diseases (CHDs) in relation to hypercholesterolemia in Asian populations. Therefore, we estimated the LTR of CHDs according to serum low-density lipoprotein cholesterol (LDL-C). Methods: The participants included in this study were 2,559 men and 2,848 women, enrolled in the Suita Cohort Study of urban residents followed up from 1989 to 2007 for a total of 69,823 person-years. We estimated the sex-and index-age-specific LTR for the first CHD event among participants with or without hypercholesterolemia (LDL-C ≥ 160 mg/dL), accounting for the competing risk for mortality. Results: For men with hypercholesterolemia, the LTR was 47.2% (95% confidence interval [CI]: 29.3–65.1%) and 44.5% (95% CI: 21.4–68.5%) for those aged 45 and 75, respectively. The LTRs of women with hypercholesterolemia were also higher than of those without hypercholesterolemia. However, their LTRs were lower for all index ages compared to men. These results did not differ for hypercholesterolemia defined by non-high-density lipoprotein cholesterol. Conclusions: The presence of hypercholesterolemia increases the LTR for CHDs in the Japanese population, especially in men. This estimate can be used in preventive knowledge translation efforts at the population level.

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Association between dyslipidemia and plasma levels of branched-chain amino acids in the Japanese population without diabetes mellitus

Fukushima K., Harada S., Takeuchi A., Kurihara A., Iida M., Fukai K., Kuwabara K., Kato S., Matsumoto M., Hirata A., Akiyama M., Tomita M., Hirayama A., Sato A., Suzuki C., Sugimoto M., Soga T., Sugiyama D., Okamura T., Takebayashi T.

Journal of Clinical Lipidology （Journal of Clinical Lipidology）  13 （ 6 ） 932 - 939.e2 2019年11月

ISSN  19332874

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Background: Branched-chain amino acids (BCAAs) play a key role in energy homeostasis. Objective: We aimed to investigate the association between plasma BCAA levels and dyslipidemia in the Japanese population without diabetes mellitus. Methods: This cross-sectional study included 4952 participants without diabetes mellitus, enrolled in the Tsuruoka Metabolomic Cohort Study. Plasma BCAA levels were measured by capillary electrophoresis–mass spectrometry. Correlations between lipid and BCAA profiles were evaluated by sex-stratified multiple linear regression analyses, after adjusting for confounders. Logistic regression was used to identify associations between BCAAs and metabolic dyslipidemia (MD) defined as triglyceride levels ≥150 mg/dL, high-density lipoprotein cholesterol levels ≤40 mg/dL for men and ≤50 mg/dL for women, or low-density lipoprotein cholesterol (LDL-C) levels ≥140 mg/dL. Results: In both sexes, the levels of individual BCAAs and the total BCAA levels correlated positively with triglyceride levels and negatively with high-density lipoprotein cholesterol levels. Valine, leucine, and total BCAA levels were weakly and positively correlated with LDL-C levels. Increased BCAA levels showed positive associations with MD. However, associations between BCAAs and elevated LDL-C levels were unclear. Furthermore, the associations between BCAA levels and MD regardless of fasting blood sugar (FBS) levels (high or low). Although valine, leucine, and total BCAA levels were weakly associated with elevated LDL-C levels in the high-FBS group, no such association was observed in the low-FBS group. Conclusions: BCAAs might be associated with MD independently of the FBS level and might play an important role in lipid metabolism and dyslipidemia.

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Effect of high-dose marine omega-3 fatty acids on atherosclerosis: A systematic review and meta-analysis of randomized clinical trials

Sekikawa A., Cui C., Sugiyama D., Fabio A., Harris W.S., Zhang X.

Nutrients （Nutrients）  11 （ 11 ）  2019年11月

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A recent randomized controlled trial (RCT), the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), reported that high-dose marine omega-3 fatty acids (OM3) significantly reduce cardiovascular disease (CVD) outcomes, yet the mechanisms responsible for this benefit remain unknown. To test the hypothesis that high-dose OM3 is anti-atherosclerotic, we performed a systematic review and meta-analysis of RCT of high-dose OM3 on atherosclerosis. The protocol of this systematic review was registered with PROSPERO (CRD42019125566). PubMed, Embase, Cochran Central Register for Controlled Trials, and Clinicaltrials.gov databases were searched using the following criteria: adult participants, high-dose OM3 (defined as ≥3.0 g/day, or in Japan 1.8 g/day and purity ≥90%) as the intervention, changes in atherosclerosis as the outcome, and RCTs with an intervention duration of ≥6 months. A random-effects meta-analysis was used to pool estimates across studies. Among the 598 articles retrieved, six articles met our criteria. Four RCTs evaluated atherosclerosis in the coronary and two in the carotid arteries. High-dose OM3 significantly slowed the progression of atherosclerosis (standardized mean difference −1.97, 95% confidence interval −3.01, −0.94, p < 0.001). The results indicate that anti-atherosclerotic effect of high-dose OM3 is one potential mechanism in reducing CVD outcomes demonstrated in the REDUCE-IT trial.

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Being conscious of water intake positively associated with sufficient non-alcohol drink intake regardless of seasons and reasons in healthy Japanese; the KOBE study: A cross sectional study

Nishikawa T., Miyamatsu N., Higashiyama A., Kubota Y., Nishida Y., Hirata T., Sugiyama D., Kuwabara K., Kubo S., Miyamoto Y., Okamura T.

International Journal of Environmental Research and Public Health （International Journal of Environmental Research and Public Health）  16 （ 21 ）  2019年11月

ISSN  16617827

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The present study sought to clarify if being conscious of water intake (CWI) is associated with sufficient non-alcohol drink (NAD) intake. We used data of healthy participants without diabetes, aged 40–74 years, in the Kobe Orthopedic and Biomedical Epidemiologic (KOBE) study. The association between being CWI and NAD intake was evaluated by multivariate linear regression analyses after adjusting for age, sex, surveyed months (seasons), alcohol drinking, health-awareness life habits, socioeconomic factors, serum osmolarity, estimated daily salt intake, and reasons for NAD intake. Among 988 (698 women and 290 men) participants eligible for the present analyses, 644 participants (65.2%) were CWI and 344 participants (34.8%) were not CWI (non-CWI). The most popular reason for being CWI was to avoid heat stroke in summer and to prevent ischemic cerebral stroke in winter. The CWI group took more NAD, especially decaffeinated beverages, than the non-CWI group (1846.7 ± 675.1 mL/day vs. 1478.0 ± 636.3 ml/day, p < 0.001). There was a significant association between being CWI and NAD intake in multivariate linear regression analyses ever after adjusting for the relevant variables (β = 318.1, p < 0.001). These findings demonstrated CWI, regardless of the reasons and the seasons, was associated with high NAD intake in Japanese healthy population.

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Daily habit of water intake in patients with cerebral infarction before its onset; Comparison with a healthy population: A cross-sectional study

Nishikawa T., Miyamatsu N., Higashiyama A., Hojo M., Nishida Y., Fukuda S., Hirata T., Ichiura K., Kubota Y., Kubo S., Ueba T., Kadota A., Sugiyama D., Okamura T.

Cerebrovascular Diseases （Cerebrovascular Diseases）  47 （ 3-4 ） 143 - 150 2019年07月

ISSN  10159770

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Background: While water intake is frequently recommended to prevent cerebral infarction (CI), only few studies have been published on this topic. Objectives: This study retrospectively estimated the daily non-alcohol drink (NAD) intake in CI patients before CI onset and compared it with NAD in healthy subjects. Methods: We performed a cross-sectional study on CI patients in 3 hospitals and healthy subjects in the Kobe Orthopedic and Biomedical Epidemiologic (KOBE) study. Data from 1,287 subjects (274 CI patients and 1,013 healthy subjects) were used for the analyses. By dividing the CI patients into "increased", "unchanged", and "decreased" groups according to their current NAD intake, we compared the NAD intake between these 3 groups and healthy subjects by analyses of covariance and the post hoc test, adjusting for sex, age, surveyed month, body mass index, alcohol drinking history, and smoking history. Under the assumption that the NAD intake in the "unchanged" group was equal to the NAD intake before CI onset, the OR of less NAD intake for CI adjusting for the relevant variables in the "unchanged" group and the healthy subjects was calculated; the cut-off point was chosen using Youden's index. Results: The mean age (mean ± SD) of the participants was 62.8 ± 9.3 years. One hundred and fifty-one patients (36 women) were included in the "increased" group; 105 (30 women), in the "unchanged" group; 18 (2 women), in the "decreased" group; and 1,013 (706 women), in the "healthy" group. The mean NAD intake was 1,702.5 ± 670.2 mL in the "increased" group, 1,494.2 ± 611.2 mL in the "unchanged" group, 1,268.0 ± 596.1 mL in the "decreased" group, and 1,720.6 ± 686.0 mL in the "healthy" group. After adjusting for the relevant variables, a significant difference in NAD intake between the groups was observed (F = 6.1, p < 0.001), and a post hoc test demonstrated significant differences (p < 0.05) in NAD intake between the "healthy" and "unchanged" groups, and between the "increased" and "unchanged" groups. The OR of less NAD intake (<1,570 mL/day, chosen using Youden's index) for CI was 2.48 (95% CI 1.52-4.07). Conclusion: This study showed that daily NAD intake before CI onset in CI patients was less than that in healthy persons, indicating that sufficient intake of NAD may be protective for CI.

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Higher serum uric acid level is inversely associated with renal function assessed by cystatin C in a Japanese general population without chronic kidney disease: The KOBE study

Kubo S., Nishida Y., Kubota Y., Higashiyama A., Sugiyama D., Hirata T., Miyamatsu N., Tanabe A., Hirata A., Tatsumi Y., Kadota A., Kuwabara K., Nishikawa T., Miyamoto Y., Okamura T.

BMC Nephrology （BMC Nephrology）  20 （ 1 ）  2019年04月

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© 2019 The Author(s). Background: Although several epidemiological studies have suggested that high serum uric acid (SUA) levels are related to a decline in kidney function, only a few studies have investigated using cystatin C to calculate estimated glomerular filtration rate (eGFR). We aimed to clarify the relationship between SUA levels and kidney function assessed by cystatin C in a Japanese general community population without chronic kidney disease (CKD). Methods: We conducted a community-based cross-sectional study that included 1086 healthy participants, aged 40-74 years, without CKD and not undergoing treatment of hyperuricemia, who had participated in the baseline survey of the Kobe Orthopedic and Biomedical Epidemiological (KOBE) study. The preconditions for participation in this study were no past histories of cardiovascular disease or cancer, and not undergoing treatment for diabetes, hypertension, or dyslipidemia. We classified the participants into quartiles stratified by sex according to their SUA level and then examined the relationship with eGFR. The odds ratios for having a low eGFR, defined as the lowest quartile of eGFR (i.e., ≤78.4 mL/min/1. 73m 2 ) was estimated according to SUA quartiles (men, Q1 ≤ 5.0, Q2 5.1-5.9, Q3 6.0-6.6, and Q4 ≥ 6.7; women, Q1 ≤ 3.8, Q2 3.9-4.3, Q3 4.4-4.9, and Q4 ≥ 5.0 mg/dL) after adjustment for age, body mass index, systolic blood pressure, HbA1c, high and low density lipoprotein cholesterol, and smoking and drinking habits. The adjusted mean of each quartile was also calculated. Results: Multivariable-adjusted means of eGFR showed a graded decrease in higher SUA quartiles (men, Q1 90.5, Q2 88.0, Q3 83.5, and Q4 82.0; women, Q1 95.7, Q2 91.3, Q3 89.2, and Q4 86.7). In addition, the multivariable-adjusted odds ratios for having a lower eGFR (95% confidence interval) for each SUA quartile compared with Q1 was Q2 2.29 (0.98, 5.35), Q3 4.94 (2.04, 11.97), and Q4 8.01 (3.20, 20.04) for men, and was Q2 2.20 (1.12, 4.32), Q3 2.68 (1.39, 5.20), and Q4 4.96 (2.62, 9.41) for women. Conclusions: There was a graded inverse relationship between mild elevations in SUA levels and eGFR assessed by cystatin C in an apparently healthy Japanese population without CKD. This association was similar in both men and women.

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Impact of hypertension on hospitalizations for cardiovascular diseases in a worksite population: An epidemiologic study using claims data for workers

Fukushima A., Khabtheni W., Guelfucci F., Onishi Y., Sugiyama D., Okamura T., Toumi M.

American Journal of Hypertension （American Journal of Hypertension）  32 （ 3 ） 298 - 307 2019年02月

ISSN  08957061

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BACKGROUND Few of studies investigated the effect of antihypertensives among working population. We aimed to describe the impact of hypertension with and without antihypertensives on hospitalizations because of cardiovascular diseases (CVDs) in the Japanese working population. METHODS This retrospective study included adults aged 40-64 years whose systolic and diastolic blood pressure (BP) readings taken between 2008 and 2015 were available in the Japanese claims database. Individuals were categorized as treated (T) or untreated (UT) depending on their hypertension treatment history. Time to first CVD-related hospitalization was compared among individuals with different BP levels using Cox models that included baseline characteristics with either baseline BP level or a time-dependent variable reflecting BP changes over time. RESULTS Of 740,784 UT individuals (male: 61.9%, mean age: 47.9 years), 2,121 individuals were hospitalized due to a CVD over a 957.3-day average follow-up. Among 72,828 T individuals (male: 74.3%, mean age: 53.7 years), the corresponding figure was 470 individuals over an 813.4-day average follow-up. The risk of hospitalization increased with baseline hypertension severity among UT (hazard ratios [HRs] = 1.93, 2.82, and 6.32 for grade 1, grade 2, and grade 3, respectively; P < 0.0001, reference: Optimal) but not among T individuals. UT individuals with hypertension at any given time had a significantly higher probability of hospitalization compared to nonhypertensive individuals (HR = 1.74, P < 0.0001). CONCLUSIONS This study adds quantitative evidence on the impact of hypertension on the risk of CVD-related hospitalization in the Japanese working population. It suggests that antihypertensive treatment had beneficial effects in this relatively young, working population aged 40-64 years.

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Outcomes of transcatheter mitral valve replacement for degenerated bioprostheses, failed annuloplasty rings, and mitral annular calcification

Yoon S., Whisenant B., Bleiziffer S., Delgado V., Dhoble A., Schofer N., Eschenbach L., Bansal E., Murdoch D., Ancona M., Schmidt T., Yzeiraj E., Vincent F., Niikura H., Kim W., Asami M., Unbehaun A., Hirji S., Fujita B., Silaschi M., Tang G., Kuwata S., Wong S., Frangieh A., Barker C., Davies J., Lauten A., Deuschl F., Nombela-Franco L., Rampat R., Nicz P., Masson J., Wijeysundera H., Sievert H., Blackman D., Gutierrez-Ibanes E., Sugiyama D., Chakravarty T., Hildick-Smith D., De Brito F., Jensen C., Jung C., Smalling R., Arnold M., Redwood S., Kasel A., Maisano F., Treede H., Ensminger S., Kar S., Kaneko T., Pilgrim T., Sorajja P., Van Belle E., Prendergast B., Bapat V., Modine T., Schofer J., Frerker C., Kempfert J., Attizzani G., Latib A., Schaefer U., Webb J., Bax J., Makkar R.

European Heart Journal （European Heart Journal）  40 （ 5 ） 441 - 451 2019年

ISSN  0195668X

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© 2018 The Author(s). All rights reserved. Aims: We sought to evaluate the outcomes of transcatheter mitral valve replacement (TMVR) for patients with degenerated bioprostheses [valve-in-valve (ViV)], failed annuloplasty rings [valve-in-ring (ViR)], and severe mitral annular calcification [valve-in-mitral annular calcification (ViMAC)]. Methods and results: From the TMVR multicentre registry, procedural and clinical outcomes of ViV, ViR, and ViMAC were compared according to Mitral Valve Academic Research Consortium (MVARC) criteria. A total of 521 patients with mean Society of Thoracic Surgeons score of 9.0± 7.0% underwent TMVR (322 patients with ViV, 141 with ViR, and 58 with ViMAC). Trans-septal access and the Sapien valves were used in 39.5% and 90.0%, respectively. Overall technical success was excellent at 87.1%. However, left ventricular outflow tract obstruction occurred more frequently after ViMAC compared with ViR and ViV (39.7% vs. 5.0% vs. 2.2%; P < 0.001), whereas second valve implantation was more frequent in ViR compared with ViMAC and ViV (12.1% vs. 5.2% vs. 2.5%; P< 0.001). Accordingly, technical success rate was higher after ViV compared with ViR and ViMAC (94.4% vs. 80.9% vs. 62.1%; P< 0.001). Compared with ViMAC and ViV groups, ViR group had more frequent post-procedural mitral regurgitation ≥moderate (18.4% vs. 13.8% vs. 5.6%; P< 0.001) and subsequent paravalvular leak closure (7.8% vs. 0.0% vs. 2.2%; P = 0.006). All-cause mortality was higher after ViMAC compared with ViR and ViV at 30 days (34.5% vs. 9.9% vs. 6.2%; log-rank P<0.001) and 1 year (62.8% vs. 30.6% vs. 14.0%; log-rank P< 0.001). On multivariable analysis, patients with failed annuloplasty rings and severe MAC were at increased risk of mortality after TMVR [ViR vs. ViV, hazard ratio (HR) 1.99, 95% confidence interval (CI) 1.27-3.12; P= 0.003; ViMAC vs. ViV, HR 5.29, 95% CI 3.29-8.51; P < 0.001]. Conclusion: The TMVR provided excellent outcomes for patients with degenerated bioprostheses despite high surgical risk. However, ViR and ViMAC were associated with higher rates of adverse events and mid-term mortality compared with ViV.

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Influence of workplace environment, working conditions and health status of taxi drivers on vehicle collisions or near-miss events

Baba M., Miyama G., Sugiyama D., Hitosugi M.

Industrial Health （Industrial Health）  57 （ 4 ） 530 - 536 2019年

ISSN  00198366

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© 2019 National Institute of Occupational Safety and Health. Sudden illness while driving has been identified as a major cause of vehicle collisions, particularly among taxi drivers. However, no previous studies have examined the factors contributing to the occurrence of health-related vehicle collisions. The current study aimed to identify the risk factors causing health-related vehicle collisions among taxi drivers, and to inform preventative interventions. A cross-sectional survey involving a written anonymous questionnaire was conducted for company-employed taxi drivers in Chiba Prefecture, Japan. A total of 1,739 drivers returned questionnaires. Drivers were classified into those who had experienced collisions or near-miss incidents caused by health problems (Event group), and those who had not (Non-event group). According to a multivariable logistic regression analysis, being unable to take vacation time (odds ratio [OR] 4.59, 95% confidence interval [CI] 2.2–9.58), having chronic diseases (OR 1.52, 95% CI 1.02–2.27), taking insufficient vacation time (OR 1.81, 95% CI 1.19–2.79), and difficulty reporting poor health conditions (OR 2.29, 95% CI 1.36–3.87) were significant factors for the likelihood of an event. Support for drivers to maintain well-balanced control of illnesses and improvement of working environments could prevent health-related events while driving.

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