古川 拓馬

OBJECTIVE: Higher N-terminal pro-brain natriuretic peptide (NT-proBNP) levels are a strong risk factor for cardiovascular disease. The current study aimed to clarify the cross-sectional association of physical activity (PA) with NT-proBNP and to identify the interaction of PA with alcohol consumption or cigarette smoking in middle-aged individuals. METHODS: The study included 4613 individuals (1824 men and 2789 women) (November 2005-November 2006). Total PA, steps, light-intensity PA (LPA), and moderate-to-vigorous-intensity PA (MVPA) were assessed using accelerometer. Serum NT-proBNP levels were measured. Cross-sectional associations of total PA and steps with NT-proBNP were analyzed using multiple regression with adjustment for potential confounders. The isotemporal substitution model was used to assess activity intensity-specific association. The interaction between PA and alcohol consumption or smoking was also examined. RESULTS: Total PA was independently and inversely associated with NT-proBNP in the entire sample (P = 0.04). The inverse association of substituting LPA with MVPA for NT-proBNP was clearer in men than in women (Pinteraction = 0.04). Inverse associations of total PA or steps with NT-proBNP were clearer in heavy drinkers than in moderate drinkers and non-drinkers in the entire sample (Pinteraction < 0.05). In men, the inverse association of substituting LPA with MVPA for NT-proBNP was also clearer in heavy drinkers (Pinteraction = 0.02). No interactions of PA with smoking were detected. CONCLUSIONS: Higher total PA was associated with better NT-proBNP in middle-aged individuals. Additionally, the effect of substituting LPA with MVPA on NT-proBNP was greater in men than in women. Furthermore, the association between PA and NT-proBNP may be modified by alcohol consumption.

We previously reported a reduced humoral immune response to the COVID-19 vaccines. Subsequently, we observed a lower susceptibility to COVID-19 in individuals carrying the ALDH2 rs671 variant through a web-based retrospective survey. Based on these findings, we hypothesized that rs671 variant was beneficial for cellular immunity against COVID-19. Using the IFN-γ enzyme-linked immunospot (ELISPOT) assay, we assessed cellular immunity before and after COVID-19 vaccination in two subcohorts of a previously reported cohort. Subcohort 1 (26 participants) had six repeated observations at baseline after one to three doses, whereas subcohort 2 (19 participants) had two observations before and after the third dose. ELISPOT counts at six months after the second dose increased from baseline in carriers of the rs671 variant but not in non-carriers. A positive effect of rs671 on ELISPOT counts was estimated using a mixed model (183 observations from 45 participants), including the random effect of subcohort, repeated measures, and fixed effects of vaccine type, age, sex, height, lifestyle, steroid use, and allergic disease. There was no association between ELISPOT counts and specific IgG levels, suggesting a limitation in estimating protective potential by humoral response. Our sequential observational studies suggest a beneficial effect of the rs671 variant in SARS-CoV-2 infection via enhanced cellular immune response, providing a potential basis for optimizing preventive measures and drug development.

The appendicular extracellular-to-intracellular water ratio (A-E/I) is a potential marker of skeletal muscle quality, reflecting the balance of water distribution between the extracellular and intracellular compartments of the appendicular limb regions. A-E/I has been increasingly used in recent studies; however, its association with adverse outcomes remains unclear. This study investigated the potential association between A-E/I and all-cause mortality. A prospective cohort study of 8015 middle-aged and older adults (comprised of 4755 women, aged 45-74 years) residing in a Japanese community was conducted. The baseline assessment was performed between 2010 and 2012, and the follow-up period lasted until July 2022. A-E/I and skeletal muscle mass were measured using segmental bioelectrical impedance spectroscopy. Handgrip strength (HGS) was measured using a Smedley-type dynamometer. Lifestyle, medical history, and physical activity (PA) were assessed by questionnaire and accelerometer. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for each quartile (Q) of A-E/I were estimated using the multivariable cox regression model. During a 10.5-year median follow-up, mortality rates were 8.9 and 3.6 per 1000 person-years for men (292 deaths) and women (174 deaths), respectively. A-E/I quartiles were positively associated with all-cause mortality in both sexes (men: Q1, HR: 1.0 [95% CI: reference], Q4, HR: 1.8 [1.1-2.9], P trend <0.05; women, Q4, HR: 2.2 [1.3-3.8], P trend <0.01). This association remained significant after further adjustment for skeletal muscle mass and HGS (P trend < 0.05). Our findings suggest that A-E/I serves as an early predictive marker for mortality in middle-aged and older Japanese adults.

OBJECTIVES: Daily step counts are an easy-to-understand indicator of physical activity; however, there is limited evidence regarding the optimal daily step count to prevent sarcopenia. This study examined the dose-response relationship between daily step count and the prevalence of sarcopenia and explored the optimal dose. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: The study included 7949 community-dwelling middle-aged and older adults (aged 45-74 years) from Japan. MEASUREMENTS: Skeletal muscle mass (SMM) was assessed using bioelectrical impedance spectroscopy, and muscle strength was quantified through handgrip strength (HGS) measurement. Participants who exhibited both low HGS (men: <28 kg, women: <18 kg) and low SMM (lowest quartile in each sex-specific category) were defined as having sarcopenia. Daily step counts were measured for 10 days using a waist-mounted accelerometer. To examine the association between daily step count and sarcopenia, a multivariate logistic regression analysis was performed, adjusting for potential confounding factors such as age, sex, body mass index, smoking status, alcohol consumption, protein intake, and medical history. The odds ratios (ORs) and confidence intervals (CIs) were calculated based on the daily step counts categorized into quartiles (Q1-Q4). Finally, a restricted cubic spline curve was fitted to further investigate the dose-response relationship between daily step count and sarcopenia. RESULTS: The prevalence of sarcopenia in the overall participants was 3.3 % (259/7949 participants), with a mean daily step count of 7292 ± 2966 steps. Expressed in quartiles, the mean daily step counts were 3873 ± 935 steps in Q1, 6025 ± 503 steps in Q2, 7942 ± 624 steps in Q3, and 11,328 ± 1912 steps in Q4. The prevalence of sarcopenia in each quartile of daily step count was 4.7 % (93/1987 participants) in Q1, 3.4 % (68/1987 participants) in Q2, 2.7 % (53/1988 participants) in Q3, and 2.3 % (45/1987 participants) in Q4. The ORs and 95 % CIs adjusted for covariates demonstrated a statistically significant inverse association between daily step count and sarcopenia prevalence (P for trend <0.01), as follows: Q1, reference; Q2, 0.79 (95 % CI: 0.55-1.11); Q3, 0.71 (95 % CI: 0.49-1.03); Q4, 0.61 (95 % CI: 0.41-0.90). The restricted cubic spline curve indicated that the ORs leveled off at approximately 8000 steps per day, and no statistically significant decrease in ORs was observed for daily step counts above this threshold. CONCLUSIONS: The study found a significant inverse association between daily step count and the prevalence of sarcopenia, with the association plateauing when the daily step count exceeded approximately 8000 steps. These findings suggest that 8000 steps per day may be the optimal dose to prevent sarcopenia. Further intervention and longitudinal studies are needed to validate the results.

BACKGROUND: The appendicular extracellular-to-intracellular water ratio (Ap ECW/ICW) has recently gained attention as a non-invasive measurable marker of muscle quality. However, there is a lack of basic evidence regarding age-related changes, sex differences, contribution to muscle strength independent of skeletal muscle mass (SMM), and potential improvement through physical activity (PA) in Ap ECW/ICW. METHODS: This cross-sectional study enrolled 8,018 middle-aged and older Japanese individuals (aged 45-75 years). The Ap ECW/ICW and SMM were measured using segmental bioelectrical impedance spectroscopy. Muscle strength was evaluated by measuring the handgrip strength (HGS) with a dynamometer, and the PA level (PAL) was measured with an accelerometer. We performed a linear regression analysis of the associations of the Ap ECW/ICW with age, HGS, and PAL. RESULTS: The Ap ECW/ICW increased by 0.019 for men and 0.014 for women per 5-year increase in age (p < 0.001), and the age-related increase was greater in men than in women (p for interaction <0.001). The Ap ECW/ICW was more strongly associated with the HGS than with the SMM in both men and women (p < 0.001). PAL showed a significant inverse association with the Ap ECW/ICW in both men and women (p < 0.001). CONCLUSIONS: Ap ECW/ICW is higher with age, and it varies by sex. The Ap ECW/ICW may reflect muscle strength more than the SMM, suggesting that the Ap ECW/ICW may be improved by PA. The findings from this study may provide a framework for further Ap ECW/ICW research.

OBJECTIVE: Findings on the increased mortality risk in individuals with insomnia are inconsistent across studies. Rather than improving insomnia by sleep control, hypnotic use may be one factor in the increased risk of death; however, the effects of hypnotics on mortality remains unclear. This study aimed to examine the association between all-cause mortality and hypnotic use in a large sample, while adjusting for the effects of comorbidities. METHODS: Overall, 92,527 individuals aged 35-69 years were followed up for mortality in the Japan Multi-Institutional Collaborative Cohort Study. Regular use of hypnotics was assessed using a self-administered questionnaire. Since cancer history carries a substantial risk of death and is associated with the treatment of insomnia with hypnotics, participants with a cancer history were excluded. The hazard ratio (HR) and 95% confidence interval (CI) for all-cause mortality related to hypnotic use were estimated using a Cox proportional hazard model with adjustments for covariates including sleeping hours and comorbidities (body mass index, ischemic heart disease, stroke, and diabetes). RESULTS: During the follow-up (mean, 8.4 ± 2.5 years), 1,492 mortalities were recorded, and the prevalence of taking hypnotics was 4.2%. Hypnotic use was associated with significantly greater risk of all-cause mortality, even after adjustment for the covariates (HR, 1.32; 95% CI, 1.07-1.63). The association between hypnotic use and all-cause mortality was robust in males (HR, 1.51; 95% CI, 1.15-1.96), and participants aged <60 years (HR, 1.75; 95% CI, 1.21-2.54). CONCLUSIONS: Our study revealed sex-age specific associations between hypnotic use and all-cause mortality.

Uncovering the predictors of vaccine immunogenicity is essential for infection control. We have reported that the most prevalent polymorphism of the aldehyde dehydrogenase 2 gene (ALDH2), rs671, may be associated with an attenuated immune system. To test the inverse relationship between rs671 and antibody production after COVID-19 vaccination, the levels of anti-SARS-CoV-2 Spike protein S1 subunit (S1) IgG were repeatedly measured for four months before and after vaccination with BNT162b2 or mRNA-1273, in 88 Japanese workers and students (including 45 females, aged 21-56 years, with an rs671 variant allele frequency of 0.3). The mixed model including fixed effects of the vaccine type, weeks post vaccination (categorical variable), sex, age, height, smoking status, ethanol intake, exercise habit, perceived stress, steroid use, allergic diseases, and dyslipidemia, indicated an inverse association between log-transformed anti-S1 IgG levels and the number of rs671 variant alleles (partial regression coefficient = -0.15, p = 0.002). Our study indicated for the first time that the variant allele of ALDH2, rs671, is associated with the attenuated immunogenicity of COVID-19 mRNA vaccines. Our finding may provide a basis for personalized disease prevention based on a genetic polymorphism that is prevalent among East Asians.

Abstract Elucidating the risk factors for chronic kidney disease is important for preventing end-stage renal disease and reducing mortality. However, little is known about the roles of psychosocial stress and stress coping behaviors in deterioration of the renal function, as measured by the estimated glomerular filtration rate (eGFR). This cross-sectional study of middle-aged and older Japanese men (n = 31,703) and women (n = 38,939) investigated whether perceived stress and coping strategies (emotional expression, emotional support seeking, positive reappraisal, problem solving, and disengagement) were related to the eGFR, with mutual interactions. In multiple linear regression analyses adjusted for age, area, lifestyle factors, and psychosocial variables, we found a significant inverse association between perceived stress and the eGFR in men (P_trend = 0.02), but not women. This male-specific inverse association was slightly attenuated after adjustment for the history of hypertension and diabetes and was more evident in lower levels of emotional expression (P_interaction = 0.003). Unexpectedly, problem solving in men (P_trend &lt; 0.001) and positive reappraisal in women (P_trend = 0.002) also showed an inverse association with the eGFR. Perceived stress may affect the eGFR, partly through the development of hypertension and diabetes. The unexpected findings regarding coping strategies require the clarification of the underlying mechanisms, including the hormonal and immunological aspects.

<sec><title>Introduction</title>Healthy diet and physical activity (PA) are essential for preventing type 2 diabetes, particularly, a combination of diet and PA. However, reports on interaction between PA and diet, especially from large epidemiological studies, are limited. We investigated the effect of interaction between PA and macronutrient intake on hemoglobin A1c (HbA1c) levels in the general population. </sec><sec><title>Research design and methods</title>We conducted a cross-sectional study of 55 469 men and women without diabetes who participated in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. A self-administered questionnaire ascertained PA and macronutrient intake (carbohydrate, fat, and protein). Multiple linear regression analyses were performed to adjust for confounding variables and examine the interactions. In addition, we conducted a longitudinal study during a 5-year period within a subcohort (n=6881) with accelerometer-assessed PA data. </sec><sec><title>Results</title>Overall, PA had a weak inverse association (β=−0.00033, p=0.049) and carbohydrate intake had a strong positive association (β=0.00393, p&lt;0.001) with HbA1c. We observed a tendency of interactions between PA and carbohydrate or fat intake, but not protein intake, on HbA1c levels after adjusting for age, sex, study area, total energy intake, alcohol consumption, smoking, and medication for hypertension or hypercholesterolemia (P_interaction=0.054, 0.006, and 0.156, respectively). The inverse associations between PA and HbA1c level were more evident in participants with high-carbohydrate (or low-fat) intake than in participants with low-carbohydrate (or high-fat) intake. Although further adjustment for body mass index slightly attenuated the above interactions (P_interaction=0.098 for carbohydrate and 0.068 for fat), the associations between PA and HbA1c level in stratified analyses remained unchanged. Similar associations and interactions were reproduced in the longitudinal study. </sec><sec><title>Conclusions</title>The present results suggest that the effect of PA on HbA1c levels is modified by intake of macronutrient composition. </sec>

AIMS: Coffee consumption has been suggested, in animal studies, to inhibit the progression of sarcopenia, possibly through its anti-inflammatory effects; however, few studies have been carried out in humans. We aimed to examine whether coffee consumption was related to indicators of sarcopenia in a Japanese population, and whether the association was mediated by reduced inflammation. METHODS: This study was a cross-sectional design. Participants were community residents (n = 6369) aged 45-74 years. We measured skeletal muscle mass index (SMI; kg/m2 ) by a bioelectrical impedance method, and grip strength with a Smedley-type dynamometer. Habitual coffee consumption was assessed by a self-administered questionnaire. Serum high-sensitivity C-reactive protein was measured as an inflammatory marker. The association between habitual coffee consumption and SMI or grip strength was analyzed with a linear regression model adjusted for covariates. RESULTS: A significant positive association was found between coffee consumption and SMI (men: β = 0.023; Ptrend  = 0.004, women: β = 0.011; Ptrend  = 0.012). Further adjustment for high-sensitivity C-reactive protein did not materially alter the results (men: β = 0.023; Ptrend  = 0.005, women: β = 0.009; Ptrend  = 0.024). The relationship between coffee consumption and grip strength did not reach statistical significance; however, a positive trend was observed (men: β = 0.208; Ptrend  = 0.085, women: β = 0.092; Ptrend  = 0.167). CONCLUSIONS: We found that coffee consumption was positively associated with SMI independently of inflammation in middle-aged and older Japanese people. Reduced inflammation by coffee does not seem to be an important mediator, and further investigations are required to explore the mechanisms of this association. Geriatr Gerontol Int 2021; 21: 950-958.

BACKGROUND: Little is known about whether insufficient moderate-to-vigorous physical activity (MVPA) and longer sedentary behavior (SB) are independently associated with estimated glomerular filtration rate (eGFR) and CKD, whether they interact with known risk factors for CKD, and the effect of replacing sedentary time with an equivalent duration of physical activity on kidney function. METHODS: We examined the cross-sectional association of MVPA and SB with eGFR and CKD in 66,603 Japanese cohort study in 14 areas from 2004 to 2013. MVPA and SB were estimated using a self-reported questionnaire, and CKD was defined as eGFR<60 mL/min/1.73 m2. Multiple linear regression analyses, logistic regression analyses, and an isotemporal substitution model were applied. RESULTS: After adjusting for potential confounders, higher MVPA and longer SB were independently associated with higher eGFR (Pfor trend MVPA<0.0001) and lower eGFR (Pfor trend SB<0.0001), and a lower odds ratio (OR) of CKD (adjusted OR of MVPA≥20 MET·h/day: 0.76 [95%CI: 0.68-0.85] compared to MVPA<5 MET·h/day) and a higher OR of CKD (adjusted OR of SB≥16 h/day: 1.81 [95%CI: 1.52-2.15] compared to SB<7 h/day), respectively. The negative association between MVPA and CKD was stronger in men, and significant interactions between sex and MVPA were detected. Replacing 1 hour of SB with 1 hour of physical activity was associated with about 3 to 4% lower OR of CKD. CONCLUSIONS: These findings indicate that replacing SB with physical activity may benefit kidney function, especially in men, adding to the possible evidence on CKD prevention.

[This corrects the article DOI: 10.1038/s41526-018-0045-0.].