Aims: Nonalcoholic fatty liver disease (NAFLD) is known to be associated with atherosclerosis. This study focused on upstream changes in the process by which NAFLD leads to atherosclerosis. The study ...aimed to confirm the association between NAFLD and the cardio-ankle vascular index (CAVI), an indicator of subclinical atherosclerosis, and explore metabolites involved in both by assessing 94 plasma polar metabolites.Methods: A total of 928 Japanese community-dwellers (306 men and 622 women) were included in this study. The association between NAFLD and CAVI was examined using a multivariable regression model adjusted for confounders. Metabolites commonly associated with NAFLD and CAVI were investigated using linear mixed-effects models in which batch numbers of metabolite measurements were used as a random-effects variable, and false discovery rate-adjusted p-values were calculated. To determine the extent to which these metabolites mediated the association between NAFLD and CAVI, mediation analysis was conducted.Results: NAFLD was positively associated with CAVI (coefficients 95% Confidence intervals (CI)=0.23 0.09–0.37; p=0.001). A total of 10 metabolites were involved in NAFLD and CAVI, namely, branched-chain amino acids (BCAAs; valine, leucine, and isoleucine), aromatic amino acids (AAAs; tyrosine and tryptophan), alanine, proline, glutamic acid, glycerophosphorylcholine, and 4-methyl-2-oxopentanoate. Mediation analysis showed that BCAAs mediated more than 20% of the total effect in the association between NAFLD and CAVI.Conclusions: NAFLD was associated with a marker of atherosclerosis, and several metabolites related to insulin resistance, including BCAAs and AAAs, could be involved in the process by which NAFLD leads to atherosclerosis.
Background: Heated tobacco products (HTPs) have gained global popularity, but their health risks remain unclear. Therefore, the current study aimed to identify plasma metabolites associated with ...smoking and HTP use in a large Japanese population to improve health risk assessment.Methods: Metabolomics data from 9,922 baseline participants of the Tsuruoka Metabolomics Cohort Study (TMCS) were analyzed to determine the association between smoking habits and plasma metabolites. Moreover, alterations in smoking-related metabolites among HTP users were examined based on data obtained from 3,334 participants involved from April 2018 to June 2019 in a follow-up survey.Results: Our study revealed that cigarette smokers had metabolomics profiles distinct from never smokers, with 22 polar metabolites identified as candidate biomarkers for smoking. These biomarker profiles of HTP users were closer to those of cigarette smokers than those of never smokers. The concentration of glutamate was higher in cigarette smokers, and biomarkers involved in glutamate metabolism were also associated with cigarette smoking and HTP use. Network pathway analysis showed that smoking was associated with the glutamate pathway, which could lead to endothelial dysfunction and atherosclerosis of the vessels.Conclusions: Our study showed that the glutamate pathway is affected by habitual smoking. These changes in the glutamate pathway may partly explain the mechanism by which cigarette smoking causes cardiovascular disease. HTP use was also associated with glutamate metabolism, indicating that HTP use may contribute to the development of cardiovascular disease through mechanisms similar to those in cigarette use.
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Studies examining long-term longitudinal metabolomic data and their reliability in large-scale populations are limited. Therefore, we aimed to evaluate the reliability of repeated measurements of ...plasma metabolites in a prospective cohort setting and to explore intra-individual concentration changes at three time points over a 6-year period. The study participants included 2999 individuals (1317 men and 1682 women) from the Tsuruoka Metabolomics Cohort Study, who participated in all three surveys-at baseline, 3 years, and 6 years. In each survey, 94 plasma metabolites were quantified for each individual and quality control (QC) sample. The coefficients of variation of QC, intraclass correlation coefficients, and change rates of QC were calculated for each metabolite, and their reliability was classified into three categories: excellent, fair to good, and poor. Seventy-six percent (71/94) of metabolites were classified as fair to good or better. Of the 39 metabolites grouped as excellent, 29 (74%) in men and 26 (67%) in women showed significant intra-individual changes over 6 years. Overall, our study demonstrated a high degree of reliability for repeated metabolome measurements. Many highly reliable metabolites showed significant changes over the 6-year period, suggesting that repeated longitudinal metabolome measurements are useful for epidemiological studies.
Introduction: Our study is aimed to examine the relationship between visit-to-visit variability (VVV) of HbA1c and development/ progression of diabetic retinopathy (DR). Methods: This retrospective ...study analyzed data on 5,898 T2DM patients that had ophthalmic follow data. The VVV of HbA1c was evaluated using the intrapersonal coefficient of variation (CV) of HbA1c during a 7-year period from 2014-2020. We divided patients as (1) diagnosed with non-DR and (2) diagnosed with DR at start of this study. DR was assessed by Davis classification. Data analyses were performed using SPSS version 29.0 software. Results: The number of patients is as follows; (1) patients with non-DR(n=4,197), (2) patients with DR(n=1,701). Multivariate logistic regression analyses indicated there is no significant association with CV of HbA1c and development of DR. There are, however, significant increase risks of development of DR with HbA1c level (OR=1.37), pulse pressure (OR=1.04) and diabetic duration (OR=1.02). Interestingly, there is significant association with CV of HbA1c and progression of DR (OR=1.04, Figure). Conclusion: This study suggests that development of DR was associated with HbA1c level, pulse pressure and diabetic duration, but not with VVV of HbA1c. Progression of DR was associated with VVV of HbA1c. Thus, the VVV of HbA1c might be a new marker of progression of diabetic retinopathy. Disclosure M. Yuki: None. T. Yamazaki: None. R. Toki: None. M. Sakamoto: None.
Background: The importance of assessing liver function in patients with type 2 diabetes (T2DM) has been well established, but few studies have examined this from a time-series view. We investigated ...the effect of seasonal fluctuations in liver function on long-term glycemic control on T2DM. Method: A total of 9,949 individuals (20-80 yo) were enrolled in a large registry study of T2DM in Japan from Jan 2014 (baseline) to Dec 2020. After excluding missing data on covariates, 9,438 were included in the analysis. Seasonal fluctuations of AST/ALT was defined as the amplitude of the seasonal component of each individual extracted by STL decomposition after multiple imputations. HbA1c at the final visit of each individual (final-visit A1c) was used as the index of glycemic control. Multivariate regression analysis was performed using standardized seasonal fluctuations in AST/ALT as explanatory variables and final-visit HbA1c as the objective variable. Covariates included sex, follow-up time, and age at baseline, BMI, HbA1c, log-transformed AST or ALT, drinking and smoking habits, diabetes duration, and insulin use. A sensitivity analysis was performed by adding seasonal BMI fluctuation during follow-up to the above model. Result: During the follow-up of 6.0 ± 1.8 yrs, AST/ALT tended to be lower in summer and higher in winter. Multivariate analysis showed that the seasonal fluctuations of AST/ALT were significantly associated with final-visit A1c, with an estimated effect of +0.044% 95% CI: 0.017, 0.071 and +0.028% 0.002, 0.054 per 1SD increase, respectively. The results of the sensitivity analysis remained consistent. Conclusion: This study indicated that seasonal fluctuations in liver enzymes might be a risk factor for poor glycemic control independent of traditional risk factors, as well as BMI fluctuation in Japanese patients with T2DM. Our results suggest that year-round assessment of liver enzymes may be important in clinical practice. Disclosure R. Toki: None. M. Sakamoto: None. M. Iida: None. M. Yuki: None. T. Takebayashi: None.
Abstract only Background and Aim: To determine the protein intake associated with the prevalence of sarcopenia, we conducted a cross-sectional study of 1251 community-dwelling older Japanese aged 60 ...years and older. Methods: The mean age of the participants was 68.8 years, and the percentage of women was 56.7%. Sarcopenia was defined according to the Asian Working Group for Sarcopenia 2019 by low muscle mass (skeletal muscle mass), muscle strength (grip strength), and physical performance (gait speed). Protein and energy intake were assessed using a food frequency questionnaire (FFQ). Logistic regression models were used to estimate the multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (95%CIs) of the prevalence of sarcopenia according to gender-specific tertiles of protein intake as a percentage of total energy. Corresponding analyses were done also for protein intake per day and for protein intake per kg of body weight, separately, instead of protein intake as a percentage of total energy. Results: The prevalence of sarcopenia was 8.0% (100/1251). The median protein intake as a percentage of total energy, protein intake per day, and protein intake per body weight by gender were, in order, 11.8%E, 59.2 g/day, and 0.9 g/kg/day for males and 14.1%E, 54.7 g/day, and 1.0 g/kg/day for females. Since there was no gender interaction in the association between each protein intake and the prevalence of sarcopenia, we performed the analysis for males and females combined. The multivariable adjusted ORs (95%CI) of the prevalence of sarcopenia was lower in the high protein intake as a percentage of total energy (>12.6%E in males and >15.2%E in females, respectively) group (0.47 (0.27-0.83)) than in the low intake (<11.1%E in males and <13.4%E in females, respectively) group; the linear trend was significant (p =0.009). Similarly, we found a significantly inverse association for sarcopenia prevalence at protein intakes higher than 54.4 g/day for males and 50.6 g/day for females, compared to those with lower intakes. However, there was no association between protein intake per body weight and the prevalence of sarcopenia. We obtained similar results when the participants were restricted to those 65 years and older as a sensitivity analysis. Conclusion: Significant inverse associations were found between the prevalence of sarcopenia and protein intake in community-dwelling older Japanese. However, we should consider that protein intake assessed by the FFQ is often underestimated when discussing absolute protein intake for sarcopenia prevention.
Aims: Nonalcoholic fatty liver disease (NAFLD) is known to be associated with atherosclerosis. This study focused on upstream changes in the process by which NAFLD leads to atherosclerosis. The study ...aimed to confirm the association between NAFLD and the cardio-ankle vascular index (CAVI), an indicator of subclinical atherosclerosis, and explore metabolites involved in both by assessing 94 plasma polar metabolites. Methods: A total of 928 Japanese community-dwellers (306 men and 622 women) were included in this study. The association between NAFLD and CAVI was examined using a multivariable regression model adjusted for confounders. Metabolites commonly associated with NAFLD and CAVI were investigated using linear mixed-effects models in which batch numbers of metabolite measurements were used as a random-effects variable, and false discovery rate-adjusted p-values were calculated. To determine the extent to which these metabolites mediated the association between NAFLD and CAVI, mediation analysis was conducted. Results: NAFLD was positively associated with CAVI (coefficients 95% Confidence intervals (CI)=0.23 0.09-0.37; p=0.001). A total of 10 metabolites were involved in NAFLD and CAVI, namely, branched-chain amino acids (BCAAs; valine, leucine, and isoleucine), aromatic amino acids (AAAs; tyrosine and tryptophan), alanine, proline, glutamic acid, glycerophosphorylcholine, and 4-methyl-2-oxopentanoate. Mediation analysis showed that BCAAs mediated more than 20% of the total effect in the association between NAFLD and CAVI. Conclusions: NAFLD was associated with a marker of atherosclerosis, and several metabolites related to insulin resistance, including BCAAs and AAAs, could be involved in the process by which NAFLD leads to atherosclerosis.
The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision ...prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35–74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study used an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability, functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women's health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.
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Objectives Neoadjuvant therapy followed by radical resection improves the borderline-resectable pancreatic cancer (BRPC) prognosis; however, the optimal therapeutic regimen remains unclear. ...Gemcitabine plus nab-paclitaxel (GnP) showed a high anti-tumor effect in primary lesions in a prospective study for metastatic disease. However, evidence concerning its feasibility is still lacking in patients with BRPC. We therefore evaluated the tolerability of neoadjuvant GnP (NAC-GnP) for BRPC. Methods This single-center prospective study evaluated 10 patients with BRPC who were treated with two cycles of NAC-GnP. The primary endpoint was feasibility for NAC-GnP. Treatment feasibility was defined as a successful outcome in at least eight patients. Results Ten patients who had BRPC in contact with the celiac artery (n=5), superior mesenteric artery (n=3), or hepatic artery (n=2) were enrolled. The median age was 75 (range, 40-82) years old. Grade 3 anorexia and grade 2 pneumonia occurred in one patient each, so treatment was feasible in eight patients. The median primary tumor reduction and response rates were 33% (range, 0-68%) and 60%, respectively. Six of eight patients who had abnormal CA19-9 levels at the time of enrolment showed a decrease in CA19-9 levels, with a median decrease of 72%. Five patients underwent radical resection, including R0 resection in four. Postoperative grade IIIa Clavien-Dindo complications occurred in one patient (upper gastrointestinal bleeding and pancreatic fistula). Conclusion Two-cycle NAC-GnP is a feasible treatment for patients with BRPC. Further studies on NAC-GnP in patients with BRPC are warranted.
Acute flaccid myelitis (AFM) is an acute flaccid paralysis syndrome with spinal motor neuron involvement of unknown etiology. We investigated the characteristics and prognostic factors of AFM ...clusters coincident with an enterovirus D68 (EV-D68) outbreak in Japan during autumn 2015.
An AFM case series study was conducted following a nationwide survey from August to December 2015. Radiographic and neurophysiologic data were subjected to centralized review, and virology studies were conducted for available specimens.
Fifty-nine AFM cases (58 definite, 1 probable) were identified, including 55 children and 4 adults (median age, 4.4 years). The AFM epidemic curve showed strong temporal correlation with EV-D68 detection from pathogen surveillance, but not with other pathogens. EV-D68 was detected in 9 patients: 5 in nasopharyngeal, 2 in stool, 1 in cerebrospinal fluid (adult case), and 1 in tracheal aspiration, nasopharyngeal, and serum samples (a pediatric case with preceding steroid usage). Cases exhibited heterogeneous paralysis patterns from 1- to 4-limb involvement, but all definite cases had longitudinal spinal gray matter lesions on magnetic resonance imaging (median, 20 spinal segments). Cerebrospinal fluid pleocytosis was observed in 50 of 59 cases (85%), and 8 of 29 (28%) were positive for antiganglioside antibodies, as frequently observed in Guillain-Barré syndrome. Fifty-two patients showed variable residual weakness at follow-up. Good prognostic factors included a pretreatment manual muscle strength test unit score >3, normal F-wave persistence, and EV-D68-negative status.
EV-D68 may be one of the causative agents for AFM, while host susceptibility factors such as immune response could contribute to AFM development.
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