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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 (P interaction  = 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 (P interaction  < 0.05). In men, the inverse association of substituting LPA with MVPA for NT-proBNP was also clearer in heavy drinkers (P interaction  = 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., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in association with the present study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Although previous polygenic risk score (PRS) studies for cardiovascular disease (CVD) focused on incidence, few studies addressed CVD mortality and quantified risks by environmental exposures in different genetic liability groups. This prospective study aimed to examine the associations of blood pressure PRS with all-cause and CVD mortality and to quantify the attributable risk by modifiable lifestyles across different PRS strata. 9,296 participants in the Japan Multi-Institutional Collaborative Cohort Study without hypertension at baseline were analyzed in this analysis. PRS for systolic blood pressure and diastolic blood pressure (PRS SBP and PRS DBP ) were developed using publicly available Biobank Japan GWAS summary statistics. CVD-related mortality was defined by the International Classification of Diseases 10th version (I00-I99). Cox-proportional hazard model was used to examine associations of PRSs and lifestyle variables (smoking, drinking, and dietary sodium intake) with mortality. During a median 12.6-year follow-up period, we observed 273 all-cause and 41 CVD mortality cases. Compared to the middle PRS group (20-80th percentile), adjusted hazard ratios for CVD mortality at the top PRS group ( > 90th percentile) were 3.67 for PRS SBP and 2.92 for PRS DBP . Attributable risks of CVD mortality by modifiable lifestyles were higher in the high PRS group ( > 80th percentile) compared with the low PRS group (0-80th percentile). In summary, blood pressure PRS is associated with CVD mortality in the general Japanese population. Our study implies that integrating PRS with lifestyle could contribute to identify target populations for lifestyle intervention even though improvement of discriminatory ability by PRS alone is limited., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Introduction: We aimed to comprehensively compile placebo-controlled trials on the efficacy and safety of romosozumab (210 mg, subcutaneously, once monthly) in postmenopausal women and men with osteoporosis., Materials and Methods: PubMed, Google Scholar, and ClinicalTrials.gov were searched for relevant placebo-controlled trials (as of January 1, 2024). Percent change in bone mineral density (BMD), falls, fractures, and adverse events (AEs) after drug administration were collected. Risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were calculated., Results: Six trials (7990 patients; follow-up period, 6-12 months) were included. Compared with placebo, romosozumab significantly increased lumbar spine BMD (MD = 12.69; 95% CI 11.10-14.29), total hip BMD (MD = 4.42; 95% CI 3.03-5.80), and femoral neck BMD (MD = 3.99; 95% CI 2.42-5.57) at 12 months. Romosozumab significantly decreased falls (RR = 0.80; 95% CI 0.68-0.93) and major osteoporotic fractures (RR = 0.37; 95% CI 0.25-0.54), but increased injection-site reactions (RR = 1.83; 95% CI 1.46-2.30) within 12 months. No significant differences were observed in other AEs (including cardiovascular AEs) within 12 months., Conclusion: Romosozumab treatment resulted in a significant BMD gain, reduced falls and major osteoporotic fractures. It was generally well-tolerated, including the cardiovascular aspects. However, clinicians should consider the occurrence of minor AEs (e.g., injection-site reactions)., (© 2024. The Japanese Society Bone and Mineral Research.)

Background/aim: Reports regarding the association of remdesivir use for the treatment of Coronavirus disease 2019 (COVID-19) with the development of acute kidney injury (AKI) are inconsistent, and the associations between the use of other antivirals and AKI remain unclear. Therefore, this study investigated whether the use of antiviral drugs for the treatment of COVID-19 is a risk factor for the development of AKI., Patients and Methods: This study analyzed 176,197 reports submitted to the Japanese Adverse Event Reporting Database between 2020 and 2022. Reporting odds ratios (RORs) and 95% confidence intervals (95%CIs) for AKI that were associated with the use of antiviral drugs in patients with COVID-19 were calculated after adjusting for potential confounders., Results: Overall, 5,879 of the reports analyzed were associated with AKI. Signs of AKI were detected with the use of remdesivir [crude ROR (cROR)=2.45; 95%CI=1.91-3.14] and nirmatrelvir/ritonavir (cROR=6.07; 95%CI=4.06-9.06). These results were maintained even after adjusting for potential confounders [remdesivir: adjusted ROR (aROR)=2.18; 95%CI=1.69-2.80, nirmatrelvir/ritonavir: aROR=5.24; 95%CI=3.48-7.90]. However, when analyzing data stratified by reporting year, the association between remdesivir and AKI appeared to diminish over time and was not sustained., Conclusion: Nirmatrelvir/ritonavir use may be associated with developing AKI. This knowledge may be useful in helping patients with COVID-19 avoid AKI complications., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Improving diets requires an awareness of the need to limit foods for which excessive consumption is a health problem. Since there are limited reports on the link between this awareness and mortality risk, we examined the association between awareness of limiting food intake (energy, fat, and sweets) and all-cause mortality in a Japanese cohort study., Methods: Participants comprised 58,772 residents (27,294 men; 31,478 women) aged 35-69 years who completed baseline surveys of the Japan Multi-Institutional Collaborative Cohort Study from 2004 to 2014. Hazard ratios (HRs) for all-cause mortality and 95% confidence intervals (CIs) were estimated by sex using a Cox proportional hazard model, with adjustment for related factors. Mediation analysis with fat intake as a mediator was also conducted., Results: The mean follow-up period was 11 years, and 2,516 people died. Estimated energy and fat intakes according to the Food Frequency Questionnaire were lower in those with awareness of limiting food intake than in those without this awareness. Women with awareness of limiting fat intake showed a significant decrease in mortality risk (HR 0.73; 95% CI, 0.55-0.94). Mediation analysis revealed that this association was due to the direct effect of the awareness of limiting fat intake and that the total effect was not mediated by actual fat intake. Awareness of limiting energy or sweets intake was not related to mortality risk reduction., Conclusion: Awareness of limiting food intake had a limited effect on reducing all-cause mortality risk.

Purpose: This study aimed to investigate the association between oxidative balance score (OBS), wherein higher OBSs indicate lower oxidative stress, and high-sensitivity C-reactive protein (hs-CRP), as well as inflammatory scores, in a large cohort of Japanese adults., Methods: In total, 9703 individuals aged 40-69 years participated in a baseline survey of a population-based cohort study in Saga, Japan (2005-2007). OBSs were calculated from 11 prooxidant and antioxidant lifestyle factors, including dietary intake, physical activity, alcohol consumption, and smoking status. Lifestyle data, including dietary intake, were obtained using a self-administered questionnaire. Adjusted geometric means of serum hs-CRP levels were calculated based on OBS quartiles, and linear trend tests were performed, with adjustments for potential confounders. In addition, an inflammatory cytokine z-score was constructed and assessed alongside individual markers., Results: After adjusting for multiple confounders in both sexes, the results showed a significant inverse association between OBS and serum hs-CRP levels in both men and women. These results remained unaltered when the OBS evaluation excluded powerful prooxidants, serum ferritin, or smoking. There was also an association between OBS and lower inflammatory z-score, indicating reduced overall systemic inflammation., Conclusions: These findings suggest that a higher OBS, indicating a greater predominance of antioxidants over prooxidant exposure, is associated with lower hs-CRP levels and reduced systemic inflammation, regardless of sex., (© 2024 The Authors. American Journal of Human Biology published by Wiley Periodicals LLC.)

Background: The present genome-wide association study (GWAS) aimed to reveal the genetic loci associated with folate metabolites, as well as to detect related gene-environment interactions in Japanese., Methods: We conducted the GWAS of plasma homocysteine (Hcy), folic acid (FA), and vitamin B 12 (VB 12 ) levels in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study participants who joined from 2005 to 2012, and also estimated gene-environment interactions. In the replication phase, we used data from the Yakumo Study conducted in 2009. In the discovery phase, data of 2,263 participants from four independent study sites of the J-MICC Study were analyzed. In the replication phase, data of 573 participants from the Yakumo Study were analyzed., Results: For Hcy, MTHFR locus on chr 1, NOX4 on chr 11, CHMP1A on chr 16, and DPEP1 on chr 16 reached genome-wide significance (P < 5 × 10 -8 ). MTHFR also associated with FA, and FUT2 on chr 19 associated with VB 12 . We investigated gene-environment interactions in both studies and found significant interactions between MTHFR C677T and ever drinking, current drinking, and physical activity >33% on Hcy (β = 0.039, 0.038 and -0.054, P = 0.018, 0.021 and <0.001, respectively) and the interaction of MTHFR C677T with ever drinking on FA (β = 0.033, P = 0.048)., Conclusion: The present GWAS revealed the folate metabolism-associated genetic loci and gene-environment interactions with drinking and physical activity in Japanese, suggesting the possibility of future personalized cardiovascular disease prevention.

Objective: Although small fish are an important source of micronutrients, the relationship between their intake and mortality remains unclear. This study aimed to clarify the association between intake of small fish and all-cause and cause-specific mortality., Design: We used the data from a cohort study in Japan. The frequency of the intake of small fish was assessed using a validated FFQ. The hazard ratio (HR) and 95 % confidence interval (CI) for all-cause and cause-specific mortality according to the frequency of the intake of small fish by sex were estimated using a Cox proportional hazard model with adjustments for covariates., Setting: The Japan Multi-Institutional Collaborative Cohort Study., Participants: A total of 80 802 participants (34 555 males and 46 247 females), aged 35-69 years., Results: During a mean follow-up of 9·0 years, we identified 2482 deaths including 1495 cancer-related deaths. The intake of small fish was statistically significantly and inversely associated with the risk of all-cause and cancer mortality in females. The multivariable-adjusted HR (95 % CI) in females for all-cause mortality according to the intake were 0·68 (0·55, 0·85) for intakes 1-3 times/month, 0·72 (0·57, 0·90) for 1-2 times/week and 0·69 (0·54, 0·88) for ≥ 3 times/week, compared with the rare intake. The corresponding HR (95 % CI) in females for cancer mortality were 0·72 (0·54, 0·96), 0·71 (0·53, 0·96) and 0·64 (0·46, 0·89), respectively. No statistically significant association was observed in males., Conclusions: Intake of small fish may reduce the risk of all-cause and cancer mortality in Japanese females.

Background: The risk factors for progression of severity of locomotive syndrome (LS) remain unclear., Methods: We conducted a longitudinal observational study of 1148 community-dwelling residents (median age, 68.0 years old; 548 males, 600 females) from 2016 to 2018. LS was assessed by the 25-question Geriatric Locomotive Function Scale (GLFS-25), and total scores of ≤6 points, 7-15 points, 16-23 points, and ≥24 points were diagnosed as non-LS, LS-1, LS-2, and LS-3, respectively. If the LS severity in 2018 was higher than in 2016, the case was defined as progression of LS severity; otherwise, it was defined as non-progressive LS. We compared the age, gender, body mass index, smoking status, alcohol consumption, living situation, car use, chronic musculoskeletal pain, comorbidities, metabolic syndrome, physical activity, and LS severity in 2016 between the progression and non-progression groups. Furthermore, a multivariate logistic regression analysis was performed to elucidate the risk factors for progression of LS severity., Results: Participants in the progression group had a significantly older age, a lower rate of car use, a higher rate of low back pain, a higher rate of hip pain, a higher rate of knee pain, a higher GLFS-25 total score, and a higher rate of LS-2 than those in the non-progression group. The multivariate logistic regression analysis revealed that older age, female gender, higher body mass index (≥25.0 kg/m 2 ), presence of low back pain, and presence of hip pain were risk factors for the progression of LS within two years., Conclusions: To prevent the progression of LS severity, related prophylaxis strategies should be implemented, especially for individuals with the above-mentioned characteristics. Further longitudinal studies with a longer observation period are necessary., (Copyright © 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Several associations between diabetes mellitus and delirium have been reported; however, they have been inconsistent, and evidence on the effects of antidiabetic medications on delirium is also limited. This study aimed to investigate whether the use of antidiabetic drugs is a risk factor for delirium development., Methods: Using the Japanese Adverse Event Reporting Database, we analyzed 662,899 reports between 2004 and 2022. Reporting odds ratios (RORs) and 95% confidence intervals (CIs) for delirium associated with diabetes and using each antidiabetic medication were calculated after adjusting for potential confounders., Results: Overall, 8892 of the reports analyzed were associated with delirium. A comparison of the incidence of delirium between patients with and without diabetes showed no significant difference, with 1.34% in patients without diabetes and 1.37% in those with diabetes. In each antidiabetic medication, signals for delirium were detected for sulfonylurea (crude ROR, 1.35; 95% CI 1.21-1.51) and insulin (crude ROR, 1.28; 95% CI 1.13-1.44). These results were maintained even after adjusting for factors with potential confounders (sulfonylurea: adjusted ROR, 1.75; 95% CI 1.54-2.00, insulin: adjusted ROR, 1.35; 95% CI 1.20-1.54)., Conclusions: Our results suggest no association between diabetes and delirium; however, using sulfonylurea and insulin may be associated with delirium development. Nonetheless, these findings should be validated in future studies., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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 8 015 middle-aged and older adults (comprised of 4 755 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 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, the mortality rates were 8.9 and 3.6 per 1 000 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], ptrend < .05; women, Q4, HR: 2.2 [1.3-3.8], ptrend < .01). This association remained significant after further adjustment for skeletal muscle mass and HGS (ptrend < .05). Our findings suggest that A-E/I serves as an early predictive marker for mortality in middle-aged and older Japanese adults., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Immune-related adverse events (irAEs) affect all organs and are associated with various symptoms. The identification of biomarkers that can predict irAEs may be particularly clinically useful. This study aimed to investigate whether the prognostic nutritional index (PNI) before the initiation of immune checkpoint inhibitor (ICI) treatment can predict the occurrence of irAEs. We conducted a survey of 111 patients with cancer who were receiving ICI fixed-dose monotherapy at Saga University Hospital from the time each ICI became available until January 2020. We compared the PNI between the patients with and without irAE expression, established a cutoff value for PNI associated with the development of irAEs, and investigated the incidence of irAEs and progression-free survival (PFS) in groups divided by the cutoff value. Patients with irAEs had significantly higher PNI than did those without, and there was a significant association between PNI and irAEs after adjusting for potential factors (odds ratio, 1.12; 95% confidence interval, 1.03-1.21). In addition, PNI ≥44.2 was associated with a significantly higher incidence of irAEs (75.0% vs. 35.2%, p = 0.0001) and significantly longer PFS than PNI <44.2 (p = 0.025). In conclusion, pretreatment PNI may be associated with the risk of developing irAEs in patients with advanced recurrent solid tumors. When the PNI is ≥44.2, patient management is important for avoiding serious AEs because while the treatment may be effective, the occurrence of irAEs is a concern.

Objective: Venetoclax, an oral B-cell lymphoma-2 inhibitor, necessitates dose adjustment when combined with a CYP3A4 inhibitor; however, the dosing regimen remains unclear on adding a CYP3A4 inhibitor after venetoclax administration., Case Summary: We present a case report of a patient who was simultaneously treated with a CYP3A4 inhibitor and a steady daily dose of venetoclax. A 30-year-old male diagnosed with acute myeloid leukemia received a combination of venetoclax and azacitidine as remission induction therapy. He was prescribed 400 mg/day venetoclax at a steady daily dose, with fosfluconazole initiated on day 18. Given that fosfluconazole can induce moderate CYP3A4 inhibitory effects, the venetoclax dosage was reduced to 200 mg/day on the same day. Despite dose reduction, plasma trough levels of venetoclax continued rising gradually. Nearly 10 days were required to decrease blood levels to a steady state., Conclusion: The risk of elevated venetoclax blood levels needs to be considered when initiating CYP3A4 inhibitors and reducing venetoclax dosage on the same day.

Guanfacine, used as a medication for attention-deficit/hyperactivity disorder (ADHD), leads to a high incidence of somnolence, in contrast to methylphenidate, which leads to a high incidence of insomnia. The impact of somnolence on continuing guanfacine treatment is unclear. Therefore, we investigated the reasons for discontinuing guanfacine and analyzed the factors associated with discontinuation caused by somnolence. We surveyed 96 patients under guanfacine from July 2017 to December 2021 at the Saga University Hospital. Patients who discontinued guanfacine by the end date of our study were divided into a median early and late group. We compared the reasons for discontinuation in both groups. Of all patients, 47 continued and 49 discontinued guanfacine. A higher percentage of patients discontinued guanfacine caused by somnolence for ≤70 d than for >70 d of treatment (44.0 vs. 8.3%; p = 0.008). When stratified by the concomitant use of other ADHD drugs, somnolence resulted in a higher discontinuation rate for ≤70 d than for >70 d of treatment without concomitant use (55.0 vs. 7.1%; p = 0.009). Nonetheless, concomitant use resulted in no difference. In conclusion, somnolence affects the early discontinuation of guanfacine as an ADHD drug. The combination of methylphenidate or atomoxetine may decrease withdrawal caused by somnolence.

Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations and has shown efficacy in patients with non-small-cell lung cancer. In this study, we created osimertinib-specific antibodies and developed an immunohistochemistry (IHC) for locating the sites of osimertinib action. Moreover, we located osimertinib-protein conjugates in intestinal, dermal, and lung tissues of rats, thereby using our IHC to visualize the sites of the adverse effects of osimertinib, including diarrhea, skin disorder, and interstitial pneumonia. This report is the first to elucidate the localization of the sites of action of osimertinib in the rat intestine, skin, and lung and is expected to help clarify the mechanism of osimertinib-induced adverse effects., Competing Interests: VThe authors declare no conflicts of interest., (2023 The Japan Society of Histochemistry and Cytochemistry.)

The oxidative balance score (OBS), wherein higher OBSs indicate lower oxidative stress, was designed to assess a composite measure of multiple pro-oxidant and antioxidant effects on an individual's oxidative stress status. This study aimed to evaluate whether OBSs were inversely associated with urinary levels of 8-hydroxydeoxyguanosine (8-OHdG)-an oxidative stress marker-among Japanese adults. This cross-sectional study was based on data obtained during 2010-2012. Overall, 7552 participants from the J-MICC Study Saga who answered a self-administered food frequency questionnaire were recruited for the final analysis. OBSs were calculated from 11 pro-oxidant and antioxidant lifestyle factors, including dietary intake, physical activity, and alcohol and smoking status. Urinary 8-OHdG values were corrected by creatinine level (ng/mg creatinine). Our findings revealed a higher total OBS was significantly associated with lower urinary 8-OHdG/creatinine levels after adjustment for covariates in men and women ( p for trend < 0.01 in both sexes). We performed a multiple regression analysis of the association between OBSs and urinary 8-OHdG/creatinine levels stratified by age, body mass index (BMI), and menopausal status and found consistent negative associations in most groups for both sexes. No significant differences in the 60-64 age group for women (standardized β = -0.09, p = 0.13) or BMI < 18.5 kg/m 2 for men (standardized β = -0.18, p = 0.17) were observed. A higher OBS had a strong inverse association with urinary 8-OHdG/creatinine levels in men and women among Japanese adults. The OBS might be a useful tool for evaluating the roles of oxidative stress-related lifestyle factors, including diet.

This study sought to develop a specific and sensitive sandwich enzyme-linked immunosorbent assay (ELISA) for pharmacokinetic studies of dasatinib, a tyrosine kinase inhibitor. Anti-dasatinib antibodies were obtained from mice or rabbits by using two partial structures of dasatinib as haptens: 2-amino-N-(2-chloro-6-methylphenyl)-thiazole-5-carboxamide and 2-{4-(2-hydroxyethyl)-1-piperazinyl}-isonicotinic acid. The best combination of two antibodies for sandwich ELISA of dasatinib was determined using four anti-dasatinib antibodies derived from mice and rabbits. Using two dasatinib-specific rabbit antibodies, we successfully developed an ultra-specific and highly sensitive sandwich ELISA that is hardly affected by the main metabolite of dasatinib. The sandwich ELISA showed a linear detection range from 320 pg/mL to 1000 ng/mL. Serum dasatinib concentrations lower than 320 pg/mL were reproducibly measurable using the sandwich ELISA. The ELISA was specific to dasatinib and there were no cross-reactivities with the major metabolites 4'-hydroxy dasatinib and dasatinib carboxylic acid. The developed sandwich ELISA will be a valuable tool for pharmacokinetic studies of dasatinib. Furthermore, this study revealed that rabbit antibodies can sandwich drug molecules of a smaller size than mouse antibodies in sandwich ELISA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Antiepileptic drugs may cause delirium, and the risk may vary with each drug. However, related studies have provided inconsistent results., Aim: The aim of this study was to investigate whether the use of antiepileptic drugs is a risk factor for delirium development., Method: Using the Japanese Adverse Drug Event Report database, we analysed 573,316 reports pertaining to the period from 2004 to 2020. Reporting odds ratios and 95% confidence intervals of delirium associated with use of antiepileptic drugs were calculated after adjusting for potential confounders. Furthermore, for each antiepileptic drug, we performed an analysis stratified based on older age and benzodiazepine receptor agonist usage., Results: There were 27,439 reports of antiepileptic drug-related adverse events. Of these, 191 reports were associated with antiepileptic drugs and delirium (crude reporting odds ratio [cROR], 1.66; 95% confidence interval [CI], 1.43-1.93). The use of lacosamide (adjusted reporting odds ratio [aROR], 2.44; 95% CI, 1.24-4.80), lamotrigine (aROR, 1.54; 95% CI, 1.05-2.26), levetiracetam (aROR, 1.91; 95% CI, 1.35-2.71), and valproic acid (aROR, 1.49; 95% CI, 1.16-1.91) was related to a significantly higher reporting odds ratio for delirium, even after adjustment for possible confounding factors. However, when used in combination with benzodiazepine receptor agonists, none of the antiepileptic drugs were found to be associated with delirium., Conclusion: Our study's findings suggest that antiepileptic drug usage may be associated with delirium development., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Aims: The association between dietary patterns and serum low density lipoprotein (LDL) cholesterol would be changing in recent dietary habits in Japan. We investigated the relationship between dietary patterns and serum LDL cholesterol in a large general population., Methods: From the baseline survey of Japan Multi-Institutional Collaborative Cohort Study between 2005 and 2013, 27,237 participants (13,994 were women) aged 35-69 years were cross-sectionally analyzed. Using a semi-quantitative food frequency questionnaire, five major sex-specific dietary patterns were identified using factor analysis. We assessed serum LDL cholesterol by quintiles of dietary pattern factor score., Results: We identified dietary patterns; "vegetable rich pattern" , "meat and fried food rich pattern" and "high bread and low rice pattern" in women and men; "fish and shellfish rich pattern" and "high confectioneries and low alcohol pattern" in men; "healthy Japanese diet pattern" and "high alcohol and low rice pattern" in women. Serum LDL cholesterol in men was associated with "high bread and low rice pattern" score (Q5 was 4.2 mg/dL higher than Q1, p for trend ＜0.001) and "high confectioneries and low alcohol pattern" scores (Q5 was 9.5 mg/dL higher than Q1, p for trend ＜0.001). In women, serum LDL cholesterol was associated with "high bread and low rice pattern" score (Q5 was 7.1 mg/dL higher than Q1, p for trend ＜0.001)., Conclusion: Some recent dietary patterns in Japan were associated with serum LDL cholesterol. Serum LDL cholesterol was associated with high bread and low rice pattern in both sex, and high confectioneries and low alcohol pattern in men.

Purpose: This study examined the association between daily green tea and coffee consumption and body iron stores among Japanese middle-aged and older adults., Methods: This cross-sectional study used data obtained from 2005 to 2007. A total of 10,435 participants were recruited for this study. The participants completed a validated, self-administered food frequency questionnaire on green tea and coffee consumption. A multivariate linear regression analysis was conducted to assess the relationship between green tea and coffee consumption and serum ferritin levels. Additionally, logistic regression analysis was performed to ascertain whether excessive consumption of these beverages was linked to iron deficiency., Results: We observed that higher green tea and coffee consumption was associated with lower ferritin levels in men and postmenopausal women, even after adjusting for covariates (all P for trends <0.05). Among premenopausal women, we found an inverse association between green tea consumption and serum ferritin levels, while no significant association was observed for coffee consumption after adjusting for covariates (green tea, P for trend <0.05; coffee, P for trend = 0.08). Notably, the association between these beverages and iron deficiency was found only in postmenopausal women; the odds ratios (95% confidence intervals) for iron deficiency associated with almost None, <1 cup/day, 1-2 cups/day, and ≥ 3 cups/day were 1.00 (reference), 0.78 (0.26-2.49), 1.29 (0.49-3.39), and 1.59 (0.63-4.04) ( P for trend = 0.05), respectively, for green tea and 1.00, 1.32 (0.64-2.73), 1.46 (0.68-3.13), and 2.20 (1.06-4.55) ( P for trend <0.01), respectively, for coffee., Conclusion: Higher green tea and coffee consumption was associated with lower serum ferritin levels in men and postmenopausal women. In premenopausal women, consumption of green tea, but not coffee, was associated with lower serum ferritin levels. However, postmenopausal women who ≥3 cups of coffee demonstrated a higher prevalence of iron deficiency compared to those who consumed almost none., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nanri, Hara, Nishida, Shimanoe, Iwasaka, Higaki and Tanaka.)

Objective: ICU delirium reportedly contributes to increased mortality attributed to underlying diseases, long-term cognitive decline, and increased healthcare costs. Dual orexin receptor antagonists (DORAs), suvorexant and lemborexant, have been suggested for preventing ICU delirium. Although ventilator management is a risk factor for delirium, no study has examined the efficacy of suvorexant and lemborexant in preventing delirium in critically ill patients requiring ventilation. Thus, we retrospectively evaluated the efficacy of DORA in preventing delirium in critically ill adult patients requiring ventilatory management in the emergency room., Method: This retrospective study included patients aged ≥18 years who were admitted to the emergency room and received ventilator support between January 2015 and April 2022. The HR (95% CI) for delirium development in patients taking DORA was estimated using a Cox proportional hazards model, which was adjusted for the patient background and concomitant medications. HRs were calculated for patients taking suvorexant and those taking lemborexant using a stratified analysis., Results: Of the 297 patients included in the study, 67 were in the DORA group; 50 were on suvorexant and 17 were on lemborexant. The DORA group had a lower incidence of delirium than the control group (p < 0.0001). The risk of delirium was lower in the DORA group compared the control group (HR, 0.22; 95% CI 0.12-0.40).The risk of developing delirium was lower with suvorexant (HR 0.22; 95% CI 0.11-0.41) and lemborexant (HR 0.25; 95% CI 0.08-0.81)., Conclusion: DORA is a promising drug that could have the potential to prevent delirium, and its efficacy in preventing delirium should be tested in randomized controlled trials in the future., Competing Interests: Declaration of Competing Interest The authors of this paper have no competing interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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 chronic kidney disease (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 m 2 . 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 (P for trend MVPA <0.0001) and lower eGFR (P for trend SB <0.0001), and a lower odds ratio (OR) of CKD (adjusted OR of MVPA ≥20 MET·h/day, 0.76; 95% confidence interval [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., Conclusion: These findings indicate that replacing SB with physical activity may benefit kidney function, especially in men, adding to the possible evidence on CKD prevention.

Objectives: The purpose of this study was to compile the currently available evidence on the clinical characteristics of the locomotive syndrome (LS) categorised by the 25-question Geriatric Locomotive Function Scale (GLFS-25) and clarify its clinical usefulness for assessing mobility function., Design: Systematic review., Data Sources: The PubMed and Google Scholar were searched for the relevant studies on 20 March 2022., Eligibility Criteria: We included relevant peer-reviewed articles, available in English language, on clinical LS characteristics categorised with the GLFS-25., Data Extraction and Synthesis: Pooled ORs or mean differences (MDs) of the LS groups were calculated and compared with the non-LS groups for each clinical characteristic., Results: In total, 27 studies that involve 13 281 participants (LS, n=3385; non-LS, n=9896) were examined in this analysis. Older age (MD 4.71; 95% (CI) 3.97 to 5.44; p<0.00001), female gender (OR 1.54; 95% CI 1.38 to 1.71; p<0.00001), higher body mass index (MD 0.78; 95% CI 0.57 to 0.99; p<0.00001), osteoporosis (OR 1.68; 95% CI 1.32 to 2.13; p<0.0001), depression (OR 3.14; 95% CI 1.81 to 5.44; p<0.0001), lower lumbar lordosis angle (MD -7.91; 95% CI -10.08 to -5.74; p<0.00001), higher spinal inclination angle (MD 2.70; 95% CI 1.76 to 3.65; p<0.00001), lower grip strength (MD -4.04; 95% CI -5.25 to -2.83; p<0.00001), lower back muscle strength (MD -15.32; 95% CI -23.83 to -6.81; p=0.0004), lower maximum stride (MD -19.36; 95% CI -23.25 to -15.47; p<0.00001), higher timed up-and-go (MD 1.36; 95% CI 0.92 to 1.79; p<0.00001), lower one-leg standing time (MD -19.13; 95% CI -23.29 to -14.97; p<0.0001) and slower normal gait speed (MD -0.20; 95% CI -0.22 to -0.18; p<0.0001) were found to be associated with LS. No significant differences were noted in other clinical characteristics between the two groups., Conclusions: GLFS-25 is clinically useful for assessing mobility function according to the evidence available on the clinical characteristics of LS categorised by the GLFS-25 questionnaire items until., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study determined the cut-off time for the one-leg standing test (OLST) to simply screen the severity of locomotive syndrome (LS). We conducted this cross-sectional study on 1860 community-dwelling residents (age, 70.5 ± 9.5 years old; males, n = 826; females, n = 1034) who underwent the OLST and completed the 25-question geriatric locomotive function scale (GLFS-25). Multivariate linear regression and multivariate logistic regression analyses were conducted to assess the relationship between the OLST and the GLFS-25 score and LS after adjusting for age, sex, and body mass index. A receiver operating characteristic (ROC) curve analysis was performed to calculate the optimal cut-off time of the OLST for determining LS severity. The multivariate linear regression and multivariate logistic regression analyses showed that the OLST was significantly associated with the GLFS-25 score and a diagnosis of LS. The optimal cut-off times of the OLST to screen LS-1, LS-2, and LS-3 were 42 s (sensitivity 65.8%, specificity 65.3%), 27 s (sensitivity 72.7%, specificity 72.5%), and 19 s (sensitivity 77.4%, specificity 76.8%), respectively. We developed a simplified screening tool for the OLST to determine LS severity.

Background: Stress coping strategies are related to health outcomes. However, there is no clear evidence for sex differences between stress-coping strategies and mortality. We investigated the relationship between all-cause mortality and stress-coping strategies, focusing on sex differences among Japanese adults., Methods: A total of 79,580 individuals aged 35-69 years participated in the Japan Multi-Institutional Collaborative Cohort Study between 2004 and 2014 and were followed up for mortality. The frequency of use of the five coping strategies was assessed using a questionnaire. Sex-specific, multivariable-adjusted hazard ratios (HRs) for using each coping strategy ("sometimes," and "often/very often" use versus "very few" use) were computed for all-cause mortality. Furthermore, relationships were analyzed in specific follow-up periods when the proportion assumption was violated., Results: During the follow-up (median: 8.5 years), 1,861 mortalities were recorded. In women, three coping strategies were related to lower total mortality. The HRs for "sometimes" were 0.81 (95% confidence interval [CI], 0.67-0.97) for emotional expression, 0.79 (95% CI, 0.66-0.95) for emotional support-seeking, and 0.80 (95% CI, 0.66-0.98) for disengagement. Men who "sometimes" used emotional expression and sometimes or often used problem-solving and positive reappraisal had a 15-41% lower HRs for all-cause mortality. However, those relationships were dependent on the follow-up period. There was evidence that sex modified the relationships between emotional support-seeking and all-cause mortality (P for interaction = 0.03)., Conclusion: In a large Japanese sample, selected coping strategies were associated with all-cause mortality. The relationship of emotional support-seeking was different between men and women.

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., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest None declared., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: No studies have provided statistical evidence of the relationship between comorbidities and locomotive syndrome (LS). We therefore investigated the association of comorbidities with the 25-question Geriatric Locomotive Function Scale (GLFS-25) and the diagnosis of LS in community-dwelling residents., Methods: This cross-sectional study was conducted on 2612 community-dwelling residents (≥40 years old) who attended a 'basic health checkup'. There were 432 participants with comorbidities (45 with cerebrovascular diseases, 133 with cardiovascular diseases, 83 with pulmonary diseases, 108 with renal diseases, and 63 with multiple diseases) and 2180 participants without comorbidities. Subjects with a GLFS-25 total score of ≤6 points, 7-15 points, 16-23 points, and ≥24 points were diagnosed with non-LS, LS-1, LS-2, and LS-3, respectively. The domain scores covered body pain (items 1-4), movement-related difficulty (items 5-7), usual care (items 8-11 and 14), social activities (items 12, 13, and 15-23), and cognition (items 24 and 25). A multivariate regression analysis and multivariate logistic regression analysis were performed to assess the association between the GLFS-25 scores and comorbidities and between the diagnosis of LS and comorbidities after adjusting for age, sex, body mass index, and smoking status., Results: A multivariate regression analysis showed that comorbidities were significantly related to the GLFS-25 total score and all domain scores. A multivariate logistic regression analysis revealed that comorbidities were significantly related to a diagnosis of LS-1 or more, LS-2 or more, and LS-3 or more., Conclusions: Comorbidities were associated with increased GLFS-25 domain scores and total score and consequent diagnosis of LS. Therefore, attention should also be paid to the presence of comorbidities when diagnosing LS. Nevertheless, the causal relationship between comorbidities and the GLFS-25 remains unclear, and further studies are therefore required., Competing Interests: Declaration of competing interest All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements) or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: The relationship between lifestyle and obesity is a major focus of research. Personalized nutrition, which utilizes evidence from nutrigenomics, such as gene-environment interactions, has been attracting attention in recent years. However, evidence for gene-environment interactions that can inform treatment strategies is lacking, despite some reported interactions involving dietary intake or physical activity. Utilizing gene-lifestyle interactions in practice could aid in optimizing interventions according to genetic risk., Methods: This study aimed to elucidate the effects of gene-lifestyle interactions on body mass index (BMI). Cross-sectional data from the Japan Multi-Institutional Collaborative Cohort Study were used. Interactions between a multi-locus genetic risk score (GRS), calculated from 76 ancestry-specific single nucleotide polymorphisms, and nutritional intake or physical activity were assessed using a linear mixed-effect model., Results: The mean (standard deviation) BMI and GRS for all participants (n = 12,918) were 22.9 (3.0) kg/m2 and -0.07 (0.16), respectively. The correlation between GRS and BMI was r(12,916) = 0.13 (95% confidence interval [CI] 0.11-0.15, P < 0.001). An interaction between GRS and saturated fatty acid intake was observed (β = -0.11, 95% CI -0.21 to -0.02). An interaction between GRS and n-3 polyunsaturated fatty acids was also observed in the females with normal-weight subgroup (β = -0.12, 95% CI -0.22 to -0.03)., Conclusion: Our results provide evidence of an interaction effect between GRS and nutritional intake and physical activity. This gene-lifestyle interaction provides a basis for developing prevention or treatment interventions for obesity according to individual genetic predisposition., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Nakamura et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: Hemoglobin A1c (HbA1c) levels are widely employed to diagnose diabetes. However, estimates of the heritability of HbA1c and glucose levels are different. Therefore, we explored HbA1c- and blood glucose-associated loci in a non-diabetic Japanese population., Methods: We conducted a two-stage genome-wide association study (GWAS) on variants associated with HbA1c and blood glucose levels in a Japanese population. In the initial stage, data of 4911 participants of the Japan Multi-Institutional Collaborative Cohort (J-MICC) were subjected to discovery analysis. In the second stage, two datasets from the Tohoku Medical Megabank project, with 8175 and 40,519 participants, were used for the replication study. Association of the imputed variants with HbA1c and blood glucose levels was determined via linear regression analyses adjusted for age, sex, body mass index (BMI), smoking, and genetic principal components (PC1-PC10). Moreover, we performed a BMI-stratified GWAS on HbA1c levels in the J-MICC. The discovery analysis and BMI-stratified GWAS results were validated with re-analyses of normalized HbA1c levels adjusted for site in addition to the above, and blood glucose adjusted for fasting time as an additional covariate., Results: Genetic variants associated with HbA1c levels were identified in KCNQ1 and TMC6 . None of the genetic variants associated with blood glucose levels in the discovery analysis were replicated. Association of rs2299620 in KCNQ1 with HbA1c levels showed heterogeneity between individuals with BMI ≥ 25 kg/m 2 and BMI < 25 kg/m 2 ., Conclusions: The variant rs2299620 in KCNQ1 might affect HbA1c levels differentially based on BMI grouping in the Japanese population., Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00618-0., Competing Interests: Conflict of interestTakuya Sakashita is an employee of Takara Bio, Inc., Japan. Dr. Hachiya is a board member of Genome Analytics Japan Inc. Dr. Nakatochi reports receiving grants from Boehringer Ingelheim outside the submitted work. All other authors declare that they have no conflicts of interest associated with this study., (© The Japan Diabetes Society 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

In this study, an HPLC analysis method using pre-column derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) was developed for the determination of o-phosphoethanolamine (PEA), which is a potential biomarker for the diagnosis of major depressive disorder, in human plasma sample. After PEA was derivatized with AQC under mild conditions, the obtained derivative was subjected to purification with a titanium dioxide-modified monolithic silica spin column (MonoSpin ® TiO). The eluate from the MonoSpin ® TiO was directly injected into an amide-type hydrophilic interaction liquid chromatography (HILIC) column-equipped HPLC system, and the resulting derivative could be separated on the column under alkaline mobile phase conditions and subsequently detected fluorometrically at excitation and emission wavelengths of 250 and 395 nm, respectively. The limit of detection and limit of quantification for a 10 µL injection volume of PEA were 0.052 and 0.17 µM, respectively. The method was validated at 0.2, 1.0, and 5.0 nmol/mL levels in plasma sample, and the precision values were 2.0-6.6% as relative standard deviation and the correlation coefficient (r) of the calibration curve was 0.9995. Furthermore, applicability of this method was demonstrated by analyzing PEA levels in plasma samples from mental illness patients.

Objective: Histamine-2 receptor antagonists (H2RAs) may induce a higher risk of developing delirium than proton pump inhibitors (PPIs), but current evidence is insufficient. Therefore, this study aimed to investigate whether anti-ulcer drugs increase delirium risk., Method: Data were obtained from the medical records of patients admitted to a hospital due to trauma. We compared the incidence of delirium in patients who received H2RAs and PPIs with that in patients who received no anti-ulcer drugs., Results: A total of 150, 158, and 238 patients received H2RAs, PPIs, and no anti-ulcer drugs, respectively. Delirium incidence was significantly higher in patients who received H2RAs (34.0%) and PPIs (44.9%) than in those who did not receive anti-ulcer drugs (22.3%). Even after adjustment for possible confounding factors, the association between H2RAs and delirium remained (adjusted OR 1.78; 95% CI 1.04-3.05), but that between PPIs and delirium was attenuated (adjusted OR 1.25; 95% CI 0.71-2.23)., Conclusions: Our results show that H2RAs are associated with delirium risk. We replicated findings of a previous data-driven study. Clinicians need to consider the effect of delirium in anti-ulcer drug selection., (Copyright © 2022 Elsevier Inc. All rights reserved.)

O-Phosphoethanolamine (PEA) is an endogenous substance that is attracting interest as a biomarker for depression, and thus there is a need to develop a simple analytical method that specifically measures PEA. Therefore, this study aimed to develop a simple and specific enzyme-linked immunosorbent assay (ELISA) for PEA. Anti-PEA antibody was obtained by immunizing mice with an antigen conjugated with mercaptosuccinyl bovine serum albumin using m-maleimidobenzoyl-N-hydroxysulfosuccinimide ester (MBS). In this assay, the PEA to be quantified is chemically modified by benzoyl chloride that is allowed to compete with a PEA-MBS-HRP conjugate for binding to a limited amount of an anti-PEA antibody, which was used to coat the wells of a microtiter plate. This ELISA shows a linear range of detection of 0.11-27 μM, and a limit of quantification of 0.144 μM. The anti-PEA antibody showed high affinity for benzoyl PEA. No detectable cross-reactivity was found with benzoyl 2-aminoethanol, O-phospho-l-tyrosine or benzoyl sphingosine-1-phosphate. The values of plasma PEA levels measured by this ELISA were comparable to those measured by HPLC, and a strong correlation was observed between the values determined by the two methods. The developed ELISA should provide a valuable new tool for the quantification of PEA in human plasma., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: There is limited evidence for the efficacy of the novel dual orexin receptor antagonists (DORAs) suvorexant and lemborexant in preventing delirium. We examined the efficacy of DORAs in preventing delirium in critically ill patients at an advanced emergency and critical care center., Methods: In this retrospective observational study, patients 18 years of age or older admitted to the emergency center between July 2018 and November 2021 with hospitalization duration of at least 72 h were included. Kaplan-Meier curves were plotted and log rank tests were performed to compare between patients with and without DORA treatment. Cox regression analyses adjusting for factors associated with delirium risk were also performed., Results: Of the 633 enrolled patients, 82 were treated with suvorexant and 41 with lemborexant. Cox regression analysis showed that, without adjustment, the hazard ratios (95% CIs) for the development of delirium were 0.56 (0.36-0.86) for patients treated with suvorexant and 0.26 (0.11-0.62) for those treated with lemborexant. After adjustment for delirium risk factors, the hazard ratios (95% CIs) remained low at 0.34 (0.20-0.58) for suvorexant and 0.21 (0.08-0.52) for lemborexant., Conclusions: Both suvorexant and lemborexant may be effective in preventing delirium in critically ill adult patients in an advanced critical care center., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

Background: Inflammation is thought to be a risk factor for kidney disease. However, whether inflammatory status is either a cause or an outcome of chronic kidney disease remains controversial. We aimed to investigate the causal relationship between high-sensitivity C-reactive protein (hs-CRP) and estimated glomerular filtration rate (eGFR) using Mendelian randomization (MR) approaches., Methods: A total of 10,521 participants of the Japan Multi-institutional Collaborative Cohort Study was analyzed in this study. We used two-sample MR approaches (the inverse-variance weighted (IVW), the weighted median (WM), and the MR-Egger method) to estimate the effect of genetically determined hs-CRP on kidney function. We selected four and three hs-CRP associated single nucleotide polymorphisms (SNPs) as two instrumental variables (IV): IV CRP and IV Asian , based on SNPs previously identified in European and Asian populations. IV CRP and IV Asian explained 3.4% and 3.9% of the variation in hs-CRP, respectively., Results: Using the IV CRP , genetically determined hs-CRP was not significantly associated with eGFR in the IVW and the WM methods (estimate per 1 unit increase in ln(hs-CRP), 0.000; 95% confidence interval [CI], -0.019 to 0.020 and -0.003; 95% CI, -0.019 to 0.014, respectively). For IV Asian , we found similar results using the IVW and the WM methods (estimate, 0.005; 95% CI, -0.020 to 0.010 and -0.004; 95% CI, -0.020 to 0.012, respectively). The MR-Egger method also showed no causal relationships between hs-CRP and eGFR (IV CRP : -0.008; 95% CI, -0.058 to 0.042; IV Asian : 0.001; 95% CI, -0.036 to 0.036)., Conclusion: Our two-sample MR analyses with different IVs did not support a causal effect of hs-CRP on eGFR.

Introduction: Health benefits of physical activity (PA) may be mediated by DNA methylation alterations. The purpose of the current study was to comprehensively identify CpG sites whose methylation levels were associated with accelerometer-assessed total PA in a general Japanese population., Methods: The study participants were from the baseline survey of Saga Japan Multi-institutional Collaborative Cohort. PA was objectively measured by a single-axis accelerometer for 7 d. We used a two-stage strategy. In the discovery stage, we performed a meta-analysis of two epigenome-wide association studies of total PA in 898 individuals (a combination of random sample ( n = 507) and case-control study sample ( n = 391)). Peripheral blood DNA methylation levels were measured using Infinium EPIC or HM450 arrays. In the replication stage, we subsequently examined whether CpG sites significantly associated ( P < 1 × 10 -5 ) with total PA were replicated in another sample ( n = 1711), in which methylation levels were measured by pyrosequencing. A multiple linear regression was performed to determine the cross-sectional association between total PA and methylation levels with adjustment for potential confounders, including body mass index. A fixed-effects model was used in the meta-analysis. Correlations between total PA-associated DNA methylation and several inflammatory markers, such as high-sensitivity C-reactive protein, were also conducted., Results: In the meta-analysis, nine CpG sites were significantly associated with total PA ( P < 1 × 10 -5 ). Among the nine sites, one site cg07030336 (annotated to VTI1A/ZDHHC6 gene) was successfully replicated ( P = 0.009)., Conclusions: The current study showed that greater accelerometer-assessed total PA was associated with higher DNA methylation levels at cg07030336 ( VTI1A/ZDHHC6 ) in the general population. In addition, we found a divergent relationship between the methylation levels at cg07030336 and several inflammatory biomarkers., (Copyright © 2022 by the American College of Sports Medicine.)

The influence of habitual physical activity (PA) on the circulating levels of secreted protein acidic and rich in cysteine (SPARC) remains unclear. The purpose of the current study was to clarify the effects of sedentary time, light-intensity PA (LPA), and moderate- to vigorous-intensity PA (MVPA) on the serum SPARC in a general middle-aged population. The current study is a cross-sectional study of 4,000 men and 6,040 women (40-69 years). Sedentary time, LPA, and MVPA were objectively measured by an accelerometer. The serum SPARC concentration was measured by enzyme-linked immunosorbent assay. Using an isotemporal substitution model, cross-sectional associations of replacing sedentary time with either LPA or MVPA on serum SPARC levels were analysed according to sex. Interactions with subject characteristics, such as the body mass index (BMI), smoking, and alcohol consumption, were also examined. In men, replacing 60 min of sedentary time with 60 min of MVPA was significantly associated with 23 ng/mL lower serum SPARC levels (confidence interval: -43, -2) after adjusting for confounders, including the BMI ( P  = 0.028). A significant interaction between replacing sedentary behaviour with LPA and the BMI on SPARC was detected in women ( P  = 0.029), although the stratified associations for each BMI level (<25 or ≥25 kg/m 2 ) did not reach significance. The current study suggests that replacing sedentary time with MVPA is associated with reduced serum SPARC levels in middle-aged men, but not in women. In addition, a potential interaction between LPA and the BMI on SPARC was also found in women. Highlights An isotemporal substitution analysis showed that replacing sedentary behaviour with moderate- to vigorous-intensity physical activity (MVPA) is associated with decreased serum SPARC levels in men.Such an inverse association between replacing sedentary behaviour with MVPA and the SPARC levels was not observed in women.A potential interaction between replacing sedentary behaviour with light-intensity PA and the body mass index on the serum SPARC levels was also found in women.

Genetic factors play a role in individual differences in pain experience. Here, we performed a genome-wide association study (GWAS) to identify novel loci regulating pain processing. We conducted a 2-stage GWAS and the candidate single-nucleotide polymorphisms (SNPs) association study on pain experience using an exploratory cohort of patients with cancer pain. The confirmatory cohort comprised of participants from the general population with and without habitual use of analgesic medication. In the exploratory cohort, we evaluated pain intensity using a numerical rating scale, recorded daily opioid dosages, and calculated pain reduction rate. In the confirmatory cohort, pain experience was defined as habitual nonsteroidal anti-inflammatory drug usage. Using linear regression models, we identified candidate SNP in the exploratory samples, and tested the association between phenotype and experienced pain in the confirmatory samples. We found 1 novel SNP (rs11764598)-located on the gene encoding for pleiotrophin on chromosome 7-that passed the genome-wide suggestive significance at 20% false discovery rate (FDR) correction in the exploratory samples of patients with cancer pain (P = 1.31 × 10-7, FDR = 0.101). We confirmed its significant association with daily analgesic usage in the confirmatory cohort (P = .028), although the minor allele affected pain experience in an opposite manner. We identified a novel genetic variant associated with pain experience. Further studies are required to validate the role of pleiotrophin in pain processing., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background/objectives: Low-carbohydrate diets (LCD) are useful for weight reduction, and 50-55% carbohydrate consumption is associated with minimal risk. Genetic differences were related to nutritional consumption, food preferences, and dietary patterns, but whether particular genetic differences in individuals influence LCD adherence is unknown., Subjects/methods: We conducted a GWAS on adherence to LCD utilizing 14,076 participants from the Japan Multi-Institutional Collaborative Cohort study. We used a previously validated semiquantitative food frequency questionnaire to estimate food consumption. Association of the imputed variants with the LCD score by Halton et al. we used linear regression analysis adjusting for sex, age, total dietary energy consumption, and components 1 to 10 by principal component analysis. We repeated the analysis with adjustment for alcohol consumption (g/day) in addition to the above-described variables., Results: Men and women combined analysis without adjustment for alcohol consumption; we found 395 variants on chromosome 12 associated with the LCD score having P values <5 × 10 -8 . A conditional analysis with the addition of the dosage data of rs671 on chromosome 12 as a covariate, P values for all 395 SNPs on chromosome 12 turned out to be insignificant. In the analysis with additional adjustment for alcohol consumption, we did not identify any SNPs associated with the LCD score., Conclusion: We found rs671 was inversely associated with adherence to LCD, but that was strongly confounded by alcohol consumption., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The optimal cut-off values of the 5-question Geriatric Locomotive Function Scale (GLFS-5) as a screening tool to identify Locomotive Syndrome (LS) diagnosed with the 25-question Geriatric Locomotive Function Scale (GLFS-25) has yet to be fully investigated. This study aimed to construct a simple screening tool, based on the GLFS-5, for the detection of LS-1, LS-2, and LS-3 diagnosed with the GLFS-25., Methods: This research was approved by the institutional review board of Fukushima Medical University School of Medicine (No. 2907). A cross-sectional study of 1258 consecutive Japanese volunteers with a mean age of 76.0 ± 6.0 years who consecutively attended a basic health checkup was conducted. We excluded individuals of <65 years of age, individuals with comorbidities, and individuals who did not fully complete the GLFS-25. Subjects with a GLFS-25 total score of 0-6 points, 7-15 points, 16-23 points, and 24-100 points were diagnosed with non-LS, LS-1, LS-2, and LS-3, respectively. A conventional receiver-operating characteristic curve analysis was used to confirm the optimal cut-off values of the GLFS-5 total score and their sensitivity and specificity in the identification of LS-1, LS-2, and LS-3, with a preference for slightly higher sensitivity as the intended use of the tool is primarily for screening purposes., Results: The diagnoses of the 1258 subjects were as follows: non-LS (n = 559), LS-1 (n = 396), LS-2 (n = 134), and LS-3 (n = 169). The mean GLFS-5 was 3.3 ± 3.5 points. The optimal cut-off values of the GLFS-5 total score for discriminating LS-1, LS-2, and LS-3 (as a screening tool) were 2 points (sensitivity 91.7% and specificity 77.8%), 4 points (sensitivity 95.7% and specificity 81.7%), and 6 points (sensitivity 92.9% and specificity 90.0%), respectively., Conclusions: This simple screening tool based on GLFS-5 could help physicians and surgeons to easily and practically predict the severity of LS., Competing Interests: Declaration of competing interest All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements) or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

What Is Known and Objective: The use of hypnotics, especially benzodiazepines (BZs), increases the risk of falls. Regarding the association of orexin receptor antagonists with fall risk, consistent results have not been obtained for suvorexant, and studies of lemborexant have not been reported. Therefore, this study investigated whether orexin receptor antagonists, including lemborexant, increase the risk of falls., Methods: Data were obtained from the medical records of patients hospitalized at Saga University Hospital in Japan between July 2020 and April 2021. Patients were retrospectively divided into the fall and non-fall groups, and the groups were compared for medication usage., Results and Discussion: The fall and non-fall groups included 132 and 6857 patients respectively. A significantly higher proportion of patients in the fall group used hypnotics (40.2% vs. 21.7%; p < 0.0001). Hypnotics remained significantly associated with a higher risk of falls after adjusting for confounders (adjusted odds ratio [OR] = 1.67, 95% confidence interval [CI] = 1.13-2.48, p = 0.01). In particular, the use of benzodiazepines was associated with a significantly higher risk of falls (adjusted OR = 2.08, 95% CI = 1.38-3.15, p = 0.0005). Meanwhile, suvorexant use was not linked to the risk of falls, and lemborexant use was associated with a significantly lower risk of falls (adjusted OR = 0.27, 95% CI = 0.09-0.84, p = 0.02)., What Is New and Conclusion: The use of hypnotics is a risk factor for falls, but orexin receptor antagonists may represent a safe option for patients requiring hypnotics. Our results provide evidence supporting the safety of these drugs., (© 2022 John Wiley & Sons Ltd.)

Background/aim: There is limited evidence about the nephrotoxicity of calcium channel blockers (CCBs) and renin-angiotensin system (RAS) inhibitors with concomitant cisplatin (CDDP). We investigated whether combinations of antihypertensive drugs are associated with CDDP-related acute kidney injury (AKI) using the Japanese Adverse Drug Event Report database., Patients and Methods: We analysed 544,864 reports in the database from 2004 to 2020. A reporting odds ratio (ROR) and confidence interval (CI) with adjustment for potential confounding factors was calculated for AKI for each drug and the combined use of the drugs and CDDP., Results: CDDP, CCBs, and RAS inhibitors were all detected signals for AKI. The ROR in cases with concomitant use of CCBs, RAS inhibitors, and CDDP (adjusted ROR 7.28; 95% CI=5.56-9.54) was higher than that in cases with use of each drug., Conclusion: AKI may require more attention when patients receiving CDDP take CCBs and RAS inhibitors together., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The loco-check has been widely used to raise awareness of locomotive syndrome (LS) not only in the general population but also among medical practitioners. However, a screening tool of the loco-check for LS-1, LS-2, and LS-3 has not yet been established. The present study developed a screening tool for use with the loco-check to detect LS-1, LS-2, and LS-3., Methods: A cross-sectional study of 1659 community-dwelling older adults (730 males, 929 females) with a mean age of 73.8 ± 6.0 years old (range, 65-96 years old) was conducted, based on the Standards for Reporting Diagnostic Accuracy (STARD). All subjects underwent the loco-check as an index test and the 25-question Geriatric Locomotive Function Scale (GLFS-25) as a reference standard at the same time. Subjects with a GLFS-25 total score of ≤6 points, 7-15 points, 16-23 points, and ≥24 points were diagnosed with non-LS, LS-1, LS-2, and LS-3, respectively. A conventional receiver-operating characteristic curve analysis was used to confirm the optimal cut-off values of the loco-check score and their sensitivity and specificity to identify LS-1, LS-2, and LS-3, with a preference for a slightly higher sensitivity as the tool is intended primarily for screening purposes., Results: The optimal cut-off values of the loco-check score to discriminate LS-1, LS-2, and LS-3 as a screening tool were 1 point (sensitivity 85.4% and specificity 64.9%), 2 points (sensitivity 88.8% and specificity 75.1%), and 3 points (sensitivity 87.6% and specificity 84.6%), respectively., Conclusions: Our findings may help both the general population and medical practitioners become roughly aware of and estimate the severity of LS, which will contribute to its use in community health activities and the dissemination of the concept of LS., Competing Interests: Declaration of competing interest All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Objective: The aim of the present study was to investigate the associations between breastfeeding and the prevalence of metabolic syndrome in community-dwelling parous women and to clarify whether the associations depend on age., Methods: The present cross-sectional study included 11,118 women, aged 35-69 years. Participants' longest breastfeeding duration for one child and their number of breastfed children were assessed using a self-administered questionnaire, and their total breastfeeding duration was approximated as a product of the number of breastfed children and the longest breastfeeding duration. The longest and the total breastfeeding durations were categorized into none and tertiles above 0 months. Metabolic syndrome and cardiovascular risk factors (obesity, hypertension, dyslipidemia, and hyperglycemia) were defined as primary and secondary outcomes, respectively. Associations between breastfeeding history and metabolic syndrome or each cardiovascular risk factor were assessed using multivariable unconditional logistic regression analysis., Results: Among a total of 11,118 women, 10,432 (93.8%) had ever breastfed, and 1,236 (11.1%) had metabolic syndrome. In participants aged <55 years, an inverse dose-response relationship was found between the number of breastfed children and the prevalence of metabolic syndrome; multivariable-adjusted odds ratios for 1, 2, 3, and ≥4 breastfed children were 0.60 (95% confidence interval [CI]: 0.31 to 1.17), 0.50 (95% CI: 0.29 to 0.87), 0.44 (95% CI: 0.24 to 0.84), and 0.35 (95% CI: 0.14 to 0.89), respectively. The longest and total breastfeeding durations of longer than 0 months were also associated with lower odds of metabolic syndrome relative to no breastfeeding history in participants aged <55 years. In contrast, all measures of breastfeeding history were not significantly associated with metabolic syndrome and cardiovascular risk factors in participants aged ≥55 years old., Conclusions: Breastfeeding history may be related to lower prevalence of metabolic syndrome in middle-aged parous women., Competing Interests: The authors have declared no conflict of interest in the present study.

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  < 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., (© 2022. The Author(s).)

Introduction: 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., Research Design and Methods: 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., Results: 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<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., Conclusions: The present results suggest that the effect of PA on HbA1c levels is modified by intake of macronutrient composition., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)