Augmented renal clearance (ARC) and febrile neutropenia (FN) increase drug clearance primarily through glomerular filtration. In this study, we evaluated the influence of ARC and FN on dose-normalized trough concentration (C/D) and/or clearance of teicoplanin (TEIC) by comparing C/D between patients with ARC and non-ARC, and C/D and clearance between patients with FN and non-FN.

This retrospective, single-center, observational cohort study enrolled 309 patients who received intravenous injections of TEIC between July 2016 and September 2021. Of the 94 patients who met the selection criteria, 25 satisfied the ARC definition, and 31 satisfied the FN definition. Using the Chronic Kidney Disease Epidemiology Collaboration formula, ARC was defined as an estimated glomerular filtration rate of 96.5 mL/min/1.73 m 2 or higher. FN was defined as an axillary temperature 37.5°C or higher and neutrophil count of less than 500/μL. TEIC clearance was estimated using a population pharmacokinetic model for adult Japanese patients with Bayesian estimation.

Compared with the non-ARC group (n = 69), the ARC group (n = 25) had a significantly lower first trough concentration ( P = 0.014) and lower C/D ( P = 0.009). By contrast, the FN (n = 31) and non-FN (n = 63) groups did not differ significantly in the first trough concentration, C/D, or clearance ( P = 0.294, 0.945, and 0.337, respectively). Forced-entry multiple regression analysis identified ARC as the only independent factor associated with C/D ( P = 0.001).

A higher TEIC loading dose may be required for patients with ARC, regardless of the presence or absence of FN.

Chronic kidney disease (CKD) awareness could help prevent disease progression through modifiable risk factors. However, few patients with CKD are aware of their disease. We aimed to investigate the factors associated with CKD awareness and impact of CKD awareness on renal prognosis.

We investigated the proportion of participants with CKD who answered 'aware of CKD' in the questionnaire among those undergoing health check-ups from 2013 to 2022. Participants included working-age employees and their dependents covered by health insurance associations for large and medium-sized companies. The outcome was defined as the change from 'unaware' to 'aware' of CKD; multivariable logistic regression analysis assessed the association of urine tests or nutritional guidance with CKD awareness. A control group was randomly selected from the unaware group and matched for age, sex, estimated glomerular filtration rate (eGFR), urinary protein categories, and follow-up period. Changes in eGFR slopes before and after awareness were compared using linear mixed-effects models.

Of the 13,489 participants, 2.8% were aware of CKD at baseline; of the 1,614 with CKD-related disease codes, only 19.6% were aware. The odds ratios of urine tests or nutritional guidance in relation to awareness occurrence were 1.98 (1.29-3.05) and 3.01 (1.38-6.53), respectively. The difference in the eGFR slope improvement from before to after CKD awareness was + 0.92 mL/min/1.73 m2 per year (0.18-1.67; P = 0.015) in the aware group.

Our findings suggest that urine tests and nutritional guidance may promote CKD awareness, which may help slow its progression.

The impact of individual biological/targeted synthetic DMARD (b/tsDMARD) on kidney function in patients with RA remains unclear. This study aimed to determine the comparative effects of b/tsDMARDs on chronic kidney disease (CKD) incidence in patients with RA.

This multicentre cohort study included patients with RA who had baseline estimated glomerular filtration rate (eGFR) of ≥60 ml/min/1.73 m2 and started a TNF inhibitor (TNFi), cytotoxic T-lymphocyte-associated antigen-4-Ig (CTLA4-Ig), interleukin-6 receptor inhibitor, or Janus kinase inhibitor (JAKi) in Japan. Multiple propensity score-based inverse probability weighting (IPW) was used to adjust confounders. The incidence of CKD was compared among b/tsDMARDs using IPW mixed-effect Cox proportional hazards models and linear mixed-effect models with IPW-examined trajectories of eGFR.

Among 2187 patients with 3068 treatment courses and up to 11 years of follow-up, CKD occurred in 275 cases. Compared with the CTLA4-Ig group, the TNFi group had a significantly lower CKD incidence [hazard ratio (HR) 0.67, 95% CI 0.46-0.97, P = 0.04], whereas the JAKi group had a significantly higher incidence (HR 2.16, 95% CI 1.23-3.79, P = 0.01). The trajectory of eGFR was significantly greater in the JAKi group than in the CTLA4-Ig group (CTLA4-Ig: -1.28 ml/min/1.73 m2/year, JAKi: -2.29 ml/min/1.73 m2/year, P < 0.001).

TNFi use was associated with reduced CKD incidence, whereas JAKi showed a less protective association for kidney function in patients with RA.

To evaluate the effects of amiodarone and/or N-desethylamiodarone concentrations on digoxin pharmacokinetics and determine the optimal dose of digoxin combined with amiodarone in Japanese patients with atrial fibrillation and heart failure.

A population pharmacokinetic analysis of 3288 points from 368 patients receiving oral digoxin, including 48 (13%) who were coadministered amiodarone, was performed. A 1-compartment model with first-order absorption with amiodarone or N-desethylamiodarone as time-varying covariates for apparent digoxin clearance was constructed using stepwise forward inclusion and backward elimination approaches. The percentage of patients with digoxin values in the toxic range (≥0.9 ng/mL) was evaluated with Monte Carlo simulation.

The median serum digoxin concentration was 0.75 ng/mL; the median plasma concentrations of amiodarone and N-desethylamiodarone were 610 and 644 ng/mL, respectively. The final model for oral clearance of digoxin was explained by creatinine clearance (CLcr) and the N-desethylamiodarone concentration. Digoxin clearance increased by 21% when CLcr was doubled and decreased by 3% when the N-desethylamiodarone concentration increased by 100 ng/mL. In the simulation, the proportion of patients with values in the toxic range was high at 0.125 mg daily among patients taking amiodarone. A daily dose of 0.0625 mg is recommended for patients with a CLcr >30 mL/min. For patients with a CLcr ≤30 mL/min and an N-desethylamiodarone concentration >600 ng/mL, a daily dose of 0.03125 mg is recommended because of reduced digoxin clearance.

This study revealed that renal impairment and high plasma N-desethylamiodarone concentrations reduce digoxin clearance in patients with atrial fibrillation and heart failure.

Background Epidemiological evidence has indicated that insulin resistance (IR), as measured by a homeostatic model assessment for IR (HOMA-IR), is strongly correlated with body mass index (BMI). However, there is a paucity of studies assessing the complex interaction between BMI and HOMA-IR with respect to all-cause mortality, particularly among Asian individuals without diabetes. Materials and methods The research centered on individuals diagnosed without diabetes, comprising 881 men with a mean age of 62 years (± standard deviation (SD): 14) and 1,159 women with a mean age of 64 years (± 11). The participants were drawn from the Nomura cohort study, consisting of two cohorts: one initiated in 2002 and the other in 2014. To assess the risk of all-cause mortality up to the end of the follow-up period, we applied a Cox proportional hazards model, adjusting for a range of covariates to calculate the hazard ratios (HRs). Results Participants were followed for a median duration of 7,691 days (interquartile range: 4,235-7,761 days). Over the course of the follow-up period, a total of 672 deaths were documented, comprising 338 deaths among men and 334 among women. The interaction between BMI and HOMA-IR (HR: 1.05; 95% confidence interval (CI): 1.02-1.09) was significantly associated with all-cause mortality, along with gender, age, BMI, history of cardiovascular disease, hyperuricemia, and HOMA-IR. Moreover, the HRs for all-cause mortality were examined for each BMI group by dividing the HOMA-IR by one SD. In the BMI < 22.0 kg/m² group, using the third HOMA-IR as the reference, significant HR (J curve) increases were observed in the first, second, and fourth HOMA-IR. In the BMI ≥ 22.0 kg/m² group, using the first HOMA-IR as the reference, a significant increase in HR was observed only in the fourth HOMA-IR. An interaction between BMI and HOMA-IR was identified for all-cause mortality (p = 0.005). Conclusions BMI confounds the association between IR, as measured by HOMA-IR, and the risk of all-cause mortality among Japanese individuals.

Decreased levels of high-molecular-weight (HMW) adiponectin are associated with metabolic syndrome and insulin resistance. This relationship may be further confounded by alcohol consumption, which plays a role in the development of liver dysfunction. In Japan, few studies have investigated the relationship between HMW adiponectin levels and alcohol consumption with mortality.

The study included 845 male participants (mean age, 61 ± 13 years; range, 20-89 years) and 1065 female participants (mean age, 63 ± 11 years; range, 22-88 years). Of the participants, 809 (42.4%) were classified as nondrinkers, 561 (29.4%) as occasional drinkers, 346 (18.1%) as daily light drinkers, and 194 (10.2%) as daily heavy drinkers. A Cox proportional hazards model was used to calculate hazard ratios (HR) for all-cause mortality, adjusting for various confounders, including HMW adiponectin levels.

Individuals who abstained from alcohol consumption (hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.00-1.52) or engaged in daily heavy drinking (HR, 1.39; 95% CI, 1.04-1.86) exhibited significantly higher overall mortality than occasional drinkers. Additionally, those with the 3rd standard deviation (SD) level of HMW adiponectin (HR, 1.39; 95% CI, 1.07-1.80) and 4th SD level (HR, 1.65; 95% CI, 1.23-2.23) had a similarly increased risk of all-cause mortality compared to those with the lowest levels. After adjusting for confounders, the HR for individuals with the 3rd + 4th SD levels of HMW adiponectin was significantly elevated in nondrinkers (HR, 1.89; 95% CI, 1.09-3.29), occasional drinkers (HR, 1.84; 95% CI, 1.05-3.21), and daily heavy drinkers (HR, 1.90; 95% CI, 1.05-3.44), but not in daily light drinkers. The interaction between alcohol consumption and HMW adiponectin levels was significantly associated with all-cause mortality.

These findings suggest that alcohol consumption and elevated HMW adiponectin levels are interactively associated with all-cause mortality in community-dwelling individuals.

Genetic factors, inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor-α (TNF-α), and uremic substances such as 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) have been reported to affect organic anion transporting polypeptide (OATP)1B1 transport activity. However, the relationship between OATP1B1 transport activity and these factors in patients with cancer cachexia has not been reported. This study aimed to identify the factors contributing to individual differences in OATP1B1 transport activity in patients with cancer cachexia, using coproporphyrin-I (CP-I) as an endogenous biomarker of OATP1B1 transport activity. The study recruited 114 patients with cancer cachexia who satisfied the selection criteria. The subjects were classified into pre-cachexia, cachexia, and refractory cachexia. Median [interquartile range] plasma CP-I level was higher in patients with pre-cachexia (0.91 [0.67-1.12] ng/mL) compared with the data in the general population reported previously and tended to be higher in patients with refractory cachexia (1.06 [0.78-1.64] ng/mL) than in those with cachexia (0.87 [0.62-1.07] ng/mL), suggesting that OATP1B1 transport activity may decrease with the progression of cancer cachexia. Plasma CP-I correlated positively with IL-6 and TNF-α concentrations but did not correlate with OATP1B1 polymorphisms or CMPF concentration, which have been reported to reduce transport activity. Multiple regression analysis using the forced entry method identified refractory cachexia as a significant factor independently affecting plasma CP-I concentration. These findings suggest that the reduction in OATP1B1 transport activity in patients with cancer cachexia may be attributed to inflammatory cytokines or some other factors that are elevated by cancer cachexia progression, rather than OATP1B1 polymorphisms and CMPF.

Lipoprotein(a) (Lp[a]) has been identified as a significant risk factor for aortic stenosis (AS). However, its impact on outcomes post-transcatheter aortic valve replacement (TAVR) remains unknown.

To investigate the association between Lp(a) levels and long-term outcomes as well as its impact on the bioprosthetic valve degeneration in patients post-TAVR.

Patients with severe AS who underwent TAVR were consecutively recruited. Lp(a) was measured before TAVR procedure. The subjects were divided according to levels of Lp(a). The outcomes were all-cause mortality and possible structural valve degeneration (SVD) measured by Doppler echocardiography. Cox regression models and competing risk models were used to explore the association between Lp(a) levels and outcomes.

Of the 601 included patients (mean age: 75.5 ± 7.2, male: 58.7%), 137 patients (22.7%) experienced mortality after a median follow-up of 3.9 years. After multivariable adjustment, elevated Lp(a) (defined as ≥30 mg/dL) was identified as an independent predictor of all-cause mortality (hazard ratio [HR]: 1.81, 95% CI: 1.27-2.57, P = .001) and cardiovascular mortality (HR: 2.02, 95% CI: 1.12-3.66, P = .020). Elevated Lp(a) was also associated with increased risk of possible SVD (subdistribution HR: 3.40, 95% CI: 1.32-8.79, P = .012). Using a threshold value of 50 mg/dL for elevated Lp(a) still supported the main findings.

Elevated baseline Lp(a) levels are associated with poor clinical outcomes and possible SVD in patients with severe AS undergoing TAVR. Further research is warranted to confirm these findings.

Chronic kidney disease affects around 10% of the global population and is associated with significant risk of progression to end-stage renal disease and vascular events. Aldosterone receptor antagonists such as spironolactone have shown prognostic benefits in patients with heart failure, but effects on patients with chronic kidney disease are uncertain.

To determine the effect of low-dose spironolactone on mortality and cardiovascular outcomes in people with chronic kidney disease stage 3b.

Prospective randomised open blinded end-point trial.

Three hundred and twenty-nine general practitioner practices throughout the United Kingdom.

Patients meeting the criteria for chronic kidney disease stage 3b (estimated glomerular filtration rate 30-44 ml/minute/1.73 m2) according to National Institute for Health and Care Excellence guidelines were recruited. Due to the higher than anticipated measurement error/fluctuations, the eligible range was extended to 30-50 ml/minute/1.73 m2 following the initial recruitment period.

Participants were randomised 1 : 1 to receive either spironolactone 25 mg once daily in addition to standard care, or standard care only.

Primary outcome was the first occurring of all-cause mortality, first hospitalisation for heart disease (coronary heart disease, arrhythmia, atrial fibrillation, sudden death, failed sudden death), stroke, heart failure, transient ischaemic attack or peripheral arterial disease, or first occurrence of any condition not listed at baseline. Secondary outcome measures included changes in blood pressure, renal function, B-type natriuretic peptide, incidence of hyperkalaemia and treatment costs and benefits.

One thousand four hundred and thirty-four participants were randomised of the 3022 planned. We found no evidence of differences between the intervention and control groups in terms of effectiveness with the primary combined vascular end points, nor with the secondary clinical outcomes, including progression in renal decline. These results were similar for the total treatment periods or a 3-year follow-up period as originally planned. More adverse events were experienced and more participants discontinued treatment in the intervention group. Two-thirds of participants randomised to spironolactone stopped treatment within six months because they met pre-specified safety stop criteria. The addition of low-dose spironolactone was estimated to have a cost per quality-adjusted life-year gained value above the National Institute for Health and Care Excellence's threshold of £30,000.

Main limitations were difficulties in recruiting eligible participants resulting in an underpowered trial with poor ethnic diversity taking twice as long as planned to complete. We have explored the data in secondary analyses that indicate that, despite these difficulties, the findings were reliable.

The benefits of aldosterone receptor antagonism in chronic kidney disease trial found no evidence to support adding low-dose spironolactone (25 mg daily) in patients with chronic kidney disease stage 3b: there were no changes to cardiovascular events during the trial follow-up, either for the combined primary or individual components. There was also no evidence of benefit observed in rates of renal function decline over the trial, but much higher initial creatinine rise and estimated glomerular filtration rate decline, and to a higher percentage rate, in the intervention arm in the first few weeks of spironolactone treatment, which resulted in a high proportion of participants discontinuing spironolactone treatment at an early stage. These higher rates of negative renal change reduced in scale over the study but did not equalise between arms. The addition of 25 mg of spironolactone therefore provided no reno- or cardio-protection and was associated with an increase in adverse events.

These findings might not be applicable to different mineralocorticoid receptor antagonists.

Current Controlled Trials ISRCTN44522369.

This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/01/52) and is published in full in Health Technology Assessment; Vol. 29, No. 5. See the NIHR Funding and Awards website for further award information.

The correlation between serum uric acid/creatinine (SUA/Cr) ratio and hypertension risk has not been well studied. This study aims to examine whether the SUA/Cr ratio is a predictor of hypertension.

This cohort study comprised 171 men aged 64 ± 11 (mean ± standard deviation) years and 266 women aged 65 ± 10 years recruited for a survey at the community-based annual medical check-up. The main outcome was the presence of hypertension (antihypertensive medication) and having systolic blood pressure (SBP) ≥ 140 mmHg and diastolic blood pressure (DBP) ≥ 90 mmHg.

The baseline SUA/Cr ratio was significantly correlated only with DBP at 3 years in men (r = 0.217, P = 0.004) and women (r = 0.126, P = 0.040), and with both SBP (r = 0.103, P = 0.031) and DBP (r = 0.15, P = 0.001) in the overall participants of men and women. A plausible prognostic cut-off of SUA/Cr ratio (≥ 7.41) was found and was the same in women and in all participants. Multivariable logistic regressions showed that SUA/Cr ratio was significantly linked with hypertension (as a categorical variable, SUA/Cr ratio-2 vs. SUA/Cr ratio-1: odds ratio [OR], 1.68; 95% confidence interval [CI], 0.66-4.30; P = 0.275, SUA/Cr ratio-3 vs. SUA/Cr ratio-1: OR, 2.86; 95% CI, 1.08-7.60; P = 0.035, SUA/Cr ratio-4 vs. SUA/Cr ratio ratio-1: OR, 4.05; 95% CI, 1.32-12.5; P = 0.031, and SUA/Cr ratio ≥ 7.41 vs. SUA/Cr ratio < 7.41: OR, 2.25; 95% CI, 1.32-3.84; P = 0.003). Significant ORs were found for age < 65 years, women, and BMI <25 kg/m2, but no interactions were identified within each group.

These results suggest that the baseline SUA/Cr ratio could be an important predictor for the incidence of hypertension in Japanese community-dwelling persons.

In aging societies, the prevalence of chronic kidney disease (CKD) is expected to increase but may be underestimated because many asymptomatic patients remain undiagnosed. This study aimed to estimate the CKD prevalence among the general older population in Japan.

This cross-sectional study used health screening data from the Japan Health Insurance Association collected between April 2014 and March 2023. Data from older people aged 65-90 years who underwent renal function screening for estimated glomerular filtration rate (eGFR) and urine protein tests were analyzed. CKD was defined as eGFR < 60 mL/min/1.73 m2 or proteinuria ≥ 1 + . Inverse probability weighting was used to account for the selection bias. The variables used for weighting were age, sex, insurance status, and the number of previous screenings.

Among 2.98 million older individuals, 588,809 (19.7%) had undergone screening (median [IQR] age, 69.9 [67.9-76.2] years, 337,862 women [57.4%]). Regarding the weighted CKD prevalence, 25.3% of the individuals aged 65-90 years had CKD; 11.8% of those aged 65-75 years and 34.6% of those aged 75 years and over showed an increase in prevalence with age. Among the patients with CKD, over half exhibited mild renal dysfunction without proteinuria. Hypertension and diabetes were common comorbidities in older patients with CKD.

This cross-sectional study revealed that the weighted prevalence of CKD in the older population aged 65-90 years was high (one in four individuals), indicating that it increases with age. Further studies are required to examine the clinical significance of these findings.

Sleep-related breathing disorder (SRBD) and exercise-induced blood pressure (BP) elevation are known risk factors for hypertension. However, the relation between them remains unknown. This cross-sectional study examined the relationship between SRBD and exercise-induced BP elevation in a Japanese occupational population. Using the 3% oxygen desaturation index (3%ODI) obtained by a portable monitor for overnight saturation of percutaneous oxygen (SpO2), participants were classified into low (0 ≤ 3%ODI < 5), medium (5 ≤ 3%ODI < 15), and high (15 ≤ 3%ODI) 3%ODI groups. We included employees who had undergone an exercise electrocardiogram test after monitoring for overnight SpO2. In total, 928 employees were included. The median age of the participants was 50 years, 96% were male, the mean body mass index was 23.9 ± 3.1 kg/m2, and the median 3%ODI was 4.9 (interquartile range: 1.6-6.5). Among them, 30% and 5% were categorized into the medium and high 3%ODI groups, respectively. At a median exercise intensity of 10.1 METs, BP changed from 124 ± 16/76 ± 12 mmHg before to 183 ± 26/85 ± 14 mmHg after exercise, with a mean systolic BP change of +59 ± 23 mmHg (-20 to +128 mmHg). When we defined systolic BP change of +60 mmHg or more as exercise-induced BP elevation, the odds ratio for exercise-induced BP elevation increased significantly with higher 3%ODI levels after multivariate adjustment for parameters including current use of antihypertensive medication and maximal exercise intensity (p for trend = 0.01). Higher 3%ODI was significantly associated with higher prevalence of exercise-induced BP elevation, suggesting sympathetic hyperactivity occurs in SRBD patients. Our results suggest the potential presence of SRBD should be considered in individuals with exercise-induced BP elevation.

Febuxostat and topiroxostat are non-purine selective xanthine oxidoreductase inhibitors commonly used for hyperuricaemia treatment in Japan. However, comparative data on the effects of febuxostat and topiroxostat on renal function and proteinuria are limited. This study compared proteinuria incidence and changes in the estimated glomerular filtration rate (eGFR) among prevalent febuxostat and topiroxostat users.

We conducted a retrospective cohort study using databases provided by DeSC Healthcare, Inc. (Tokyo, Japan). We identified 17,446 individuals (11.8% women; mean age 67.4 years) with eGFR ≥ 30 mL/min/1.73 m2 and no history of cardiovascular disease or proteinuria at baseline. Separate analyses were performed for individuals with eGFR < 60 mL/min/1.73 m2 and those with eGFR ≥ 60 mL/min/1.73 m2. The adjusted hazard ratio (HR) for proteinuria incidence in topiroxostat users compared with febuxostat users was assessed using the Cox model. Changes in eGFR were compared between the two groups using multiple regression analysis.

During the mean follow-up period of 1.79 years, 1,433 participants developed proteinuria. In non-diabetic individuals with eGFR ≥ 60 mL/min/1.73 m2, the adjusted HR for proteinuria incidence in topiroxostat users compared with febuxostat users was 0.60 (95% confidence interval, 0.40-0.91; p = 0.016). No significant differences were observed in eGFR changes between the two groups with eGFR < 60 and ≥ 60 mL/min/1.73 m2.

Topiroxostat prevalent users had a lower risk of proteinuria than febuxostat prevalent users in non-diabetic individuals with eGFR ≥ 60 mL/min/1.73 m2. Our findings suggest that topiroxostat might be more effective than febuxostat in preventing proteinuria in non-diabetic individuals with eGFR ≥ 60 mL/min/1.73 m2.

An initial decline in estimated glomerular filtration rate (eGFR) often leads to reluctance to continue life-saving therapies in patients with heart failure (HF).

The goal of this study was to describe the association between initial decline in eGFR and subsequent clinical outcomes in patients randomized to placebo or finerenone.

In this prespecified analysis of FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure), we examined the association between initial decline in eGFR (≥15%) from randomization to 1 month and subsequent outcomes in patients assigned to finerenone or placebo. The primary outcome was the composite of total HF events and cardiovascular death.

Among 5,587 patients with an eGFR measurement at both baseline and 1 month, 1,018 (18.2%) experienced a ≥15% decline in eGFR. The proportion of patients experiencing a ≥15% decline in eGFR was 23.0% with finerenone and 13.4% with placebo (OR: 1.95; 95% CI: 1.69-2.24; P < 0.001). After adjustment, an eGFR decline was associated with a higher risk of the primary outcome in patients assigned to placebo (adjusted rate ratio: 1.50; 95% CI: 1.20-1.89) but not in those assigned to finerenone (adjusted rate ratio: 1.07; 95% CI: 0.84-1.35; Pinteraction = 0.04). By contrast, the efficacy of finerenone was consistent across the range of change in eGFR from baseline to 1 month (Pinteraction = 0.50 for percent change in eGFR), and safety, including hyperkalemia, was similar regardless of an early eGFR decline.

Although an initial decline in eGFR was associated with worse outcomes in patients assigned to placebo, this relationship was not as strong in those treated with finerenone. An early decline in eGFR can be anticipated with finerenone and should not automatically lead to the discontinuation of this disease-modifying therapy (FINEARTS-HF Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure [NCT04435626]; A Multicenter, Randomized, Double-Bline, Parallel-Group, Placebo-Controlled Study to Evaluate the efficacy and safety of finerenone on morbidity and mortality in participants With Heart Failure [NYHA II-IV] and left ventricular ejection fraction ≥40% [EudraCT 2020-000306-29]).

Chronic kidney disease (CKD) represents a significant public health challenge, with rates consistently on the rise. Enhancing kidney function prediction could contribute to the early detection, prevention, and management of CKD in clinical practice. We aimed to investigate whether deep learning techniques, especially those suitable for processing missing values, can improve the accuracy of predicting future renal function compared to traditional statistical method, using the Japan Chronic Kidney Disease Database (J-CKD-DB), a nationwide multicenter CKD registry.

From the J-CKD-DB-Ex, a prospective longitudinal study within the J-CKD-DB, we selected individuals who had at least two eGFR measurements recorded between 12 and 20 months apart (n = 22,929 CKD patients). We used the multiple linear regression model as a conventional statistical method, and the Feed Forward Neural Network (FFNN) and Gated Recurrent Unit (GRU)-D (decay) models as deep learning techniques. We compared the prediction accuracies of each model for future eGFR based on the existing data using the root mean square error (RMSE).

The RMSE values were 7.5 for multiple regression analysis, 7.9 for FFNN model, and 7.6 mL/min/1.73 m2 for GRU-D model. In the subgroup analysis according to CKD stages, lower RMSE values were observed in higher stages for all models.

Our result demonstrate the predictive accuracy of future eGFR based on the existing dataset in the J-CKD-DB-Ex. The accuracy was not improved by applying deep learning techniques compared to conventional statistical methods.

Dietary sodium restriction is important in the prognosis of patients with chronic kidney disease (CKD). The association between saltiness perception and sodium intake among CKD patients is unclear, and the factors that influence saltiness are also not fully understood. We evaluated saltiness perception in CKD patients employing a cost-effective saltiness perception test using sodium solutions and evaluated the association between saltiness perception, sodium intake, and the influencing factors.

CKD outpatients not undergoing dialysis were enrolled from two medical centers and underwent saltiness perception tests together with 24-hour urine collections to measure daily sodium intake. Participants who perceived saltiness using the test solution containing 25 mM sodium were regarded to have "preserved" saltiness perception, while those unable to perceive saltiness were regarded as having "impaired" saltiness perception.

Of the total 132 participants, the median daily sodium intake was 3.36 g (range; 0.51-9.95 g/day), and 43 (32.6%) were ex- or current smokers. When participants were divided into 3 groups (G) according to daily sodium intake level: low (G1; 0.51-2.61 g/day), middle (G2; 2.62-3.99 g/day), and high (G3; 4.06-9.95 g/day), there was an obvious difference in impaired saltiness perception between three groups: 6.8% in G1, 50.0% in G2 and 86.4% in G3 (P value = 8.035 × 10-14, Cochran-Armitage test). In a multiple regression analysis in which the saltiness perception was adopted as a subjective variable, smoking habit (ex- or current smoker) and nonadherence to dietary sodium restriction were identified as significant explanatory variables.

We revealed the clear relationship between higher daily sodium intake and impaired saltiness perception that is related to nonadherence to dietary sodium restriction and smoking habit, both of which could be intervened by nutritional counseling and public health education.

Oral frailty, first identified in Japan in 2014, refers to a state between healthy oral function and severe decline, marked by minor issues, such as tooth loss and chewing difficulties. The oral frailty five-item checklist (OF-5) enables non-dental professionals to evaluate oral frailty using five key indicators: remaining teeth count, chewing difficulties, swallowing difficulties, dry mouth, and articulatory oral skills. Limited studies exist.

This study examined the relationship between oral and physical frailties in older adults and assessed the prognosis of physical frailty using the OF-5. Participants aged ≥65 years were recruited from the frail elderly in the Sasayama-Tamba area, Hyogo, Japan, and their physical function was assessed in terms of grip strength, walking speed, and skeletal muscle mass. Blood markers, such as cystatin C, an indicator of renal function, were also analyzed.

A cross-sectional analysis indicated that oral frailty was correlated with reduced muscle mass, walking speed, and physical function. Women had lower hemoglobin and albumin levels and a greater prevalence of frailty than men. Longitudinal analysis revealed that initial OF-5 scores predicted increased physical frailty after 2-3 years, especially in those with higher baseline scores. The OF-5 was a significant factor for frailty progression in both sexes.

These results suggest that early detection of oral frailty via the OF-5 may be useful in preventing the progression of overall frailty in older adults.

There are limited data on how advancing age influences prediction of cardiovascular disease (CVD) risk based on the estimated glomerular filtration rate (eGFR) and proteinuria, especially in older adults, including those aged ≥85 years old. This study aimed to clarify the association of eGFR and proteinuria with CVD outcomes and the impact of age on this association.

The distribution of eGFR and urine protein in Japan was assessed retrospectively using real-world administrative claims and health checkup data collected between April 2014 and November 2022. We investigated the associations of these two parameters with the incidence of CVD, with an emphasis on the impact of aging.

We assessed 1 829 020 individuals for distribution of eGFR and proteinuria; after excluding those with known CVD, their association with CVD risk was examined in 1 040 101 individuals aged ≥40 years. The prevalence of impaired kidney function (eGFR <60 mL/min/1.73 m2) increased with age, being 0.7%, 9.2%, 21.9%, 40.2% and 60.2% at the ages of 18-39, 40-64, 65-74, 75-84 and ≥85 years, respectively (P for trend <.001); similarly, the proportion with positive proteinuria increased with age, being 2.7%, 4.3%, 5.6%, 9.2% and 15.8%, respectively (P for trend <.001). Both eGFR and urine protein were identified to be independent risk factors for CVD. Hazard ratios for CVD increased significantly when eGFR was <45 mL/min/1.73 m2 at the ages of 40-64, 65-74 and 75-84 years and <30 mL/min/1.73 m2 at ≥85 years, while proteinuria remained significantly associated with a high CVD risk regardless of age. These findings were consistent even when analyzed separately by sex.

This study identified eGFR and urine dipstick proteinuria to be independent risk factors for CVD, even among individuals aged ≥85 years. However, the contribution of eGFR to the CVD risk was attenuated by aging, whereas proteinuria remained less affected by advancing age.

Blood lipid management is a key approach in the prevention of chronic kidney disease (CKD). Remnant cholesterol (RC) plays an important role in the development of multiple diseases via chronic inflammation. The aim of our study was to determine the relationship between RC and CKD and explore the role of inflammation in this relationship. The 7696 subjects from the Chinese Health and Nutrition Survey were divided into four subgroups according to the quartile of RC. The estimated glomerular filtration rate was calculated using the CKD Epidemiology Collaboration equation. Fasting RC was calculated as total cholesterol minus low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. Logistic regression analysis was employed to evaluate the relationships between RC and CKD. Mediation analysis was undertaken to identify potential mediators of high-sensitivity C-reactive protein (hs-CRP) and white blood cells (WBCs). Of all participants, the mean age was 51 years, and the male accounted for 47.8%. The multivariable-adjusted odds ratios (95% CIs) for the highest versus lowest quartile of remnant cholesterol were 1.40 (1.10-1.78, p for trend = 0.006) for CKD. RC and preinflammatory markers have combined effect on CKD. The preinflammatory state, presented by increased hs-CRP or WBCs, partially mediated the association between RC and CKD with proportion of 10.14% (p = 0.002) and 11.65% (p = 0.012), respectively. In conclusion, this study suggested a positive relationship between RC and CKD, which was partially mediated by preinflammatory state. These findings highlight the importance of RC and inflammation in renal dysfunction.IMPACT STATEMENTWhat is already known on this subject?: Dyslipidemia plays an important role in the development of chronic kidney disease (CKD). Remnant cholesterol (RC), as a triglyceride-rich particle, can contribute to target organ damage, primarily through inflammatory pathways. However, the relationship between RC and CKD in the community-dwelling population, particularly the role of inflammation, is not yet fully understood.What do the results of this study add?: This study shows that RC was significantly associated with CKD. RC and preinflammatory status exhibit a combined effect on CKD. Preinflammatory state, presented by increased high-sensitivity C-reactive protein or white blood cells, partially mediated the association between RC and CKD.What are the implications of these findings for clinical practice and/or further research?: The study provides us with a better understanding of the role of RC and inflammation in kidney dysfunction and raises the awareness of RC in the management of CKD.

Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 and European Kidney Function Consortium (EKFC) 2023 both recently updated the equations to estimate the glomerular filtration rate (eGFR) using cystatin C; however, little is known about the benefits of using the equations for the risk stratification of health outcomes. We conducted this longitudinal study to compare the cystatin C CKD-EPI and EKFC equations to track the risks of cardiovascular disease and all-cause mortality among Chinese adults.

We used data from China Health and Retirement Longitudinal Study (CHARLS) between 2011 and 2018. Adjusted logistic regression models and restricted cubic spline functions were used to evaluate the relationships of cystatin C-based eGFR values with incidence of cardiovascular disease and mortality.

A total of 6 496 participants were finally included in this study. The mean age of the participants was 59.6 (± 9.5) years, including 2996 (46.1%) males. There were 473 deaths and 1996 cases of cardiovascular disease observed during a maximum follow-up of 7.0 years. Using cystatin C-based CKD-EPI equation, people of eGFR < 60 mL/min/1.73 m2 had an increased risk of mortality (risk ratio [RR], 1.527; 95% CI, 1.068-2.178) and incident cardiovascular disease (RR, 1.363; 95% CI, 1.006-1.844), compared to those of eGFR ≥ 90 mL/min/1.73 m2. On the contrary, we did not observe significant associations of eGFR levels by EKFC equation with mortality nor cardiovascular disease.

The findings indicated that cystatin C-based eGFR using CKD-EPI equation is more closely associated with all-cause mortality and cardiovascular disease compared to EKFC equation among Chinese adults. The cystatin C-based eGFR by CKD-EPI equation should be monitored in health practice, which needs further validation in other populations.

To investigate the association between hemoglobin (Hb) levels and incident diabetic kidney disease (DKD) in patients with type 2 diabetes.

This retrospective cohort study included 1,657 patients with diabetes, without DKD at baseline, recruited from six clinics affiliated with Lee's United Clinic in Taiwan. Demographic data and laboratory results were collected and analyzed. Participants were stratified into quartiles based on their baseline Hb levels. A subgroup analysis was conducted specifically for patients with normal Hb levels (men: Hb ≥ 120 g/l, women: Hb ≥ 110 g/l). Cox regression analysis assessed the relation between Hb levels and incident DKD, adjusting for relevant covariates.

Among the initial cohort, 93 (5.6 %) had anemia at baseline. Over an average follow-up period of 5.7 ± 2.6 years, 594 patients (35.8 %) developed DKD. Cox regression analysis revealed that, after adjusting for multiple variables, compared with patients in the highest quartile of baseline Hb levels (Q4: Hb ≥ 154 g/l), the hazard of DKD was 1.6 times higher in the lowest quartile (Q1: Hb ≤ 130 g/l) HR [95 % CI] 1.58 [1.19;2.21] P < 0.001. In patients with normal Hb levels, Cox regression analysis also revealed that compared to the highest quartile (Q'4, Hb ≥ 154 g/l) the hazard of developing DKD was 1.3 times higher in the lowest quartile (Q'1, Hb ≤ 132 g/l) HR [95 % CI ] 1.29 [1.08;1.72] P = 0.042.

Lower Hb is associated with incident DKD, even in patients with normal Hb levels, independent of other risk factors.

The frequency of behavioral and psychological symptoms of dementia (BPSD) is high, and it is a challenge to elucidate its neural substrates underlying their development. In recent years, many findings have been reported on the relationship between BPSD and brain volume in dementia patients. However, the results are not fully conclusive. Furthermore, there have been few population-based studies. Therefore, the relationship between BPSD and brain volume was investigated as an exploratory study. Of the 927 older persons who participated in the fifth Nakayama study, 90 were included in this analysis, consisting of 52 patients with mild cognitive impairment and 38 patients with dementia, with head MRI and the Neuropsychiatric Inventory (NPI) data. Multiple regression analysis was used to examine the association between the total score of each BPSD score on the NPI and brain volume estimated by FreeSurfer. On multivariate adjustment, even after false discovery rate correction, insular cortical volumes decreased significantly as total scores for apathy/indifference increased (p value = 0.002, q-value = 0.01). Similarly, total brain volume decreased significantly as total scores for appetite and eating disturbance increased (p value = 0.03), and parietal, temporal, and hippocampal cortical volumes also decreased significantly as total scores for appetite and eating disturbance increased (all p and q values < 0.05). This study's results suggest that apathy is negatively correlated with insular cortical volume, and that appetite and eating disturbance are also correlated with brain regions, including parietal, temporal, and hippocampal volume in a community-dwelling older population.

Although studies have assessed the association of metals and bisphenols with lipid metabolism, the observed results have been controversial, and limited knowledge exists about the combined and interactive effects of metals and bisphenols exposure on lipid metabolism.

Plasma metals and serum bisphenols concentrations were evaluated in 888 participants. Multiple linear regression and logistic regression models were conducted to assess individual associations of 18 metals and 3 bisphenols with 5 lipid profiles and dyslipidemia risk, respectively. The dose-response relationships of targeted contaminants with lipid profiles and dyslipidemia risk were captured by applying a restriction cubic spline (RCS) function. The bayesian kernel machine regression (BKMR) model was used to assess the overall effects of metals and bisphenols mixture on lipid profiles and dyslipidemia risk. The interactive effects of targeted contaminants on interested outcomes were explored by constructing an interaction model.

Single-contaminant analyses revealed that exposure to iron (Fe), nickel (Ni), copper (Cu), arsenic (As), selenium (Se), strontium (Sr), and tin (Sn) was associated with elevated lipid levels. Cobalt (Co) showed a negative association with high density lipoprotein cholesterol (HDL-C). Bisphenol A (BPA) and bisphenol AF (BPAF) were associated with decreased HDL-C levels, with nonlinear associations observed. Vanadium (V), lead (Pb), and silver (Ag) displayed U-shaped dose-response relationships with most lipid profiles. Multi-contaminant analyses indicated positive trends between contaminants mixture and total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C). The interaction analyses showed that Se-Fe exhibited synergistic effects on LDL-C and non-HDL-C, and Se-Sn showed a synergistic effect on HDL-C.

Our study suggested that exposure to metals and bisphenols was associated with changes in lipid levels, and demonstrated their combined and interactive effects.

Background: Smoking status is known to be an independent and significant predictor of health outcomes related to aging and plays a crucial role in overall mortality rates. This cohort study investigated the relationship between smoking status and survival outcomes over follow-up periods of 9 and 21 years. Methods: The sample consisted of 3526 participants with a mean age of 64 ± 12 years, 44.1% of whom were male. The median follow-up duration was 6315 days, with an interquartile range of 3441 to 7727 days. Smoking status [i.e., Brinkmann index (BI)] was calculated by multiplying the number of years smoked by the number of cigarettes smoked daily. Based on this, participants were categorized into non-smokers, former smokers, and current smokers. The data were analyzed using Cox regression, employing age as the time variable and accounting for various risk factors. Results: A total of 1111 participants (49.2%) were confirmed to have died. Among these, 564 were male (36.2% of all male participants), and 547 were female (27.8% of all female participants). The multivariate-adjusted odds ratio (95% confidence interval) for all-cause mortality compared with never-smokers was 1.51 (1.17-1.96) for former smokers with BI > 800, 1.61 (1.20-2.17) for current smokers with BI of 400-799 and 1.62 (95% CI, 1.24-2.10) with BI of ≥800 (P for trend <0.001). Participants who died within three years of follow-up were excluded to avoid the possibility of reverse causation, but the results were essentially unchanged. Conclusion: We found that the BI is a valid predictor of future mortality risk and that BI 800 for former smokers and BI 400 for current smokers were useful cutoff values. Efforts to control smoking should focus not only on current smokers but also on former smokers to reduce the risk of premature death associated with smoking.

There is no established risk score for anticoagulant-related bleeding during the acute phase in patients with pulmonary embolism (PE). The PE-Syncope, Anemia, and Renal Dysfunction (PE-SARD) bleeding score was developed to predict early major bleeding but has not yet been fully externally validated.

To externally validate the PE-SARD bleeding score.

Using the COntemporary ManageMent AND outcomes in patients with Venous ThromboEmbolism (COMMAND VTE) Registry-2 database, which enrolled 5197 consecutive acute symptomatic venous thromboembolism patients among 31 centers in Japan between January 2015 and August 2020, we identified acute PE patients. We divided them into 3 groups by the score: high-risk (>2.5 points), intermediate-risk (1-2.5 points), and low-risk (0 points). The discriminating and calibration performances of the score for 30-day major bleeding were assessed. Subgroup analyses based on active cancer were also performed.

Of 2781 eligible patients, the high-risk group accounted for 557 patients (20%), intermediate-risk group for 1412 (51%), and low-risk group for 812 (29%). Major bleeding occurred in 121 patients within 30 days. The cumulative 30-day incidence of major bleeding substantially increased in the higher risk categories by the score (high-risk group, 8.2% [95% CI, 5.9%-10.5%]; intermediate-risk group, 4.6% [95% CI, 3.5%-5.7%]; and low-risk group, 1.8% [95% CI, 0.8%-2.7%]). The discriminating power of the score was modest with a C statistic of 0.65 (95% CI, 0.61-0.70), with a good calibration performance with a score of <4 points, except for that in active cancer patients.

The PE-SARD bleeding score had a modest discriminating performance with a limited calibration performance in acute PE patients without active cancer.

To evaluate the efficacy and safety of first-line biological disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) with chronic kidney disease (CKD), including those undergoing haemodialysis (HD).

This retrospective cohort study included 425 patients with RA prescribed their first bDMARDs at two hospitals from 2004 to 2021. Patients were categorised by kidney function and bDMARD modality (TNFα inhibitors (TNFαis), interleukin-6 inhibitors (IL-6is), cytotoxic T-lymphocyte antigen-4 immunoglobulin (CTLA4-Ig)). The primary outcome was the 36-month drug retention rate, with secondary outcomes including changes in Disease Activity Score 28 (DAS28)-C reactive protein (CRP)/erythrocyte sedimentation rate (ESR), prednisolone dosage and reasons for discontinuation.

The 36-month drug retention rates by estimated glomerular filtration rate (eGFR) (≥60, 30-60, <30 mL/min/1.73 m2) were as follows: all bDMARDs (45.2%, 32.0%, 41.4%), TNFαis (45.3%, 28.2%, 34.0%), IL-6is (47.4%, 66.7%, 71.4%) and CTLA-4Ig (50.0%, 31.3%, 33.3%). Even in groups with lower kidney function, the drug retention rate of bDMARDs was generally maintained. However, the retention rate of TNFαis was significantly lower in patients with eGFR <30 mL/min/1.73 m2. IL-6is showed the highest retention rate and the lowest discontinuation rate due to ineffectiveness in this group (HR 0.11, 95% CI 0.02 to 0.85, p=0.03). All bDMARDs improved DAS28-CRP/ESR and reduced prednisolone dosage across all groups.

bDMARDs demonstrated effective and safe profiles in patients with RA with CKD, even among patients on HD. In particular, IL-6is had a significantly higher drug retention rate in patients with an eGFR of <30 mL/min/1.73 m2 and fewer discontinuations due to ineffectiveness. IL-6is were more efficacious as monotherapy compared with the other bDMARDs.

To investigate the association between corneal hysteresis and the presence of glaucoma and its subtypes in a general Japanese population.

We analysed the data of 2338 Japanese community-dwellers aged ≥40 years (1059 men, 1279 women) who underwent an eye examination in 2018 as part of the population-based, cross-sectional Hisayama Study. Participants were divided into quartile levels of corneal hysteresis, which had been measured with an ocular response analyzer. Glaucoma was defined based on the International Society of Geographical and Epidemiological Ophthalmology criteria. We conducted a logistic regression analysis to determine the ORs and their 95% CIs for the presence of outcomes according to the corneal hysteresis quartiles.

Glaucoma was diagnosed in 154 participants: primary open-angle glaucoma (POAG), n=115; primary angle-closure glaucoma, n=17; exfoliation glaucoma, n=21 and secondary glaucoma without exfoliation glaucoma, n=1. After adjustment for confounders, the OR for prevalent glaucoma was significantly increased in the participants in the first corneal-hysteresis quartile compared with those in the fourth quartile (OR: 1.80; 95% CI: 1.03 to 3.17). Regarding glaucoma subtypes, the first-quartile participants had significantly greater likelihoods of the presence of POAG (OR: 1.63; 95% CI: 1.02 to 2.61) and exfoliation glaucoma (OR: 6.49; 95% CI: 1.44 to 29.30) compared with those in the third and fourth quartiles after adjustment for potential confounders.

These results demonstrated a significant inverse association between corneal hysteresis and the likelihood of glaucoma, suggesting that the measurement of corneal hysteresis would provide useful information for elucidating the aetiology of glaucoma.

To evaluate the seasonal variability of urinary albumin to creatinine ratio (UACR) and eGFR and these effects on three-year eGFR slope in persons with type 2 diabetes (T2D).

A total of 1135 persons with T2D were analyzed in this single-center, retrospective cohort study in Japan. The standard deviation (SD) of UACR (SD [UACR]) and SD of eGFR (SD [eGFR]) were calculated for each person's 10-point data during the three years, and a multiple linear regression analysis was performed to evaluate associations with eGFR slope. A sensitivity analysis was performed in a group with no medication changes (n = 801).

UACR exhibited seasonal variability, being higher in winter and lower in spring, early summer, and autumn especially in the UACR ≥ 30 mg/g subgroup, while eGFR showed no seasonal variability. The eGFR slope was significantly associated with SD (eGFR) (regression coefficient -0.170 [95% CI -0.189--0.151]) and SD (UACR) (0.000 [-0.001-0.000]). SGLT-2 inhibitors, baseline eGFR, and baseline systolic blood pressure (SBP) were also significantly associated. These associated factors, except baseline SBP, were still significant in the sensitivity analysis.

The UACR showed clear seasonal variability. Moreover, SD (UACR) and SD (eGFR) were independently associated with a three-year eGFR slope in persons with T2D.

This study was not registered for clinical trial registration because it was a retrospective observational study.

Diabetic kidney disease is a major vascular complication in patients with diabetes mellitus (DM). However, the association between the hemoglobin (Hb)A1c levels, notably the prediabetic levels, and renal pathological changes remains unclear. We investigated the association between the HbA1c levels and renal arteriolar lesions in subjects without any apparent kidney dysfunction using a living kidney donor cohort.

Between January 2006 and May 2016, 393 living kidney donors underwent a "zero-time" biopsy at Kyushu University Hospital. The patients were divided into four groups (HbA1c levels ＜5.6%, 5.6%-5.7%, 5.8%-6.4%, and ≥ 6.5%, or diagnosed with DM [DM group]). Renal arteriolar hyalinization and wall thickening were assessed using semi-quantitative grading. We then investigated the association between the HbA1c levels and renal pathological changes.

158 (40.2%) patients had arteriolar hyalinization and 148 (37.6%) showed wall thickening. A significant correlation was observed between the HbA1c levels and wall thickening (p for trend ＜0.001). An elevated HbA1c level was significantly associated with wall thickening according to a multivariable logistic analysis in subjects with HbA1c levels of 5.6%-5.7% and 5.8%-6.4%, and the DM group, compared with those with HbA1c levels of ＜5.6% (odds ratio [OR], 1.91; 95% confidence interval [CI]: [1.03-3.54] for 5.6%-5.7%, OR, 1.96; 95% CI: [1.09-3.53] for 5.8%-6.4%, and OR, 2.86; 95% CI: [0.91-9.01] for the DM group), whereas arteriolar hyalinization did not increase within the nondiabetic HbA1c levels.

Elevated high-normal HbA1c levels are considered to be independent risk factors for arteriolar wall thickening. Subclinical renal arteriolar sclerosis may develop in patients with prediabetic HbA1c levels.

PIONEER REAL Japan was a non-interventional, multicenter, prospective study investigating oral semaglutide in adults with type 2 diabetes in routine clinical practice. We report baseline characteristics of participants enrolled in this study.

Adults aged ≥20 years with type 2 diabetes but no previous treatment with injectable glucose-lowering medication were enrolled. Participants initiated oral semaglutide at their treating physician's discretion and were followed for 34-44 weeks. Participants were stratified into <75-year-old and ≥75-year-old subgroups.

A total of 624 participants initiated the study. The mean (standard deviation) age was 64.1 years (14.1), the mean (standard deviation) body weight was 72.4 kg (16.1), and the mean (standard deviation) body mass index was 27.5 kg/m2 (5.0). Participants had a median (interquartile range) type 2 diabetes duration of 9.3 years (4.2, 15.2) and mean (standard deviation) glycated hemoglobin 7.7% (1.1). Most (75.6%) participants were taking glucose-lowering medications at baseline; the most common was metformin (51.9%). The main reasons for initiating oral semaglutide were glycemic control and weight loss. Most (86.0%) participants had an individualized target for glycemic control of glycated hemoglobin ≤7%. The <75-year-old subgroup was heavier (mean [standard deviation] body mass index 28.6 kg/m2 [5.2] vs 25.1 kg/m2 [3.4]) but had comparable glycated hemoglobin levels (mean [standard deviation] 7.7% [1.2] vs 7.8% [1.0]) to the ≥75-year-old subgroup.

PIONEER REAL Japan describes the characteristics of individuals with type 2 diabetes prescribed oral semaglutide. The baseline characteristics provide insights into Japanese individuals with type 2 diabetes prescribed oral semaglutide in clinical practice.

Introduction In this investigation, the focus was on exploring the connection between serum gamma-glutamyl transferase (GGT), a vital element that influences health and mortality in relation to aging, and all-cause mortality. The study was conducted using a follow-up approach at eight- and 20-year intervals. Methods The study involved 1,101 female participants, with an average age of 69 years (± 9), and 916 male participants, with an average age of 67 years (± 11), who were all diagnosed with hypertension. These individuals were drawn from the Nomura cohort study, which consisted of two separate cohorts: the initial cohort established in 2002 and the subsequent cohort in 2014. We used a Cox proportional hazards model to calculate the hazard ratios (HRs), adjusted for multiple variables, for mortality risk from the initial health examination until the conclusion of the follow-up periods. Results The study followed the participants for a median period of 13.9 years (interquartile range: 8.5-20.2 years). During this follow-up period, 716 deaths were recorded in this population (360 in men and 356 in women), resulting in a mortality rate of 25.5 deaths per 1,000 person-years. Male participants categorized with serum GGT levels ranging from 42 to 86 IU/L showed a 64% increased risk of all-cause mortality (HR: 1.64; 95% confidence interval (CI): 1.11-2.40), while those with GGT levels of 87 IU/L or higher exhibited a 93% elevated risk (HR: 1.93; 95% CI: 1.18-3.16) compared to individuals with GGT levels below 19 IU/L. The association between higher GGT levels and increased all-cause mortality was more evident in men than in women, with a significant interaction between gender and baseline serum GGT (p = 0.020). Conclusions Our findings suggest a notable correlation between irregular GGT levels and the overall mortality rate among Japanese individuals with hypertension living in community settings. Notably, especially in older males, GGT activity turns out to be a critical biomarker for predicting long-term survival.

Little is known about the combined effect of bisphenol mixtures and metal mixtures on type 2 diabetes mellitus (T2DM) risk, and the mediating roles of metabolites.

The study included 606 pairs of T2DM cases and controls matched by age and sex, and information of participants was collected through questionnaires and laboratory tests. Serum bisphenol and plasma metal concentrations were measured using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) and inductively coupled plasma-mass spectrometry (ICP-MS), respectively. Widely targeted metabolomics was employed to obtain the serum metabolomic profiles. Conditional logistic regression models were used to assess the single associations of bisphenols and metals with T2DM risk after multivariable adjustment. Additionally, the joint effects of bisphenol mixtures and metal mixtures were examined using quantile-based g-computation (QG-C) models. Furthermore, differential metabolites associated with T2DM were identified, and mediation analyses were performed to explore the role of metabolites in the associations of bisphenols and metals with T2DM risk.

The results showed bisphenol mixtures were associated with an increased T2DM risk, with bisphenol A (BPA) identified as the primary contributor. While the association between metal mixtures and T2DM remained inconclusive, cobalt (Co), iron (Fe), and zinc (Zn) showed the highest weight indices for T2DM risk. A total of 154 differential metabolites were screened between the T2DM cases and controls. Mediation analyses indicated that 9 metabolites mediated the association between BPA and T2DM, while L-valine mediated the association between Zn and T2DM risk.

The study indicated that BPA, Co, Fe, and Zn were the primary contributors to increased T2DM risk, and metabolites played a mediating role in the associations of BPA and Zn with the risk of T2DM. Our findings contribute to a better understanding of the mechanisms underlying the associations of bisphenols and metals with T2DM.

Several prospective studies have reported that higher visit-to-visit blood pressure variability (BPV) is associated with atrial fibrillation (AF). However, no studies have investigated the association between day-to-day BPV assessed by home blood pressure measurement and the development of AF.

A total of 2829 community-dwelling Japanese aged ≥40 years without prior AF were followed up for 10 years (2007-17). Day-to-day home BPV [defined as coefficient of variation (CoV) of home systolic blood pressure (SBP) for 28 days] was categorized into four groups according to the quartiles: Q1, ≤ 4.64%; Q2, 4.65-5.70%; Q3, 5.71-7.01%; Q4, ≥ 7.02%. The hazard ratios for developing AF were estimated using a Cox proportional hazards model. During the follow-up period, 134 participants developed new-onset AF. The crude incidence rates of AF increased significantly with higher CoV levels of home SBP: 2.1, 4.9, 5.2, and 8.8 per 1000 person-years in the first, second, third, and fourth quartiles, respectively (P for trend < 0.01). After adjusting for potential confounders, increased CoV levels of home SBP were associated significantly with a higher risk of AF (P for trend = 0.02). The participants in the highest quartile of CoV had a 2.20-fold (95% confidence intervals: 1.18-4.08) increased risk of developing AF compared with those in the lowest quartile.

The present findings suggest that increased day-to-day home BPV levels are associated with a higher risk of the development of AF in a general Japanese population.