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ABSTRACT Aims/Introduction We assessed the modification effect of adherence to diabetes care on the association between HbA1c levels and the risk of coronavirus disease 2019 (COVID‐19) among individuals with diabetes using a population‐based database. Material and Methods We retrospectively identified individuals with diabetes during routine health checkups performed in 2019 in Japan using a population‐based claims database (JMDC, Tokyo, Japan). We assessed the risk of COVID‐19 infection in 2020 in relation to HbA1c levels during routine checkups, stratified by the presence/absence of follow‐up for diabetes care in 2019. Several sensitivity analyses were performed. Results We identified 65,956 individuals with an HbA1c ≥6.5% and fasting glucose ≥126 mg/dL in routine checkups, including 52,637 and 13,319 with and without at least one physician consultation for diabetes care in 2019, respectively. Although high HbA1c levels were associated with an increased risk of COVID‐19 infection in a dose‐dependent manner among individuals without diabetes care in 2019 (odds ratios, 1.53 and 2.17 in individuals with HbA1c of 7.0–7.9% and ≥8.0%, respectively) with a reference to HbA1c of 6.5–6.9%, individuals with diabetes care had no such trend in 2019 (odds ratios, 0.99 and 0.97 among individuals with HbA1c of 7.0–7.9% and ≥8.0%, respectively). Sensitivity analyses yielded consistent results when the variable definitions were changed and after multivariable adjustment with multiple imputation. Conclusions This population‐based study suggests that adherence to diabetes care may modify the association between HbA1c levels and the risk of COVID‐19 infection.

Abstract Background The risk of subsequent cardiovascular disease (CVD) is high in cancer survivors. Although metabolic syndrome is an established risk factor for CVD, its association with cancer survivors has not yet been established. This study aimed to clarify whether metabolic syndrome is associated with subsequent CVD risk in patients with cancer using a nationwide epidemiological dataset. Methods We retrospectively analysed 53 510 patients with a history of breast, colorectal, or stomach cancer, which is reportedly a major site for developing cancer in Japan. Study participants were categorized into two groups based on the presence of metabolic syndrome, defined using the Japanese criteria (high waist circumference and ≥2 metabolic parameters including elevated blood pressure, elevated triglycerides, reduced high‐density lipoprotein cholesterol, or elevated fasting plasma glucose). The clinical outcomes were collected between 2005 and 2021. The primary endpoint was defined as the composite CVD outcome, including myocardial infarction, angina pectoris, stroke, and heart failure. Results The median patient age was 54 years, and 37.5% of the patients were men. Metabolic syndrome was observed in 5558 (10.4%) patients. Over a mean follow‐up period of 973 ± 791 days, 3085 composite CVD outcomes were recorded. Multivariable Cox regression analyses showed that metabolic syndrome was associated with a greater risk of developing CVD events (HR = 1.29, 95% CI = 1.15–1.45). Metabolic syndrome was also associated with an increased risk of CVD in patients with a follow‐up period ≥1 year (HR = 1.33, 95% CI = 1.15–1.53). This relationship was also observed when metabolic syndrome was defined according to the International Diabetes Federation criteria (HR = 1.34, 95% CI = 1.21–1.49) and the National Cholesterol Education Program Adult Treatment Panel III criteria (HR = 1.32, 95% CI = 1.19–1.46). Subgroup analyses showed that the relationship between metabolic syndrome and incident CVD was more pronounced in the non‐obese participants than in the obese participants. Conclusions Metabolic syndrome is associated with a greater risk of developing CVD, even among cancer survivors.

BackgroundHereditary angioedema (HAE), a rare genetic disease, induces acute attacks of swelling in various regions of the body. Its prevalence is estimated to be 1 in 50,000 people, with no reported bias among different ethnic groups. However, considering the estimated prevalence, the number of patients in Japan diagnosed with HAE remains approximately 1 in 250,000, which means that only 20% of potential HAE cases are identified. ObjectiveThis study aimed to develop an artificial intelligence (AI) model that can detect patients with suspected HAE using medical history data (medical claims, prescriptions, and electronic medical records [EMRs]) in the United States. We also aimed to validate the detection performance of the model for HAE cases using the Japanese dataset. MethodsThe HAE patient and control groups were identified using the US claims and EMR datasets. We analyzed the characteristics of the diagnostic history of patients with HAE and developed an AI model to predict the probability of HAE based on a generalized linear model and bootstrap method. The model was then applied to the EMR data of the Kyoto University Hospital to verify its applicability to the Japanese dataset. ResultsPrecision and sensitivity were measured to validate the model performance. Using the comprehensive US dataset, the precision score was 2% in the initial model development step. Our model can screen out suspected patients, where 1 in 50 of these patients have HAE. In addition, in the validation step with Japanese EMR data, the precision score was 23.6%, which exceeded our expectations. We achieved a sensitivity score of 61.5% for the US dataset and 37.6% for the validation exercise using data from a single Japanese hospital. Overall, our model could predict patients with typical HAE symptoms. ConclusionsThis study indicates that our AI model can detect HAE in patients with typical symptoms and is effective in Japanese data. However, further prospective clinical studies are required to investigate whether this model can be used to diagnose HAE.

Background Observational studies have reported associations between primary aldosteronism (PA) and cardiovascular outcomes, including coronary artery diseases (CAD), congestive heart failure (CHF), and stroke. However, establishing causality remains a challenge due to the lack of randomized controlled trial data on this topic. We thus aimed to investigate the causal relationship between PA and the risk of developing CAD, CHF, and stroke. Methods and Results Cross‐ancestry meta‐analysis of genome‐wide association studies combining East Asian and European ancestry (1560 PA cases and 742 139 controls) was conducted to identify single‐nucleotide variants that are associated with PA. Then, using the identified genetic variants as instrumental variables, we conducted the 2‐sample Mendelian randomization analysis to investigate the causal relationship between PA and incident CAD, CHF, and stroke among both East Asian and European ancestry. Summary association results were extracted from large genome‐wide association studies consortia. Our cross‐ancestry meta‐analysis of East Asian and European populations identified 7 genetic loci significantly associated with the risk of PA, for which the genes nearest to the lead variants were CASZ1, WNT2B, HOTTIP, LSP1, TBX3, RXFP2, and NDP. Among the East Asian population, the pooled odds ratio estimates using these 7 genetic instruments of PA were 1.07 (95% CI, 1.03–1.11) for CAD, 1.10 (95% CI, 1.01–1.20) for CHF, and 1.13 (95% CI, 1.09–1.18) for stroke. The results were consistent among the European population. Conclusions Our 2‐sample Mendelian randomization study revealed that PA had increased risks of CAD, CHF, and stroke. These findings highlight that early and active screening of PA is critical to prevent future cardiovascular events.

Background: Despite the widespread practice of Japanese traditional Kampo medicine, the characteristics of patients receiving various Kampo formulations have not been documented in detail. We applied a machine learning model to a health insurance claims database to identify the factors associated with the use of Kampo formulations. Methods: A 10% sample of enrollees of the JMDC Claims Database in 2018 and 2019 was used to create the training and testing sets, respectively. Logistic regression analyses with lasso regularization were performed in the training set to construct models with prescriptions of 10 commonly used Kampo formulations in 1 year as the dependent variable and data of the preceding year as independent variables. Models were applied to the testing set to calculate the C-statistics. Additionally, the performance of simplified scores using 10 or 5 variables were evaluated. Results: There were 338,924 and 399,174 enrollees in the training and testing sets, respectively. The commonly prescribed Kampo formulations included kakkonto, bakumondoto, and shoseityuto. Based on the lasso models, the C-statistics ranged from 0.643 (maoto) to 0.888 (tokishakuyakusan). The models identified both the common determinants of different Kampo formulations and the specific characteristics associated with particular Kampo formulations. The simplified scores were slightly inferior to full models. Conclusion: Lasso regression models showed good performance for explaining various Kampo prescriptions from claims data. The models identified the characteristics associated with Kampo formulation use.

Background There are few data on sex differences in the association between schizophrenia and the development of cardiovascular disease (CVD). We sought to clarify the relationship of schizophrenia with the risk of developing CVDs and to explore the potential modification effect of sex differences. Methods and Results We conducted a retrospective analysis using the JMDC Claims Database between 2005 and 2022. The study population included 4 124 508 individuals aged 18 to 75 years without a history of CVD or renal replacement therapy. The primary end point is defined as a composite end point that includes myocardial infarction, angina pectoris, stroke, heart failure, atrial fibrillation, and pulmonary thromboembolism. During a mean follow‐up of 1288±1001 days, we observed 182 158 composite end points. We found a significant relationship of schizophrenia with a greater risk of developing composite CVD events in both men and women, with a stronger association observed in women. The hazard ratio for the composite end point was 1.63 (95% CI, 1.52–1.74) in women and 1.42 (95% CI, 1.33–1.52) in men after multivariable adjustment (P for interaction=0.0049). This sex‐specific difference in the association between schizophrenia and incident CVD was consistent for angina pectoris, heart failure, and atrial fibrillation. Conclusions Our analysis using a large‐scale epidemiologic cohort demonstrated that the association between schizophrenia and subsequent CVD events was more pronounced in women than in men, suggesting the clinical importance of addressing schizophrenia and tailoring the CVD prevention strategy based on sex‐specific factors.

ABSTRACT Aim/Introduction This study aimed to investigate the clinical utility of 3 Screen ICA ELISA in identifying immune‐mediated type 1 diabetes in Japanese subjects. Methods We compared the positivity of 3 Screen ICA were compared with autoantibodies against GAD, IA‐2, and ZnT8 in 638 patients with type 1 diabetes and 159 healthy control subjects. Results With a cut‐off value of 20.0 index, 67.4% of acute‐onset type 1 diabetic patients, 71.8% of slowly progressive type 1 diabetic (SPIDDM) patients, and none of the fulminant type 1 diabetic patients showed 3 Screen ICA levels above this threshold. The prevalence of 3 Screen ICA was 14.2% higher in acute‐onset type 1 diabetes and 1.6% higher in SPIDDM than in GADA. 3 Screen ICA‐positive cases were found in 4.8% of cases of individual autoantibody‐negative acute‐onset type 1 diabetes and 3.8% of SPIDDM, indicating improved diagnostic sensitivity with the 3 Screen ICA. Among individual autoantibody‐negative patients, the sum of each autoantibody level was significantly lower in fulminant type 1 diabetes than in acute onset type 1 diabetes and in SPIDDM (P

Abstract Aims/Introduction Although several noninvasive predictive markers for fatty liver and metabolic markers have been used for fatty liver prediction, whether such markers can also predict metabolic‐associated fatty liver disease (MAFLD) remains unclear. We aimed to examine the ability of existing fatty liver or metabolic markers to predict MAFLD. Materials and Methods Participants in a high‐volume center in Tokyo were classified into groups with and without MAFLD, based on the presence of metabolic abnormalities and fatty liver diagnosed through abdominal ultrasonography, between 2008 and 2018. The diagnostic abilities of three fatty liver markers: fatty liver index (FLI), hepatic steatosis index (HSI), and lipid accumulation product (LAP), and three common metabolic markers: waist‐to‐height ratio (WHR), body mass index (BMI), and waist circumference (WC), for predicting MAFLD, were evaluated. Analyses stratified by MAFLD subtypes were performed. Results Of 92,374 individuals, 19,392 (36.1%) had MAFLD. The diagnostic performances for MAFLD prediction, measured as c‐statistics, for FLI, HSI, LAP, WHR, BMI, and WC were 0.906, 0.892, 0.878, 0.844, 0.877, and 0.878, respectively. Optimal cutoff values for diagnosing MAFLD for FLI, HSI, LAP, WHR, BMI, and WC were 20.3, 32.7, 20.0, 0.49, 22.9, and 82.1, respectively. Analyses stratified by MAFLD subtypes, based on BMI and metabolic/glycemic abnormalities, suggested that FLI and HSI had acceptable (c‐statistics >0.700) diagnostic abilities throughout all the analyses. Conclusions All six markers were excellent predictors of MAFLD in diagnosing among the general population, with FLI and HSI particularly useful among all sub‐populations.

ABSTRACT Aims/Introduction Little is known about the relationship between cardiovascular health (CVH) metrics and the risk of developing prediabetes or diabetes. We examined the association of CVH metrics with the annual risk of developing prediabetes or diabetes. Materials and Methods We carried out this study including 403,857 participants aged 18–71 years with available data on fasting plasma glucose (FPG) data for five consecutive years and with normal FPG (

Abstract Background Although weight loss in heart failure (HF) is a detrimental condition known as cachexia, weight gain caused by fluid retention should also be considered harmful. However, studies with sufficient number of patients examining the impact of weight change and its interval on in‐hospital mortality in HF have not been conducted thus far. We sought to elucidate the association of weight change with in‐hospital mortality in patients with HF. Methods This retrospective observational study used data from the Diagnosis Procedure Combination database, a nationwide inpatient health claims database in Japan. In total, 48 234 patients repeatedly hospitalized for HF (median 82 [74–87] years; 46.4% men) between 2010 and 2018 were included. Weight change was derived from body weight at the first and second admissions. Results The median weight change and interval between two hospitalizations were −3.1 [−8.3 to −1.8] % and 172 [67–420] days, with 66.9% of overall cohort experiencing any weight loss. As a result of multivariable‐adjusted logistic regression analysis, weight loss +5.0% were associated with increased in‐hospital mortality (adjusted odds ratio [OR] [95% confidence interval]: 1.46 [1.31–1.62], P

Abstract Background An increasing number of studies are evaluating the safety of intravenous sedation compared with that of general anesthesia; however, data on bleeding complications after pediatric percutaneous renal biopsy performed under intravenous sedation or general anesthesia are lacking. We aimed to examine differences in bleeding complications between intravenous sedation and general anesthesia in pediatric patients. Methods Data of pediatric patients aged ≤ 15 years undergoing percutaneous kidney biopsy for kidney disease between July 2007 and March 2019 were retrieved from a national inpatient database in Japan. We examined differences in bleeding complications after renal biopsy performed under intravenous sedation, defined by the absence of the record of general anesthesia with intubation but by the presence of intravenous sedation during biopsy, and general anesthesia, defined by the presence of the record of general anesthesia with intubation during biopsy, among pediatric patients admitted for percutaneous renal biopsy. We performed binomial regression using overlap weights based on propensity scores for patients receiving intravenous sedation. Analyses stratified by age or sex, a sensitivity analysis using generalized estimating equations considering cluster effects by hospital among a propensity score-matched cohort, and another sensitivity analysis using the instrumental variable method were performed to confirm the robustness of the results. Results We identified 6,560 biopsies performed in 5,999 children aged 1–15 years from 328 hospitals and 178 events. Only three severe complications and no death were observed. No significant difference in the proportion of bleeding complications was observed between procedures performed under intravenous sedation and those performed under general anesthesia (unadjusted proportions, 2.8% and 2.3%; adjusted proportions, 2.5% and 2.2%), with an unadjusted relative risk of 1.21 (95% confidence interval, 0.80–1.81) and adjusted relative risk of 1.13 (95% confidence interval, 0.74–1.73). Both age- and sex-stratified analyses yielded similar results. The analysis using generalized estimating equation and the instrumental variable method showed relative risks of 0.95 (95% confidence interval, 0.48–1.88) and 1.18 (95% confidence interval, 0.74–1.89), respectively. Conclusion This retrospective cohort study using a national database revealed that the risk of biopsy-related bleeding was comparable between intravenous sedation and general anesthesia during pediatric percutaneous kidney biopsy, suggesting that intravenous sedation alone and general anesthesia may have a similar bleeding risk in pediatric percutaneous kidney biopsies.

Abstract Background Low body mass index (BMI) in older individuals with decreased kidney function is important because of its association with poor prognosis and frailty. Herein, we aimed to clarify the association between BMI and in-hospital mortality among older patients with non-dialysis-dependent chronic kidney disease (CKD) stratified by kidney function. Methods Using data from the Medical Vision Database, this multicentre cohort study included people aged ≥ 60 years with an estimated glomerular filtration rate of

Abstract Aim Although major complication rates following percutaneous liver biopsy (PLB) have been reported to be higher in children than in adults, scarce data are available regarding pediatric patients stratified by native and transplanted liver. We aimed to assess the factors associated with major complications after percutaneous biopsy of native or transplanted liver using a nationwide inpatient database. Methods Using the Japanese Diagnosis Procedure Combination database, we retrospectively identified pediatric patients who underwent PLB between 2010 and 2018. We described major complication rates and analyzed factors associated with major complications following PLB, stratified by native and transplanted liver. Results We identified 3584 pediatric PLBs among 1732 patients from 239 hospitals throughout Japan during the study period, including 1310 in the native liver and 2274 in the transplanted liver. Major complications following PLB were observed in 0.5% (n = 18) of the total cases; PLB in the transplanted liver had major complications less frequently than those in the native liver (0.2% vs. 1.0%, p = 0.002). The occurrence of major complications was associated with younger age, liver cancers, unscheduled admission, anemia or coagulation disorders in cases with native liver, while it was associated with younger age alone in cases with transplanted liver. Conclusions The present study, using a nationwide database, found that major complications occurred more frequently in pediatric cases with native liver and identified several factors associated with its major complications.

Abstract Little is known regarding the relationship between self-reported gait speed and the subsequent risk of heart failure (HF) and cardiovascular disease (CVD). We sought to clarify the clinical utility of self-reported gait speed in primary CVD prevention settings. This is an observational cohort study using the JMDC Claims Database, which is an administrative health claims database. Data were collected between January 2005 and April 2020. Medical records of 2,655,359 participants without a prior history of CVD were extracted from the JMDC Claims Database. Gait speed was assessed using information from questionnaires provided at health check-ups, and study participants were categorized into fast or slow gait speed groups. The primary outcome was HF. The secondary outcomes included myocardial infarction (MI), angina pectoris (AP), and stroke. The median age was 45.0 years, and 55.3% of participants were men. 46.1% reported a fast gait speed. The mean follow-up period was 1180 ± 906 days. HF, MI, AP, and stroke occurred in 1.9%, 0.2%, 1.9%, and 1.0% of participants, respectively. Multivariable Cox regression analyses showed that, compared with slow gait speed, fast gait speed was associated with a lower incidence of HF, MI, AP, and stroke. The discriminative predictive ability for HF significantly improved by adding self-reported gait speeds to traditional risk factors (net reclassification improvement 0.0347, p

We sought to clarify the incidence of major adverse cardiac events (MACE) after the initiation of immune checkpoint inhibitors (ICIs). We analyzed the JMDC Claims Database between 2005 and 2021. The study included 2972 patients with no history of cardiovascular disease and a prescription for an ICI. The primary outcome was the incidence of MACE, including myocarditis, pericarditis, Takotsubo cardiomyopathy, atrio-ventricular block, heart failure, myocardial infarction, and stroke. The median age of study participants was 59 (Q1-Q3 53–65) years, and 2163 participants (72.8%) were male. Lung cancer was the most common cancer site (n = 1603). Among ICIs, programmed cell death-1 (PD-1) was most frequently used, and a combination ICI treatment was conducted in 110 patients (3.7%). During a mean follow-up of 358 ± 327 days, 419 MACE events were recorded. The incidence rate of myocarditis, pericarditis, Takotsubo cardiomyopathy, atrio-ventricular block, heart failure, myocardial infarction, and stroke was 3.4, 142.3, 10.3, 17.2, 1191.2, 55.2, and 278.5 per 10,000 person-years, respectively. The incidence of cardiovascular events was higher within 180 days after the initial prescription of ICI. The continuation rate of ICI after MACE was 38.4%. In conclusion, our analysis of a nationwide epidemiological dataset demonstrated the incidence of MACE after the initiation of ICI treatment. The incidence of heart failure was higher than expected, and the continuation rate of ICI treatment after MACE was low. Our results indicated the importance of monitoring and prevention of cardiovascular events in cancer patients requiring ICI treatment.

Background Limited evidence is available on sex differences about the association between hypertension and incident atrial fibrillation (AF). Methods and Results We used a nationwide health checkup and claims database to analyze 3 383 738 adults (median age, 43 (36–51) years, 57.4% men). We investigated the relationship between hypertension and incident AF in men and women using a Cox regression model. We used restricted cubic spline functions to identify the association of blood pressure (BP) as a continuous parameter with incident AF. We categorized the men and women into 4 groups according to the 2017 American College of Cardiology/American Heart Association BP guidelines. During a mean follow‐up of 1199±950 days, 13 263 AF diagnoses were recorded. The incidence (95% CI) of AF was 15.8 (15.5–16.1) per 10 000 person‐years in men and 6.1 (5.9–6.3) per 10 000 person‐years in women. Compared with normal BP, elevated BP, stage 1 hypertension, and stage 2 hypertension were associated with an increased risk AF in both men and women. However, the hazard ratios were greater in women than in men, and the P value for interactions in the multivariable model was 0.0076. The models using restricted cubic spline showed that the risk of AF associated with elevated systolic BP increased steeply above an approximate threshold of systolic BP of 130 mm Hg in men and 100 mm Hg in women. Although our primary findings were consistent across subgroup analyses, this association was most significant in younger individuals. Conclusions Although the incidence of AF was higher in men, the association between hypertension and incident AF was more pronounced in women than in men, suggesting a potential sex difference in the relationship between hypertension and incident AF.

Abstract Background There have been scarce data comparing cardiovascular outcomes between individual sodium-glucose cotransporter-2 (SGLT2) inhibitors. We aimed to compare the subsequent cardiovascular risk between individual SGLT2 inhibitors. Methods We analyzed 25,315 patients with diabetes mellitus (DM) newly taking SGLT2 inhibitors (empagliflozin: 5302, dapagliflozin: 4681, canagliflozin: 4411, other SGLT2 inhibitors: 10,921). We compared the risks of developing heart failure (HF), myocardial infarction (MI), angina pectoris (AP), stroke, and atrial fibrillation (AF) between individual SGLT2 inhibitors. Results Median age was 52 years, and 82.5% were men. The median fasting plasma glucose and HbA1c levels were 149 (Q1-Q3:127–182) mg/dL and 7.5 (Q1-Q3:6.9–8.6) %. During a mean follow-up of 814 ± 591 days, 855 HF, 143 MI, 815 AP, 340 stroke, and 139 AF events were recorded. Compared with empagliflozin, the risk of developing HF, MI, AP, stroke, and AF was not significantly different in dapagliflozin, canagliflozin, and other SGLT inhibitors. For developing HF, compared with empagliflozin, hazard ratios of dapagliflozin, canagliflozin, and other SGLT2 inhibitors were 1.02 (95% confidence interval [CI] 0.81–1.27), 1.08 (95% CI 0.87–1.35), and 0.88 (95% CI 0.73–1.07), respectively. Wald tests showed that there was no significant difference in the risk of developing HF, MI, AP, stroke, and AF among individual SGLT2 inhibitors. We confirmed the robustness of these results through a multitude of sensitivity analyses. Conclusion The risks for subsequent development of HF, MI, AP, stroke, and AF were comparable between individual SGLT2 inhibitors. This is the first study comparing the wide-range cardiovascular outcomes of patients with DM treated with individual SGLT2 inhibitors using large-scale real-world data.

Introduction: Nephrologists have recently recognized the heterogeneity of kidney diseases among patients with diabetes and begun to actively perform percutaneous renal biopsies (PRBs). Nevertheless, the association between diabetes and major bleeding complications of PRB remains unclear. Methods: In this retrospective cohort study using the Diagnosis Procedure Combination database in Japan, we identified patients who underwent an elective PRB from July 2010 to March 2018. The primary outcome was the occurrence of major bleeding complications, defined as red blood cell transfusion within 7 days after PRB or invasive hemostasis after PRB. Multivariable regression analysis was performed to analyze the association between diabetes and major bleeding complications with adjustment for patient and hospital characteristics. Results: We identified 76,302 patients, including 8245 with diabetes. The proportion of PRBs performed for patients with diabetes continuously increased over time. Major bleeding complications occurred in 678 patients (0.9%), including 622 (0.8%) with red blood cell (RBC) transfusion and 109 (0.1%) with invasive hemostasis. Diabetes was significantly associated with major bleeding complications (relative risk [RR] = 2.41; 95% CI 2.00–2.90). Among patients with diabetes, multiagent or insulin treatment had significant association with major bleeding complications (RR = 1.57; 95% CI 1.18–2.10), compared with single-agent diabetes treatment. Conclusion: Diabetes is significantly associated with major bleeding complications of PRBs. Moreover, severity of diabetes has association with increases in major bleeding complications. Thus, nephrologists should carefully judge whether the anticipated benefits outweigh the relatively high risk of major bleeding complications when considering PRB for patients with diabetes.

Background There have been limited data examining the age‐dependent relationship of wide‐range risk factors with the incidence of each subtype of cardiovascular disease (CVD) event. We assessed age‐related associations between modifiable risk factors and the incidence of CVD. Methods and Results We analyzed 3 027 839 participants without a CVD history enrolled in the JMDC Claims Database (mean age, 44.8±11.0 years; 57.6% men). Each participant was categorized as aged 20 to 49 years (n=2 008 559), 50 to 59 years (n=712 273), and 60 to 75 years (n=307 007). Using Cox proportional hazards models and the relative risk reduction, we identified associations between risk factors and incident CVD, consisting of myocardial infarction, angina pectoris, stroke, and heart failure (HF). We assessed whether the association of risk factors for developing CVD would be modified by age category. Over a mean follow‐up of 1133 days, 6315 myocardial infarction, 56 447 angina pectoris, 28 079 stroke, and 56 369 HF events were recorded. The incidence of myocardial infarction, angina pectoris, stroke, and HF increased with age category. Hazard ratios of obesity, hypertension, and diabetes in the multivariable Cox regression analyses for myocardial infarction, angina pectoris, stroke, and HF decreased with age category. The relative risk reduction of obesity, hypertension, and diabetes for CVD events decreased with age category. For example, the relative risk reduction of hypertension for HF decreased from 59.2% in participants aged 20 to 49 years to 38.1% in those aged 60 to 75 years. Conclusions The contribution of modifiable risk factor to the development of CVD is greater in younger compared with older individuals. Preventive efforts for risk factor modification may be more effective in younger people.

Background Hypertension and diabetes frequently coexist. However, little is known about the interaction between high blood pressure (BP) and hyperglycemia in the development of cardiovascular disease (CVD). Methods and Results We conducted an observational cohort study that included 3 336 363 patients (median age, 43 years old; men, 57.2%). People taking BP‐ or glucose‐lowering medications or those with prior history of CVD were excluded. We defined stage 1 hypertension as having systolic BP of 130 to 139 mm Hg or diastolic BP of 80 to 89 mm Hg and stage 2 hypertension as having systolic BP of ≥140 mm Hg or diastolic BP of ≥90 mm Hg. We defined prediabetes as having fasting plasma glucose of 100 to 125 mg/dL and diabetes as having fasting plasma glucose of ≥126 mg/dL. Over a mean follow‐up period of 1185 ± 942 days, 5665 myocardial infarction, 52 475 angina pectoris, 25 436 stroke, 54 508 heart failure, and 12 932 atrial fibrillation events occurred. The BP and fasting plasma glucose categories additively increased the risk of myocardial infarction, angina pectoris, stroke, heart failure, and atrial fibrillation. However, the relative risk of stage 1 and stage 2 hypertension developing into CVD was attenuated with deteriorating glycemic status. Similarly, the relative risk of prediabetes and diabetes developing into CVD was attenuated with increasing BP. For example, the relative risk reduction of stage 2 hypertension for heart failure was 53.5% in individuals with normal fasting plasma glucose, 46.4% in those with prediabetes, and 37.2% in those with diabetes. The robustness of our findings was confirmed using a multitude of sensitivity analyses. Conclusions Although hypertension and hyperglycemia additively increase the risk of developing CVD, the relative contribution of hypertension to the development of CVD decreased with deteriorating glycemic status and that of hyperglycemia was attenuated with increasing BP. Our results indicate a potential interaction between hypertension and hyperglycemia in the development of CVD.

Background and study aims Despite the widespread use of direct oral anticoagulants (DOACs), the association between DOAC use and complications (e. g., bleeding) following gastrointestinal endoscopic biopsy remains unclear. This study aimed to evaluate complications after biopsy in patients treated with DOACs in Japan, where biopsies would be generally performed without DOAC withdrawal based on guideline recommendations. Patients and methods Using a Japanese nationwide database, we identified patients taking DOACs who underwent gastrointestinal endoscopic biopsy (n = 2,769, DOAC group) and those not taking DOACs (n = 129,357, control group) from April 2015 to November 2020. We conducted 1:4 propensity score (PS) matching and overlap PS-weighting analyses with adjustment for background characteristics to compare occurrence of post-procedure hemorrhage and stroke within 1 week after biopsy, and thrombin use on the day of biopsy without a diagnosis of hemorrhage. Results In total, 578 patients (0.44 %) developed post-procedure hemorrhage, and 13 patients (0.01 %) developed stroke. The DOAC group had more comorbidities than the control group. The PS matching analysis revealed no significant differences in post-procedure hemorrhage (odds ratio, 1.52 [95 % confidential interval, 0.96–2.41]) or stroke (1.00 [0.21–4.71]), whereas the DOAC group received thrombin more often than the control group (1.60 [1.30–1.95]). The results were equivalent in the overlap PS-weighting analysis. Conclusions The PS analyses showed no significant differences in complications following gastrointestinal endoscopic biopsy between DOAC users and non-users. These results suggest the safety of endoscopic biopsy without DOAC withdrawal although the need for careful hemostasis remains.

Abstract Aims/Introduction Discontinuation of diabetes care has been studied mostly in patients with prevalent diabetes and not in patients with newly diagnosed diabetes, whose dropout risk is highest. Because enrolling patients in a prospective study will influence adherence, we retrospectively examined whether guideline‐recommended practices, defined as nutritional guidance or ophthalmological examination, can prevent patient discontinuation of diabetes care after its initiation. Materials and Methods We retrospectively identified adults with newly screened diabetes during checkups using a large Japanese administrative claims database (JMDC, Tokyo, Japan) that contains laboratory data and lifestyle questionnaires. We defined discontinuation of physician visits as a follow‐up interval exceeding 6 months. We divided the patients into those who received guideline‐recommended practices (nutritional guidance or ophthalmology consultation) within the same month as the first visit and those who did not. We calculated propensity scores and carried out inverse probability of treatment weighting analyses to compare discontinuation between the two groups. Results We identified 6,508 patients with at least one physician consultation for diabetes care within 3 months after their checkup, including 4,574 patients without and 1,934 with guideline‐recommended practices. After inverse probability of treatment weighting, patients with guideline‐recommended practices had a significantly lower proportion of discontinuation than those without (17.2% vs 21.8%; relative risk 0.79, 95% confidence interval 0.69–0.91). Conclusions This study is the first to show that after adjustment for both patient and healthcare provider factors, guideline‐recommended practices within the first month of physician consultation for diabetes care can decrease subsequent discontinuation of physician visits in patients with newly diagnosed diabetes.

Objectives To examine the incidence of stroke or systemic embolic events (SSEs) and bleeding events in untreated patients with non-valvular atrial fibrillation (NVAF) after widespread use of direct oral anticoagulant agents (DOACs).Design Multicentre, non-interventional, observational, retrospective cohort study using real-world data in Japan (2016-2018).Setting The Mie, Musashino University study of NVAF, which used the Mie-Life Innovation Promotion Center Database. This is a regional clinical database involving one university hospital and eight general hospitals in Mie Prefecture in Japan.Participants Japanese patients with NVAF (n=7001).Primary and secondary outcome The incidence of SSEs and bleeding events.Results A total of 7001 patients with NAVF were registered, and 53.0% were treated with DOACs, 10.6% were treated with warfarin and 36.4% had no treatment. Additionally, 29.5% of patients with a CHADS2 (congestive heart failure, hypertension, age≥75 years, diabetes, previous stroke or transient ischemic attack) score of 3–6 were untreated. In the no treatment group, the SSE rates by the CHADS2 score (0, 1, 2 and 3–6) were 1.4%, 1.4%, 3.2% and 8.0%, respectively. The rates of bleeding events by the CHADS2 score (0, 1, 2 and 3–6) in the no treatment group were 0.7%, 1.0%, 1.2% and 2.9%, respectively. A multivariate analysis of SSEs in components of the CHADS2 showed that the adjusted HRs were 2.32 for heart failure, 1.66 for an age ≥75 years, 1.81 for diabetes mellitus and 5.84 for prior stroke or transient ischaemic attack.Conclusions Approximately one-third of the patients do not receive any anticoagulation in the modern DOAC era in Japan. The SSE rate increases by the CHADS2 score. The SSE rate is low in patients with a CHADS2 score 1, the use of anticoagulant drug therapy is recommended because of a higher risk of stroke.

Abstract Clinical trials for pediatric indications and new pediatric drugs face challenges, including the limited blood volume due to the patients’ small bodies. In Japan, the Evaluation Committee on Unapproved or Off‐labeled Drugs with High Medical Needs has discussed the necessity of pediatric indications against the background of a lack of Japanese pediatric data. The limited treatment options regarding antibiotics for pediatric patients are associated with the emergence of antibiotic‐resistant bacteria. Regulatory guidelines promote the use of model‐based drug development to reduce practical and ethical constraints for pediatric patients. Sampling optimization is one of the key study designs for pediatric drug development. In this simulation study, we evaluated the precision of the empirical Bayes estimates of pharmacokinetic (PK) parameters based on the sampling times optimized by published pediatric population PK models. We selected three previous PK studies of cefepime and ciprofloxacin in infants and young children as paradigms. The number of sampling times was reduced from original full sampling times to two to four sampling times based on the Fisher information matrix. We observed that the precision of empirical Bayes estimates of the key PK parameters and the predicted efficacy based on the reduced sampling times were generally comparable to those based on the original full sampling times. The model‐based approach to sampling optimization provided a maximization of PK information with a minimum burden on infants and young children for the future development of pediatric drugs.

Abstract Background Long-term care (LTC) prevention is a pressing concern in ageing societies. To understand the risk factors of LTC, it is vital to consider psychological and social factors in addition to physical factors. Owing to a lack of relevant data, we aimed to investigate the social, physical and psychological factors associated with LTC using large-scale, nationally representative data to identify a high-risk population for LTC in terms of multidimensional frailty. Methods We performed a cross-sectional study using anonymised data from the 2013 Comprehensive Survey of Living Conditions conducted by the Ministry of Health, Labour and Welfare of Japan. Among the 23,730 eligible people aged 65 years or older and those who were not in hospitals or care facilities during the survey, 1718 stated that they had LTC certification. Univariate and multivariate logistic regression analyses were performed to determine the factors associated with LTC certification. Results Factors positively associated with LTC certification in the multivariate analyses included older age, the interaction term between sex and age group at age 85–89 years, limb movement difficulties, swollen/heavy feet, incontinence, severe psychological distress (indicated by a Kessler Psychological Distress Scale [K6] score ≥ 13), regular hospital visits for dementia, stroke, Parkinson’s disease, chronic obstructive pulmonary disease, fracture, rheumatoid arthritis, kidney disease, diabetes and osteoporosis. Factors negatively associated with LTC certification included the presence of a spouse, regular hospital visits for hypertension and consulting with friends or acquaintances about worries and stress. Conclusions In summary, we identified the physical, psychological and social factors associated with LTC certification using nationally representative data. Our findings highlight the importance of the establishment of multidimensional approaches for LTC prevention in older adults.

Abstract Aims/Introduction This study aimed to investigate the dynamics associated with autoantibodies to insulinoma‐associated antigen‐2 (IA‐2A) and zinc transporter 8 (ZnT8A) relating to the onset age and disease duration in patients with type 1 diabetes. Methods Using bridging‐type enzyme‐linked immunosorbent assay, IA‐2A, ZnT8A and glutamic acid decarboxylase autoantibodies were evaluated in 269 patients with type 1 diabetes (median onset age 18.2 years, range 0.8–86 years; median diabetes duration 7 years, range 0–58 years). We then compared the prevalence of these autoantibodies among the different age groups, along with the duration of diabetes using the Cochran–Armitage trend test and multivariate logistic regression analysis. Results The prevalence of IA‐2A, ZnT8A and glutamic acid decarboxylase autoantibodies in patients with duration of ≤3 years was 41.1, 36.7 and 72.2%, respectively, with 80.0% expressing one or more of these autoantibodies. This prevalence declined according to the disease duration (P

Background The prevalence of hypertension subtypes changes with age. However, little is known regarding the age‐dependent association of hypertension subtypes with incident heart failure (HF). Methods and Results We conducted an observational cohort study including 2 612 570 people (mean age, 44.0 years; 55.0% men). No participants were taking blood pressure–lowering medications or had a known history of cardiovascular disease. Participants were categorized as aged 20 to 49 years (n=1 825 756), 50 to 59 years (n=571 574), or 60 to 75 years (n=215 240). We defined stage 1 hypertension as systolic blood pressure (SBP) 130 to 139 mm Hg or diastolic blood pressure (DBP) 80 to 89 mm Hg and stage 2 hypertension as SBP ≥140 mm Hg or DBP ≥90 mm Hg. Among participants with stage 2 hypertension, isolated diastolic hypertension was defined as SBP

Objectives This study aimed to assess whether adults with proteinuria were at a higher risk of incident colorectal cancer (CRC) than those without proteinuria using a large-scale population-based database.Design A retrospective observational study.Setting The JMDC Claims Database, an administrative health claims database, was used. Data were collected between 2005 and 2020.Participants We selected records of participants (n=3 543 705) who underwent health check-ups, including physical examinations, blood tests and urine dipstick tests. We excluded participants who were aged

Objectives We aimed to investigate the impact of the first and second waves of the COVID-19 pandemic on healthcare service use by non-COVID-19 patients.Design Retrospective cohort study.Setting Hospital-based claims database from anonymised hospitals in Japan.Participants Patients (n=785 495) who visited and/or were hospitalised in 26 anonymised hospitals in Japan between January 2017 and November 2020.Outcome measures We compared changes in the monthly number of hospitalisations (overall or by diagnosis), outpatient visits, endoscopic fibrescopies (EFs), rehabilitations, outpatient chemotherapy treatments, maintenance haemodialysis treatments and outpatient prescriptions between pre-COVID-19 years and the same period in 2020.Results The overall number of hospitalisations and outpatient visits decreased by 27% and 22%, respectively, in May 2020, of which the most substantial decrease was observed in the paediatrics department (65% and 51%, respectively). The number of hospitalisations for respiratory diseases, circulatory diseases, malignant neoplasms and digestive diseases decreased by a maximum of 55%, 32%, 10% and 26%, respectively, in 2020. The number of hospitalisations for non-COVID-19 pneumonia in patients aged 30%. In contrast, outpatient chemotherapy and maintenance haemodialysis treatments decreased by

To prevent cisplatin (CDDP)-induced nephrotoxicity, co-treatment with massive hydration is essential for its clinical use. However, some patients are ineligible for this treatment. For such patients, a split dose of CDDP has been suggested as an alternative strategy. This study aimed to evaluate the nephrotoxicity of a split dose of CDDP by direct comparison with the conventional single dose of CDDP in rats. Rats were allocated to single- or split-dose groups. In the single-dose group, rats received the total dose of CDDP (from 0 to 7.5 mg/kg) with a single injection, whereas the same total dose of CDDP was split equally across five doses in the corresponding split-dose group. Blood samples were taken until day 21 after the first CDDP injection to monitor the plasma creatinine (Cr) concentration as an index of nephrotoxicity. CDDP-induced nephrotoxicities from day 1–10 and from day 15–21 were defined as acute kidney injury (AKI) and subchronic kidney injury (sCKI), respectively. The toxicity of CDDP-induced AKI in the split-dose group was found to be significantly lower than that in the single-dose group at any given total dose level. At a total dose of 7.5 mg/kg, a decrease of approximately 90% in AKI was found in the split-dose group, while the extent of attenuation of CDDP-induced sCKI in this group was approximately 30%. Our results provide evidence that a split-dose regimen could be an alternative strategy for CDDP-ineligible patients; however, the optimal regimen needs to be determined in future studies.

Abstract Aims/Introduction This study aimed to investigate the significance of zinc transporter 8 autoantibody (ZnT8A) in identifying and characterizing autoimmune‐mediated type 1 diabetes in Japanese individuals. Methods ZnT8A were determined in 324 patients with type 1 diabetes, 191 phenotypic type 2 diabetes and 288 healthy control individuals using bridging‐type enzyme‐linked immunosorbent assay in addition to autoantibodies to glutamic acid decarboxylase and insulinoma‐associated antigen‐2. Results We set a cut‐off value of 10.0 U/mL, and 25% of the type 1 diabetic patients had ZnT8A levels exceeding this level. The prevalence of ZnT8A was significantly higher in patients with acute‐onset type 1 diabetes than in those with slowly progressive and fulminant type 1 diabetes (P

With recent improvements in adhesive performance, adhesive joints are being increasingly used in various industrial fields. Despite their advantage of joining dissimilar adherends, adhesive joints are considered unsuitable for key components of mechanical structures due to their large variation in joint strengths. There are many factors that affect the strength of adhesive joints. However, the general bonding mechanisms are (1) mechanical, (2) physical, and (3) chemical bonding. The adhesion mechanism is complex because these phenomena occur simultaneously. Thus, it is necessary to consider these factors separately. Moreover, it is important to understand the bonding mechanism of interfaces in adhesive joints and to improve the reliability of the joint strength. In this study, the tensile strengths of single lap joints were measured to investigate the influence of large-area EB irradiation on strength characterization of adhesive joints. Aluminum alloy plates (A6061) were used as the adherend. Other surface treatments, which were sanding by emery paper, shot blast, and plasma irradiation, were also conducted for comparisons. Each treated surface of the adhered was examined with respect to the surface profile, wettability, and surface analysis by XPS. Results showed that the wettability of treated surfaces of adherend improved, and tensile strength of surface treated adhesive joints was also improved compared with that of the non-treated specimen. Specifically, the strength of the joint with EB irradiation was 1.9 times larger than that of the non-treated specimen. Finally, the effect of large-area EB irradiation on adhesive characterization was discussed.

Abstract Background Acute kidney injury (AKI), which may progress to end-stage kidney disease (ESKD), is a potential complication of aortic dissection. Notably, in all reported ESKD cases secondary to aortic dissection, imaging evidence of static obstruction of the renal arteries always shows either renal artery stenosis or extension of the dissection into the renal arteries. Case presentation We present the case of a 58-year-old man with hypertension who was diagnosed with a Stanford type B aortic dissection and treated with medications alone because there were no obvious findings indicative of dissection involving the renal arteries. He had AKI, which unexpectedly progressed to ESKD, without any radiological evidence of direct involvement of the renal arteries. Thus, we failed to attribute the ESKD to the dissection and hesitated to perform any surgical intervention. Nevertheless, the patient’s hormonal levels, fractional excretion values, ankle brachial indices, and Doppler resistive indices seemed to indirectly suggest kidney malperfusion and implied renal artery hypo-perfusion. However, abdominal computed tomography imaging only revealed progressive thrombotic obstruction of the false lumen and compression of the true lumen in the descending thoracic aorta, despite the absence of anatomical blockage of renal artery perfusion. Later, signs of peripheral malperfusion, such as intermittent claudication, necessitated surgical intervention; a graft replacement of the aorta was performed. Post-operatively, the patient completely recovered after 3 months of haemodialysis, and the markers that had pre-operatively suggested decreased renal bloodstream normalised with recovery of kidney function. Conclusions To the best of our knowledge, this is the first report of severe AKI, secondary to aortic dissection, without direct renal artery obstruction, which progressed to “temporary” ESKD and was resolved following surgery. This case suggests that only coarctation above the renal artery branches following an aortic dissection can progress AKI to ESKD, despite the absence of radiological evidence confirming an obvious anatomical blockage. Further, indirect markers suggestive of decreased renal blood flow, such as ankle brachial indices, renal artery resistive indices, urinary excretion fractions, and hormonal changes, are useful for evaluating concomitant AKI and may indicate the need for surgical intervention after a Stanford type B aortic dissection.

Abstract Aim/Introduction Autoantibodies to the 65 kDa isoform of glutamic acid decarboxylase (GADA) are a valuable diagnostic and predictive marker for type 1 diabetes. Recently, it has been reported that a significant proportion of sera in the commercial RSR radioimmunoassay (RIA) that have tested positive for GADA have then turned negative in RSR enzyme‐linked immunosorbent assay (ELISA) tests in patients with type 1 diabetes. The present study aimed to investigate whether the GADA result discrepancies between RSR‐RIA and RSR‐ELISA are related to autoantibody affinity. Methods GADA affinity was measured by a competitive binding experiment using unlabeled recombinant human GAD65 in 12 discordant samples (5 RIA[+]/ELISA[−] and 7 RIA[−]/ELISA[+] sera). Furthermore, the effect of the initial incubation time on the GADA positivity was also examined using the ELISA test. Results GADA affinities were >1010 L/mol in two of five RIA(+)/ELISA(−) and all of seven RIA(−)/ELISA(+) sera. After an initial incubation time longer than the recommended 1 h, the GADA titer in three of five RIA(+)/ELISA(−) sera and all RIA(−)/ELISA(+) sera increased 1.6‐ to 100‐fold. However, the titer in 12 GADA‐negative sera from healthy controls remained unchanged after the longer incubation. The increment ratio of GADA titer was positively correlated with GADA affinity (r = 0.991, P

Background: Whether acute-phase cardiac rehabilitation (CR) is beneficial for short-term improvement in activities of daily living (ADL) in patients hospitalized for acute heart failure (AHF) remains unclear. Aim: To investigate the association of acute-phase initiation of CR with short-term improvement in ADL in patients hospitalized for AHF. Methods: We retrospectively analyze data from the Diagnosis Procedure Combination Database, a nationwide inpatient database. Patients hospitalized for HF between January 2010 and March 2018 are included. Propensity score matching and generalized linear models are built to examine the association between improvement in ADL and acute-phase CR initiation, defined as the initiation of CR within two days of admission. Results: Among 306,826 eligible patients, CR is initiated in 45,428 patients (14.8%) within two days of hospital admission. Propensity score matching creates 45,427 pairs. CR initiation within two days of hospital admission is associated with ADL improvement (risk ratio: 1.018; 95% confidence interval: 1.004–1.032), particularly in elderly patients, females, and individuals with low ADL at admission, body mass index of 18.5–24.9 kg/m2, and New York Heart Association class IV. Conclusions: Our analyses highlight the possibility that acute-phase CR initiation may result in short-term improvement in ADL in patients hospitalized for AHF.

Demand for high precision machining of complicated shapes has recently increased with the miniaturization of mechanical and electronic products. Therefore, further development of fine wire electrical discharge machining (EDM) technology using a thin wire electrode has been also requested. However, there might be a limit in improving the machining performance of fine wire EDM using conventional wire only by optimizing discharge pulse conditions and gap control. Therefore, it is essential to develop a new type of thin wire electrode for further improvement of wire EDM performance. In this study, high-zinc-content brass (γ-phase brass) coated steel core wire as a new type wire electrode was trially made to improve the machining stability. In wire EDM, zinc content of wire surface would contribute to rapidly cool down the gap by the evaporation due to its low boiling point. However, the surface of γ-phase brass coated wire tends to become rough in the heat treatment process of the wire. Thus, another type of the γ-phase brass coated wire with smoothed surface was also made by an extra finish drawing. The wire EDM characteristics using these wires were compared with those using conventional brass coated steel wire. Furthermore, the distribution of spark locations during process was evaluated by high-speed observation to investigate the influence of γ-phase brass and the surface roughness of wire. As a result, the cutting speed using the γ-phase brass coated steel wire with smoothed surface is faster than that using conventional wire because of uniform distribution of spark location.

In current mechanical machining technology, it is not easy to form an internal space shape inside a metal workpiece through a small-diameter entrance hole only by removal process. On the other hand, EDM is one of thermal machining methods that removes the material by the high temperature of discharges, and the tool electrode does not contact to the workpiece. The machining force acting on the electrode is very small. Therefore, it is highly expected that internal space shape may be machined if an optimum electrode structure can be designed. This study proposes a new internal space machining method by EDM using a revolution ball electrode consisting of a vertical rotation rod, a tilting rod, and an electrode ball. Experimental results show that the tilting angle between the vertical rotation rod and the tilting one can be changed by the rotation speed, and the electrode ball position can be controlled. Then, machining of some axially-symmetric spacial shapes, such as cylindrical shape and spherical one into a zinc alloy workpiece was succeeded. In addition, machining of internal space shapes by simultaneous two-axis control of the tilting angle and Z coordinate of electrode was possible. Therefore, this method has high possibility to create axially symmetric spatial shapes inside the metal.

In recent years, CVD diamond-coated tungsten carbide (WC-Co) tools have been widely utilized due to their benefits in the machining of non-ferrous alloys and polymer composite materials, especially carbon-fiber-reinforced plastics (CFRPs). The reconditioning of such coated tools is economically attractive due to their high cost and short tool life. The decoating of the remaining diamond film from the used tools and the subsequent surface preparation by wet chemical pretreatment are essential steps for new CVD diamond film formation. Previously, it was shown that reactive ion beam etching (RIBE) could effectively remove CVD diamond films. However, some degree of WC-Co tool substrate damage is expected due to the high ion energy in RIBE and the chemical activity in wet etching. This study addresses the effects of RIBE decoating and surface pretreatment steps on WC-Co tools with a complex shape in terms of the ion-induced surface damage, geometry alteration, and adhesion of a subsequently re-applied CVD diamond film. Moreover, the cutting performance of the tools subjected to the RIBE decoating and repeated film deposition was studied via CFRP cutting tests. It has been shown that the RIBE decoated and recoated tools had a high level of cutting performance comparable to the new tools.

Abstract Background Patients with end-stage kidney disease (ESKD) most commonly complain of gastrointestinal symptoms, such as diarrhea. Diarrhea negatively affects patient quality of life and has miscellaneous etiologies, such as Clostridium difficile-associated diarrhea (CDAD) and ischemic colitis. However, it is sometimes extremely difficult to determine the true etiology given the comorbidities and complications the patients have. A rare cause of diarrhea is ulcerative colitis (UC), which commonly affects the rectum and proximal colon in a continuous fashion. UC with rectal sparing or segmental distribution, although atypical, sometimes leads to misdiagnosis. Herein, we present a case of UC in a patient on hemodialysis with intractable diarrhea; we initially considered that the diarrhea was caused by CDAD and ischemic colitis. Case presentation A 69-year-old man with a history of hypertension, bilateral thalamic hemorrhage, and decreased kidney function was admitted to our hospital because of congestive heart failure. Volume control was impossible due to renal dysfunction and he was started on hemodialysis. Thereafter, he received various antibiotics for bacterial infections. Simultaneously, he experienced continuous watery, and sometimes bloody, diarrhea, which was diagnosed as CDAD owing to a positive stool test for Clostridium difficile toxins. Antibiotic treatment for CDAD did not result in symptom relief. Subsequently, we performed colon biopsy via colonoscopy, and the pathology showed virtually no inflammation with rectal sparing and segmental distributions. These findings favored the presence of ischemic colitis due to arteriosclerosis and ESKD rather than infections. He died of cardiac arrest before the diarrhea was alleviated. Finally, UC was revealed on autopsy as the main cause of the uncontrollable diarrhea. Conclusions Patients with ESKD have a greater risk of developing CDAD and ischemic colitis, which have clinical features that sometimes overlap with those of UC, as in the present case. This case emphasizes the importance of correctly diagnosing the etiology of intractable diarrhea and the fact that other diarrhea etiologies can obscure the existence of inflammatory bowel disease, which should be considered and treated properly when patients on hemodialysis present with intractable diarrhea.

Objective: Type 1 diabetes (T1D) is known to be caused by Th1 cell-dependent autoimmunity. Recently, we reported that TYK2 promoter variant serves as a putative virus-induced diabetes susceptibility gene associated with deteriorated interferon-dependent antiviral response. TYK2 is also related to HIES, that is, Th2 cell-dependent. Therefore, TYK2 promoter variant may be also associated with the pathogenesis of T1D, modulating Th1/Th2 balance. Research Design and Methods: We assessed the association between anti- GAD Ab, IgE levels, and TYK2 promoter variant among 313 T1D patients, 184 T2D patients, and 264 YH controls in the Japanese. Results: T1D patients had elevated IgE (median, 56.7 U/ml; p

In wire electrical discharge machining (wire EDM), debris tends to stagnate around the wire electrode, since the machined kerf is very narrow. Then, secondary discharges often occur and discharges easily concentrate on the same location, which leads to unstable machining performance, such as frequent wire breakage, low machining rate and low shape accuracy. Thus, better exclusion of debris and bubbles from the gap is very important to obtain stable electrical discharges and high machining accuracy. Conventionally, the debris exclusion from the gap has been carried out by jet flushing of working fluid from upper and lower nozzles. However, in the case of conventional nozzle flushing method, a vortex flow area around middle region behind the wire electrode always generates by inclined flows from the upper and lower nozzles. Therefore, much debris generating in the front surface of wire electrode stagnates in the area. In order to improve the wire EDM characteristics, the vortex flow area should be eliminated or reduced, for improvement of the wire EDM characteristics. This study aims to propose new jet flushing methods for smooth debris exclusion from the gap in wire EDM, leading to high-performance wire EDM characteristics. In this paper, a nozzle jet flushing method with a fine insert following behind the wire electrode is newly proposed, considering smooth debris exclusion by utilizing computational fluid dynamics (CFD) analysis, and the effectiveness of the jet flushing method are experimentally investigated.The analysis results clarify that debris exclusion can be greatly improved by the insert nozzle flushing method, since the working fluid flow around the wire electrode is optimally controlled with a reduced stagnation area, resulting in low debris stagnation. It is also confirmed that the wire EDM characteristics can be improved practically by using the insert nozzle flushing method.

In a large-area electron beam (EB) irradiation method developed recently, the large-area EB with high energy density can be obtained without focusing the beam. It can be used for melting and evaporating metal surface instantly. Therefore, highly efficient surface finishing for mold steels can be done by the EB irradiation. It was also clarified that surface functions such as wear resistance and corrosion resistance of mold steels were improved by formation of modified layer on the surface after melting and resolidification of workpiece surface. On the other hand, the workpiece surface was slightly removed by evaporating the surface. Then, control and prediction of modified layer and removal thickness are effective to maintain the surface function. In this study, influence of magnetic property for workpiece on thickness of removal and modified layers in large-area EB irradiation is investigated. Experimental results show that the thickness of removal and modified layers on workpiece with high relative permeability is larger than that with low one. These results suggest that high energy density of EB is irradiated to the workpiece with high relative permeability. Therefore, the analyzed energy density on workpiece surface is calculated by using an electron track analysis. The energy density on workpiece with high relative permeability is larger than that with low one since EB more concentrates on the surface of workpiece with high relative permeability. Variations of removal and modified layer thickness for workpiece with different magnetic property can be precisely predicted by using an unsteady heat conduction analysis with considering EB concentration.

Laser micro-grooving has excellent potential to improve the surface properties of metals. In this study, high-speed micro-grooving of the surfaces of mild steel SS400 and aluminum alloy A1050 was investigated using a single-mode continuous-wave fiber laser with an average power of 200 W. Experiments were conducted at laser beam scanning speeds of 1 to 6 m/s. The incident angle of the laser beam in the plane perpendicular to the scanning axis was varied from 0 to 60°. A relatively deep groove (approximately 30 µm in depth) and a high upheaval (10 µm in height) were formed along the scanning line at an incident angle of 45° on the SS400, whereas only shallow grooves were formed on A1050. The micro-groove formation mechanism was discussed on the basis of high-speed camera observation, groove shapes, and the thermophysical properties of the metal. Asymmetric molten metal flow and solidification around the keyhole are thought to play important roles in micro-groove formation. Although the laser irradiation conditions must be optimized according to the thermophysical properties of the material, angled laser irradiation has the potential to effectively form micro-grooves.

Silver nanowire transparent conductive film is expected as a new material of transparent electrode, because of its superior flexibility and electrical conductivity with transparency at visible wavelength. It is essential to form insulation areas on the silver nanowire transparent conductive film in electronic circuit. Laser beam processing has been widely used for this application, since high efficiency and high quality removal is possible without mechanical contact. On the other hand, laser beam is an electromagnetic wave, and it has unique characteristics such as refraction and polarization. These characteristics have a great influence on laser-material interaction, especially in nanosize materials. However, laser processing characteristics and its mechanism have not yet been clarified. Therefore, polarization indicated by electric and magnetic fields was discussed in this study, and effects of polarization direction on removal characteristics of silver nanowire transparent conductive film by ultrashort pulsed laser with linear polarization were experimentally and numerically investigated. Removal phenomena of silver nanowire transparent conductive film by linear polarization was different from that by circular polarization. Silver nanowires arranged in the parallel direction to polarization plane were preferentially removed. In the case of crossed two silver nanowires, electromagnetic field analysis revealed that electric field intensity of silver nanowire arranged in parallel direction to polarization plane is higher than that in perpendicular direction to polarization. Therefore, silver nanowires were selectively removed depending on the polarization plane of laser beam. Electric field intensities of silver nanowire arranged in not only parallel but also perpendicular direction to polarization plane were enhanced at intersection of silver nanowires, and holes as removal marks become remarkably large at intersections of silver nanowires.

Background: Recently, natural mutation of Tyrosine kinase 2 (Tyk2) gene has been shown to determine susceptibility to murine virus-induced diabetes. In addition, a previous human genome-wide study suggested the type 1 diabetes (T1D) susceptibility region to be 19p13, where the human TYK2 gene is located (19p13.2). Methods: Polymorphisms of TYK2 gene at the promoter region and exons were studied among 331 healthy controls, and 302 patients with T1D and 314 with type 2 diabetes (T2D) in the Japanese. Findings: A TYK2 promoter haplotype with multiple genetic polymorphisms, which are in complete linkage disequilibrium, named TYK2 promoter variant, presenting decreased promoter activity, is associated with an increased risk of not only T1D (odds ratio (OR), 2.4; 95% confidence interval (CI), 1.2 to 4.6; P = 0.01), but also T2D (OR, 2.1; 95% CI, 1.1 to 4.1; P = 0.03). The risk is high in patients with T1D associated with flu-like syndrome at diabetes onset and also those without anti-glutamic acid decarboxylase autoantibody. Interpretation: The TYK2 promoter variant is associated with an overall risk for diabetes, serving a good candidate as a virus-induced diabetes susceptibility gene in humans. Funding: Ministry of Education, Culture, Sports, Science and Technology and of Health, Labor and Welfare of Japan.

Focusing condition such as numerical aperture (N.A.) has a great influence on the creation of molten area and the stable welding process in fusion micro-welding of glass. In this study, a picosecond pulsed laser of 1064 nm in wavelength and 12.5 ps in pulse duration was tightly focused inside a borosilicate glass using objective lenses of numerical apertures 0.45, 0.65, and 0.85 with spherical aberration correction. Influence of numerical aperture on molten area formation was experimentally investigated through analysis of focusing situation in glass, and movement of absorption point, and then molten area characteristics were discussed. It is concluded that N.A. of 0.65 with superior focusing characteristics can form a large and continuous molten area without cracks, which enables achievement of stable joining of glass material by picosecond pulsed laser.

Laser welding of copper is characterized by low and unstable light absorption around 1000 nm wavelength. Combination of high thermal conductivity and low melting point makes it difficult to obtain good welding quality and leads to low energy utilization. To improve efficiency and welding quality, a technique to enhance process stability using 1064 nm wavelength Nd:YAG laser has been proposed, and absorption rate and molten volume in laser micro-welding were discussed. Since the surface state of specimen affects absorption phenomena, effects of surface shape and surface roughness were investigated. Absorption rate and molten volume were increased by creating appropriate concave holes and by controlled surface roughness. Stable micro-welding process with deep penetration and good surface quality was achieved for transitional processing condition between heat conduction and keyhole welding, by enhanced absorption rate.

The purpose of this study is to develop a new type of wire electrode, in which piano wire with very high tensile strength is coated with electrically conductive layer, such as brass or zinc, in order to attain high speed and high precision wire EDM. In this report, using a trial-made thin wire of 50μm in diameter, the optimum thickness and quality of brass layer were experimentally investigated for higher performance fine wire EDM. Furthermore, the influence of the tensile strength of piano wire used as a core wire was discussed. As a result, the coated brass with copper content of 60-70% is effective and the thickness of coated brass is needed to be more than 1.45μm for high removal rate.

A new surface modification for bio-titanium alloy products by electron beam (EB) polishing is proposed. In this EB polishing method, high energy density EB can be irradiated without concentrating the beam. Therefore, large-area EB with a maximum diameter of 60mm can be used for instantaneously melting or evaporating metal surface. Experimental results made it clear that surface characteristics, such as repellency, corrosion resistance and coefficient of friction could be improved simultaneously with the surface smoothing in a few minutes under a proper condition. Therefore, EB polishing method has a possibility of high efficient surface smoothing and surface modification process for bio-titanium alloy.