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Takuya Nikaido,1 Shingo Fukuma,2,3 Takafumi Wakita,4 Miho Sekiguchi,1 Shoji Yabuki,1 Yoshihiro Onishi,5 Shunichi Fukuhara,2,3 Shin-ichi Konno1 On behalf of the profile scoring system for multilateral assessment of social factors in patients with chronic musculoskeletal pain study group 1Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, 2Department of Healthcare Epidemiology, Kyoto University, Graduate School of Medicine and Public Health, Kyoto, 3Center for Innovative Research for Communities and Clinical Excellence (CIRC2LE), Fukushima Medical University, Fukushima, 4Department of Sociology, Kansai University, Osaka, 5Institute for Health Outcomes and Process Evaluation Research (iHope International), Kyoto, Japan Abstract: Chronic pain is a manifestation of interactions among physical, psychological, and social conditions, but the latter two, that is, the nonphysical correlates of chronic pain, are only rarely measured. This study aimed to develop a profile scoring system for assessing the psychosocial situation of patients with chronic musculoskeletal pain. An expert panel chose social and psychological domains considered to be relevant to patients with chronic pain and wrote questions asking about each of those domains. The questionnaire was completed by 252 patients with chronic musculoskeletal pain. Factor analysis was used to select questionnaire items for each domain. Associations and interactions of pain severity and each domain score with pain-related quality of life (PRQOL) were examined using linear regression models. Five domains were chosen: work, family, sleep, mental health, and PRQOL. Then, a total of 17 questions were created for the work, family, and sleep domains. Using the likelihood-ratio test, we found significant interactions with PRQOL in four pairs: severity–family, severity–mental, family–sleep, and work–mental. The association between pain severity and PRQOL was related to each patient’s social and psychological situation. These results suggest that interventions for patients with chronic pain may be personalized to account for each individual’s psychosocial situation. Keywords: chronic musculoskeletal pain, psychosocial factors, family and work environment, pain-related quality of life, profile scoring system

Aims: Natriuretic peptide-based pre-heart failure screening has been proposed in recent guidelines. However, an effective strategy to identify screening targets from the general population, more than half of which are at risk for heart failure or pre-heart failure, has not been well established. This study evaluated the performance of machine learning prediction models for predicting elevated N terminal pro brain natriuretic peptide (NT-proBNP) levels in the US general population., Methods and Results: Individuals aged 20-79 years without cardiovascular disease from the nationally representative National Health and Nutrition Examination Survey 1999-2004 were included. Six prediction models (two conventional regression models and four machine learning models) were trained with the 1999-2002 cohort to predict elevated NT-proBNP levels (>125 pg/mL) using demographic, lifestyle, and commonly measured biochemical data. The model performance was tested using the 2003-2004 cohort. Of the 10 237 individuals, 1510 (14.8%) had NT-proBNP levels >125 pg/mL. The highest area under the receiver operating characteristic curve (AUC) was observed in SuperLearner (AUC [95% CI] = 0.862 [0.847-0.878], P < 0.001 compared with the logistic regression model). The logistic regression model with splines showed a comparable performance (AUC [95% CI] = 0.857 [0.841-0.874], P = 0.08). Age, albumin level, haemoglobin level, sex, estimated glomerular filtration rate, and systolic blood pressure were the most important predictors. We found a similar prediction performance even after excluding socio-economic information (marital status, family income, and education status) from the prediction models. When we used different thresholds for elevated NT-proBNP, the AUC (95% CI) in the SuperLearner models 0.846 (0.830-0.861) for NT-proBNP > 100 pg/mL and 0.866 (0.849-0.884) for NT-proBNP > 150 pg/mL., Conclusions: Using nationally representative data from the United States, both logistic regression and machine learning models well predicted elevated NT-proBNP. The predictive performance remained consistent even when the models incorporated only commonly available variables in daily clinical practice. Prediction models using regularly measured information would serve as a potentially useful tools for clinicians to effectively identify targets of natriuretic-peptide screening., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Patients with low-to-normal body mass index (BMI; < 25.0 kg/m 2 ) were underrepresented in major randomized controlled trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors for type 2 diabetes. The present study aims to investigate the effectiveness of SGLT2 inhibitors for cardiovascular outcomes among patients with type 2 diabetes and low-to-normal BMI, using finer stratification than previous trials., Methods: This cohort study with a target trial emulation framework was conducted using insurance claims and health screening records of more than 30 million working-age citizens in Japan acquired from April 1, 2015 to March 31, 2022. 139,783 new users of SGLT2 inhibitors matched to 139,783 users of dipeptidyl protease (DPP) 4 inhibitors with stratification by BMI category (< 20.0, 20.0-22.4, 22.5-24.9, 25.0-29.9, 30.0-34.9, and 35.0 ≤ kg/m 2 ). The primary outcome was a composite of all-cause death, myocardial infarction, stroke, or heart failure. Secondary outcomes were the components of the primary outcome. Cox proportional hazard models were used to compare SGLT2 inhibitors with DPP4 inhibitors in the whole population and subgroups defined by the BMI category., Results: Among participants, 17.3% (n = 48,377) were female and 31.0% (n = 86,536) had low-to-normal BMI (< 20.0 kg/m 2 , 1.9% [n = 5,350]; 20.0-22.4 kg/m 2 , 8.5% [n = 23,818]; and 22.5-24.9 kg/m 2 , 20.5% [n = 57,368]). Over a median follow-up of 24 months, the primary outcome occurred in 2.9% (n = 8,165) of participants. SGLT2 inhibitors were associated with a decreased incidence of the primary outcome in the whole population (HR [95%CI] = 0.92 [0.89 to 0.96]), but not in patients with low-to-normal BMI (< 20.0 kg/m 2 , HR [95%CI] = 1.08 [0.80 to 1.46]; 20.0-22.4 kg/m 2 , HR [95%CI] = 1.04 [0.90 to 1.20]; and 22.5-24.9 kg/m 2 , HR [95%CI] = 0.92 [0.84 to 1.01])., Conclusions: The protective effect of SGLT2 inhibitors on cardiovascular events among patients with type 2 diabetes appeared to decrease with lower BMI and was not significant among patients with low-to-normal BMI (< 25.0 kg/m2). These findings suggest the importance of considering BMI when initiating SGLT2 inhibitors., (© 2024. The Author(s).)

Early detection of cognitive decline is essential for timely intervention and effective management of age-related impairments. We monitored repetitive reaction times to a simple task on senior-friendly tablet computers among 72 functionally independent older adults, with a mean age of 82, ranging up to 100 years, within natural settings over two years. Functional principal component analyses revealed a consistent decrease in reaction time in line with their task experience among those without subjective cognitive decline. Conversely, individuals reporting subjective cognitive decline showed no consistent trend and exhibited wide variability over time. These distinctive reaction time trajectories in very old adults suggest the potential for monitoring as a non-invasive, convenient method for early detection of cognitive impairment., (© 2024. The Author(s).)

Although community-acquired acute kidney injury (CA-AKI) represents a significant subset of all AKI incidence, evidence is limited due to the lack of comprehensive data prior to diagnosis. Here, we examined the risk of drug use for CA-AKI by using exhaustive pre-diagnostic prescription data. We included 78,754 working-age healthy individuals who underwent an annual health checkup program. We conducted a cohort study to assess the association between prevalent drug use and subsequent CA-AKI incidence using the Cox proportional hazard model. Subsequently, we conducted a case-crossover study to compare the new drug use in the case period directly before the CA-AKI incidence (- 3 to 0 months) with that in the control period far before the CA-AKI incidence (- 15 to - 12 months and - 9 to - 6 months) using the conditional Poisson regression model. The prevalent use of renin-angiotensin-aldosterone system (RAAS) inhibitors was associated with an increased CA-AKI incidence, but the new use was not. The new use of diuretics, anti-infectious drugs, and contrast medium was also associated with an increased CA-AKI incidence. These results suggest we need to pay attention for the incidence of AKI among the general population taking those common drugs., (© 2024. The Author(s).)

Aims: In patients with advanced heart failure requiring dobutamine infusion, it is usually recommended to initiate beta-blockers after weaning from dobutamine. However, beta-blockers are sometimes initiated under dobutamine infusion in a real-world scenario. The association between such early beta-blocker initiation with clinical outcomes is unknown. Therefore, this study investigates the association between initiating beta-blockers under dobutamine infusion and survival outcomes., Methods and Results: This observational study with a multicentre inpatient-care database emulated a pragmatic randomized controlled trial (RCT) of the beta-blocker initiation strategy. First, 1151 patients on dobutamine and not on beta-blockers on the day of heart failure admission (Day 0) were identified. Among 1095 who met eligibility criteria, patients who were eventually initiated beta-blockers under dobutamine infusion by Day 7 (early initiation strategy) were 1:1 matched to those who were not initiated (conservative strategy). The methods of cloning, censoring, and weighting were applied to emulate the target trial. Patients were followed up for up to 30 days. The primary outcome was all-cause death. Among 780 matched patients (median age, 81 years), the adjusted hazard ratio was 1.11 (95% confidence interval 0.75-1.64, P = 0.59) for the early initiation strategy. The estimated 30-day all-cause mortalities in the early initiation strategy and the conservative strategy were 19.3% (10.6-30.7) and 16.2% (9.2-25.3), respectively. The results were consistent when we used different days to determine strategies (i.e. 5 and 9) instead of 7 days., Conclusion: The present observational study emulating a pragmatic RCT found no positive or negative association between beta-blocker initiation under dobutamine infusion and overall survival., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Healthcare Workers (HCWs) are susceptible to hepatitis B virus (HBV) infection and are advised to receive vaccination. However, vaccination rates remain low in developing countries. There is little data concerning Hepatitis B (HepB) vaccination and information regarding HBV knowledge among HCWs in Cambodia. This study aimed to evaluate the knowledge of HBV infection, HepB vaccine, and vaccination status with its associated factors among HCWs in Cambodia., Methods: A Cross-sectional study was conducted among HCWs in Kampot and Kep Provinces, Cambodia, from September to October 2023 using a questionnaire survey. A total of 261 HCWs were recruited from 1,309 individuals working in all 83 health facilities using systematic random sampling methods. Statistical analyses including the χ 2 -test and multivariate logistic regression were conducted to identify factors associated with vaccination among the participants., Results: Among 259 participants, 62.9% showed good knowledge of HBV infection, and 65.6% demonstrated good knowledge of the HepB vaccine. 59.8% of the participants had received the HepB vaccine, while 40.2% remained unvaccinated. Analysis showed that HCWs working at Provincial Health Department/Operational Districts and Provincial Referral Hospital/Referral Hospitals were more likely to be vaccinated compared to those at Health Centers [AOR = 6.5; CI = 1.1-39.5, p = 0.0403; AOR = 2.8, CI = 1.0-7.8, p = 0.0412], respectively. Furthermore, individuals with good knowledge of the HBV infection and vaccine were more likely to receive the vaccine compared to those with inadequate knowledge [AOR = 6.3; CI = 3.3-12.3, p < .0001; AOR = 3.7, CI = 1.9-7.4, p = 0.0001], respectively. Within the unvaccinated HCWs, 32% reported high vaccine costs as a barrier, 33% mentioned workplace vaccine was not for adults, and 59% reported insufficient education on adult HepB vaccination., Conclusions: The HepB vaccination coverage among HCWs is at 59.8%, which is below the World Health Organization's (WHO) recommendation rate of 100%. Knowledge of HBV infection and HepB vaccine were good predictive factors for vaccination. The high cost of vaccine, workplace vaccine not for adults, and insufficient education on adult vaccination were found as barriers to vaccination. This study underscores the importance of providing education to HCWs on HBV infection and the HepB vaccine. Furthermore, it highlights the need for a policy that ensures free vaccination for HCWs., (© 2024. The Author(s).)

Importance: The global burden of chronic kidney disease (CKD) is substantial and potentially leads to higher health care resource use., Objective: To examine the association between early-stage CKD and health care spending and its changes over time in the general population., Design, Setting, and Participants: Cohort study using nationwide health checkup and medical claims data in Japan. Participants included individuals aged 30 to 70 years with estimated glomerular filtration rates (eGFR) of 30 mL/min/1.73 m2 or greater at the baseline screening in 2014. Data analyses were conducted from April 2021 to October 2023., Exposure: The CKD stages at baseline, defined by the eGFR and proteinuria, were as follows: eGFR of 60 mL/min/1.73 m2 or greater without proteinuria, eGFR of 60 mL/min/1.73 m2 or greater with proteinuria, eGFR of 30 to 59 mL/min/1.73 m2 without proteinuria, and eGFR of 30 to 59 mL/min/1.73 m2 with proteinuria., Main Outcome and Measures: The primary outcome was excess health care spending, defined as the absolute difference in health care spending according to the baseline CKD stages (reference group: eGFR ≥60 mL/min/1.73 m2 without proteinuria) in the baseline year (2014) and in the following 5 years (2015 to 2019)., Results: Of the 79 988 participants who underwent a health checkup (mean [SD] age, 47.0 [9.4] years; 22 027 [27.5%] female), 2899 (3.6%) had an eGFR of 60 mL/min/1.73 m2 or greater with proteinuria, 1116 (1.4%) had an eGFR of 30 to 59 mL/min/1.73 m2 without proteinuria, and 253 (0.3%) had an eGFR of 30 to 59 mL/min/1.73 m2 with proteinuria. At baseline, the presence of proteinuria and an eGFR less than 60 mL/min/1.73 m2 were associated with greater excess health care spending (adjusted difference, $178; 99% CI, $6-$350 for proteinuria; $608; 99% CI, $233-$983 for an eGFR of 30-59 mL/min/1.73 m2; and $1254; 99% CI, $134-$2373 for their combination). The study consistently found excess health care spending over the following 5 examined years., Conclusions and Relevance: In this cohort study of nationwide health checkup and medical claims data in Japan, early-stage CKD was associated with excess health care spending over the 5 examined years, and the association was more pronounced with a more advanced disease stage.

Finding the ideal balance between efficacy and safety of immunosuppression is challenging, particularly in cases of severe TAFRO syndrome. We herein report a 60-year-old man diagnosed with grade 5 TAFRO syndrome mimicking hepatorenal syndrome that was successfully treated by glucocorticoid, tocilizumab, and cyclosporin despite virus infection. Furthermore, by examining 14 peer-reviewed remission cases, we revealed that the recovery periods among inflammation, renal dysfunction, and thrombocytopenia were quite different, with recovery from thrombocytopenia notably slow. All patients requiring dialysis were successfully withdrawn from dialysis, and the reversibility from kidney injury was good. This clinical information will help clinicians plan treatments and tailor the intensity of immunosuppression.

Objectives: We aimed to investigate the association between repetitive proteinuria and cardiovascular events among the middle-aged and older general Japanese population., Design: Retrospective cohort study., Setting: We used repeated health screening results and medical claim data from one of the largest health insurers in Japan., Participants: Among the middle-aged and older participants (40-74 years, n=179 840), 90 752 were excluded for undergoing health screening fewer than two times and 344 were excluded for having a history of cardiovascular diseases; 88 744 who underwent kidney function screenings at least two times (from April 2011 to March 2015) were included in the analysis. Based on dipstick proteinuria test results, the participants were divided into 'Repetitively-positive' (positive two times or more (positive proteinuria was defined as≥1+)), 'Once-positive' and 'All-negative' groups., Primary and Secondary Outcome Measures: The primary outcome of major cardiovascular events from baseline screening to June 2021 was hospitalisation or death due to acute myocardial infarction (AMI), cerebrovascular diseases, heart failure (HF) or peripheral vascular diseases (PVDs). The association between proteinuria and major cardiovascular events was assessed using a Cox proportional hazards model., Results: Of the 88 744 participants, 8775 (9.9%) and 5498 (6.2%) had Once-positive and Repetitively-positive proteinuria, respectively. During the follow-up period of 402 799 person-years (median 5.25 years), 660 cardiovascular events were observed, with an incidence of 1.64 per 1000 person-years (95% CI 1.52 to 1.77). Despite adjusting for major cardiovascular risk factors, we observed a high incidence of cardiovascular events in the Repetitively-positive (HR 2.08, 95% CI 1.67 to 2.59) and Once-positive groups (HR 1.36, 95% CI 1.07 to 1.72). We found similar associations for AMI, cerebrovascular disease, HF and PVD., Conclusions: Proteinuria is often repeatedly detected during annual renal screening in the general population. Repetitive proteinuria is a risk factor for major cardiovascular events., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale & Objective: Despite α-blockers' use for hypertension as add-on therapy in patients treated with hemodialysis, scant information is available on their association, particularly with safety, in these patients., Study Design: Prospective cohort study., Setting & Participants: patients treated with hemodialysis and receiving antihypertensive agents in the Japan Dialysis Outcomes and Practice Patterns Study, phases 4-6, were analyzed., Exposure: Primary exposure was the prescription of α-blocking antihypertensive agents at baseline., Outcomes: Incident fractures, falls, and all-cause mortality., Analytical Approach: Multivariable Cox and modified Poisson regression analysis., Results: Of 5,149 patients treated with hemodialysis (mean age, 65 years; 68% men) receiving antihypertensive drugs, 717 (14%) received α-blocking agents. During a mean follow-up period of 2.0 years, 247 fractures, 525 falls, and 498 deaths occurred. Multivariable analysis showed no significant association of α-blocker use and increased risk of fractures (hazard ratio [HR], 0.92 [95% confidence interval {CI}, 0.61-1.38]), falls (HR, 0.94 [95% CI, 0.74-1.20]), or all-cause deaths (HR, 0.87 [95% CI, 0.64-1.20]) compared with α-blocker nonuse. α-Blocker use was, however, significantly associated with a decreased risk of all-cause mortality in the subgroup analysis, for example, patients who were older (HR, 0.71 [95% CI, 0.51-0.99]), were women (HR, 0.68 [95% CI, 0.48-0.95]), or reported a history of cardiovascular disease (HR, 0.67 [95% CI, 0.48-0.95]) or a predialysis blood pressure of ≥140 mm Hg (HR, 0.69 [95% CI, 0.49-0.98])., Limitations: Selection bias cannot be ruled out given the prevalent user analysis., Conclusions: No significant association between α-blocker use and the risk of worse safety-related outcomes was seen, indicating that clinicians may safely prescribe α-blockers to patients receiving hemodialysis who require blood pressure lowering., Plain-Language Summary: α-Blockers have been generally reserved for use as add-on therapy for resistant or refractory hypertension. However, little is known about the safety of α-blockers in patients treated by hemodialysis. We analyzed 5,149 patients receiving hemodialysis in Japan who were receiving antihypertensive drugs from the Japan Dialysis Outcomes and Practice Patterns Study. The results showed no significant increase in the risk of fractures, falls, or deaths for patients using α-blockers compared with those who did not, suggesting that α-blockers may be safely prescribed for patients receiving hemodialysis who need to lower their blood pressure., (© 2023 The Authors.)

Background and Objectives: The relationship between social isolation/loneliness and oral health is unclear. This study investigated the association between social isolation/loneliness and tooth loss in older Japanese adults., Research Design and Methods: This was a cross-sectional study of a population-based cohort (the Sukagawa Study); 5,490 cohort study participants aged ≥75 years and who were independent answered a self-administered questionnaire in 2018. Social isolation was defined based on the 6-item Japanese version of the Lubben Social Network Scale. Loneliness was measured by the 3-item Japanese version of the University of California, Los Angeles (UCLA) Loneliness Scale version 3. The primary outcome was tooth loss, defined as having fewer than 20 teeth. The secondary outcomes were decreased toothbrushing frequency and diminished ability to chew food. Prevalence ratios (PRs) were estimated using a modified Poisson regression analysis in 2 models-Model 1, which adjusted for age, gender, smoking status, alcohol consumption, low annual income, and short education period, and Model 2, which added history of depression, history of diabetes mellitus, history of stroke, and cognitive impairment to Model 1., Results: The primary analysis included 4,645 participants. Adjusted PRs of social isolation and loneliness for tooth loss (Model 1) were 0.97 (95% confidence interval [CI] 0.92-1.01) and 1.06 (95% CI 1.01-1.12), respectively; those for decreased toothbrushing frequency were 1.13 (95% CI 0.95-1.36) and 1.56 (95% CI 1.26-1.92), respectively; and those for chewing difficulty were 1.61 (95% CI 1.06-2.43) and 2.94 (95% CI 1.91-4.53), respectively. The adjusted PRs in Model 2 demonstrated results similar to that of Model 1., Discussion and Implications: Loneliness is associated with tooth loss among older adults, whereas social isolation is not. Our findings can inform plans for policymakers, professionals, and organizations to identify lonely older adults and provide social prescriptions to improve their access to oral health care services., Competing Interests: None., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Japan has conducted a nationwide annual health check-up program since 2008, focusing on metabolic syndrome and subsequent health guidance in individuals at high risk for cardiovascular disease. However, the adherence rate to health guidance invitations was assumed to be low in previous reports. Therefore, this study aimed to characterize adherence patterns in the program and identify major predictors of adherence to health guidance invitations., Methods: We studied 186,316 adults (aged 40-74 years) who were included in a nationwide employer-sponsored insurer's database in Japan at the beginning of the fiscal year 2017. We first described adherence to health check-ups, the proportion of individuals with high cardiovascular risk, and adherence to health guidance invitations. Predictors of adherence to the invitation were then identified among eligible high-risk individuals., Results: In 2017, 71.7% of the study population (n = 133,573) underwent health check-ups, among whom 23.2% (n = 30,979) were invited for health guidance because of their high cardiovascular risk. Among those individuals, 35.2% (n = 10,614) received health guidance. Predictors of improved adherence to health guidance invitation were older age, more concerning blood pressure or laboratory data results, and self-reported motivation for a lifestyle change., Conclusion: Though 70% of eligible adults attended Japan's annual cardiovascular risk check-ups, only 35% of individuals with high cardiovascular risk adhered to health guidance invitations. Future policy reforms to improve adherence to this program should target younger individuals and those with mild stages of hypertension, diabetes, or dyslipidemia., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mori et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To describe the prevalence of multimorbidity and its associations with clinical outcomes across age groups., Design: Retrospective cohort study using nationwide medical claims data., Setting: Carried out in Japan between April 2014 and March 2019., Participants: N=246 671 Japanese individuals aged 20-74 enrolled in the health insurance were included into the baseline data set for fiscal year (FY) 2014. Of those, N=181 959 individuals were included into the cohort data set spanning FY2014-FY2018., Exposures: Multimorbidity was defined as having ≥2 of 15 chronic conditions according to the International Classification of Diseases 10th Revision codes of the Charlson Comorbidity Index., Primary and Secondary Outcomes: Primary outcome: the standardised prevalence of multimorbidity across age groups was evaluated using data from FY2014 and extrapolated to the Japanese total population., Secondary Outcome: hospitalisation or death events were traced by month using medical claims data and insurer enrolment data. Associations between multimorbidity and 5-year hospitalisation and/or death events across age groups were analysed using a Cox regression model., Results: The standardised prevalence rate of multimorbidity in the nationwide Japanese total population was estimated to 26.1%. The prevalence rate with age was increased, approximately 5% (ages 20-29), 10% (30-39), 20% (40-49), 30% (50-59), 50% (60-69) and 60% (70-74). Compared with individuals aged 20-39 without multimorbidity, those with multimorbidity had a higher incidence of clinical events in any age group (HR=2.43 (95% CI 2.30 to 2.56) in ages 20-39, HR=2.55 (95% CI 2.47 to 2.63) in ages 40-59 and HR=3.41 (95% CI 3.23 to 3.53) in ages ≥60). The difference in the incidence of clinical events between multimorbidity and no multimorbidity was larger than that between age groups., Conclusions: Multimorbidity is already prevalent in the middle-aged generation and is associated with poor clinical outcomes. These findings underscore the significance of multimorbidity and highlight the urgent need for preventive intervention at the public healthcare level., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The health burden due to depression is ever increasing in the world. Prevention is a key to reducing this burden. Guided internet cognitive-behavioural therapies (iCBT) appear promising but there is room for improvement because we do not yet know which of various iCBT skills are more efficacious than others, and for whom. In addition, there has been no platform for iCBT that can accommodate ongoing evolution of internet technologies., Methods and Analysis: Based on our decade-long experiences in developing smartphone CBT apps and examining them in randomised controlled trials, we have developed the Resilience Training App Version 2. This app now covers five CBT skills: cognitive restructuring, behavioural activation, problem-solving, assertion training and behaviour therapy for insomnia. The current study is designed as a master protocol including four 2×2 factorial trials using this app (1) to elucidate specific efficacies of each CBT skill, (2) to identify participants' characteristics that enable matching between skills and individuals, and (3) to allow future inclusion of new skills. We will recruit 3520 participants with subthreshold depression and ca 1700 participants without subthreshold depression, to examine the short-term efficacies of CBT skills to reduce depressive symptoms in the former and to explore the long-term efficacies in preventing depression in the total sample. The primary outcome for the short-term efficacies is the change in depressive symptoms as measured with the Patient Health Questionnaire-9 at week 6, and that for the long-term efficacies is the incidence of major depressive episodes as assessed by the computerised Composite International Diagnostic Interview by week 50., Ethics and Dissemination: The trial has been approved by the Ethics Committee of Kyoto University Graduate School of Medicine (C1556)., Trial Registration Number: UMIN000047124., Competing Interests: Competing interests: TAF, MH and TA jointly possess intellectual properties of the Resilience Training App. TAF reports personal fees from Boehringer-Ingelheim, DT Axis, Kyoto University Original, Shionogi and SONY, and a grant from Shionogi, outside the submitted work; In addition, TAF has patents 2020-548587 and 2022-082495 pending, and intellectual properties for Kokoro-app licensed to Mitsubishi-Tanabe. AT received lecture fees from Sumitomo Dainippon Pharma, Eisai, Janssen Pharmaceutical, Meiji-Seika Pharma, Mitsubishi Tanabe Pharma, Otsuka, and Takeda Pharmaceutical. MS reports personal fee from SONY outside the submitted work. TA has received lecture fees from Chugai, Daiichi-Sankyo, Dainippon-Sumitomo, Eizai, Janssen, Kyowa, Lilly, MSD, Meiji-Seika Pharma, Mochida, Nipro, Nihon-Zoki, Otsuka, Pfizer, Takeda and Viatris; and royalties from Igaku-shoin, outside the submitted work. TA has patents (2019-01749 and 2020-135195&2022-069057) pending. NKa reports personal fees from Junpukai Foundation, Riken Institute, JAXA, Sekisui Chemical Co and SB@Work, outside the submitted work; and Department of Digital Mental Health is an endowment department, supported with an unrestricted grant from 15 enterprises (https://dmh.m.u-tokyo.ac.jp/c). TN reports personal fees from Pfizer, MSD, Ohtsuka, Chuga, Dentsu, Takeda, Janssen, Boehringer Ingelheim, Eli Lilly, Mitsubishi Tanabe, Novartis, Allergan, Maruho, Novo Nordisk, TOA EIYO; and research grants from I&H Co, Cocokarafine Group Co and Konica Minolta, all outside the submitted work. HN received a research fund from GlaxoSmithKline and consulting fees from Kyowa Kirin, GlaxoSmithKline, Ono Pharmaceutical, Sony, Terumo, outside the submitted work. JMSW reports research funding from Boehringer-Ingelheim, GSK, Intercept, UCB, all outside the current work. All the other coauthors declare no conflicts of interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: The preventive effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors for new-onset diabetes was investigated in secondary analyses of several randomized controlled trials (RCTs). However, the results were inconsistent., Objective: This work aimed to synthesize available evidence and evaluate whether SGLT2 inhibitors are effective in preventing new-onset diabetes., Methods: In this systematic review and meta-analysis of RCTs, MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched through February 11, 2022. Two independent authors screened the search results and extracted summary data from eligible RCTs (including original and post hoc analyses) comparing SGLT2 inhibitors and placebo for the risk of new-onset diabetes among adults with prediabetes. Meta-analysis was conducted using random-effects models to calculate risk ratios and 95% CIs., Results: We included 4 RCTs with 5655 participants who had prediabetes. Based on the random-effects meta-analysis, SGLT2 inhibitors were significantly associated with a lower risk of new-onset diabetes (relative risk, 0.79; 95% CI, 0.68-0.93). The relative risks of new-onset diabetes in dapagliflozin and empagliflozin were 0.68 (95% CI, 0.52-0.89) and 0.87 (95% CI, 0.72-1.04), respectively (P-for-heterogeneity = .14). The frequency of severe hypoglycemia was not elevated in the SGLT2 inhibitors group compared to the placebo group., Conclusion: In this meta-analysis, SGLT2 inhibitors were associated with a reduced risk of new-onset type 2 diabetes among adults with prediabetes and heart failure or chronic kidney disease. These findings indicate the potential usefulness of SGLT2 inhibitors in preventing diabetes among high-risk populations with prediabetes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Increases in obesity and cardiovascular diseases contribute to rapidly growing healthcare expenditures in many countries. However, little is known about whether the population-level health guidance intervention for obesity and cardiovascular risk factors is associated with reduced healthcare utilisation and spending. The aim of this study was to investigate the effect of population-level health guidance intervention introduced nationally in Japan on healthcare utilisation and spending., Design: Retrospective cohort study, using a quasiexperimental regression discontinuity design., Setting: Japan's nationwide employment-based health insurers., Participants: Participants in the national health screening programme (from January 2014 to December 2014) aged 40-74 years., Predictors: Assignment to health guidance intervention (counselling on healthy lifestyles, and referral to physicians as needed) determined primarily on whether the individual's waist circumference was above or below the cut-off value in addition to having at least one cardiovascular risk factor., Primary and Secondary Outcome Measures: Healthcare utilisation (the number of outpatient visits days, any medication use and any hospitalisation use) and spending (total medical expenditure, outpatient medical expenditure and inpatient medical expenditure) within 3 years of the intervention., Results: A total of 51 213 individuals within the bandwidth (±6 cm of waist circumference from the cut-off) out of 113 302 screening participants (median age 50.0 years, 11.9% woman) were analysed. We found that the assignment to the national health guidance intervention was associated with fewer outpatient visit days (-1.3 days; 95% CI, -11.4 to -0.5 days; p=0.03). We found no evidence that the assignment to the health guidance intervention was associated with changes in medication or hospitalisation use, or healthcare spending., Conclusion: Among working-age, male-focused Japanese from a health insurer of companies of civil engineering and construction, the national health guidance intervention might be associated with a decline in outpatient visits, with no change in medication/hospitalisation use or healthcare spending., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We aimed to develop and externally validate a novel machine learning model that can classify CT image findings as positive or negative for SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR)., Methods: We used 2,928 images from a wide variety of case-control type data sources for the development and internal validation of the machine learning model. A total of 633 COVID-19 cases and 2,295 non-COVID-19 cases were included in the study. We randomly divided cases into training and tuning sets at a ratio of 8:2. For external validation, we used 893 images from 740 consecutive patients at 11 acute care hospitals suspected of having COVID-19 at the time of diagnosis. The dataset included 343 COVID-19 patients. The reference standard was RT-PCR., Results: In external validation, the sensitivity and specificity of the model were 0.869 and 0.432, at the low-level cutoff, 0.724 and 0.721, at the high-level cutoff. Area under the receiver operating characteristic was 0.76., Conclusions: Our machine learning model exhibited a high sensitivity in external validation datasets and may assist physicians to rule out COVID-19 diagnosis in a timely manner at emergency departments. Further studies are warranted to improve model specificity., Competing Interests: All authors have completed the ICMJE uniform disclosure form. Yoshiro Kitamura and Tsubasa Goto are employees of Fujifilm Corporation. Shoji Kido is an endowed chair funded by Fujifilm Corporation. Tomohisa Baba, Tomohiro Handa, Toyohiro Hirai, Noriyuki Tomiyama, Takashi Ogura, and Kiminobu Tanizawa received research grants from FUJIFILM Corporation. Tomohiro Handa is an employee of the Collaborative Research Laboratory funded by Teijin Pharma Co., Ltd., (© 2022 Society for Clinical Epidemiology.)

Objectives: Trajectories of estimated glomerular filtration rate (eGFR) decline vary highly among patients with chronic kidney disease (CKD). It is clinically important to identify patients who have high risk for eGFR decline. We aimed to identify clusters of patients with extremely rapid eGFR decline and develop a prediction model using a machine learning approach., Design: Retrospective single-centre cohort study., Settings: Tertiary referral university hospital in Toyoake city, Japan., Participants: A total of 5657 patients with CKD with baseline eGFR of 30 mL/min/1.73 m 2 and eGFR decline of ≥30% within 2 years., Primary Outcome: Our main outcome was extremely rapid eGFR decline. To study-complicated eGFR behaviours, we first applied a variation of group-based trajectory model, which can find trajectory clusters according to the slope of eGFR decline. Our model identified high-level trajectory groups according to baseline eGFR values and simultaneous trajectory clusters. For each group, we developed prediction models that classified the steepest eGFR decline, defined as extremely rapid eGFR decline compared with others in the same group, where we used the random forest algorithm with clinical parameters., Results: Our clustering model first identified three high-level groups according to the baseline eGFR (G1, high GFR, 99.7±19.0; G2, intermediate GFR, 62.9±10.3 and G3, low GFR, 43.7±7.8); our model simultaneously found three eGFR trajectory clusters for each group, resulting in nine clusters with different slopes of eGFR decline. The areas under the curve for classifying the extremely rapid eGFR declines in the G1, G2 and G3 groups were 0.69 (95% CI, 0.63 to 0.76), 0.71 (95% CI 0.69 to 0.74) and 0.79 (95% CI 0.75 to 0.83), respectively. The random forest model identified haemoglobin, albumin and C reactive protein as important characteristics., Conclusions: The random forest model could be useful in identifying patients with extremely rapid eGFR decline., Trial Registration: UMIN 000037476; This study was registered with the UMIN Clinical Trials Registry., Competing Interests: Competing interests: Yes, there are competing interests for one or more authors and I have provided a Competing Interests statement in my manuscript and in the box below., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: An inappropriately low frequency of healthcare utilization has been reported to be associated with poor control of chronic diseases, accelerating healthcare disparities. However, the evidence is limited regarding the association between no healthcare utilization and mortality., Objectives: To examine whether individuals without healthcare utilization have the increased risks of mortality among the US general population., Design: Prospective cohort study PARTICIPANTS: Adults aged ≥ 20 years (n = 39,067) in the National Health and Nutrition Examination Survey (NHANES)1999-2014 linked to national mortality data through December 2015., Main Measures: The exposure was the number of visits to healthcare providers during the past year (healthcare utilization): none, 1-3 times (referent), 4-9 times, or ≥ 10 times. Cox hazard regression models were employed to estimate the adjusted hazard ratios (aHR) of all-cause, cardiovascular, and cancer mortality adjusting for socio-demographic characteristics and comorbidities., Key Results: During a median follow-up of 7.4 years, participants without visit over the past year showed higher risks of all-cause mortality (aHR [95% CI] = 1.16 [1.04-1.30]) and cardiovascular mortality (aHR [95% CI] = 1.62 [1.28-2.05]) than those who visited the office 1-3 times. We found no evidence of the association between no visit and cancer mortality. The association between no providers' office visit and all-cause mortality was stronger among males (aHR [95% CI] = 1.22 [1.06-1.40]) than females (aHR [95% CI] = 0.97 [0.79-1.19]; p-for-interaction = 0.01) and among uninsured individuals (aHR [95% CI] = 1.22 [0.98-1.51]) than insured individuals (aHR [95% CI] = 1.09 [0.95-1.25]; p-for-interaction = 0.04)., Conclusion: No providers' office visit over a year was associated with increased risks of all-cause and cardiovascular mortality. Further investigations are warranted to identify the underlying reasons for the elevated mortality risks due to no healthcare utilization., (© 2021. Society of General Internal Medicine.)

Background: We developed and validated a machine learning diagnostic model for the novel coronavirus (COVID-19) disease, integrating artificial-intelligence-based computed tomography (CT) imaging and clinical features., Methods: We conducted a retrospective cohort study in 11 Japanese tertiary care facilities that treated COVID-19 patients. Participants were tested using both real-time reverse transcription polymerase chain reaction (RT-PCR) and chest CTs between January 1 and May 30, 2020. We chronologically split the dataset in each hospital into training and test sets, containing patients in a 7:3 ratio. A Light Gradient Boosting Machine model was used for the analysis., Results: A total of 703 patients were included, and two models-the full model and the A-blood model-were developed for their diagnosis. The A-blood model included eight variables (the Ali-M3 confidence, along with seven clinical features of blood counts and biochemistry markers). The areas under the receiver-operator curve of both models [0.91, 95% confidence interval (CI): 0.86 to 0.95 for the full model and 0.90, 95% CI: 0.86 to 0.94 for the A-blood model] were better than that of the Ali-M3 confidence (0.78, 95% CI: 0.71 to 0.83) in the test set., Conclusions: The A-blood model, a COVID-19 diagnostic model developed in this study, combines machine-learning and CT evaluation with blood test data and performs better than the Ali-M3 framework existing for this purpose. This would significantly aid physicians in making a quicker diagnosis of COVID-19., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE unified disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-21-5571/coif). Yuki Kataoka serves as an unpaid editorial board member of Annals of Translational Medicine from July 2020 to June 2022. Yuki Kataoka, Yuya Kimura, TI, YM, JM, JK, KT, HF, TH, AK, FH, SI, SF report that this study was partially supported by Kyoto University managing fund for English editing; the article processing fee was supported by the Scientific Research Works Peer Support Group (SRWS-PSG); M3 Inc. and Clinical Porter provided free Ali-M3 analysis and data storage. TI also reports that the analysis of the CT by Ali-M3 was carried out by Nobori on behalf of M3. M3 and Nobori did not know the patients’ data including the result of RT-PCR. JM also reports that receiving a lecture fee from M3 Inc. The other author has no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Purpose: The global burden of kidney failure is increasing, but the treatment of kidney failure varies widely between patients, between dialysis facilities and over time. The Alliance for Quality Assessment in Healthcare-Dialysis (AQuAH-D) aims to conduct efficient and timely cohort studies on associations between those variations and clinical and patient-reported outcomes., Participants: Included are outpatients aged 20 years old or older who are undergoing haemodialysis and have consented to participate. A total of 2895 patients were enrolled from 25 facilities in Japan between August 2018 and July 2020 and are to be followed until 31 December 2026. Chart review and annual questionnaires are used to collect data on patient characteristics and on outcomes including quality of life. Data on medications, haemodialysis prescriptions and blood tests are obtained from existing electronic records. Data are collected retrospectively from 1 January 2017 to patient enrolment, and prospectively from patient enrolment until the end of December 2026., Findings to Date: To date, the mean age is 68.3 (SD 12.2) years and 35.2% are female. The most common cause of kidney failure is diabetic nephropathy (37.4%). In January 2020, the facilities' median weekly doses of erythropoietin stimulating agent (ESA) and of intravenous vitamin D ranged from 1846 to 9692 IU (epoetin alfa equivalent) and 0.78 to 2.25 µg (calcitriol equivalent), respectively. The facilities' percentages of patients to whom calcimimetics are prescribed varied from 19% to 79%. During the retrospective period (averaging 1.85 years per participant), the incidence rates of any hospitalisation and of hospitalisation due to cardiovascular disease were 67.2 and 12.0 per 100 person-years, respectively., Future Plans: AQuAH-D data will be updated every 6 months and will be available for studies addressing a wide range of research questions, using the advantages of granular data and quality-of-life measurement of ageing patients on haemodialysis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Tertiary lymphoid tissues (TLTs) are ectopic lymphoid tissues found in chronically inflamed organs. Although studies have documented TLT formation in transplanted kidneys, the clinical relevance of these TLTs remains controversial. We examined the effects of TLTs on future graft function using our histologic TLT maturity stages and the association between TLTs and Banff pathologic scores. We also analyzed the risk factors for the development of TLTs., Methods: Serial protocol biopsy samples (0 hour, 1, 6, and 12 months) without rejection were retrospectively analyzed from 214 patients who underwent living donor kidney transplantation. TLTs were defined as lymphocyte aggregates with signs of proliferation and their stages were determined by the absence (stage I) or presence (stage II) of follicular dendritic cells., Results: Only 4% of patients exhibited TLTs at the 0-hour biopsy. Prevalence increased to almost 50% at the 1-month biopsy, and then slightly further for 12 months. The proportion of advanced stage II TLTs increased gradually, reaching 19% at the 12-month biopsy. Presence of stage II TLTs was associated with higher risk of renal function decline after transplantation compared with patients with no TLT or stage I TLTs. Stage II TLTs were associated with more severe tubulitis and interstitial fibrosis/tubular atrophy at 12 months and predicted poorer graft function independently from the degree of interstitial inflammation. Pretransplantation rituximab treatment dramatically attenuated the development of stage II TLTs., Conclusions: TLTs are commonly found in clinically stable transplanted kidneys. Advanced stage II TLTs are associated with progressive graft dysfunction, independent of interstitial inflammation., (Copyright © 2022 by the American Society of Nephrology.)

Background: Although CKD screening programs have been provided in many settings, little is known as to how we can effectively translate those screening programs into improved health., Methods: We conducted a randomized clinical trial on national health screening for CKD in Japan between April 2018 and March 2019. A total of 4011 participants in CKD screening programs aged 40-63 years were randomly assigned to two interventions or the control, with a ratio of 2:2:1, respectively: ( 1 ) the nudge-based letter that contained a message on the basis of behavioral economics, ( 2 ) the clinical letter including general information about CKD risks, and ( 3 ) the control (informed only of the screening results). The main outcome was adherence to a recommended physician visit within 6 months of the intervention. The secondary outcomes were eGFR, proteinuria, and BP 1 year after the intervention., Results: Compared with the control group, the probability of undergoing a recommended physician visit was higher among participants who received the nudge-based letter (19.7% for the intervention group versus 15.8% for the control; difference, +3.9 percentage points [pp]; 95% CI, +0.8 to +7.0; P =0.02) and the clinical letter (19.7% versus 15.8%; difference, +3.9 pp; 95% CI, +0.8 to +7.0; P =0.02). We found no evidence that interventions were associated with improved early health outcomes., Conclusions: The behavioral economics intervention tested in this large RCT had limited effect on changing behavior or improving health outcomes. Although the approach has promise, this study demonstrates the challenge of developing behavioral interventions that improve the effectiveness of CKD screening programs. Clinical Trial registry name and registration number: University Hospital Medical Information Network Clinical Trial Registry, UMIN000035230., (Copyright © 2022 by the American Society of Nephrology.)

Background: Given the growing diversity among cancer survivors and the fact that oncologists typically do not perform long-term care, the expected role of primary care physicians (PCPs) in survivor care is expanding. However, communication and collaboration between oncologists and PCPs are lacking. Therefore, we assessed the perception of cancer survivor care among PCPs., Methods: We sent a questionnaire to 767 Japanese Board-certified PCPs, regardless of facility type (clinics and hospitals), inquiring about PCPs' perceptions of their role in survivor care. Additionally, we included vignette-based scenarios focused on colorectal and prostate cancer survivors to explore factors associated with their clinical decisions., Results: We obtained 91 replies (response rate: 11.9%). A total of 75% of PCPs had encountered at least 1 cancer patient in actual practice. Even for patients actively receiving cancer treatment, >70% of PCPs reported that they were willing to engage in comprehensive survivor care, except for the administration of anticancer drugs. Further, 49% of PCPs considered that both PCPs and oncologists were suited to performing regular screening for cancer recurrence in high-risk patients. Multivariable logistic regression analyses revealed that clinic PCPs were less inclined to conduct screening for recurrence than hospital PCPs in both colorectal (odds ratio, 3.85 [95% confidence interval 1.40-10.6]) and prostate (4.36 [95% confidence interval 1.51-12.6]) cancer scenarios., Conclusions: Our findings suggest that Japanese PCPs are willing to engage in survivor care and encourage closer collaboration between oncologists and PCPs. However, oncologists might need to request cooperation, considering the facility type with which PCPs are affiliated., Competing Interests: The authors have stated explicitly that there are no conflicts of interest in connection with this article., (© 2021 The Authors. Journal of General and Family Medicine published by John Wiley & Sons Australia, Ltd on behalf of Japan Primary Care Association.)

Ali-M3, an artificial intelligence program, analyzes chest computed tomography (CT) and detects the likelihood of coronavirus disease (COVID-19) based on scores ranging from 0 to 1. However, Ali-M3 has not been externally validated. Our aim was to evaluate the accuracy of Ali-M3 for detecting COVID-19 and discuss its clinical value. We evaluated the external validity of Ali-M3 using sequential Japanese sampling data. In this retrospective cohort study, COVID-19 infection probabilities for 617 symptomatic patients were determined using Ali-M3. In 11 Japanese tertiary care facilities, these patients underwent reverse transcription-polymerase chain reaction (RT-PCR) testing. They also underwent chest CT to confirm a diagnosis of COVID-19. Of the 617 patients, 289 (46.8%) were RT-PCR-positive. The area under the curve (AUC) of Ali-M3 for predicting a COVID-19 diagnosis was 0.797 (95% confidence interval: 0.762‒0.833) and the goodness-of-fit was P = 0.156. With a cut-off probability of a diagnosis of COVID-19 by Ali-M3 set at 0.5, the sensitivity and specificity were 80.6% and 68.3%, respectively. A cut-off of 0.2 yielded a sensitivity and specificity of 89.2% and 43.2%, respectively. Among the 223 patients who required oxygen, the AUC was 0.825. Sensitivity at a cut-off of 0.5% and 0.2% was 88.7% and 97.9%, respectively. Although the sensitivity was lower when the days from symptom onset were fewer, the sensitivity increased for both cut-off values after 5 days. We evaluated Ali-M3 using external validation with symptomatic patient data from Japanese tertiary care facilities. As Ali-M3 showed sufficient sensitivity performance, despite a lower specificity performance, Ali-M3 could be useful in excluding a diagnosis of COVID-19., Competing Interests: At the start of the study, Ali-m3 existed as a tool produced by Alibaba Damo (Hangzhou) Technology Co., Ltd for research use that had not received any approval. With the results of this study, we have confirmed that the Ali-M3 has clinical benefits. Therefore, under a special expedited review in Japan, Ali-M3 has been approved by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) and licensed for use as a diagnostic tool in actual practice. For the license in Japan, Ali-m3 should have been a commercial tool. Therefore, it was not planned that M3 Inc would benefit from the commercialization of the Ali-M3 as a result of our research for which M3 provided the Ali-M3 and storage free of charge. The authors have no patents, products in development, or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials. In Japan, the M3.inc completely held the right of Ali-M3. This study was utterly free from Alibaba Damo Technology except Alibaba platform by the right of M3.inc.

Here, we present a method for preparing vesicles by combining hydrothermal emulsification with solvent diffusion (SD). The sorbitan monolaurate/polyoxyethylene (20) sorbitan monolaurate (Span 20/Tween 20) system was used as the target lipid because these lipids are cheap and advantageous for the production scale. The water-in-oil (W/O) emulsion stabilized with lipids was formed under hydrothermal conditions (240 °C under 10 MPa), followed by mixing with water that included lipids to obtain a W/O-in-water (W/O/W) emulsion. The SD for the W/O/W emulsion as a subsequent process yielded vesicles. The optimal preparation conditions were 50:50 wt% Span 20/Tween 20 as a mixing ratio (final lipid concentration 12 mM), octanoic acid as an organic solvent, 240 °C for 4 min during the hydrothermal treatment, and 4 °C for 24 h in the SD process. The diameter of the vesicles obtained was at most 100 nm, which was comparable to that of the W/O/W emulsion before SD. This suggested that the W/O/W emulsion acted as a template for vesicle formation. The number density, diameter, and membrane properties of vesicles depend on the mixing ratio of the water/oil/lipid system. Specifically, the number density of vesicles was low relative to that of vesicles prepared by the conventional method., (Copyright © 2021. Published by Elsevier B.V.)

Background: Breaches of ethics undermine the practice of medicine. In Japan, two major scandals involving clinical research and drug marketing occurred after the publication of clinical trials. To study the effects of those scandals, we evaluated changes in the use of first-generation angiotensin II receptor blockers (ARBs) after publication of relevant clinical trials and also after the subsequent scandals., Methods: We conducted a quasi-experimental design of an interrupted time series analysis (ITSA) on nationwide monthly drug-market data covering 12 years (2005 to 2017) in Japan. The main outcome was the use of first-generation ARBs (valsartan, candesartan, and losartan). The two exposures were the publication of ARB-related clinical-trial results (October 2006) and subsequent ARB-related scandals involving research and marketing (February 2013). A generalized estimating equation model was fitted for ITSA with a log link, Poisson distribution, robust variance estimators, and seasonality adjustment., Results: The publication of clinical trials was associated with 12% increase in the use of first-generation ARBs in Japan, and the subsequent ARB-related scandals was associated with 19% decrease. The decrease in the use of first-generation ARBs after the scandals was greater than the increase in their use after the publication of clinical-trial results. The net effect of the two exposures was a 9% decrease in the use of first-generation ARBs., Conclusions: The scandals were associated with decrease in the use of first-generation ARBs, and that decrease was greater than the increase associated with the publication of "successful" clinical trials, making the net effect not zero but negative.

Objective: This study aimed to evaluate the influence of advanced glycation end-product (AGE) accumulation on the prevalence and severity of overactive bladder (OAB) in community-dwelling elderly adults., Methods: We conducted a cross-sectional study involving 269 Japanese community dwellers aged ≥75 years in 2015. AGE accumulation was non-invasively measured via skin autofluorescence (SAF) values using AGE Reader. The primary and secondary outcomes were the presence and severity of OAB evaluated using the Overactive Bladder Symptom Score (OABSS). Individuals with an urgency score of ≥2 and sum score of ≥3 were considered to have OAB. The associations of SAF with the prevalence and severity of OAB were assessed using logistic and linear regression models, respectively, adjusted for clinically important confounders., Results: The median age of participants was 78 years. Of 269 participants, 110 (40.9%) were men and 75 (27.9%) had OAB. The median SAF was 2.2 arbitrary units (AUs). Increasing median SAF was observed with increasing age. Multivariable analysis revealed that SAF was not associated with either the likelihood of having OAB (odds ratio per AU=0.77, 95% confidence interval: 0.37-1.62) or the natural log-transformed OABSS (β per AU=-0.07, 95% confidence interval: -0.26-0.12)., Conclusions: In this study, AGE accumulation, as assessed by SAF, was not associated with the prevalence and severity of OAB in Japanese community-dwelling elderly people aged ≥75 years., Competing Interests: The authors declare no conflict of interest., (© 2021 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V.)

Chronic kidney disease (CKD) is associated with a high incidence of fractures. However, the pathophysiology of this disease is not fully understood, and limited therapeutic interventions are available. This study aimed to determine the impact of type 1 angiotensin II receptor blockade (AT-1RB) on preventing CKD-related fragility fractures and elucidate its pharmacological mechanisms. AT-1RB use was associated with a lower risk of hospitalization due to fractures in 3276 patients undergoing maintenance hemodialysis. In nephrectomized rats, administration of olmesartan suppressed osteocyte apoptosis, skeletal pentosidine accumulation, and apatite disorientation, and partially inhibited the progression of the bone elastic mechanical properties, while the bone mass was unchanged. Olmesartan suppressed angiotensin II-dependent oxidation stress and apoptosis in primary cultured osteocytes in vitro. In conclusion, angiotensin II-dependent intraskeletal oxidation stress deteriorated the bone elastic mechanical properties by promoting osteocyte apoptosis and pentosidine accumulation. Thus, AT-1RB contributes to the underlying pathogenesis of abnormal bone quality in the setting of CKD, possibly by oxidative stress. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Background: Depletion of ATP in renal tubular cells plays the central role in the pathogenesis of kidney diseases. Nevertheless, inability to visualize spatiotemporal in vivo ATP distribution and dynamics has hindered further analysis., Methods: A novel mouse line systemically expressing an ATP biosensor (an ATP synthase subunit and two fluorophores) revealed spatiotemporal ATP dynamics at single-cell resolution during warm and cold ischemic reperfusion (IR) with two-photon microscopy. This experimental system enabled quantification of fibrosis 2 weeks after IR and assessment of the relationship between the ATP recovery in acute phase and fibrosis in chronic phase., Results: Upon ischemia induction, the ATP levels of proximal tubule (PT) cells decreased to the nadir within a few minutes, whereas those of distal tubule (DT) cells decreased gradually up to 1 hour. Upon reperfusion, the recovery rate of ATP in PTs was slower with longer ischemia. In stark contrast, ATP in DTs was quickly rebounded irrespective of ischemia duration. Morphologic changes of mitochondria in the acute phase support the observation of different ATP dynamics in the two segments. Furthermore, slow and incomplete ATP recovery of PTs in the acute phase inversely correlated with fibrosis in the chronic phase. Ischemia under conditions of hypothermia resulted in more rapid and complete ATP recovery with less fibrosis, providing a proof of concept for use of hypothermia to protect kidney tissues., Conclusions: Visualizing spatiotemporal ATP dynamics during IR injury revealed higher sensitivity of PT cells to ischemia compared with DT cells in terms of energy metabolism. The ATP dynamics of PTs in AKI might provide prognostic information., (Copyright © 2020 by the American Society of Nephrology.)

Background: There is limited evidence on the association between short-term changes in mineral and bone disorder parameters and survival in maintenance hemodialysis patients., Methods: We investigated the association between changing patterns of phosphorus, calcium and intact parathyroid hormone levels and all-cause mortality in hemodialysis patients with secondary hyperparathyroidism. Each parameter was divided into three categories (low [L], middle [M] and high [H]), and the changing patterns between two consecutive visits at 3-month intervals were categorized into nine groups (e.g., L-L and M-H). The middle category was defined as 4.0-7.0 mg/dL for phosphorous, 8.5-9.5 mg/dL for calcium and 200-500 pg/mL for intact parathyroid hormone. Adjusted incidence rates and rate ratios were analyzed by weighted Poisson regression models accounting for time-dependent exposures., Results: For phosphorus, shifts from low/high to middle category (L-M/H-M) were associated with a lower mortality compared with the L-L and H-H groups, whereas shifts from middle to low/high category (M-L/M-H) were associated with a higher mortality compared with the M-M group. For calcium, shifts from low/middle to high category (L-H/M-H) were associated with a higher mortality compared with the L-L and M-M groups, whereas shifts from high to middle category (H-M) were associated with a lower mortality compared with the H-H group. For intact parathyroid hormone, shifts from low to middle category (L-M) were associated with a lower mortality compared with the L-L group., Conclusions: Changes in the 3-month patterns of phosphorus and calcium toward the middle category were associated with lower mortality. Our study also suggests the importance of avoiding hypercalcemia.

Background: Patient journeys for hypertensive individuals after detection at screening have not been well examined in a general population. Thus, we aimed to assess the medical treatment status and subsequent longitudinal changes in blood pressure in a middle-aged Japanese population., Methods: We conducted a cohort study using a nationwide Japanese health screening cohort, from April 2014 to March 2019. Among health screening participants aged 40-74 years who had not previously received treatment for hypertension, hypertensive patients were newly identified based on screening results, and their medical treatment status for hypertension during the year following their initial screening was assessed. The main outcomes were longitudinal changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) over 4 years after initial screening., Results: Of the 153,523 screening participants (mean age = 49.7 years), 16,720 (10.9%) and 4150 (2.7%) were newly detected as having hypertension, with baseline SBP of 140-159 mmHg (grade 1) and ≥ 160 mmHg (grade 2-3), respectively. Among them, 15.9% of the grade 1 hypertensive participants and 36.3% of the grade 2-3 hypertensive participants started receiving medical treatment during the year following initial screening. A linear generalised estimating equation with propensity score matching showed that receiving medical treatment was associated with 5.77 mmHg lower SBP (95% CI - 6.64 to - 4.90) and 3.82 mmHg lower DBP (95% CI - 4.47 to - 3.16) in the grade 1 hypertensive group, and 14.69 mmHg lower SBP (95% CI - 16.35 to - 13.04) and 8.42 mmHg lower DBP (95% CI - 9.49 to - 7.34) in the grade 2-3 hypertensive group., Conclusions: Health screenings detected hypertension in a substantial percentage of the middle-aged population in this study. However, detection was often followed by insufficient medical treatment and inappropriate blood pressure management. These findings indicate an inadequate link between health screenings and medical treatments in patients with hypertension.

Background: Obesity is a growing public health problem worldwide. We evaluated the mediators and association between changes in obesity metrics and renal outcomes in the general population., Methods: Using the Japanese nationwide health check-based cohort from April 2011 to March 2019, we selected individuals aged 40-74 years, with a baseline estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m 2 , whose body mass index (BMI) change was assessed. The primary outcome was combined 30% decline in eGFR, eGFR <15 mL/min/1.73 m 2 and end-stage renal disease., Results: During 245 147 person-years' follow-up among 50 604 participants (mean eGFR, 83.7 mL/min/1.73 m 2 ; mean BMI, 24.1 kg/m 2 ), 645 demonstrated eGFR decline (incidence rate 2.6/1000 person-years, 95% CI: 2.4 to 2.8). We observed continued initial changes in BMI for over 6 years and a U-shaped association between BMI change and eGFR decline. Compared with 0% change in BMI, adjusted HRs for changes of -10%, -4%, 4% and 10% were 1.53 (95% CI: 1.15 to 2.04), 1.14 (95% CI: 1.01 to 1.30), 1.16 (95% CI: 1.02 to 1.32) and 1.87 (95% CI: 1.25 to 2.80), respectively. The percentage of excess risk of BMI increase (>4%) mediated by three risk factors (blood pressure, haemoglobin A1c and total cholesterol), was 13.3%., Conclusion: In the middle-aged Japanese population, both, increase and decrease in BMI were associated with subsequent eGFR decline. Changes in risk factors mediated a small proportion of the association between BMI increase and eGFR decline. Our findings support the clinical significance of monitoring BMI as a renal risk factor., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Tertiary lymphoid tissues (TLTs) are inducible ectopic lymphoid tissues in chronic inflammatory states and function as sites of priming local immune responses. We previously demonstrated that aged but not young mice exhibited multiple TLTs after acute kidney injury and that TLTs were also detected in human aged and diseased kidneys. However, the forms of progression and the implication for kidney injury remain unclear. To clarify this we analyzed surgically resected kidneys from aged patients with or without chronic kidney disease as well as kidneys resected for pyelonephritis, and classified TLTs into three distinct developmental stages based on the presence of follicular dendritic cells and germinal centers. In injury-induced murine TLT models, the stages advanced with the extent of kidney injury, and decreased with dexamethasone accompanied with improvement of renal function, fibrosis and inflammation. Kidneys from aged patients with chronic kidney disease consistently exhibited more frequent and advanced stages of TLTs than those without chronic kidney disease. Kidneys of patients with pyelonephritis exhibited more frequent TLTs with more advanced stages than aged kidneys. Additionally, TLTs in both cohorts shared similar locations and components, suggesting that TLT formation may not be a disease-specific phenomenon but rather a common pathological process. Thus, our findings provide the insights into biological features of TLT in the kidney and implicate TLT stage as a potential marker reflecting local injury and inflammation., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The geriatric nutritional risk index (GNRI) and creatinine (Cr) index are indexes often used as nutritional surrogates in patients receiving hemodialysis. However, few studies have directly compared the clinical characteristics of these two indexes. We investigated 3,536 hemodialysis patients enrolled in the Japan DOPPS phases 4 and 5. The primary outcome was all-cause mortality and the main exposures were the GNRI and Cr index. We confirmed and compared the association between these indexes and mortality risk as estimated by a multivariable-adjusted Cox proportional hazards model. During the median 2.2-year follow-up period, 414 patients died of any cause. In the multivariable-adjusted model, lower GNRI and Cr index were both associated with increased risk of all-cause mortality, and these associations were further confirmed by restricted cubic spline curves. The predictability of all-cause mortality, as represented by the c-statistic, was comparable between the two indexes. Furthermore, baseline nutritional surrogates that corresponded with lower GNRI or Cr index values were comparable between the two indexes. Given that calculating the GNRI is simpler than calculating the Cr index, our data suggest that the GNRI may be preferable to the Cr index for predicting clinical outcomes in patients undergoing maintenance hemodialysis.

Background: Excessive salt intake is widely known to be a cause of hypertension, cardiovascular events, and so on. However, simple tools for screening excessive salt intake are lacking., Objective: We aimed to develop a simple screening tool to identify community-dwelling adults with excessive salt intake., Methods: The present study involved participants who received health check-ups in Fukushima, Japan, in 2016 and 2017. We defined data from the 2016 check-up as the derivation set, and data from those who received check-ups in 2017 but not 2016 as the validation set. The outcome measure was excessive salt intake, defined as the estimated daily salt intake of 1 SD or more. Candidate predictors associated with the outcome were extracted using the Delphi method by an expert panel and narrowed down with clinical expertise and stepwise backward selection. The screening tool was developed using a coefficient-based multivariable scoring method and externally validated., Results: A total of 1101 participants were included in the derivation set and 249 in the validation set. At the conclusion of the deviation process, 8 predictors were selected and scored. The areas under the receiver operating characteristic curve for derivation and external validation were 0.70 (95% CI: 0.67, 0.74) and 0.71 (95% CI: 0.62, 0.80), respectively. The calibration slope and intercept for external validation were 1.16 and -0.03, respectively., Conclusion: We developed a screening tool to identify adults with excessive salt intake. By extracting groups with excessive salt intake, target populations needing intervention for salt reduction can be highlighted efficiently., (Copyright © The Author(s) 2020.)

The aim of this study was to explore enhancement patterns of different types of primary lung cancers on 2-phase dynamic computed tomography (CT). This study included 217 primary lung cancer patients (141 adenocarcinomas [ADs], 48 squamous cell carcinomas [SCCs], 20 small cell lung carcinomas [SCLCs], and 8 others) who were examined using a 2-phase dynamic scan. Regions of interest were identified and mean enhancement values were calculated. After excluding the 20 SCLCs because these lesions had different clinical stages from the other cancer types, the mean attenuation values and subtractions between phases were compared between types of non-small cell lung carcinomas (NSCLCs) using the Kruskal-Wallis test. Late phase attenuation and attenuation of the late minus unenhanced phase (LMU) of SCCs were significantly higher than those of ADs (p<0.05). To differentiate SCC and AD in the late phase, a threshold of 80.21 Hounsfield units (HU) gave 52.9% accuracy. In LMU, a threshold of 52.16 HU gave 59.3% accuracy. Dynamic lung CT has the potential to aid in differentiating among NSCLC types., Competing Interests: No potential conflict of interest relevant to this article was reported.

The aim of this study was to evaluate the ability of pretreatment 90-min 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) to predict the extranodular spread of lymph node metastases in oral squamous cell carcinoma. We retrospectively reviewed the cases of 56 patients who underwent pretreatment 18F-FDG PET/CT and surgery with neck dissection. Maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis were measured for the 56 primary sites and maximum standardized uptake value was measured for 115 lymph node levels. Extranodular spread was present at 9 lymph node levels in 7 patients. Significant differences were found in metabolic tumor volume and total lesion glycolysis of the primary site, and in lymph node maximum standardized uptake value, between patients with and without extranodular spread (p<0.05). Combining primary site total lesion glycolysis and lymph node maximum standardized uptake volume at their respective optimal cutoffs, the sensitivity, specificity, and accuracy for predicting extranodular spread were 89%, 92%, and 92%, respectively. Pretreatment 18F-FDG PET/CT is useful for predicting extranodular spread in patients with oral squamous cell carcinoma. The combined use of primary site total lesion glycolysis and lymph node maximum standardized uptake value showed greater predictive value than either predictor singly., Competing Interests: No potential conflict of interest relevant to this article was reported.

Background: The impact of length of hospital stay on activities of daily living (ADLs) has not specifically been investigated among dialysis patients. Therefore, we attempt to verify the association between the length of hospital stay and the decline in ADLs among hemodialysis patients., Methods: This prospective cohort study used data from the Japanese Dialysis Outcomes and Practice Patterns Study (J-DOPPS). We included 2442 hemodialysis patients aged ≥40 years from the J-DOPPS phase V (2012-2015) and subsequently excluded those who had already lost basic activities of daily living (BADLs) as demonstrated by dependency in at least three of the five BADLs at baseline and for whom changes in ADLs had been evaluated for less than 90 days. The main exposure was the cumulative length of hospital stay during the follow-up period. The primary outcomes were a decline in at least one of the five BADLs and eight instrumental activities of daily living (IADLs). We compared risk ratios (RRs) for 30-day increments for hospital stays with 10-year increments for age and having diabetes., Results: A total of 849 patients were included in the statistical analysis. The cumulative length of hospital stay was significantly associated with a risk of decline in ADLs (adjusted RRs [95% confidence intervals] per 30-day increments: 1.42 [1.15 to 1.75] for BADLs, 1.38 [1.13 to 1.68] for IADLs). The adjusted RRs [95% CI] for 10-year increments in age were 1.20 [0.96 to 1.50] and 1.21 [1.00 to 1.47]. The adjusted RRs [95% CI] for having diabetes were 1.36 [0.97 to 1.91] for BADLs and 1.38 [1.04 to 1.84] for IADLs., Conclusion: The impact of a 30-day increment in the cumulative length of hospital stay on the decline in ADLs was comparable to that of a 10-year increase in age and having diabetes.

BACKGROUND Although knowledge is an important factor that influences decisions regarding deceased organ donation, the associations of knowledge with attitude and behavior regarding organ donation remain uncertain in countries with low organ donation rates like Japan. MATERIAL AND METHODS We conducted a cross-sectional survey of hospital medical and non-medical staff in 15 Japanese medical facilities. The questionnaire included items on knowledge, attitude, and behavior toward deceased organ donation and transplantation. Participants were divided into 3 groups according to the tertile of knowledge score. Modified Poisson regression models were used for associations of knowledge score with organ donor registration and willingness to become an organ donor after death. RESULTS Of the 1967 staff, 1275 returned the questionnaires (response rate, 64.8%). There were 1190 study subjects with complete data for analysis. For the lowest (n=512), middle (n=428), and highest (n=250) tertile knowledge groups, the proportions of participants who registered and expressed willingness to donate organs were 20.1%, 23.4%, and 28.4% and 31.1%, 38.3%, and 44.0%, respectively. The adjusted proportion ratios for organ donor registration were 0.90 (95% CI, 0.73-1.10) for the middle and 1.00 (0.80-1.26) for the highest tertile of knowledge, compared with the lowest tertile. However, participants with the highest tertile of knowledge score expressed higher willingness for organ donation than the lowest tertile (adjusted proportion ratio, 1.37; 95% CI, 1.13-1.66). CONCLUSIONS For hospital staff in Japanese medical facilities, high knowledge about organ donation and transplantation was not associated with donor registration, but was associated with willingness to become an organ donor.

Tracheobronchial adenoid cystic carcinoma is a rare malignancy. To the best of our knowledge, its enhancement pattern on multiphasic contrast-enhanced multidetector computed tomography has not been reported. Herein, we report the computed tomography findings of three consecutive cases of tracheobronchial adenoid cystic carcinoma. All lesions presented a gradual enhancement pattern on multiphasic contrast-enhanced computed tomography. We speculate that the gradual enhancement pattern on multiphasic contrast-enhanced computed tomography could potentially serve as a characteristic imaging feature and may therefore be a clue to diagnose tracheobronchial adenoid cystic carcinoma. J. Med. Invest. 67 : 378-381, August, 2020.

Background/aims: Strategies for an effective intervention after chronic kidney disease (CKD) screening have not been well examined. We describe the rationale and design of a protocol of a pragmatic randomized controlled trial (RCT) to test the effect of a behavioral intervention using the nudge approach in behavioral economics on CKD patients' visiting behaviors to physicians and change in their kidney function after CKD screening., Methods: The RCT will include CKD patients (N = 4500) detected at screening (estimated glomerular filtration rate [eGFR] <60 mL/min/1.74 m 2 or urine protein ≥1+), aged 40-63 years. The two intervention groups will receive a "usual letter" and "nudge-based letter," while the control group will only receive a conventional follow-up. Our primary outcome is proportion of patients' visiting physicians for 6 months after the intervention; the secondary outcome is change in the eGFR at 2 years after the intervention., Results: We developed an efficient intervention program after CKD screening and designed the pragmatic RCT to assess its effectiveness in the real world. Our trial is unique in that it investigates the effect of the nudge approach in behavioral economics. By the end of 2018, we have enrolled 1,692 participants, and randomized 677 participants into the usual letter group, 677 participants into the nudge-based letter group, and 338 participants into the control group. We have confirmed that health checkup data could identify a large number of eligible participants., Conclusion: The trial's results will contribute to filling in the gap between screening and subsequent medical interventions for preventing CKD progression.

Achieving calcium, phosphorus, and intact parathyroid hormone (PTH) targets helps improve dialysis population outcomes. We aimed to assess the population-level associations of achievement of those targets with survival using population-attributable-fractions (PAFs). We conducted a case-cohort study using data from 8229 haemodialysis patients with mildly elevated intact PTH, treated at 86 dialysis facilities in Japan. We examined associations among calcium, phosphorus, intact PTH, and mortality over 3 years. We estimated PAFs for achieving the targets of calcium, phosphorus, and intact PTH from the adjusted hazard ratios by Cox regression models. Proportions within the recommended range were 55.8%, 63.3%, and 39.1% for calcium (8.4-10.0 mg/dL), phosphorus (3.5-6.0 mg/dL) and intact PTH (60-240 pg/mL), respectively. The mortality rate was 5.7 per 100 person-years. Mortality was independently associated with non-achievement of targets. Regarding the population-level impact, statistically significant PAFs were found for achieving the combination of calcium and phosphorus (8.8%; 95% CI, 1.1-16.0). Further, PAF for combined calcium, phosphorus, and intact PTH was the largest (16.8%; 95% CI, 5.6-30.4). In conclusion, there might be additive and substantial population-level associations between survival and the achievement of calcium, phosphorus, and intact-PTH targets in the haemodialysis population with mildly elevated intact PTH.