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Takahiro Ito,1 Sachiko Tanaka-Mizuno,2,3 Narihito Iwashita,4 Ikuo Tooyama,5 Akihiko Shiino,6 Katsuyuki Miura,1,7 Sei Fukui4 1Department of Public Health, Shiga University of Medical Science, 2Department of Medical Statistics, Shiga University of Medical Science, Otsu, Japan; 3The Center for Data Science Education and Research, Shiga University, Hikone, Japan; 4Department of Anesthesiology, Interdisciplinary Pain Management Center, Shiga University of Medical Science Hospital, 5Molecular Neuroscience Research Center, Shiga University of Medical Science, 6Biomedical MR Science Center, Shiga University of Medical Science, 7Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan Background: Chronic pain is a common cause of reduced quality of life. Recent studies suggest that chronic pain patients have a different brain neurometabolic status to healthy people. Proton magnetic resonance spectroscopy (1H-MRS) can determine the concentrations of metabolites in a specific region of the brain without being invasive. Patients and methods: We recruited 56 chronic pain patients and 60 healthy controls to compare brain metabolic characteristics. The concentrations of glutamic acid (Glu), myo-inositol (Ins), N-acetylaspartate (NAA), Glu + glutamine (Glx), and creatine + phosphocreatine (total creatine [tCr]) in the anterior cingulate cortex of participants were measured using 1H-MRS. We used age- and gender-adjusted general linear models and receiver-operating characteristic analyses for this investigation. Patients were also assessed using the Hospital Anxiety and Depression Scale (HADS) to reveal the existence of any mental health issues. Results: Our analysis indicates that pain patients have statistically significantly higher levels of Glu/tCr (p=0.039) and Glx/tCr (p

Abstract Background This study evaluates the cost-effectiveness of implants (Implant), insurance fixed dental prosthesis (IFDP) and private fixed dental prosthesis (PFDP) for a single intermediate missing tooth in the molar region to calculate the Incremental Cost Effectiveness Ratio (ICER). Methods The Markov model for cost-effectiveness analysis of the Implant, IFDP and PFDP was carried over maximum 30 years. The starting age for prosthetic treatment was decided to be 50 years. The General Oral Health Assessment Index (GOHAI) was used for the indicator of effectiveness as an oral health QOL value. The GOHAI value was collected from patients who visited the Department of Oral Implantology of Osaka Dental University between September 2014 and March 2016. In addition, the Tornado diagram was drawn and Monte-Carlo simulations made for sensitivity analysis. Results From the analysis of survey of QOL of each stage and treatment, the selection of an Implant led to a higher QOL value than FDP. However, the estimated 30-year cost for IFDP was lower than Implant. It also became evident that PFDP had an extended dominated condition compared with IFDP and Implants. The ICER on the Implant versus IFDP was €1423.00. Conclusions These results suggest that a better of QOL value can be obtained from an Implant than from IFDP or PFDP. An evaluation form using an indexed scale for oral health-related aspects needs to be developed that is also consistent as an indicator of effect.

Epidemiological studies have reported that Asian dust (AD), a type of desert dust, has harmful effects on human health. This study aimed to examine the association between AD exposure and hospitalization due to pneumonia. Data on patients in Western Japan admitted for pneumonia were included from a real-world database derived from electronic medical records. We used the meteorological observatory data of the most populous city in each prefecture, in which AD event was defined as a loss of visibility from a distance ≤10 km. A case-crossover design and conditional logistic regression model were used. Overall, 12 938 patients were included, and AD exposure events were observed for 557 days. Exposure to an AD event five days prior to hospitalization was significantly associated with hospitalization for pneumonia after adjusting for weather variables (odds ratio = 1.17). These findings suggest that AD exposure is associated with an increased rate of admission for pneumonia in Western Japan., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Low plasma levels of eicosapentaenoic acid (EPA) are associated with cardiovascular events. This trial aimed to assess the clinical benefits of icosapent ethyl in patients with coronary artery disease, a low EPA/arachidonic acid (AA) ratio, and statin treatment., Methods: In this prospective, multicenter, randomized, open-label, blinded end-point study, patients with stable coronary artery disease and a low EPA/AA ratio (<0.4) were randomized to EPA (1800 of icosapent ethyl administered daily) or control group. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina pectoris, and coronary revascularization. The secondary composite end points of coronary events included sudden cardiac death, fatal and nonfatal myocardial infarction, unstable angina requiring emergency hospitalization and coronary revascularization, or coronary revascularization., Results: Overall, 3884 patients were enrolled at 95 sites in Japan. Among them, 2506 patients had a low EPA/AA ratio, and 1249 and 1257 patients were randomized to the EPA and control group, respectively. The median EPA/AA ratio was 0.243 (interquartile range, 0.180-0.314) and 0.235 (interquartile range, 0.163-0.310) in the EPA and control group, respectively. Over a median period of 5 years, the primary end point occurred in 112 of 1225 patients (9.1%) and 155 of 1235 patients (12.6%) in the EPA and control group, respectively (hazard ratio, 0.79 [95% CI, 0.62-1.00]; P =0.055). Meanwhile, the secondary composite end point of coronary events in the EPA group was significantly lower (81/1225 [6.6%] versus 120/1235 [9.7%] patients; hazard ratio, 0.73 [95% CI, 0.55-0.97]). Adverse events did not differ between the groups, but the rate of new-onset atrial fibrillation was significantly higher in the EPA group (3.1% versus 1.6%; P =0.017)., Conclusions: Icosapent ethyl treatment resulted in a numerically lower risk of cardiovascular events that did not reach statistical significance in patients with chronic coronary artery disease, a low EPA/AA ratio, and statin treatment., Registration: URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000012069., Competing Interests: Dr Miyauchi has received lecture fees from Amgen Astellas BioPharma, Astellas Pharma, MSD, Bayer Yakuhin, Sanofi, Takeda Pharmaceutical, Daiichi-Sankyo, Nippon Boehringer Ingelheim, and Bristol-Myers Squibb. Dr Iwata has received lecture fees from Kowa, Daiichi-Sankyo, Sumitomo Pharma, MSD, Novo Nordisk, Mochida Pharmaceutical, and Bayer Yakuhin. Dr Hirayama has received lecture fees from Bayer Yakuhin and Daiichi-Sankyo. Dr Kimura has received grants from Bayer Yakuhin, consulting fees from Idorsia Pharmaceuticals Japan, and lecture fees from Bayer Yakuhin and Daiichi-Sankyo. Dr Ozaki has received grants from Takeda Pharmaceutical, Daiichi-Sankyo, and Otsuka Pharmaceutical. Dr Murohara has received from Daiichi-Sankyo, Jansen Pharmaceutical, Bayer Yakuhin, Ono Pharmaceutical, Mochida Pharmaceutical, Pfizer, AstraZeneca, and Boehringer Ingelheim Japan. Dr Daida has received grants from Philips Japan, FUJIFILM Holdings Corp, Asahi Kasei Corp, Inter Reha, TOHO HOLDINGS, GLORY, Bristol-Myers Squibb, Abbott Japan, Boehringer Ingelheim Japan, Eisai, Bayer Yakuhin, and Daiichi-Sankyo, as well as lecture fees from Novartis Pharma, Bayer Yakuhin, Sanofi, Kowa, Taisho Pharmaceutical, Abbott Medical Japan, Otsuka Pharmaceutical, Amgen, MSD, Daiichi-Sankyo, Pfizer Japan, FUKUDA DENSHI, Tsumura, and TOA EIYO. The other authors report no conflicts.

Background: When considering changing hypnotic pharmacotherapy, lemborexant has attracted attention as a candidate due to its effectiveness and safety profile. However, few studies have investigated switching patterns in clinical practice., Research Design and Methods: We conducted a retrospective cohort study using a nationwide claims database. Patients prescribed a single hypnotic who either subsequently switched to (switching cohort) or were additionally prescribed (add-on cohort) lemborexant between July 2020 and December 2021 were identified. Proportion of successful switching was defined as remaining on lemborexant alone or without any hypnotic at 6 months after lemborexant initiation., Results: The success proportion was 70.1% in the switching cohort ( n  = 4,861) and 38.6% in the add-on cohort ( n  = 9,423). In the add-on cohort, the success proportion was lower in patients with a hypnotic history of ≥180 days (31.4%) and in patients whose prescribed hypnotic was a benzodiazepine or non-benzodiazepine (31.5% and 37.6%, respectively)., Conclusion: The proportion of successful switching was higher in patients who switched to lemborexant than in those who added lemborexant as a concomitant treatment. The lower success proportion in the add-on cohort might be related to clinically more severe insomnia, and/or a concomitant prescription of benzodiazepine or non-benzodiazepine, from which discontinuation may be challenging.

Background: Understanding the different patterns of adherence to istradefylline treatment is essential to identifying Parkinson's disease (PD) patients who might benefit from targeted interventions., Objectives: This descriptive study aimed to identify longitudinal istradefylline adherence patterns and to characterize factors associated with them., Methods: We identified PD patients aged 21-99 years who initiated istradefylline treatment in a Japanese hospital administrative database. Group-based trajectory modeling was used to model the monthly proportion of days covered over time to identify distinct 360-day adherence patterns. Factors associated with each adherence pattern were assessed using univariable multinomial logistic regression models., Results: Of 2088 eligible PD patients, 4 distinct adherence groups were identified: consistently high adherence (56.8%); rapidly declining adherence (25.8%); gradually declining adherence (8.5%); and gradually declining and then recovering adherence (9.0%). Compared to the consistently high adherence group, the other groups had the following characteristics associated with a likelihood of lower adherence: the rapidly declining adherence group received fewer dopamine agonists (63.8% vs. 69.4%), monoamine oxidase B (MAO-B) inhibitors (26.8% vs. 31.6%), and catechol-O-methyl transferase inhibitors (31.6% vs. 37.0%) and had a higher prevalence of anxiety/mood disorders (29.9% vs. 24.6%); the gradually declining adherence group received fewer MAO-B inhibitors (22.5% vs. 31.6%) and amantadine (8.4% vs. 16.1%) and had a higher prevalence of mild cognitive impairment/dementia (27.0% vs. 18.8%); and the declining and then recovering adherence group had a higher prevalence of anxiety/mood disorders (34.2% vs. 24.6%)., Conclusions: Clinicians should be aware of the heterogeneous patterns of adherence to istradefylline., Competing Interests: Declaration of competing interest T.F. has been employed by the Department of Digital Health and Epidemiology with support from Eisai Co., Ltd. and Kyowa Kirin Co., Ltd.; and has received consulting fees from Real World Data Co., Ltd. and honoraria from EPS Corporation and Research Institute of Healthcare Data Science (RIHDS). E.N. has received consulting fees from Kyowa Kirin Co., Ltd., and honoraria from AbbVie GK, Daiichi Sankyo Co., Ltd., EA Pharma Co., Ltd., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Ono Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd., and Takeda Pharmaceutical Co., Ltd. H.S., K.S., S.I., and S.A. have been employed by Kyowa Kirin Co., Ltd. S.Y. has no conflicts of interest. S.T.-M. has been employed by the Department of Digital Health and Epidemiology with support from Eisai Co., Ltd. and Kyowa Kirin Co., Ltd.; and has received consulting fees from Real World Data Co., Ltd. and honoraria from RIHDS. K.M. has been employed by the Department of Digital Health and Epidemiology with support from Eisai Co., Ltd. and Kyowa Kirin Co., Ltd. R.T. has received consulting fees from Kyowa Kirin Co., Ltd., and grants from Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Sumitomo Pharma Co., Ltd., honoraria from AbbVie Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Ono Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd., and Takeda Pharmaceutical Co., Ltd., and subcontracting fees (trial cases) from Sanofi K.K., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd. K.K. has received consulting fees from Advanced Medical Care Inc., JMDC Inc., LEBER Inc., and Shin Nippon Biomedical Laboratories Ltd., executive compensation from Cancer Intelligence Care Systems, Inc., honoraria from Chugai Pharmaceutical Co., Ltd., Kaken Pharmaceutical Co., Ltd., and Pharma Business Academy, and grants from Eisai Co., Ltd., Kyowa Kirin Co., Ltd., OMRON Corporation, and Toppan Inc., (Copyright © 2023. Published by Elsevier B.V.)

Objective: Postoperative nonfunctioning pituitary tumor (NFPT) regrowth is a significant concern, but its predictive factors are not well established. This study aimed to elucidate the pathological characteristics of NFPTs indicated for reoperation for tumor regrowth., Methods: Pathological, radiological, and clinical data were collected from patients who underwent repeat operation for NFPT at Moriyama Memorial Hospital (MMH) between April 2018 and September 2023. For comparison, we also gathered data from patients who underwent initial surgery for NFPT during the same period at MMH., Results: Overall, 61 and 244 NFPT patients who respectively underwent reoperation and initial operation were evaluated. The mean period between the previous operation and reoperation was 113 months. Immunonegativity for any adenohypophyseal hormone was significantly more frequent in the reoperation group than in the initial operation group. In addition, the rate of hormone-negative but transcription factor-positive (H-/TF+) tumors among silent gonadotroph tumors was significantly higher in the reoperation group than in the initial operation group. Furthermore, seven silent corticotroph tumors (SCTs) in the reoperation group were ACTH-negative but TPIT-positive. Because most of the previous surgeries were performed in other hospitals a long time ago, we could procure the previous pathological results with immunohistochemistry (IHC) only from 21 patients. IHC for TF had not been performed in all the previous specimens. IHC for adenohypophyseal hormone was almost the same as the current results, and many H-/TF+ tumors were previously diagnosed as NCT. In addition, the reoperated patients were classified into 3 groups on the basis of the condition of the previous operation: gross total resection (GTR), 12 patients; subtotal resection (STR), 17 patients; and partial resection (PR), 32 patients. The mean Ki-67 LI in the GTR, STR, and PR subgroups were 1.82, 1.37, and 0.84, respectively, with the value being significantly higher in the GTR subgroup than in the PR subgroup (P < 0.05)., Conclusions: The ratio of H-/TF+ tumors is significantly higher in symptomatically regrown tumors than in the initial cases, which used to be diagnosed as NCT. PR cases tend to grow symptomatically in a shorter period, even with lower Ki-67 LI than GTR cases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ishida, Inoshita, Tanabe, Takano, Tanaka-Mizuno, Kato, Yoshimoto, Shiramizu, Matsuoka and Yamada.)

Background: Pregnancy and lactation-associated osteoporosis (PLO), as well as premenopausal osteoporosis, might be a predictor of future fracture. This study aimed to describe the clinical features of PLO as a subtype of premenopausal osteoporosis and to evaluate medical interventions for it., Methods: From an administrative claims database including 4,224,246 people in Japan, we classified women for whom the date of childbirth had been defined and who had suffered low-trauma fracture between the ages of 18-47 years as the premenopausal osteoporosis group. A fracture site for which the odds ratio for fractures occurring between 5 months before and 12 months after childbirth (around childbirth) was greater than 1 was considered the PLO site. We classified patients with a fracture at the PLO site around childbirth as the PLO group. The control group consisted of 500 women without fragility fractures. We investigated some drugs and diseases to explore fracture-causing factors, as well as medical interventions such as osteoporosis diagnosis, bone densitometry, anti-osteoporosis pharmacotherapy, and lactation inhibitors., Results: In total, 231 parous women were classified into the premenopausal osteoporosis group. The most common fracture was vertebral fracture and was likely to occur around childbirth, followed by distal radius and sacral fractures, which were rare around childbirth. Considering vertebral, pelvic, and proximal femoral fractures as PLO sites, 56 women with 57 PLO fractures were classified into the PLO group. The incidence of PLO was estimated at 460 per million deliveries. Ovulation disorder and high maternal age were associated with the development of PLO. Vertebral fracture was the most common PLO fracture. It was mainly diagnosed a few months, and possibly up to 1 year, postpartum. PLO patients with vertebral fractures underwent more medical interventions than did those with other fractures, but they were still inadequate., Conclusions: PLO with vertebral fracture was one of the major types of premenopausal osteoporosis. The prevalence of PLO is considered to be higher than previously thought, indicating the presence of potentially overlooked patients. More timely interventions for PLO might lead to the improved management of latent patients with premenopausal osteoporosis and reduce future fracture risk., (© 2024. The Author(s).)

Background: Pediatric allergic rhinitis (AR), including cedar pollinosis (CP), is increasing in Japan. We investigated the effects of sublingual immunotherapy (SLIT), which has limited studies of its effectiveness in real-world settings, on children with CP., Methods: This retrospective cohort study used a claim database in 2018-2021. Children aged ≤15 years with CP records in 2019 were eligible and were followed up through 2021. We included 2962 CP children undergoing SLIT and 547 who were not. The medication score was used to evaluate SLIT effectiveness in the cedar pollen dispersal season each year. Adverse events and the occurrence of allergic diseases were also evaluated., Results: Medication score was higher in the SLIT group during the index period but lower in 2021 compared to the non-SLIT group (mean ± standard deviation: 5.17 ± 2.39 and 4.74 ± 2.38 in 2019, 3.13 ± 2.30 and 3.55 ± 2.48 in 2021, respectively). The adjusted mean difference between groups from 2019 to 2021 was -0.62 (95% confidence interval: -0.86 to -0.39, p < .0001), and the medication score was reduced in the SLIT group (risk ratio: 1.2: 1.1 to 1.3). The occurrence of adverse events involving abdominal disorders (adjusted odds ratio [aOR]: 0.64: 0.51 to 0.81), asthma exacerbation (aOR: 0.37: 0.24 to 0.57), and allergic diseases involving hay fever unrelated to CP (aOR: 0.60: 0.45 to 0.80) or asthma (aOR: 0.71: 0.58 to 0.86) was lower in the SLIT group., Conclusion: In children with CP, SLIT is effective, well tolerated, and could decrease the occurrence of other allergic diseases., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Aim: To examine the effect of nutritional guidance (NG) provided by a registered dietitian under the direction of a physician on the development of subsequent cardiovascular events in patients with early-stage type 2 diabetes mellitus (T2DM)., Materials and Methods: This retrospective cohort study used the JMDC claims database to explore patients aged 18 years or older who first met the diagnostic criteria for T2DM at a health checkup between January 2011 and January 2019. The last day of the observation period was set for 28 February, 2021. Exposure was defined as receiving NG within 180 days of diagnosis of T2DM. The primary outcome was a composite endpoint of coronary artery disease (CAD) and cerebrovascular disease, and the secondary outcomes were each event, and time to event was compared. The propensity score weighting method was used for adjusting the distribution of confounding variables. Cox regression was conducted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: Overall, 31,378 patients met the eligibility criteria at an annual health checkup. 9.6% received NG (n = 3013). Patients who attended ≥ 1 NG after diagnosis had significantly reduced risk of cardiovascular composite (adjusted HR 0.75, 95% CI 0.58-0.97) and cerebrovascular disease (adjusted HR 0.65, 95% CI 0.47-0.90) during approximately 3.3 years of follow-up. In contrast, no difference was observed for CAD., Conclusions: Receiving NG in early-stage diabetes may reduce the incidence of cardiovascular events, especially cerebrovascular events., (© 2023. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Little is known about antipsychotic prescription patterns among children and adolescents in Japan, particularly in outpatient settings. We investigated the prevalence and trends of antipsychotic prescription for outpatients aged ≤ 17 years receiving a first antipsychotic prescription from 2006 to 2012 based on a large-scale dispensation dataset. Measurements included age, sex, department of diagnosis and treatment, type of prescription (monotherapy or polytherapy), antipsychotic dosage, and concomitant psychotropic drugs. Of the 10,511 patients, 65.1% were aged 13-17 years, and 52.9% were males. Second-generation antipsychotic monotherapy prescriptions increased from 53.8% in 2006 to 78.3% in 2012. Risperidone was the most frequently prescribed antipsychotic, followed by aripiprazole and olanzapine. Approximately 25.0% of patients were prescribed an initial dose less than recommended. Second-generation antipsychotic monotherapy is currently the most frequent prescription pattern among outpatients aged ≤ 17 years receiving an initial antipsychotic prescription., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: To investigate the incidence and in-hospital mortality of acute myocardial infarction (AMI) by conforming to the Universal Definition of Myocardial Infarction (UDMI) in a population-based registry., Methods: The Shiga Stroke and Heart Attack Registry is a multicenter, population-based registry in the Shiga Prefecture, designed to evaluate the incidence and prognosis of acute cerebro-cardiovascular diseases. We registered patients with AMI as defined by the UDMI, who developed AMI from January 2014 to December 2015 in the Shiga Prefecture. The incidence rate of AMI was calculated and standardized for age by a direct method using the 2015 Japanese population. We also evaluated the in-hospital mortality among hospitalized patients with ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI)., Results: A total of 1,587 patients were diagnosed with AMI, and the age-adjusted incidence rate was 61.9 per 100,000 person-years. The proportions of patients with STEMI, NSTEMI, and type 3 myocardial infarction were 57%, 30%, and 12%, respectively. The incidence rates of AMI increased with age regardless of sex, which was the highest in those 85 years and older, with 389.7 per 100,000 person-years in men and 221.8 per 100,000 person-years in women. Age-adjusted in-hospital mortality among hospitalized patients with STEMI and NSTEMI was 12.3% and 5.8%, respectively., Conclusions: This population-based registry clarified the age-adjusted incidence rate of AMI under the application of the UDMI, highlighting that in-hospital mortality is still high among patients with STEMI in Japan.

Background: Acute aortic dissection (AAD) is a life-threatening cardiovascular disease, with a reported incidence rate ranging from 2.5 to 7.2 per 100,000 person-years in several population-based registries in Western countries, but epidemiological data are lacking in Japan., Methods and results: The Shiga Stroke and Heart Attack Registry is an ongoing multicenter population-based registry of cerebro-cardiovascular diseases. We enrolled patients who developed AAD, defined by any imaging examination method from 2014 to 2015 in Shiga Prefecture. Death certificates were used to identify cases that were not registered at acute care hospitals. The incidence rates of AAD were calculated by age categories and adjusted using standard populations for comparison. We evaluated differences in patient characteristics between Stanford type A-AAD and type B-AAD subtypes. A total of 402 incident cases with AAD were analyzed. The age-adjusted incidence rates using the 2015 Japanese population and the 2013 European Standard Population were 15.8 and 12.2 per 100,000 person-years, respectively. Compared with cases of type B-AAD, those with type A-AAD were older (75.0 vs. 69.9 years, P=0.001) and more likely to be women (62.3% vs. 28.6%, P<0.001)., Conclusions: Population-based incidence rates of AAD in Japan appear to be higher than in previous reports from Western countries. Incident cases with type A-AAD were older and female predominance.

Background: Omega-3 polyunsaturated fatty acids (PUFAs) have been a hot topic since the Japan EPA Lipid Intervention Study (JELIS), the first landmark study using a highly purified eicosapentaenoic acid (EPA), indicated that EPA could decrease the incidence of cardiovascular events. Over 20 years have passed since the JELIS was conducted, and the standard treatment for dyslipidemia has altered significantly since then. The JELIS subjects did not undertake the current risk management especially current standard statins and did not exclusively target secondary prevention patients. In addition, the subjects included are relatively high EPA population. Furthermore, the clinical implication of the plasma EPA/arachidonic acid (AA) ratio as a biomarker has not yet been validated. Therefore, the Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy - Statin and EPA (RESPECT-EPA) was planned and is currently underway in Japan., Methods: The RESPECT-EPA comprises two parts: the open-label randomized controlled trial (RCT) and biomarker study (prospective cohort study design). The RCT included patients with a low EPA/AA ratio. These patients were then randomized to highly purified EPA (1800 mg/day) or control groups. The primary endpoint was cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, unstable angina pectoris, and clinically indicated coronary revascularization. The biomarker study assesses the EPA/AA ratio's usefulness as a biomarker for cardiovascular events prediction., Results: In the RCT, a total of 2,460 patients were enrolled in 95 sites in Japan. Patients' baseline characteristics were similar between intervention and control groups in the RCT. The baseline median EPA/AA ratio was 0.243 and 0.235, respectively. A total of 1,314 patients were participated in the observational part, and the baseline median EPA/AA ratio was 0.577., Conclusions: After this study is completed, we will have further evidence on whether a highly purified EPA is effective in reducing cardiovascular events for secondary prevention or not, as well as whether if EPA/AA ratio is a predictor for future cardiovascular events. This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000012069)., Competing Interests: Disclosures YN reports no conflicts of interest. KM received honoraria from Daiichi Sankyo and Bayer Health Care. HI received research grants from Mitsubishi Tanabe Pharma Corp., Kowa Pharmaceuticals Co., Ltd., and Novo Nordisk, and honoraria from Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co. Ltd., MSD KK, Kowa Pharmaceuticals Co., Ltd., and Mitsubishi Tanabe Pharma Corp. TI reports no conflicts of interest. AH reports no conflicts of interest. KK received research grants from Takeda Pharmaceutical, Kowa Pharmaceuticals, CSL Behring, Otsuka Pharmaceutical, Bayer Yakuhin, Research Institute for Production Development, Bristol-Myers Squib, and honoraria from Bayer Yakuhin, Daiichi Sankyo, Sanofi, Bristol-Myers Squibb, and Idorsia Pharmaceuticals Japan, Boehringer Ingelheim, Otsuka Pharmaceutical, Amgen, Pfizer, FUJIFILM Toyama Chemical, Novartis Japan, Astellas Pharma Inc, AstraZeneca, Abbott Medical, Eli Lilly Japan, Kowa Pharmaceuticals, Sumitomo Dainippon Pharma, Teijin Pharma, TOA EIYO Mitsubishi Tanabe Pharma Corporation. YO received a research grant from Takeda, Daiichi Sankyo, Otsuka, Bayer, and Terumo. TM received research grants from Daiichi Sankyo, Takeda, Astellas, Pfizer Japan, and Mitsubishi Tanabe, and honoraria from Bayer, MSD, Kowa, AstraZeneca, Novo Nordisk, and Nippon Boehringer Ingelheim. KU reports no conflicts of interest. YK reports no conflicts of interest. ST-M reports no conflicts of interest. NY reports no conflicts of interest. TS reports no conflicts of interest. HD received honoraria from Amgen Inc, Daiichi Sankyo Company, Ltd., Kowa Company, Ltd., MSD K.K., Sanofi K.K., Pfizer Japan Inc, FUKUDA DENSHI., TSUMURA & CO., TOAEIYO LTD, Taisho Pharmaceutical Co., Ltd., Abbott, Novartis Pharma K.K., and Bayer Yakuhin, Ltd., a research grant from Philips Japan Inc, GLORY LTD., Fujifilm Holdings Corporation, Asahi Kasei Corp., Inter Reha Co., Ltd., TOHO HOLDINGS CO., LTD., and scholarship grant from Eisai Co., Ltd., Bayer Yakuhin, Ltd., Daiichi Sankyo Company, and courses endowed by Philips Japan Inc, ResMed, FUKUDA DENSHI, and PARAMOUNT BED HOLDINGS CO., LTD., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The relationship between diabetes control status and long-term prognosis after stroke incidence remains unclear. This study aimed to investigate the effect of diabetes status at admission on long-term survival in patients with first-ever stroke., Methods: A retrospective cohort study was conducted based on the Shiga Stroke and Heart Attack Registry in Japan. Patients were classified according to their diabetes status and glycated hemoglobin (HbA1c) value at hospital admission into the following: (1) free of diabetes (no history of diabetes and HbA1c <6.5%); (2) good control (history of diabetes and HbA1c <7%; free of history and 6.5% ≤HbA1c <7%); and (3) poor control (with or without a history of diabetes and HbA1c ≥7%). Multivariable Cox regression models were used to evaluate the association between diabetes status and long-term survival from stroke onset. Additionally, we also evaluated the association between diabetes status and conditional survival, beginning 29 days after stroke onset., Results: A total of 6,331 first-ever stroke patients were eligible for this study. Among study patients, the mean (±SD) age was 72.85 ± 13.19 years, and the mean (±SD) follow-up year was 2.76 ± 1.66 years; additionally, 42.09% of patients were women. Among patients with all strokes, considering the free-of-diabetes group as the reference group, the adjusted hazard ratio (95% confidence interval) for mortality was 1.26 (1.10, 1.44) in the good control group and 1.22 (1.05, 1.41) in the poor control group. Among patients with ischemic stroke, the adjusted hazard ratio was 1.24 (1.06, 1.46) in good control group and 1.27 (1.08, 1.50) in poor control group. After excluding patients who died within 28 days, the adjusted hazard ratio for conditional mortality in the poor control group was 1.31 (1.12, 1.54) among all stroke patients and 1.29 (1.08, 1.54) among ischemic stroke patients. No significant associations were observed between diabetic status and long-term mortality in intracerebral hemorrhage patients., Conclusions: The findings suggest that first-ever stroke patients with diabetes exhibited a higher risk of all-cause mortality than those without diabetes, particularly in the overall stroke and ischemic stroke populations. Additionally, in stroke populations after 28 days of onset, high risk of long-term mortality was stated in stroke patients with poor HbA1c control., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Aims: School-based routine screenings of electrocardiograms (ECGs) have been performed upon admission to primary school (PS), junior high school (JHS), and high school (HS) in Japan. Though ECGs with prolonged QT intervals are occasionally found, the role of regular ECG screening tests in identifying long QT syndrome (LQTS) remains to be determined. We investigated the usefulness of the ECG screenings by comparing the results of genetic tests between students who showed QT-prolongation in the screenings and patients with LQTS., Methods and Results: We genetically screened 341 students (106 PS, 173 JHS, and 62 HS). Of these, 230 subjects showed QT-prolongation during regular screenings (S-S group), and the other 111 patients were clinically consulted with suspected LQTS by paediatricians (C-C group). Genotype-phenotype relationships were compared between the two groups. The positive rates in the genetic tests were comparable among the two groups; however, symptomatic subjects were significantly fewer in the S-S group than the C-C group (3% vs. 70%). Compared to the genotype-negative subjects, the positive subjects showed significantly longer QTc (P < 0.0001) and more frequently presented LQTS risk scores with ≥3.5 points (P < 0.0001). Lethal arrhythmic events (LAE) occurred only in the C-C group; 18 subjects experienced LAE and 83% of them were found to carry variant(s) in the LQTS-related genes., Conclusion: The school-based ECG screenings are effective in identifying young patients with LQTS who require genetic analysis. If individuals are screened at a younger age, we can identify patients at risk earlier and provide preventative treatments., Competing Interests: Conflict of interest: none declared., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

We aimed to evaluate the changes in maternal and neonatal complications such as threatened preterm labor (TPL) and preterm birth before and during the coronavirus disease 2019 (COVID-19) pandemic using large-scale real-world data in Japan. We obtained data from the Japan Medical Data Center claims database and evaluated differences in maternal and neonatal complications, such as the prevalence of TPL and preterm birth before the COVID-19 pandemic (in the year 2018 or 2019) and during the COVID-19 pandemic (in 2020). We included 5533, 6257, and 5956 deliveries in the years 2018, 2019, and 2020, respectively. TPL prevalence and preterm birth had significantly decreased in 2020 (41.3%, 2.6%, respectively) compared with those reported in 2018 (45.3%, 3.9%, respectively) and 2019 (44.5%, 3.8%, respectively). Neonatal outcomes such as low-birth-weight infants and retinopathy of prematurity were also improved during the pandemic. There were no clear trends in the prevalence of maternal complications such as hypertensive disorders of pregnancy; hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; and preeclampsia. Oral ritodrine hydrochloride usage in all participants had significantly decreased during the COVID-19 pandemic. In conclusion, our results suggest that the COVID-19 pandemic has ameliorated TPL and consequently reduced the number of preterm births., (© 2022. The Author(s).)

We investigated the prevalence of hypertensive patients and treated hypertensive patients using a Japanese nationwide administrative claims database. We analyzed national database data from 2014, including all claims data, provided by the Ministry of Health, Labour and Welfare of Japan. Hypertensive diseases were identified using Japanese standardized disease codes. Among hypertensive patients, treated hypertensive patients were defined by the prescription of any antihypertensive medication, identified using national health insurance price listing codes. We calculated and compared the number and age-adjusted prevalence of hypertensive patients and treated hypertensive patients by prefecture and the proportion of these patients by the size of medical facilities. In 2014, approximately 27 million Japanese people were identified as hypertensive, among which 89.6% were treated. The age-adjusted prevalence of hypertensive patients (per 100,000 persons) among women and men was 21,414 and 21,084, respectively. The age-adjusted prevalence of treated hypertensive patients (per 100,000 persons) among women and men was 19,118 and 18,974, respectively. While the prevalence of hypertensive and treated hypertensive patients varied geographically, the prevalence remained similar between the sexes. Approximately 59% of hypertensive patients visited clinics (0 to 19 beds) in Japan. In Japan, 27 million people were diagnosed with hypertensive diseases, and approximately 90% of these patients were treated with any antihypertensive medication in 2014. The distribution of hypertensive patients varied geographically throughout Japan., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Background: Immune-mediated pneumonitis has a high mortality rate; however, information regarding the related risk factors remains limited. This study aimed to analyze risk factors for pneumonitis, including smoking and lung metastasis (LM), in patients with extrapulmonary primary tumors., Methods: Data of 110 patients treated with immune checkpoint inhibitors (ICIs) (nivolumab/pembrolizumab) for treating extrapulmonary primary tumors at the Shiga University of Medical Science Hospital between January 2015 and December 2019 were retrospectively collected. The association between the onset of pneumonitis and treatment-related factors was analyzed by logistic regression. The severity of pneumonitis was graded according to the Common Terminology Criteria for Adverse Events version 5.0. Risk factors, such as the absence or presence of interstitial lung disease (ILD) and LM, or other clinical factors, including smoking status before ICI administration, were analyzed., Results: Multivariate analyses indicated that the amount of smoking was significantly associated with an increase in the development of all-grade pneumonitis types (odds ratio (OR) = 20.33, 95% confidence interval (CI) = 20.03-20.66; p = 0.029). LM and ILD were significantly related to an increase in the development of symptomatic pneumonitis (≥ Grade 2) (OR = 10.08, 95% CI = 1.69-199.81; p = 0.076, and OR = 6.76, 95% CI = 1.13-40.63; p = 0.037, respectively)., Conclusions: Pre-screening for ILD and LM and recognizing patients' smoking history is important for determining the risk of ICI-induced pneumonitis and allowing safe ICI administration., (© 2022. The Author(s).)

Aim: We aimed to determine whether SGLT2 inhibitor dapagliflozin treatment affects body composition and amino acid (AA) metabolism., Methods: Fifty-two overweight patients treated by oral antidiabetic agents were randomly assigned to dapagliflozin (Dapa) or a standard treatment (Con) and followed for 24 weeks. The primary outcome was the change in body mass (BM) between baseline and week 24. Body composition, intrahepatic triglyceride (IHTG) content, and plasma AA concentrations were examined as secondary outcomes., Results: The change in BM was significantly larger in the Dapa than in the Con group, with a difference in the mean change of -1.72 kg (95 %CI: -2.85, -0.59; P = 0.004) between the groups. Total fat mass was reduced by dapagliflozin treatment, but fat-free mass was maintained. IHTG content was significantly reduced in the Dapa than in the Con (P = 0.033). Changes in AAs showed small differences between the groups, but only serine concentrations were significantly reduced in the Dapa. Intra-group analysis showed that positive associations were observed between changes in branched chain AA concentrations and body composition only in the Dapa., Conclusions: Dapagliflozin treatment causes a reduction in BM mainly by reducing fat mass. AA metabolism shows subtle changes with dapagliflozin treatment., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: High levels of participation in leisure-time and household physical activity lower the risk of cardiovascular disease (CVD), although it is unclear whether the number of activity types is related to new-onset CVD. We aimed to evaluate the effect of the amount of leisure-time physical activity and the number of types of leisure-time physical activities on the risk of CVD incidence., Methods: From 2002 to 2003, 3,741 participants without any history of CVD participated in the Takashima Study. Data on the amount of leisure-time and household physical activity and the types of leisure-time and household physical activity were obtained from a self-administered questionnaire. Hazard ratios for CVD (acute myocardial infarction and stroke) incidence (follow-up data from 2002 to 2013), according to the participation level and number of activity types, were calculated using Cox proportional hazards models., Results: The mean age of the subjects was 58.7 ± 13.1 years. During the mean follow-up period of 8.0 ± 1.1 years, 92 participants developed CVD. An inverse dose-response relationship was noted between the amount of leisure-time and household physical activity and CVD events. After adjusting for baseline characteristics, lifestyle-related diseases, and the amount of physical activity other than leisure-time and household, the risk of CVD onset was compared by dividing the participants into two groups by the level of participation; the highest activity group had an adjusted hazard ratio (95% confidence interval) of 0.40 (0.20-0.82) compared to the lowest activity group. Compared to participants who engaged in 0-1 type of activity, participants who engaged in two or more types of activities had a multivariable-adjusted hazard ratio (95% confidence interval) of 0.31 (0.12-0.79)., Conclusion: Increasing the amount of leisure-time and household physical activity and promoting engagement in two or more types of such activities may reduce the rate of CVD incidence in the Japanese general population., (© 2022. The Author(s).)

Purpose: We aimed to evaluate adherence and persistence to warfarin therapy among patients with antiphospholipid syndrome (APS) and investigate the association between adherence and thrombotic events in those patients., Methods: We conducted a retrospective cohort study using the Japan Medical Data Center claims database from 2005 to 2018. Patients with APS receiving warfarin treatment were included in this study. Adherence and persistence were evaluated using the proportion of days covered (PDS) and refill gap methods, respectively. Demographic characteristics of patients were obtained. Kaplan-Meier curves with log-rank tests and Cox regression models were used to examine the association between adherence or persistence and time to thrombotic events., Results: A total of 186 patients (mean age: 46.5 ± 12.4 years, females 68.8%) were included in this study. No significant differences were observed in risk factors for thrombosis and cardiovascular diseases among groups. Most patients were adherent (91.4%) and persistent (88.2%) to warfarin treatment. Adherent and persistent patients had a significantly higher rate of thrombotic event-free survival than nonadherent and nonpersistent patients (p < 0.05). Multivariable Cox regression showed that the risk of thrombotic events was higher in nonadherent patients (with a hazard ratio of 3.23 [95% confidence interval CI: 1.15-9.11]) and in nonpersistent patients (with a hazard ratio of 3.45 [95% CI: 1.35-8.82])., Conclusions: In patients with APS, nonadherence and nonpersistence to warfarin treatment was associated with a higher risk of thrombotic events, suggesting the careful monitoring of those patients., (© 2021 John Wiley & Sons Ltd.)

Background: Both physical and psychological factors have been associated with functional disability. However, the associations between stress-coping strategies and future functional disability remain unclear., Methods: We analyzed 2,924 participants who did not have incidence of functional disability or death within the first 3 years of the baseline survey and were aged 65 years or more at the end of follow-up. Stress-coping strategies were assessed via a self-administered questionnaire (emotional expression, emotional support seeking, positive thought, problem-solving, and disengagement) in a baseline survey from 2006 to 2014. Levels of coping strategies were classified as low, middle, and high based of frequency. Functional disability decline was followed up using the long-term-care insurance program until November 1, 2019. Functional disability decline was defined as a new long-term-care insurance program certification. Cox proportional hazards model with competing risk analysis for death was used to evaluate associations between coping strategy levels and functional disability., Results: During the follow-up period, we observed 341 cases of functional disability and 73 deaths without previous incidence of functional disability. A significant inverse association between "positive thought" and "problem-solving" and future functional disability was observed. Multivariable adjusted hazard ratios (95% confidence interval) for functional disability were 0.68 (0.51-0.92) for high levels of "positive thought" and 0.73 (0.55-0.95) for high levels of "problem-solving," compared with low levels of the coping strategies. The inverse association was stronger in men., Conclusions: Some subcomponents of stress-coping strategies might be associated with future incidence of functional disability among older adults., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Introduction: The purpose of this study was to investigate seasonal variation in stroke incidence using data from a large-scale stroke registry of general population in current Japan., Methods: Shiga Stroke Registry (SSR) is an ongoing population-based registry of stroke that occurred in the Shiga Prefecture in central Honshu, Japan. A total 6,688 cases of first-ever stroke, with onset dates ranging from 1 January 2011 to 31 December in 2013 were included in this study. Incidence rates of first-ever stroke in each season were estimated using the person-year approach and adjusted for age and sex using the Poisson regression models., Results: From 2011 to 2013, we identified a total of 6,688 stroke cases (3,570 men, 3,118 women), of which 4,480 cases had ischemic stroke (2,518 men, 1,962 women), 1,588 had intracerebral hemorrhage (857 men, 731 women) and 563 had subarachnoid hemorrhage (166 men, 397 women). Age- and sex-adjusted incidence rates of total stroke were 151 (95% confidence interval [CI] 144-160, p = <0.001 vs. summer) in spring, 130 (95% CI 122-137) in summer, 141 (95% CI 133-149, p = 0.020 vs. summer) in autumn and 170 (95% CI 161-179, p = <0.001 vs. summer) in winter. Seasonal variation was more pronounced in intracerebral hemorrhage than in ischemic stroke., Conclusion: In the present large-scale stroke registry of general population, incidence rates of stroke were highest in winter and lowest in summer in current Japan., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Hospital-based registry data, including patients' information collected by academic societies or government based research groups, were previously used for clinical research in Japan. Now, real-world data routinely obtained in healthcare settings are being used in clinical epidemiology and pharmacoepidemiology. Real-world data include a database of claims originating from health insurance associations for reimbursement of medical fees, diagnosis procedure combinations databases for acute inpatient care in hospitals, a drug prescription database, and electronic medical records, including patients' medical information obtained by doctors, derived from electronic records of hospitals. In the past ten years, much evidence of clinical epidemiology and pharmacoepidemiology studies using real-world data has been accumulated. The purpose of this review was to introduce clinical epidemiology and pharmacoepidemiology approaches and studies using real-world data in Japan.

Background: Using a population-based stroke registry system, we evaluated the relationship between ambient temperature parameters and stroke incidence in a Japanese population., Methods and results: We analyzed data from the Takashima Stroke Registry, which records all stroke occurrences in Takashima City, Japan. The study period of 8,401 days was divided into quintiles of daily weather parameters, and the middle quintile was used as the reference category. Incidence rates (IR per 100,000 person-years) were calculated across the quintiles. Poisson regression analysis was used to calculate the effect of temperature parameters on stroke incidence. There were 2,405 first-ever strokes (1,294 men), including 1,625 ischemic, 545 cerebral hemorrhages, 213 subarachnoid hemorrhages, and 22 unclassified strokes. The stroke IR was higher in the middle quintile of average temperature, 357.3 (328.4-388.8), and for other parameters. After adjustment for age and sex, for all stroke, the incidence rate ratio (IRR) in the highest (Q5: IRR 0.81, 95% confidence interval (CI) 0.71-0.92) and the second-highest (Q4: IRR 0.80, 95% CI 0.71-0.91) quintile was lower than that in the middle quintile (Q3: Reference). Analogous results were observed for the minimum, maximum, and lag-days temperatures, also in the subtypes and across ≥65 years of age, also in females., Conclusions: Higher temperatures, irrespective of the parameter (average, minimum, or maximum), had a protective effect against stroke occurrence in Japan.

Introduction: Cost-effectiveness analyses are becoming increasingly important in Japan following the introduction of a health technology assessment scheme. The study objective was to develop an economic model to evaluate the cost-effectiveness of two interventions for type 2 diabetes in a Japanese population., Research Design and Methods: The Japan Diabetes Complications Study/Japanese Elderly Diabetes Intervention Trial risk engine (JJRE) Cost-Effectiveness Model (JJCEM) was developed, incorporating validated risk equations in Japanese patients with type 2 diabetes from the JJRE. Weibull regression models were developed for progression of the model outcomes, and a targeted literature review was performed to inform default values for utilities and costs. To illustrate outcomes, two simulated analyses were performed in younger (aged 40 years) and older (aged 80 years) Japanese populations, comparing a hypothetical treatment with placebo., Results: The model considers a population based on user-defined values for 11 baseline characteristic parameters and simulates rates of diabetic complications over a defined time horizon. Costs, quality-adjusted life years, and an incremental cost-effectiveness ratio are estimated. The model provides disaggregated results for two competing interventions, allowing visualization of the key drivers of cost and utility. A scatterplot of simulations and cost-effectiveness acceptability curve are generated for each analysis., Conclusions: This is the first cost-effectiveness model for East Asian patients with type 2 diabetes, developed using Japan-specific risk equations. This population constitutes the largest share of the global population with diabetes, making this model highly relevant. The model can be used to evaluate the cost-effectiveness of anti-diabetic interventions in patients with type 2 diabetes in Japan and other East Asian populations., Competing Interests: Competing interests: JL is an employee of Novo Nordisk Pharma Ltd. TMorton and NH are consultants at DRG Abacus. ST has received lecture fees from Bayer Yakuhin, Amgen Astellas BioPharma, and the Research Institute of Healthcare Data Science. ST has received consultation fees and outsourcing fees from Boehringer Ingelheim, Satt and the Public Health Research Foundation. ST has received research grants from the Japan Agency for Medical Research and Development, the Japanese Ministry of Health Labor and Welfare, the Japanese Ministry of Education, Science, and Technology, and Novo Nordisk Pharma Ltd. AA has received speaker honoraria from pharmaceutical companies, Merck Sharp & Dohme, Dainippon Sumitomo Parma Co, Kyowa Hakko Kirin Co, Tanabe Mitsubishi Pharma Corporation, Eli Lilly Japan Co, and Takeda Pharmaceutical Co. HS has received a research grant from Novo Nordisk Pharma Ltd., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: Lifetime risk (LTR) indicates the absolute risk of disease during the remainder of an individual's lifetime. We aimed to assess the LTRs for coronary heart disease (CHD) mortality associated with blood pressure (BP) and total cholesterol levels in an Asian population using a meta-analysis of individual participant data because no previous studies have assessed this risk., Methods: We analyzed data from 105,432 Japanese participants in 13 cohorts. Apart from grade 1 and 2-3 hypertension groups, we defined "normal BP" as systolic/diastolic BP ＜130/＜80 mmHg and "high BP" as 130-139/80-89 mmHg. The sex-specific LTR was estimated while considering the competing risk of death., Results: During the mean follow-up period of 15 years (1,553,735 person-years), 889 CHD deaths were recorded. The 10-year risk of CHD mortality at index age 35 years was ≤ 0.11%, but the corresponding LTR was ≥ 1.84%. The LTR of CHD at index age 35 years steeply increased with an increase in BP of participants with high total cholesterol levels [≥ 5.7 mmol/L (220 mg/dL)]. This risk was 7.73%/5.77% (95% confidence interval: 3.53%-10.28%/3.83%-7.25%) in men/women with grade 2-3 hypertension and high total cholesterol levels. In normal and high BP groups, the absolute differences in LTRs between the low and high total cholesterol groups were ≤ 0.25% in men and ≤ 0.40% in women., Conclusions: High total cholesterol levels contributed to an elevated LTR of CHD mortality in hypertensive individuals. These findings could help guide high-risk young individuals toward initiating lifestyle changes or treatments.

Several studies have reported a J-shaped relationship between alcohol consumption and coronary heart disease (CHD) risk. However, the mechanisms of this relationship remain unclear. This study aimed to evaluate the relationships of alcohol consumption with established CHD risk factors and with macro-/micro-nutrient intake among Japanese people. Participants were 1,090 Japanese men and women aged 40-59 y enrolled in the INTERLIPID study, excluding former drinkers. Based on two 7-d alcohol records, participants were classified as non-drinkers (0 g/wk), light-drinkers (<100 g/wk), moderate-drinkers (100-299 g/wk), or heavy-drinkers (≥300 g/wk). Detailed macro-/micro-nutrient intake was evaluated using four in-depth 24-h dietary recalls and adjusted for total energy intake excluding alcohol. We analyzed the associations of CHD risk factors and nutrient intake with alcohol consumption. Serum high-density lipoprotein cholesterol and blood pressure were higher and low-density lipoprotein cholesterol was lower among those with higher alcohol consumption. J-shaped relationships with alcohol consumption were observed for the proportion of current smokers, number of cigarettes smoked, and prevalence of hypertension; these risk factors were lowest among light-drinkers. Carbohydrate and total fiber intakes were lower and protein and dietary cholesterol intakes were higher among those with higher alcohol consumption. These associations were similar for men and women. Alcohol consumption was related to nutrient intake as well as established CHD risk factors. Non-drinkers were higher on some CHD risk factors than were light-drinkers. These findings may influence the J-shaped relationship between alcohol consumption and CHD risk.

The constraint values of dose-volume histogram (DVH) parameters for radiation pneumonitis (RP) prediction have not been uniform in previous studies. We compared the differences between conventional DVH parameters and DVH parameters with high attenuation volume (HAV) in CT imaging in both esophageal cancer and lung cancer patients to determine the most suitable DVH parameters in predicting RP onset. Seventy-seven and 72 patients who underwent radiation therapy for lung cancer and esophageal cancer, respectively, were retrospectively assessed. RP was valued according to the Common Terminology Criteria for Adverse Events. We quantified HAV with quantitative computed tomography analysis. We compared conventional DVH parameters and DVH parameters with HAV in both groups of patients. Then, the thresholds of DVH parameters that predicted symptomatic RP and the differences in threshold of DVH parameters between lung cancer and esophageal cancer patient groups were compared. The predictive performance of DVH parameters for symptomatic RP was compared using the area under the receiver operating characteristic curve. Mean lung dose, HAV30% (the proportion of the lung with HAV receiving ≥30 Gy), and HAV20% were the top three parameters in lung cancer, while HAV10%, HAV5%, and V10 (the percentage of lung volume receiving 10 Gy or more) were the top three in esophageal cancer. By comparing the differences in the threshold for parameters predicting RP between the two cancers, we saw that HAV30% retained the same value in both cancers. DVH parameters with HAV showed narrow differences in the threshold between the two cancer patient groups compared to conventional DVH parameters. DVH parameters with HAV may have higher commonality than conventional DVH parameters in both patient groups tested., Competing Interests: Daiichi-Sankyo Company, Limited, Ono Pharmaceutical Company, Limited, Pfizer Japan, Bayer Corporation, Boehringer Ingelheim GmbH, and Astelas Pharma Global Development funded this study and had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors received no specific funding for this work and declare that they have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The consumption of red meat has been recommended for individuals with reduced kidney function. However, red meat intake was recently suspected to increase cardiovascular disease (CVD) risk. We evaluated the association of red meat intake with CVD mortality risk in Japanese with/without reduced kidney function. Overall, 9112 participants of a Japanese national survey in 1980, aged ≥30 years, were followed for 29 years. Red meat intake was assessed using weighed dietary record. Cox proportional hazards models were used to estimate the hazard ratio (HR) of CVD mortality according to sex-specific tertiles of red meat intake. We also performed stratified analyses with/without reduced kidney function defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m 2 . Red meat intake was not associated with CVD mortality risk in men and women. In stratified analyses, the HR of the highest compared with the lowest tertile of red meat intake was lower only in women with reduced kidney function (0.67, 95% confidence interval 0.46-0.98). In conclusion, there were no clear associations between red meat intake and CVD mortality risk in Japanese population; however, a higher intake of red meat was associated with lower risk of future CVD mortality in women with reduced kidney function.

Certain studies previously pointed out that treating pregnant women with antidepressants may increase risks of congenital anomalies in their children. However, to date, the study results are not conclusive. Furthermore, most studies have been performed using data from Western countries; therefore, we examined this association using Japanese data. This retrospective cohort study was based on claims data of mothers and their children from January 2005 to July 2014, obtained from the JMDC Inc. Information on antidepressant prescriptions was extracted from the database. Children were followed up from birth through July 2014 or until their withdrawal from the database and were identified for obtaining information on their congenital anomalies. We used logistic regression analysis to evaluate the association between maternal antidepressant use during pregnancy and the children's congenital anomalies. Of 53 864 eligible pairs of mothers and children, 53 697 pairs met the study criteria. No increased risk of total congenital anomalies in children whose mothers used antidepressants of any type during the first trimester of pregnancy was found in the analysis (adjusted analysis with confounders, odds ratio: 0.86; 95% confidence interval: 0.52, 1.42). In addition, there was no increased risk of organ specific anomalies in the analysis by type of antidepressant. We found no increased risk of congenital anomalies in children whose mothers used antidepressants during the first trimester of pregnancy compared to that of non-users based on the Japanese claims data. Additional studies are necessary to further clarify the association between antidepressant use during pregnancy and congenital anomalies in children., (© 2020 Japanese Teratology Society.)

Background: The prevalence of obesity in Russia has increased sharply since the mid-1990s. Interestingly, the prevalence of obesity in Japan is lower than in many Western countries. Japan has implemented different types of weight control programs using a smart device to monitor patients remotely. New health promotion methods from Japan are now being used in Russia. The Russian-Japanese "Tackle Obesity and Metabolic Syndrome Outcome by Diet, Activities and Checking Body Weight Intervention" (RJ-TOMODACHI) study aims to evaluate a preventive intervention using Japanese health monitoring technology in reducing excess body weight, compared with standard care, in Russia. Methods and Results: The trial is a single-center, 3-armed, parallel group randomized controlled trial conducted among overweight/obese adults. It has been designed to compare the effectiveness of 2 newly developed interventions against standard care for 6 months. Participants in the low- and high-intensity intervention groups will have 3 and 6 consultations over the study period, respectively. In all, 260 adults were screened at baseline; 65 did not participate in the trial for various reasons. The remaining 195 people were randomized into 3 groups (high-intensity intervention, n=73, low-intensity, n=73; standard care group, n=49). Conclusions: The trial protocol has been designed so that the methodology can be adapted for use in Russia., Competing Interests: Y.M. is a member of Circulation Reports’ Editorial Team. The other authors have no conflicts of interest to declare., (Copyright © 2020, THE JAPANESE CIRCULATION SOCIETY.)

The well-known gene-environment interaction between alcohol consumption and aldehyde dehydrogenase 2 (ALDH2) genotype in upper aerodigestive tract cancer risk may improve our ability to identify high-risk subjects. Here, we developed and validated risk prediction models for this cancer in Japanese men and evaluated whether adding the gene-environment interaction to the model improved the predictive performance. We developed two case-cohort datasets in the Japan Public Health Center-based Prospective Study: one from subjects in the baseline survey for model development (108 cases and 4049 subcohort subjects) and the second from subjects in the 5-year follow-up survey for model validation (31 cases and 1527 subcohort subjects). We developed an environmental model including age, smoking status, and alcohol consumption, and a gene-environment interaction model including age, smoking status, and the combination of alcohol consumption and the ALDH2 genotype. We found a statistically significant gene-environment interaction for alcohol consumption and the ALDH2 genotype. The c-index for the gene-environment interaction model (0.71) was slightly higher than that for the environmental model (0.67). The values of integrated discrimination improvement and net reclassification improvement for the gene-environment interaction model were also slightly higher than those for the environmental model. Goodness-of-fit tests suggested that the models were well calibrated. Results from external model validation by the 5-year follow-up survey were consistent with those from the model development by the baseline survey. The addition of a gene-environment interaction to a lifestyle-based model might improve the performance to estimate the probability of developing upper aerodigestive tract cancer for Japanese men., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background and Purpose: Although numerous measures for stroke exist, stroke remains one of the leading causes of death in Japan. In this study, we aimed to determine the long-term survival rate after first-ever stroke using data from a large-scale population-based stroke registry study in Japan., Methods: Part of the Shiga Stroke and Heart Attack Registry, the Shiga Stroke Registry is an ongoing population-based registry study of stroke, which covers approximately 1.4 million residents of Shiga Prefecture in Japan. A total 1,880 patients with non-fatal first-ever stroke (among 29-day survivors after stroke onset) registered in 2011 were followed up until December 2016. Five-year cumulative survival rates were estimated using the Kaplan-Meier method, according to subtype of the index stroke. Cox proportional hazards models were used to assess predictors of subsequent all-cause death., Results: During an average 4.3-year follow-up period, 677 patients died. The 5-year cumulative survival rate after non-fatal first-ever stroke was 65.9%. Heterogeneity was present in 5-year cumulative survival according to stroke subtype: lacunar infarction, 75.1%; large-artery infarction, 61.5%; cardioembolic infarction, 44.9%; intracerebral hemorrhage, 69.1%; and subarachnoid hemorrhage, 77.9%. Age, male sex, Japan Coma Scale score on admission, and modified Rankin Scale score before stroke onset were associated with increased mortality during the chronic phase of ischemic and hemorrhagic stroke., Conclusions: In this study conducted in a real-world setting of Japan, the 5-year survival rate after non-fatal first-ever stroke remained low, particularly among patients with cardioembolic infarction and large-artery infarction in the present population-based stroke registry.

Purpose: Severe adverse events frequently occur in patients treated with sorafenib, whereas some patients have suboptimal response to sorafenib. We aimed to evaluate the association of sorafenib-induced toxicities and clinical outcomes with the pharmacokinetics of sorafenib in patients with hepatocellular carcinoma (HCC)., Methods: This was a retrospective, observational study in which 26 HCC patients who had been treated with sorafenib were enrolled between September 2010 and March 2015. The association between trough sorafenib concentration and occurrence of grade ≥ 3 toxicities was evaluated. In addition, we estimated the association of trough sorafenib concentration with overall survival (OS)., Results: The median sorafenib concentration was 2.91 μg/mL (range 0.74-8.8 μg/mL). Based on the receiver operating characteristic curve, the threshold value of the trough sorafenib concentration for predicting grade ≥ 3 toxicities and responder (complete response or partial response at best response, or stable disease for ≥ 3 months) was 3.45 μg/mL [area under the curve (AUC) 0.74, 95% confidence interval (CI) 0.54-0.93; p <0.05] and 1.40 μg/mL (AUC 0.97, 95% CI 0.97-1.00; p <0.05), respectively. OS of patients with sorafenib 1.40-3.45 µg/mL had a tendency to be longer than those of patients administered < 1.40 μg/mL and ≥ 3.45 μg/mL [median 17.8 months (1.40-3.45 μg/mL) vs. 5.3 months (< 1.40 μg/mL) and 9.5 months (≥ 3.45 μg/mL)]., Conclusions: From results of this study, we proposed that the target range of sorafenib may be a trough concentration of 1.40-3.45 μg/mL in patients with HCC.

Background: Despite many effective strategies for the prevention of recurrent stroke, individuals who survive an initial stroke have been shown to be at high risk of recurrent stroke. The aim of this study was to investigate the current status of stroke recurrence after first-ever stroke using a population-based stroke registry in Japan.Methods and Results:As part of the Shiga Stroke and Heart Attack Registry, the Shiga Stroke Registry is an ongoing population-based stroke registry study that covers approximately 1.4 million residents of Shiga Prefecture, Japan. A total of 1,883 first-ever stroke survivors at 28 days was registered in 2011 and followed-up until the end of 2013. Recurrence was defined as any type of stroke after 28 days from the onset of an index event. Two-year cumulative recurrence rates were estimated using cumulative incidence function methods. Over a mean 2.1-year follow-up period, 120 patients experienced recurrent stroke and 389 patients died without recurrence. The 2-year cumulative recurrence rate was higher in patients with index ischemic stroke (6.8%) than in those with index hemorrhagic stroke (3.8%)., Conclusions: Two-year cumulative recurrence rate after first-ever stroke remained high, particularly among patients with ischemic stroke, in the present population-based registry study in a real-world setting in Japan. Further intensive secondary prevention strategies are required for these high-risk individuals.

Aim: The management of hepatitis C virus (HCV) has changed with the advent of interferon (IFN)-free treatment and the declining prevalence of HCV infection, which may impact the cost-effectiveness of the screening. We aimed to compare the cost-effectiveness and clinical outcomes of three screening strategies in the Japanese general population: no screening, screening plus IFN-based therapy, and screening plus IFN-free therapy., Methods: We developed a decision analytic Markov model for screening intervention and natural history of HCV. Model parameters were derived from published literature. A lifetime horizon and the healthcare payer perspective were taken. Subanalyses included high screening scenario with improved rates of screening and attending referral, in addition to heterogeneity analysis by age subgroup., Results: In the base case, the incremental cost-effectiveness ratio in the Japanese general population aged 40-89 years was ¥1 124 482 and ¥1 085 183 per quality-adjusted life year gained for screening plus IFN-free therapy compared with no screening and screening plus IFN-based therapy, respectively. Screening plus IFN-free therapy remained cost-effective below ¥5 000 000 per quality-adjusted life year gained in sensitivity analyses. Incremental cost-effectiveness ratios were lower in the younger population. Nearly 0.2% of HCV-related deaths were avoided by 1.5% of the general population screened followed by IFN-free therapy relative to no screening; the impact was greater with improved rates of screening and attending referral., Conclusions: Screening and subsequent IFN-free therapy for HCV appears to be cost-effective. Early diagnosis and treatment would produce a favorable incremental cost-effectiveness ratio. Improved rates of screening and attending referral would result in further reduction of disease progression., (© 2020 The Japan Society of Hepatology.)

Purpose: Our primary objective was to determine the benefit/risk of anthracycline-free regimens by comparing docetaxel + cyclophosphamide (TC) alone, fluorouracil + epirubicin + cyclophosphamide (FEC) followed by TC, or TC followed by FEC as a primary treatment for patients with HR-positive, HER2-negative BC., Methods: We randomized patients with stage I-III HR-positive HER2-negative, operable BC to receive either six cycles of TC (TC6), three cycles of FEC followed by three cycles of TC (FEC-TC), or three cycles of TC followed by three cycles of FEC (TC-FEC). The primary endpoint was the pathological response. Secondary endpoints included clinical response, type of surgical procedure, recurrence, death, and adverse events (by NCI-Common Terminology Criteria for Adverse Events v.3.0). We conducted all statistical analyses using SAS Version 9.2., Results: We enrolled 195 patients and analyzed data from 193 as the intention-to-treat population. Pathological complete response rates were numerically higher in the TC6 group than in the other groups (p = 0.321). The breast conservation rate was significantly higher in the TC6 group (73%) than in the other groups (FEC-TC 51%, TC-FEC 45%, p = 0.007). Adverse events with grade > 3 were not common in the treatment groups (p = 0.569). The overall and distant disease-free survivals were similar among the groups with median follow-up of 5.80 years., Conclusions: Despite similar long-term efficacy and safety profile, the higher breast conservation rate in the TC6 group suggests that preoperative chemotherapy without an anthracycline may benefit patients with HR-positive HER2-negative BC., Trial Registration: UMIN000003283 https://upload.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000003873.

Background: While being obese in mid-life is associated with an increased risk of dementia and cognitive decline in late-life, being obese in late-life is shown to be associated with a lower risk of these outcomes in some studies. This phenomenon is known as the "obesity paradox", but the underlying reasons and potential sex difference have not been well understood., Objective: To investigate the association between cognition and waist circumference (WC), an alternative measure of body fat which can be measured easier than body mass index (BMI), among older adults in each generation of late-life for men and women separately., Methods: Three hundred thirty-five participants were used in the current study who were identified by random sampling of residents aged 65-74, 75-84, and 85 + years in Takashima County, Shiga Prefecture, Japan during 2005-2006. Associations between WC and domain-specific cognitive functions measured by 12 neuropsychological tests were examined using multivariable linear regression models with covariates: age, education, and hypertension., Results: Larger WC was associated with better attention/working memory among 65-74-year old women and with better learning/acquisition among 65-74-year-old men, while larger WC was associated with worse learning/acquisition, memory, attention/working memory, and language/fluency among 75-84-year old men., Conclusion: We found age and sex differences in the association between WC and domain-specific cognitive functions. Among older old men (age 75-84), larger WC had negative effects on various domains including memory, attention, language, and executive functions, while we did not find any negative effects of larger WC on cognition among women in any age groups.

Background: We sought to investigate the optimal values of BMI for the lowest risk of all-cause death and whether the optimal BMI differs according to smoking status in large-scale pooled analysis of 13 Japanese cohorts., Methods: Data from 179,987 participants of 13 well-qualified cohort studies conducted throughout Japan were used for our analysis. A cohort-stratified Cox proportional hazard model was used. P values for interactions were calculated based on the cross product of BMI and age, sex, or smoking status., Results: In the entire study population, all-cause mortality risk was lowest when the BMI was 22.0-24.9 kg/m 2 . This was also the case for selected healthy participants (never smoked, baseline total cholesterol level ≥4.1 mmol/L; the first 5 years of follow-up data were excluded). No effect modification of age, sex, or smoking status was observed. Regardless of their BMI, never smokers always had a lower all-cause mortality risk than did current smokers even with an ideal BMI in terms of mortality risk., Conclusion: A BMI of 22-24.9 kg/m 2 correlated with the lowest risk of mortality, regardless of whether all participants or selected healthy participants were analyzed. The fact that smoking was more strongly associated with mortality than obesity emphasizes the urgency for effective anti-smoking programs.

The Na/K ratio may be more strongly related to blood pressure and cardiovascular disease than sodium or potassium. The casual urine Na/K ratio can provide prompt on-site feedback, and with repeated measurements, may provide useful individual estimates of the 24-h ratio. The World Health Organization has published guidelines for sodium and potassium intake, but no generally accepted guideline prevails for the Na/K ratio. We used standardized data on 24 h and casual urinary electrolyte excretion obtained from the INTERSALT Study for 10,065 individuals aged 20-59 years from 32 countries (52 populations). Associations between the casual urinary Na/K ratio and the 24-h sodium and potassium excretion of individuals were assessed by correlation and stratification analyses. The mean 24-h sodium and potassium excretions were 156.0 mmol/24 h and 55.2 mmol/24 h, respectively; the mean 24-h urinary Na/K molar ratio was 3.24. Pearson's correlation coefficients (r) for the casual urinary Na/K ratio with 24-h sodium and potassium excretions were 0.42 and -0.34, respectively, and these were 0.57 and -0.48 for the 24-h ratio. The urinary Na/K ratio predicted a 24-h urine Na excretion of <85 mmol/day (the WHO recommended guidelines) with a sensitivity of 99.7% and 94.0%, specificity of 39.5% and 48.0%, and positive predictive value of 96.3% and 61.1% at the cutoff point of 1 in 24 h and casual urine Na/K ratios, respectively. A urinary Na/K molar ratio <1 may be a useful indicator for adherence to the WHO recommended levels of sodium and, to a lesser extent, the potassium intake across different populations; however, cutoff points for Na/K ratio may be tuned for localization.

Aims/introduction: Sodium-glucose cotransporter 2 inhibitors reduce bodyweight (BW) by creating a negative energy balance. Previous reports have suggested that this BW reduction is mainly loss of body fat and that ~20% of the reduction is lean mass. However, the effects of sodium-glucose cotransporter 2 inhibitors on BW and body composition remain unclear. We examined these effects in Japanese patients with type 2 diabetes mellitus treated with insulin., Materials and Methods: In this open-label, randomized controlled trial, 49 overweight patients (body mass index ≥23 kg/m 2 ) with inadequate glycemic control (hemoglobin A1c >7.0%) receiving insulin treatment were randomly assigned to receive add-on ipragliflozin or no additional treatment (control group). Patients were followed for 24 weeks. The goal for all patients was to achieve glycated hemoglobin <7.0% without hypoglycemia. The primary end-point was a change in BW from baseline to week 24. Body composition was assessed with dual-energy X-ray absorptiometry and bioelectrical impedance analysis., Results: BW change was significantly larger in the ipragliflozin group than in the control group (-2.78 vs -0.22 kg, P < 0.0001). Total fat mass was reduced evenly in the arms, lower limbs and trunk in the ipragliflozin group. Total muscle mass and bone mineral content were maintained, but muscle mass in the arms might have been affected by ipragliflozin treatment., Conclusions: Ipragliflozin treatment for 24 weeks resulted in reduced BW, mainly from fat mass loss. Muscle mass and bone mineral content were maintained. Further study is necessary to elucidate the long-term effects of ipragliflozin., (© 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)