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Aim: A new treatment interval for nivolumab administration at 480 mg every 4 weeks, in addition to 240 mg every 2 weeks, was approved in Japan in 2020. Using model-based evaluation, it was speculated that the effects or safety of nivolumab do not differ between the two treatment intervals; however, real-world data on nivolumab efficacy, safety, and economic impact are lacking. Accordingly, we aimed to examine the effects of nivolumab treatment intervals (2 weeks vs. 4 weeks) in terms of efficacy, safety, and economic impact in Japanese patients with cancer., Methods: We retrospectively analyzed 126 patients treated with nivolumab. The patients were divided into two groups depending on whether they received nivolumab at 240 mg every 2 weeks (2-week group) or 480 mg every 4 weeks (4-week group)., Results: Efficacy results found no significant difference between the 4- and 2-week groups considering median overall survival (p = 0.70) and median progression-free survival (p = 0.57). The incidence of any grade and ≥  grade 3 immune-related adverse events did not differ between the 4-week and 2-week groups (any grade, p = 0.13; ≥  grade 3, p = 0.36). Excluding drug costs, the 4-week group had significantly lower medical costs than the 2-week group (2-week vs. 4-week: mean, 94,659 JPY [679.0 USD] vs. 58,737 JPY [421.3 USD]; p < 0.05)., Conclusion: Collectively, our findings suggest that nivolumab 480 mg every 4 weeks may be more effective than nivolumab 240 mg every 2 weeks in terms of economic impact., (© 2024 John Wiley & Sons Australia, Ltd.)

Introduction: A remission induction therapy of granulocyte and monocyte adsorptive apheresis (GMA) was given to patients with Crohn's disease (CD). However, establishing an appropriate treatment strategy for GMA in patients with CD remains unclear., Methods: This study evaluated the clinical efficacy and subsequent clinical progression after GMA in patients with CD who underwent GMA in seven independent institutions in Japan from 2010 to 2023., Results: Sixteen patients were enrolled. The overall remission and response rates were 25.0% and 68.8%, respectively. All patients responding to GMA received biologics that were continuously used and 36.4% of patients remained on the same biologics 52 weeks after GMA. Notably, all patients who continued the same biologics had previously experienced a loss of response to biologics., Conclusion: GMA may exhibit effectiveness even in cases with refractory CD. Moreover, it represents a potential novel therapeutic option for refractory CD with loss of response to biologics., (© 2024 International Society for Apheresis and Japanese Society for Apheresis.)

Introduction: The Lesbian, Gay, Bisexual, and Transgender Development of Clinical Skills Scale (LGBT-DOCSS) is a validated self-assessment tool for health and mental health professionals who provide healthcare for sexual and gender minority patients. This study aimed to develop and validate a Japanese version of LGBT-DOCSS (LGBT-DOCSS-JP) and examine its psychometric properties., Methods: LGBT-DOCSS was translated into Japanese and cross-culturally validated using cognitive debriefing. We then evaluated the structural validity, convergent and discriminant validity, internal consistency, and test-retest reliability of LGBT-DOCSS-JP using an online survey., Results: Data were analyzed for 381 health and mental health professionals aged 20 years or older from three suburban medical institutions. The confirmatory factor analysis indicated that the original three-factor model did not fit well with LGBT-DOCSS-JP. Exploratory factor analysis revealed four new factors: Attitudinal Awareness, Basic Knowledge, Clinical Preparedness, and Clinical Training. Convergent and discriminant validity were supported using four established scales that measured attitudes toward lesbians and gay men, genderism and transphobia, authoritarianism and conventionalism, and social desirability. The internal consistency of LGBT-DOCSS-JP was supported by the Cronbach's alpha values for the overall scale (0.84), and for each of its subscales (Attitudinal Awareness and Basic Knowledge both 0.87, Clinical Preparedness 0.78, and Clinical Training 0.97). The test-retest reliability for the overall LGBT-DOCSS-JP was supported by an intraclass correlation coefficient score of 0.86., Conclusions: LGBT-DOCSS-JP has the potential to serve as a valuable tool in the development and assessment of effective curricula for LGBT healthcare education, as well as a means to promote self-reflection among trainees and professionals., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: YK and EY serve as members of the board of Nijiiro Doctors, an organization dedicated to promoting awareness and education within the medical community regarding LGBTQ issues, while also providing support for the LGBTQ community. EY has received speaker’s honoraria from Stryker Japan K.K. MM’s son-in-law worked at IQVIA Services Japan K.K., which is a contract research organization and a contract sales organization. MM’s son-in-law works at Syneos Health Clinical K.K. which is a contract research organization and a contract sales organization. The other authors declare that no competing interests exist., (Copyright: © 2024 Kanakubo 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.)

Objectives: The Japanese herbal medicine kyoseihatekigan (KHG) has been used to alleviate the symptoms of croaky voice and globus hystericus, and each of its components has anti-inflammatory and antioxidant effects. However, the mechanisms underlying these beneficial actions of KHG on the vocal folds remain largely unknown. We examined the effects of KHG on rat vocal fold wound healing and assessed its anti-inflammatory and antioxidant properties., Study Design: Animal model., Methods: The vocal folds of Sprague-Dawley rats were unilaterally injured under endoscopy. Rats were divided into three groups based on KHG dosing from pre injury day 4 to post injury day 3: 0 mg/kg/day (sham group), 500 mg/kg/day (1% KHG group) and 1000 mg/kg/day (2% KHG group). Histologic changes were examined to assess the degree of inflammation and oxidative stress at day 3, and fibrosis at day 56. In addition, gene expression related to pro-inflammatory cytokines and transforming growth factor-beta1 (TGF-β1) signaling was examined by quantitative real-time polymerase chain reaction (qPCR)., Results: Histologic analysis showed that the 1% and 2% KHG treatments significantly decreased cell infiltration and the 4-hydroxy-2-nonenalx-immunopositive area, and increased hyaluronic acid at day 3. Both KHG treatments significantly decreased fibrosis at day 56. qPCR revealed that mRNA of interleukin-1β and cyclooxygenase-2 were significantly suppressed at day 1 and TGF-β1 mRNA was significantly downregulated at day 5 in both KHG groups., Conclusions: The current findings suggest that KHG has anti-inflammatory and antioxidant effects in the early phase of vocal fold wound healing, which can lead to better wound healing with less scar formation., (Copyright © 2021 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Nintedanib is recommended for the treatment of idiopathic pulmonary fibrosis (IPF); however, treatment discontinuation due to adverse events (AEs) is common. A large-scale post-marketing surveillance study is investigating the real-world tolerability/safety of nintedanib in Japanese patients with IPF in routine clinical practice. Here, we report a 12-month interim analysis of this study., Methods: The study included Japanese patients with IPF who started nintedanib between 31 August 2015 and 25 December 2018. The primary outcome was the frequency of adverse drug reactions (ADRs), defined as AEs for which a causal relationship with nintedanib could not be excluded. The secondary outcome was change from baseline in forced vital capacity (FVC). Outcomes were analysed in patients who stopped ('discontinued' subgroup) and continued ('continued' subgroup) nintedanib after 12 months. A multivariate analysis was performed to determine potential risk factors for treatment discontinuation., Results: Of 5578 patients in the safety analysis set, 2795 (50.1%) discontinued nintedanib within 12 months of treatment initiation. Overall, 3767 patients (67.5%) had ADRs, with 1356 (24.3%) discontinuing nintedanib because of an ADR. Among patients in the 'discontinued' subgroup (n = 2795), 1442 (51.6%) discontinued because of an ADR. The most common ADRs causing discontinuation within 3 and 12 months were hepatic function abnormal (n = 137/730; 18.8%) and diarrhoea (n = 190/1442; 13.2%), respectively. At 12 months, the decrease in FVC from baseline was smaller in the 'continued' versus the 'discontinued' subgroup (adjusted mean ± standard error change - 104.4 ± 10.9 ml vs. - 311.2 ± 29.2 ml). Stage III/IV IPF and FVC < 70% predicted at baseline were risk factors for early treatment discontinuation., Conclusion: About 50% of Japanese patients with IPF discontinued nintedanib within the first year of treatment, with worse lung function being associated with an increased risk of early treatment discontinuation., Trial Registration: ClinicalTrials.gov: NCT02607722; European Union electronic register of Post-Authorisation Studies: EUPAS10891., (© 2023. The Author(s).)

Background: To explore the predictive value of the Thompson score during the first 4 days of life for estimating short-term adverse outcomes in neonatal encephalopathy., Methods: This observational study evaluated infants with neonatal encephalopathy (≥36 weeks of gestation) registered in a multicenter cohort of cooled infants in Japan. The Thompson score was evaluated at 0-24, 24-48, 48-72, and 72-90 h of age. Adverse outcomes included death, survival with respiratory impairment (requiring tracheostomy), or survival with feeding impairment (requiring gavage feeding) at discharge., Results: Of the 632 infants, 21 (3.3%) died, 59 (9.3%) survived with respiratory impairment, and 113 (17.9%) survived with feeding impairment. The Thompson score throughout the first 4 days accurately predicted death, respiratory impairment, or feeding impairment. The 72-90 h score showed the highest accuracy. A cutoff of ≥15 had a sensitivity of 0.85 and specificity of 0.92 for death or respiratory impairment, while a cutoff of ≥14 had a sensitivity of 0.71 and a specificity of 0.92 for death, respiratory or feeding impairment., Conclusion: A high Thompson score during the first 4 days of life, especially at 72-90 h could thus be useful for estimating the need for prolonged life support., Impact: The Thompson score on days 1-4 of age was useful in predicting death and respiratory or feeding impairments. The 72-90 h Thompson score showed the highest predictive capability. Owing to the rarity of withdrawal of life-sustaining treatment in Japan, 43% of infants with persistent severe encephalopathy with a Thompson score of ≥15 at 72-90 h of age could regain spontaneous breathing, be extubated, and survive without tracheostomy. Meanwhile, approximately 50% of infants who survived without tracheostomy required gavage feeding. Our results could provide useful information for clinical decision making regarding infants with persistent severe encephalopathy., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Purpose: During a pandemic, when there are many barriers to providing preventive care, chronic disease management, and early response to acute common diseases for primary care providers, it is unclear whether primary care attributes contribute to reducing hospitalization. We aimed to examine the association between core primary care attributes and total hospitalizations during the COVID-19 pandemic., Methods: We conducted a nationwide prospective cohort study during the pandemic using a representative sample of the Japanese adult population aged 40 to 75 years. Primary care attributes (first contact, longitudinality, coordination, comprehensiveness, and community orientation) were assessed using the Japanese version of Primary Care Assessment Tool (JPCAT). The primary outcome measure was any incidence of hospitalization during a 12-month period from May 2021 through April 2022., Results: Data from 1,161 participants were analyzed (92% follow-up rate). After adjustment for possible confounders, overall primary care attributes (assessed by the JPCAT total score) were associated in a dose-dependent manner with a decrease in hospitalizations (odds ratio [OR] = 0.37, 95% CI, 0.16-0.83 for the highest score quartile, compared with no usual source of care). All associations between each domain score of the JPCAT and hospitalization were statistically significant when comparing the highest quartile with no usual source of care., Conclusions: Our study revealed that the provision of primary care, particularly high-quality primary care, was associated with decreased total hospitalization, even during a pandemic when there are many barriers to providing usual medical care. These findings support policies that seek to strengthen primary care systems during and after the COVID-19 pandemic., (© 2023 Annals of Family Medicine, Inc.)

Background: The Japanese government is promoting physician-led home visits as well as end-of-life care at home. However, the proportion of deaths occurring at home has remained unchanged for the past 20 years., Objectives: To report the cumulative incidence of deaths at home and to explore the factors associated with deaths at home versus other places, mainly hospitals., Methods: This was a multicenter prospective cohort study in a primary care setting. We enrolled patients aged ≥65 years who had started to receive regular visits by family physicians from 13 facilities in and around Tokyo between February 1, 2013 and January 31, 2016. Patients were followed-up until January 31, 2017. The primary outcome measures were mortality rate and cumulative incidence of deaths at home., Results: We enrolled 762 patients. Of 368 deaths, 133 occurred in the patient's home. The mortality rates at home were 137.6/1000 person-years (95% confidence interval 116.1-163.1). In cumulative incidence function, the longer duration of care at home lowers the likelihood of death at home. Multivariable multinomial logistic models showed that younger age and higher Barthel Index score reduced the likelihood of deaths at home, while receiving oxygen therapy and the presence of a full-time caregiver increased the likelihood of deaths at home relative to deaths at other locations., Conclusions: Of deceased patients, only one-third died in patients' homes. We found several factors associated with deaths at home, which appeared to reflect the readiness of patients and their families for death. Geriatr Gerontol Int 2022; 22: 1005-1012., (© 2022 The Authors. Geriatrics & Gerontology International published by John Wiley & Sons Australia, Ltd on behalf of Japan Geriatrics Society.)

Background: Evidence is still limited on the prevalence of multimorbidity and complex multimorbidity in Japan, as well as their associated factors. Additionally, no studies regarding multimorbidity and complex multimorbidity in Japan have used patient data obtained directly from medical records. The primary objective was to clarify the prevalence of multimorbidity and complex multimorbidity using patient data obtained directly from medical records. The secondary objective was to elucidate factors associated with multimorbidity and complex multimorbidity., Methods: We conducted a cross-sectional study at Tarama Clinic on Tarama Island, a remote island in Okinawa, Japan. Among patients who visited Tarama Clinic from April 1 to June 30, 2018, those who were ≥ 20 years of age, lived on Tarama Island, and had capacity to give consent were eligible for study inclusion. We collected the following data using medical records, medical expense receipts, and self-administered questionnaires: multimorbidity and complex multimorbidity, participants' characteristics, and potentially associated factors. Multimorbidity was defined as having ≥ 2 among 17 chronic health conditions, in accordance with previous studies conducted in Japan, and having ≥ 2 among 16 chapters of the International Classification of Primary Care, 2nd edition (ICPC-2). Complex multimorbidity was defined as having ≥ 3 among 16 chapters of the ICPC-2., Results: We included 355 study participants. Descriptive analysis showed multimorbidity prevalence measured using the 17 chronic health conditions in this area was 30.0% (age ≥ 20 years) and 57.5% (age ≥ 65 years). Multimorbidity prevalence measured using the ICPC-2 was 32.9% (age ≥ 20 years) and 60.3% (age ≥ 65 years). We also found a 20.9% (age ≥ 20 years) and 45.1% (age ≥ 65 years) prevalence of complex multimorbidity, respectively. Poisson regression with robust error variance showed that age ≥ 60 years was associated with multimorbidity. Age ≥ 60 years (adjusted prevalence ratio [aPR] 1.887 and 1.831 for ages 60-79 and ≥ 80 years, respectively) and being unemployed (aPR 1.251) were associated with complex multimorbidity. However, having hazardous drinking or more was inversely associated with complex multimorbidity (aPR 0.745)., Conclusions: The population-based prevalence of multimorbidity and its upward trend with increasing age on a remote island in Japan was consistent with previous reports in the country. Multimorbidity was associated with age 60 years or older, and complex multimorbidity was associated with age 60 years or older, being unemployed, and not having hazardous drinking or more. Our study findings indicated a possible association between the coexistence of diseases and social determinants of health (SDH) in Japan. To improve care for patients with multimorbidity and complex multimorbidity, more research that takes SDH into account is warranted, and evidence-based policymaking is essential for Japan. The present study can provide a foundation for accumulating such evidence., (© 2022. The Author(s).)

Penile cancer is a rare cancer for which no medical guidelines have been established before in Japan. These guidelines aim to standardize, as much as possible, the therapeutic modality for penile cancer, for which empirical evidence is limited on a global scale, thereby bolstering therapeutic outcomes for patients with penile cancer. The new guidelines conform to the Minds Guide for Developing Clinical Practice Guidelines (2017) as much as possible. However, virtually no randomized comparative studies and meta-analyses based on such randomized studies have been conducted. Therefore, only the findings available at present were listed after conducting an exhaustive literature review of items with extremely low evidence levels and for which bodies of evidence and grades of recommendation were not evaluated. Clinical questions were set for items with a relatively large number of studies, including retrospective studies. However, since it is virtually impracticable to summarize bodies of evidence by systematic reviews, recommendation grades and evidence levels were discussed and determined by the consensus panel of the Preparatory Committee. The following were outlined: epidemiological, pathological, diagnostic, therapeutic, follow-up, and quality of life-related findings. Additionally, seven clinical questions were established to determine recommendation grades and evidence levels. We hope that these guidelines will prove to be useful to medical professionals engaged in clinical practice related to penile cancer in Japan and anticipate that critical reviews of the guidelines will lead to further refinement of the next edition., (© 2022 The Japanese Urological Association.)

Objectives: The objective of this study was to examine the structural validity and internal consistency of the original English version of the Patient Centred Assessment Method (PCAM) in a primary care setting in a Japanese island area., Design: Cross-sectional study., Setting: A clinic on a remote island in Okinawa, Japan, that provides general outpatient and 24-hour emergency services., Participants: This study included 355 patients who visited Tarama Clinic from 1 April 2018 to 30 June 2018, were aged ≥20 years, lived in Tarama Village and had decision-making capacity., Main Outcome Measures: Patient complexity scored by the PCAM., Results: The mean (SD) PCAM score was 21.4 (5.7). The distribution was skewed to the right and there were no ceiling and floor effects. Confirmatory factor analysis found that the previously reported two-factor and three-factor structures did not show a good fit (root mean square error of approximation 0.18 and 0.16, comparative fit index 0.83 and 0.89 and standardised root mean square residual 0.14 and 0.11, respectively). Exploratory factor analysis revealed a new two-factor structure: 'Biomedical complexity' and 'Psychosocial complexity'. The Cronbach's alpha values for the total PCAM score, the 'Biomedical complexity' factor, and the 'Psychosocial complexity' factor were 0.81, 0.82 and 0.74, respectively., Conclusions: In this study, confirmatory factor analysis found that the data did not fit sufficiently using the previously reported two-factor and three-factor structures. Instead, exploratory factor analysis revealed a new two-factor structure, for which the Cronbach's alpha values exceeded the threshold level. Therefore, the structural validity and internal consistency of the English version of the PCAM were verified in a primary care setting in a Japanese island area., Competing Interests: Competing interests: YS, HY and SY are former trainees of the Jikei Clinical Research Programme for Primary-care. MM received lecture fees and lecture travel fees from the Centre for Family Medicine Development of the Japanese Health and Welfare Co-operative Federation. MM is an adviser for the Centre for Family Medicine Development Practice-Based Research Network and a programme director of the Jikei Clinical Research Programme for Primary-care. MM’s son-in-law worked at IQVIA Services Japan K.K., which is a contract research organisation and a contract sales organisation. MM’s son-in-law works at Syneos Health Clinical K.K., which is a contract research organisation and a contract sales organisation., (© 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: Combining abiraterone (Abi) with androgen deprivation therapy (ADT) improves overall survival, compared to ADT only, in patients with metastatic castration-sensitive prostate cancer (mCSPC). In Japan, bicalutamide (Bica) and ADT (combined androgen blockade: CAB) is frequently provided for mCSPC. Because these two treatments have not been compared, mCSPC patients who received either treatment were retrospectively analyzed., Methods: Of 178 patients with LATITUDE high-risk mCSPC, 103 had received ADT plus upfront Abi (Abi group) and 75 had received ADT plus Bica (Bica group) in multiple institutions of the Tokai Urologic Oncology Research Seminar. Kaplan-Meir curves were used to retrospectively analyze survival and cancer recurrence. Univariate and multivariate Cox regression analyses identified potential prognostic factors for progression-free survival (PFS)., Results: Significant differences in major clinicopathological characteristics between the two groups were not observed. The rate of castration-resistant development was higher in the Bica compared to Abi group (50.6 vs. 25.2%, p < 0.001). The median PFS in the Bica group was 13.6 months {95% confidence interval [CI] 9.2-22.2}; however, in the Abi group, PFS did not reach the median {95% CI 18.5-not assessed [NA]; p < 0.001}. Time to second progression for the Abi group was superior (p = 0.07). Univariate and multivariate analyses revealed Gleason pattern 5, high alkaline phosphatase levels, and conventional CAB using Bica as significant prognostic factors for short PFS., Conclusions: In patients with LATITUDE high-risk mCSPC, upfront use of Abi combined with ADT resulted in favorable prognostic outcomes compared with conventional ADT with Bica., (© 2021. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background/aim: To assess the efficacy of novel therapeutic agents, such as androgen receptor axis-targeted agents (ARATs) and cabazitaxel, for relapse of metastatic castration-resistant prostate cancer (mCRPC) after docetaxel in real-world practice, we performed a subanalysis using database from PROSTAT-BSI, a prospective observational study to evaluate the utility of software for quantifying bone metastases on bone scintigraphy., Patients and Methods: Patients with clinically relapsed mCRPC after docetaxel treatment who received the new agents (NEW group) and those who did not (standard of care, SOC group) were included; patients who received ARAT before DOC treatment were excluded. Overall survival (OS) after docetaxel treatment was compared between the NEW and SOC groups., Results: Patients in the NEW group had significantly better OS from the start of docetaxel than those in the SOC group (the median OS in NEW and SOC was 28.9 months vs. 14.5 months, respectively). Furthermore, regardless of the time from androgen-deprivation therapy to the start of docetaxel at mCRPC, the NEW group had a better OS from relapse after docetaxel than the SOC group., Conclusion: In clinical practice, OS of patients with relapse after docetaxel was significantly improved in the NEW group over the SOC group., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Hypophosphatasia (HPP) is a rare inherited metabolic disorder caused by mutations in the ALPL gene, which encodes tissue nonspecific alkaline phosphatase. The severity of HPP is widely diverse from the perinatal form to the adult mild form. The former represents the most severe form and was earlier associated with high mortality due to pneumonia which was caused by severe hypomineralization of the bones-such as chest deformity and fractured ribs-and muscle weakness. Enzyme replacement therapy using asfotase alfa (AA) was approved in 2015 in Japan for treating patients with HPP and has improved their pulmonary function and life prognosis. There are several practical and ethical challenges related to using orphan drugs for a rare disorder in a publicly funded healthcare system. Sharing experiences about their application is essential towards formulating guidelines to assist clinicians with decisions about their initiation and withdrawal. We report the details of AA experience in ten cases of pediatric-onset HPP in nine families from January 2015 to November 2019 (median [interquartile range] age 11.0 [7.6-12.5] years; 60% male). This is a study of a single-center cohort describing the clinical course of patients with HPP, mainly consisting of the mild childhood form of HPP, treated with AA in Japan., Results: One case of perinatal form of HPP, two cases of benign prenatal form, and seven cases of childhood form were observed. The most common symptom at onset was pain. All patients had low serum alkaline phosphatase levels as compared to the age-matched reference range before the commencement of AA. All HPP patients seem to have responded to AA treatment, as evidenced by pain alleviation, increased height standard deviation, improvement in respiratory condition and 6-min walk test result improvement, disappearance of kidney calcification, alleviation of fatigue, and/or increases in bone mineralization. There were no serious adverse events, but all patients had an injection site reaction and skin changes at the injection sites. Genetic analysis showed that eight out of ten patients had compound heterozygosity., Conclusions: AA may be effective in patients with mild to severe pediatric-onset forms of HPP., (© 2022. The Author(s).)

Background: We performed subgroup analyses of the AFTER I-O study to clarify the association of time-to-treatment failure (TTF) and discontinuation reason of prior immune-oncology (I-O) therapy, and molecular targeted therapy (TT) regimen with the outcomes of TT after I-O., Methods: The data of Japanese metastatic renal cell carcinoma patients treated with TT after nivolumab (NIVO) (CheckMate 025) or NIVO + ipilimumab (IPI) (CheckMate 214) were retrospectively analyzed. The objective response rates (ORRs), progression-free survival (PFS) and overall survival (OS) of TT after I-O were analyzed by subgroups: TTF (<6 or ≥6 months) and discontinuation reason of prior I-O (progression or adverse events), and TT regimen (sunitinib or axitinib). We also analyzed PFS2 of prior I-O and OS from first-line therapy., Results: The ORR and median PFS of TT after NIVO and NIVO+IPI among the subgroups was 17-36% and 20-44%, and 7.1-11.6 months and 16.3-not reached (NR), respectively. The median OS of TT after NIVO was longer in patients with longer TTF of NIVO and treated with axitinib. Conversely, median OS of TT after NIVO+IPI was similar among subgroups. The median PFS2 of NIVO and NIVO+IPI was 36.7 and 32.0 months, respectively. The median OS from first-line therapy was 70.5 months for patients treated with NIVO and NR with NIVO+IPI. The safety profile of each TT after each I-O was similar to previous reports., Conclusions: The efficacy of TT after NIVO or NIVO+IPI was favorable regardless of the TTF and discontinuation reason of prior I-O, and TT regimen., (© The Author(s) 2021. Published by Oxford University Press.)

Abstract: The transtheoretical model (TTM) is a promising approach to the promotion of behavior change, but it remains to be established whether there is an association between the TTM approach and intradialytic exercise among patients on hemodialysis (HD) with low motivation to exercise in a real-world setting.This retrospective cohort study, conducted in a regional hospital in Japan, included adult outpatients receiving HD 3 times per week who had never participated in intradialytic pedaling exercise despite the encouragement of the HD personnel. Patients were divided into 2 groups according to HD weekday. Patients undergoing HD on Tuesday, Thursday, and Saturday were encouraged by the HD unit team to exercise during HD based on the TTM (exposure group) and those receiving HD on Monday, Wednesday, and Friday were encouraged to exercise as usual (control group). The primary outcome was sustained intradialytic exercise using a leg ergometer, defined as a total of 72 sessions of 30-minute pedaling exercise (duration of at least 6 months).Overall, 85 patients were included in the analysis (mean age: 67.1 ± 11.9 years, 22% female). Of 33 patients in the exposure group, 10 (30%) maintained intradialytic exercise, compared with 2 of 52 patients (4%) in the control group. Log-binomial regression models with stabilized inverse probability of treatment weighting showed a significant association between the TTM approach and sustained intradialytic exercise (adjusted risk ratio 9.23 [95% confidence interval 2.13-40.00]). There were no exercise-related cardiovascular events.Among patients with low motivation to exercise during HD, use of the TTM approach in clinical practice was associated with sustained intradialytic exercise compared with usual care., Competing Interests: The authors have no conflicts of interest to disclose except M. Matsushima., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Lexical pitch accent in Japanese is primarily realized as a steep fall in f o from an accented syllable into the following one. In addition, when a phrase that contains an accented syllable is followed by another phrase, the following phrase undergoes downstep, a compression of the f o range. Furthermore, while their acoustic identity is not yet clear, secondary cues to Japanese pitch accent are known to exist. The present study examined how speakers of Tokyo Japanese used acoustic information from these three sources in perceiving lexical pitch accent in Tokyo Japanese. Listeners heard stimuli in which the acoustic cues related to accent were independently manipulated and were asked to identify if a word presented sentence-medially was a final-accented word or its unaccented counterpart. Results found that listeners' judgments of words were most consistent with the presence or absence of downstep. That is, listeners identified that the preceding phrase contained an accented word when the following phrase was downstepped. Listeners also used the f o fall to determine if the word in question was a final-accented word or an unaccented word. Secondary cues to pitch accent were most weakly related to listeners' identification of accent.

Objective: To determine prognostic factors including the Bone Scan Index in prostate cancer patients receiving standard hormonal therapy and chemotherapy., Methods: This multicenter Prostatic Cancer Registry of Standard Hormonal and Chemotherapy Using Bone Scan Index study involved 30 hospitals and enrolled 247 patients (age 71 ± 8 years) with metastatic hormone-sensitive prostate cancer (n = 148) under hormone therapy and metastatic castration-resistant prostate cancer (n = 99) under chemotherapy. The Bone Scan Index (%) was determined by whole-body bone scintigraphy using 99m Tc-methylenediphosphonate. Patients were classified into tertiles and binary groups, and predictors of all-cause death including Bone Scan Index, prostate-specific antigen, and bone metabolic markers were determined using survival and proportional hazard analyses., Results: During a mean follow-up period of 716 ± 404 days, 81 (33%) of the patients died, and 3-year mortality rates were 20% and 52% in the metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer groups, respectively. Survival analysis showed that a Bone Scan Index >3.5% was a significant determinant of death in the metastatic hormone-sensitive prostate cancer group, whereas prostate-specific antigen >55 ng/mL before chemotherapy was a determinant of prognosis in the metastatic castration-resistant prostate cancer group. A Bone Scan Index >3.5% was also associated with a high incidence of prostate-specific antigen progression in the metastatic hormone-sensitive prostate cancer group. Patients with metastatic hormone-sensitive prostate cancer and a better Bone Scan Index response (>45%) to treatment had lower mortality rates than those without such response., Conclusion: The Bone Scan Index and hot spot number are significant determinants of 3-year mortality, and combining the Bone Scan Index with prostate-specific antigen should contribute to the management of prostate cancer patients with bone metastasis., (© 2021 The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological Association.)

Background: Asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap (ACO) are complex and heterogeneous diseases that share clinical characteristics (phenotypes) and molecular mechanisms (endotypes). Whilst physicians make clinical decisions on diagnostic groups, for some such as ACO there is no commonly accepted criteria. An alternative approach is to evaluate phenotypes and endotypes that are considered to respond well to a specific type of treatment ("treatable traits") rather than diagnostic labels., Purpose: The prospective, longitudinal, and observational TRAIT study will evaluate disease characteristics, including both phenotypes and endotypes, in relation to the presentation of obstructive respiratory disease characteristics in patients diagnosed with asthma, COPD, or ACO in Japan, with the aim of further understanding the clinical benefit of a treatable traits-based approach., Patients and Methods: A total of 1500 participants will be enrolled into three cohorts according to their treating physician's diagnosis of asthma, COPD, or ACO at screening. Part 1 of the study will involve cross-sectional phenotyping and endotyping at study enrollment. Part 2 of the study will evaluate the progression of clinical characteristics, biomarker profiles, and treatment over a 3-year follow-up period. The follow-up will involve three annual study visits and three telephone calls scheduled at 6-month intervals. A substudy involving 50 participants from the asthma cohort (in which the ratio will be approximately 1:1 including 25 participants with a smoking history of ≥10 pack-years and 25 participants with no smoking history), 100 participants from the ACO cohort, and 100 participants from the COPD cohort will evaluate disease phenotypes using inspiratory and expiratory computed tomography scans., Conclusion: TRAIT will describe clinical characteristics of patients with obstructive respiratory diseases to better understand potential differences and similarities between clinical diagnoses, which will support the improvement of personalized treatment strategies., Competing Interests: This is a prospective, three-group cohort study with no study treatment intervention administered to participants. Nobuyuki Hizawa received scholarship donation (research grant) from GSK in 2018 and lecture fees from GSK, AstraZeneca, and Novartis. Koichi Fukunaga received personal fees from AstraZeneca and Boehringer Ingelheim. Hisatoshi Sugiura received lecture fees from GSK, AstraZeneca, Novartis, and Boehringer Ingelheim. Yasutaka Nakano received personal fees from Nippon Boehringer Ingelheim, GSK, Novartis, Shionogi, Kyorin Pharmaceutical, Daiichi Sankyo, Chugai Pharmaceutical, Eli Lilly Japan, Sumitomo Dainippon Pharma, Eisai, Olympus, and AstraZeneca. Motokazu Kato received lecture fees from GSK. Yutaro Sugiyama and Tomohiro Hanazawa are GSK employees. Toshihiko Kaise, Paul W Jones, Neil Barnes, Chris Compton, and Takeo Ishii are GSK employees and hold stocks/shares in GSK. Ruth Tal-Singer was a GSK employee at the time of the study, holds stocks/shares in GSK, and received personal fees from Immunomet, Vocalis Health, Teva, and Ena Respiratory and Ena Therapeutics. The authors report no other conflicts of interest in this work., (© 2021 Hizawa et al.)

Objectives: Guidelines for treatment of mRCC recommend nivolumab monotherapy (NIVO) for treated patients, and nivolumab plus ipilimumab combination therapy (NIVO+IPI) for untreated IMDC intermediate and poor-risk mRCC patients. Although molecular-targeted therapies (TTs) such as VEGFR-TKIs and mTORi are recommended as subsequent therapy after NIVO or NIVO+IPI, their efficacy and safety remain unclear., Methods: Outcome of Japanese patients with mRCC who received TT after NIVO (CheckMate 025) or NIVO+IPI (CheckMate 214) were retrospectively analyzed. Primary endpoints were investigator-assessed ORR of the first TT after either NIVO or NIVO+IPI. Secondary endpoints included TFS, PFS, OS and safety of TTs., Results: Twenty six patients in CheckMate 025 and 19 patients in CheckMate 214 from 20 centers in Japan were analyzed. As the first subsequent TT after NIVO or NIVO+IPI, axitinib was the most frequently treated regimen for both CheckMate 025 (54%) and CheckMate 214 (47%) patients. The ORRs of TT after NIVO and NIVO+IPI were 27 and 32% (all risks), and median PFSs were 8.9 and 16.3 months, respectively. During the treatment of first TT after either NIVO or NIVO+IPI, 98% of patients experienced treatment-related adverse events, including grade 3-4 events in 51% of patients, and no treatment-related deaths occurred., Conclusions: TTs have favorable antitumor activity in patients with mRCC after ICI, possibly via changing the mechanism of action. Safety signals of TTs after ICI were similar to previous reports. These results indicate that sequential TTs after ICI may contribute for long survival benefit., (© The Author(s) 2021. Published by Oxford University Press.)

Objectives: The primary objective was to describe the characteristics of Otōri, a regionally specific drinking custom in the Miyakojima region of Okinawa, Japan, and its participants. The secondary objective was to clarify the distribution of alcohol consumption/alcohol use disorders as measured by the Alcohol Use Disorders Identification Test (AUDIT) and its association with the frequency of engagement in Otōri per month., Design: Cross-sectional study., Setting: Tarama Island, a remote island in Okinawa, Japan., Participants: Individuals who lived on Tarama Island, participated in a mass general health check or mass influenza vaccination programme, were aged ≥20 years and had decision-making capacity were eligible to participate., Primary Outcome Measures: Alcohol consumption/alcohol use disorders as measured by the AUDIT, frequency of engagement in Otōri per month, settings in which people engage in Otōri and attitudes toward Otōri., Results: Among 478 eligible participants, 401 answered the questionnaire. Approximately 15% reported attitudes toward Otōri of 'like' or 'somewhat like'; around 80% of these participants were middle-aged to older adult men. Compared with the national average, a higher percentage of people (9.2% and 40.9% of women and men, respectively) had AUDIT scores indicating 'hazardous drinking or more', which was associated with 'low or intermediate frequency' and 'high frequency' of engagement in Otōri per month (ORs of 7.626 and 20.321, respectively)., Conclusions: Social obligation generated by some community members could pressure most of the population into participating in Otōri, possibly leading to a higher percentage of people engaging in hazardous/harmful alcohol consumption and alcohol dependence. However, healthcare professionals should carefully consider the beneficial and detrimental effects of the custom on biomedical and social conditions and avoid advocating to promote or abolish the custom by only highlighting one aspect., Competing Interests: Competing interests: YS, HY and KI are former trainees of the Jikei Clinical Research Program for Primary-care. MM is a programme director of the Jikei Clinical Research Program for Primary-care., (© 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.)

Background: We hypothesized that Behçet's disease (BD) consists of several clinical subtypes with different severity, resulting in heterogeneity of the disease. Here, we conducted a study to identify clinical clusters of BD., Methods: A total of 657 patients registered in the Yokohama City University (YCU) regional BD registry between 1990 and 2018, as well as 6754 patients who were initially registered in the Japanese Ministry of Health, Labour and Welfare (MHLW) database between 2003 and 2014, were investigated. The YCU registry data regarding the clinical manifestations of BD, human leukocyte antigen (HLA) status, treatments, and hospitalizations were analyzed first, followed by similar analyses of the MHLW for validation. A hierarchical cluster analysis was independently performed in both patient groups., Results: A hierarchical cluster analysis determined five independent clinical clusters in the YCU cohort. Individual counterparts of the YCU clusters were confirmed in the MHLW registry. Recent phenotypical evolutions of BD in Japan, such as increased gastrointestinal (GI) involvement, reduced complete type according to the Japan Criteria, and reduced HLA-B51 positivity were associated with chronologically changing proportions of the clinical clusters., Conclusions: In this study, we identified independent clinical clusters among BD patients in Japan and found that the proportion of each cluster varied over time. We propose five independent clusters namely "mucocutaneous", "mucocutaneous with arthritis", "neuro", "GI", and "eye."

To identify oral drugs that likely display nonlinear pharmacokinetics due to saturable metabolism by intestinal CYP3A, our previous report using CYP3A substrate drugs proposed an approach using thresholds for the linear index number (LIN3A = dose/K m ; K m , Michaelis-Menten constant for CYP3A) and the intestinal availability (F a F g ). Here, we aimed to extend the validity of the previous approach using both CYP3A substrate and non-substrate drugs and to devise a decision tree suited for early drug candidates using in vitro metabolic intrinsic clearance (CL int, vitro ) instead of F a F g . Out of 152 oral drugs (including 136 drugs approved in Japan, US or both), type I nonlinearity (in which systemic drug exposure increases in a more than dose-proportional manner) was noted with 82 drugs (54%), among which 58 drugs were identified as CYP3A substrates based on public information. Based on practical feasibility, 41 drugs were selected from CYP3A substrates and subjected to in-house metabolic assessment. The results were used to determine the thresholds for CL int, vitro (0.45 μL/min/pmol CYP3A4) and LIN3A (1.0 L). For four drugs incorrectly predicted, potential mechanisms were looked up. Overall, our proposed decision tree may aid in the identification of early drug candidates with intestinal CYP3A-derived type I nonlinearity., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Objectives: The primary objective of this study was to develop the Japanese version of the Patient Centred Assessment Method (PCAM) and its user guide. The secondary objective was to examine the validity and reliability in the primary care setting., Design: Cross-sectional study., Setting: Three family physician teaching clinics located in urban residential areas in Tokyo, Japan., Participants: Patients who were aged 20 years or older, and who had an appointment with physicians at the three participating clinics., Main Outcome Measures: Patient complexity measured by PCAM and complexity/burden level measured by a Visual Analogue Scale (VAS)., Results: Although confirmatory factor analysis using a model described in a previous study revealed that the indices did not meet the criteria for good fit, exploratory factor analysis revealed a new three-factor structure of 'Personal well-being,' 'Social interaction' and 'Needs for care/service.' Cronbach's alpha of PCAM was 0.86. Spearman's rank correlation coefficients between PCAM scores and VAS scores were 0.51 for complexity (p<0.001) and 0.41 for burden (p<0.001). There were 42 patients (14.3% of total patients) with PCAM scores greater than its mean of 16.5 but with complexity VAS scores less than its mean of 20.8., Conclusions: The Japanese version of PCAM and its user guide were developed through Japanese translation and cultural adaptation by cognitive debriefing. PCAM is a valid and reliable tool to assess patient complexity in the primary care settings in Japan. Additionally, although the correlation between total PCAM scores and complexity/burden as assessed by VAS was moderate, PCAM can more precisely identify patient complexity than skilled physician's intuition., Competing Interests: Competing interests: MM received lecture fees and lecture travel fees from the Centre for Family Medicine Development of Japanese Health and Welfare Co-operative Federation. MM is an adviser of the Centre for Family Medicine Development practice-based research network. MM is a program director of The Jikei Clinical Research Program for Primary-care. YS, SY, MK, TW and TT are former trainees of The Jikei Clinical Research Program for Primary-care. TW currently is and SY, MK and TT used to be family physicians at the Centre for Family Medicine Development of Japanese Health and Welfare Co-operative Federation. RM, RH and DH have nothing to disclose., (© 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.)

In recent years, several treatment options for patients with pre-capillary pulmonary hypertension (PH) have improved the short-term prognosis. However, the long-term survival for pre-capillary PH has not been well investigated. This study sought to investigate the long-term survival for pre-capillary PH in Kurume University Hospital. A total of 144 patients with pre-capillary PH (110 women, mean age 55.1 ± 17.9 years) were enrolled. The maximal duration of followup was 15 years with a mean followup of 5.77 years. The 15 year survival was 59.1% for pre-capillary PH, 68.5% for pulmonary arterial hypertension (PAH), and 44.3% for chronic thromboembolic PH. The 5 year survival was 50.9% for PH due to lung disease (PH-LD), indicating the worst in the pre-capillary PH subgroups. The survival for portopulmonary hypertension was the lowest among PAH groups, and PAH associated with connective tissue disease and congenital heart disease decreased 10 years after diagnosis. A 6 min walk distance and elevated brain natriuretic peptide were significantly associated with survival outcome in pre-capillary PH patients and diastolic pulmonary arterial pressure was related to survival for PH-LD. The survivals were different among pre-capillary PH groups in our hospital. Above all, the long-term survival was better than in previous reports.

Sarcoidosis is a genetically complex systemic inflammatory disease that affects multiple organs. We present a GWAS of a Japanese cohort (700 sarcoidosis cases and 886 controls) with replication in independent samples from Japan (931 cases and 1,042 controls) and the Czech Republic (265 cases and 264 controls). We identified three loci outside the HLA complex, CCL24, STYXL1-SRRM3, and C1orf141-IL23R, which showed genome-wide significant associations (P < 5.0 × 10 -8 ) with sarcoidosis; CCL24 and STYXL1-SRRM3 were novel. The disease-risk alleles in CCL24 and IL23R were associated with reduced CCL24 and IL23R expression, respectively. The disease-risk allele in STYXL1-SRRM3 was associated with elevated POR expression. These results suggest that genetic control of CCL24, POR, and IL23R expression contribute to the pathogenesis of sarcoidosis. We speculate that the CCL24 risk allele might be involved in a polarized Th1 response in sarcoidosis, and that POR and IL23R risk alleles may lead to diminished host defense against sarcoidosis pathogens.

Objectives: The objective was to clarify the relationship between alcohol consumption/alcohol use disorders and patient complexity., Design: Cross-sectional study., Setting: A clinic located on a remote island in Okinawa, Japan, providing general outpatient practices and round-the-clock emergency services., Participants: Patients who lived on the island, visited Tarama Clinic from 1 April 2018 to 30 June 2018, were aged ≥20 years and had decision-making capacity were judged to be eligible for this study., Main Outcome Measures: Alcohol consumption/alcohol use disorders as measured by the Alcohol Use Disorders Identification Test (AUDIT) and patient complexity as scored by the Patient Centered Assessment Method (PCAM)., Results: During the 3-month study period, 355 patients (163 women and 192 men) with mean (SD) age of 66.4 (13.6) years were included. Multiple regression analysis of PCAM scores showed that, after adjusting for age, sex, education, occupation, physical activity, smoking, annual medical expenses and number of family members living with the patient, AUDIT scores classified as 'dependence likely' were associated with PCAM scores (p value=0.040)., Conclusions: Alcohol consumption and alcohol use disorders classified as dependence likely are associated with patient complexity., Competing Interests: Competing interests: YS and HY are former trainees of the Jikei Clinical Research Program for Primary-care. MM is a programme director of the Jikei Clinical Research Program for Primary-care., (© 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.)

Background: Japan faces the most elderly society in the world, and the Japanese government has launched an unprecedented health plan to reinforce home care medicine and increase the number of home care physicians, which means that an understanding of future needs for geriatric home care is vital. However, little is known about the future need for home care physicians. We attempted to estimate the basic need for home care physicians from 2020 to 2060., Methods: Our estimation is based on modification of major health work force analysis methods using previously reported official data. Two models were developed to estimate the necessary number of full-time equivalent (FTE) home care physicians: one based on home care patient mortality, the other using physician-to-patient ratio, working with estimated numbers of home and nursing home deaths from 2020 to 2060. Moreover, the final process considered and adjusted for future changes in the proportion of patients dying at home. Lastly, we converted estimated FTE physicians to an estimated head count., Results: Results were concordant between our two models. In every instance, there was overlap of high- and low-estimations between the mortality method and the physician-to-patient method, and the estimates show highly similar patterns. Furthermore, our estimation is supported by the current number of physicians, which was calculated using a different method. Approximately 1.7 times (1.6 by head count) the current number of FTE home care physicians will be needed in Japan in the late 2030's, peaking at 33,500 FTE (71,500 head count). However, the need for home care physicians is anticipated to begin decreasing by 2040., Conclusion: The results indicate that the importance of home care physicians will rise with the growing elderly population, and that improvements in home care could partially suppress future need for physicians. After the late 2030's, the supply can be reduced gradually, accounting for the decreasing total number of deaths after 2040. In order to provide sufficient home care and terminal care at home, increasing the number of home care physicians is indispensable. However, the unregulated supply of home care physicians will require careful attention in the future.

Background: Hepatocerebral mitochondrial DNA depletion syndrome (MTDPS) is a disease caused by defects in mitochondrial DNA maintenance and leads to liver failure and neurological complications during infancy. Liver transplantation (LT) remains controversial due to poor outcomes associated with extrahepatic symptoms. The purposes of this study were to clarify the current clinical and molecular features of hepatocerebral MTDPS and to evaluate the outcomes of LT in MTDPS patients in Japan., Results: We retrospectively assessed the clinical and genetic findings, as well as the clinical courses, of 23 hepatocerebral MTDPS patients from a pool of 999 patients who were diagnosed with mitochondrial diseases between 2007 and 2019. Causative genes were identified in 18 of 23 patients: MPV17 (n = 13), DGUOK (n = 3), POLG (n = 1), and MICOS13 (n = 1). Eight MPV17-deficient patients harbored c.451dupC and all three DGUOK-deficient patients harbored c.143-307&#95;170del335. The most common initial manifestation was failure to thrive (n = 13, 56.5%). The most frequent liver symptom was cholestasis (n = 21, 91.3%). LT was performed on 12 patients, including nine MPV17-deficient and two DGUOK-deficient patients. Among the 12 transplanted patients, five, including one with mild intellectual disability, survived; while seven who had remarkable neurological symptoms before LT died. Five of the MPV17-deficient survivors had either c.149G > A or c.293C > T., Conclusions: MPV17 was the most common genetic cause of hepatocerebral MTDPS. The outcome of LT for MTDPS was not favorable, as previously reported, however, patients harboring MPV17 mutations associated with mild phenotypes such as c.149G > A or c.293C > T, and exhibiting no marked neurologic manifestations before LT, had a better prognosis after LT.

Ectomycorrhizal (ECM) fungal communities show temporal dynamics. Such dynamics have been mainly assessed with 1 year of investigations and have been related to the seasonal changes in environment. Recent study in sub-tropical region has revealed that stochastic temporal-based process can affect ECM fungal community, making the community of the same season different between years. The different community structures across years have also been observed in the Arctic region with a grass host. Nevertheless, in temperate zones, the effect of temporal-based processes and the consistency of seasonal dynamics have never been investigated. We conducted a 2-year root sampling in a cool temperate Fagus crenata forest to test whether the temporal variation of ECM fungal community composition could be explained by season. The explanation powers of temporal distance and environmental factors for the temporal dynamics of ECM fungal community were simultaneously evaluated. The variation in community structure was significantly explained by year but not by season, indicating that seasonal community structure differed between years. This difference in the community structure across years was partly explained by temporal factors. Our study implies that the temporal dynamics of ECM fungal communities in temperate forests are affected by temporal-based factors and can vary across years., (© FEMS 2020.)

Purpose: To optimize the implantable collamer lens (ICL) sizing method using anterior segment optical coherence tomography (AS-OCT)., Setting: Nagoya Eye Clinic, Nagoya, Japan., Design: Interventional case series., Methods: A stepwise multiple regression analysis was performed using the optimal ICL size as a dependent variable and preoperative AS-OCT parameters as explanatory variables for 81 eyes of 41 patients, and the NK-formula version 2 (NK-formula V2) was obtained. Thereafter, 68 eyes of 42 patients were implanted with the ICLs selected as closest to the optimal ICL size calculated by the NK-formula V2. At 3 months postoperatively, the achieved vault was measured by AS-OCT to evaluate the optimization of the sizing method., Results: The anterior chamber width (ACW) and crystalline lens rise were selected as significant parameters for the regression model (R = 0.61, P < .001), as with the previous NK-formula. Of the 68 eyes, 36 patients/62 eyes (91.2%), 5 patients/5 eyes (7.3%), and 1 patient/1 eye (1.5%) were in the moderate, high, and low vault categories, respectively. In the 68 eyes, the vault showed no correlation with the optimal ICL size (R = 0.0185, P = .269), whereas the vault showed a negative correlation with the optimal ICL size in both the 12.6 mm ICL subgroup (R = -0.409, P = .0088) and the 13.2 mm ICL subgroup (R = -0.818, P = .0013)., Conclusions: This optimization approach showed excellent ability to select an appropriate ICL to be implanted regardless of the value of other ocular parameters and age, except ACW.

The present study investigated whether the clinical pharmacokinetics of atorvastatin can be predicted from the results of microdosing study in Japanese patients with hypercholesterolemia whose SLCO1B1 and ABCG2 polymorphisms were analyzed. Forty seven statin-naive patients clinically indicated to LDL cholesterol-lowering therapy with atorvastatin were enrolled in a two-period crossover study. Microdose (100 μg) of atorvastatin was orally administered followed by therapeutic dose (10 mg) administration. Transport studies were performed with BCRP-expressing membrane vesicles. The dose-normalized plasma AUC following the therapeutic dose of atorvastatin was positively correlated with that following its microdose, but the AUC increased more than dose proportionally from microdose to therapeutic dose. The patients carrying SLCO1B1 c.521TC showed a significantly higher AUC compared with those carrying c.521TT following the microdose (175%) and therapeutic dose (139%). On the other hand, SLCO1B1 c.388G or ABCG2 c.421A variant alleles did not significantly affect the pharmacokinetics of atorvastatin. Atorvastatin showed ATP-dependent transport in BCRP-expressing membrane vesicles and it inhibited rosuvastatin transport with K i of 6.3 ± 2.9 μM (mean ± SD). Microdosing study appears to be feasible to roughly estimate the pharmacokinetic and pharmacogenetic profiles of atorvastatin following the oral therapeutic dose in hypercholesterolemic patients., (Copyright © 2019 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Aim: To determine characteristics of rheumatoid arthritis (RA) patients in Japan who received the same biological disease-modifying antirheumatic drugs (bDMARDs) for at least 6 months and to identify factors associated with successful down-titration of bDMARDs dependent on shared decision-making., Methods: We included consecutive RA patients who received the same bDMARD with low disease activity or remission for at least 6 months in our two university hospitals. Patients treated with the bDMARD standard dose were defined as SD, while those treated with bDMARD down-titration were defined as DT. We retrospectively reviewed clinical charts and compared data between the two groups., Results: Of 288 patients with RA, 204 (70.8%) and 84 (29.2%) continued standard dose treatment and underwent down-titration treatment, respectively. Sixty-six of 84 (78.6%) down-titration-treated patients continued to show low disease activity or remission, whereas 18 (21.4%) relapsed 18.9 ± 24.4 months after bDMARD down-titration was started. Univariate predictor analysis showed that the probable factors of down-titration were no history of bDMARD treatment (P = .001) and low initial Disease Activity Assessment of 28 joint score (P = .048). Other clinical characteristics had no significant relationship with successful down-titration., Conclusions: Thus, bDMARD-naïve patients and those with low initial disease activity are more likely to agree to attempt down-titration. However, the timing and method of down-titration should be made in shared decision-making between patients and rheumatologists., (© 2019 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) are the leading causes of acute respiratory tract infection in children, and clinical manifestations of these virus infections are considered similar. To investigate the differences in clinical characteristics between HMPV and RSV infections in young children, we prospectively enrolled children ＜ 3 years old who required hospitalization with acute respiratory tract infection due to HMPV or RSV at 10 hospitals in Japan. We enrolled 48 children with HMPV infection and 141 with RSV infection. Patients with HMPV infection were older than those with RSV infection. High-grade fever was more frequently observed in patients with HMPV infection, whereas no significant differences in respiratory symptoms were apparent. Abnormal serum lactate dehydrogenase values and consolidation shadows on chest X-ray were more frequently observed in patients with HMPV infection. During hospitalization, nasal mucus suction was more frequently required in patients with RSV infection. On the other hand, β2-adrenergic agonists, corticosteroids, and leukotriene receptor antagonists were more frequently used in patients with HMPV infection. These findings suggest that HMPV and RSV infections show similar respiratory symptoms, but HMPV infection is more likely to lead to the development of pneumonia, at least among hospitalized young children.

Ectomycorrhizal (ECM) symbiosis is essential for the survival of both host trees and associated ECM fungi. However, during conservation activities of endangered tree species, their ECM symbionts are largely ignored. Here, we investigated ECM fungi in ex situ populations established for the conservation of Pinus amamiana, an endangered species distributed on Yakushima Island, Japan. Our objective was to determine whether ECM fungi in natural forests are conserved in ex situ populations on the same island. In particular, we focused on the existence of Rhizopogon yakushimensis, which is specific to P. amamiana and the most dominant in natural P. amamiana forests. Molecular identification of ECM fungi in resident tree roots and soil propagule banks indicated that ECM fungal species native to natural forests were rarely conserved in ex situ populations. Furthermore, R. yakushimensis was not confirmed in any of the resident root or spore bioassay samples from the ex situ populations. Thus, ECM fungal spores may not be effectively dispersed from natural forests located on the same island. Instead, ECM fungi distributed in other geographical regions occurred more frequently in the ex situ populations, indicating unintentional introductions of non-native ECM fungi from the nurseries where seedlings were raised before transplanting. These findings imply that the current ex situ conservation practices of endangered tree do not work for the conservation of native ECM fungi, and instead may need modification to avoid the risk of introducing non-native ECM fungi near the endangered forest sites.

Candida blood stream infection (candidemia) is severe systemic infection mainly develops after intensive medical cares. The mortality of candidemia is affected by the underlying conditions, causative agents and the initial management. We retrospectively analyzed mortality-related risk factors in cases of candidemia between April 2011 and March 2016 in five regional hospitals in Japan. We conducted bivariate and multivariate analysis of factors including causative Candida species, patients' predisposing conditions, and treatment strategies, such as empirically selected antifungal drug and time to appropriate antifungal treatment, to elucidate their effects on 30-day mortality. The study enrolled 289 cases of candidemia in adults. Overall 30-day mortality was 27.7%. Forty-nine cases (17.0%) were community-acquired. Bivariate analysis found advanced age, high Sequential Organ Failure Assessment (SOFA) score, and prior antibiotics use as risk factors for high mortality; however community-acquired candidemia, C. parapsilosis candidemia, obtaining follow-up blood culture, and empiric treatment with fluconazole were associated with low mortality. Logistic regression revealed age ≥65 years (adjusted odds ratio, 2.13) and sequential organ failure assessment (SOFA) score ≥6 (6.30) as risk factors for 30-day mortality. In contrast, obtaining follow-up blood culture (0.38) and empiric treatment with fluconazole (0.32) were found to be protective factors. The cases with candidemia in associated with advanced age and poor general health conditions should be closely monitored. Obtaining follow-up blood culture contributed to an improved prognosis., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: An ageing society includes high patient complexity. Various biopsychosocial problems result in a high burden for health-related professionals. The direct relationship between the burden and patient complexity, however, has not been reported. We aimed to examine correlations between the burden for the attending physicians and nurses, and Patient Centred Assessment Method (PCAM) scores of patient complexity., Design: Prospective cohort study., Setting: A regional secondary care hospital in Japan., Participants: We included all inpatients admitted to our acute care unit between 1 July 2014 and 30 September 2014. Exclusion criteria were age <20 years, refusal to participate in the study and length of stay fixed at the time of admission., Main Predictor: PCAM total score in the initial phase of hospital admission., Main Outcome: The burden for each profession (measured on a Visual Analogue Scale)., Results: In total, 201 inpatients participated [female/male=98/103, mean (SD) age of 77.4±11.9 years]. Spearman's rank correlation coefficients between the burden and the PCAM score ranged from 0.23 to 0.32. All p values were <0.05. Multivariate analysis was conducted using multilevel mixed-effects linear regression to determine the association between the burden and the PCAM score in two models. Model 1 used the total PCAM score as the predictive variable. Model 2 used the PCAM factors, patient-oriented complexity and medicine-oriented complexity, as predictive variables. In Model 2, with the burden of physicians, medicine-oriented complexity was statistically significant, whereas with the burden of nurses, both age and patient-oriented complexity were statistically significant., Conclusions: PCAM scores correlated with the burden for physicians and nurses. Individual PCAM factors affected the burden for each profession differently., Competing Interests: Competing interests: SY worked at Ouji Coop Hospital. YF and TW work as part-time physicians at Ouji Coop Hospital. MM is an adviser of Centre for Family Medicine Development practice-based research network. MM received lecture fee and travel fee for lecture from Centre for Family Medicine Development. MM received the grant from Japan Society for the Promotion of Science. SY and TW were former residents in family medicine at the Centre for Family Medicine Development. MM is a Program Director for Jikei Clinical Research Program of Primary-care. YF is a lecturer of Jikei Clinical Research Program for Primary-care. YS is a trainee of Jikei Clinical Research Program for Primary-care. SY, HW, TY and TW were former trainees of Jikei Clinical Research Program for Primary-care. This work was supported by a research grant of fiscal year 2015 from The Jikei University School of Medicine and Postgraduate Medical School. There is no potential competing interest to be declared relevant to this work other than the above description., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine the presence and predictors of depression and anxiety in pet owners after a diagnosis of cancer in their pets., Design: Cross-sectional study., Setting: A veterinary medical centre specialised in oncology for dogs and cats and two primary veterinary clinics in Japan., Participants: The participants for analysis were 99 owners of a pet with cancer diagnosis received in the past 1-3 weeks and 94 owners of a healthy pet., Main Outcome Measures: Self-reported questionnaires were used to assess depression and anxiety. Depression was assessed using the Center of Epidemiologic Studies Depression Scale, and anxiety was measured by using the State-Trait Anxiety Inventory-Form JYZ., Results: Depression scores were significantly higher in owners of a pet with cancer than owners of a healthy pet, even after adjustment for potential confounders (p<0.001). Within the owners of a pet with cancer, depression was significantly more common in those who were employed than those who were unemployed (p=0.048). State anxiety scores were significantly higher in owners of a pet with cancer than owners of a healthy pet, even after adjustment for potential confounders, including trait-anxiety scores (p<0.001). Furthermore, in owners of a pet with cancer, state anxiety was higher in owners with high trait anxiety (p<0.001) and in owners whose pets had a poor prognosis (p=0.027)., Conclusion: The results indicate that some owners tended to become depressed and anxious after their pets had received a diagnosis of cancer. Employment may be a predictor of depression. High trait anxiety and a pet with a poor prognosis may increase owners' state anxiety. Including the pet in a family genogram and attention to the pet's health condition may be important considerations for family practice., Competing Interests: Competing interests: MM received a lecture fee from the Japan Small Animal Medical Center, MM is an adviser of the Centre for Family Medicine Development practice-based research network, MM received a lecture fee and lecture travel fee from the Centre for Family Medicine Development, MM received a grant from the Japan Society for the Promotion of Science and MM is a Program Director of the Jikei Clinical Research Program for Primary-care., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We have found that anagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4) significantly ameliorates arterial stiffness in Type 2 Diabetes Mellitus (T2DM) patients compared with an equivalent hypoglycaemic agent, glimepiride. However, it remains unclear whether switching DPP-4 inhibitors to tofogliflozin, a selective inhibitor of Sodium-Glucose Cotransporter 2 (SGLT2) improves arterial stiffness in T2DM patients., Methods: Nineteen T2DM patients who had received DPP-4 inhibitors for at least 1 year were enrolled in this study. Clinical parameters and arterial stiffness evaluated by cardio-ankle vascular index (CAVI) were measured at baseline and after 6-months treatment with tofogliflozin., Results: At 6 months after switching to tofogliflozin, CAVI, waist circumference, body weight, body mass index, subcutaneous and visceral fat volume, white blood cell number, fasting plasma insulin, uric acid, aspartate transaminase (AST), γ-glutamyl transferase (GTP), and advanced glycation end products (AGEs) were significantly reduced, while red blood cell number, haemoglobin, and HbA1c values were increased. When stratified by median values of change in CAVI after switching to tofogliflozin (ΔCAVI), baseline serum levels of AGEs were significantly higher in the low ΔCAVI group (high responder) than in the high one (low responder). ΔAST and ΔGTP were positively correlated with ΔCAVI., Conclusion: The present study suggests that switching DPP-4 inhibitors to tofogliflozin ameliorates arterial stiffness in T2DM patients partly via improvement of liver function. Baseline serum levels of AGEs may identify patients who improve arterial stiffness more after treatment with tofogliflozin., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Venous thromboembolism (VTE) has been shown to be more frequent in inflammatory bowel disease (IBD) than in the general population in Western studies. However, the actual state of VTE in Asian IBD remains poorly understood., Aims: To reveal the incidence of VTE in IBD patients in Japan., Methods: Eighty-five patients admitted to 3 gastroenterology centers were registered from 2013 to 2018. The incidence of VTE in patients with IBD (n = 42) was prospectively compared to that among patients with other digestive diseases (n = 43). The presence of VTE was surveyed using contrast-enhanced computed tomography and/or ultrasonography at admission and at 1-2 weeks after admission. The patient characteristics and laboratory data of IBD patients with or without VTE were compared to determine the risk factors for VTE., Results: The incidence of VTE with IBD was 16.7%, which was significantly more frequent than with other digestive diseases (2.3%; p = 0.0296). In IBD patients, VTE was detected in 6 of 22 patients with ulcerative colitis (27.2%) but in only 1 of 20 patients with Crohn's disease (5.0%). VTE was diagnosed at admission in 4 IBD patients and 2 weeks after admission in 3 IBD patients. The risk factors of VTE in IBD were the presence of an indwelling central venous catheter, a low level of total protein, a low activated partial thromboplastin time, and a high level of fibrinogen degradation products., Conclusion: VTE was frequently detected in Japanese IBD patients both at and after admission. Adequate screening and prophylaxis for VTE is deemed necessary in IBD., (© 2018 S. Karger AG, Basel.)

Previous studies attempted to characterize the subjects with sarcoidosis according to differences in sex, age, and the presence of specific organ involvement. However, significant interactions among these factors precluded a clear conclusion based on simple comparison. This study aimed to clarify the age- and sex-stratified prevalence of specific organ involvement and the heterogenous nature of sarcoidosis. Using the data of 9,965 patients who were newly registered into a database at the Ministry of Health, Labour and Welfare, Japan between 2002 and 2011, we evaluated the age- and sex-specific prevalence of the eye, lung, and skin involvement of sarcoidosis. We also attempted corresponding analysis considering multiple factors. As compared with several decades ago, the monophasic age distribution in men became biphasic, and the biphasic distribution in women, monophasic. The prevalence of pulmonary and cutaneous lesions was significantly associated with age, whereas the prevalence of ocular involvement showed a biphasic pattern. The prevalence of bilateral hilar lymphadenopathy was significantly higher, whereas the prevalence of diffuse lung shadow was significantly lower, in subjects with ocular involvement than those without ocular involvement. Corresponding analysis visually clarified the complex interactions among factors. Our results contribute to a better understanding of the heterogeneous features of sarcoidosis.

We performed a multicenter observational study to assess the prevalence and risk factors of persistent pain after lung cancer surgery and total knee arthroplasty (TKA) in the Japanese population. After receiving Ethics Committee approval, a retrospective chart review was performed for patients who underwent surgery at seven university hospitals in Japan in 2013. A total of 511 patients who underwent lung cancer surgery and 298 patients who underwent TKA were included. The prevalence of chronic postsurgical pain (CPSP) at 3 and 6 months was 18 and 12% after lung surgery and 49 and 33% after TKA, respectively. The prevalence of analgesic use at 3 and 6 months was 16 and 9% after lung surgery and 34 and 22% after TKA, respectively. In both groups, preoperative analgesic use was associated with CPSP. Anesthetic methods or techniques during both types of surgery did not significantly affect the prevalence of CPSP. This is the first study in which the prevalence of CPSP after lung surgery and TKA in Japanese population was extensively evaluated in a multicenter trial. Further prospective studies are needed to confirm the prevalence of CPSP in the Japanese population and to identify risk factors and prevention methods.

Objective: To present the study design and rationale of Prostatic Cancer Registry of Standard Hormonal and Chemotherapy Using Bone Scan Index, a prospective study aiming to determine the role of the bone scan index, the amount of bone metastasis, in the treatment and prognosis of prostate cancer patients., Methods: A total of 237 patients were recruited at 30 hospitals in Japan. All had prostate cancer with bone metastasis and were scheduled to undergo either hormonal therapy (group H) or chemotherapy (group C). Bone scans were carried out with 99m Tc-methylenediphosphonate. Follow-up studies are planned to continue for 3 years, and changes in biochemical and tumor markers in response to hormonal therapy and chemotherapy will be recorded in addition to skeletal-related events, recurrence, disease progression and death., Results: The basic characteristics of the patients (n = 200) at the time of registration during December 2016 were as follows: mean age 71 ± 8 years; median bone scan index calculated on-site 1.9% (range 0.02-13.3%); median number of hot spots 18 (range 1-128); median prostate-specific antigen 155 ng/mL (range 0.04-22 412 ng/mL); and the most frequent Gleason score 9 (47%). The prostate-specific antigen value was higher in group H than group C (288 vs 33 ng/mL, P < 0.0001), whereas bone scan indexes were comparable (1.7 vs 2.3%, not significant) between the two groups. Liver metastasis was more frequent in group C than group H (6.1% vs 0.8%, P = 0.035)., Conclusions: The baseline characteristics of the Prostatic Cancer Registry of Standard Hormonal and Chemotherapy Using Bone Scan Index database have been established. This collaborative study can now proceed with clarifying the role of the bone scan index for patient management including treatment strategies and prognosis., (© 2018 The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological Association.)

Background: The role of surgery in the onset of sarcoidosis is unclear. We investigated whether surgery is an internal environmental factor for sarcoidosis onset within the Japanese population., Methods: We enrolled 222 patients diagnosed with sarcoidosis (78 men, 144 women) who were admitted to our department between 1984 and 2012. We also enrolled 529 control subjects (251 men, 278 women), who were matched for sex, age at admission, and year of admission. Surgical history, family history, and smoking status were evaluated., Results: Multivariate analysis correlated history of appendectomy (OR, 1.55; 95% CI, 1.05-2.29) and tonsillectomy (OR, 2.79; 95% CI, 0.91-8.56) with the occurrence of sarcoidosis; other surgical procedures had no correlation. In women, appendectomy had a stronger association with sarcoidosis (OR, 1.69; 95% CI, 1.05-2.73), as opposed to that in men (OR, 1.39; 95% CI, 0.68-2.85). This association was greater in women aged ≥45 years than in those aged <45 years. There was a stronger correlation between tonsillectomy and sarcoidosis in women (OR, 3.30; 95% CI, 0.88-12.39), than in men (OR, 1.26; 95% CI, 0.10-16.52). ORs for sarcoidosis were 5.55 (95% CI, 2.02-15.27) and 0.97 (95% CI, 0.52-1.84) in women aged ≥45 years with a history of appendectomy at <20 years and ≥20 years, respectively, with the former being statistically significant., Conclusions: Appendix and tonsil removal was associated with sarcoidosis onset, suggesting their potential protective role against sarcoidosis development. Further studies are needed to minimize possible confounding factors., (Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Objectives: Although some interstitial pneumonia (IP) cases are not detected on computed tomography (CT) before surgery, they are confirmed by pathological diagnosis after pulmonary resection. In the present study, we aimed to investigate patients who underwent pulmonary resection for non-small-cell lung cancer (NSCLC) and subsequently showed pathological findings of IP but no apparent interstitial changes on CT., Methods: We retrospectively analysed 1688 patients with NSCLC who underwent pulmonary resection and presented with a radiological or pathological diagnosis of IP in 64 institutions between January 2000 and December 2009. We compared 135 patients without radiological findings but with pathological findings of IP (Group A) with 1553 patients with radiological findings of IP (Group B)., Results: The percent vital capacity and predicted diffusing capacity for carbon monoxide were higher in Group A than in Group B. Although there was no significant difference in the occurrence of acute exacerbation (AE) between both groups, the mortality after AE in Group A was significantly lower than that in Group B. The overall survival rates of patients in Groups A and B at 5 years were 59.1 and 40.9%, respectively (P = 0.0031)., Conclusions: The mortality after AE in patients with only pathological findings of IP was significantly lower than in those with radiological findings of IP. Moreover, the patients with only pathological findings of IP had a better prognosis than those with radiological findings of IP. Thus, our findings suggest that patients with pathological findings of IP and without radiological abnormality had early-stage IP., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

A randomised, double-blind, phase II, dose escalation trial was conducted to assess the safety, tolerability and pharmacokinetics of the tyrosine kinase inhibitor nintedanib, alone and when added to ongoing pirfenidone therapy, in Japanese patients with idiopathic pulmonary fibrosis. 50 Japanese patients were randomised to receive nintedanib or placebo in one of three cohorts (nintedanib 50 mg twice daily or 100 mg twice daily for 14 days, or 150 mg twice daily for 28 days). Patients receiving pirfenidone at inclusion were stratified to every nintedanib dose group and placebo. Adverse events were reported in nine out of 17 patients receiving nintedanib alone and 10 out of 21 patients receiving nintedanib added to pirfenidone. All adverse events were mild or moderate in intensity. Gastrointestinal disorders were the most common adverse event. Maximum plasma concentration and area under the curve at steady state for nintedanib and its metabolites tended to be lower when nintedanib was added to pirfenidone. Nintedanib had no effect on the pharmacokinetics of pirfenidone. In conclusion, further study is needed to evaluate the safety and tolerability profile of nintedanib when added to pirfenidone in patients with idiopathic pulmonary fibrosis. There was a trend toward lower exposure of nintedanib when it was added to pirfenidone., (Copyright ©ERS 2015.)

Background: There have been no prospective large-scale multicenter epidemiological studies on the clinical course and treatment from the time of diagnosis of idiopathic interstitial pneumonias (IIPs) in Japan. The purpose of this study was to clarify the current clinical situation of IIP in Japan., Methods: This study was supported by a grant from the Ministry of Health, Labour and Welfare to the Diffuse Lung Diseases Research Group. Data including clinical findings, course, and treatment of IIP from a web database created by a collaborative effort of medical institutions across Japan that specialize in the care of interstitial pneumonias were collected and analyzed., Results: A total of 436 IIP patients from 19 institutions were newly registered during a 5-year period. Idiopathic pulmonary fibrosis (IPF) was the most frequently encountered IIP, and 28% of the IPF cases were initially diagnosed by abnormal chest X-ray or CT in asymptomatic patients. Until the 2008 fiscal year, no treatment was given for most cases of IPF. After the end of 2008, when pirfenidone was approved for manufacture, the number of patients for whom no treatment was recommended declined, and pirfenidone therapy was initiated in 32.9% of cases in 2009. The median survival times for IPF from the onset symptoms and from the initial visit were 105 months and 69 months, respectively., Conclusions: This study should provide valuable information for understanding the current state of IIP in Japan., (Copyright © 2014 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: National surveys conducted in Japan between 1960 and 2004 suggest a gradually increasing incidence of sarcoidosis in women >50 years old with increased involvement of the eye, skin, and heart. However, whether this involvement is due to the increased age at diagnosis is still unclear. We aimed here to identify the age-related differences in organ involvement in sarcoidosis in Japan, as well as the historical changes in clinical characteristics and the age-specific distribution of cases at diagnosis., Methods: We reviewed 588 consecutive Japanese patients newly diagnosed with sarcoidosis between 1974 and 2012 at Jichi Medical University Hospital. We compared organ involvement between subgroups differentiated by sex and age (<45 years; n = 275; ≥45 years; n = 313) at diagnosis and identified historical changes in the age-specific distribution in 10-year intervals., Results: Younger patients had more common involvement of extrathoracic lymph nodes, parotid/salivary gland, and liver, while older patients had more common involvement of non-lymphatic extrathoracic organs such as the eye, heart, muscle, and kidney. The age at diagnosis has consistently increased over the past four decades. The monophasic distribution in men has tended to become biphasic, and the biphasic distribution in women monophasic. Increasing trends were apparent for hypercalcemia and involvement of the gastrointestinal tract, skin, nervous system, muscle, and kidney., Conclusions: Elderly patients at diagnosis had various extrathoracic involvement including eye, skin, and cardiac lesions. Moreover, the age at diagnosis of sarcoidosis has continued to increase in both sexes, influencing the recent trends in clinical characteristics., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: Patients with interstitial lung diseases have a poor prognosis and are at increased risk of developing lung cancer. We evaluated the survival and predictors of survival after surgical resection in lung cancers in patients with interstitial lung diseases., Methods: We retrospectively analyzed data from 1763 patients with non-small cell lung cancer with a clinical diagnosis of interstitial lung disease who underwent pulmonary resection between 2000 and 2009 at 61 Japanese institutions., Results: Male patients (90.4%) and smokers (93.8%) were in the majority. The overall 5-year survival was 40%. The 5-year survivals were 59%, 42%, 43%, 29%, 25%, 17%, and 16% for patients with stage Ia, Ib, IIa, IIb, IIIa, IIIb, and IV, respectively. Patients with stage IA had a 5-year survival of 33.2%, 61.0%, and 68.4% in the wedge resection, segmentectomy, and lobectomy groups, respectively (log-rank test, P = .0038). The leading cause of death was cancer recurrence (50.2%), followed by respiratory failure (26.8%). Wedge resection reduced mortality due to respiratory failure when compared with that of lobectomy (P = .022). Multivariable analysis revealed that the type of surgical procedure, predicted percent vital capacity, and tumor locations were independent predictors for survival. The 5-year survival was 20% for patients with stage Ia with a predicted percent vital capacity of 80% or less, and 64.3% for patients with a predicted percent vital capacity greater than 80% (log-rank test, P < .0001)., Conclusions: In these patients, there are competing risks of death. Wedge resection reduced death caused by respiratory failure but resulted in poorer long-term prognosis than lobectomy. For patients with poor predictors of survival, such as predicted percent vital capacity of 80% or less, surgical resection should be limited., (Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)