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Background: Chest computed tomography (CT) is a valuable tool for diagnosing and predicting the severity of coronavirus disease 2019 (COVID-19) and assessing extrapulmonary organs. Reduced muscle mass and visceral fat accumulation are important features of a body composition phenotype in which obesity and muscle loss coexist, but their relationship with COVID-19 outcomes remains unclear. In this study, we aimed to investigate the association between the erector spinae muscle (ESM) to epicardial adipose tissue (EAT) ratio (ESM/EAT) on chest CT and disease severity in patients with COVID-19., Methods: We analysed data from 1074 COVID-19 patients enrolled in the Japan COVID-19 Task Force database. The primary outcome was the rate of critical outcomes (requiring high-flow oxygen therapy, invasive ventilator support or death). The incidence of critical outcomes was compared between patients with high and low ESM/EAT ratios., Results: The low ESM/EAT group (n = 353) had a higher incidence of critical outcomes (13.3% vs. 5.13%, p < 0.001) and mortality (2.55% vs. 0.69%, p = 0.019) than the high ESM/EAT group (n = 721). In multivariable analysis, the low ESM/EAT ratio was associated with critical outcomes (adjusted odds ratio [aOR] 2.11, 95% confidence interval [CI] 1.22-3.66) independently of the known COVID-19 severity factors including age, sex, body mass index (BMI), smoking history, lifestyle-related comorbidities and pneumonia volume., Conclusion: The low ESM/EAT ratio in COVID-19 patients can be obtained on chest CT and used to predict critical outcomes after disease onset, demonstrating the importance of detailed body composition assessments in COVID-19 practice., (© 2025 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Adverse childhood experiences (ACEs) have been reported to detrimentally impact physical and mental health. While experiencing multiple ACEs is common, previous research primarily assessed ACEs by their total count, neglecting the impacts of different experience types. Furthermore, sex-based differences in ACEs and their influences remain unclear. This study employed Latent Class Analysis (LCA) to uncover patterns of ACEs with consideration for sex differences, aiming to elucidate their effects on adult physical and mental health. A geographically nationally representative dataset from the "Japan COVID-19 and Society Internet Study (JACSIS)" conducted in 2022 was used. 13,715 men and 14,327 women retrospectively reported their experiences across fifteen ACEs. The analysis revealed four distinct ACE patterns for both sexes: a Multiple Adversities class with a wide range of severe ACEs, a Psychological Abuse class experiencing emotional abuse at home and bullying at school, a Poverty class facing economic hardships, and a Low Adversities class with the fewest ACEs. Multinomial logistic regression analysis indicated that more severe patterns of exposure correlated with heightened adverse adult outcomes. However, the extent of these impacts varied by sex and ACE pattern. For instance, men in Multiple Adversities and Psychological Abuse classes exhibited higher tendencies towards conducting physical and psychological abuse behaviors. While ACEs in men were linked to both underweight (in cases of psychological abuse) and obesity (across all classes), women with ACEs generally leaned towards higher body weight. These findings highlight the importance of developing support strategies sensitive to sex differences and the specific content of ACEs., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Although sex differences in the prevalence of sleep disordered breathing (SDB) is recognized, whether a sex difference exists among obese individuals with SDB with or without comorbidities has not been well investigated. This study aimed to explore the relationships of sex differences among SDB, obesity, and metabolic comorbidities., Methods: This study evaluated 7713 community participants with nocturnal oximetry ≥2 nights. SDB was assessed by the 3% oxygen desaturation index corrected for sleep duration obtained by wrist actigraphy (Acti-ODI3%), and moderate-to-severe SDB was defined as Acti-ODI3% levels ≥15/h. Obesity was defined as body mass index ≥25 kg/m 2 ., Results: The prevalence of moderate-to-severe SDB was 21.6%/0% among those with obesity/without obesity in women under 40 years old. The adjusted odds ratios for moderate-to-severe SDB in those with both diabetes/metabolic syndrome and obesity compared to others were 86.4 (95%CI 24.2-308.8)/40.4 (95%CI 15.0-108.8) in pre-menopausal women. The association among SDB, obesity, and metabolic comorbidities showed significant interactions between pre-menopausal women and men or post-menopausal women., Conclusions: Sex differences exist among the prevalence of SDB and the relationships among SDB, obesity, and metabolic comorbidities. Especially, pre-menopausal women are more vulnerable to the consequences of obesity. SDB prevalence may be impacted by the coexistence of obesity and diabetes or metabolic syndrome in pre-menopausal women., Competing Interests: Conflicts of interest Takeshi Matsumoto, Takuma Minami, Osamu Kanai, Kiminobu Tanizawa, Tomoko Wakamura, Naoko Komenami, Kazuya Setoh, Takahisa Kawaguchi, Satoshi Morita, Yoshimitsu Takahashi, and Toyohiro Hirai have nothing to disclosure. Hironobu Sunadome and Naomi Takahashi reports grants from Philips Japan, grants from ResMed, grants from Fukuda Denshi, grants from Fukuda Lifetec Keiji, outside the submitted work. Kimihiko Murase reports grants from Philips Japan, grants from Teijin Pharma, grants from Fukuda Denshi, grants from Fukuda Lifetec Keiji, outside the submitted work. Yasuharu Tabara reports grants from the Ministry of Education, Culture, Sports, Science & Technology in Japan, grants from Japan Science and Technology Agency, grants from Mitsubishi Foundation, grants from Daiwa Securities Health Foundation, and grants from Sumitomo Foundation, outside the submitted work. Satoshi Hamada reports grants from Teijin Pharma, outside the submitted work. Takeo Nakayama reports grants from Special Health Check-up Research Group from the Ministry of Health, Labor and Welfare of Japan, personal fees from Pfizer Japan Inc., personal fees from MSD K.K., personal fees from Ohtsuka Pharmaceutical co., personal fees from Dainippon Sumitomo Pharmaceutical co., personal fees from Ono Pharmaceutical co., personal fees from Chugai Pharmaceutical co., personal fees from Dentsu co., personal fees from Takeda Pharmaceutical co., personal fees from Novo Nordisk Pharma. co., personal fees from Janssen Pharmaceutical K.K., personal fees from Boehringer Ingelheim International GmbH, personal fees from Nikkei Business Publications, Inc., personal fees from Eli Lilly Japan K.K., personal fees from Novartis Pharma K.K., personal fees from Baxter, personal fees from Alexion Pharma, personal fees from Mitsubishi Tanabe Pharma Corporation, grants for the collaborative study from HANSHIN Dispensing Holding Co. Ltd., grants from Nakagawa Pharmacy Co., Ltd., grants from Konica Minolta, Inc., donations for the department from Nakamura hospital, donations from Japan Medical Data Center Toyota, donations from Tsusho All Life Co., outside the submitted work. Susumu Sato reports grants from Philips Japan, ResMed, Fukuda Denshi, Fukuda Lifetec Keiji, Fuji Film corporation and Nippon Boehringer Ingelheim, outside the submitted work. Fumihiko Matsuda reports grants from Kyoto University, grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan, grants from the Center of Innovation Program, grants from Japan Science and Technology Agency, from the Practical Research Project for Rare/Intractable Diseases, during the conduct of the study. Kazuo Chin reports grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology, grants from the Intractable Respiratory Diseases and Pulmonary Hypertension Research Group, the Ministry of Health, Labor and Welfare, Japan, grants from the Japan Vascular Disease Research Foundation, grants from Health, Labour and Welfare Sciences Research Grants, Research on Region Medical, during the conduct of the study; grants and personal fees from Philips Japan, grants and personal fees from Teijin Pharma, grants and personal fees from Fukuda Denshi, grants and personal fees from Fukuda Lifetec Keiji, grants from KYORIN Pharmaceutical Co., Ltd, grants from Nippon Boehringer Ingelheim Co., Ltd, grants and personal fees from GlaxoSmithKline, personal fees from MSD, personal fees from Resmed, personal fees from Astellas Pharma, personal fees from Eisai Co., Ltd., outside the submitted work., (Copyright © 2024. Published by Elsevier B.V.)

Background: Efforts to promote antimicrobial stewardship aimed at reducing antimicrobial resistance are necessary regardless of hospital scale owing to delays in new antimicrobial development. We aimed to evaluate the effects of pharmacist-driven interventions on broad-spectrum antimicrobial usage and the prognosis of patients with bacteremia in a medium-sized hospital lacking infectious disease physicians and a microbiology laboratory., Methods: This single-center, retrospective, pragmatic, quasi-experimental study was conducted to compare pre- and post-intervention effects at Saiseikai Futsukaichi Hospital. We analyzed the days of therapy (DOT) for carbapenems and days of antibiotic spectrum coverage (DASC) for antimicrobials using an interrupted time series analysis. Cox proportional hazards analysis was performed to assess 30-day mortality using propensity score and inverse probability of treatment weighting in patients with bacteremia., Results: Pharmacist-driven interventions significantly reduced the DOT (incidence rate ratio [IRR]: 0.53, 95 % confidence intervals [CI]: 0.33-0.81, p = 0.003) and DASC (IRR: 0.87, 95 % CI: 0.78-0.97, p = 0.016). The 30-day mortality due to bacteremia did not significantly differ between pre- and post-intervention in all patients (adjusted hazard ratio [HR]: 0.92, 95 % CI: 0.56-1.51, p = 0.74). Conversely, pharmacist-driven interventions significantly reduced the 30-day mortality owing to bacteremia with Pitt bacteremia score (PBS) ≥4 (adjusted HR: 0.52, 95 % CI: 0.28-0.99, p = 0.047)., Conclusions: Pharmacist-driven interventions may represent a valuable approach for optimizing antimicrobial treatment and improving prognosis, especially in patients with PBS ≥4, which will potentially benefit patients in similar healthcare environments facing challenges related to antimicrobial stewardship and patient prognosis., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background and Objective: Mucus plugs and underlying airway tree structure can affect airflow limitation and prognosis in patients with chronic obstructive pulmonary disease (COPD), but their relative roles are unclear. This study used two COPD cohorts to examine whether mucus plugs on computed tomography (CT) were associated with airflow limitation and clinical outcomes independent of other airway structural changes and emphysema., Methods: Based on visual CT assessment, patients with mucus plugs in 0, 1-2 and ≥3 lung segments were assigned to no-, low- and high-mucus groups. Loss of health-related independence and mortality were prospectively recorded for 3 and 10 years in the Kyoto-Himeji and Hokkaido cohorts, respectively. The percentages of the wall area of the central airways (WA%), total airway count (TAC) and emphysema were quantified on CT., Results: Of 199 and 96 patients in the Kyoto-Himeji and Hokkaido cohorts, 34% and 30%, respectively, had high mucus scores. In both cohorts, TAC was lower in the high-mucus group than in the no-mucus group, whereas their emphysema severity did not differ. High mucus score and low TAC were independently associated with airflow limitation after adjustment for WA% and emphysema. In multivariable models adjusted for WA% and emphysema, TAC, rather than mucus score, was associated with a greater rate of loss of independence, whereas high mucus score, rather than TAC, was associated with increased mortality., Conclusion: Mucus plugs and lower airway branch count on CT had distinct roles in airflow limitation, health-related independence and mortality in patients with COPD., (© 2024 The Author(s). Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Background: Increasing expectations that biologics can be used as disease-modifying agents have introduced the concept of clinical remission (CR) in managements of severe asthma. Given the clinical relevance of computed tomography (CT) and blood biomarkers, we hypothesized that further refinement of CR criteria as well as incorporation of CT and blood biomarkers as indicators for structural and biological remission (SR, BR) would enable predicting long-term disease stability in patients with severe asthma treated with biologics., Methods: This Japanese multicenter prospective observational cohort will enroll patients with severe asthma who will start a new biologic (including a change from another biologic). The enrolled patients will be longitudinally followed up for 3 years. At enrollment, patients will undergo postbronchodilator spirometry, blood tests, fractional exhaled nitric oxide, chest and sinus CT, and patient-reported outcome questionnaires. Follow-up examinations will be performed at 1, 3, 6, 12, 24, and 36 months. The rates of CR resulting from different criteria after 1 year of treatment with biologics will be compared, and factors associated with long-term disease stability after 3 years of biologic treatments will be identified., Discussion: This multicenter study in Japan will provide data that will help establish more appropriate criteria for CR, structural remission, and biological remission to predict long-term disease stability in patients with severe asthma who receive biologic therapy., Ethics and Dissemination: The study was approved by the Ethics Committee of Kyoto University (No. R4419, approval date June 11th, 2024)., Trial Registration: The University Hospital Medical Information Network (UMIN000053771)., Competing Interests: Declaration of competing interest N.T. received honoraria for lectures for AstraZeneca and research funding from Fujifilm, and Daiichi Sankyo. Y.H. received honoraria for lectures for AstraZeneca, GlaxoSmithKline, Sanofi, Boehringer Ingelheim JP. S.M. received honoraria for lectures for AstraZeneca, GlaxoSmithKline, Sanofi. J.M. received honoraria for lectures for AstraZeneca, GlaxoSmithKline, Sanofi and research funding from AstraZeneca, GlaxoSmithKline, Novartis. T.W. received honoraria for lectures for AstraZeneca, GlaxoSmithKline, Sanofi. K.O. received honoraria for lectures for AstraZeneca, Boehringer Ingelheim JP. M.Y. received honoraria for lectures for AstraZeneca, GlaxoSmithKline and research funding from Boehringer Ingelheim JP, GlaxoSmithKline, Clairvo technologies Inc. K.A. received honoraria for lectures for AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim JP. Y.N. received honoraria for lectures for AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim JP and research funding from Boehringer Ingelheim JP, GlaxoSmithKline, Clairvo technologies Inc. T. Hirano received honoraria for lectures for AstraZeneca, GlaxoSmithKline, Sanofi. K. Matsunaga received honoraria for lectures for AstraZeneca, GlaxoSmithKline, Kyorin Pharma, Novartis, Sanofi. T. Koya received honoraria for lectures for AstraZeneca, GlaxoSmithKline, Sanofi, Novartis. H.M. received honoraria for lectures for AstraZeneca, Sanofi, GlaxoSmithKline, Novartis. K.F. received honoraria for lectures for AstraZeneca, GlaxoSmithKline, Sanofi, Novartis, Boehringer Ingelheim JP, Kyorin Pharma and research funding from AstraZeneca, GlaxoSmithKline, Novartis, Boehringer Ingelheim JP, Chugai Pharmaceutical. S. K. received honoraria for lectures for AstraZeneca, Boehringer Ingelheim JP and research funding from Novartis. T. Kaneko received honoraria for lectures for AstraZeneca, Kyorin Pharma, Novartis, Sanofi, Boehringer Ingelheim JP. T. Hirai. received research funding from Fujifilm and Daiichi Sankyo., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Nocturnal blood pressure (BP) is associated with cardiovascular disease independently of awake BP. However, nocturnal BP measured using an ambulatory monitoring device has limited reproducibility because it is a single-day measurement. We investigated the association between sleep BP measured on multiple days using a timer-equipped home BP monitor and cardiovascular diseases in a general population., Methods: The study population comprised 5814 community residents. Participants were required to sleep with wrapping cuffs on their upper arm and BP was measured automatically at 0 : 00, 2 : 00, and 4 : 00. Actigraph was used to determine BP measured during sleep. Participants were also measured home morning and evening BP manually using the same device., Results: During the 7.3-year mean follow-up period, we observed 117 cases of cardiovascular diseases. The association between sleep BP (per 10 mmHg hazard ratio = 1.31, P  < 0.001) and cardiovascular events remained significant (hazard ratio = 1.22, P  = 0.036) even after adjusting for office BP and confounding factors, such as sleep-disordered breathing. Individuals with sleep-only hypertension ( n  = 1047; hazard ratio = 2.23, P  = 0.005) had a significant cardiovascular risk. Daytime-only hypertension ( n  = 264; hazard ratio = 3.57, P  = 0.001) and combined sleep and daytime hypertension ( n  = 1216; hazard ratio = 3.69, P  < 0.001) was associated with cardiovascular events to the same extent. Sleep BP dipping was not identified as a significant determinant of cardiovascular events., Conclusion: Sleep BP measured using a home BP monitor was independently associated with the incidence of cardiovascular disease in a general population., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

α 1 -antitrypsin deficiency (AATD) is a hereditary disorder with a global prevalence that differs across regions. AATD is highly prevalent in Europe and North America but rarely found in Asian countries, including Japan, possibly because of the founder effect of the pathogenic SERPINA1 variants PI*Z and PI*S. However, AATD remains underdiagnosed even in high-prevalence and low-prevalence regions, possibly because of lack of awareness. In this study, we surveyed open Japanese genetic variation databases to estimate AATD prevalence in Japan. We identified allelic frequencies (AFs) of 5 among the 14 major pathogenic SERPINA1 variants from three datasets, collectively derived from 63,119 Japanese participants. The mean AF was determined to be 8.56 × 10 -4 (95% confidence interval [CI]: 6.43 × 10 -4 to 1.12 × 10 -3 ). Given that this represents the entire Japanese population, one AATD patient was speculated to be born per 1.37 × 10 6 births (95% CI: 7.97 × 10 5 to 2.42 × 10 6 ) in Japan. Our results support the prevailing notion that AATD is extremely rare in Japan., Competing Interests: Declaration of competing interest Susumu Sato received honoraria for lectures from Nippon Boehringer Ingelheim and AstraZeneca; Susumu Sato received a research grant from Nippon Boehringer Ingelheim, Philips-Respironics, Fukuda Denshi, Fukuda Lifetec, and ResMed; Susumu Sato endowed departments by commercial entitles from Philips-Respironics, Fukuda Denshi, Fukuda Lifetec, and ResMed; Kuniaki Seyama, Tadashi Sato, and Toyohiro Hirai have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: The clinical characteristics, outcomes, and prognostic factors of adult embryonal rhabdomyosarcomas (ERMS) and alveolar rhabdomyosarcomas (ARMS), particularly the differences among adolescents/young adults (AYA), adults, and older adults, remain unclear. We assessed the clinicopathological features and survival outcomes of adult patients with ERMS and ARMS in Japan and to compare these features among AYA, adult, and older adult patients., Methods: We retrospectively analyzed data from the Bone and Soft Tissue Tumor Registry of Japan and enrolled patients aged ≥15 years with ERMS and ARMS. Disease-specific overall survival (DOS) was estimated using the Kaplan-Meier method, and a Cox regression model was used to identify prognostic factors., Results: Among 184 patients with ERMS and ARMS (median age, 27 years; interquartile range, 18-49 years), a high rate of distant and regional nodal metastases was initially observed in 65 (35%) and 66 (36%) cases, respectively. Older age and distant metastasis at first presentation were statistically poor prognostic factors, and histological subtype and site of tumor origin were not associated with DOS. In patients with localized ERMS and ARMS, older age and nodal metastasis were poor prognostic factors; the 5-year DOS rates of patients with and without nodal metastasis were 23% and 72%, respectively., Conclusions: Older patients with rhabdomyosarcoma had a dismal prognosis, and distant metastasis was a poor prognostic factor. The prognostic factors differed between adult and pediatric patients with rhabdomyosarcoma; biological analyses, such as genome analysis of adult rhabdomyosarcoma and clinical trials with pediatric oncologists, are needed to improve the prognosis of adult rhabdomyosarcoma., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Although posterior decompression with fusion (PDF) are effective for treating thoracic myelopathy, surgical treatment has a high risk of various complications. There is currently no information available on the perioperative complications in thoracic ossification of the longitudinal ligament (T-OPLL) and thoracic ossification of the ligamentum flavum (T-OLF). We evaluate the perioperative complication rate and cost between T-OPLL and T-OLF for patients underwent PDF., Methods: Patients undergoing PDF for T-OPLL and T-OLF from 2012 to 2018 were detected in Japanese nationwide inpatient database. One-to-one propensity score matching between T-OPLL and T-OLF was performed based on patient characteristics and preoperative comorbidities. We examined systemic and local complication rate, reoperation rate, length of hospital stays, costs, discharge destination, and mortality after matching., Results: In a total of 2,660 patients, 828 pairs of T-OPLL and T-OLF patients were included after matching. The incidence of systemic complications did not differ significantly between the T-OPLL and OLF groups. However, local complications were more frequently occurred in T-OPLL than in T-OLF groups (11.4% vs. 7.7% P = 0.012). Transfusion rates was also significantly higher in the T-OPLL group (14.1% vs. 9.4%, P = 0.003). T-OPLL group had longer hospital stay (42.2 days vs. 36.2 days, P = 0.004) and higher medical costs (USD 32,805 vs. USD 25,134, P < 0.001). In both T-OPLL and T-OLF, the occurrence of perioperative complications led to longer hospital stay and higher medical costs. While fewer patients in T-OPLL were discharged home (51.6% vs. 65.1%, P < 0.001), patients were transferred to other hospitals more frequently (47.5% vs. 33.5%, P = 0.001)., Conclusion: This research identified the perioperative complications of T-OPLL and T-OLF in PDF using a large national database, which revealed that the incidence of local complications was higher in the T-OPLL patients. Perioperative complications resulted in longer hospital stays and higher medical costs., (© 2024. The Author(s).)

Background: Both cancer diagnosis/treatment modality and surgical technique for the spine have been developed recently. Nationwide trends in the surgical treatment for metastatic spinal tumors have not been reported in the last decades. This study aimed to examine recent trends in the surgical treatment for spinal metastasis and in-hospital patient outcomes using nationwide administrative hospital discharge data., Methods: The Diagnosis Procedure Combination database from 2012 to 2020 was used to extract data from patients who underwent surgical procedures for spinal metastasis with the number of non-metastatic spinal surgery at the institutions that have performed metastatic spine surgeries at least one case in the same year. Trends in the surgical treatment for spinal metastasis, patients' demographics, and in-hospital mortality/outcomes were investigated., Results: This study analyzed 10,321 eligible patients with spinal metastasis. The surgical treatment for spinal metastasis increased 1.68 times from 2012 to 2020, especially in fusion surgery, whereas the proportion of metastatic spinal surgery retained with a slight increase in the 2%s. Distributions of the primary site did not change, whereas age was getting older. In-hospital mortality and length of stay decreased over time (9.9-6.8%, p < 0.001; 37-30 days, p < 0.001). Postoperative complication and unfavorable ambulatory retained stable and slightly decreased, respectively., Conclusion: During the last decade, surgical treatment for spinal metastasis, especially fusion surgery, has increased in Japan. In-hospital mortality and length of stay decreased. Recent advances in cancer treatment and surgical techniques might influence this trend., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Purpose: To describe the real-world treatment patterns of systemic therapies for biliary tract cancer (BTC) and to examine the frequency and management of biliary infection in Japan., Methods: Patients diagnosed with BTC and prescribed systemic therapy between January 2011 and September 2020 were retrieved from the Japanese Medical Data Vision database. The look-back period was set to 5 years. Patient characteristics, treatment patterns, and biliary infection-induced treatment interruption were analyzed., Results: The full analysis set comprised 22 742 patients with a mean age of 71.0 years and 61.6% were male. The most common BTC type was extrahepatic cholangiocarcinoma (44.6%). The three most common first-line regimens were S-1 monotherapy (33.0%), gemcitabine+cisplatin (32.5%), and gemcitabine monotherapy (18.7%) over the entire observation period (January 2011-September 2021). Patients who received monotherapies tended to be older. Biliary infection-induced treatment interruption occurred in 29.5% of patients, with a median time to onset of 64.0 (interquartile range 29.0-145.0) days. The median duration of intravenous antibiotics was 12.0 (interquartile range 4.0-92.0) days., Conclusions: These results demonstrated potential challenges of BTC in Japanese clinical practice particularly use of multiple regimens, commonly monotherapies, which are not recommended as first-line treatment, and the management of biliary infections during systemic therapy., (© 2024 The Authors. Journal of Hepato‐Biliary‐Pancreatic Sciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Hepato‐Biliary‐Pancreatic Surgery.)

The low vertebral bone computed tomography (CT) Hounsfield unit values measured on CT scans reflect low bone mineral density (BMD) and are known as diagnostic indicators for osteoporosis. The potential prognostic significance of low BMD defined by vertebral bone CT values for the coronavirus disease 2019 (COVID-19) remains unclear. This study aimed to assess the impact of BMD on the clinical outcome in Japanese patients with COVID-19 and evaluate the association between BMD and critical outcomes, such as high-flow nasal cannula, non-invasive and invasive positive pressure ventilation, extracorporeal membrane oxygenation, or death. We examined the effects of COVID-19 severity on the change of BMD over time. This multicenter retrospective cohort study enrolled 1132 inpatients with COVID-19 from the Japan COVID-19 Task Force database between February 2020 and September 2022. The bone CT values of the 4th, 7th, and 10th thoracic vertebrae were measured from chest CT images. The average of these values was defined as BMD. Furthermore, a comparative analysis was conducted between the BMD on admission and its value 3 months later. The low BMD group had a higher proportion of critical outcomes than did the high BMD group. In a subanalysis stratifying patients by epidemic wave according to onset time, critical outcomes were higher in the low BMD group in the 1st-4th waves. Multivariable logistic analysis of previously reported factors associated with COVID-19 severity revealed that low BMD, chronic kidney disease, and diabetes were independently associated with critical outcomes. At 3 months post-infection, patients with oxygen demand during hospitalization showed markedly decreased BMD than did those on admission. Low BMD in patients with COVID-19 may help predict severe disease after the disease onset. BMD may decrease over time in patients with severe COVID-19, and the impact on sequelae symptoms should be investigated in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Treatment for diabetes includes anti-diabetic medication in addition to lifestyle improvements through diet and exercise. In Japan, protocol-based pharmacotherapy management allows drug treatment to be provided through cooperation between physicians and pharmacists, based on a protocol that is prepared and agreed upon in advance. However, there are no studies to clarify the relationship between patient characteristics and therapeutic effects after pharmacist intervention in protocol-based pharmacotherapy management for patients with diabetes. Therefore, this study aimed to use protocol-based reports from pharmacies to understand the status of outpatient diabetes medication compliance. We classified patients with diabetes on the basis of patient characteristics that can be collected in pharmacies and investigated the characteristics that impacted diabetes treatment. Patients were prescribed oral anti-diabetic drugs at outpatient clinics of Hitachinaka General Hospital, Hitachi, Ltd., from April 2016 to March 2021. Survey items included patient characteristics (sex, age, number of drugs used, observed number of years of anti-diabetic drug prescription, number of anti-diabetic drug prescription days, and presence or absence of leftover anti-diabetic drugs) and HbA1c levels. Graphical analyses indicated the relationship between each categorised patient characteristic using multiple correspondence analyses. Subsequently, the patients were clustered using K-means cluster analysis based on the coordinates obtained for each patient. Patient characteristics and HbA1c values were compared between the groups for each cluster. A total of 1,910 patients were included and classified into three clusters, with clusters 1, 2, and 3 containing 625, 703, and 582 patients, respectively. Patient characteristics strongly associated with Cluster 1 were ages between 65 and 74 years, use of three or more anti-diabetic drugs, use of 3 years or more of anti-diabetic drugs, and leftover anti-diabetic drugs. Furthermore, Cluster 1 had the highest number of patients with worsening HbA1c levels compared with other clusters. Using the leftover drug adjustment protocol, we clarified the patient characteristics that affected the treatment course. We anticipate that through targeted interventions in patients exhibiting these characteristics, we can identify those who are irresponsibly continuing with drug treatment, are not responding well to therapy, or both. This could substantially improve the efficacy of their anti-diabetic care., Competing Interests: Authors TH, YT, and TS were employed by the company Hitachi, Ltd. The remaining 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 Hirai, Hanaoka, Terakado, Seki and Watanabe.)

Introduction: Recombinant viral-based gene therapy products, such as those incorporating adeno-associated viruses (AAVs), fall under the category of genetically modified organisms (GMOs). The European Union (EU) countries and Japan must obtain environmental risk assessment (ERA) approval for the use of GMOs before starting any clinical trials. It has been reported that the development of GMO-containing products in these two regions encounters several regulatory obstacles due to the longer regulatory procedures and document preparation for ERA., Areas Covered: In this article, we comparatively analyzed the ERA document requirements in the EU and Japan for AAV-based recombinant medicinal products to highlight the differences in the context of potential future attempts of convergence. Additionally, we analyzed non-clinical and clinical shedding data requirements, which are key components of ERA reviews in the EU and Japan. Lastly, we compared the containment measures to minimize the spread of GMOs in the environment in the EU and Japan., Expert Opinion: Based on our comparative analysis, we present several policy recommendations of standardizing and simplifying the application materials and procedures for the ERA regulations on GMOs in the EU and Japan in the mid-, and long-term timeframe to achieve global regulatory convergence.

Severe fever with thrombocytopenia syndrome (SFTS) is a fatal zoonosis caused by ticks in East Asia. As SFTS virus (SFTSV) is maintained between wildlife and ticks, seroepidemiological studies in wildlife are important to understand the behavior of SFTSV in the environment. Miyazaki Prefecture, Japan, is an SFTS-endemic area, and approximately 100 feral horses, called Misaki horses (Equus caballus), inhabit Cape Toi in Miyazaki Prefecture. While these animals are managed in a wild-like manner, their ages are ascertainable due to individual identification. In the present study, we conducted a seroepidemiological survey of SFTSV in Misaki horses between 2015 and 2023. This study aimed to understand SFTSV infection in horses and its transmission to wildlife. A total of 707 samples from 180 feral horses were used to determine the seroprevalence of SFTSV using enzyme-linked immunosorbent assay (ELISA). Neutralization testing was performed on 118 samples. In addition, SFTS viral RNA was detected in ticks from Cape Toi and feral horses. The overall seroprevalence between 2015 and 2023 was 78.5% (555/707). The lowest seroprevalence was 55% (44/80) in 2016 and the highest was 92% (76/83) in 2018. Seroprevalence was significantly affected by age, with 11% (8/71) in those less than one year of age and 96.7% (435/450) in those four years of age and older (p < 0.0001). The concordance between ELISA and neutralization test results was 88.9% (105/118). SFTS viral RNA was not detected in ticks (n = 516) or feral horses. This study demonstrated that horses can be infected with SFTSV and that age is a significant factor in seroprevalence in wildlife. This study provides insights into SFTSV infection not only in horses but also in wildlife in SFTS-endemic areas., (© 2024. The Author(s).)

Objective: This study aimed to investigate the utility of CT quantification of lung volume for predicting critical outcomes in COVID-19 patients., Methods: This retrospective cohort study included 1200 hospitalised patients with COVID-19 from 4 hospitals. Lung fields were extracted using artificial intelligence-based segmentation, and the percentage of the predicted (%pred) total lung volume (TLC (%pred)) was calculated. The incidence of critical outcomes and posthospitalisation complications was compared between patients with low and high CT lung volumes classified based on the median percentage of predicted TLC ct (n=600 for each). Prognostic factors for residual lung volume loss were investigated in 208 patients with COVID-19 via a follow-up CT after 3 months., Results: The incidence of critical outcomes was higher in the low TLC ct (%pred) group than in the high TLC ct (%pred) group (14.2% vs 3.3%, p<0.0001). Multivariable analysis of previously reported factors (age, sex, body mass index and comorbidities) demonstrated that CT-derived lung volume was significantly associated with critical outcomes. The low TLC ct (%pred) group exhibited a higher incidence of bacterial infection, heart failure, thromboembolism, liver dysfunction and renal dysfunction than the high TLC ct (%pred) group. TLC ct (%pred) at 3 months was similarly divided into two groups at the median (71.8%). Among patients with follow-up CT scans, lung volumes showed a recovery trend from the time of admission to 3 months but remained lower in critical cases at 3 months., Conclusion: Lower CT lung volume was associated with critical outcomes, posthospitalisation complications and slower improvement of clinical conditions in COVID-19 patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Advances in percutaneous coronary intervention (PCI) devices and techniques have expanded the pool of eligible patients for revascularization, including those with comorbidities, reduced left ventricular function, or anatomical complexity (defined as CHIP: complex and high-risk interventions in indicated patients). CHIP interventions are typically performed by selected operators who specialize in complex PCI. This review presents two cases performed in the USA, to discuss the similarities and differences in practice patterns between CHIP operators in Japan and the USA. The first case involves a 58-year-old male presenting with myocardial infarction and cardiogenic shock, and the second case involves a 51-year-old female with a history of coronary artery bypass grafting presenting with a chronic total occlusion and PCI complicated by vessel perforation. The discussion focuses on appropriate patient selection, the role of the heart team approach for decision-making, the use of hemodynamic support devices, and other relevant factors. By comparing practices in Japan and the USA, this review highlights opportunities for knowledge exchange and potential areas for improving patient outcomes., Competing Interests: Declaration of competing interest Dr. Davies reports speaking honoraria from Abiomed, Asahi Intec, Boston Sci, Medtronic, Shockwave, and Teleflex. She also serves on advisory boards for Abiomed, Avinger, Boston Sci, Medtronic, and Rampart. Dr. Kato has received honoraria for speaker from Abbott Medical Japan and Kaneka Medix. Dr. Maran is a consultant for Boston Scientific, Medtronic, and Philips. Dr. Kearney reports consulting fees or honoraria from Asahi Intecc, Abiomed, Boston Scientific, Philips, Medtronic, Teleflex, and Reflow medical. Dr. Kohsaka has received research grants from Novartis and AstraZeneca. Dr. Hirai received speaking honoraria from Abiomed and Asahi Intecc. He received institutional research grant from Abiomed and Asahi Intecc. The remaining authors have nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: Genotype-guided dosing algorithms can explain about half of the interindividual variability in prothrombin time-international normalized ratio (PT-INR) under warfarin treatment. This study aimed to refine a published kinetic-pharmacodynamic model and guide warfarin dosage for an optimal PT-INR based on renal function., Methods: Using a retrospective cohort of adult patients (>20 years) who were administered warfarin and underwent PT-INR measurements, we refined the kinetic-pharmacodynamic model with age and the genotypes of cytochrome P450 2C9 and vitamin K epoxide reductase complex subunit 1 using the PRIOR subroutine in the nonlinear-mixed-effect modelling programme. We searched the significant covariates for parameters, such as the dose rate for 50% inhibition of coagulation (EDR 50 ), using a stepwise forward and backward method. Monte Carlo simulation determined a required daily dose of warfarin with a target range of PT-INR (2.0-3.0 or 1.6-2.6) based on the significant covariates., Results: A total of 350 patients with 2762 PT-INR measurements were enrolled (estimated glomerular filtration rate [eGFR]: 47.5 [range: 2.6-199.0] mL/min/1.73 m 2 ). The final kinetic-pharmacodynamic model showed that the EDR 50 changed power functionally with body surface area, serum albumin level and eGFR. Monte Carlo simulation revealed that a lower daily dose of warfarin was required to attain the target PT-INR range as eGFR decreased., Conclusions: Model-informed precision dosing of warfarin is a valuable approach for estimating its dosage in patients with renal impairment., (© 2023 British Pharmacological Society.)

Background: Effective use of lung volume data measured on computed tomography (CT) requires reference values for specific populations. This study examined whether an equation previously generated for multiple ethnic groups in the United States, including Asians predominantly composed of Chinese people, in the Multi-Ethnic Study of Atherosclerosis (MESA) could be used for Japanese people and, if necessary, to optimize this equation. Moreover, the equation was used to characterize patients with chronic obstructive pulmonary disease (COPD) and lung hyperexpansion., Methods: This study included a lung cancer screening CT cohort of asymptomatic never smokers aged ≥40 years from two institutions (n = 364 and 419) to validate and optimize the MESA equation and a COPD cohort (n = 199) to test its applicability., Results: In all asymptomatic never smokers, the variance explained by the predicted values (R 2 ) based on the original MESA equation was 0.60. The original equation was optimized to minimize the root mean squared error (RMSE) by adjusting the scaling factor but not the age, sex, height, or body mass index terms of the equation. The RMSE changed from 714 ml in the original equation to 637 ml in the optimized equation. In the COPD cohort, lung hyperexpansion, defined based on the 95th percentile of the ratio of measured lung volume to predicted lung volume in never smokers (122 %), was observed in 60 (30 %) patients and was associated with centrilobular emphysema and air trapping on inspiratory/expiratory CT., Conclusions: The MESA equation was optimized for Japanese middle-aged and elderly adults., Competing Interests: Declaration of competing interest N.T. and T.H. received research grants from Daiichi Sankyo and FUJIFILM Co., Ltd., outside of the submitted work. S.S. received grants from Nippon Boehringer Ingelheim, Philips-Respironics, Fukuda Denshi, Fukuda Lifetec Keiji, and ResMed outside of the submitted work. None of these companies played a role in the design or analysis of the study or the writing of the manuscript. The other authors have no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

BRAF alterations, including V600E and non-V600E mutations and fusions, in soft tissue sarcoma (STS) have been identified in a limited case series. Here, we aimed to evaluate the frequency of BRAF mutations and concurrent alterations in STS to understand their therapeutic action. In this retrospective analysis, we included data from 1964 patients with advanced STS who underwent comprehensive genomic profiling tests at hospitals in Japan between June 2019 and March 2023. The prevalence of BRAF and recurrent concurrent gene alterations were also investigated. BRAF mutations were detected in 24 (1.2%) of 1964 STS patients, with a median age of 47 (range 1-69) years. BRAF V600E was detected in 11 (0.6%) of the 1964 patients with STS, BRAF non-V600E mutations in 9 (4.6%), and BRAF fusions were detected in 4 (0.2%). BRAF V600E was identified in 4 (0.2%) cases of malignant peripheral nerve sheath tumors. The most common concurrent alteration was CDKN2A (11 cases, 45.8%), and the frequency was equivalent to that of the BRAF V600E (5/11 cases, 45.5%) and non-V600E (5/9 cases, 55.6%) groups. Recurrent concurrent alterations, such as TERT promoter mutations (7 cases, 29.2%), were detected at the same frequency in the V600E and non-V600E groups. In contrast, TP53 alterations (4/9 cases, 44.4%) and mitogen-activated protein kinase (MAPK)-activating genes, including NF1, GNAQ, and GNA11 (3/9 cases, 33.3%), were identified as relatively higher in the non-V600E group than in the V600E group (each 1/11 case, 9.1%). We identified BRAF alterations at a rate of 1.2% in all patients with advanced STS. Among them, BRAF V600E and BRAF fusions account for 45.8% and 16.7%, respectively. Collectively, our findings support the clinical characteristics and therapeutic strategies for patients with BRAF-altered advanced STS., (© 2023 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

Background: Computed tomography (CT) imaging and artificial intelligence (AI)-based analyses have aided in the diagnosis and prediction of the severity of COVID-19. However, the potential of AI-based CT quantification of pneumonia in assessing patients with COVID-19 has not yet been fully explored. This study aimed to investigate the potential of AI-based CT quantification of COVID-19 pneumonia to predict the critical outcomes and clinical characteristics of patients with residual lung lesions., Methods: This retrospective cohort study included 1,200 hospitalized patients with COVID-19 from four hospitals. The incidence of critical outcomes (requiring the support of high-flow oxygen or invasive mechanical ventilation or death) and complications during hospitalization (bacterial infection, renal failure, heart failure, thromboembolism, and liver dysfunction) was compared between the groups of pneumonia with high/low-percentage lung lesions, based on AI-based CT quantification. Additionally, 198 patients underwent CT scans 3 months after admission to analyze prognostic factors for residual lung lesions., Results: The pneumonia group with a high percentage of lung lesions (N = 400) had a higher incidence of critical outcomes and complications during hospitalization than the low percentage group (N = 800). Multivariable analysis demonstrated that AI-based CT quantification of pneumonia was independently associated with critical outcomes (adjusted odds ratio [aOR] 10.5, 95% confidence interval [CI] 5.59-19.7), as well as with oxygen requirement (aOR 6.35, 95% CI 4.60-8.76), IMV requirement (aOR 7.73, 95% CI 2.52-23.7), and mortality rate (aOR 6.46, 95% CI 1.87-22.3). Among patients with follow-up CT scans (N = 198), the multivariable analysis revealed that the pneumonia group with a high percentage of lung lesions on admission (aOR 4.74, 95% CI 2.36-9.52), older age (aOR 2.53, 95% CI 1.16-5.51), female sex (aOR 2.41, 95% CI 1.13-5.11), and medical history of hypertension (aOR 2.22, 95% CI 1.09-4.50) independently predicted persistent residual lung lesions., Conclusions: AI-based CT quantification of pneumonia provides valuable information beyond qualitative evaluation by physicians, enabling the prediction of critical outcomes and residual lung lesions in patients with COVID-19., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Excessive daytime sleepiness (EDS) is a symptom of sleep apnea syndrome (SAS). In some patients with SAS who undergo continuous positive airway pressure (CPAP) therapy, EDS persists (residual EDS). However, knowledge of residual EDS in Japan is limited. Therefore, we examined EDS as defined by the Japanese version of the Epworth Sleepiness Scale (a score of ≥11) before and after long-term (≥1 year) CPAP therapy in 490 patients with SAS. Good adherence to CPAP therapy was defined as its use for at least 4 h during 70% of the nights. The prevalence of residual EDS was 9.4%. Residual EDS was negatively associated with good adherence to CPAP therapy. Furthermore, the longer the CPAP therapy duration after initiation, the lower the prevalence of residual EDS. Therefore, the findings on the prevalence of residual EDS and its association with CPAP therapy in Japan are probably similar to those of other countries., Competing Interests: Conflict of interest Satoshi Hamada received research grants from Teijin Pharma outside the submitted work; Susumu Sato received research grants from Philips Japan, ResMed Japan, Fukuda Denshi, Fukuda Lifetec Keiji, Fuji Film Corporation, and Nippon Boehringer Ingelheim, outside the submitted work; Jumpei Togawa, Hironobu Sunadome, Tadao Nagasaki, and Naomi Takahashi received research grants from Philips Japan, ResMed Japan, Fukuda Denshi, and Fukuda Lifetec Keiji, outside the submitted work; Toyohiro Hirai has no conflict of interest., (Copyright © 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Teicoplanin can cause acute kidney injury, but little is known about the risk of acute kidney injury when teicoplanin is co-administered with loop diuretics (a powerful diuresis), which can alter renal hemodynamics and glomerular filtration rate. We performed a signal detection analysis using a Japanese adverse event database to determine the additive impact of loop diuretics on acute kidney injury associated with teicoplanin. The dataset originated between April 2004 and August 2022. Disproportionality analysis was performed to detect the signals for acute kidney injury (the Standardized MedDRA Query) when co-administered teicoplanin or vancomycin (a positive control) with individual diuretics, including loop diuretics. Multivariate logistic regression analysis was tested to estimate the adjusted reporting odds ratio (aROR) and 95% confidence interval (95% CI). There were 147 and 515 events of acute kidney injury associated with teicoplanin and vancomycin, respectively. A significant positive signal for acute kidney injury when teicoplanin was co-administered with loop diuretics was present (aROR 4.83, 95% CI 3.52-6.61, p < 0.0001). Contrastingly, no significant signals were observed when vancomycin was co-administered with any diuretics. These findings suggest that co-administered loop diuretics may have an unfavorable effect on acute kidney injury while undertaking teicoplanin but not vancomycin., (© 2023. Springer Nature Limited.)

Currently, many types of cell-based therapeutic products (CTPs) derived from pluripotent stem cells (PSCs) are being developed in a lot of countries, some of which are in clinical trial stages. CTPs are classified differently in different countries and regions. The evaluation of their efficacy, safety, and quality also differs from that for conventional small-molecule drugs and biopharmaceuticals, which reflects the complex properties of living cells and unmet medical needs. Since there are no international guidelines to evaluate CTPs, including PSC-derived products, it is necessary to be aware of differences in relevant laws and regulations in different countries and regions. International consortia are organized and actively working to standardize/harmonize the evaluation methods and regulations to facilitate the development and global distribution of PSC-derived CTPs. In this paper, we outline the regulations related to PSC-derived CTPs in the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use founding regions (US, EU/UK, Japan) and introduce representative consortia working on their standardization., Competing Interests: Conflict of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Interstitial lung abnormalities (ILAs) are subtle or mild parenchymal abnormalities observed in more than 5% of the lungs on computed tomography (CT) scans in patients in whom interstitial lung disease was not previously clinically suspected and is considered. ILA is considered to be partly undeveloped stages of idiopathic pulmonary fibrosis (IPF) or progressive pulmonary fibrosis (PPF). This study aims to clarify the frequency of subsequent IPF or PPF diagnosis, the natural course from the preclinical status of the diseases, and the course after commencing treatment., Methods: This is an ongoing, prospective, multicentre observational cohort study of patients with ILA referred from general health screening facilities with more than 70,000 annual attendances. Up to 500 participants will be enrolled annually over 3 years, with 5-year assessments every six months. Treatment intervention including anti-fibrotic agents will be introduced in disease progression cases. The primary outcome is the frequency of subsequent IPF or PPF diagnoses. Additionally, secondary and further endpoints are associated with the efficacy of early therapeutic interventions in cases involving disease progression, including quantitative assessment by artificial intelligence., Discussion: This is the first prospective, multicentre, observational study to clarify (i) the aetiological data of patients with ILA from the largest general health check-up population, (ii) the natural course of IPF or PPF from the asymptomatic stage, and (iii) the effects and outcomes of early therapeutic intervention including anti-fibrotic agents for progressive cases of ILA. The results of this study could significantly impact the clinical practice and treatment strategy for progressive fibrosing interstitial lung diseases., Trial Registration Number: UMIN000045149., (© 2023. The Author(s).)

Pulmonologists in primary care clinics are positioned between those in tertiary hospitals and general practitioners in clinics and are anticipated to promote hospital-clinic collaboration for patients with chronic obstructive pulmonary disease (COPD). However, the clinical features of patients in primary respiratory clinics are unclear. This multicenter study cross-sectionally compared the characteristics of patients with COPD in a respiratory clinic (n = 69) with those in a university hospital (n = 124). More patients visited the clinic for symptom relief without a referral, whereas more visited the hospital for consultation of abnormal spirometry/computed tomography (CT). The patients in the clinic showed female predilection, higher prevalence of current smokers, severe dyspnea, and concomitant heart failure, and higher CT-measured cross-sectional area ratio of pectoralis muscle to adjacent subcutaneous adipose tissue compared to those in the hospital (all p < 0.05). The observed differences between the two groups suggest the need to establish the role of primary pulmonologists in hospital-clinic collaboration for better COPD management., Competing Interests: Conflict of Interest N.T., S.S., and T.H. were supported by a grant from FUJIFILM Co., Ltd. S.S. received grants from Nippon Boehringer Ingelheim, Philips-Respironics, Fukuda Denshi, Fukuda Lifetec Keiji, and ResMed outside of the submitted work. None of these companies played a role in the design or analysis of the study or the writing of the manuscript. The other authors have no conflicts of interest to declare., (Copyright © 2022 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Low-grade osteosarcomas, namely parosteal osteosarcoma (POS) and low-grade central osteosarcoma (LGCOS), occasionally dedifferentiate into high-grade malignancy, referred to as dedifferentiation in low-grade osteosarcoma (DLOS). This study aimed to elucidate the clinicopathologic features of DLOS, which are poorly described to date due to the extreme rarity of the disease., Methods: A total of 33 patients with DLOS were included. Clinical characteristics, including the diagnostic accuracy of tumor biopsy, multimodal treatments, and clinical course, were retrospectively reviewed. Univariate analysis was performed to identify prognostic factors associated with overall survival (OS) and metastasis-free survival (MFS)., Results: The tumor subtypes comprised 10 cases (30.3%) of LGCOS and 23 cases (69.7%) of POS. The timing of dedifferentiation was synchronous in 25 (75.8%) and metachronous in 8 (24.2%) patients. The rates of preoperative diagnosis of DLOS were 40.0% and 65.4% for core needle biopsy and incisional biopsy, respectively. All patients underwent surgery and 25 patients received perioperative chemotherapy. Of the 13 patients who received neoadjuvant chemotherapy, 11 exhibited a poor histological response. The 5-year OS and MFS rates were 88.1% and 77.7%, respectively. Univariate analysis revealed that local recurrence was associated with poor OS (P < 0.01) and MFS (P < 0.01). Perioperative chemotherapy did not affect OS or MFS., Conclusions: The diagnostic accuracy of tumor biopsy for DLOS was lower than that for bone sarcomas, as reported previously. In contrast to conventional osteosarcomas with high chemosensitivity, both histological responses and survival analysis revealed low efficacy of chemotherapy for DLOS., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Objectives: Eating disorders (ED) are serious psychiatric disorders that affect individuals, especially adolescents. It has been suggested that nonclinical ED-like characteristics are related to sleep problems. We conducted a survey of Japanese adolescents to investigate this claim., Method: In this cross-sectional study, 398 adolescents aged 12-18 years responded to a self-administered questionnaire survey. We used the Eating Attitudes Test-26 (EAT-26) and the Athens Insomnia Scale (AIS) to measure potential ED and sleep problems, respectively., Results: Adolescents with potential ED had significantly higher daytime functional vulnerability potentially associated with sleep problems than those without ED. In particular, problems with a sense of well-being and physical and mental functioning during the day were significant. In contrast, no significant associations were found between potential ED and sleep initiation, awakenings during the night, early morning awakening, total sleep duration, or overall quality of sleep. Finally, nocturnal and daytime sleep scores were significantly associated with dieting, bulimia, and oral control EAT-26 subscores., Discussion: Participants with possible ED experienced problems related to well-being and mental and physical functioning, which are indicators of daytime functional vulnerability potentially associated with sleep problems. Further, adolescents with more severe ED characteristics are more likely to have a higher degree of daytime psychological vulnerability potentially attributable to sleep problems. The study suggested that professionals treating adolescent mental health issues need an approach that comprehensively integrates both sleep problems and potential ED., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Digoxin is an important treatment option for reducing the ventricular rate in patients with atrial fibrillation (AF) and heart failure (HF). Digoxin has a narrow therapeutic window and large interindividual variability. A low target blood concentration, especially ≤0.9 ng/mL, is recommended for patients with HF who are taking digoxin. This study aimed to develop a population pharmacokinetic model and to identify clinical factors that affect digoxin exposure and an optimal digoxin dosing regimen in Japanese patients with AF and HF., Methods: A population pharmacokinetic analysis was performed by using a nonlinear mixed effects model based on 3465 concentration points from 391 patients (>18 years) who were receiving oral digoxin. Using trough serum digoxin concentrations and clinical data, a population pharmacokinetic model was developed for determining covariates of clearance. A 1-compartment model was used to examine the interindividual variability of the oral clearance (CL/F) of digoxin. An appropriate dosage of digoxin was identified using Monte Carlo simulation., Results: The final model demonstrated that creatinine clearance (CL CR ) and the use of amiodarone were factors that contributed to the CL/F of digoxin. Monte Carlo simulation results showed that with a daily maintenance dose of 0.25 mg, the intoxication risk window of a trough serum concentration of ≥0.9 ng/mL could be reached in more than half of patients regardless of renal function category or concurrent use of amiodarone. The appropriate maintenance dosage was 0.125 mg daily for most Japanese patients with AF and HF. However, with a daily dose of 0.125 mg, a trough serum concentration of ≥0.9 ng/mL could be reached in more than half of patients with renal impairments (CL CR 30 mL/min) or concurrent use of amiodarone. A daily maintenance dose of 0.0625 mg was acceptable for these patients., Conclusions: CL CR and the use of amiodaron were found to contribute to digoxin clearance using a population pharmacokinetic methodology. For Japanese patients with AF and HF, 0.125 mg is an appropriate daily digoxin maintenance dose, but a dose reduction is required for patients with CL CR  <30 mL/min or concurrent amiodarone use., (© 2022. The Author(s).)

Background The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) was established in 2004. Since then, various pieces of legislation, notices, and guidelines have been issued, and the regulatory approval pathways for domestic drugs have been diversified. However, the effects of these measures have not been fully examined. We examined the impact of these measures on the approval of antineoplastic drugs and the design of pivotal clinical trials for efficacy assessment by the PMDA. Methods We collected data on the antineoplastic drugs approved by the PMDA in fiscal years 2004-2019. We extracted the approval review pathways and the pivotal clinical trial designs from the PMDA review reports, and analyzed them to identify patterns. Results In total, 387 indications in oncology were approved by the PMDA in fiscal years 2004-2019, or 365 indications excluding multiple regulatory pathways. The number of approved indications generally increased year on year (p < 0.001). The largest number of approved indications was under the Orphan Drug Designation (31%, 114/365) and this continues to increase (p < 0.001). In the 288 indications for which clinical trial data were submitted for review, the pivotal clinical trial designs changed significantly (p < 0.001) after the guideline on clinical evaluation for antineoplastic drugs was revised in 2006. Conclusion The number of indications in oncology approved by the PMDA has been increasing over the past 16 years, alongside changes in regulatory pathways. The 2006 guideline on clinical evaluation had a particular impact on pivotal clinical trial designs., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This prospective multicenter study, established by the Japanese Ministry of Health, Labour and Welfare and involving 27 institutions, aimed to compare postoperative outcomes between laminoplasty (LM) and posterior fusion (PF) for cervical ossification of the posterior longitudinal ligament (OPLL), in order to address the controversy surrounding the role of instrumented fusion in cases of posterior surgical decompression for OPLL. 478 patients were considered for participation in the study; from among them, 189 (137 and 52 patients with LM and PF, respectively) were included and evaluated using the Japanese Orthopaedic Association (JOA) scores, the JOA Cervical Myelopathy Evaluation Questionnaire (JOACMEQ), and radiographical measurements. Basic demographic and radiographical data were reviewed, and the propensity to choose a surgical procedure was calculated. Preoperatively, there were no significant differences among the participants in terms of patient backgrounds, radiographical measurements (K-line or cervical alignment on X-ray, OPLL occupation ratio on computed tomography, increased signal intensity change on magnetic resonance imaging), or clinical status (JOA score and JOACMEQ) after adjustments. The overall risk of perioperative complications was found to be lower with LM (odds ratio [OR] 0.40, p = 0.006), and the rate of C5 palsy occurrence was significantly lower with LM (OR 0.11, p = 0.0002) than with PF. The range of motion (20.91° ± 1.05° and 9.38° ± 1.24°, p < 0.0001) in patients who had PF was significantly smaller than in those who had LM. However, multivariable logistic regression analysis showed no significant difference among the participants in JOA score, JOA recovery rate, or JOACMEQ improvement at two years. In contrast, OPLL progression was greater in the LM group than in the PF group (OR 2.73, p = 0.0002). Both LM and PF for cervical myelopathy due to OPLL had resulted in comparable postoperative outcomes at 2 years after surgery., (© 2022. The Author(s).)

Remdesivir, a prodrug of the nucleoside analog GS-441524, plays a key role in the treatment of coronavirus disease 2019 (COVID-19). However, owing to limited information on clinical trials and inexperienced clinical use, there is a lack of pharmacokinetic (PK) data in patients with COVID-19 with special characteristics. In this study, we aimed to measure serum GS-441524 concentrations and develop a population PK (PopPK) model. Remdesivir was administered at a 200 mg loading dose on the first day followed by 100 mg from day 2, based on the package insert, in patients with an estimated glomerular filtration rate (eGFR) greater than or equal to 30 ml/min. In total, 190 concentrations from 37 Japanese patients were used in the analysis. The GS-441524 trough concentrations were significantly higher in the eGFR less than 60 ml/min group than in the eGFR greater than or equal to 60 ml/min group. Extracorporeal membrane oxygenation in four patients hardly affected the total body clearance (CL) and volume of distribution (V d ) of GS-441524. A one-compartment model described serum GS-441524 concentration data. The CL and V d of GS-441524 were significantly affected by eGFR readjusted by individual body surface area and age, respectively. Simulations proposed a dose regimen of 200 mg on day 1 followed by 100 mg once every 2 days from day 2 in patients with an eGFR of 30 ml/min or less. In conclusion, we successfully established a PopPK model of GS-441524 using retrospectively obtained serum GS-441524 concentrations in Japanese patients with COVID-19, which would be helpful for optimal individualized therapy of remdesivir., (© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: To investigate safety management at Japanese facilities performing human MRI studies., Methods: All Japanese facilities performing human MRI studies were invited to participate in a comprehensive survey that evaluated their MRI safety management. The survey used a questionnaire prepared with the cooperation of the Safety Committee of the Japanese Society for Magnetic Resonance in Medicine. The survey addressed items pertaining to the overall MRI safety management, questions on the occurrence of incidents, and questions specific to facility and MRI scanner or examination. The survey covered the period from October 2017 to September 2018. Automated machine learning was used to identify factors associated with major incidents., Results: Of 5914 facilities, 2015 (34%) responded to the questionnaire. There was a wide variation in the rate of compliance with MRI safety management items among the participating facilities. Among the facilities responding to this questionnaire, 5% reported major incidents and 27% reported minor incidents related to MRI studies. Most major incidents involved the administration of contrast agents. The most influential factor in major incidents was the total number of MRI studies performed at the facility; this number was significantly correlated with the risk of major incidents (P < 0.0001)., Conclusion: There were large variations in the safety standards applied at Japanese facilities performing clinical MRI studies. The total number of MRI studies performed at a facility affected the number of major incidents.

Following isolation of pseudorabies virus (PRV) from two hunting dogs in Oita prefecture, Japan, we investigated the PRV antigen distribution in the tissues of the infected animals. At necropsy, PRV-associated lesions included facial oedema, tonsillar and meningeal congestion, blotchy haemorrhages on the pericardium and mitral valves, and incomplete splenic contraction in one dog, with less prominent findings in the other dog. Multiple pulmonary nodules were seen in both cases, caused by the diploid form of Paragonimus westermani lung flukes, as confirmed by PCR-restriction fragment length polymorphism and gene sequencing analyses. Histological examination revealed that the PRV infection was associated with lesions of non-suppurative encephalitis in the brainstem. PRV antigen was detected in the cerebrum, cerebellum, brainstem, submucosal and myenteric plexuses, and mononuclear cells, mainly in the bone marrow, lymph nodes, tonsils and spleen tissues. There was evidence of PRV dissemination to the brain via the trigeminal or olfactory routes, in addition to possible spread to lymphoid organs via infected mononuclear cells., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: In chronic obstructive pulmonary disease (COPD), chest computed tomography (CT) provides clinically important cardiovascular findings, which include diameter of pulmonary artery (PA), its ratio to the diameter of the aorta (PA:A ratio), and coronary artery calcium score (CACS). The clinical importance of these cardiovascular findings has not been fully assessed in Japan, where cardiovascular morbidity and/or mortality is reported to be much less compared with Western counterparts., Methods: PA diameter and PA:A ratio were measured in 172 and 130 patients with COPD who enrolled in the Hokkaido COPD cohort study and the Kyoto University cohort, respectively. CACS was measured in 131 and 128 patients in each cohort., Results: While the highest quartile group in PA diameter was associated with higher all-cause mortality compared to the lowest quartile group in both cohorts, individual assessments of PA:A ratio and CACS were not associated with the long-term clinical outcomes. When PA diameter and CACS were combined, patients with PA enlargement (diameter >29.5 mm) and/or coronary calcification (score >440.8) were associated with higher all-cause mortality in both cohorts., Conclusion: Combined assessment of PA enlargement and CACS was associated with poor prognosis, which provides a clinical advantage in management of patients with COPD even in geographical regions with lower risk of cardiovascular diseases., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Social determinants of health (SDHs) are social factors that affect human health; loneliness and social isolation are core SDH factors. There is a possibility that SDHs are related to passive decision-making. However, few studies have evaluated SDHs, especially social isolation and loneliness, among lung cancer patients. This study aims to investigate the effects of social isolation and loneliness on the diagnosis and treatment of Japanese lung cancer patients., Methods: This is a prospective cohort study that was conducted in a tertiary referral hospital in Japan (University Hospital Medical Information Network registration: UMIN000031810). The enrollment period was between April 2018 and March 2020. Patients with clinical and/or pathological diagnosis of lung cancer were enrolled in this study. Exposures were social isolation and loneliness, and main outcomes were diagnosis methods and whether the initial treatment involved active therapy or best supportive care (BSC). The confounding factors were defined as sex, age, smoking status, respiratory symptoms, weight loss, presentation with any symptoms, Eastern Cooperative Oncology Group (ECOG) performance status, tumor nodes metastasis (TNM) classification, driver gene mutations [i.e., epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK)], and programmed death-ligand 1 (PD-L1) tumor proportion score., Results: The study enrolled 264 patients who were divided into quartiles according to their loneliness scores and into two groups according to the social isolation level. Univariate analysis, complete case analysis, and multivariate analysis with multiple imputation failed to detect significant differences in diagnostic method or initial treatment strategy according to loneliness or social isolation level., Conclusions: Physicians may not need to consider a patient's loneliness and/or social isolation when diagnosing lung cancer and selecting treatment under universal health insurance coverage. Further studies are needed to understand the influences of loneliness and social isolation on the prognosis of lung cancer patients.

Background: Degenerative cervical myelopathy (DCM) can significantly impair a patient's quality of life (QOL). In this study, we aimed to identify predictors associated with QOL improvement after surgery for DCM., Methods: This study included 148 patients who underwent surgery for DCM. The European QOL-5 Dimension (EQ-5D) score, the Japanese Orthopedic Association for the assessment of cervical myelopathy (C-JOA) score, and the Nurick grade were used as outcome measures. Radiographic examinations were performed at enrollment. The associations of baseline variables with changes in EQ-5D scores from preoperative to 1-year postoperative assessment were investigated using a multivariable linear regression model., Results: The EQ-5D and C-JOA scores and the Nurick grade improved after surgery (P < 0.001, P < 0.001, and P < 0.001, respectively). Univariable analysis revealed that preoperative EQ-5D and C-JOA scores were significantly associated with increased EQ-5D scores from preoperative assessment to 1 year after surgery (P < 0.0001 and P = 0.045). Multivariable regression analysis showed that the independent preoperative predictors of change in QOL were lumbar lordosis (LL), sacral slope (SS), and T1 pelvic angle (TPA). According to the prediction model, the increased EQ-5D score from preoperatively to 1 year after surgery = 0.308 - 0.493 × EQ-5D + 0.006 × LL - 0.008 × SS + 0.004 × TPA., Conclusions: Preoperative LL, SS, and TPA significantly impacted the QOL of patients who underwent surgery for DCM. Less improvement in QOL after surgery was achieved in patients with smaller LL and TPA and larger SS values. Patients with these risk factors may therefore require additional support to experience adequate improvement in QOL.

Background: Little is known about the outcome of living-donor kidney transplantation (LDKT) performed in low-volume centers lacking the services of full-time transplant surgeons. This retrospective cohort study assessed the outcome of LDKT performed in a low-volume center by visiting transplant surgeons from a high-volume center and managed perioperatively by transplant nephrologists., Methods: We compared Japanese adult patients who had no donor-specific antibodies and underwent LDKT between 2006 and 2015 either in a low-volume (n = 31) or high-volume (n = 481) center. In the low-volume center, visiting transplant surgeons from the high-volume center conducted LDKT and transplant nephrologists managed the recipients peri- and postoperatively. The primary outcome was the composite of infection, cardiovascular disease, or cancer during 1-year follow-up. The outcomes of the low- and high-volume centers were compared using 1:2 propensity score matching., Results: After matching, 9 of 29 patients in the low-volume center (31.0%) and 16 of 58 patients in the high-volume center (27.6%) experienced the primary composite outcome (risk ratio = 1.13; 95% confidence interval, 0.57-2.23). There were no significant differences between the 2 groups in graft function at 1 year, all-cause graft loss, biopsy-proven rejection, and urological complications. However, the median duration of post-LDKT hospitalization was significantly longer in the low-volume center than in the high-volume center (23 and 16 days, respectively)., Conclusions: Among Japanese patients without preformed donor-specific antibodies, LDKT conducted at a low-volume center by visiting transplant surgeons from a high-volume center and managed clinically by transplant nephrologists was not associated with significantly higher risk of postoperative complications., (Copyright © 2021. Published by Elsevier Inc.)

Background/aim: To evaluate complications and risk factors associated with transumbilical incision as an organ removal site in laparoscopic pancreatectomy (LP)., Patients and Methods: In total, 52 patients who underwent LP between 2009 and 2017 were included in this study. The development of superficial surgical site infection (SSI) and transumbilical port-site incisional hernia was recorded., Results: None of the patients had SSI. However, three (5.77%) presented with transumbilical incisional hernia. No variables were significantly associated with the risk of transumbilical incisional hernia., Conclusion: No evident risk factors correlated with hernia formation. Hence, incisional hernia might have occurred at a certain probability. In some cases, it was caused by technical problems. However, the use of transumbilical incision as an organ removal site was feasible, and a new incision for organ removal alone was not required., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: To prove the efficacy of contrast-enhanced ultrasound (CEUS) in determining the extent of resection, more evidence about B-mode and CEUS as opposed to pathology is required. We compared maximum tumor width measured on B-mode/CEUS images with that determined pathologically., Methods: In this retrospective multicenter study, 152 operable breast cancer patients who had undergone both B-mode and CEUS were analyzed. Maximum tumor width on B-mode and CEUS, and on the postoperative pathological examination (P), was measured by the participating investigators. In addition, maximum width was assessed in B-mode and CEUS image sets by independent reviewers blinded to all patient information. We analyzed differences in maximum width between CEUS, B-mode and P., Results: The mean widths as measured by the participating investigators were 15 ± 7 mm (B-mode), 19 ± 8 mm (CEUS), and 17 ± 9 mm (P). The difference subtracted P from B-mode was - 3 ± 7 mm (p < 0.0001), and that from CEUS was 1 ± 6 mm (p = 0.0163). The mean widths as measured by the independent reviewers were 16 ± 7 mm (B-mode) and 18 ± 7 mm (CEUS). The difference subtracted P from B-mode was - 2 ± 8 mm (p = 0.0114), while that from CEUS was 1 ± 7 mm (p = 0.1921)., Conclusions: Maximum lesion width measurement showed a tendency to increase in the order of B-mode, to P and CEUS. The difference in measurement between P and B-mode was significant, but there was no significant between CEUS and P. These results provide additional information of tendency patterns in measuring the maximum lesion width through enhancement on CEUS.

Infectious bursal disease (IBD), caused by IBD virus (IBDV), is highly contagious, immunosuppressive and causes a negative economic impact on poultry industry. IBDV-vaccinated broiler farms at south Kyushu, Japan had a bursa-to-bodyweight ratio (BB ratio) reduction at 28 days (d) old, followed by high mortality 30 d later. We analysed the influence of the IBDV on atrophy of the bursa of fabricius (BF) and the subsequent mortality after 30 d. Ten broilers were sampled at each timepoint from the farm with high mortality at 21, 25, 28 and 35 d. A second flock from the same farm was sampled at 14, 21, 25, 28, 35 and 42 d. IBDV was detected in BF samples at 25, 28 and 35 d and at 21, 25, 28 and 35 d in the first and second flocks, respectively, using immunohistochemical staining and RT-PCR. IBDV isolates from both flocks were closely related to the China KM523643 strain. Histopathology and TUNEL assay indicated apoptosis, severe lymphoid depletion, vacuoles within follicles, lymphoid follicle atrophy and fibrosis in the BF. We observed 75% of the polyserositis and 10% of the airsacculitis at 30 D in dead broilers. The antigenic variant IBDV infection was appeared to be the main influencing factor on BF atrophy and BB ratio reduction in the broilers. High mortality in the broilers after 30 d could be due to secondary infection. The disease caused by IBDV had a negative economic impact in the farm. RESEARCH HIGHLIGHTS New variant IBDV caused bursa atrophy and reduced BB ratio in 28-day-old broilers. After vIBDV had infected broilers, at 21 days old they became immunosuppressed. High mortality at 30 days old in broilers was due to secondary infection. New vIBDV has a negative economic impact on broiler farms in Japan.

On a coastline in Miyazaki Prefecture, Japan, a wild subadult female striped dolphin was found dead. Necropsy revealed poor nutritional status and bilateral pneumonia, which was histologically diagnosed as severe suppurative necrotizing bronchopneumonia. Special staining detected numerous intralesional filamentous, branching bacteria, which was identified as Nocardia cyriacigeorgica by sequencing of 16S ribosomal RNA and gyrB genes. Other main histological findings included lymphoid depletion in the spleen and superficial cervical and pulmonary lymph nodes. Suppurative nocardiosis without a granulomatous reaction is uncommon, and it is assumed its pathogenesis was related to the host's immune status. This paper discusses the variable inflammatory response to nocardiosis and describes the first case of N. cyriacigeorgica infection in a wild striped dolphin in Japan.

Background: Chronic sputum production in the general population is historically associated with clinical indices including male sex and smoking history. However, its relationship with gastroesophageal reflux disease (GERD), which may prove an underlying factor in sputum production, is unclear. We aimed to clarify factors associated with sputum production in the general population in cross-sectional and longitudinal manners., Methods: In the Nagahama study, a community-based cohort study, 9804 subjects were recruited between 2008 and 2010 (baseline assessment), 8293 of whom were followed from 2013 to 2015 (follow-up assessment). This study contained a self-completed questionnaire which included medical history, assessment of sputum production, and a frequency scale for symptoms of GERD. A Frequency Scale for Symptoms of Gastroesophageal Reflux Disease score of ≥ 8 was defined as GERD. In addition to the frequency of sputum production at each assessment, frequency of persistent sputum production defined as sputum production at both assessments was examined., Results: Frequency of sputum production was 32.0% at baseline and 34.5% at follow-up. Multivariable analysis demonstrated that sputum production at baseline was significantly associated with GERD [odds ratio (OR), 1.92; 95% confidence interval (CI) 1.73-2.13] and post-nasal drip (PND) (OR, 2.40; 95% CI 2.15-2.68), independent of other known factors such as older age, male sex and smoking history. These associations between sputum production and GERD or PND were also observed at follow-up. In longitudinal analysis, 19.4% had persistent sputum production and 12.3% had transient sputum production, i.e., at baseline only. Multivariable analysis for risk of persistence of sputum production revealed that persistent sputum production was associated with GERD and PND, in addition to the known risk factors listed above. The proportion of subjects with GERD at both assessments was highest among subjects with persistent sputum production., Conclusions: Cross-sectional and longitudinal analysis demonstrated an association in the general population between sputum production and GERD, as well as PND, independent of known risk factors. The presence of GERD should be assessed in patients complaining of sputum production.

Forced expiratory volume in 1 s (FEV 1 ) is a standard physiological index of chronic obstructive pulmonary disease (COPD), but reflects emphysema and vascular abnormalities less sensitively than diffusion capacity for carbon monoxide (D LCO ). This study tested whether a disproportionally impaired D LCO relative to FEV 1 (FEV 1 z -score>-3 and D LCO was available. The cross-sectional and longitudinal analyses of the Kyoto University Cohort (single-center study in Japan) included 195 males with COPD who were prospectively followed for 10 years. A disproportionally impaired D z -score≤-3) is a common functional COPD phenotype associated with distinct clinical and structural features and the prognosis of two cohorts. The cross-sectional analyses of the Korea COPD Subgroup Study (KOCOSS) cohort (multicenter study in Korea) included 743 males with COPD whose D LCO was available. The cross-sectional and longitudinal analyses of the Kyoto University Cohort (single-center study in Japan) included 195 males with COPD who were prospectively followed for 10 years. A disproportionally impaired D LCO relative to FEV 1 was observed in 29% and 31% of patients in the KOCOSS and Kyoto University cohorts, respectively. In the multivariable analysis, the disproportionally impaired D LCO was associated with worse symptoms, shorter 6-minute walking distance, paraseptal and centrilobular emphysema on computed tomography, and reduced arterial oxygen and carbon dioxide pressures compared to the reference (FEV 1 z -score>-3 and D LCO z -score>-3). In the multivariable Cox proportional hazard model, a higher long-term mortality was observed in the disproportionally impaired D LCO group than in the reference group (hazard ratio [95% confidence interval] = 3.09 [1.52-6.29]) and similar to the D LCO z -score≤-3 and FEV 1 z -score≤-3 group. The disproportionally impaired D LCO relative to FEV 1 is common and associated with increased symptoms, emphysema, arterial blood gas abnormalities, and increased long-term mortality in patients with COPD.

Background: The surgical treatment of osteoporotic vertebral fractures (OVF) is generally associated with a high risk of complications due to an aging population with osteoporosis; however, the detailed risk factors for systemic complications and mortality have not been clarified. We evaluated the risk factors for systemic complications and mortality in surgically treated OVF patients using a large national inpatient database., Methods: Patients over 65 years old who were diagnosed with OVF and received either anterior fusion (AF) or posterior fusion (PF), from 2012 to 2016, were extracted from the diagnosis procedure combination (DPC) database. In each of the perioperative systemic complications (+) or (-) group, and the in-hospital death (+) or (-) group, we surveyed the various risk factors related to perioperative systemic complications and in-hospital death., Results: The significant factors associated with systemic complications were older age (OR 1.38, 95% CI 1.09-1.74), a lower activity of daily living score upon admission (OR 1.52, 95%CI 1.19-1.94), atrial fibrillation (OR 2.14, 95%CI 1.25-3.65), renal failure (OR 2.29, 95%CI 1.25-4.20), and surgical procedure (AF, OR 1.73, 95%CI 1.35-2.22). The significant explanatory variables for in-hospital death were revealed to be male sex (OR 3.26, 95%CI 1.20-8.87), a lower body mass index (OR 3.97, 95%CI 1.23-12.86), unscheduled admission (OR 3.52, 95%CI 1.17-10.63), atrial fibrillation (OR 8.31, 95%CI 2.25-30.70), renal failure (OR 7.15, 95%CI 1.32-38.77), and schizophrenia (OR 8.23, 95%CI 1.66-42.02)., Conclusions: Atrial fibrillation and renal failure as preoperative comorbidities were common factors between perioperative systemic complications and mortality in elderly patients for OVF.

Objective: Thrombotic microangiopathy (TMA), often described as thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS), is clinically problematic because it is life-threatening. However, up-to-date information on drugs inducing TMA is limited in the real-world setting. The purpose of this study was to clarify drugs associated with TMA using a spontaneous reporting system database., Material and Methods: We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between 2004 and 2017 were analyzed. The drug-induced TMA, TTP, and HUS signals were estimated using disproportionality analysis with calculation of the reporting odds ratio (ROR) and 95% confidence interval (CI)., Results: A total of 3,292 TMA cases were identified. In the overall analysis, approximately half of the TMA cases involved males, and the most patients were in their 60s. Signal scores of TMA were high for ticlopidine hydrochloride (ROR: 16.2, 95% CI: 12.9 - 20.5), busulfan (ROR: 15.2, 95% CI: 11.5 - 20.3), tacrolimus hydrate (ROR: 10.6, 95% CI: 9.59 - 11.8), gemcitabine hydrochloride (ROR: 10.5, 95% CI: 8.96 - 12.2), and cyclosporine (ROR: 8.70, 95% CI: 7.67 - 9.86). As for TTP or HUS, signal scores of TTP and HUS for tacrolimus and cyclosporine were similar; however, those of TTP for ticlopidine and those of HUS for gemcitabine were noteworthy, and other drugs showed varied likelihoods of reporting TTP and HUS., Conclusion: Our results should raise physicians' awareness of drugs associated with TMA, but further investigation of these medications is warranted.

Background: Ossification of the posterior longitudinal ligament of the spine (OPLL) is characterized by heterotopic bone formation in the posterior longitudinal ligament of the spine. We know that the size and distribution of the ossified lesions in patients with OPLL are different in each case. However, the characteristics of the patients with radiologically severe cervical OPLL remain unknown., Methods: The participants of our study were symptomatic patients with cervical OPLL who were diagnosed by standard radiographs of the cervical spine. Whole-spine CT data and demographic data such as age and sex were obtained from 20 institutions belonging to the Japanese Multicenter Research Organization for Ossification of the Spinal Ligament. According to the number of the levels involved by OPLL, we stratified the patients into two subgroups: severe group (S-group) and non-severe group (NS-group) to delineate the characteristics of radiologically severe patients with cervical OPLL. We also evaluated the most compressed level and the degree of occupying ratio of cervical spinal canal by OPLL at the most compressed level., Results: A total of 234 patients with a mean age of 65 years were recruited. The S-group consisted of 48 patients (21%, 12 females and 36 males) and the NS-group consisted of 92 patients (79%, 22 females and 70 males). The mean age of males in the S-group (68 years old) was significantly higher than that of males in the NS-group (64 years old); however there was no significant difference in the mean age in females between the S-group (69 years old) and the NS-group (66 years old). No significant difference of body mass index, ossification of the nuchal ligament-positivity and presence of diabetes mellitus were found between the S- and the NS-group., Conclusions: It is likely that the manner of extension of cervical OPLL is different between male and female patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: Abnormalities of lipid metabolism contributing to the autism spectrum disorder (ASD) pathogenesis have been suggested, but the mechanisms are not fully understood. We aimed to characterize the lipid metabolism in ASD and to explore a biomarker for clinical evaluation., Methods: An age-matched case-control study was designed. Lipidomics was conducted using the plasma samples from 30 children with ASD compared to 30 typical developmental control (TD) children. Large-scale lipoprotein analyses were also conducted using the serum samples from 152 children with ASD compared to 122 TD children. Data comparing ASD to TD subjects were evaluated using univariate (Mann-Whitney test) and multivariate analyses (conditional logistic regression analysis) for main analyses using cofounders (diagnosis, sex, age, height, weight, and BMI), Spearman rank correlation coefficient, and discriminant analyses., Findings: Forty-eight significant metabolites involved in lipid biosynthesis and metabolism, oxidative stress, and synaptic function were identified in the plasma of ASD children by lipidomics. Among these, increased fatty acids (FAs), such as omega-3 (n-3) and omega-6 (n-6), showed correlations with clinical social interaction score and ASD diagnosis. Specific reductions of very-low-density lipoprotein (VLDL) and apoprotein B (APOB) in serum of ASD children also were found by large-scale lipoprotein analysis. VLDL-specific reduction in ASD was correlated with APOB, indicating VLDL-specific dyslipidaemia associated with APOB in ASD children., Interpretation: Our results demonstrated that the increases in FAs correlated positively with social interaction are due to VLDL-specific degradation, providing novel insights into the lipid metabolism underlying ASD pathophysiology., Funding: This study was supported mainly by MEXT, Japan., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The optimal treatment of osteoporosis after reconstruction surgery for osteoporotic vertebral fractures (OVF) remains unclear. In this multicentre retrospective study, we investigated the effects of typically used agents for osteoporosis, namely, bisphosphonates (BP) and teriparatide (TP), on surgical results in patients with osteoporotic vertebral fractures., Methods: Retrospectively registered data were collected from 27 universities and affiliated hospitals in Japan. We compared the effects of BP vs TP on postoperative mechanical complication rates, implant-related reoperation rates, and clinical outcomes in patients who underwent posterior instrumented fusion for OVF. Data were analysed according to whether the osteoporosis was primary or glucocorticoid-induced., Results: A total of 159 patients who underwent posterior instrumented fusion for OVF were included. The overall mechanical complication rate was significantly lower in the TP group than in the BP group (BP vs TP: 73.1% vs 58.2%, p = 0.045). The screw backout rate was significantly lower and the rates of new vertebral fractures and pseudoarthrosis tended to be lower in the TP group than in the BP group. However, there were no significant differences in lumbar functional scores and visual analogue scale pain scores or in implant-related reoperation rates between the two groups. The incidence of pseudoarthrosis was significantly higher in patients with glucocorticoid-induced osteoporosis (GIOP) than in those with primary osteoporosis; however, the pseudoarthrosis rate was reduced by using TP. The use of TP also tended to reduce the overall mechanical complication rate in both primary osteoporosis and GIOP., Conclusions: The overall mechanical complication rate was lower in patients who received TP than in those who received a BP postoperatively, regardless of type of osteoporosis. The incidence of pseudoarthrosis was significantly higher in patients with GIOP, but the use of TP reduced the rate of pseudoarthrosis in GIOP patients. The use of TP was effective to reduce postoperative complications for OVF patients treated with posterior fusion.