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Toshinori Nishizawa,1,2 Kosuke Ishizuka,3 Yuki Otsuka,4 Toshiyuki Nakanishi,5 Akira Kawashima,6 Taiju Miyagami,7 Shun Yamashita8,9 1Department of General Internal Medicine, St Luke’s International Hospital, Tokyo, Japan; 2Department of Global Health Promotion, Tokyo Medical and Dental University, Tokyo, Japan; 3Department of General Medicine, Yokohama City University School of Medicine, Kanagawa, Japan; 4Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; 5Department of Emergency and General Medicine, Nerima Hikarigaoka Hospital, Tokyo, Japan; 6Department of General Internal Medicine, National Center for Global Health and Medicine, Tokyo, Japan; 7Department of General Medicine, Faculty of Medicine, Juntendo University, Tokyo, Japan; 8Department of General Medicine, Saga University Hospital, Saga, Japan; 9Education and Research Center for Community Medicine, Faculty of Medicine, Saga University, Saga, JapanCorrespondence: Kosuke Ishizuka, Department of General Medicine, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan, Tel +81-45-787-2800, Fax +81-45-350-2728, Email e103007c@yokohama-cu.ac.jpAbstract: Case reports provide scientific knowledge and opportunities for new clinical research. However, it is estimated that less than 5% of cases presented by Japanese generalists at academic conferences are published due to various barriers such as the complex process of writing articles, conducting literature searches, the significant time required, the reluctance to write in English, and the challenge of selecting appropriate journals for publication. Therefore, the purpose of this opinion paper is to provide clinicians with practical tips for writing case reports that promote diagnostic excellence. In recent years, clinical practitioners have been striving for diagnostic excellence and optimal methods to accurately and comprehensively understand the patient’s condition. To write a case report, it is essential to be mindful of the elements of diagnostic excellence and consider the quality of the diagnostic reasoning process. We (the authors) are seven academic generalists who are members of the Japanese Society of Hospital General Medicine (JSHGM) – Junior Doctors Association, with a median of 7 years after graduation and extensive experience publishing case reports in international peer-reviewed journals. We conducted a narrative review and discussed ways to write case reports to promote diagnostic excellence, leveraging our unique perspectives as academic generalists. Our review did not identify any reports addressing the critical points in writing case reports that embody diagnostic excellence. Therefore, this report proposes a methodology that describes the process involved in writing diagnostic excellence-promoting case reports and provides an overview of the lessons learned. Based on our review and discussion, we explain the essential points for promoting diagnostic excellence through case reports categorized into seven components of clinical reasoning. These strategies are useful in daily clinical practice and instrumental in promoting diagnostic excellence through case reports.Keywords: case reports, clinical reasoning, diagnostic excellence

Yuya Yokota, Yuki Otsuka, Fumio Otsuka Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, JapanCorrespondence: Yuki Otsuka, Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan, Tel +81-86-235-7342, Fax +81-86-235-7345, Email otsuka@s.okayama-u.ac.jp

Masaki Tago,1 Risa Hirata,1 Naoko E Katsuki,1 Yuki Otsuka,2 Taro Shimizu,3 Yosuke Sasaki,4 Kiyoshi Shikino,5 Takashi Watari,6 Hiromizu Takahashi,7 Kazunobu Une,8 Toshio Naito,7 Fumio Otsuka,2 Rachel Thompson,9 Susumu Tazuma8,10 1Department of General Medicine, Saga University Hospital, Saga, Japan; 2Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; 3Department of Diagnostic and Generalist Medicine, Dokkyo Medical University, Tochigi, Japan; 4Department of General Medicine and Emergency Care, Toho University School of Medicine, Tokyo, Japan; 5Department of General Medicine, Chiba University Hospital, Chiba, Japan; 6General Medicine Center, Shimane University Hospital, Izumo, Japan; 7Department of General Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; 8Department of Critical Care and General Medicine, Onomichi General Hospital, Hiroshima, Japan; 9Executive Team, Snoqualmie Valley Hospital, Snoqualmie, WA, USA; 10JR Hiroshima Hospital, Hiroshima, JapanCorrespondence: Masaki Tago, Department of General Medicine, Saga University Hospital, 5-1-1 Nabeshima, Saga, 849-8501, Japan, Tel +81 952 34 3238, Fax +81 952 34 2029, Email tagomas@cc.saga-u.ac.jpIntroduction: Hospitalists in Japan have been at the forefront of the COVID-19 pandemic. However, contributions of Japanese hospitalists during the COVID-19 pandemic and hospitalists’ awareness of crisis management education remain unclear.Material and Methods: We conducted a questionnaire survey to investigate the role of Japanese hospitalists during the COVID-19 pandemic. The questionnaire was conducted using email and Google Forms targeting the chairpersons of facilities certified by the Japanese Society of Hospital General Medicine (JSHGM). Members of the academic committee of the JSHGM and several hospitals conducted a narrative review and determined the questions for the survey in a discussion.Results: We conducted descriptive statistics based on the responses of 97 hospitals that agreed to participate in this survey. In total, 91.8% of general medicine departments in the included hospitals were involved in the medical care of COVID-19 patients. Furthermore, in 73.2% of hospitals, hospitalists were involved in infection control for COVID-19 inside or outside the hospital. Our survey revealed that Japanese hospitalists were responsible for COVID-19 treatment in over 60% of hospitals and contributed to hospital management, infection control, and vaccination. In total, 79.4% of hospitals answered that “training of personnel who can provide practical care for emerging infectious diseases is necessary”, 78.4% indicated that “the establishment of an infection control system in advance to prepare emerging infectious diseases in the hospital is necessary”, and 74.2% stated that “the establishment of an educational system for responding to emerging infectious diseases is necessary.”.Conclusion: In conclusion, during the pandemic, in addition to inpatient care, Japanese hospitalists provided outpatient care for COVID-19, which is the role of primary care physicians in other countries. Furthermore, Japanese hospitalists who experienced the COVID-19 pandemic expressed the need for personnel development and education to prepare for future emerging infectious disease pandemics.Keywords: COVID-19 pandemic, hospitalist, hospital management

Xin Gao,1 Xuemei He,1 Hiroyuki Oshima,2 Daisuke Miyatake,2 Yukio Otsuka,2 Kota Kato,3 Chunxiao Cai,4 Tomasz Wojtkowski,5 Nan Song,6 Yuichiro Kaneko,7 Aixin Shi1 1Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Clinical Pharmacology and Exploratory Development, Astellas Pharma Inc., Tokyo, Japan; 3Analysis & Pharmacokinetics Research Labs., Astellas Pharma Inc., Ibaraki, Japan; 4Development Medical Department, Astellas (China) Investment Co., Ltd, Beijing, People’s Republic of China; 5Data Science Development, Astellas Pharma US, Inc., Northbrook, IL, USA; 6Development Division Biostatistics and Statistical Programming, Astellas (China) Investment Co., Ltd, Beijing, People’s Republic of China; 7Biostatistics Group, Japan-Asia Data Science, Development, Astellas Pharma Inc, Tokyo, JapanCorrespondence: Aixin Shi, Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing, 100730, People’s Republic of China, Tel +86-10-85133632, Email aixins0302@126.comObjective: To investigate the pharmacokinetics and safety of peficitinib (Janus kinase inhibitor for the treatment of rheumatoid arthritis) in healthy Chinese subjects following single and multiple doses.Methods: This open-label, randomized study was conducted at one site in China. Subjects received peficitinib 50, 100 or 150 mg as a single dose on Day 1 (fasted) and once daily from Days 8 to 13 in the multiple-dose period (fed). Blood samples were collected before administration each day, and up to 72h post administration. Pharmacokinetic assessments included area under the concentration curve (AUC), half-life (t1/2), maximum concentration (Cmax), and time to maximum concentration (tmax) of peficitinib and its metabolites (H1, H2 and H4). Treatment-emergent adverse events (TEAEs) were evaluated.Results: Thirty-six subjects were enrolled (12 per dose group). After a single dose of peficitinib, median tmax was 1.0– 1.5h and mean t1/2 was 7.4– 13.0h for all doses. In the multiple-dose period, median tmax was 1.5– 2.0h. Dose-proportional increases in Cmax and AUC24h were observed for peficitinib and its metabolites following single and multiple doses, with minimal drug accumulation. The major metabolite was H2, with a systemic exposure of > 150% of the parent AUC. Drug-related TEAEs were experienced by 5 (13.9%) and 12 (33.3%) subjects in the single- and multiple-dose periods, respectively. Following multiple doses of peficitinib, TEAEs were more frequent in higher than lower dose groups but were mild in severity with no related discontinuation or death.Conclusion: Following single and multiple doses of peficitinib in healthy Chinese subjects, peficitinib demonstrated rapid absorption and was well tolerated at all doses.Clinicaltrials.gov Identifier: NCT04143477.Keywords: rheumatoid arthritis, treatment, dose-proportionality, tsDMARDs

Teppei Hagino,1,2 Shizuka Okazaki,1 Naotaka Serizawa,1 Kaori Suzuki,1 Mio Kaga,2 Yohei Otsuka,2 Erina Mikami,2 Toshihiko Hoashi,2 Hidehisa Saeki,2 Hiroki Matsuda,3 Hiroshi Mitsui,3 Naoko Kanda1 1Department of Dermatology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan; 2Department of Dermatology, Nippon Medical School, Tokyo, Japan; 3Department of Dermatology, Tokyo Teishin Hospital, Tokyo, JapanCorrespondence: Naoko KandaDepartment of Dermatology, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba, 270-1694 JapanTel +81 476 99 1111Fax +81 476 99 1909Email n-kanda@nms.ac.jpPurpose: Alopecia areata (AA) is characterized by non-scarring, patchy hair loss caused by autoimmune reactions to anagen hair follicles. The pathogenesis of AA may be affected by the diet. However, the dietary habits of patients with AA have not been precisely examined. Therefore, the aim of this study was to investigate the dietary habits of patients with AA in comparison to those of healthy controls.Patients and Methods: We evaluated the dietary habits of 70 adult Japanese patients with AA using a brief-type self-administered diet history questionnaire and compared them to the habits of age- and sex-matched healthy controls.Results: Japanese patients with AA had a higher body mass index (BMI) and higher intakes of vitamin C and fruit than the controls. Logistic regression analysis showed that AA was associated with BMI. Retinol intake was positively correlated with severity of alopecia tool (SALT) score, and linear regression analysis revealed that retinol intake was a predictor of SALT score. Retinol intake among patients with moderate to severe AA (ie, a SALT score > 25) was higher than that in patients with mild AA (a SALT score ≤ 25). The mean age of AA patients with atopic dermatitis (AD) was lower than that of AA patients without AD; however, there were no differences in nutrient or food intake between these two groups. Logistic regression analysis showed that the comorbidity AD was negatively associated with age.Conclusion: AA was associated with a high BMI, and high retinol intake was a predictor of SALT score. Further studies should be conducted to clarify whether dietary intervention to reduce BMI or limit retinol intake can alter the development or severity of AA.Keywords: retinol, vitamin C, body mass index, atopic dermatitis

Equatorial Plasma Bubbles (EPBs) can generate ionospheric scintillation at GHz frequencies used in the Global Navigation Satellite System (GNSS). Emerging at any longitude following sunset and typically moving eastward, monitoring the EPBs is essential for space weather services. Using three GNSS receivers positioned at the same latitude (∼0°N) but separated in longitudes (∼9°, ∼16°, and ∼25°) and the 47 MHz Equatorial Atmosphere Radar (EAR) in Indonesia, our study delineates the zonal extent of eastward‐traveling post‐sunset EPB inducing ionospheric GNSS scintillation. Typically, the scintillation occurrences detected by a ground receiver concentrate between 19 and 01 local time (LT), with a peak incidence observed at 21 LT. Furthermore, an experiment combining EAR observations with GNSS receiver data allowed for the determination of the linear change in the speed of eastward‐traveling EPB inducing scintillation during this time period. Interestingly, the longitudinal range of eastward‐traveling EPBs increased with higher solar flux (F10.7) levels. Our findings suggest that EPB can induce scintillation up to a longitudinal distance of approximately 25° from the onset location at sunset to the eastern midnight region, particularly in F10.7 ranging from 90 to 150 solar flux units. Moreover, experiments using longitudinally separated GNSS receivers indicated that scintillations during 19–01 LT originate from post‐sunset EPBs within a longitudinal range extending 25° to the west. In conclusion, our research provides valuable insight into the ability of eastward‐traveling EPB to induce GNSS scintillation within a longitudinal range of 25°, thereby enhancing EPB and scintillation monitoring and prediction in regional space weather services. Plain Language Summary: Many modern technologies rely on Global Navigation Satellite Systems (GNSS). GNSS refers to satellites constellations, including Global Positioning Systems, that send signals from space to the receivers on the ground, providing positioning and timing data. However, GNSS signals can be disrupted by natural phenomena in the Earth's ionosphere, a layer of charged particles in the upper atmosphere. One such phenomenon is the Equatorial Plasma Bubble (EPB) occurring at night, which can cause fluctuations or scintillations in GNSS signals, leading to errors in positioning and timing. Understanding how EPBs affect GNSS is essential for maintaining the reliability of navigation systems and ensuring the smooth operation of various technological applications that rely on GNSS data. EPBs usually move eastward and can cause scintillation in the longitude where they are generated and in other longitudes. Previous studies have not determined how far eastward‐traveling EPB can induce scintillation. Our recent discovery shows that EPBs can induce scintillation within a longitudinal range of up to 25°. This insight is essential for mitigating the adverse effects of EPBs on GNSS applications in regional or longitudinal sectors. Key Points: A ground GNSS receiver typically detects scintillations due to Equatorial Plasma Bubbles (EPBs) from 19 to 01 local time (LT) with the peak occurrence at 21 LTThe furthest longitudinal range of EPB inducing GNSS scintillation depends on solar flux (F10.7) levelEPBs can cause GNSS scintillation within a 25° longitudinal range at F10.7 levels of 90–150 solar flux units [ABSTRACT FROM AUTHOR]

Asuka Katsuki,1 Shingo Kakeda,2 Keita Watanabe,2 Ryohei Igata,1 Yuka Otsuka,1 Taro Kishi,3 LeHoa Nguyen,1 Issei Ueda,2 Nakao Iwata,3 Yukunori Korogi,2 Reiji Yoshimura11Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 8078555, Japan; 2Department of Radiology, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 8078555, Japan; 3Department of Psychiatry, Fujita Health University, Toyoake, Aichi 4701192, JapanCorrespondence: Reiji YoshimuraDepartment of Psychiatry, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 8078555, JapanTel +81 93 691 7253Fax +81 93 692 4894Email yoshi621@med.uoeh-u.ac.jpObjective: Recently, a genome-wide association study successfully identified genetic variants associated with major depressive disorder (MDD). The study identified 17 independent single-nucleotide polymorphisms (SNPs) significantly associated with diagnosis of MDD. These SNPs were predicted to be enriched in genes that are expressed in the central nervous system and function in transcriptional regulation associated with neurodevelopment. The study aimed to investigate associations between 17 SNPs and brain morphometry using magnetic resonance imaging (MRI) in drug-naïve patients with MDD and healthy controls (HCs).Methods: Forty-seven patients with MDD and 42 HCs were included. All participants underwent T1-weighted structural MRI and genotyping. The genotype–diagnosis interactions associated with regional cortical thicknesses were evaluated using voxel-based morphometry for the 17 SNPs.Results: Regarding rs301806, an SNP in the RERE genomic regions, we found a significant difference in a genotype effect in the right-lateral orbitofrontal and postcentral lobes between diagnosis groups. After testing every possible diagnostic comparison, the genotype–diagnosis interaction in these areas revealed that the cortical thickness reductions in the MDD group relative to those in the HC group were significantly larger in T/T individuals than in C-carrier ones. For the other SNPs, no brain area was noted where a genotype effect significantly differed between the two groups.Conclusions: We found that a RERE gene SNP was associated with cortical thickness reductions in the right-lateral orbitofrontal and postcentral lobes in drug-naïve patients with MDD. The effects of RERE gene polymorphism and gene–environment interactions may exist in brain structures of patients with MDD.Keywords: single-nucleotide polymorphism, brain morphology, major depressive disorder, genome-wide association

Yuka Otsuka,1 Shingo Kakeda,2 Koichiro Sugimoto,2 Asuka Katsuki,1 Le Hoa Nguyen,1 Ryohei Igata,1 Keita Watanabe,2 Issei Ueda,2 Taro Kishi,3 Nakao Iwata,3 Yukunori Korogi,2 Reiji Yoshimura11Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Japan; 2Department of Radiology, University of Occupational and Environmental Health, Kitakyushu, Japan; 3Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, JapanPurpose: Compared with healthy subjects (HS), patients with major depressive disorder (MDD) exhibit volume differences that affect the volume changes in several areas such as the limbic, cortical, subcortical, and white matter. Catechol-O-methyltransferase (COMT) is a methylation enzyme that catalyzes endogenous catecholamines. The Val158Met polymorphism of COMT has been reported to affect the dopamine (DA) levels, which plays an important role in psychiatric diseases. However, the relationships among both DA levels, COMT genotype, and brain morphology are complicated and controversial. In previous studies that investigated the hippocampal subfields, the greatest brain abnormalities in MDD patients were observed in Cornu Ammonis (CA)1 and the subiculum, followed by that in CA2-3. We have prospectively demonstrated the relationship between the single-nucleotide polymorphism of the Val158Met COMT gene (rs4680) and the hippocampal subfields in drug-naive MDD patients.Patients and methods: In this study, we compared 27 MDD patients and 42 HS who were divided into groups based on their COMT genotype. The effects of the diagnosis, genotype, and genotype–diagnosis interaction related to CA1 and the subiculum volumes, as well as the whole-brain cortical thickness, were evaluated by performing a FreeSurfer statistical analysis of high-resolution magnetic resonance imaging (MRI) findings.Results: The results revealed that there was a statistically significant interaction between the effects of diagnosis and genotype on the right subiculum (a component of the hippocampus).Conclusion: This Val158Met COMT polymorphism may influence the subiculum volume in drug-naive, first-episode MDD patients.Keywords: major depressive disorder, COMT gene, brain morphology, hippocampal subfields volume, subiculum, surface-based morphometry

Noriyuki Kanzaki,1 Yuta Otsuka,1 Takayuki Izumo,1 Hiroshi Shibata,1 Hideyuki Nagao,2 Keita Ogawara,3 Hiroshi Yamada,3 Seiji Miyazaki,3 Yutaka Nakamura3 1Institute for Health Care Science, Suntory Wellness Ltd, Seika-cho, Soraku-gun, Kyoto, Japan; 2Research Institute of Sports Medical Science, Tokai University, Hiratsuka, Kanagawa, Japan; 3School of Physical Education, Tokai University, Hiratsuka, Kanagawa, Japan Background: Previously, we demonstrated that glucosamine-containing supplementation was effective for improving locomotor functions, especially walking speed. However, the biomechanical mechanism of efficacy has not been elucidated. This study aimed to address this challenge in subjects with knee pain, using a motion capture system. Methods: An open label study was conducted in 30 Japanese subjects with knee pain. The subjects were administered a daily supplement containing 1,200 mg of glucosamine hydrochloride, 60 mg of chondroitin sulfate, 45 mg of type II collagen peptides, 90 mg of quercetin glycosides, 10 mg of imidazole peptides, 1 mg of proteoglycan, and 5 µg of vitamin D (GCQID). The intervention continued for 16 weeks. Efficacy for locomotor functions involving the knee joint was evaluated mainly using the Japanese Knee Osteoarthritis Measure (JKOM) and the 5-question Geriatric Locomotive Function Scale (GLFS-5). To examine the biomechanical mechanism of efficacy for locomotor functions, motions of subjects in a normal walking state were captured. Gait analysis was conducted and efficacy for gait parameters such as normal walking speed, stride length, cadence, and angle of soles was evaluated. Results: GCQID significantly improved total scores on the JKOM and GLFS-5. In gait analysis, normal walking speed, stride length, and angle of soles at the end of the stance phase were all significantly increased, but cadence did not change significantly during the intervention period. There were significant intercorrelations of changes in normal walking speed, stride length, and angle of soles at the end of the stance phase, and between changes in stride length and total JKOM score. Conclusion: A GCQID supplement may increase walking speed through increased stride length and angle of kicking from the ground during steps, which might be mainly associated with alleviated knee pain. Keywords: locomotive syndrome, GLFS-5, normal walking speed, stride length, toe angle