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Risa Hirata,1 Masaki Tago,1 Kiyoshi Shikino,2,3 Takashi Watari,4 Hiromizu Takahashi,5 Yosuke Sasaki,6 Taro Shimizu7 1Department of General Medicine, Saga University Hospital, Saga, Japan; 2Department of General Medicine, Chiba University Hospital, Chiba, Japan; 3Department of Community-Oriented Medical Education, Chiba University Graduate School of Medicine, Chiba, Japan; 4Integrated Clinical Education Center, Kyoto University Hospital, Kyoto, Japan; 5Department of General Medicine, Faculty of Medicine, Juntendo University, Tokyo, Japan; 6Department of General Medicine and Emergency Care, Toho University School of Medicine, Tokyo, Japan; 7Department of Diagnostic and Generalist Medicine, Dokkyo Medical University, Tochigi, 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.jpPurpose: There has been growing interest in generalists in Japan in recent years. However, due to the diverse use of the term “generalist”, the specific roles of these physicians remain ambiguous. Consequently, the target population for research on generalists is unclear, making it challenging to conduct studies within the generalist practice framework. Therefore, a literature search was conducted to examine how generalists are defined and classified in research worldwide.Methods: We conducted a literature search that focused exclusively on articles written in English and used keywords related to generalists, general medicine (GM), primary care, and family medicine. Based on the results, six physicians working in GM reviewed the findings and discussed the identified issues and their potential solutions.Results: The definition of generalists in studies targeting GM, family medicine, and primary care conducted worldwide, including Japan, varies. Generalists exhibit diverse roles even within university hospitals in Japan. No studies provide a precise categorization or definition of generalists based on specific medical practices or roles, except for hospitalists, who are primarily involved in inpatient management in the United States.Conclusion: The definition of GM was unclear based on the results of the literature search, and the lack of uniformity in backgrounds has rendered the target population unclear. Consequently, in healthcare settings where medical systems vary by country or region, evidence from studies targeting generalists cannot readily apply to actual practice. Clarifying generalists through an explicit definition based on clinical practice will allow for a more precise target population for research on generalists and enable the accumulation of evidence related to well-defined groups of generalists, contributing to the advancement of GM. Therefore, future research is required to develop new indicators to precisely classify and define generalists.Keywords: generalist, general medicine, definition, hospitalist

Masaki Tago,1 Risa Hirata,1 Hiromizu Takahashi,2 Shun Yamashita,1,3 Masayuki Nogi,4,5 Kiyoshi Shikino,6 Yosuke Sasaki,7 Takashi Watari,8 Taro Shimizu9 1Department of General Medicine, Saga University Hospital, Saga, Japan; 2Department of General Medicine, Faculty of Medicine, Juntendo University, Tokyo, Japan; 3Education and Research Center for Community Medicine, Faculty of Medicine, Saga University, Saga, Japan; 4Hospitalist Division, The Queen’s Medical Center, Honolulu, HI, USA; 5Department of General Internal Medicine, Kameda Medical Center, Chiba, Japan; 6Department of General Medicine, Chiba University Hospital, Chiba, Japan; 7Department of General Medicine and Emergency Care, Toho University School of Medicine, Tokyo, Japan; 8General Medicine Center, Shimane University Hospital, Shimane, Japan; 9Department of Diagnostic and Generalist Medicine, Dokkyo Medical University, Tochigi, 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.jpAbstract: Hospital Medicine in the United States has achieved significant progress in the accumulation of evidence. This development has influenced the increasing societal demand for General Medicine in Japan. Generalists in Japan actively engage in a wide range of interdisciplinary clinical practices, education, and management. Furthermore, Generalists have also contributed to advances in research. However, there is limited evidence regarding the benefits of General Medicine in Japan in all these areas, with most of the evidence derived from single-center studies. In Japan, the roles of Generalists are diverse, and the comprehensive definition of General Medicine makes it difficult to clearly delineate its scope. This results in an inadequate accumulation of evidence regarding the benefits of General Medicine, potentially making it less attractive to the public and younger physicians. Therefore, it is necessary to categorize General Medicine and collect clear evidence regarding its benefits.Keywords: classification, evidence, general medicine

Risa Hirata,1 Masaki Tago,1 Kiyoshi Shikino,2,3 Takashi Watari,4 Hiromizu Takahashi,5 Yosuke Sasaki,6 Taro Shimizu7 1Department of General Medicine, Saga University Hospital, Saga, Japan; 2Department of General Medicine, Chiba University Hospital, Chiba, Japan; 3Department of Community-Oriented Medical Education, Chiba University Graduate School of Medicine, Chiba, Japan; 4Integrated Clinical Education Center, Kyoto University Hospital, Kyoto, Japan; 5Department of General Medicine, Faculty of Medicine, Juntendo University, Tokyo, Japan; 6Department of General Medicine and Emergency Care, Toho University School of Medicine, Tokyo, Japan; 7Department of Diagnostic and Generalist Medicine, Dokkyo Medical University, Tochigi, 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.jp

Yumi Otaka,1 Yukinori Harada,1 Norio Sugawara,2 Taro Shimizu,1 Norio Yasui-Furukori2 1Department of Diagnostic and Generalist Medicine, Dokkyo Medical University, School of Medicine, Tochigi, Japan; 2Department of Psychiatry, Dokkyo Medical University, School of Medicine, Tochigi, JapanCorrespondence: Norio Yasui-Furukori, Department of Psychiatry, Dokkyo Medical University, School of Medicine, Mibu, Shimotsuga, Tochigi, 321-0293, Japan, Tel +81-282-86-1111, Fax +81-282-86-5187, Email furukori@dokkyomed.ac.jpBackground: Diabetic chorea is a rare complication of diabetes mellitus for which head MRI is the most common diagnostic imaging modality. Cases have been reported where CT and/or MRI findings are inconsistent or clinical symptoms and imaging findings do not appear simultaneously. We aimed to compile the cases in which imaging findings appeared on MRI retests and to examine in a systematic review whether temporal differences in the appearance of imaging findings correlate with clinical characteristics.Case Presentation: An 80-year-old man with type 2 diabetes mellitus came to a hospital with abnormal movements of the left upper and lower extremities. Two days after the first visit, his symptoms flared up, and his head MRI showed an old cerebral infarction and no new lesion. On day 14, he retested T1-weighted imaging and showed a high signal in the right putamen, which was considered diabetic chorea. Blood glucose was controlled with insulin, and the involuntary movements disappeared.Methods: PubMed and ICHUSHI were searched to identify patients with diabetic chorea who had undergone MRI retests. Patients grouped by the temporal change in the presence/absence of imaging findings were compared on age, sex, duration of diabetes mellitus, blood glucose level, HbA1c level, side of involuntary movement, time to first MRI, and follow-up MRI.Results: Of the 64 cases analyzed, 43 (67.2%) were female. The mean age was 69.0 years. 16 (25.0%) had worsening findings upon MRI retesting, 37 (57.8%) had improvement, and 10 (15.6%) had unchanged findings. There were no significant differences in age, sex, mean blood glucose level or HbA1c at onset among the groups.Conclusion: There was no association between the pattern of appearance of imaging findings over time and clinical characteristics, including glucose levels. If initial MRI findings are negative, MRI retesting after a certain time may help diagnose diabetic chorea.Keywords: hyperglycemia, hemichorea, hemiballismus, diabetes, movement disorders

Yoshihisa Ishiura, Shosaku Nomura, Yuka Ishii, Kai Imai, Yusuke Sawai, Takeshi Tamaki, Toshiki Shimizu, Naoyuki Miyashita, Tomoki Ito First Department of Internal Medicine, Kansai Medical University, Osaka, JapanCorrespondence: Yoshihisa Ishiura, First Department of Internal Medicine, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan, Tel +81-6-6992-1001, Fax +81-6-6993-9837, Email ishiuray@takii.kmu.ac.jpAbstract: Cough, a frequent symptom encountered in clinical practice, often has a considerable impact on patients’ lives. There is an urgent need to investigate more potent antitussive treatments for chronic refractory cough, particularly atopic cough, which is a major cause of chronic refractory cough in Japan. Previous studies have shown that eosinophilic tracheobronchitis with hypersensitivity to sensory nerve C-fibers is the pathophysiology of atopic cough. Gefapixant is a first-in-class P2X3 antagonist that has recently become available for clinical use in patients with refractory coughs. A 64-year-old female non-smoker presented to our hospital with a complaint of chronic intractable cough due to atopic cough. Addition of gefapixant (90 mg/day) to her previous treatment improved her distressing cough, despite the partial efficacy of many other drugs. The findings of this case demonstrate that P2X3 inhibition is a viable therapeutic option for patients with chronic refractory cough caused by atopic cough. This case report offers valuable information regarding currently available treatment options for refractory chronic refractory cough caused by atopic cough. There remains an urgent need to clarify the disease entities presenting with chronic cough that can be effectively treated by inhibiting P2X3.Plain Language Summary: There is an urgent need to investigate more potent antitussive treatments for chronic refractory cough, because cough has a considerable impact on patients’ lives. Previous studies have shown that eosinophilic tracheobronchitis with hypersensitivity of sensory nerve C-fibers is the pathophysiology of atopic cough, which is a major cause of chronic cough in Japan. Gefapixant is a first-in-class P2X3 antagonist that has recently become available for clinical use in patients with refractory coughs. Herein, we present the case of a 64-year-old female with a refractory atopic cough. The gefapixant add-on improved her distressing cough, indicating that P2X3 inhibition could be a viable therapeutic option for patients with chronic refractory cough caused by atopic cough.Keywords: chronic cough, atopic cough, gefapixant, P2X3

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

Masaki Tago,1 Risa Hirata,1 Kiyoshi Shikino,2 Takashi Watari,3 Yosuke Sasaki,4 Hiromizu Takahashi,5 Taro Shimizu6 1Department of General Medicine, Saga University Hospital, Saga, Japan; 2Department of General Medicine, Chiba University Hospital, Chiba, Japan; 3General Medicine Center, Shimane University Hospital, Shimane, Japan; 4Department of General Medicine and Emergency Care, Toho University School of Medicine, Tokyo, Japan; 5Department of General Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; 6Department of Diagnostic and Generalist Medicine, Dokkyo Medical University, Tochigi, 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.jpAbstract: Clinical physicians have the potential to contribute to the progress of medicine and healthcare through research based on their diagnostic and treatment practices and supported by their educational background. However, in the field of general medicine in Japan, publication of such research in international journals may be limited by challenges in English proficiency and the lack of opportunities to focus on specific research themes amidst the diverse range of diseases treated in clinical practice. Furthermore, novice researchers without prior research experience may lack a comprehensive understanding of the overall research process, including study design and article publication. To address these challenges, we developed a set of 22 milestones that highlight the necessary skills required to conduct and successfully publish clinical research. This guideline will enable novice researchers to identify and address individual barriers to undertaking a research project. These milestones are categorized into five parts: 1) preparing to undertake research; 2) conducting clinical research; 3) writing the article; 4) submitting and achieving acceptance for publication; and 5) advanced skills. For each part, we provide detailed recommendations on the specific steps and methods involved. By working through these 22 milestones, novice researchers can objectively assess their own level of achievement as researchers and continuously clarify the next step of each round of research. Through this set of milestones, we aim to increase the quality and quantity of research publications in general medicine in academic journals, ideally enhancing the overall research process and advancing the field of medicine and healthcare overall.Keywords: clinical research, original research, young physicians

Takanobu Hirosawa,1 Tetsu Sakamoto,1 Shogo Hanai,2 Yukinori Harada,1 Taro Shimizu1 1Department of Diagnostic and Generalist Medicine, Dokkyo Medical University, Shimotsuga, Tochigi, Japan; 2Departments of Microbiology and Infectious Diseases, Fujita Health University School of Medicine, Aichi, JapanCorrespondence: Takanobu Hirosawa, Department of Diagnostic and Generalist Medicine, Dokkyo Medical University, 880 Kitakobayashi, Mibu-cho, Shimotsuga, Tochigi, 321-0293, Japan, Tel +81 282 87 2498, Fax +81 282 87 2502, Email hirosawa@dokkyomed.ac.jpPurpose: The effect of antibiotics administered before blood cultures performed in general internal medicine outpatient settings is not well known.Patients and Methods: We conducted a retrospective case–control study including adult patients who underwent blood cultures in the general internal medicine outpatient department of a Japanese university hospital between 2016 and 2022. Patients with positive blood cultures were included as cases and matched patients with negative blood cultures were included as controls. Univariable and multivariable logistic regression analyses were performed.Results: A total of 200 patients and 200 controls were included. Antibiotics were administered prior to blood culture in 20% of patients (79/400). Oral antibiotics were prescribed to 69.6% of the prior antibiotics (55/79). Prior antibiotic use was significantly lower among patients with positive than negative blood cultures (13.5% vs 26.0%, p = 0.002) and was an independent predictive factor in univariable (odds ratio, 0.44; 95% confidence interval, 0.26– 0.73; p = 0.002) and multivariable (adjusted odds ratio, 0.31; 95% confidence interval, 0.15– 0.63; p = 0.002) logistic regression models for positive blood culture. The area under the receiver operating characteristic (AUROC) curve of the multivariable model for predicting positive blood cultures was 0.86.Conclusion: There was a negative correlation between prior antibiotic use and positive blood cultures in the general internal medicine outpatient department. Therefore, physicians should interpret the negative results of blood cultures performed after the administration of antibiotics with care.Keywords: bacteremia, fever, infection, antibacterial agent, antimicrobial, sepsis

Taro Shimizu Department of Diagnostic and Generalist Medicine, Dokkyo Medical University Hospital, Mibu, Tochigi, JapanCorrespondence: Taro Shimizu, Department of Diagnostic and Generalist Medicine, Dokkyo Medical University Hospital, Dokkyo Medical University, Graduate School of Medicine, Kitakobayashi 880, Mibu, Tochigi, 321-0293, Japan, Email shimizutaro7@gmail.comAbstract: Diagnostic excellence is an important goal in medicine. The enhancement of clinical reasoning skills of physicians, which is at the core of this concept, is a significant challenge. To achieve this improvement, it is necessary to enhance the ability to collect patient history information and to integrate the information. Additionally, the complexity of diagnosis is confounded by biases, noise, uncertainty, and contextual factors, and the impact of these factors is particularly prominent in complex cases. In such cases, the dual process theory, which is a classical reasoning measure, alone is insufficient to cope with these challenges, and a multifaceted and comprehensive approach is required to supplement its limitations. Therefore, the author presents six concrete steps, represented by the acronym DECLARE (Decomposition, Extraction, Causation Link, Assessing Accountability, Recomposition, Explanation and Exploration), that implement the concept of cognitive forcing strategy that has been shown to be effective in bias control, and include reflection, meta-cognition, and the recently popularized decision hygiene procedure. DECLARE is a strategy that should be deployed when faced with more complex diagnostic scenarios. By examining each of the six steps that comprise DECLARE individually, cognitive load can be reduced. Furthermore, by verifying causation and accountability when constructing diagnostic hypotheses, biases can be mitigated, which can also help to address noise and uncertainty, leading to an improvement in the quality of diagnosis and effectiveness in medical education.Keywords: diagnostic excellence, diagnostic strategy, meta-cognition, reflection, causal inference, decision hygiene

Ren Kawamura, Yukinori Harada, Masashi Yokose, Shogo Hanai, Yudai Suzuki, Taro Shimizu Department of Diagnostic and Generalist Medicine, Dokkyo Medical University Hospital, Mibu, Tochigi, JapanCorrespondence: Taro Shimizu, Department of Diagnostic and Generalist Medicine, Dokkyo Medical University Hospital, 880 Kitakobayashi, Shimotsuga, Mibu, Tochigi, 321-0293, Japan, Tel +8128286-1111, Email shimizutaro7@gmail.comPurpose: The general internal medicine (GIM) department can be an effective diagnostic coordinator for undiagnosed outpatients. We investigated the contribution of GIM consultations to the diagnosis of patients admitted to specialty departments in hospitals in Japan that have not yet adopted a hospitalist system.Patients and Methods: This single-center, retrospective observational study was conducted at a university hospital in Japan. GIM consultations from other departments on inpatients aged ≥ 20 years, from April 2016 to March 2021, were included. Data were extracted from electronic medical records, and consultation purposes were categorized into diagnosis, treatment, and diagnosis and treatment. The primary outcome was new diagnosis during hospitalization for patients with consultation purpose of diagnosis or diagnosis and treatment. The secondary outcomes were the purposes of consultation with the Diagnostic and Generalist Medicine department.Results: In total, 342 patients were included in the analysis. The purpose of the consultations was diagnosis for 253 patients (74%), treatment for 60 (17.5%), and diagnosis and treatment for 29 patients (8.5%). In 282 consultations for diagnosis and diagnosis and treatment, 179 new diagnoses were established for 162 patients (57.5%, 95% confidence interval [CI], 51.5– 63.3).Conclusion: The GIM department can function as a diagnostic consultant for inpatients with diagnostic problems admitted to other specialty departments in hospitals where hospitalist or other similar systems are not adopted.Keywords: diagnosis, diagnostic excellence, consultation, consultative medicine, hospital admission

Masayuki Amano,1,2 Yukinori Harada,2 Taro Shimizu2 1Department of Generalist Medicine, Minaminara General Medical Center, Oyodo, Nara, Japan; 2Department of Diagnostic and Generalist Medicine, Dokkyo Medical University Hospital, Mibu, Tochigi, JapanCorrespondence: Taro Shimizu, Department of Diagnostic and Generalist Medicine, Dokkyo Medical University Hospital, 880, Kitakobayashi, Shimotsuga, Mibu, 321-0923, Japan, Tel +81-282-86-1111, Fax +81-282-86-4775, Email shimizutaro7@gmail.comAbstract: The accumulation of optimal decision-making is vital to achieving diagnostic excellence and preventing diagnostic errors. Diagnostic uncertainty (DU) determines the difficulty of each team member’s decision-making process, including the patient, care partners, physicians, and healthcare professionals. The diagnostic approach in the low DU is already available, while the one in the high DU still needs to be clarified. In cognitive science, Sarasvathy et al established “effectuation”, a theory of decision-making under the high-uncertainty condition, by analyzing how outstanding entrepreneurs make decisions when the future is unpredictable. Based on this theory, we developed the “effectual diagnostic approach (EDA).” This simple approach allows patients and physicians to “set” problems co-creatively, emerging the outlines of the clusters of health issues under high DU conditions. After DU declines enough, the traditional problem-solving approach will help the diagnostic team achieve the patient’s well-being. EDA will offer us a guiding principle for action in the high DU. The co-creation of the “patient as an entrepreneur” with the “physician as a co-founder” will contribute to achieving diagnostic excellence.Keywords: diagnostic excellence, diagnostic uncertainty, diagnostic error, effectuation, co-creation

Masashi Yokose, Yukinori Harada, Shogo Hanai, Shusaku Tomiyama, Taro Shimizu Department of Diagnostic and Generalist Medicine, Dokkyo Medical University Hospital, Mibu, Tochigi, 321-0293, JapanCorrespondence: Taro Shimizu, Department of Diagnostic and Generalist Medicine, Dokkyo Medical University Hospital, Kitakobayashi 880, Shimotsuga, Mibu, Tochigi, 321-0293, Japan, Tel +81 282 86-1111, Email shimizutaro7@gmail.comPurpose: The data on the diagnostic contribution of general internal medicine (GIM) consultations for undiagnosed health problems from specialists are scarce. This study aims to explore the role of generalists as diagnostic medicine consultants in tertiary care settings.Patients and Methods: We conducted a retrospective observational study at a Japanese university hospital. GIM consultations for diagnosis from other departments on outpatients aged ≧ 20 years from January 2018 to December 2020 were included. Data were extracted from electronic medical records. The primary outcome was new diagnosis rates. The secondary outcomes were new diagnosis rates with clinical significance and clinical outcomes at 90 days from the index visit.Results: A total of 328 patients were included. The top five consulting departments were orthopedics (17.0%), cardiovascular (10.3%), otorhinolaryngology (8.8%), neurology (8.8%), and gastroenterology (7.9%). GIM identified 456 chief complaints (CCs), and the top five were fever (10.9%), abnormal laboratory results (8.3%), fatigue (5.9%), and pain (7.4%) or numbness (4.6%) in the extremities. There were 139 (104/328 patients: 31.8%) specialty consultations from GIM, and the top five departments were rheumatology (21.1%), gastroenterology (19.2%), orthopedics (9.6%), psychiatry (9.6%), and neurology (9.6%). In total, 277 new diagnoses were established in 232 patients (70.7%), and 203 patients had new diagnoses with clinical significance (61.8%). Clinical outcomes at 90 days from the time of the index visit were resolution/improvement (60.7%), unchanged/worsened (22.3%), and unknown (17.0%).Conclusion: Over 70% of GIM consultations from other departments established new diagnoses with favorable outcomes in > 60% of the patients.Keywords: consultation, specialists, diagnostic error, diagnostic excellence, diagnostic uncertainty

Masaki Tago,1 Risa Hirata,1 Takashi Watari,2 Kiyoshi Shikino,3 Yosuke Sasaki,4 Hiromizu Takahashi,5 Taro Shimizu6 1Department of General Medicine, Saga University Hospital, Saga, Japan; 2General Medicine Center, Shimane University Hospital, Shimane, Japan; 3Department of General Medicine, Chiba University Hospital, Chiba, Japan; 4Department of General Medicine and Emergency Care, Toho University School of Medicine, Tokyo, Japan; 5Department of General Medicine, Faculty of Medicine, Juntendo University, Tokyo, Japan; 6Department of Diagnostic and Generalist Medicine, Dokkyo Medical University, Tochigi, 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.jpAbstract: In Japan, general medicine is still relatively new as a specialty, having been established in 2018 as the 19th primary specialty. The relevant research field has therefore not been fully established yet, and the detailed research areas in this field have not been identified. We conducted a descriptive questionnaire-based web survey of members of the Japanese Society of Hospital General Medicine. Respondents were asked to highlight their research topics from the following categories: diagnostic excellence, design (problem-solving and thinking methodology), symptomatology, physical examination, clinical epidemiology, home and community medicine, general medicine education, organizational management, hospital administration, and “none of the above (add description of your work if desired)”. The respondents could choose multiple topics. There were 276 respondents (14% response rate), of whom 240 (86.9%) were male, 103 (37.3%) worked at universities, and 232 (84.1%) had previous research experience. Diagnostic excellence was the most common research topic category among generalists (n=87, 21.3%), followed by clinical epidemiology (n=83, 20.3%), symptomatology (n=41, 10.0%), home and community medicine (n=39, 9.6%), and general medicine education (n=36, 8.8%). Seventy-eight respondents (19.1%) chose “none of the above (add description of your work if desired)”. The main research topics were in areas fundamental to diagnostic excellence, ie, diagnostics, diagnostic error, clinical epidemiology, and symptomatology. Home and community medicine and general medicine education were also included as research topics because of their diverse roles. The research interests of generalists are therefore diverse, and new areas and frameworks are likely to be created in the future.Keywords: clinical research, diagnostic excellence, general medicine, medical education, research topic

Takanobu Hirosawa, Arisa Hayashi, Yukinori Harada, Taro Shimizu Department of Diagnostic and Generalist Medicine, Dokkyo Medical University, Tochigi, JapanCorrespondence: Taro Shimizu, Department of Diagnostic and Generalist Medicine, Dokkyo Medical University, 880 Kitakobayashi, Mibu-cho, Shimotsuga, Tochigi, 321-0293, Japan, Tel + 81 282 87 2498, Fax + 81-282-87-2502, Email shimizu7@dokkyomed.ac.jpPurpose: The clinical presentation of iron deficiency is not well understood. We aimed to identify the clinical manifestations of iron deficiency without anemia in women.Patients and Methods: We conducted a retrospective cohort study of women who visited the general internal medicine outpatient department of a university hospital in Japan between 2016 and 2022. Women who were prescribed iron supplements were included in the study. Anemia was defined as hemoglobin levels below 12 g/dl. Iron deficiency was defined as serum ferritin levels < 30.0 μg/l. The primary outcome was the difference in symptoms between patients with iron deficiency with and without anemia. The secondary outcome was the ratio of symptom, hemoglobin, and serum ferritin improvement (levels > 30.0 μg/l after treatment), comparing the measurements at the beginning and after supplementation.Results: A total of 147 women were included in the final analysis. There were no significant differences in the initial symptoms and the ratio of symptom improvement between the groups. Compared to patients with iron deficiency anemia, patients with iron deficiency without anemia had high initial serum ferritin levels (14.8 vs 7.1 μg/l, p< 0.001), and hemoglobin (13.2 vs 9.9 g/dl, p< 0.001). Iron supplements significantly improved the serum ferritin level in two groups and the hemoglobin in iron deficiency anemia. After treatment, iron deficiency without anemia still had high serum ferritin levels (37.7 vs 28.2 μg/l, p=0.017) and hemoglobin (13.3 vs 12.3 g/dl, p < 0.001).Conclusion: There were no differences in any of the investigated symptoms and the ratio of the symptom improvement depending on the anemic state in iron deficiency. After iron supplementation, the serum ferritin levels in the iron deficiency without anemia group improved. Hemoglobin and serum ferritin in iron deficiency without anemia were still highly comparable to that of iron deficiency anemia.Keywords: women, hemoglobin, iron deficiency without anemia, serum ferritin

Yoshihisa Ishiura,1 Masaki Fujimura,2 Noriyuki Ohkura,3 Johsuke Hara,3 Kahori Nakahama,1 Yusuke Sawai,1 Takeshi Tamaki,1 Ryuta Murai,1 Toshiki Shimizu,1 Naoyuki Miyashita,1 Shosaku Nomura1 1First Department of Internal Medicine, Kansai Medical University, Osaka, Japan; 2Respiratory Medicine, National Hospital Organization Nanao Hospital, Nanao, Japan; 3Respiratory Medicine, Kanazawa University Hospital, Kanazawa, JapanCorrespondence: Yoshihisa Ishiura, First Department of Internal Medicine, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan, Tel +81-6-6992-1001, Fax +81-6-6993-9837, Email ishiura-@p2322.nsk.ne.jp; ishiuray@takii.kmu.ac.jpPurpose: The ‘treatable traits’ strategy for patients with chronic inflammatory airway diseases, especially asthma and chronic obstructive pulmonary disease (COPD), is a focus of interest, because it implements precision and personalized medicine. Asthma-COPD overlap (ACO), a phenotype involving both asthma and COPD, is an important disease entity because patients with ACO have significantly worse outcomes, conferring greater economical and social burdens. Some guidelines for ACO recommend add-on therapy of long-acting muscarinic antagonists to inhaled corticosteroids and long-acting β2 agonists. However, this approach is based on extrapolation from patients with asthma or COPD alone. Consequently, a ‘treatable traits’ approach suitable for ACO remains obscure.Methods: A 12-week open-label cross-over pilot study was conducted in patients with ACO to investigate the effect of tiotropium bromide (TIO) 5 μg/day add-on therapy to fluticasone propionate/formoterol fumarate (FP/FM) 500/20 μg/day compared with FP/FM 500/20 μg/day alone. A 4-week run-in period and two 4-week treatment periods were included.Results: A total of 18 male patients with stable ACO participated in this pilot study. All patients were ex-smokers. Mean values ± standard deviation (SD) for forced expiratory volume in 1 second (FEV1) were 1.21 ± 0.49 L after the run-in period, 1.20 ± 0.51 L after the FP/FM combination therapy period, and 1.30 ± 0.48 L after the TIO add-on therapy to FP/FM period. FEV1 values after the TIO add-on therapy FP/FM period were significantly higher than those after the run-in period (p < 0.01).Conclusion: TIO add-on therapy to FP/FM in patients with ACO, considered difficult to treat because of the presence of both asthma and COPD, resulted in improvements in lung function parameters in this real-world pilot study, indicating the potential value of TIO add-on therapy as a “treatable traits” option for standard treatment for ACO.Keywords: treatable trait, asthma-COPD overlap, tiotropium, fluticasone, formoterol, triple therapy

Makito Miyake,1 Nobutaka Nishimura,1,2 Takuto Shimizu,1,3 Mikiko Ohnishi,4 Masaomi Kuwada,4 Yoshitaka Itami,5 Takeshi Inoue,5 Kenta Ohnishi,6 Yoshihiro Matsumoto,6 Takanori Yoshida,7 Yoshihiro Tatsumi,8 Masatake Shinohara,9 Shunta Hori,1 Yosuke Morizawa,1 Daisuke Gotoh,1 Yasushi Nakai,1 Satoshi Anai,1 Kazumasa Torimoto,1 Katsuya Aoki,1 Tomomi Fujii,10 Nobumichi Tanaka,1,11 Kiyohide Fujimoto1 1Department of Urology, Nara Medical University, Kashihara, Nara, 634-8522, Japan; 2Department of Urology, Okanami General Hospital, Iga, Mie, Japan; 3Department of Urology, Saiseikai Chuwa Hospital, Nara, Japan; 4Department of Urology, Matsusaka Chuo General Hospital, Matsusaka, Mie, Japan; 5Department of Urology, Nara Prefecture General Medical Center, Nara, Japan; 6Department of Urology, Hoshigaoka Medical Center, Hirakata, Osaka, Japan; 7Department of Urology, Tane General Hospital, Osaka, Japan; 8Department of Urology, JCHO Yamato Koriyama Hospital, Koriyama, Nara, Japan; 9Department of Urology, Osaka Gyoumeikan Hospital, Osaka, Japan; 10Department of Diagnostic Pathology, Nara Medical University, Kashihara, Nara, 634-8522, Japan; 11Department of Prostate Brachytherapy, Nara Medical University, Kashihara, Nara, 634-8522, JapanCorrespondence: Makito Miyake, Department of Urology, Nara Medical University, 840 Shijo-cho, Nara, 634-8522, Japan, Tel +81-744-22-3051 (ext 2338), Fax +81-744-22-9282, Email makitomiyake@yahoo.co.jpPurpose: The treatment landscape for advanced, unresectable, or metastatic urothelial carcinoma (aUC) has shifted substantially since the advent of immune checkpoint inhibitors (ICIs). We investigated the extent to which pembrolizumab therapy is superior to conventional chemotherapy as a second-line treatment.Patients and Methods: A multicenter-derived database registered 454 patients diagnosed with aUC between 2008 and 2020. Of these, 94 patients (21%) who received second-line pembrolizumab and 75 (17%) who received second-line chemotherapy but never received third-line or later ICI therapy were included. We compared overall survival (OS) from the initial date of first-line chemotherapy between two groups by adjusting for prognostic factors through propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). The IPTW-adjusted hazard ratio and 95% confidence interval were estimated using a multivariate Cox regression analysis. To identify patients who were more likely to benefit from second-line pembrolizumab than from chemotherapy, we performed a subgroup analysis for OS with an IPTW-adjusted model.Results: The PSM-adjusted comparison showed a significant improvement in the prognosis with second-line pembrolizumab use (P = 0.01). The OS benefit with the advent of pembrolizumab was 8 months (18 months vs 26 months). Multivariable analyses using IPTW adjustment demonstrated that lymph node metastasis (P = 0.001), lung metastasis (P = 0.013), and bone metastasis (P = 0.003) were poor independent prognostic factors, and pembrolizumab use (P = 0.021) was a favorable independent prognostic factor. Subgroup analyses revealed that pembrolizumab was associated with survival benefits over chemotherapy in all subgroups, including young patients (age < 70 years), those who received radical surgery, and those without visceral metastasis.Conclusion: We demonstrated a significant improvement in prognosis after the advent of pembrolizumab for patients with aUC. ICIs should not be restricted based on patient characteristics.Keywords: urinary bladder neoplasms, immunotherapy, chemotherapy, survival, propensity score

Mutsuko Kato, Michie Namba, Sachika Shimoyama, Mayumi Inoue, Chihiro Ouchi, Takehiro Shimizu Department of Ophthalmology, Japan Red Cross Okayama Hospital, Okayama, JapanCorrespondence: Mutsuko KatoDepartment of Ophthalmology, Japan Red Cross Okayama Hospital, 2-1-1 Aoe, Kita-ward, Okayama, 700-8607, JapanTel +81 86 222 8811Fax +81 86 222 8841Email mutsukato@okayama-med.jrc.or.jpPurpose: To report our modified simple technique for optic capture and the clinical results of intrascleral IOL fixation preserving the lens capsule, without vitrectomy, in cases of cataract with insufficient zonular support to stabilize the intraocular lens (IOL).Patients and Methods: In 37 eyes of 25 patients with phacodonesis and two or more risk factors for progressive zonular insufficiency, we inserted a CTR to support the capsule and zonules during cataract surgery and IOL fixation; an optic was inserted into the lens capsule, and a haptic was fixed in the scleral tunnel without vitrectomy. In all cases, anterior or total vitrectomy was not needed.Results: The postoperative mean (± standard deviation) tilt and decentration of the implanted IOL did not change from 6 to 12 months (6.77 ± 3.15° to 6.33 ± 3.38° and 0.60 ± 0.30 to 0.61 ± 0.35 mm, respectively). We encountered no late IOL dislocation and no retinal complications, including retinal breaks or cystoid macular oedema, postoperatively (follow-up = 21.1 ± 5.2 months).Conclusion: Our modified techniques preclude the need for vitrectomy. If the lens capsule can be preserved using a CTR, our modified technique can be used to stabilize IOL.Keywords: insufficient zonular support, phacodonesis, lens capsule, capsular tension ring, intrascleral IOL fixation

Taiju Miyagami,1 Toru Yamada,2 Yohei Kanzawa,3 Shunsuke Kosugi,4 Kazuya Nagasaki,5 Hiroyuki Nagano,6 Taro Shimizu,7 Kazutoshi Fujibayashi,1 Gautam A Deshpande,1 Toshio Naito1 1Department of General Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; 2Department of Family Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; 3Department of General Internal Medicine, Akashi Medical Center, Hyogo, Japan; 4Department of General Internal Medicine, Iizuka Hospital, Iizuka, Fukuoka, Japan; 5Department of Internal Medicine, Mito Kyodo General Hospital, Ibaraki, Japan; 6Emergency Medicine and General Internal Medicine, Rakuwakai Marutamachi Hospital, Kyoto, Japan; 7Department of Diagnostic and Generalist Medicine, Dokkyo Medical University Hospital, Tochigi, JapanCorrespondence: Toru YamadaDepartment of Family Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 1138519, Japan, Tel +81 3 5803 5229, Fax +81 3 5803 0276, Email toru.y.fmed@tmd.ac.jpPurpose: To identify the current ambiguous status of general medicine (GM) and assess current problems and weaknesses for further development of GM.Patients and Methods: This study adopted an observational design. GM practitioners were selected from the mailing lists of two primary professional associations for Japanese GM doctors. We included physicians currently working in a GM department, those self-described as GM doctors, and those board-certified in family medicine or general internal medicine. Respondents replied to survey questions about their sociodemographic data, job descriptions, and the requisite skills for practice. GM doctors’ job description and required skills were categorized into “clinical,” “management,” “education,” and “research.” Participants (n = 971) were compared based on job descriptions and important skills in each category by facility type, size, and position.Results: “Clinical” was indicated as the most important category for both job description and important skills, followed by “management,” “education,” and “research.” For job description details, “follow-up outpatient” (35.6%) ranked first for “clinical,” and “resident education” (57.3%) ranked first for “education.” By facility type and size, job description and important skills decreased for clinical and management categories as facility sizes increased; the opposite was true for “education.” “Research” was generally rated low. By position, no significant difference was found in effort or importance given to research.Conclusion: This study is the first survey on GM physicians across Japan. The results show that while Japanese GM physicians focus on and place importance on clinical practice, they are less involved in research and do not consider research skills to be important. The challenge for the future development of GM lies in research.Keywords: general medicine doctors, job description, observational study, research skills

Masaki Tago,1 Takashi Watari,2 Kiyoshi Shikino,3 Yosuke Sasaki,4 Hiromizu Takahashi,5 Taro Shimizu6 1Department of General Medicine, Saga University Hospital, Saga, Japan; 2General Medicine Center, Shimane University Hospital, Shimane, Japan; 3Department of General Medicine, Chiba University Hospital, Chiba, Japan; 4Department of General Medicine and Emergency Care, Toho University School of Medicine, Tokyo, Japan; 5Department of General Medicine, Faculty of Medicine, Juntendo University, Tokyo, Japan; 6Department of Diagnostic and Generalist Medicine, Dokkyo Medical University, Tochigi, JapanCorrespondence: Masaki TagoDepartment of General Medicine, Saga University Hospital, 5-1-1 Nabeshima, Saga, 849-8501, JapanTel +81 952 34 3238Fax +81 952 34 2029Email tagomas@cc.saga-u.ac.jpAbstract: Owing to the social structure issues caused by Japan’s super-aged society, health-care roles have become more complex, and the need for general physicians has increased. General hospitalists in Japan perform various roles. Thus, the ideal image of general hospitalists there has been unclear. We summarize the 10 key skills for Japanese hospitalists indicated in the specialty programs of the Japanese Society of Hospital General Medicine. We identified the following five crucial points for ideal general hospitalists: general mindset; leadership and management; community-based comprehensive care and cooperation with various professions; appropriate medical interviewing, physical examination, and diagnostic reasoning; and proactive education and academic activities. This paper presents five tips, which deal with why those items are necessary and how they should be learned.Keywords: academic activity, diagnostic reasoning, education, general hospitalist, general mindset, leadership and management

Kazuya Nagasaki,1 Yuji Nishizaki,2,3 Masanori Nojima,4 Taro Shimizu,5 Ryota Konishi,6 Tomoya Okubo,7 Yu Yamamoto,8 Ryo Morishima,9 Hiroyuki Kobayashi,1 Yasuharu Tokuda10 1Department of Internal Medicine, Mito Kyodo General Hospital, University of Tsukuba, Ibaraki, Japan; 2Medical Technology Innovation Center, Juntendo University, Tokyo, Japan; 3Division of Medical Education, Juntendo University School of Medicine, Tokyo, Japan; 4Center for Translational Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; 5Department of Diagnostic and Generalist Medicine, Dokkyo Medical University Hospital, Tochigi, Japan; 6Education Adviser Japan Organization of Occupational Health and Safety, Kanagawa, Japan; 7Research Division, The National Center for University Entrance Examinations, Tokyo, Japan; 8Division of General Medicine, Center for Community Medicine, Jichi Medical University School of Medicine, Tochigi, Japan; 9Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan; 10Muribushi Okinawa for Teaching Hospitals, Okinawa, JapanCorrespondence: Yuji NishizakiMedical Technology Innovation Center, Juntendo University, 2-1-1 Hongo Bunkyo-ku, Tokyo, 113-8421, JapanTel +81-3-3813-3111Fax +81-3-5689-0627Email ynishiza@juntendo.ac.jpPurpose: In Japan, the General Medicine In-training Examination (GM-ITE) was developed by a non-profit organization in 2012. The GM-ITE aimed to assess the general clinical knowledge among residents and to improve the training programs; however, it has not been sufficiently validated and is not used for high-stake decision-making. This study examined the association between GM-ITE and another test measure, the Professional and Linguistic Assessments Board (PLAB) 1 examination.Methods: Ninety-seven residents who completed the GM-ITE in fiscal year 2019 were recruited and took the PLAB 1 examination in Japanese. The association between two tests was assessed using the Pearson product-moment statistics. The discrimination indexes were also assessed for each question.Results: A total of 91 residents at 17 teaching hospitals were finally included in the analysis, of whom 69 (75.8%) were women and 59 (64.8%) were postgraduate second year residents. All the participants were affiliated with community hospitals. Positive correlations were demonstrated between the GM-ITE and the PLAB scores (r = 0.58, p < 0.001). The correlations between the PLAB score and the scores in GM-ITE categories were as follows: symptomatology/clinical reasoning (r = 0.54, p < 0.001), physical examination/procedure (r = 0.38, p < 0.001), medical interview/professionalism (r = 0.25, p < 0.001), and disease knowledge (r = 0.36, p < 0.001). The mean discrimination index of each question of the GM-ITE (mean ± SD; 0.23 ± 0.15) was higher than that of the PLAB (0.16 ± 0.16; p = 0.004).Conclusion: This study demonstrates incremental validity evidence of the GM-ITE to assess the clinical knowledge acquisition. The results indicate that GM-ITE can be widely used to improve resident education in Japan.Keywords: in-training examination, validity, extrapolation, General Medicine In-Training Examination, Professional and Linguistic Assessments Board, medical knowledge, postgraduate medical education

Akinori Tasaka,1 Takahiro Shimizu,1 Takeshi Hirabayashi,2 Shuichiro Yamashita1 1Department of Removable Partial Prosthodontics, Tokyo Dental College, Tokyo, Japan; 2Dental Laboratory of Suidobashi Hospital, Tokyo Dental College, Tokyo, JapanCorrespondence: Akinori TasakaDepartment of Removable Partial Prosthodontics, Tokyo Dental College, 2-9-18 Kandamisakicho Chiyoda-ku, Tokyo, 101-0061, JapanTel +81-3-6380-9167Fax +81-3-6380-9167Email atasaka@tdc.ac.jpAbstract: This clinical report describes a technique for fabricating a retrofit zirconia crown and clasp for an existing removable partial denture (RPD) using computer-aided design and computer-aided manufacturing (CAD/CAM). A 58-year-old patient developed acute pulpitis of a tooth, and the RPD clasp was broken on the tooth. A pre-preparation scan was captured using an intraoral scanner. The existing RPD was placed in the mouth, and scans of the post-preparation, antagonist arch, and interocclusal record were made. A zirconia crown was designed by superimposing the pre-preparation scan and the post-preparation scan of the abutment tooth. The design data were transferred to a 5-axis milling machine, and the crown was milled from zirconia. The crown was luted using resin cement. An intraoral scan of the crown with RPD was taken, and the RPD was removed to re-scan the proximal guide plane of the crown. The I-bar clasp was designed, and the casting pattern was built using a 3D printer. The pattern was used to cast the clasp. The clasp was set using autopolymerizing acrylic resin to the RPD. The main advantages of this efficient process are that patients can use their RPDs during fabrication of the crown of the abutment tooth. The limitations of using this technique include the cost of the intraoral scanner and the education for the dental clinicians and technicians. In this clinical report, CAD/CAM technology prevented human error, required no adjustment, and uninterrupted use of the RPD for fabricating a retrofit zirconia crown and clasp for an existing RPD.Keywords: removable partial denture, denture repair, CAD/CAM, zirconia crown, I bar clasp

Nobuyasu Ishii, Toshiki Shimizu, Yoshihisa Ishiura, Hideki Amuro, Tohru Nishizawa, Takeshi Tamaki, Shosaku Nomura First Department of Internal Medicine, Kansai Medical University, Moriguchi-City, Osaka, 570-8507, JapanCorrespondence: Toshiki ShimizuFirst Department of Internal Medicine, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi-City, Osaka, 570-8507, JapanTel + 81-6-6992-1001Fax + 81-6-6992-1066Email shimizto@takii.kmu.ac.jpBackground: Tocilizumab (TCZ) is humanized monoclonal antibody against the interleukin-6 (IL-6) and receptor that has prominent efficacy for the treatment of rheumatoid arthritis (RA). We conducted a retrospective observational study to determine how long TCZ controls RA.Patients and Methods: We retrospectively reviewed the medical records of RA patients treated with TCZ. The aim of this study was to evaluate the contribution of clinical parameters to disease control time (DCT) in RA patients.Results: Overall, 144 patients were enrolled in the study. The median age of patients was 66 years (range: 34– 85 years). In univariate analysis, DCT was significantly increased in patients who had never received previous biologic disease-modifying anti-rheumatic drugs treatment (P = 0.0064). We also analyzed the contribution of the base line value of C-reactive protein (CRP) to DCT. We divided the patients with RA into two groups according to a cutoff value of 1.000 mg/dl. The median control times were 77.5 months (95% confidence interval [CI]: 44.8–not reached to median) and 34.5 months (95% CI: 17.0– 79.3) for patients with high and low CRP value, respectively. In univariate analysis, DCT was significantly increased in patients with a high CRP value (P = 0.0283). Multivariate analysis clearly revealed that a high baseline CRP value was an independent favorable predictive factor for longer DCT (hazard ratio, 0.608, 95% CI: 0.378– 0.981, P = 0.0416).Conclusion: These data clearly demonstrate that the baseline value of CRP was closely associated with long time DCT in patients of RA treated with TCZ.Keywords: rheumatoid arthritis, tocilizumab, C-reactive protein, platelet large cell ratio, disease control time

Yoshihisa Ishiura,1,2 Masaki Fujimura,3 Noriyuki Ohkura,4 Johsuke Hara,4 Kazuo Kasahara,4 Nobuyasu Ishii,1 Yusuke Sawai,1 Toshiki Shimizu,1 Takeshi Tamaki,1 Shosaku Nomura1 1First Department of Internal Medicine, Kansai Medical University, Moriguchi, Osaka, Japan; 2Respiratory Medicine, Toyama City Hospital, Toyama, Japan; 3Respiratory Medicine, National Hospital Organization Nanao Hospital, Nanao, Japan; 4Respiratory Medicine, Kanazawa University Hospital, Kanazawa, JapanCorrespondence: Yoshihisa IshiuraFirst Department of Internal Medicine, Kansai Medical University, Kansai Medical University Medical Center, 10-15 Fumizono-Cho, Moriguchi, Osaka 570-8507, JapanTel +81-6-6992-1001Fax +81-6-6993-9837Email ishiura-@p2322.nsk.ne.jpPurpose: Asthma-chronic obstructive pulmonary disease overlap (ACO), characterized by airway limitation, is an important condition with high incidence and mortality. Although some guidelines recommend triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β2 agonists, this treatment approach is based on the extrapolation of data from studies of asthma or chronic obstructive pulmonary disease (COPD) alone.Methods: A 12-week, randomized, open-label cross-over pilot study was conducted in 19 patients with ACO to investigate the effect of triple therapy with glycopyrrolate (GLY) 50 μg/day on budesonide/formoterol fumarate (BUD/FORM) 640/18 μg/day. The study period included a 4-week wash-out, 4-week run-in, and 4-week treatment period. Respiratory function tests, fractional exhaled nitric oxide (FeNO), a COPD assessment test (CAT) and an asthma control questionnaire (ACQ) were carried out 0, 4, and 8 weeks after randomization.Results: A total of 19 patients with stable ACO (19 males and no females) with a mean age of 70.7 ± 7.6 years (± standard deviation, SD; range 55– 83 years) participated in this study. All patients were ex-smokers with a smoking history of 63.1 ± 41.1 pack-years (± SD). Mean values for inspiratory capacity (IC), an index of hyperinflation of the lung that causes exertional dyspnea and reduced exercise, were 1.93 L (± 0.47 L) after the run-in, 1.85 L (± 0.51 L) after the BUD/FORM dual therapy period and 2.11 L (± 0.58 L) after the BUD/GLY/FORM triple therapy period. IC values after the BUD/GLY/FORM triple therapy were significantly higher than those after the run-in (p < 0.02). FeNO values, ACQ, and CAT scores were not significantly different among the run-in, wash-out, and triple-therapy periods.Conclusion: The present pilot study showed that triple therapy with BUD/GLY/FORM results in an improvement in lung function parameters including IC, indicating the potential value of triple therapy as standard treatment for ACO.Keywords: asthma-COPD overlap, budesonide, glycopyrrolate, formoterol fumarate, triple therapy

Taro Shimizu Department of Diagnostic and Generalist Medicine, Dokkyo Medical University, Tochigi 321-0297, JapanCorrespondence: Taro ShimizuDepartment of Diagnostic and Generalist Medicine, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0297, JapanTel +81 80 3518 8884Email shimizutaro7@gmail.comAbstract: The ability to make a correct diagnosis is one of the physicians’ core competencies. In view of continuous medical education, the way to establish and maintain this expertise has been explored. Reflection has been reported to serve as an effective measure of remediating individual diagnostic skill. This article highlights three reflections which are reflection in action, reflection on action, and reflection for action, evidenced by past reports. Applying these reflections allows physicians to revisit the link between fundamental and interdisciplinary medical knowledge in conjunction with prior experience, thereby developing enhanced levels of diagnostic expertise and mastery.Keywords: reflection, diagnostic error, diagnostic reasoning, continuous medical education, applied expertise

Yuka Sugawara Kikuchi, Tetsuo ShimizuDepartment of Neuropsychiatry, Akita University Graduate School of Medicine, Akita 010-8543, JapanPurpose: The core features of dementia with Lewy bodies (DLB) are cognitive fluctuations, visual hallucinations, and parkinsonian symptoms. Although there have been several reports on the efficacy of treatments for psychotic symptoms in patients with DLB, little is known regarding the treatment effects of aripiprazole. The aim of this study was to evaluate the efficacy and safety of aripiprazole for the treatment of psychotic symptoms in patients with DLB.Patients and methods: We employed a 10-week, open-label study design with 11 patients who met the criteria for DLB. The patients had previously experienced persistent or intermittent delusions, hallucinations, or both for at least 1 month. Aripiprazole was initiated at a low dose (3 or 6 mg/day) and titrated to higher doses at 2-week intervals or more rapidly, as needed. The Neuropsychiatric Inventory (NPI), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression-Severity (CGI-S) were administered at baseline and 1, 2, 4, 8, and 10 weeks later. The Simpson–Angus Scale (SAS), Clinical Dementia Rating (CDR), and Mini-Mental State Examination (MMSE) Scale were evaluated at baseline and at week 10. The NPI, CGI-S, and BPRS scores were compared between the baseline and each assessment point and between each assessment point and the one before assessment point. The SAS, CDR, and MMSE scores were compared between the baseline and the end point.Results: The mean NPI and BPRS scores improved until the fourth week; they significantly decreased at each assessment point compared to the previous one. Afterward, improvements slowed and continued without significant decrease. The median SAS scores significantly decreased at the end point compared to the baseline (P

Masahiro Takeshima,1 Hiroyasu Ishikawa,2 Takashi Kanbayashi,1 Tetsuo Shimizu3 1Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita City, Akita 010-8543, Japan; 2Department of Neuropsychiatry, Nakadori Rehabilitation Hospital, Akita City, Akita 010-0001, Japan; 3Akita Prefectural Mental Health and Welfare Center, Akita City, Akita 010-0001, Japan Objective: Gabapentin and its prodrug are candidate therapeutic agents for akathisia. An open-label pilot study was conducted to investigate the therapeutic potential of gabapentin enacarbil (GE) for akathisia.Methods: In an open-labeled investigator-initiated clinical trial, nine outpatients with antipsychotics-induced akathisia were administered GE (300 or 600 mg/day) over 2 weeks. The BARS global akathisia score was used to assess akathisia. The BPRS was used to assess psychiatric symptoms. The subjects were also systematically questioned regarding the adverse events described in an interview form following GE treatment. An intension-to-treat analysis including all patients enrolled in the present study was completed.Results: One patient declined to participate further in the study on the third day after the start of treatment. Eight patients thus completed the entire trial (male: 2, female: 6, age [mean±SD]: 38.8±11.6 years). The average dosage of GE was 567 mg/day (300 mg/day [n=1], 600 mg/day [n=8]). The BARS global akathisia score significantly decreased after 1 and 2 weeks of treatment when compared to baseline (P=0.01 and P=0.01, respectively). There were no significant differences in BPRS score 1 or 2 weeks after the start of treatment. No serious adverse events occurred.Conclusion: GE has therapeutic potential for antipsychotics-induced akathisia. No additional risk of GE use for the management of akathisia was indicated. Keywords: clinical trial, antipsychotic agents, restless legs syndrome, schizophrenia

Shunta Hori, Tatsuki Miyamoto, Keiichi Sakamoto, Takuto Shimizu, Kazuki Ichikawa, Yosuke Morizawa, Daisuke Gotoh, Yasushi Nakai, Makito Miyake, Tatsuo Yoneda, Nobumichi Tanaka, Katsunori Yoshida, Kiyohide Fujimoto Department of Urology, Nara Medical University, Kashihara, Nara 634-8522, Japan Background: Transplant renal vein thrombosis (TRVT) is a severe vascular complication and is caused by various factors, including recipient factors, donor factors, immunosuppression regimens, and surgical techniques. Despite adequate interventions, including thrombolytic therapy or surgical thrombectomy, successful salvage of the allograft is often difficult. We observed a case of TRVT induced by compression of the renal vein immediately after intraoperative abdominal closure.Case presentation: A 41-year-old male underwent ABO-compatible living kidney transplantation. The donor was his 45-year-old sister, and her right kidney was donated. The allograft had a single artery and vein. One of the preoperative recipient problems was obesity (body mass index, 33.4 kg/m2). Intraoperative Doppler ultrasonography (US) revealed sufficient blood flow throughout the allograft, and urine output was also observed. After surgery, hematuria was observed; the urine output decreased and serum creatinine levels increased to 7.0 mg/dL. Doppler US showed a decrease in diastolic flow and an elevated resistive index, which were similar findings to those noted in acute rejection. Although steroid pulse therapy was initiated, allograft dysfunction was worsening. On postoperative day 4, surgical exploration revealed TRVT; consequently, thrombectomy was performed. The urine output increased, and serum creatinine levels decreased to 1.8 mg/dL. The cause of TRVT development may be that the transplant renal vein was relatively short, due to the right kidney being compressed by surrounding tissues after abdominal closure, and that TRVT was gradually developing due to stagnant blood flow.Conclusion: Although TRVT is induced by multiple factors, an accurate diagnosis is often difficult. Understanding these factors, including obesity, and considering TRVT as a cause of allograft dysfunction are important during the pre-, peri-, and postoperative periods. Knowledge of TRVT can lead to early and accurate diagnosis and intervention, resulting in better outcomes for the patients with allograft dysfunction. Keywords: kidney transplantation, surgical exploration, transplant renal vein thrombosis, thrombectomy

Tamás Mészáros,1,2,* Gergely Tibor Kozma,2,* Taro Shimizu,3 Koga Miyahara,3 Keren Turjeman,4 Tatsuhiro Ishida,3 Yechezkel Barenholz,4 Rudolf Urbanics,1,2 János Szebeni1,2,5 1Nanomedicine Research and Education Center, Department of Pathophysiology, Semmelweis University, Budapest, Hungary; 2SeroScience Ltd, Budapest, Hungary; 3Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan; 4Laboratory of Membrane and Liposome Research, Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel; 5Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, Hungary *These authors contributed equally to this work Background: It has been proposed that many hypersensitivity reactions to nanopharmaceuticals represent complement (C)-activation-related pseudoallergy (CARPA), and that pigs provide a sensitive animal model to study the phenomenon. However, a recent study suggested that pulmonary hypertension, the pivotal symptom of porcine CARPA, is not mediated by C in cases of polystyrene nanoparticle (PS-NP)-induced reactions.Goals: To characterize PS-NPs and reexamine the contribution of CARPA to their pulmonary reactivity in pigs.Study design: C activation by 200, 500, and 750 nm (diameter) PS-NPs and their opsonization were measured in human and pig sera, respectively, and correlated with hemodynamic effects of the same NPs in pigs in vivo.Methods: Physicochemical characterization of PS-NPs included size, ζ-potential, cryo-transmission electron microscopy, and hydrophobicity analyses. C activation in human serum was measured by ELISA and opsonization of PS-NPs in pig serum by Western blot and flow cytometry. Pulmonary vasoactivity of PS-NPs was quantified in the porcine CARPA model.Results: PS-NPs are monodisperse, highly hydrophobic spheres with strong negative surface charge. In human serum, they caused size-dependent, significant rises in C3a, Bb, and sC5b-9, but not C4d. Exposure to pig serum led within minutes to deposition of C5b-9 and opsonic iC3b on the NPs, and opsonic iC3b fragments (C3dg, C3d) also appeared in serum. PS-NPs caused major hemodynamic changes in pigs, primarily pulmonary hypertension, on the same time scale (minutes) as iC3b fragmentation and opsonization proceeded. There was significant correlation between C activation by different PS-NPs in human serum and pulmonary hypertension in pigs.Conclusion: PS-NPs have extreme surface properties with no relevance to clinically used nanomedicines. They can activate C via the alternative pathway, entailing instantaneous opsonization of NPs in pig serum. Therefore, rather than being solely C-independent reactivity, the mechanism of PS-NP-induced hypersensitivity in pigs may involve C activation. These data are consistent with the “double-hit” concept of nanoparticle-induced hypersensitivity reactions involving both CARPA and C-independent pseudoallergy. Keywords: adverse drug reactions, immunotoxicity, nanoparticles, pseudoallergy, anaphylatoxins, PIM cells, phagocytosis

Masahiro Takeshima,1 Tetsuo Shimizu,2 Masaru Echizenya,3 Hiroyasu Ishikawa,1,4 Takashi Kanbayashi1 1Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, Japan; 2Mental Health and Welfare Center, Akita, Japan; 3Echizenya Sleep and Mental Clinic, Akita, Japan; 4Department of Neuropsychiatry, Nakadori Rehabilitation Hospital, Akita, Japan Purpose: The efficacy of inpatient phase-advance therapy among patients with delayed sleep–wake phase disorder (DSWPD) has not been adequately investigated because response rates are considered low. We aimed to examine the efficacy of such treatment in this patient population.Patients and methods: The present retrospective study included data from 66 patients with DSWPD who had been admitted to Akita University Hospital for inpatient phase-advance therapy between September 1, 2005, and April 30, 2018. DSWPD was diagnosed based on the International Classification of Sleep Disorders, 3rd edition, criteria using electronic medical records. We examined remission rates during inpatient therapy as well as relapse rates at the time of the first outpatient examination following discharge. Univariate analysis was performed to investigate predictive factors for postinpatient therapy relapse.Results: The rate of DSWPD remission over the course of inpatient phase-advance therapy was 100% (95% CI: 95.6%–100%), with a median duration of 1 day (IQR: 1–2 days; range: 1–9 days) until remission. The rate of relapse following discharge was 45.8% (95% CI: 32.7%–59.2%). Univariate analysis indicated that the rate of relapse was significantly higher for minors (under 18) than adults (18 and over), for those whose age at onset was below 16 years than for those whose age at onset was 16 or above, and for those with relatively low motivation for their occupation (P=0.0339, P=0.0136, and P

Kenji Mizumura, Shuichiro Maruoka, Tetsuo Shimizu, Yasuhiro Gon Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan Abstract: COPD is characterized by persistent respiratory symptoms and airflow limitation, caused by a mixture of small airway disease and pulmonary emphysema. Programmed cell death has drawn the attention of COPD researchers because emphysema is thought to result from epithelial cell death caused by smoking. Although apoptosis has long been thought to be the sole form of programmed cell death, recent studies have reported the existence of a genetically programmed and regulated form of necrosis called necroptosis. Autophagy was also previously considered a form of programmed cell death, but this has been reconsidered. However, recent studies have revealed that autophagy can regulate programmed cell death, including apoptosis and necroptosis. It is also becoming clear that autophagy can selectively degrade specific proteins, organelles, and invading bacteria by a process termed “selective autophagy” and that this process is related to the pathogenesis of human diseases. In this review, we outline the most recent studies implicating autophagy, selective autophagy, and necroptosis in COPD. Strategies targeting these pathways may yield novel therapies for COPD. Keywords: ciliophagy, mitophagy, programmed cell death, pulmonary emphysema