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Yumi Kotoda,1 Sohei Hishiyama,2 Jaehoon Shim,3,4 Hiroki Kobayashi,2 Ayasa Takamino,2 Masako Abe,2 Kenji Kashiwagi,1 Takashi Matsukawa,2 Masakazu Kotoda2 1Department of Ophthalmology, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan; 2Department of Anesthesiology, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan; 3F.M. Kirby Neurobiology Center and Department of Neurology, Boston Children’s Hospital, Boston, MA, USA; 4Department of Neurobiology, Harvard Medical School, Boston, MA, USACorrespondence: Masakazu Kotoda, Department of Anesthesiology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, Japan, Tel +81-55-273-9690, Email mkotoda@yamanashi.ac.jpPurpose: Corneal pain is one of the most common eye symptoms caused by various types of epithelial injuries, including traumatic abrasion, chemical injury, ulcers, ultraviolet exposure, and infection. However, current therapeutic options for corneal pain are limited. In this study, we synthesized a novel quaternary ammonium compound, N-propylamiodarone bromide (NPA), and employed a rodent model of corneal injury to investigate whether NPA offers prolonged corneal analgesia through transient receptor potential vanilloid 1 (TRPV1) channel-mediated selective cellular entry, without hindering corneal epithelial recovery.Methods: In the corneal injury model, 24 adult Wistar rats received a topical application of normal saline, oxybuprocaine, or NPA (n = 8 each), and corneal pain sensitivity was assessed using the von Frey technique. Another set of 32 rats with intact corneas received oxybuprocaine, capsaicin (a TRPV1 agonist), or NPA with or without capsaicin (n = 8 each), followed by a mechanical sensitivity evaluation. Potential adverse effects on normal epithelial recovery were evaluated using fluorescence and hematoxylin–eosin staining in an additional 8 rats with corneal injury.Results: In the corneal injury model, NPA produced significantly longer-lasting analgesia than oxybuprocaine (duration of the maximum effect: 215 ± 11 vs 25 ± 2 min, P < 0.001). None of the animals presented any signs of eye irritability. In contrast to injured eyes, NPA alone did not significantly increase mechanical sensitivity in naïve eyes. However, the co-administration of NPA and capsaicin produced significantly longer-lasting corneal anesthesia than oxybuprocaine (duration of the maximum effect: 165 ± 15 vs 31 ± 2 min, P < 0.001). NPA did not hamper wound healing.Conclusion: The novel quaternary ammonium NPA produced long-lasting analgesia against corneal injury without hampering corneal recovery, suggesting that it is a potential candidate for analgesic medicine targeting corneal pain.Keywords: analgesics, capsaicin, corneal injury, pain, TRPV1 channel

Saori Kawamura,1,&ast; Fumihiro Yamaguchi,1,&ast; Rui Kusakado,1 Yoshihiro Go,1 Shiho Nohmi,1 Chinatsu Yoshizaki,1 Yuki Yoshida,1 Kensuke Izumizaki,1 Yuichiro Saito,1 Hitoshi Kobayashi,1 Kento Hirata,1 Kenta Miyo,1 Chika Kondo,1 Mamiko Kanzaki,1 Yize Ding,1 Takuya Yokoe,1 Sei Kobayashi,2 Hiroshi Suzuki3 1Department of Respiratory Medicine, Showa University Fujigaoka Hospital, Yokohama, Japan; 2Department of Otolaryngology, Showa University Fujigaoka Hospital, Yokohama, Japan; 3Department of Cardiovascular Medicine, Showa University Fujigaoka Hospital, Yokohama, Japan&ast;These authors contributed equally to this workCorrespondence: Saori Kawamura, Department of Respiratory Medicine, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama, 227-8501, Japan, Tel +81-45-971-1151, Email s.kashima@med.showa-u.ac.jpBackground: The emergence of the Omicron variant of severe acute respiratory syndrome coronavirus-2 has significantly altered the clinical features and severity of coronavirus disease 2019 (COVID-19).Objective: This study aims to evaluate whether the clinical factors that previously predicted COVID-19 remain valid following the emergence of the Omicron variant.Methods: This cross-sectional study was conducted at Showa University Fujigaoka Hospital from April 2022 to March 2023. A total of 576 patients with suspected COVID-19 were included, of which 258 (44.8%) were diagnosed with COVID-19 based on real-time reverse-transcription polymerase chain reaction tests. Clinical data were collected retrospectively, and multivariate logistic regression was used to analyze factors associated with a COVID-19 diagnosis.Results: Of the 258 patients diagnosed with COVID-19, 60% had mild disease, and the overall severity was lower than in previous reports prior to the emergence of the Omicron variant. In the multivariate analysis, only C-reactive protein (CRP) levels were significantly associated with COVID-19 (odds ratio, 0.3164; 95% confidence interval, 0.2077– 0.4819), while factors such as age, sex, body mass index, lactate dehydrogenase, and comorbidities were not significantly associated. Non-COVID-19 cases were primarily bacterial infections, accounting for 57.2% of the non-COVID-19 diagnoses. Mortality rates did not differ significantly between the COVID-19 and non-COVID-19 groups.Conclusion: The clinical characteristics of COVID-19 have become less distinct since the emergence of the Omicron variant, with CRP being the primary marker associated with a COVID-19 diagnosis. As COVID-19 continues to transition towards a more common infectious disease, distinguishing it will become increasingly challenging.Keywords: severe acute respiratory syndrome coronavirus-2, coronavirus disease 2019, Omicron variants, C-reactive protein

Hiroshi Kobayashi,1 Miho Sekiguchi,1 Koji Otani,1 Rei Ono,2 Takuya Nikaido,1 Kazuyuki Watanabe,1 Kinshi Kato,1 Yoshihiro Kobayashi,1 Shoji Yabuki,1 Shin-ichi Konno,1 Yoshihiro Matsumoto1 1Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan; 2Department of Physical Activity Research, National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Settsu, JapanCorrespondence: Hiroshi Kobayashi, Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Tokyo, 960-1295, Japan, Tel +8124-547-1276, Fax +8124-548-5505, Email hiroshik@fmu.ac.jpPurpose: Insomnia has been reported to coexist with various musculoskeletal disorders. Although lumbar spinal stenosis (LSS) is the most frequently operated on spinal disease, the causal relationship between LSS and development of sleep disorders remains unclear due to lack of longitudinal studies. This study aimed to determine whether LSS was a risk factor for developing new sleep disorders, primarily insomnia, using a prospective cohort of community residents.Patients and Methods: This study was a prospective cohort study. Participants aged ≥ 65 years from the “Locomotive Syndrome and Health Outcomes in Aizu Cohort Study (LOHAS)” conducted in 2008 formed our study population. LSS was diagnosed using the self-administered, self-reported history questionnaire, a validated diagnostic support tool for LSS. Sleep disorder was investigated using a questionnaire during the 2-year follow-up. The impact of LSS on sleep disorder onset was analyzed after adjusting for potential confounders, such as age, sex, obesity, hypertension, diabetes, depression, and smoking habits, using propensity score matching.Results: Of the 489 participants who were followed up for two years, 38 (7.8%) had newly developed a sleep disorder in 2010. After adjusting for confounding factors, a comparison of 133 participants each in the control and LSS groups showed significantly higher frequency of new-onset sleep disorders (19 [14.3%] in the LSS group versus 6 [4.5%] in the control group).Conclusion: LSS was found to be an independent risk factor for sleep disorders.Keywords: lumbar spinal stenosis, sleep disorder, insomnia, cohort study, musculoskeletal disorder, locomotive syndrome

Hiroshi Kobayashi, Koji Otani, Takuya Nikaido, Kazuyuki Watanabe, Kinshi Kato, Junichi Handa, Shoji Yabuki, Shin-Ichi Konno Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, JapanCorrespondence: Hiroshi Kobayashi 1-Hikarigaoka, Fukushima, 960-1295, JapanTel +8124-547-1276Fax +81 24-548-5505Email hiroshik@fmu.ac.jpPurpose: Early diagnosis of degenerative cervical spondylosis (DCM) is desirable because late treatment can lead to irreversible sequelae. No screening method has yet been established. Grip strength is commonly used in primary care settings to evaluate disease activity and diagnose sarcopenia. This single-center, cross-sectional study aimed to determine the diagnostic accuracy of grip strength for cervical myelopathy (DCM) and cutoff values for primary care DCM screening using area under the curve (AUC) and sensitivity values.Patients and Methods: The DCM group comprised 249 consecutive participants (165 males, 84 females; mean age, 65.1 years) with DCM who had undergone surgery at the affiliated hospital. The control group comprised 735 (280 males, 455 females; mean age, 65.8 years) participants undertaking a local government health checkup. Stratifying by age and sex, receiver operating characteristic (ROC) analyses were constructed for each group using minimum grip strength values for both hands. Based on ROC analysis, cut-off values were established so that the screening sensitivity would be 90% for either sex or age group, respectively.Results: According to age group and sex (males/females [M/F]), AUC values for a diagnosis of DCM in M/F were as follows: 40– 59 years, 0.92/0.87; 60– 69 years, 0.94/0.89; 70– 79 years, 0.89/0.91; and 80– 89 years, 0.97/0.97. Calculated M/F cutoff values were 41/24.5, 27/16, 27/15, and 20/10 kg, which were similar to cutoff scores for sarcopenia in M/F patients aged 60– 69 and 70– 79 years. M/F sensitivities in each age groups were 0.94/0.91, 0.92/0.90, 0.95/0.96, and 0.92/0.93. M/F specificities were 0.62/0.59, 0.84/0.83, 0.61/0.71, and 0.83/0.88.Conclusion: Grip strength had moderate-to-high diagnostic accuracy for DCM between participants in the control and DCM groups. We developed easily applicable cutoff values for primary care DCM screening with ≥ 90% sensitivity. In patients with sarcopenia, DCM should be differentially diagnosed in primary care.Keywords: degenerative cervical myelopathy, cervical spondylotic myelopathy, ossification of posterior longitudinal ligament, cervical disc herniation, primary care, early detection, sarcopenia

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

Tetsumasa Kamei,1 Hiroyuki Kobayashi,2,3 Maika Nishida,2 Kenzo Muramoto,2 Shohei Nishimoto2 1Shonan Fujisawa Tokushukai Hospital, Kanagawa, Japan; 2Eisai Co., Ltd., Medical Headquarters, Tokyo, Japan; 3Department of Neuropsychiatry, School of Medicine, Toho University, Tokyo, JapanCorrespondence: Shohei NishimotoEisai Co., Ltd., 4-6-10 Koishikawa, Bunkyo-ku, Tokyo, 112-8088, JapanTel +81-3-3817-3700Fax +81-3-5229-0705Email s-nishimoto@hhc.eisai.co.jpPurpose: Medication discontinuation for patients with Alzheimer’s dementia (AD) influences treatment efficacy. This study aimed to evaluate the effect of psychoeducational intervention (PI) on donepezil retention rates and identify the factors associated with donepezil continuation in patients with AD.Patients and Methods: One hundred and seventeen patients with AD were randomly allocated to the PI (n = 58) or standard care (SC; n = 59) groups. All patients were prescribed donepezil for 48 weeks. Primary endpoints were the 48-week donepezil retention rate and the reasons for donepezil discontinuation in the PI and SC groups. The secondary endpoint was the predictive factors, among the baseline clinical variables, for donepezil continuation in all patients.Results: The donepezil retention rate was 62.1% (36/58) in the PI group and 66.1% (39/59) in the SC group. The most common reason for discontinuation in both groups was adverse events (PI, 12.1%; SC, 10.2%). Logistic regression analysis revealed that the results of the pentagon copying test in the Mini-Mental State Examination administered at baseline was a significant predictor of donepezil continuation for all patients in both the groups (odds ratio: 0.359; 95% confidence interval: 0.154– 0.839).Conclusion: There was no significant difference between the PI and SC groups concerning donepezil retention rate in patients with AD. Our results demonstrate that the pentagon copying test can significantly predict donepezil continuation in patients with AD, indicating that impaired visuospatial and executive functions may reflect medication discontinuation.Trial Registration: UMIN-CTR:UMIN000012617.Keywords: adherence, cholinesterase inhibitors, medication discontinuation, Mini-Mental State Examination, pentagon copying task

Takashi Ohnishi,1 Akihide Wakamatsu,1 Hisanori Kobayashi2 1Medical Affairs Division, Janssen Pharmaceutical K.K., Tokyo, Japan; 2Research and Development Clinical Science Division, Janssen Pharmaceutical K.K., Tokyo, JapanCorrespondence: Takashi OhnishiMedical Affairs Division, Janssen Pharmaceutical K.K., 5-2, Nishi-kanda 3-chome Chiyoda-ku, Tokyo, 101-0065, JapanTel +81-3-4411-7700Fax +81-3-4411– 5031Email tohnish8@its.jnj.comPurpose: The aim of this study was to clarify whether early symptomatic improvement in response to a long-acting injectable antipsychotic (LAI) contributes to subsequent social functional remission in patients with schizophrenia using the previous clinical trial data (EudraCT registration number: 2011-004889-15). Associations between other factors and social functional remission were also explored.Patients and Methods: We analyzed 428 patients with schizophrenia in which the personal and social performance scale (PSP) and the involvement evaluation questionnaire (IEQ) at the time of the base line were recorded. Social functional remission was defined as participants who scored PSP > 70 at the end of 65 weeks. Logistic regression analyses were done to examine associations between social functional remission and clinical and demographic characteristics including early symptomatic response evaluated by Positive and Negative Syndrome Scale (PANSS) at week one.Results: One hundred out of 428 patients showed social functional remission at the end of the observation period. Shorter duration of illness, higher baseline score of supervision evaluated by IEQ and higher baseline PSP were significantly associated with the social functional remission. Improvement of positive subscale of PANSS at one week was significantly associated with later social functional remission when baseline PSP scores were excluded from predictive variables.Conclusion: Shorter duration of illness, residual type of schizophrenia, higher baseline score of supervision and higher baseline social functioning were predictors of subsequent social functional remission. Although its effect seems to be limited, early symptomatic improvement could be also was a predictor of social functional remission.Keywords: schizophrenia, social function, functional outcome, long-acting injectable antipsychotics; LAI

Tomoki Nakamura,1 Jun Sugaya,2 Norifumi Naka,3 Hiroshi Kobayashi,4 Tomotake Okuma,5 Toshiyuki Kunisada,6 Kunihiro Asanuma,1 Hedetatsu Outani,7 Shunji Nishimura,8 Hiroyuki Kawashima,9 Toru Akiyama,10 Taketoshi Yasuda,11 Shinji Miwa,12 Akihiro Sudo,1 Takafumi Ueda13 1Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu 514-8507, Japan; 2Department of Musculoskeletal Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo 104-0045, Japan; 3Musculoskeletal Oncology Service, Osaka International Cancer Institute, Chuo-ku, Osaka 541-8567, Japan; 4Department of Orthopaedic Surgery, The University of Tokyo Hospital, Bunkyo-ku, Tokyo 113-8655, Japan; 5Department of Musculoskeletal Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Bunkyo-ku, Tokyo 113-8677, Japan; 6Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan; 7Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; 8Department of Orthopaedic Surgery, Kindai University Hospital, Osaka-Sayama, Osaka 589-8511, Japan; 9Division of Orthopaedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata 951-8510, Japan; 10Department of Orthopaedic Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8503, Japan; 11Department of Orthopaedic Surgery, University of Toyama, Toyama 930-0194, Japan; 12Department of Orthopaedic Surgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Japan; 13Department of Orthopaedic Surgery, Osaka National Hospital, Chuo-ku, Osaka 540-0006, JapanCorrespondence: Tomoki NakamuraDepartment of Orthopedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, JapanTel +81-592315022Fax +81-592315211Email tomoki66@clin.medic.mie-u.ac.jpBackground: The outcomes of unplanned surgery for bone sarcomas have not been frequently discussed. However, it is important to recognize patterns, treatment, and clinical outcomes of unplanned surgeries for patients with bone sarcomas. This multicenter study aimed to characterize the clinical outcomes of patients with bone sarcomas who underwent unplanned surgeries.Patients and Methods: Data of 43 patients with bone sarcomas who underwent unplanned surgery between 2006 and 2017 were obtained from 23 hospitals in Japan. These included 18 cases of osteosarcoma, 9 of Ewing sarcoma, 8 of chondrosarcoma, and 6 of undifferentiated pleomorphic sarcoma. The study included 28 men and 15 women, with a mean age of 46 years. The mean follow-up duration was 59 months.Results: The main primary tumor sites were the femur (n = 19), spine (n = 6), pelvis (n = 5), tibia (n = 3), and humerus (n = 3). The primary diagnoses were benign bone tumor (n = 24), trauma (n = 7), bone metastasis (n = 5), osteomyelitis (n = 4), degeneration (n=2), and unknown (n = 1). As unplanned surgeries, curettage, with or without bone graft, was performed in 26 patients; internal fixation was performed in 7; spinal surgery in 5; arthroplasty in 4; and arthroscopy in one. Thirty-eight patients received additional standard treatments. Thirty-four of these patients underwent surgical tumor resections, including amputation (n = 10), and the remaining 4 received radiotherapy or carbon ion radiotherapy as additional standard treatments. The 5-year disease-specific survival (DSS) rates in patients with osteosarcoma, Ewing sarcoma, and chondrosarcoma were 65.5%, 58.3%, and 72.9%, respectively. Twelve (27.9%) patients developed local recurrences (LR); among the total 43 patients studied, the 5-year DSS rates were significantly worse for those who developed LR compared to those who did not (p = 0.03). The 5-year DSS rates in patients with and without LR were 44% and 73.8%, respectively.Conclusion: We recommend that patients who have undergone unplanned surgery be administered standard treatment, including the option of amputation because herein, LR was shown to be a risk factor for decreased DSS.Keywords: bone sarcoma, unplanned surgery, local recurrence, osteosarcoma, Ewing sarcoma, chondrosarcoma

Koichiro Takahashi,1 Masaru Uchida,2 Go Kato,3 Ayako Takamori,4 Takashi Kinoshita,5 Makoto Yoshida,6 Ryo Tajiri,4 Keisuke Kojima,7 Hiroshi Inoue,8 Hiromi Kobayashi,9 Hironori Sadamatsu,1 Hiroki Tashiro,1 Masahide Tanaka,1 Shinichiro Hayashi,10 Atsushi Kawaguchi,4,11 Shinya Kimura,1 Naoko Sueoka-Aragane,1 Tomotaka Kawayama5 Saga-naïve COPD Physical Activity Evaluation (SCOPE) Study Investigator Group1Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan; 2Division of Internal Medicine, Japan Community Health Care Organization Saga Central Hospital, Saga, Japan; 3Division of Respiratory Medicine, Saga Prefectural Medical Center Koseikan, Saga, Japan; 4Clinical Research Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga, Japan; 5Division of Respirology, Neurology, and Rheumatology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan; 6Division of Respiratory Medicine, National Hospital Organization Fukuoka Hospital, Fukuoka, Japan; 7Division of Internal Medicine, Imari Arita Kyouritsu Hospital, Saga, Japan; 8Division of Internal Medicine, Karatsu Red Cross Hospital, Saga, Japan; 9Division of Respiratory Medicine, National Hospital Organization East Saga Hospital, Saga, Japan; 10Division of Internal Medicine, Kouhoukai Takagi Hospital, Fukuoka, Japan; 11Education and Research Center for Community Medicine, Faculty of Medicine, Saga University, Saga, JapanCorrespondence: Koichiro TakahashiDivision of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, JapanEmail takahak@cc.saga-u.ac.jpBackground: Comparative effects on physical activity of mono and dual bronchodilators remain unclear in patients with treatment-naïve chronic obstructive pulmonary disease (COPD). We sought to compare the changes in physical activity before and after tiotropium and tiotropium/olodaterol treatment in treatment-naïve COPD patients.Methods: A prospective, multicenter, randomized, open-labeled, and parallel interventional study was conducted. Eighty Japanese patients with treatment-naïve COPD were randomized to receive either tiotropium or tiotropium/olodaterol treatment for 12 weeks. Spirometry and dyspnea index were assessed, and COPD assessment test (CAT) and the 6-minute walk distance (6MWD) were conducted before and after treatment. Evaluation of physical activity was assessed by a triaxle accelerometer over a 2-week period before and after treatment.Results: There were no differences in the mean age (69.8 vs 70.4 years), body mass index (BMI) (22.5 vs 22.6 kg/m2) and mean % forced expiratory volume in 1 second (%FEV1) at baseline (61.5 vs 62.6%) between the two groups. Changes in FEV1 (mean±standard error, 242.8± 28.8 mL) and transient dyspnea index (TDI) (2.4± 0.3 points) before and after tiotropium/olodaterol treatment were greater than with tiotropium treatment (104.1± 31.9 mL, p< 0.01 and 1.5± 0.3, p=0.02, respectively). Changes in the duration of physical activity with 1.0– 1.5 metabolic equivalents (METs) estimated in the sedentary position following tiotropium/olodaterol treatment (− 38.7± 14.7 min) tended to be reduced more than with tiotropium treatment (− 4.6± 10.6 min) (p=0.06), although those with ≥ 2.0 METs numerically increased with both treatments (+10.8± 7.6 min for tiotropium/olodaterol vs +8.3± 7.6 min for tiotropium, p=0.82). Tiotropium/olodaterol treatment reduced the duration of physical activity with 1.0– 1.5 METs (regression coefficient, − 43.6 [95% CI − 84.1, − 3.1], p=0.04) in a multiple regression model adjusted for cofounding factors such as age, FEV1, total CAT scores, 6MWD, and TDI.Conclusion: This is the first study to report the impact of dual bronchodilator on physical activity in treatment-naïve COPD patients of Japanese with low BMI.Keywords: chronic obstructive pulmonary disease, physical activity, long-acting muscarinic antagonist, long-acting beta 2 agonist

Yuta Takano,1 Hiroto Kobayashi,2 Takuma Yuri,1 Saori Yoshida,2 Akira Naito,2 Yoshiro Kiyoshige1 1Graduate School of Health Science, Yamagata Prefectural University of Health Science, Yamagata, Japan; 2Department of Anatomy, Yamagata University Faculty of Medicine, Yamagata, Japan Purpose: Fat infiltration (FI) in the gluteus minimus muscle (GMin) has been reported as being restricted to the anterior part. The aim of this study was to verify whether FI is localized only to the anterior part of the GMin through the dissection of large number of elderly cadavers and to clarify the underlying mechanism of FI localized to a specific region. Materials and methods: Thirty-eight hips from 20 embalmed elder cadavers were dissected for verification of FI localization. The samples of three regions – the fat infiltrated region of the anterior part (FI), the region without FI (non-FI), and the posterior region – were harvested from nine hips for the histological fiber type assessment. Results: The FI area was distributed at 2.6°–38° from the anterior border within the anterior part, of which function is responsible for hip extension and internal rotation and is likely reduced by disuse following aging. The number of type I fibers was lowest in FI, followed by non-FI, while the number of type I fibers was highest in the posterior. Meanwhile, the number of type II fibers was equivalent across the three regions. Atrophic type II fibers were observed in overall samples of the three regions, and grouped atrophy, which is evidence of denervation, was observed in FI and non-FI samples. Type grouping, which suggests to be reinnervated, was found in the non-FI and posterior samples but very little in the FI samples. Conclusion: FI in the GMin in older adults restricted to deep within the anterior part is secondary to disuse and is strongly related to impaired denervation–reinnervation process. Keywords: gluteus minimus, fat infiltration, disuse, denervation, fiber type

Keisuke Ueda,1,2 Hiroyuki Sasai,3 Takehiko Tsujimoto,4 Chiaki Sanbongi,1 Shuji Ikegami,1 Hiroyuki Kobayashi,5 Nobuhiko Shioya,6 Satoru Suzuki,7 Yoshio Nakata5 1Food Science and Technology Research Laboratories, Meiji Co., Ltd, Hachiouji, 2Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, 3Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, 4Faculty of Human Sciences, Shimane University, Matsue, 5Faculty of Medicine, University of Tsukuba, Tsukuba, 6KSO Corporation, Tokyo, 7Shinagawa Season Terrace Health Care Clinic, Tokyo, Japan Purpose: The purpose of this study was to test the efficacy of arginine, alanine, and phenylalanine mixture (A-mix) ingestion at 1,500 mg/day in combination with the promotion of physical activity for abdominal fat reduction in overweight adults.Methods: A placebo-controlled, double-blind, parallel-group, randomized trial for 12 weeks combined with a 4-week follow-up period was conducted at a single center in Minato-ku, Tokyo, Japan, between December 2016 and May 2017. Data were analyzed between June and August 2017. The study participants were 200 overweight adults within the age range of 20–64 years. The participants were randomly assigned to the A-mix group (n=100) or a placebo group (n=100) and were administered 500 mL of test beverage containing 1,500 or 0 mg of A-mix, respectively, for 12 weeks. All participants maintained a physically active lifestyle between week 0 and week 12 through monthly sessions of physical activity. The primary outcomes were the 12-week changes in the abdominal total, subcutaneous, and visceral fat areas, as assessed by computed tomography.Results: Of the 200 enrolled participants, 199 (99%) accomplished the 12-week intervention and 4-week follow-up period. The per-protocol-based analysis for 194 participants demonstrated that the abdominal total fat area decreased significantly in the A-mix group compared with that in the placebo group (difference, 10.0 cm2; 95% confidence interval [CI]: 0.4–19.6 cm2; P=0.041). Comparable outcomes were obtained for the abdominal subcutaneous fat area (difference, 7.4 cm2; 95% CI: 0.1–14.7 cm2; P=0.047). No study-related unfavorable events occurred.Conclusion: A-mix supplementation in combination with physical activity promotion facilitated abdominal fat reduction in overweight adults. Keywords: amino acid supplementation, physical activity promotion, abdominal fat, randomized controlled trial

Hiroyuki Sasai,1–3,* Keisuke Ueda,4,5,* Takehiko Tsujimoto,6,7 Hiroyuki Kobayashi,1 Chiaki Sanbongi,4 Shuji Ikegami,4 Yoshio Nakata1 1Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 2Japan Society for the Promotion of Science, Chiyoda, Tokyo, 3Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Meguro, Tokyo, 4Food Science Research Laboratories, Meiji Co., Ltd., Odawara, Kanagawa, 5Graduate School of Comprehensive Human Sciences, 6Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Ibaraki, 7Faculty of Human Sciences, Shimane University, Matsue, Shimane, Japan *These authors contributed equally to this work Objective: The objective of this study was to determine the effective dose of an amino acid mixture comprising arginine, alanine, and phenylalanine combined with physical activity promotion in reducing abdominal fat among overweight adults.Methods: A 12-week randomized, double-blind, placebo-controlled, dose-ranging, pilot trial was conducted in Mito, Japan, from January through April 2016, and the data were analyzed from May through November 2016. The study participants were 35 overweight adults, aged 20–64 years, with no regular exercise habit. Participants were randomly assigned to high-dose (3,000 mg/d, n=9), medium-dose (1,500 mg/d, n=9), low-dose (750 mg/d, n=8), or placebo (0 mg/d, n=9) groups, and the test beverage containing the amino acid mixture or placebo was administered for 12 weeks. All participants maintained a physically active lifestyle during the study period through monthly physical activity promotion sessions and smartphone-based self-monitoring with wearable trackers. Primary outcomes were changes in abdominal total, subcutaneous, and visceral fat areas, assessed by computed tomography.Results: Of the 35 enrolled participants, 32 completed the 12-week follow-up visit. The intention-to-treat analysis revealed that the changes in abdominal total fat area were −14.6 cm2 (95% confidence interval [CI], −39.6 cm2 to 10.4 cm2), −25.3 cm2 (95% CI, −71.0 cm2 to 20.3 cm2), −23.2 cm2 (95% CI, −48.0 cm2 to 1.6 cm2), and −12.5 cm2 (95% CI, −29.1 cm2 to 4.0 cm2) in the high-dose, medium-dose, low-dose, and placebo groups, respectively. Similar results were obtained for visceral and subcutaneous fat areas. No study-related adverse events were reported.Conclusion: Compared with placebo, a medium or low dose of the amino acid mixture may facilitate abdominal fat reduction among overweight adults. A larger randomized trial with sufficient statistical power should be implemented to validate the effectiveness of this supplement. Keywords: amino acid mixture, dose–response relationship, physical activity promotion, abdominal fat

Ryoko Nakagawa,1 Takashi Ohnishi,1 Hisanori Kobayashi,1 Toshio Yamaoka,2 Tsutomu Yajima,3 Ai Tanimura,4 Toshiya Kato,4 Kazutake Yoshizawa1 1Evidence Generation Department, Medical Affairs Division, 2Clinical Data Management Department, R&D Division, 3Biostatistics Department, Quantitative Science Division, 4Drug Surveillance Department, R&D Division, Janssen Pharmaceutical K.K., Tokyo, Japan Background: Long-term maintenance of cognitive function is an important goal of treatment for Alzheimer’s disease (AD), but evidence about the long-term efficacy of cholinesterase inhibitors is sparse. To evaluate the long-term efficacy and safety of galantamine for AD in routine clinical practice, we conducted a 72-week post-marketing surveillance study. The effect of galantamine on cognitive function was estimated in comparison with a simulated disease trajectory. Patients and methods: Patients with mild-to-moderate AD received flexible dosing of galantamine (16–24 mg/day) during this study. Cognitive function was assessed by the mini mental state examination (MMSE) and the clinical status was determined by the Clinical Global Impression-Improvement (CGI-I). Changes of the MMSE score without treatment were estimated in each patient using Mendiondo’s model. Generalized linear mixed model analysis was performed to compare the simulated MMSE scores with the actual scores. Results: Of the 661 patients who were enrolled, 642 were evaluable for safety and 554 were assessed for efficacy. The discontinuation rate was 46.73%. Cognitive decline indicated by the mean change of actual MMSE scores was significantly smaller than the simulated decline. Individual analysis demonstrated that >70% of patients had better actual MMSE scores than their simulated scores. Significant improvement of CGI-I was also observed during the observation period. Adverse events occurred in 28.5% of patients and were serious in 8.41%. The reported events generally corresponded with the safety profile of galantamine in previous studies. Conclusion: These findings support the long-term efficacy of galantamine for maintaining cognitive function and the clinical state in AD patients. Treatment with galantamine was generally safe. Importantly, this study revealed that galantamine improved cognitive function above the predicted level in >70% of the patients. Keywords: Alzheimer’s disease, cholinesterase inhibitor, cognitive function, disease progression, real-world evidence

Ryoko Nakagawa,1 Takashi Ohnishi,1 Hisanori Kobayashi,1 Akihide Wakamatsu,2 Ai Tanimura,3 Kazuo Morita,3 Toshio Yamaoka,3 Hideo Usui,3 Yoshimasa Ogawa,3 Akiko Fujino,3 Kazutake Yoshizawa11Evidence Generation Department, Medical Affairs Division, 2Medical Affairs Strategy Department, Medical Affairs Division, 3Drug Safety Surveillance Department, Japan Safety and Surveillance Division, Janssen Pharmaceutical K.K., Tokyo, JapanBackground: Social functioning is an important outcome for patients with schizophrenia. To evaluate the effects of paliperidone extended-release (PAL-ER) on social function, symptomatology, and safety in the routine clinical practice, we conducted a 1-year post-marketing surveillance study of PAL-ER. We also explored relationships between symptomatic improvement and socially functional outcome in patients with schizophrenia.Patients and methods: Patients with an established diagnosis of schizophrenia were allowed flexible 3–12 mg/day dosing during the surveillance. Patients were assessed on social functioning using the Social and Occupational Functioning Assessment Scale (SOFAS) and on symptomatology using the Clinical Global Impression–Schizophrenia scale. All adverse events (AEs) were also collected.Results: A total of 1,429 patients were enrolled in the surveillance study, of whom 1,405 were evaluable for safety and 1,142 were evaluable for efficacy. The treatment discontinuation rate for any reason during the observation period was 34.66%. Significant improvements were observed on both Social and Occupational Functioning Assessment Scale and Clinical Global Impression–Schizophrenia scale during the observation period. The percentage of patients with socially functional remission (SOFAS ≥61) also increased significantly. A significant association between early improvements in positive symptoms, sex, severity of negative symptoms at baseline, and socially functional remission was observed. A total of 33.52% of patients had AEs and 8.75% of patients had serious AEs. Despite the recommendation of monotherapy with PAL-ER, 65.84% of patients were given additional antipsychotics (polypharmacy). Post hoc comparisons of monotherapy versus polypharmacy revealed that the monotherapy group had better outcomes and fewer AEs than the polypharmacy treated group. The improvement in social functioning and the rate of socially functional remission did not differ between groups.Conclusion: PAL-ER treatment showed effective symptom control and improvement in social functioning. The data suggest that early response to antipsychotic treatment should be important for functional outcomes.Keywords: paliperidone, social function, schizophrenia, naturalistic study

The HEK 293 cell line (293 cells) was derived from human embryonic kidney (HEK) cells grown in tissue culture. 293 cells are very easy to grow and transfect and have been widely used in cell biological research for many years. 293 cells have many of the properties of immature neurons, suggesting that they represent a transformed neuronal cell present in the original kidney culture, and they are not useful as an in vitro model for kidney cell function. The 293T cell line contains the SV40 large T-antigen, which allows the episomal replication of transfected plasmids containing the SV40 origin of replication, and 293FT cells are a fast-growing variant. A recent report showed that introducing a set of transcription factors associated with pluripotency into human somatic cells can directly reprogram them to produce induced pluripotent stem (iPS) cells. To date, however, iPS cells have not been generated from immortalized cells. We examined whether iPS cells could be generated from 293 FT cells transfected with four transcription factors (OCT4, SOX2, NANOG, and LIN28). The obtained cells morphologically resembled human ES cells, and showed a similar marker gene expression pattern. These cells had an impaired ability to differentiate, and formed immature ectodermal tumors after they were transplanted into nude mice. Thus, we could not derive fully reprogrammed iPS cells from 293FT cells. We conclude that the 293FT cells transduced with OCT4, SOX2, NANOG, and LIN28 produced aberrant ES-like cells.

The indentation properties of pure aluminum (99.9%, 3N aluminum) and high purity aluminum (99.999%, 5N aluminum) with respect to the strain rate dependence of strength are experimentally investigated in order to clarify the effect of strain rate on the micro-indentation test. A micro-indentation test using a Berkovich indenter was performed at loading rates of 0.7, 7, and 70 mN/s. In all of the specimens, the indenter was loaded to a maximum value of 1200 mN, and then was maintained for 30 s. In the 3N specimen, the dependence of the loading rate on the load was slight at loading rates of 0.7 and 7 mN/s, whereas the load at the loading rate of 70 mN/s was higher than the loads at loading rates of 0.7 and 7 mN/s. On the other hand, the load for the 5N specimen increased with the increasing loading rate. Thus, the effect of the loading rate on the load-displacement curve for the 3N and 5N specimens was similar to the strain rate dependence of strength for theses metals. In addition, the micro-indentation test was demonstrated to be strongly affected by high strain rate at a loading rate of 70 mN/s.

In this study, at first, the effect of strain rate on the strength and the absorbed energy of polyimide foam was experimentally examined by carrying out a series of compression tests at various strain rates, from 10−3 to 103 s−1. This polyimide foam has open cell structure with small cell size of 0.3 ∼ 0.6 mm. In the measurement of impact load, a special load cell with a small part for sensing load was adopted. For the measurement of the displacement, a high-speed camera was used. It was found that the flow stress of polyimide foam and the absorbed energy up to a strain of 0.4 increased with the increase of the strain rates. Secondly, the effect of ambient temperature on the strength and absorbed energy of polyimide foam was also investigated by using a sprit Hopkinson pressure bar apparatus and testing at elevated temperatures of 100 and 200 ∘C. With the increase of temperature, the strength and absorbed energy decreased and the effect is smaller in dynamic tests than static tests.

Large datasets of greenhouse gas and energy surface-atmosphere fluxes measured with the eddy-covariance technique (e.g., FLUXNET2015, AmeriFlux BASE) are widely used to benchmark models and remote-sensing products. This study addresses one of the major challenges facing model-data integration: To what spatial extent do flux measurements taken at individual eddy-covariance sites reflect model- or satellite-based grid cells? We evaluate flux footprints—the temporally dynamic source areas that contribute to measured fluxes—and the representativeness of these footprints for target areas (e.g., within 250–3000 m radii around flux towers) that are often used in flux-data synthesis and modeling studies. We examine the land-cover composition and vegetation characteristics, represented here by the Enhanced Vegetation Index (EVI), in the flux footprints and target areas across 214 AmeriFlux sites, and evaluate potential biases as a consequence of the footprint-to-target-area mismatch. Monthly 80% footprint climatologies vary across sites and through time ranging four orders of magnitude from 103 to 107 m2 due to the measurement heights, underlying vegetation- and ground-surface characteristics, wind directions, and turbulent state of the atmosphere. Few eddy-covariance sites are located in a truly homogeneous landscape. Thus, the common model-data integration approaches that use a fixed-extent target area across sites introduce biases on the order of 4%–20% for EVI and 6%–20% for the dominant land cover percentage. These biases are site-specific functions of measurement heights, target area extents, and land-surface characteristics. We advocate that flux datasets need to be used with footprint awareness, especially in research and applications that benchmark against models and data products with explicit spatial information. We propose a simple representativeness index based on our evaluations that can be used as a guide to identify site-periods suitable for specific applications and to provide general guidance for data use.