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Stabilisation splint therapy has long been thought to be effective for the management of temporomandibular disorders (TMD). However, the superiority of stabilisation splint therapy compared to other TMD treatments remains controversial. The aim of this study was to determine the efficacy of stabilisation splint therapy combined with non-splint multimodal therapy for TMD. A total of 181 TMD participants were randomly allocated to a non-splint multimodal therapy (NS) group (n = 85) or a nonsplint multimodal therapy plus stabilisation splint (NS+S) group (n = 96). Non-splint multimodal therapy included self-exercise of the jaw, cognitive--behavioural therapy, self-management education and additional jaw manipulation. Three outcome measurements were used to assess treatment efficacy: mouth-opening limitation, oro-facial pain and temporomandibular joint sounds. A two-factor repeated-measures analysis of variance (ANOVA) was used to evaluate the efficacy of the two treatment modalities (NS vs. NS+S), and Scheffe's multiple comparison test was used to compare the treatment periods. Subgroup analyses were performed to disclose the splint effects for each TMD diagnostic group. All three parameters significantly decreased over time in both groups. However, there were no significant differences between the two treatment groups in the total comparison or subgroup analyses; an exception was the group with degenerative joint disease. No significant difference between the NS and NS+S treatment approaches was revealed in this study. Therefore, we conclude that the additional effects of stabilisation splint are not supported for patients with TMD during the application of multimodal therapy. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to evaluate the age-based enrolment of cancer patients into registration trials of new drug applications or expanding the indications for use.Materials and methods: The data from 234 registration trials in Japan and overseas of 43 drugs, which were reviewed by the Pharmaceuticals and Medical Devices Agency and approved by the Ministry of Health, Labour and Welfare in Japan between 1999 and 2008, were retrospectively analyzed according to the age distribution of enrolled patients. The age distribution of the Japanese cancer population was derived from Cancer Statistics in Japan 2003 and Annual Report on Health, Labour and Welfare 2003–2004.Results: In the Japanese cancer population, the estimated median age of cancer patients is 70 years, and 66% of cancer patients are aged 65 years or more. The estimated median age of cancer patients in all registration trials conducted in Japan was 59 years, whereas it was 55 years in the registration trials conducted overseas. The proportion of patients aged 65 years or more enrolled in registration trials conducted in Japan was 35%; this number was 28% in registration trials conducted overseas.Conclusion: Elderly patients are underrepresented in oncology registration trials in Japan. [ABSTRACT FROM AUTHOR]

UCHL1 plays an important role in the ubiquitin-proteasome system and is a biologically plausible candidate gene for Parkinson's disease (PD). However, results from genetic association studies of the UCHL1 S18Y polymorphism have been equivocal. Meta-analyses indicate that the polymorphism's risk effect might be restricted to Asian populations and early-onset disease. To further explore the role of UCHL1 in PD, we genotyped S18Y in 605 PD patients and 1620 controls of Japanese ancestry. We did not find evidence of an association in the overall sample (SY vs. SS: adjusted OR=1.11, P=0.37; YY vs. SS: adjusted OR=1.01, P=0.94). In the early-onset stratum, however, we observed a trend toward a reduction in risk for those with the Y allele (SY vs. SS, adjusted OR, 0.75; 95% CI, 0.47-1.20; YY vs. SS, OR, 0.64; 95% CI, 0.36-1.14; trend test, P=0.12). These results indicate that, if involved in PD, the S18Y variant is not a major determinant of risk and its effect might be restricted to early-onset disease. [ABSTRACT FROM AUTHOR]

Introduction/aims: The common presentations of statin intolerance are muscle-specific symptoms. Although statins are one type of drug reported to cause myasthenic worsening, myasthenic worsening has not been recognized as statin intolerance. The purpose of the present study is to investigate in a large cohort the safety profiles of statins in patients with myasthenia gravis (MG)., Methods: A total of 1710 consecutive patients with MG who visited sites associated with the Japan MG registry 2021 group between April and October 2021 were reviewed. Statin-associated myasthenic worsening was defined as worsening of any myasthenic symptoms on statin use and improvement of the symptom by stopping the statin or by undertaking additional treatment with patient and doctor confirmation., Results: Among the 400 patients who used statins, 8 (2%) patients experienced statin intolerance and 6 (1.5%) patients experienced myasthenic worsening. No patients developed MG on the statin. Ptosis was a main symptom of myasthenic worsening in 4 (67%) patients. Atorvastatin was used in all patients with statin-associated myasthenic worsening. The symptoms of statin intolerance and statin-associated myasthenic worsening were improved within 2 months and 3 months, respectively, in all patients by cessation of statin use., Discussion: Regarding statin-associated myasthenic worsening, prevalence was low, and severity was mild; with cessation of statin use, symptoms improved within a few months, and outcomes were generally good. Although statins can be used in MG patients with little concern, statin-associated myasthenic worsening should be noted in addition to the classical statin intolerance associated with statin use., Competing Interests: Declaration of competing interest T. Sugimoto declares no potential conflicts of interest related to this article. S. Suzuki received speakers' fees from Alexion Pharmaceuticals, the Japan Blood Products Organization, Asahi Kasei Medical, and Argenx and participated in advisory board meetings of Alexion Pharmaceuticals and Argenx. A. Uzawa has received honoraria from Alexion Pharmaceuticals and Argenx. T. Yamawaki declares no potential conflicts of interest related to this article. M, Masuda declares no potential conflicts of interest related to this article. N. Minami declares no potential conflicts of interest related to this article. N. Kawaguchi declare no financial or other conflicts of interest. T. Kubota reports honoraria for lectures from Alexon Pharmaceuticals. M. P. Takahashi reports unrestricted research grants from Japan Blood Products Organization, Astellas Pharma, Mitsubishi Tanabe Pharma and Pfizer, outside the submitted work, and has served as a paid Consultant for Alexion, Argenx, Sanofi, and UCB Pharma and received honoraria for lectures from Argenx, Alexion Pharmaceuticals and UCB Pharma. Y. Suzuki declares no potential conflicts of interest related to this article. G Watanabe declares no potential conflicts of interest related to this article. S. Konno declares no potential conflicts of interest related to this article. T. Kimura declares no potential conflicts of interest related to this article. M. Samukawa declares no potential conflicts of interest related to this article. K. Ishizuchi declares no potential conflicts of interest related to this article. H. Akamine declares no potential conflicts of interest related to this article. Y. Onishi declares no potential conflicts of interest related to this article. M. Yasuda declares no potential conflicts of interest related to this article. Y. Nagane has received honoraria from Alexion Pharmaceuticals, Argenx, the Japan Blood Products Organization, and UCB Pharma. H. Maruyama declares no potential conflicts of interest related to this article. H. Murai has served as a paid consultant for UCB Pharma, Argenx, Janssen Pharma, Viela Bio, Chugai Pharma, Hanall BioPharma, and Mitsubishi Tanabe Pharma, and has received speaker honoraria from Argenx, Alexion Pharmaceuticals, and the Japan Blood Products Organization. K. Utsugisawa has served as a paid consultant for UCB Pharma, Argenx, Janssen Pharma, Viela Bio, Chugai Pharma, Hanall BioPharma, Merck and Mitsubishi Tanabe Pharma, and has received speaker honoraria from Argenx, Alexion Pharmaceuticals, UCB Pharma and the Japan Blood Products Organization., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: This study aimed to clarify surgical complications associated with open surgery for congenital diaphragmatic hernia (CDH)., Methods: We performed an exploratory data analysis of the clinical characteristics of surgical complications of neonates with CDH who underwent laparotomy or thoracotomy between 2006 and 2021. Data of these patients were obtained from the database of the Japanese CDH Study Group., Results: Among 1,111 neonates with left or right CDH, 852 underwent open surgery (laparotomy or thoracotomy). Of these 852 neonates, 51 had the following surgical complications: organ injury (n = 48; 6% of open surgeries); circulatory failure caused by changes in the organ location (n = 2); and skin burns (n = 1). Injured organs included the spleen (n = 30; 62% of organ injuries), liver (n = 7), lungs (n = 4), intestine (n = 4), adrenal gland (n = 2), and thoracic wall (n = 2). Fourteen of the patients who experienced organ injury required a blood transfusion (2% of open surgeries). The adjusted odds ratio of splenic injury for patients with non-direct closure of the diaphragm was 2.2 (95% confidence interval, 1.1-4.9)., Conclusion: Of the patients who underwent open surgery for CDH, 2% experienced organ injury that required a blood transfusion. Non-direct closure of the diaphragmatic defect was a risk factor for splenic injury., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective　The Kawagoe City Public Health Center implemented a project to reduce salt intake through specific food service facility guidance in workplace cafeterias. Here, we report the study results.Methods　The target worksite was company A, with approximately 270 employees, located in Kawagoe City, Saitama Prefecture. There were 214 participants (approximately 80%). The project was conducted from November 2019 to November 2021. The long-term goal was to decrease the number of hypertensive cases in the city. Project outcomes included decreased salt intake, urinary sodium/potassium ratio, and average blood pressure. The project aimed to improve the cafeteria menu, focusing on salt reduction by offering Smart Meals ® and reducing the salt equivalents in all menus. The project output indicators included reduced amount of salt in cafeteria menu items, increased frequency of cafeteria use, increased positive evaluations of the cafeteria, and increased daily awareness of the need for salt reduction. Spot urine samples, blood pressure measurements, and self-administered questionnaire data were collected during annual physical examinations. The amount of salt in the cafeteria menu was evaluated by receiving monthly data from the food service company to which company A outsourced its cafeteria operations.Results　The analysis included 102 individuals with complete data from to 2019-2021. Estimated salt intake (g/day) from spot urine decreased from 10.3±2.1 in 2019 to 9.8±2.4 in 2020 and 9.5±2.0 in 2021 (P=0.003). Systolic blood pressure (mmHg) decreased from 114.7±12.5 in 2019 to 111.7±12.1 in 2020 and 110.6±12.0 in 2021 (P=0.010). Compared to 2019, changes in dietary salt equivalents in cafeteria menus in 2020 and 2021decreased for set meals A and B, curries, and noodles (P<0.001).Conclusion　We offered Smart Meals ® and reduced salt equivalents in all workplace cafeteria menus. After 1-2 years, employees' salt intake and blood pressure levels were lower. These results provide implications for the implementation of food environment improvements in public health centers and other local government agencies to promote the Health Japan 21 (third term) strategy.

Aim: To identify factors associated with locomotive syndrome (LS) using medical questionnaire data and machine learning., Methods: A total of 1575 participants underwent the LS risk tests from the third survey of the research on osteoarthritis/osteoporosis against disability study (ROAD) study. LS was defined as stage 1 or higher based on clinical decision limits of the Japanese Orthopaedic Association. A total of 1335 items of medical questionnaire data came from this study. The number of medical questionnaire items was reduced from 1335 to 331 in data cleaning. From the 331 items, identify factors associated with LS use by light gradient boosting machine-based recursive feature elimination with cross-validation. The performance of each set was evaluated using an average of seven performance metrics, including 95% confidence intervals, using a bootstrapping method. The smallest set of items is determined with the highest average of receiver operating characteristic area under the curve (ROC-AUC) under 20 items as association factors of LS. Additionally, the performance of the selected items was compared with the LS risk tests and Loco-check., Results: The nine items have the best average ROC-AUC under 20 items. The nine items show an average ROC-AUC of 0.858 (95% confidence interval 0.816-0.898). Age and back pain during walking were strongly associated with the prevalence of LS. The ROC-AUC of nine items is higher than that of existing questionnaire-based LS assessments, including the 25-question Geriatric Locomotor Scale and Loco-check., Conclusions: The identified nine items could aid early LS detection, enhancing understanding and prevention. Geriatr Gerontol Int 2024; 24: 806-813., (© 2024 The Author(s). Geriatrics & Gerontology International published by John Wiley & Sons Australia, Ltd on behalf of Japan Geriatrics Society.)

Objectives: We evaluated the on-scene time of emergency medical services (EMS) for cases where discrimination between acute stroke and epileptic seizures at the initial examination was difficult and identified factors linked to delays in such scenarios., Materials and Methods: A retrospective review of cases with suspected seizure using the EMS database of fire departments across six Japanese cities between 2016 and 2021 was conducted. Patient classification was based on transport codes. We defined cases with stroke-suspected seizure as those in whom epileptic seizure was difficult to differentiate from stroke and evaluated their EMS on-scene time compared to those with epileptic seizures., Results: Among 30,439 cases with any seizures, 292 cases of stroke-suspected seizure and 8,737 cases of epileptic seizure were included. EMS on-scene time in cases of stroke-suspected seizure was shorter than in those with epileptic seizure after propensity score matching (15.1±7.2 min vs. 17.0±9.0 min; p = 0.007). Factors associated with delays included transport during nighttime (odds ratio [OR], 1.73, 95 % confidence interval [CI] 1.02-2.93, p = 0.041) and transport during the 2020-2021 pandemic (OR, 1.77, 95 % CI 1.08-2.90, p = 0.022)., Conclusion: This study highlighted the difference between the characteristics in EMS for stroke and epileptic seizure by evaluating the response to cases with stroke-suspected seizure. Facilitating prompt and smooth transfers of such cases to an appropriate medical facility after admission could optimize the operation of specialized medical resources., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Patients with end-stage kidney disease (ESKD) are at high risk of cardiovascular disease including stroke, heart failure, and ischemic heart disease (IHD). To prevent the occurrence and progression of CVD, a reliable prognostic cardiac biomarker is essential. We investigated the prognostic value of NT-proBNP for each incident type of CVD., Methods: Male patients from the Ibaraki Dialysis Initiation Cohort (iDIC) study with preserved serum samples from dialysis initiation day (n = 212) were analyzed. Patients were classified into four groups according to quartiles of baseline NT-pro BNP levels. The relationship between NT-proBNP levels at the initiation of dialysis and the subsequent incidence of hospitalization events due to IHD, heart failure, and stroke was analyzed., Results: The incidence rate for hospitalization due to IHD was significantly higher in the highest NT-proBNP category (Log rank p = 0.008); those of stroke and heart failure showed no significant differences among quartiles. Cox proportional hazards regression analysis revealed that serum NT-proBNT was the only prognostic factor for hospitalization for IHD after adjustment by major known IHD risk factors. (HR, 1.008; 95% confidence interval, 1.002-1.014; p = 0.01) The ROC curve analysis for the incidence of hospitalization due to IHD showed that NT-proBNP had an area under the curve (AUC) of 0.759 (95% CI 0.622-0.897; p = 0.004) at a cut-off value of 956.6 pg/mL., Conclusion: NT-proBNP measurement at the initiation of dialysis therapy is useful to predict later hospitalization for IHD., Trial Registration: UMIN000010806., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Objective: Prescription trends and patterns of anti-COVID-19 drugs in hospitalized patients were examined based on real world data to understand the use of anti-COVID-19 drugs in clinical practice in Japan., Design: The longitudinal and cross-sectional study was conducted utilizing data from January 1, 2019 to December 31, 2021 of the MID-NET® medical information database, which stored the electronic medical records, administrative claim data, and diagnosis procedure combination data of patients in Japan., Participants: Hospitalized patients with a COVID-19-related diagnosis who received at least one anti-COVID-19 drug between April 1, 2020 and December 31, 2021., Exposures: The following 14 drugs were included in this study: remdesivir, baricitinib, combination product of casirivimab and imdevimab, favipiravir, dexamethasone, ivermectin, azithromycin, nafamostat mesylate, camostat mesylate, ciclesonide, tocilizumab, sarilumab, combination product of lopinavir and ritonavir, and hydroxychloroquine., Results: We identified 5,717 patients hospitalized with COVID-19 and prescribed at least one anti-COVID-19 drug. The entire cohort generally included patients over 41-50 years and more males. The most common prescription pattern was dexamethasone monotherapy (22.9%), followed by the concomitant use of remdesivir and dexamethasone (15.0%), azithromycin monotherapy (15.0%), remdesivir monotherapy (10.2%), and nafamostat mesylate monotherapy (8.5%). However, an often prescribed anti-COVID-19 drug differed depending on the period., Conclusions and Relevance: This study revealed the real-world situation of anti-COVID-19 drug prescriptions in hospitalized COVID-19 patients in Japan. A prescribed drug would depend on the latest scientific evidence, such as efficacy, safety, and approval status, at the time of prescription. Understanding the prescription of anti-COVID-19 drugs will be important for providing the most up-to-date treatments to patients and evaluating the benefit and/or risk of anti-COVID-19 drugs based on the utilization of an electronic medical record database., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Shida et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Radiocesium dynamics data during food processing are required for the realistic estimation of internal radiation content in food. Radiocesium contamination of leafy vegetables can occur externally due to the adhesion of fallout and/or resuspension from the air, and internally from soil via the root transport. Information regarding the dynamics of both surface and internal radiocesium contamination during food processing is required; however, such information for leafy vegetables is limited compared to other major agricultural products. In this study, the effect of washing on the removal of surface radiocesium contamination by resuspended materials and that of cooking (grilling, boiling, and microwave heating) on internal radiocesium contamination were investigated using komatsuna (Brassica rapa var. perviridis), a leafy vegetable. The surface-contaminated samples were experimentally grown in a difficult-to-return area in Fukushima Prefecture, which has not yet been decontaminated. The internally contaminated komatsuna were obtained after experimental cultivation in a greenhouse with soil containing 137 Cs and no surface contamination. The concentration of 137 Cs in surface-contaminated komatsuna was reduced to approximately half (processing factor: 0.55) after washing with water. However, the annual processing factor ranged from 0.12 to 0.95, suggesting that the growing environment and climatic conditions may affect the removal rate of radiocesium by washing. Internal contamination of 137 Cs was removed by 23% and 14% by boiling and grilling, respectively, but no effect was observed for microwaving. Moreover, the concentration of 137 Cs decreased by 0.66-fold after boiling, while it increased by 1.19- and 1.20-fold after grilling and microwaving, respectively. Therefore, boiling was found to be preferable than grilling or microwaving for radiocesium removal., Competing Interests: Declaration of Competing Interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hideshi FUJIWARA reports financial support was provided by Agriculture Forestry and Fisheries Research Council. Takuro SHINANO reports financial support was provided by Tojuro Iijima Foundation for Food Science and Technology., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

To mitigate radioactive cesium from soil to plant, increasing and maintaining the exchangeable potassium (ExK) level during growth is widely accepted after Tokyo Electric Company's Fukushima Dai-ichi Nuclear Plant accident in Japan. This is because the antagonistic relationship between soil solution K and 134 Cs + 137 Cs (RCs) concentrations changes the transfer factor (TF: designated as the ratio of radioactivity of plant organ to soil) of RCs. As the relationship between ExK and TF depends on the soil types, crop species, and other environmental factors, the required amount of ExK should be set to a safe side. Eleven years after the accident, as the activity of 134 Cs was almost negligible, 137 Cs became the main RCs in most of the agricultural fields in Fukushima Prefecture. We propose a new indicator, the concentration ratio of plant 137 Cs to soil exchangeable 137 Cs (Ex 137 Cs), instead of TF, which showed a better correlation with ExK even among soils with different properties (or mineralogy)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aim: Matrix metalloproteinases (MMPs) play critical roles in acute myocardial infarction (AMI). This trial was conducted to determine the potential effects of higher-dose rosuvastatin on circulating MMP levels in patients with AMI., Methods: This was a multicenter, open-label, 1:1 randomized, parallel-group study. Patients with AMI were randomly assigned to the appropriate-dose group (10 mg rosuvastatin once daily) or the low-dose group (2.5 mg rosuvastatin once daily) within 24 hours after percutaneous coronary intervention. MMP-2 and MMP-9 levels were measured on day 1 and at week 4, 12, and 24 after enrollment. The primary endpoint was the change in MMP levels at 24 weeks after enrollment. The secondary endpoints were change in MMP levels at day 1 and weeks 4 and 12 after enrollment., Results: Between August 2017 and October 2018, 120 patients with AMI from 19 institutions were randomly assigned to either the appropriate-dose or the low-dose group. There were 109 patients who completed the 24-week follow-up. The primary endpoint for both MMP-2 and MMP-9 was not significantly different between the two groups. The change in the active/total ratio of MMP-9 at week 12 after baseline was significantly lower in the appropriate-dose group compared with the low-dose group (0.81 [-52.8-60.1]% vs. 70.1 [-14.5-214.2]%, P=0.004), while the changes in MMP-2 were not significantly different between the two groups during the study period., Conclusions: This study could not demonstrate the superiority of appropriate-dose of rosuvastatin in inhibiting serum MMPs levels in patients with AMI.

A total of 306 patients with eosinophilic esophagitis (EoE) were analyzed at our department. Proton pump inhibitors or potassium-competitive acid blockers were used as the first-line treatment in 286 (93.5%) patients. Fifty-five (18.0%) patients received topical steroid swallowing therapy. During 17.7-month mean follow-up, 46.4% of the patients were followed-up with no medications, 37.3% of the patients received maintenance or on-demand therapy using acid-suppressive drugs, and 9.8% of the patients received maintenance therapy with steroid swallowing. The majority of patients with EoE were treated using a therapeutic strategy similar to that used for gastroesophageal reflux disease. However, some patients were refractory to the treatment. Current real-world treatment strategies for Japanese patients with EoE are clarified.

Aging is an important issue in Japan that has led to a large number of older adults requiring long-term care/support. Therefore, we determined the range of measurement error in the measurement of handgrip strength and gait speed which are representative tests. This cross-sectional study included 111 community-dwelling Japanese older adults aged ≥65 years who required long-term care/support and underwent ambulatory rehabilitation. Handgrip strength and usual and maximum gait speed were measured on two days in one single week. Minimal detectable change (MDC) was calculated. The MDC in handgrip strength was 2.9 kg for the overall population, 3.2 kg for the male participants, and 2.4 kg for the female participants. For the overall population, the MDC in usual gait speed was 0.18 m/s and that in maximum gait speed was 0.23 m/s. These MDCs are expected to be suitable for judging clinical changes because this study considered gender and typical tests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Fabry disease is an X-linked disorder of α-galactosidase A (GLA) deficiency. Our previous interim analysis (1 July 2014 to 31 December 2015) revealed plasma globotriaosylsphingosine as a promising primary screening biomarker for Fabry disease probands. Herein, we report the final results, including patients enrolled from 1 January to 31 December 2016 for evaluating the potential of plasma globotriaosylsphingosine and GLA activity as a combined screening marker. We screened 5691 patients (3439 males) referred from 237 Japanese specialty clinics based on clinical findings suggestive of Fabry disease using plasma globotriaosylsphingosine and GLA activity as primary screening markers, and GLA variant status as a secondary screening marker. Of the 14 males who tested positive in the globotriaosylsphingosine screen (≥2.0 ng/mL), 11 with low GLA activity (<4.0 nmol/h/mL) displayed GLA variants (four classic, seven late-onset) and one with normal GLA activity and no pathogenic variant displayed lamellar bodies in affected organs, indicating late-onset biopsy-proven Fabry disease. Of the 19 females who tested positive in the globotriaosylsphingosine screen, eight with low GLA activity displayed GLA variants (six classic, two late-onset) and five with normal GLA activity displayed a GLA variant (one classic) and no pathogenic variant (four late-onset biopsy-proven). The combination of plasma globotriaosylsphingosine and GLA activity can be a primary screening biomarker for classic, late-onset, and late-onset biopsy-proven Fabry disease probands.

Treatment of intractable Pneumocystis jirovecii pneumonia (PCP) patients with primaquine (PQ) in combination with clindamycin (CLDM) was conducted by the Research Group on Chemotherapy of Tropical Diseases (RG-CTD), as a kind of compassionate use. Primaquine was not nationally licensed at the time but imported by RG-CTD for the use in a clinical research to investigate safety and efficacy in malaria treatment. Eighteen Japanese adult patients thus treated were analyzed. Prior to the treatment with PQ-CLDM, most of the patients had been treated with trimethoprim-sulfamethoxazole first, all of which being followed by pentamidine and/or atovaquone treatment. This combination regimen of PQ-CLDM was effective in 16 (89%) patients and developed adverse events (AEs) in five (28%) patients. AEs included skin lesions, methemoglobinemia, and hepatic dysfunction, though none of them were serious. As a second-line or salvage treatment for PCP, PQ-CLDM appears to be a better option than pentamidine or atovaquone. Currently in Japan, both PQ and CLDM are licensed drugs but neither of them is approved for treatment of PCP. Considering the potentially fatal nature of PCP, approval of PQ-CLDM for treating this illness should be urged., Competing Interests: Declaration of competing interest All authors have no conflict of interest to declare., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: Adrenomedullin (AM), a vasoactive peptide, has strong anti-inflammatory and angiogenic properties, which have been reported to ameliorate the consequences of ischemic stroke in several animal models. After a phase I study in healthy volunteers, two phase II trials of AM for inflammatory bowel diseases have been recently completed. The current AdrenoMedullin For Ischemic Stroke (AMFIS) study aims to assess the safety and efficacy of AM in patients with acute ischemic stroke., Materials and Methods: The AMFIS study is an investigator-initiated, randomized, double-blind, phase-II trial. AM or placebo will be administered to patients with non-cardioembolic ischemic stroke within 24 h after stroke onset. In the first cohort of the AMFIS study, patients will be randomly allocated to the investigation treatment A (30 μg/kg of AM in total for 7 days, n = 20) or placebo group (n = 10). In the second cohort, patients will be assigned to the investigation treatment B (56 μg/kg of AM in total for 7 days, n = 20) or placebo group (n = 10)., Results: Serious adverse events related to the protocol treatment will be evaluated as the primary outcome. All adverse events will be analyzed as the secondary outcome. Regarding efficacy endpoints, the change in National Institutes of Health Stroke Scale and modified Rankin Scale scores will be compared between investigation treatment and placebo groups., Conclusions: AM is expected to be a safe and effective treatment for ischemic stroke., Competing Interests: Declaration of Competing Interest All authors declared no potential conflicts of interest with respect to the research., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction. An on-going coronavirus disease 2019 (COVID-19) has become a challenge all over the world. Since an endoscopy unit and its staff are at potentially high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we conducted a survey for the management of the gastrointestinal endoscopic practice, personal protective equipment (PPE), and risk assessment for COVID-19 during the pandemic at multiple facilities. Methods. The 11-item survey questionnaire was sent to representative respondent of Department of Gastroenterology, Osaka City University Hospital, and its 19 related facilities. Results. A total of 18 facilities submitted valid responses and a total of 373 health care professionals (HCPs) participated. All facilities (18/18: 100%) were screening patients at risk for SARS-CoV-2 infection before endoscopy. During the pandemic, we found that the total volume of endoscopic procedures decreased by 44%. Eleven facilities (11/18: 61%) followed recommendations of the Japan Gastroenterological Endoscopy Society (JGES); consequently, about 35%-50% of esophagogastroduodenoscopy and colonoscopy were canceled. Mask (surgical mask or N95 mask), face shield/goggle, gloves (one or two sets), and gown (with long or short sleeves) were being used by endoscopists, nurses, endoscopy technicians, and endoscope cleaning staff in all the facilities (18/18: 100%). SARS-CoV-2 infection risk assessment of HCPs was conducted daily in all the facilities (18/18: 100%), resulting in no subsequent SARS-CoV-2 infection in HCPs. Conclusion. COVID-19 has had a dramatic impact on the gastrointestinal endoscopic practice. The recommendations of the JGES were appropriate as preventive measures for the SARSCoV-2 infection in the endoscopy unit and its staff., (© 2021 Hirotsugu Maruyama et al., published by Sciendo.)

We encountered an outbreak of paragonimiasis among Cambodian technical intern trainees (TITs) at a food-processing factory in Fukuoka, Japan. The patients were 20-28 years old, seven females and two males, who had been in Japan for one to four years. All of them had consumed raw or undercooked Japanese mitten crab they purchased at a local grocery store near their training place. CT images showed multiple lesions not only in the lungs but in the extrapulmonary organs as well, such as subcutaneous tissues, abdominal muscles, and mesentery, in most of the patients. Their medical records indicated that all of them acquired infection in Japan, not in Cambodia. Diagnosis was made serologically and the patients were treated with praziquantel successfully. Foreign workers and TITs are increasing in Japan so rapidly, that food borne-infections, including paragonimiasis, should be considered in people from developing countries who have exotic dietary habits., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Abstract: Escherichia albertii is an emerging foodborne pathogen. The source of the E. albertii infection in most foodborne outbreaks is unknown because E. albertii is difficult to isolate from suspected food or water. E. albertii has a broad host range among birds and can be isolated from chicken meat. In this study, PCR assay, enrichment, and isolation conditions for detecting E. albertii in chicken meat were evaluated. The growth of 47 E. albertii strains isolated in Japan between 1994 and 2018 and a type strain was evaluated in modified EC broth (mEC) and mEC supplemented with novobiocin (NmEC) and on media containing carbohydrates. The enzyme used for the nested PCR, the enrichment conditions, the most-probable-number (MPN) method, and agar media were also evaluated with chicken meat. To distinguish E. albertii from presumptive non-E. albertii bacteria, desoxycholate hydrogen sulfide lactose agar (DHL), MacConkey agar (MAC), and these agars supplemented with rhamnose and xylose (RX-DHL and RX-MAC, respectively) were used. All E. albertii strains grew in mEC and NmEC at both 36 and 42°C and did not utilize rhamnose, sucrose, or xylose. Both the first and nested PCRs with TaKaRa Ex Taq, which was 10 to 100 times more active than the other enzymes, produced positive results in enrichment culture of 25 g of chicken meat inoculated with >20 CFU of E. albertii and incubated in mEC and NmEC at 42°C for 22 ± 2 h. Thus, the first PCR was sensitive enough to detect E. albertii in chicken meat. The MPN values in mEC and NmEC were 0.5- and 2.3-fold higher than the original inoculated bacterial levels, respectively. E. albertii in chicken meat was more efficiently isolated with enrichment in NmEC (70.1 to 100%) and plating onto RX-DHL (85.4%) and RX-MAC (100%) compared with enrichment in mEC (53.5 to 83.3%) and plating onto DHL (70.1%) and MAC (92.4%). Thus, optimized conditions for the surveillance of E. albertii contamination in food and investigations of E. albertii outbreaks, including the infectious dose, were clarified., (Copyright ©, International Association for Food Protection.)

The intestinal microbiome changes dynamically in early infancy. Colonisation by Bifidobacterium and Bacteroides and development of intestinal immunity is interconnected. We performed a prospective observational cohort study to determine the influence of antibiotics taken by the mother immediately before delivery on the intestinal microbiome of 130 healthy Japanese infants. Faecal samples (383) were collected at 1, 3, and 6 months and analysed using next-generation sequencing. Cefazolin was administered before caesarean sections, whereas ampicillin was administered in cases with premature rupture of the membranes and in Group B Streptococcus-positive cases. Bifidobacterium and Bacteroides were dominant (60-70% mean combined occupancy) at all ages. A low abundance of Bifidobacterium was observed in infants exposed to antibiotics at delivery and at 1 and 3 months, with no difference between delivery methods. A lower abundance of Bacteroides was observed after caesarean section than vaginal delivery, irrespective of antibiotic exposure. Additionally, occupancy by Bifidobacterium at 1 and 3 months and by Bacteroides at 3 months differed between infants with and without siblings. All these differences disappeared at 6 months. Infants exposed to intrapartum antibiotics displayed altered Bifidobacterium abundance, whereas abundance of Bacteroides was largely associated with the delivery method. Existence of siblings also significantly influenced the microbiota composition of infants.

Purpose: To analyze the impact of postoperative remote infections (PRIs) on medical expenditure., Methods: The subjects of this retrospective study were 338 patients who had undergone gastroenterological surgery at one of the 20 Japanese institutions within the Japan Society for Surgical Infection (JSSI) and mainly authorized as educational institutions. The patients were allocated to 169 pairs of those with a PRI (PRI (+) group) matched with those without a PRI (PRI (-) group). PRIs included pneumonia, urinary tract infection (UTI), catheter-associated blood stream infection (CA-BSI), and antibiotic-associated enteritis., Results: SSI developed in 74 of the 338 patients (22 without PRI and 52 with PRI). The SSI incidence was significantly higher in the PRI (+) group (p < 0.001). The difference in the median postoperative length of hospital stay was 15 days, indicating a significant prolongation in the PRI (+) group (p < 0.001). The PRI (+) group also had a higher rate of inter-hospital transfer (p < 0.01) and mortality (p < 0.001). Similarly, the difference in median postoperative medical fees was $6832.3, representing a significant increase in the PRI (+) group (p < 0.001)., Conclusions: The postoperative length of hospital stay is longer and the postoperative medical expenditure is higher for patients with a PRI than for those without a PRI.

In the last decade, methicillin-resistant Staphylococcus aureus (MRSA) has been identified in livestock animals, such as swine, poultry, and veal calves, and has been termed livestock-associated MRSA (LA-MRSA). LA-MRSA sequence type (ST) 398 strains can effectively infect and colonize humans, with subsequent human-to-human transmission in both community and hospital settings. Unlike other countries, LA-MRSA had not been reported in Japanese patients until 2019. However, we recently reported a case of intractable arthritis caused by an LA-MRSA CC398 (ST1232) clone, which is a single-locus variant of ST398, in a patient in Tokyo, Japan, with no animal contact (Nakaminami H, et al. Emerg Infect Dis. 2020; 26: 795-7.). Uniquely, the strain was positive for Panton-Valentine leukocidin. Here, we report the second such case in Japan. To prevent the dissemination of LA-MRSA in the Japanese community, the prevalence of the CC398 MRSA clone should be closely monitored in the future.

Background: Although previous phase II and III clinical trials conducted in Japan showed that zonisamide improved parkinsonism in patients with dementia with Lewy bodies (DLB), some differences in efficacy outcomes were observed between the trials., Objective: We aimed to further examine the efficacy and safety of zonisamide in DLB patients with parkinsonism in a post hoc analysis of pooled data from the previous phase II and III trials., Methods: Both trials featured a 4-week run-in period followed by a 12-week treatment period with a double-blind, placebo-controlled, parallel-group, randomized, multicenter trial design. In our pooled analysis, the primary outcome was the change in Unified Parkinson's Disease Rating Scale (UPDRS) part III total score. Other outcomes included the changes in Mini-Mental State Examination (MMSE) and Neuropsychiatric Inventory-10 (NPI-10) scores, and the incidence of adverse events., Results: Zonisamide significantly decreased the UPDRS part III total and individual motor symptom scores but did not affect the MMSE or NPI-10 scores at week 12. There was no difference in the incidence of adverse events between the zonisamide and placebo groups except for decreased appetite, which had an increased frequency in the zonisamide 50 mg group compared with placebo., Conclusion: Our findings indicate that zonisamide improved parkinsonism with DLB without deterioration of cognitive function and or worsening behavioral and psychological symptoms of dementia.

Background: Postoperative infections can be classified as surgical site infections and remote infections. Postoperative respiratory tract infections (PRTI) are a type of remote infection and may be associated with prolonged hospitalization and increased medical expenses. This study compared postoperative duration of hospitalization and medical expenses between patients with and without PRTI after gastrointestinal surgery., Methods: We retrospectively analyzed data from a multicenter study of centers affiliated with the Japan Society for Surgical Infection and used 1-to-1 matching analysis to evaluate 86 patients who underwent gastrointestinal surgery during the period from March 1, 2014 through February 29, 2016., Results: Duration of postoperative hospitalization was significantly longer for patients with PRTI (38.6 days) than for those without PRTI (16.1 days), and postoperative medical expenses were significantly higher for patients with PRTI (1388.2 USD) than for those without PRTI (629.4 USD)., Conclusions: Duration of hospitalization is longer and medical expenses are higher for patients that develop surgical site infections. This study found that this was also the case for patients with PRTI after gastrointestinal surgery. However, further studies are needed in order to confirm these results.

Strongyloides stercoralis is a parasitic nematode and a major pathogen responsible for human strongyloidiasis. The presence of this species in the dog population has led to an interest in studying the phylogenetic relationships among Strongyloides spp. in carnivore hosts. In the present study, Strongyloides spp. from various carnivore hosts (raccoon, Japanese badger, Siberian weasel, raccoon dog, masked palm civet, and domestic cat) were sought. Except for civets, Strongyloides spp. were identified in all host species. Based on 18S rDNA sequences, nine OTUs (operational taxonomy units) were identified. Molecular phylogenetic analyses using 18S28S rDNA and mitochondrial cox1 (cytochrome c oxidase subunit 1) sequences clustered them into two groups. The first group (named the stercoralis/procyonis group) was comprised of six OTUs and occurred in cats, raccoon dogs, raccoons (S. procyonis), Siberian weasels, and Japanese badgers and included S. stercoralis from humans and dogs. The second group (named the planiceps group) was made up of Strongyloides spp. from raccoon dogs (two OTUs) and one OTU from Siberian weasels. Subsequent analysis using almost the full-length nucleotide sequences of protein-coding genes in their mitochondrial genomes placed Strongyloides spp. of cats in a sister taxon position to S. stercoralis, whereas S. procyonis from raccoons was more distantly related to them. The presence of Strongyloides spp. from various carnivore hosts, which are close relatives of S. stercoralis, suggests this group of Strongyloides (the stercoralis/procyonis group) essentially evolved as parasites of carnivores, although more data on Strongyloides spp. from primate hosts are needed., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Most surveillance programs for postoperative infection focus on surgical site infections (SSI). However, postoperative remote infections are of emerging clinical importance. Using data from a multicenter survey administered to patients who underwent gastrointestinal surgery, we investigated the incidence of SSI and remote infection after colorectal surgery., Methods: From September 2015 through March 2016, 1,724 patients underwent colorectal surgery in 28 affiliated centers in Japan. We retrospectively recorded patient age, sex, surgical site, surgical approach, wound classification, performance status at discharge, and postoperative infection status., Results: Postoperative infection was noted in 236 (13.7%) patients; 150 and 86 patients underwent colon and rectal surgeries, respectively (incidence of postoperative infection: 13.7% and 14.8%). The incidence of postoperative infection was significantly lower after laparoscopic surgery than after open surgery, in colon and rectal surgery (p < 0.001). Among patients with postoperative infections, 211 (89.4%) had a single infection and 25 (10.6%) had multiple infections. Among patients with a single postoperative infection, SSI and remote infection occurred in 143 (60.6%) and 68 (28.8%) patients, respectively. The most common multiple postoperative infections were "incisional and organ/space SSIs" and "organ/space SSI and bacteremia of unknown origin" (n = 3 each)., Conclusions: This study revealed the prevalence distributions for postoperative SSI and remote infections. Because of the substantial effect of remote infections on patient quality of life and the associated social burden, prospective periodic surveillance for SSI and remote infection is necessary for careful evaluation and prevention.

Aim: We aimed to determine systematic bias and the range of random error in tongue pressure measurements among young healthy adults and elderly patients with certification of requiring long-term care or support, considering sex, and to establish a measurement method., Methods: Subjects were 226 adults (88 young healthy adults and 138 elderly patients with certification of requiring long-term care or support). Tongue pressure was measured thrice. Bland-Altman analysis was performed for the first and second trials, and second and third trials., Results: Fixed bias was revealed for the first and second trials among young healthy adults. Systematic bias was not found for the second and third trials. Fixed bias was revealed for the first and second trials among elderly patients, with a proportional bias with a negative slope for the second and third trials. For young healthy adults, the minimal detectable change was 6.0 and 5.4 kPa in males and females, respectively. For elderly patients, the limit of agreement ranged from -5.9 to 8.6 and from -5.4 to 8.8 kPa in males and females, respectively., Conclusions: There was a difference in systematic bias in tongue pressure measurement between young healthy adults and elderly patients with certification of needing long-term care or support. In young healthy adults, the third trial results showed stability, whereas they decreased in elderly patients. In elderly patients, it was suggested that the number of measurements reduced from three to two when a maximum value was adopted. No differences were observed among sexes in either young or elderly patients. Geriatr Gerontol Int 2020; 20: 488-493., (© 2020 Japan Geriatrics Society.)

Aims: To understand the different influences of statins on the incidence rate of each stroke subtype in association with low-density lipoprotein (LDL) cholesterol levels, we performed a post hoc analysis on the data from the Japan Statin Treatment Against Recurrent Stroke (J-STARS) study., Methods: Subjects (n=1,578) were divided into three groups according to their mean postrandomized LDL cholesterol level (＜100, 100-120, and ≥ 120 mg/dL) until the last observation before the event or the end of follow-up. A Cox proportional hazard model for time to events was used for calculating adjusted hazard ratios, 95% confidence intervals, and the trend tests., Results: The event rates for atherothrombotic stroke did not decrease in accordance with the postrandomized LDL cholesterol level subgroups of either the control or the pravastatin group (p=0.15 and 0.33 for the trend, respectively). In the control group, however, no atherothrombotic stroke event was observed in the subgroup of the low postrandomized LDL cholesterol level (less than 100 mg/dL). The event rates for atherothrombotic stroke were lower in the middle postrandomized LDL cholesterol level subgroup (100-120 mg/dL) of the pravastatin group than that of the control group. The event rates for lacunar stroke decreased in the lower postrandomized LDL cholesterol level subgroup of the control group but not of the pravastatin group (p=0.004 and 0.06 for the trend, respectively)., Conclusions: Statins showed different influences on the risks of atherothromobotic and lacunar stroke according to postrandomized LDL cholesterol levels.

Aim: This study aimed to evaluate the associations of blood pressure (BP) variability in patients with ischemic stroke during the subacute phase using ambulatory blood pressure monitoring and the ankle-brachial index (ABI)., Methods: We retrospectively examined 831 consecutive patients (women 44.8%, mean age 76 ± 12 years) with acute ischemic stroke who underwent 24-h ambulatory blood pressure monitoring during the subacute phase of stroke (median 9 days from onset) and an ABI examination. BP variability was evaluated by assessing the standard deviation and coefficient of variation of systolic BP and diastolic BP. A low ABI was defined as an ABI <0.9., Results: Of the 831 patients, 201 (24.2%) had a low ABI. Older age, lower body mass index, diabetes mellitus, chronic kidney disease, atrial fibrillation and a higher National Institutes of Health Stroke Scale score at admission were independently associated with a low ABI. The patients with a low ABI had a higher mean 24-h diastolic BP, higher standard deviation of both BP measurements (systolic BP and diastolic BP) and a higher coefficient of variation in both BP measurements than those with a higher ABI. According to the multivariable linear regression analysis, a low ABI was independently associated with increased BP variability (a high standard deviation or coefficient of variation of both BP measurements) after adjusting for baseline confounders., Conclusions: A low ABI was associated with increased BP variability during the subacute ischemic phase. Geriatr Gerontol Int 2020; 20: 448-454., (© 2020 Japan Geriatrics Society.)

Background: Pharmacological prevention against relapses in patients with neuromyelitis optica spectrum disorder (NMOSD) is developing rapidly. We aimed to investigate the safety and efficacy of rituximab, an anti-CD20 monoclonal antibody, against relapses in patients with NMOSD., Methods: We did a multicentre, randomised, double-blind, placebo-controlled clinical trial at eight hospitals in Japan. Patients aged 16-80 years with NMOSD who were seropositive for aquaporin 4 (AQP4) antibody, were taking 5-30 mg/day oral steroids, and had an Expanded Disability Status Scale (EDSS) score of 7·0 or less were eligible for the study. Individuals taking any other immunosuppressants were excluded. Participants were randomly allocated (1:1) either rituximab or placebo by a computer-aided dynamic random allocation system. The doses of concomitant steroid (converted to equivalent doses of prednisolone) and relapses in previous 2 years were set as stratification factors. Participants and those assessing outcomes were unaware of group assignments. Rituximab (375 mg/m 2 ) was administered intravenously every week for 4 weeks, then 6-month interval dosing was done (1000 mg every 2 weeks, at 24 weeks and 48 weeks after randomisation). A matching placebo was administered intravenously. Concomitant oral prednisolone was gradually reduced to 2-5 mg/day, according to the protocol. The primary outcome was time to first relapse within 72 weeks. Relapses were defined as patient-reported symptoms or any new signs consistent with CNS lesions and attributable objective changes in MRI or visual evoked potential. The primary analysis was done in the full analysis set (all randomly assigned patients) and safety analyses were done in the safety analysis set (all patients who received at least one infusion of assigned treatment). The primary analysis was by intention-to-treat principles. This trial is registered with the UMIN clinical trial registry, UMIN000013453., Findings: Between May 10, 2014, and Aug 15, 2017, 38 participants were recruited and randomly allocated either rituximab (n=19) or placebo (n=19). Three (16%) patients assigned rituximab discontinued the study and were analysed as censored cases. Seven (37%) relapses occurred in patients allocated placebo and none were recorded in patients assigned rituximab (group difference 36·8%, 95% CI 12·3-65·5; log-rank p=0·0058). Eight serious adverse events were recorded, four events in three (16%) patients assigned rituximab (lumbar compression fracture and infection around nail of right foot [n=1], diplopia [n=1], and uterine cancer [n=1]) and four events in two (11%) people allocated to placebo (exacerbation of glaucoma and bleeding in the right eye chamber after surgery [n=1], and visual impairment and asymptomatic white matter brain lesion on MRI [n=1]); all patients recovered. No deaths were reported., Interpretation: Rituximab prevented relapses for 72 weeks in patients with NMOSD who were AQP4 antibody-positive. This study is limited by its small sample size and inclusion of participants with mild disease activity. However, our results suggest that rituximab could be useful maintenance therapy for individuals with NMOSD who are AQP4 antibody-positive., Funding: Japanese Ministry of Health, Labour and Welfare, Japan Agency for Medical Research and Development, and Zenyaku Kogyo., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Recently, the use of various endoscopic procedures under X-ray fluoroscopic guidance, such as endoscopic retrograde cholangiopancreatography (ERCP), interventional endoscopic ultrasonography (EUS), enteral endoscopy and stenting, has been rapidly increasing because of the minimally invasive nature of these procedures compared with that of surgical intervention. With the spread of CT and fluoroscopic interventions, including endoscopic procedures under X-ray guidance, high levels of radiation exposure (RE) from medical imaging have led to major concerns throughout society. However, information about RE related to these image-guided procedures in gastrointestinal endoscopy is scarce, and the RE reference levels have not been established. The aim of this study is to prospectively collect the actual RE dose and to help establish diagnostic reference levels (DRLs) in the field of gastroenterology in Japan., Methods and Analysis: This is a multicentre, prospective observational study that is being conducted to collect the actual RE from treatments and diagnostic procedures, including ERCP, interventional EUS, balloon-assisted enteroscopy, enteral metallic stent placement and enteral tube placement. We will measure the total fluoroscopy time (min), the total dose-area product (Gycm 2 ) and air-kerma (mGy) of those procedures. Because we are collecting the actual RE data and identifying the influential factors through a prospective, nationwide design, this study will provide guidance regarding the DRLs of ERCP, interventional EUS, balloon-assisted enteroscopy, enteral metallic stent placement and enteral tube placement., Ethics and Dissemination: Approval was obtained from the Institutional Review Board of Toyonaka Municipal Hospital (25 April 2019). The need for informed consent will be waived via the opt-out method of each hospital website., Trial Registration Number: The UMIN Clinical Trials Registry, UMIN000036525., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A "biosimilar" is a biotechnological product with a lower cost profile and equivalent efficacy and safety to the originator, but post-marketing clinical evaluation of biosimilar products has not been adequately conducted. We prospectively investigated the utility of biosimilar filgrastim in 13 peripheral blood stem cell (PBSC) donors from June 2014 to January 2017. In addition, we retrospectively compared these to another 13 PBSC donors mobilized with the originator filgrastim in the same period. Donor characteristics were equivalent between the groups. The median number of CD34 + cells per donor body weight (BW) and blood volume processed (BV) were 4.87 × 10 6 /kg and 25.5 × 10 3 /mL in the biosimilar group and 4.93 × 10 6 /kg and 16.6 × 10 3 /mL in the originator group, respectively. There were no significant differences between the groups in the number of CD34 + cells per donor BW or BV. All adverse events associated with G-CSF were permissive. The total G-CSF cost was significantly lower in the biosimilar group than in the originator group. These findings suggest that biosimilar filgrastim has the same efficacy and short-term safety as originator filgrastim for PBSC mobilization in healthy donors, with economic superiority. Longer follow-up studies are needed to evaluate the incidence of long-term adverse events.

Objective: To clarify clinical and genetic features of Japanese children with congenital chloride diarrhea (CCD)., Study Design: This was a multi-institutional, retrospective survey of 616 pediatric centers in Japan with identified patients with CCD between 2014 and 2018. Mutations involving SLC26A3 were detected by Sanger sequencing., Results: Thirteen patients met all entry criteria including mutations in SLC26A3, and 14 patients satisfied clinical diagnostic criteria. Homozygous or compound heterozygous mutations in SLC26A3, including 6 novel mutations, were identified in 13 of these 14 patients (93%). The most common (detected in 7 of 13) was c.2063-1g>t. Median age at diagnosis was 1 day. Nine of the patients meeting all criteria were diagnosed as neonates (69%). Median follow-up duration was 10 years. When studied, 8 patients had <5 stools daily (62%), and all had fewer than in infancy. Only 1 patient had nephrocalcinosis, and 3 (23%) had mild chronic kidney disease. Neurodevelopment was generally good; only 1 patient required special education. Five patients (38%) received long-term sodium, potassium, and chloride supplementation., Conclusions: Early fetal ultrasound diagnosis and prompt long-term sodium, potassium, and chloride supplementation were common management features. Genetic analysis of SLC26A3 provided definitive diagnosis of CCD. In contrast with previously reported localities, c.2063-1g>t might be a founder mutation in East Asia., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Traditionally, Strongyloides nematode infecting cattle had been thought to be a single species, S. papillosus. Surprisingly, Eberhardt et al. in 2008 reported two, rather than one Strongyloides species infected cattle, with one being S. papillosus and the other S. vituli. However, there was no subsequent report to support their findings. In July 2018, a case of a sudden death of a calf believed to be due to heavy infection with S. papillosus at a dairy farm in Miyazaki Prefecture, Japan, was reported. One month after the initiation of a deworming program to prevent further sudden deaths, fecal specimens from 24 cattle housed in the same barn were examined. Eight samples were positive for Strongyloides eggs. For species determination, the nucleotide sequences of 18S rDNA (small subunit ribosomal DNA gene), rpl-10 (ribosomal protein L10 gene), and mitochondrial (mt) cox1 (cytochrome c oxidase subunit 1 gene) were obtained. Typing data for all three marker genes indicated the presence of both species, S. papillosus and S. vituli, in the fecal samples. To our knowledge, this study is the first to support the original report by Eberhardt et al. regarding the sympatric existence of S. papillosus and S. vituli in cattle, and to report the presence of S. vituli in Japan. Interestingly, phylogenetic analyses of both rpl-10 and mt cox1 sequences indicated a closer genetic relationship of S. vituli with S. venezuelensis (Strongyloides of rats) than with S. papillosus, shedding light on the speciation history of Strongyloides nematodes., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Cutaneous gnathostomiasis (CG) is a disease caused by ingestion of third-stage Gnathostoma larva in raw snakes, freshwater fish or frogs. The common causative organisms of CG in Japan include G. nipponicum, G. spinigerum, G. doloresi, G. binucleatum and G. hispidum. We report two cases of CG after eating many raw Japanese icefishes (Salangichthys microdon). In both cases, linear itchy eruptions on the trunk developed after eating many S. microdon. We performed genetic analysis in the first case, which revealed G. nipponicum. Of note, this is the first case of CG diagnosed based on genetic analysis in Japan. In Japan, eating whole small raw freshwater fish is common. The most popular types of raw small freshwater fish consumed in Japan are S. microdon (shirauo in Japanese) and Leucopsarion petersii (shirouo in Japanese). Usually, S. microdon are born in rivers, but live in both the sea and rivers. They feed on small fish and freshwater water fleas and spawn in rivers in the spring. On the other hand, L. petersii are born in rivers, but move to the sea soon after hatching. They feed on plankton such as copepod in the sea. They do not feed on anything when they return to rivers to spawn in the spring. Therefore, we hypothesize that S. microdon are more easily parasitized by G. nipponicum., (© 2019 Japanese Dermatological Association.)

Background: Although previous studies have suggested a certain prevalence of Fabry disease (FD) in left ventricular hypertrophy (LVH) patients, the screening of FD is difficult because of its wide-ranging clinical phenotypes. We aimed to clarify the utility of combined measurement of plasma globotriaosylsphingosine (lyso-Gb3) concentration and α-galactosidase A activity (α-GAL) as a primary screening of FD in unexplained LVH patients.Methods and Results:Between 2014 and 2016, both lyso-Gb3 and α-GAL were measured in 277 consecutive patients (male 215, female 62, age 25-79 years) with left ventricular wall thickness >12 mm on echocardiogram: 5 patients (1.8%) screened positive (2 (0.7%) showed high lyso-Gb3 and 4 (1.4%) had low α-GAL levels). Finally, 2 patients (0.7%) were diagnosed with clinically significant FD. In 1 case, a female heterozygote with normal α-GAL levels had genetic variants of unknown significance and was diagnosed as FD by endomyocardial biopsy. The other case was a male chronic renal failure patient requiring hemodialysis, and he had a p.R112H mutation. In both cases there were high lyso-Gb3 levels., Conclusions: The serum lyso-Gb3 level can be relevant for clinically significant FD, and combined measurement of lyso-Gb3 and α-GAL can provide better screening of FD in unexplained LVH patients.

Background and Purpose: The influence of a weather front passage is rarely evaluated on stroke events. We hypothesized that a weather front passage on the stroke onset day or during the previous days may play an important role in the incidence of stroke., Methods: A multicenter retrospective study was conducted to evaluate the frequency of stroke events and their interaction with weather front passages. Consecutive acute stroke patients (n = 3935, 73.5 ± 12.4 years, 1610 females) who were admitted to 7 stroke hospitals in 3 cities from January 2012 to December 2013 were enrolled in this study. Multivariate Poisson regression models involving time lag variables were used to compare the daily rates of stroke events with the day of a weather front passage and the previous 6 days, adjusting for considerable influences of ambient temperature and atmospheric pressure., Results: There were a total of 33 cold fronts and 13 warm fronts that passed over the 3 cities during the study period. The frequency of ischemic stroke significantly increased when a warm front passed on the previous day (risk ratio 1.34, 95% confidence interval 1.07-1.69, P= .016)., Conclusions: This study indicated that a weather front passage on the previous days may be associated with the occurrence of stroke., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: To investigate the relative contribution of on-treatment low-density lipoprotein (LDL) cholesterol and C-reactive protein (CRP) to the risk of recurrent stroke and transient ischemic attack (TIA) in patients with history of ischemic stroke., Methods: A total of 1095 patients with non-cardioembolic ischemic stroke were randomized into two groups: control and patients receiving 10 mg of pravastatin per day. After excluding 18 patients who did not have baseline CRP data, the effects of LDL cholesterol and CRP on recurrent stroke and TIA were prospectively assessed in 1077 patients., Results: During the follow-up of 4.9±1.4 years, there were 131 recurrent stroke or TIA cases. Patients with ontreatment LDL cholesterol ＜120 mg/dL showed 29% reduction in recurrent stroke and TIA than those with LDL cholesterol ≥ 120 mg/dL (event rate 2.20 vs. 3.11 per 100 person-years, hazard ratio [HR] 0.71, 95% confidence interval (CI) 0.50-0.99, p＝0.048). Patients with CRP ＜1 mg/L had 32% reduction compared with that of patients with CRP ≥ 1 mg/L (event rate 2.26 vs. 3.40 per 100 person-years; HR 0.68, 95% CI 0.48-0.96, p＝0.031). Although LDL cholesterol and CRP levels were not correlated in individual patients, those who achieved both LDL cholesterol ＜120 mg/dL and CRP ＜1 mg/L showed 51% reduction compared with that of patients with LDL cholesterol ≥ 120 mg/dL and CRP ≥ 1 mg/L (event rate 2.02 vs. 4.19 per 100 person-years; HR 0.49, 95% CI 0.31-0.79)., Conclusions: The control of both LDL cholesterol and CRP levels appears to be effective for preventing recurrent stroke and TIA in patients with non-cardiogenic ischemic stroke.

Background: Various differences between China and Japan in approaches to medical treatment have been noted, but a few studies have examined differences in medical decision-making, especially in neonatal care. The aim of this study was to clarify these differences by means of a questionnaire., Methods: The subjects were physicians on the staff of NICUs in China and Japan. The study questionnaire consisted of three parts dealing with the general characteristics of the participants, questions about treatment strategies for hypothetical, critically ill infants, and general questions about the treatment of foreign patients. The Likert scale was used to assess the treatment strategies and the results were analyzed statistically. Subgroup analysis by age, sex, and medical and NICU experience was also performed., Results: The proportion of respondents in the Chinese and Japanese groups was 26/26 (100%) and 26/31 (84%), respectively. There was a significant difference between the Chinese and Japanese groups for 8 of 75 questions; Chinese physicians chose the positive treatment or examination options for these eight questions unlike their Japanese counterparts. The responses of the younger, less experienced physicians in both countries were more similar to each other, and more positive than those of their older, more experienced colleagues., Conclusion: Chinese physicians showed a more positive attitude toward examination and treatment, whereas Japanese physicians showed a more cautious attitude.

Background: Larva migrans syndrome is a food-borne parasitic disease in humans, caused by accidental ingestion of eggs or larvae of ascarid nematodes, namely, Toxocara canis, Toxocara cati, or Ascaris suum, the roundworms commonly found in the intestines of dogs, cats and pigs respectively. When a patient is diagnosed as having larva migrans syndrome, oral-administration of albendazole is recommended, however, the regimen remains controversial worldwide. In Japan, the duration of albendazole administration is longer than those of European and North American countries. The purpose of this study was to assess the efficacy and safety of long-term administration treatment of albendazole for larva migrans syndrome., Methods: From 2004 to 2014, our laboratory was involved in the diagnosis of 758 larva migrans syndrome cases, of which 299 cases could be followed up after the treatment. We analyzed these 299 follow-up cases on the ELISA results before and after the treatment as well as on anthelmintic used, dose and duration of medication, clinical findings, and side effects, recorded on a consultation sheet provided by the attending physicians. We have 288 cases as the subjects of this study., Results: Albendazole represented a 78.0% efficacy rate. The side effects represented 15.0% in using albendazole alone cases; however, the side effects were mild to moderate and there were no severe cases reported., Conclusions: The long-term administration treatment of albendazole is safe and effective for larva migrans syndrome., (Copyright © 2017. Published by Elsevier B.V.)

Background: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in GLA, which encodes the enzyme α-galactosidase A (α-Gal A). Although the prevalence of Fabry disease in patients with stroke has been reported to range from 0% to 4%, few cohort studies have examined Japanese stroke patients. We aimed to clarify the prevalence of Fabry disease and the frequency of GLA mutations among patients with young-onset stroke in Japan., Methods: From April 2015 to December 2016, we enrolled patients with young-onset (≤60 years old) ischemic stroke or intracerebral hemorrhage. We measured α-Gal A activity and the concentration of globotriaosylsphingosine in plasma. Genetic evaluations were performed in patients with low α-Gal A activity or high concentrations of globotriaosylsphingosine., Results: Overall, 516 patients (median age of onset, 52 years old; 120 women) were consecutively enrolled in this study. Five patients (4 men and 1 woman) had low α-Gal A activity, and no patients were detected with the screen for plasma globotriaosylsphingosine levels. The genetic analysis did not identify a causative mutation responsible for classic Fabry disease in any of the patients, but 2 patients (.4%) carried the p.E66Q in GLA., Conclusions: No patient with Fabry disease was detected in our young-onset stroke cohort., (Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Although recent clinical trials have revealed that immune checkpoint inhibitors significantly improved the overall survival (OS) of patients with advanced melanoma, these previous studies comprised mainly white populations, in which superficial spreading melanoma (SSM) and lentigo maligna melanoma are the major clinical types of melanoma. In contrast, Asians manifest a distinct clinicopathological type of melanoma from that of whites and show much higher frequencies of acral lentiginous melanoma (ALM) and mucosal melanoma, which have been shown to be less susceptible to immune checkpoint inhibitors. Because no comparative studies have been published showing improvement of OS by immune checkpoint inhibitors in Asian melanoma patients, we retrospectively collected the data for 45 melanoma patients treated with checkpoint inhibitors and 24 melanoma patients treated with chemotherapy alone before immune checkpoint inhibitors became available, and compared their OS. The results showed that the patients treated with immune checkpoint inhibitors had significantly better OS than did those treated with chemotherapy alone (P < 0.0001). Improved OS was observed in both the SSM and the ALM patients. In addition, multivariate Cox regression analyses revealed that use of immune checkpoint inhibitors was associated with favorable prognosis (P = 0.0001), indicating that use of immune checkpoint inhibitors is an independent factor for favorable survival. Our study showed that immune checkpoint inhibitors may also improve the prognosis of Asian melanoma patients., (© 2018 Japanese Dermatological Association.)

Objectives: The American and Japanese Societies for Gastrointestinal Endoscopy Guidelines recommend heparin-bridging therapy for patients whose oral anticoagulants are interrupted for endoscopic procedures. However, little is known about the potential association between heparin-bridging therapy and post-polypectomy bleeding (PPB). The aim was to investigate the incidence of PPB associated with heparin-bridging therapy administered to patients whose anticoagulants were interrupted., Materials and Methods: This was a retrospective observational study using inverse propensity analysis. Between 2013 and 2015, 1004 patients with 2863 lesions were included. The primary outcomes were the rates of PPB and thromboembolism associated with heparin-bridging therapy. The risk factors associated with PPB were identified using multivariate logistic regression analysis involving probability of treatment weighting (IPTW)., Results: The patients were categorized into a heparin-bridging therapy group (78 patients with 255 lesions) or a control group (926 patients with 2608 lesions). The PPB rate in the heparin-bridging therapy group (10.2%, 8/78) was significantly higher than in the control group (1.1%, 11/926) (p <.01). Thromboembolism occurred in one patient in the control group. The multivariate analysis revealed that heparin-bridging therapy was an independent risk factor associated with PPB (odds ratio [OR], 8.21; 95% confidence interval [95% CI], 2.32-29.10; p <.01). IPTW showed heparin-bridging therapy increased PPB (OR, 7.68; 95% CI, 1.83-32.28; p <.01)., Conclusions: Heparin-bridging therapy administered to patients whose oral anticoagulants were interrupted was associated with an increased PPB risk.

Skin grafts are frequently used for the reconstruction of skin defects, and optimal stabilization of the graft is essential for successful reconstruction. Although the tie-over technique has been widely used as a standard method in Japan, we sometimes encounter cases with significant graft loss due to suboptimal stabilization of the graft. Reported risk factors for increased graft loss include the following: defects of a large size, with muscle exposure, and located in the trunk and extremities. Recent studies have demonstrated the usefulness of negative-pressure closure (NPC) for the stabilization of skin grafts due to the uniform pressure it provides across the graft. Therefore, since March 2017, we have used NPC for skin graft stabilization in patients with defects in the trunk and extremities of more than 10 cm in size or with muscle exposure. We carried out a retrospective comparative study of the outcome of the conventional tie-over technique versus NPC. Mann-Whitney U-test revealed that NPC showed significantly higher graft survival rate than tie-over method (P = 0.0012). In addition, NPC showed a tendency toward shorter operative times (from skin graft harvest to the completion of the graft stabilization) than the tie-over method (P = 0.0931). These results suggest that NPC may be superior to the tie-over method for stabilization of skin grafts especially in large or muscle-exposing defects in the trunk or extremities., (© 2018 Japanese Dermatological Association.)

Background: Acute myocardial infarction (AMI) is mainly characterized by the rupture of lipid-rich vulnerable atherosclerotic plaque. The matrix metalloproteinases (MMPs) have been shown to play a critical role in inflammatory processes underlying plaque rupture. Some reports suggested statins inhibit the increased MMP levels after AMI. However, there are a few comparison studies between the different dosages of the same statin and circulating levels of MMPs., Purpose: This study will preliminarily investigate the potential effects of appropriate or low dose of rosuvastatin on circulating MMPs levels in AMI patients. Moreover, we will also obtain plasma from patients while undergoing diagnostic angiography to determine differences in various cardiac sites and peripheral vessels., Methods: This study is a multicenter, open-label, randomized, parallel-group study to be conducted to compare the appropriate or low dose of rosuvastatin in the effect on serum levels of inflammatory markers in AMI patients. The eligible patients undergoing percutaneous coronary intervention (PCI) will be randomly assigned to receive either appropriate or low-dose rosuvastatin daily using a web-based randomization software within 24h after PCI. The low-dose group will be treated with rosuvastatin 2.5mg once daily with a follow-up. The appropriate-dose group will begin treatment with rosuvastatin 5mg once daily, and the dose of rosuvastatin will be titrated to 10mg within 4 weeks. During administration of the study treatment, subjects will undergo laboratory testing including MMPs and be monitored for the occurrence of adverse events up to 24 weeks. The primary endpoint will be the change rate of MMPs at 24 weeks after administration., Conclusions: INVITATION will compare the appropriate or low dose of rosuvastatin in the effects on serum levels of inflammatory markers including MMPs in AMI patients. This study will provide significant information on rosuvastatin as an anti-inflammatory agent for AMI., (Copyright © 2018 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Appropriate calcium and phosphate supplementation is essential for bone growth in preterm infants. Using Rehabix-K2™ (AY Pharmaceuticals, Tokyo, Japan) and Pleamin-P Injection™ (Fuso Pharmaceutical Industries, Osaka, Japan) as the total parenteral nutrition (TPN) and amino acid solution, respectively, we investigated ways of maximizing calcium and phosphate in the TPN solution., Methods: Rehabix-K2, Pleamin-P, calcium gluconate, sodium phosphate, 50% glucose, and water were mixed in varying proportions to create 16 formulations. Precipitation assessment was done three times for each of the 16 formulations, and was based on the Japanese Pharmacopeia., Result: Precipitation was observed 24 h after mixing when the calcium and phosphate were 60 mEq/L and 30 mmol/L or 80 mEq/L and 40 mmol/L, respectively. No precipitation was observed when the calcium and phosphate were 20 mEq/L and 10 mmol/L, respectively. Precipitation was observed once out of three times, when the calcium and phosphate were 40 mEq/L and 20 mmol/L, respectively, and the amino acids were 2% and 3% (mean pH, 6.13 and 6.26, respectively). No precipitation was observed, however, when the calcium and phosphate were 40 mEq/L and 20 mmol/L, respectively, and the amino acids were 0% and 1% (mean pH, 5.88 and 6.05, respectively)., Conclusion: Not only the concentration of calcium and phosphate, but also the pH of the TPN solution, are crucial factors for precipitation. Based on these results, a well-balanced TPN solution maximizing calcium and phosphate availability will be able to be formulated., (© 2018 Japan Pediatric Society.)

Background and Purpose: To define desirable target low-density lipoprotein (LDL) cholesterol levels for the prevention of stroke recurrence, a post hoc analysis was performed in the J-STARS study (Japan Statin Treatment Against Recurrent Stroke)., Methods: Subjects (n=1578) were divided into groups based on mean value of postrandomized LDL cholesterol levels until the last observation in 20 mg/dL increments. Adjusted hazard ratios (HRs) and 95% confidence intervals were analyzed for each group, with adjustments for baseline LDL cholesterol, baseline body mass index, hypertension, diabetes mellitus, and statin usage., Results: The postrandomized LDL cholesterol level until the last observation were 104.1±19.3 mg/dL in the pravastatin group and 126.1±20.6 mg/dL in the control group. The adjusted HRs for stroke and transient ischemic attack and all vascular events decreased in the postrandomized LDL cholesterol level of 80 to 100 mg/dL ( P =0.23 and 0.25 for the trend, respectively). The adjusted HR for atherothrombotic infarction significantly reduced with the usage of statin after adjusting baseline LDL cholesterol levels (HR, 0.39; 95% confidence intervals, 0.19-0.83). The adjusted HR for atherothrombotic infarction and intracranial hemorrhage were similar among the postrandomized LDL-cholesterol-level subgroups ( P =0.50 and 0.37 for the trend, respectively). The adjusted HR for lacunar infarction decreased in the postrandomized LDL cholesterol level of 100 to 120 mg/dL (HR, 0.45; 95% confidence intervals, 0.20-0.99; P =0.41 for the trend)., Conclusions: The composite risk of stroke and transient ischemic attack reduced in the postrandomized LDL cholesterol level of 80 to 100 mg/dL after adjusting for statin usage., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00221104., (© 2018 American Heart Association, Inc.)

Background: Interruption of sedation due to a poor response to modified neuroleptanalgesia (m-NLA) with midazolam often occurs during endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) because most patients have a history of heavy alcohol intake. Recently, propofol has been used feasibly and safely during endoscopic procedures. The aim of this study was to clarify the efficacy and safety of propofol compared with that of midazolam during ESD for ESCC., Methods: This was a single-blind, randomized controlled trial in a single center. Patients with ESCC scheduled for ESD were included in the study. Patients were randomly assigned to one of two groups: the propofol group and the midazolam group. The main outcome was the incidence of discontinuation of the procedure due to a poor response to sedation. Secondary outcomes included risk factors for a poor response to sedation., Results: Between April 2014 and October 2015, 132 patients (n = 66 per group) who underwent ESD for ESCC were enrolled in this study. The incidence of discontinuation due to a poor response to sedation in the propofol and midazolam groups was 0% (0/66) and 37.9% (25/66), respectively (p < 0.01). Multivariate analyses revealed that use of midazolam [Odds ratio (OR), 7.61; 95% confidence interval (CI), 2.64-21.92; p < 0.01] and age (OR, 0.93; 95% CI, 0.86-0.98; p < 0.01) were risk factors for a poor response to sedation., Conclusions: Our study indicates that, compared with midazolam, propofol is a more efficient sedative for m-NLA during ESD for ESCC.