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Kae Sunagawa,1,2 Keiji Hirai,3 Sumito Sunagawa,1,2 Norifumi Kamiya,1 Isao Komesu,1 Yusako Sunagawa,1 Hiroshi Sunagawa,1 Ken Nakachi,4 Aizan Hirai,5 Susumu Ookawara,3 Yoshiyuki Morishita3 1Sunagawa Medical Clinic, Okinawa, Japan; 2Division of Endocrinology, Diabetes and Metabolism, Hematology, and Rheumatology, University of the Ryukyus, Okinawa, Japan; 3Division of Nephrology, Saitama Medical Center, Jichi Medical University, Saitama, Japan; 4Department of Internal Medicine, Shonan Hospital, Okinawa, Japan; 5Department of Internal Medicine, Chiba Cerebral and Cardiovascular Center, Chiba, JapanCorrespondence: Keiji Hirai, Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Saitama-shi, Saitama-ken, 330-8503, Japan, Tel +81 48 647 2111, Fax +81 48 647 6831, Email keijihirai@kfy.biglobe.ne.jpPurpose: The aim of this study was to investigate the additional effects of empagliflozin on liraglutide in patients with advanced-stage type 2 diabetic kidney disease.Patients and Methods: Forty-one patients were randomly assigned (1:1) to treatment with liraglutide alone during the first 6 months and subsequent treatment with liraglutide plus empagliflozin during the next 6 months (liraglutide plus empagliflozin group) (n = 20) or treatment with liraglutide alone for 12 months (liraglutide group) (n = 21). Liraglutide was administered subcutaneously once daily at a starting dose of 0.3 mg/day and up-titrated weekly by 0.3 mg to a maximum dose of 0.9 mg/day. Empagliflozin was administered orally at a dose of 10 mg once daily. The primary outcome was the change in renal function (estimated glomerular filtration rate) during the latter 6 months. Secondary outcomes were changes in body weight, systolic blood pressure, hemoglobin, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, uric acid, blood glucose, hemoglobin A1c, and urine protein creatinine ratio during the latter 6 months.Results: Empagliflozin significantly increased the hemoglobin concentration (from 12.9 ± 1.9 to 13.7 ± 1.9 g/dL; p< 0.05) and decreased body weight (from 66.1 ± 12.9 to 64.5 ± 12.6 kg; p< 0.05). No significant differences were observed between the groups for estimated glomerular filtration rate, systolic blood pressure, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, uric acid, blood glucose, hemoglobin A1c, and urine protein creatinine ratio.Conclusion: Empagliflozin increased hemoglobin concentration and decreased body weight in patients with advanced-stage type 2 diabetic kidney disease who received liraglutide. However, empagliflozin did not provide short-term benefits with regard to renal function decline, urinary protein excretion, or glycemic control in these patients.Keywords: empagliflozin, sodium-glucose co-transporter 2 inhibitor, liraglutide, glucagon-like peptide-1 receptor agonist, diabetic kidney disease, diabetic nephropathy

The human estrogen receptor (ER) gene has recently been shown to transcribe two types of mRNA originating from two distinct promoters in mammary tumor cell lines, which encode the same protein. However, use of the two promoters has not been addressed in human breast cancer, which reveals a heterogeneity in terms of ER expression status and clinical characteristics. In this report, we investigated which promoter is responsible for the expression of ER in human mammary tumors by a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis for discriminatory detection of the two transcripts in mammary tissues obtained from patients with breast cancer. First, the use of distinct promoters was confirmed in several mammary tumor cell lines by the present RT-PCR method. Secondly, expression levels of total ER mRNA and two types of mRNAs from the different promoters were analysed in tumor, surrounding tissue and normal tissue obtained from 12 patients with breast cancer, which showed various levels of ER protein. In tumors, levels of total ER mRNA and the mRNA transcribed from a distal promoter showed remarkable correlation to the ER protein levels with correlation coefficients 0.946 (P < 0.001) and 0.746 (P < 0.005), respectively. In contrast, mRNA from a proximal promoter showed no correlation to the ER protein levels. Our results indicate that the enhancement of the ER mRNA expression from the distal promoter plays an essential role in the mechanisms of overexpressing ER protein in human mammary tumors, implying that a tumor-specific regulation of ER expression involved use of the distal promoter. [ABSTRACT FROM PUBLISHER]

A multifactorial approach to the aetiology of oesophageal cancer was made on the basis of a case-control study in Saitama prefecture, Japan. The joint risks of two factors were calculated directly from joint distributions, following a dichotomous exposure model. Three models of factor combinations were taken into account: two risk enhancing factors, two risk reducing factors, and risk enhancing and reducing factors. We observed remarkable risk elevations in the first model, and the observed joint risks were in the neighbourhood of the multiplicative products of single acting risks of individual factors. The highest odds ratios of about 10 or more were found with combinations of salty foods, excessive intake of rice and alcohol abuse. The second and third models also followed a multiplicative modification of risk. The lowest odds ratios of less than 0.2 were observed in the second model, with combinations of fruits and raw vegetables, fruits and seaweed, and raw vegetables and meat. In the third model, the increased risk caused by an enhancing factor was reduced proportionately to the presence of a risk reducing factor. Finally the dose-response relations of two factors were observed and shown to be categorised into three typical patterns of risk modification, following a three exposure level model. These patterns could be explained by both the dose-response relations of individual factors and the multiplicative modification of risk. [ABSTRACT FROM PUBLISHER]

Background: Insomnia is common in patients with psychiatric disorders. However, patients' awareness of sleep has seldom been examined in detail. In this study, we investigated sleep awareness in outpatients at the psychiatry department of a university hospital. Methods: The participants ( n = 241) were recruited at the psychiatry department of Ehime University Hospital between 11 October and 5 November 2021. The following questionnaires were used: Clinical Global Impression Scale of Severity (CGI-S), Global Assessment of Functioning (GAF), General Health Questionnaire (GHQ-30), Athens Insomnia Scale (AIS), and Epworth Sleepiness Scale (ESS). Psychiatric disorders were diagnosed by certified psychiatrists using the International Statistical Classification of Diseases and Related Health Problems 10. Participants with an AIS score of ≥6 were allocated to the insomnia group for statistical analysis. A logistic regression analysis was conducted to identify which items of sleep hygiene the patients with insomnia practiced using the Sleep Guidelines for Health Promotion. Results: Of 241 participants, 133 (55.2%) were allocated to the insomnia group. The mean scores for the CGI were significantly higher and the GAF scores were significantly lower in the insomnia group than in the healthy sleep group ( p < 0.01). Of the 12 sleep guidelines proposed by the Japanese Government, "Do not go to bed until you are sleepful, do not delay getting up", was the item that maximally influenced insomnia. Conclusions: The insomnia group had worse scores on various medical assessment scales compared to the healthy sleep group. Based on a survey of outpatients at the psychiatry department of the university hospital, appropriate stimulus control techniques may help clinicians to treat outpatients with insomnia.

A 66-year-old man presented to the gastroenterology department with anal pain. For >10 years, he had used an electric bidet toilet while defecating for >5 min at a time, because of constipation. Two weeks prior to his visit, he became aware of discomfort in his anal area and had used an enema 1 week previously. He had persistent diarrhea and began to use the electric bidet toilet at the highest water pressure for long periods. As a result, his anal pain worsened. A colonoscopy revealed circumferential inflammation and ulceration extending from the anal canal to the lower rectum. Approximately half of the Japanese population washes their anuses before and after defecation. Cleaning the anus after defecation using a bidet contributes to hand hygiene and local comfort, and may be effective against constipation. However, excessive bidet use may cause rectal disorders, such as rectal mucosal prolapse syndrome and solitary rectal ulcers. Herein, we report a rare case of a patient with advanced rectal ulceration caused by electric bidet toilet usage., Competing Interests: None., (© 2024 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Attention-deficit hyperactivity disorder (ADHD) is characterized by persistent symptoms of inattention, hyperactivity, and impulsivity. Both, stimulant and nonstimulant medications have been approved for the treatment of this disorder. Several Western guidelines recommend the use of prescribed Food and Drug Administration (FDA)-approved medications for ADHD along with parental training in behavior management and behavioral classroom intervention. In 2022, new Japanese guidelines for ADHD were issued, which recommended school environment management and psychosocial treatment as the first-line treatment, with pharmacological treatment added as the second-line treatment. Although Japanese guidelines, including pharmacological treatments, have been established, the guidelines and utilization of ADHD medications across Asian regions are unclear. Therefore, to appropriately evaluate the strategy of pharmacological treatments for ADHD, we investigated Asian regional guidelines for ADHD medication in children. We also reviewed the guidelines in Malaysia, Singapore, India, and the Republic of Korea and found that these guidelines differ from Western guidelines., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Introduction: Since May 2019, comprehensive genomic profiling (CGP) has been covered by Japan's health insurance system for patients with solid tumours that have progressed on standard chemotherapy, rare tumours or tumours of unknown primary origin. Although CGP has the potential to identify actionable mutations that can guide the selection of genomically matched therapies for patients with advanced cancer and limited treatment options, less than 10% of patients benefit from CGP testing, which may have a negative impact on patients' mental status. The aim of this study is to investigate the prevalence of psychological distress and associated factors among patients with advanced cancer who are undergoing CGP testing across Japan., Methods and Analysis: This multicentre, prospective cohort study will enrol a total of 700 patients with advanced cancer undergoing CGP testing. Participants will be asked to complete questionnaires at three timepoints: at the time of consenting to CGP testing (T1), at the time of receiving the CGP results (T2; 2-3 months after T1) and 4-5 months after T2 (T3). Primary outcome is the prevalence of depression as measured by the Patient Health Questionnaire-9 at the three timepoints. Secondary outcomes are the prevalence of anxiety and Quality of Life Score. Associated factors with psychological distress will also be examined, including knowledge about CGP, attitudes, values and preferences towards CGP, satisfaction with oncologists' communication and patient characteristics as well as medical information including CGP test results and genomically matched therapies if provided. The prevalence of depression and anxiety will be estimated using the unadjusted raw rates observed in the total sample. Longitudinal changes in measures will be explored by calculating differences between the timepoints. Multivariate associations between variables will be examined using multiple or logistic regression analysis depending on the outcomes to adjust for confounders and to identify outcome predictors., Ethics and Dissemination: This study was approved by the Institutional Review Board of the National Cancer Center Japan on 5 January 2023 (ID: 2022-228). Study findings will be disseminated through peer-reviewed journals and conference presentations., Trial Status: The study is currently recruiting participants and the enrolment period will end on 31 March 2025, with an expected follow-up date of 31 March 2026., Trial Registration Number: UMIN000049964., Competing Interests: Competing interests: All authors declare that they have no competing interests regarding this work. TK reports grants from PACT Pharma, Chugai Pharmaceutical, Daiichi Sankyo, Novartis, Eli Lilly Japan and Takeda Pharmaceutical, consulting fees from AMGEN and honoraria from Chugai Pharmaceutical, Sysmex Corporation and AstraZeneca outside the submitted work. KM reports honoraria from Chugai Pharmaceutical, Ono Pharmaceutical, Daiichi Sakyo and Eli Lilly Japan outside the submitted work. NT reports honoraria from Myriad Genetics, AstraZeneca, Takeda Pharmaceutical, Konica Minolta REALM, Taiho Pharmaceutical, Eisai, LSI Medience and QLife outside the submitted work. HO reports grants from Bristol-Myers Squibb, Chugai Pharmaceutical, Taiho Pharmaceutical, Astellas Pharma, Eli Lilly Japan and Merck Biopharma Japan outside the submitted work. MI reports honoraria from Chugai Pharmaceutical and AstraZeneca outside the submitted work. TM reports honoraria from Pfizer, Ayumi Pharmaceutical Corporation, Welby and Impute outside the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The first randomized controlled trial of adjuvant chemotherapy for biliary tract cancer was reported in 2002. Since then, studies have continued, with efficacy reported for capecitabine in 2018 and S-1 in 2023. Oral fluoropyrimidines have become established as the standard of care. This article reviews the evidence from the randomized controlled trials reported to date and those that are ongoing or from which results have not yet been reported., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In recent years, concerns about internet addiction (IA) among children have been increasing. This study focused on the awareness of IA in elementary school teachers. A web-based anonymous survey was conducted in November 2021. The participants completed an original questionnaire about their awareness of IA. The participants were divided into three groups based on their positions in the classroom: class teachers, support teachers, and administrative teachers. Out of 283 participants, over 70% had not approached students with IA and had little practical knowledge about the disorder. Support and administrative teachers had more opportunities to interact with students with IA than class teachers ( p < 0.001 in both cases). Support teachers had more opportunities to ask their colleagues about IA than class teachers ( p < 0.01); similarly, administrative teachers also had more opportunities to discuss IA with colleagues than class teachers ( p = 0.04). Preventive interventions are recommended for people who communicate with children with IA. Students with IA might cause anxiety among teachers; therefore, preventive education strategies should be implemented with the cooperation of psychiatrists, psychologists, and public health nurses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kawabe, Horiuchi, Hosokawa, Nakachi, Soga and Ueno.)

Introduction: This study aimed to evaluate the impacts of dapagliflozin on 24-hour glucose variability and diabetes-related biochemical variables in Japanese patients with type 2 diabetes who had received basal insulin supported oral therapy (BOT)., Research Design and Methods: Changes in mean daily blood glucose level before and after 48-72 hours of add-on or no add-on of dapagliflozin (primary end point) and diabetes-related biochemical variables and major safety variables during the 12 weeks (secondary end point) were evaluated in the multicenter, randomized, two-arm, open-label, parallel-group comparison study., Results: Among 36 participants, 18 were included in the no add-on group and 18 were included in the dapagliflozin add-on group. Age, gender, and body mass index were comparable between the groups. There were no changes in continuous glucose monitoring metrics in the no add-on group. In the dapagliflozin add-on group, mean glucose (183-156 mg/dL, p=0.001), maximum glucose (300-253, p<0.01), and SD glucose (57-45, p<0.05) decreased. Time in range increased (p<0.05), while time above the range decreased in the dapagliflozin add-on group but not in the no add-on group. After 12-week treatment with dapagliflozin add-on, 8-hydroxy-2'-deoxyguanosine (8OHdG), as well as hemoglobin A1c (HbA1c), decreased., Conclusions: This study showed that the mean daily blood glucose and other daily glucose profiles were amended after 48-72 hours of dapagliflozin add-on in Japanese patients with type 2 diabetes who received BOT. The diabetes-related biochemical variables such as HbA1c and urinary 8OHdG were also obtained during the 12 weeks of dapagliflozin add-on without major adverse events. A preferable 24-hour glucose profile in 'time in ranges' and an improvement in reactive oxygen species by dapagliflozin warrant us to evaluate these benefits in larger clinical studies., Trial Registration Number: UMIN000019457., Competing Interests: Competing interests: YT and KO have received lecture fees from Ono Pharmaceutical. SY have received lecture fees from AstraZeneca. KK, MSa, and MSh have received lecture fees from Ono Pharmaceutical and AstraZeneca., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Esophageal varices (EVs) are often treated using endoscopic injection sclerotherapy. Endoscopic submucosal dissection (ESD) has been used for early esophageal epithelial neoplasia worldwide. We report a case of early esophageal squamous cell carcinoma (ESCC) that occurred over EVs, in which the EVs were treated with endoscopic injection sclerotherapy before the early ESCC was treated with endoscopic submucosal dissection. Argon plasma coagulation was finally performed to prevent the recurrence of varices. No serious complications, such as severe bleeding or perforation, were observed. Histopathological examination revealed submucosal veins occluded with an organized thrombus for which endoscopic injection sclerotherapy with an intravariceal injection of sclerosant had been performed, but no fibrosis was observed outside the blood vessels. This explains that the injected sclerosant into EVs did not cause any tissue reaction like fibrosis in the submucosa surrounding the vein, which may have made endoscopic submucosal dissection safer and easier. Varices have not recurred, and ESCC has also not recurred for 5 years. We demonstrated a successful treatment of ESCC on EVs and no submucosal fibrosis other than inside the occluded vessels and verified it histologically., Competing Interests: Masayuki Kitano received honoraria for lectures from Olympus Co., Ltd. None of the other authors have any conflicts of interest to declare., (© 2022 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Esports (electronic sports) programs are a variant of competitive gaming and have expanded worldwide in recent years. The prevalence of problematic gaming and gaming disorders (GD) is predicted to increase in adolescents. Children with autism spectrum disorder (ASD) have a high rate of digital gaming use, and their characteristics, such as social communication deficits and restricted interests, might contribute to problematic gaming. In this study, we aimed to examine whether participation in an Esports program would lead to problematic gaming or GD in children with ASD. The Internet Gaming Disorder Test (IGD-20) scores, Kid-KINDL scores, and gaming time at home were assessed in eight children with ASD before beginning the Esports program and at the three-month follow-up timepoint. The program was held once a week at the welfare service center, where the participants played a set game for 60 min. The results indicated there was no significant worsening in any of the scores after the program. Our program provided the participation time and frequency of Esports, type of game, and motivation of the participants are adequately considered. Even though this pilot study is limited by the small sample size, we concluded that the risk of these activities leading to problematic gaming might be low.

Objective The change in serum lipid levels by direct-acting antiviral (DAA) treatment for chronic hepatitis C varies depending on the type of DAA. How the lipid level changes induced by glecaprevir-pibrentasvir (G/P) treatment contribute to the clinical outcome remains unclear. We conducted a prospective observational study to evaluate the effectiveness of G/P treatment and the lipid level changes. Methods The primary endpoint was a sustained virologic response at 12 weeks (SVR12). The total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels and LDL-C/HDL-C (L/H) ratio were measured every two weeks. Patients This study included 101 patients. Seventeen cases of liver cirrhosis and nine cases of DAA retreatment were registered. The G/P treatment period was 8 weeks in 74 cases and 12 weeks in 27 cases. Results SVR12 was evaluated in 96 patients. The rate of achievement of SVR12 in the evaluable cases was 100%. We found significantly elevated TC and LDL-C levels over the observation period compared to baseline. The serum levels of HDL-C did not change during treatment but were significantly increased after treatment compared to baseline. The L/H ratio was significantly increased two weeks after the start of treatment but returned to the baseline after treatment. Conclusion The primary endpoint of the SVR12 achievement rate was 100%. G/P treatment changed the serum lipid levels. Specifically, the TC and LDL-C levels increased during and after treatment, and the HDL-C levels increased after treatment. G/P treatment may be associated with a reduced thrombotic risk. Therefore, validation in large trials is recommended.

Case : A 66-year-old man started carboplatin + etoposide + atezolizumab therapy for advanced small cell lung cancer. Seventeen days after the start of treatment, the patient presented with hematemesis and underwent emergency endoscopy, which revealed multiple erosions and ulcers in the duodenum. Some ulcers showed pulsating bleeding, which was stopped by clipping and cauterization using hemostats. Biopsy of the mucosal peri-ulcer showed lymphocyte, eosinophil, and plasma cell infiltration. The patient was suggested to have acute hemorrhagic duodenitis, which was associated with immune checkpoint inhibitors (ICIs), and conservative treatment with blood transfusion and antacids was continued. However, 11 days after hemostasis, bleeding from a new ulcer was observed. Hemostasis was achieved by coagulation and clipping again, but the general condition of the patient deteriorated owing to the rapid progression of the primary disease, and he died 8 weeks after the start of treatment. Discussion : Although there have been several reports of colitis and other adverse events caused by ICIs, there have been very few reports of duodenitis. Endoscopic findings include diffuse erythema, erosions/ulcerations, and villous atrophy, and pathological findings include eosinophilic infiltration and increased levels of CD8-positive T cells. However, there have been no reports of duodenal mucosal damage caused after administration of atezolizumab nor of severe cases of massive bleeding requiring endoscopic hemostasis and blood transfusion, as in this case., Competing Interests: Authors declare no conflict of interests for this article., (© 2021 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

School closure due to coronavirus disease 2019 (COVID-19) pushed children across ages and nationalities into a state of mental health crisis. In Japan, children between the ages of 6 and 18 were ordered to stay at home and observe social distancing for several months. This study is aimed at investigating the effects of quarantine due to COVID-19 on children belonging to different developmental stages in life. Data were collected from mothers of typically developing children aged between 6 and 18 years. The differences in psychological and behavioral changes following school closure during the COVID-19 pandemic were explored. A total of 535 children, including 145 students in lower grades of elementary school (6-9 years), 124 students in higher grades of elementary school (9-12 years), 132 students in junior high school (12-15 years), and 134 students in high school (15-18 years), were recruited. Children in lower grades of elementary school (lower grades group) gained significantly lower understanding about COVID-19 and the necessity of COVID-19 restrictions than children in the other groups. Moreover, they had more psychological problems: they easily cried and complained, were unable to keep calm, and were dependent on parents and family members. Changes in sleep patterns were more prevalent in junior and senior high school students. We concluded that mental health care should be provided based on the growth period of each child not only during school closure but also after school reopening., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Kiwamu Nakachi et al.)