Background: The potassium voltage-gated channel subfamily Q member 1 (KCNQ1) gene has recently received much attention as a candidate susceptibility gene for type 2 diabetes mellitus, especially in Asian populations. We previously reported that Kcnq1 mutant mice exhibit reduced insulin secretion and hyperglycemia due to a decrease in pancreatic β-cell mass. Through in vivo and in vitro analyses, we ascertained that this mechanism is the result of the downregulation of the non-coding RNA ‘Kcnq1ot1,’ which is expressed in the paternal allele of the Kcnq1 gene region, causing an increase in the expression of the cell cycle inhibitor cyclin dependent kinase inhibitor 1C (Cdkn1c). It was found that decreased Kcnq1ot1 expression resulted in pancreatic β-cell failure; however, the degree of pancreatic β-cell volume reduction was not severe. Methods: We induced obesity in Kcnq1ot1 truncation mice by feeding them a high-fat diet and evaluated pancreatic β-cell mass. Results: In the present study, we reveal that CCAAT/enhancer binding protein beta (C/EBPβ), which is expressed at higher levels in pancreatic β-cells in obese individuals, further increases the expression of Cdkn1c, which is upregulated by the Kcnq1 gene mutation. We found that simultaneous Cdkn1c hypomethylation and C/EBPβ overexpression in pancreatic β-cells causes a synergistic decrease in pancreatic β-cell mass. Conclusion This finding suggests that the synergistic effect of genetic factors such as Kcnq1 gene mutations and environmental factors such as obesity and overeating, which lead to increased expression of C/EBPβ, contribute to the regulation of pancreatic β-cell mass. This study is the first to show that the Kcnq1 gene is related to pancreatic β-cell mass through genetic-environment interactions.

Purpose: Adjuvant pembrolizumab improved disease-free survival (DFS) and overall survival (OS) versus placebo in participants with renal cell carcinoma (RCC) at increased risk of recurrence after nephrectomy in the global phase 3 KEYNOTE-564 study. This post hoc subgroup analysis evaluated the efficacy and safety of adjuvant pembrolizumab in East Asian (Japan, South Korea, and Taiwan) participants enrolled in KEYNOTE-564. Materials and Methods: Eligible participants were randomly assigned 1:1 to receive adjuvant pembrolizumab 200 mg or placebo intravenously every 3 weeks for ≤ 17 cycles. The primary endpoint was DFS by investigator assessment. OS was a key secondary endpoint. Safety was a secondary endpoint. Results: The East Asian subgroup included 126 participants (pembrolizumab, n=58; placebo, n=68). Median follow-up was 62.1 months (range, 49.6 to 73.0 months). Hazard ratio for DFS with pembrolizumab versus placebo was 0.70 (95% confidence interval 0.41 to 1.20). Median DFS was not reached with pembrolizumab versus 58.8 months with placebo; estimated 48-month rate was 61.3% versus 51.2%. Hazard ratio for OS was 0.47 (95% confidence interval, 0.15 to 1.49). Median OS was not reached with pembrolizumab and placebo; estimated 48-month rate was 94.8% versus 91.2%. Treatment-related adverse events occurred in 70.7% of participants (29.3% grade 3 or 4) receiving pembrolizumab and 36.8% of participants (0.0% grade 3 or 4) receiving placebo. No pembrolizumab-related deaths occurred. Conclusion In the KEYNOTE-564 East Asian subgroup, adjuvant pembrolizumab provided DFS and OS benefits versus placebo and had a safety profile consistent with the global results. These results further support pembrolizumab as adjuvant treatment for East Asian patients with RCC at increased risk of recurrence after nephrectomy.

Background: and Purpose To investigate the association between derivatives of reactive oxygen metabolites (d-ROMs), biological antioxidant potential (BAP) and the risk of stroke by subtype, and ischemic heart disease (IHD). Methods: We employed a case cohort design consisting of cardiovascular disease cases (n=1,521; stroke, n=1,271; IHD, n=265) and a random sub-cohort (n=4,761) in a large Japanese population-based study. d-ROMs and BAP were measured in plasma samples collected between 1995 and 1999. Hazard ratios (HRs) were estimated using weighted Cox proportional hazards methods according to d-ROMs and BAP quartiles, adjusted for age, sex, area, and potential confounding factors. Results: Analysis revealed a positive association between d-ROMs and the risk of total stroke, ischemic stroke, IHD, and the composite outcome of ischemic stroke and IHD. The multivariable HRs and 95% confidence intervals (CIs) for the highest versus lowest quartiles for d-ROMs were 1.34 (95% CI: 1.11–1.63) for total stroke (P for trend<0.001), 1.47 (1.16–1.86) for ischemic stroke (P for trend<0.001), 1.47 (1.02–2.11) for IHD (P for trend=0.072), 1.47 (0.87–2.49) for subarachnoid hemorrhage (P for trend=0.101), and 1.01 (0.72–1.41) for intraparenchymal hemorrhage (P for trend=0.618). In contrast, no significant association was detected between BAP levels and the risk of cardiovascular disease. Conclusions Analysis revealed that d-ROMs levels were positively associated with the risk of ischemic stroke and heart disease but not with hemorrhagic stroke.

We report a successful case of aortic valve-sparing root replacement for dilated aortic root after a Ross procedure. A 29-year-old male underwent a Ross procedure when he was 11 years old for congenital aortic bicuspid valve. The right ventricular outflow tract was reconstructed using an autologous pericardium as a single leaflet valve. Aortic root dilatation and moderate aortic valve regurgitation were noted. Further investigation with enhanced computed tomography and ultrasonic cardiography revealed good quality of leaflets and sufficient geometric height, and aortic valve-sparing root replacement was performed. In addition, we performed pulmonary valve replacement with a biological valve. The post-operative course was uneventful and the patient was discharged after 8 days with a completely controlled aortic valve regurgitation. No recurrence of aortic valve regurgitation was observed 1 year later. Because surgical outcomes of congenital heart diseases have improved and more patients have an increasing life expectancy, several other problems were revealed, such as the occurrence of aortic root dilatation after a Ross procedure. Aortic roots may dilate due to arterial pressure; however, valve-sparing procedures may be performed if the volume of the leaflets is sufficient.

Dopamine supersensitivity psychosis (DSP) is an unstable clinical condition observed in individuals with schizophrenia who have been treated with an antipsychotic medication at a high dosage and/or for a long period. An up-regulation of dopamine D2 receptors (DRD2) is thought to be involved in the essential pathology of DSP. An antipsychotic agent with both tight binding to DRD2 and a long half-life is generally effective for treating DSP, but a patient who meets the criteria of treatment-resistant schizophrenia sometimes needs treatment with clozapine. We report the case details of two patients whose DSP was not controlled with several antipsychotics but was successfully controlled with asenapine.Asenapine binds to a broad range of dopamine receptors and serotonin receptors, and it is thus distinct from other atypical antipsychotics. The unique profile of asenapine may contribute to the control of severe DSP symptoms in individuals with schizophrenia.

Background: and Purpose Differences in measurement of the extent of acute ischemic stroke using the Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) by non-contrast computed tomography (CT-ASPECTS stratum) and diffusion-weighted imaging (DWI-ASPECTS stratum) may impact the efficacy of endovascular therapy (EVT) in patients with a large ischemic core. Methods: The RESCUE-Japan LIMIT (Recovery by Endovascular Salvage for Cerebral Ultra-acute Embolism Japan–Large IscheMIc core Trial) was a multicenter, open-label, randomized clinical trial that evaluated the efficacy and safety of EVT in patients with ASPECTS of 3–5. CT-ASPECTS was prioritized when both CT-ASPECTS and DWI-ASPECTS were measured. The effects of EVT on the modified Rankin Scale (mRS) score at 90 days were assessed separately for each stratum. Results: Among 183 patients, 112 (EVT group, 53; No-EVT group, 59) were in the CT-ASPECTS stratum and 71 (EVT group, 40; No-EVT group, 31) in the DWI-ASPECTS stratum. The common odds ratio (OR) (95% confidence interval) of the EVT group for one scale shift of the mRS score toward 0 was 1.29 (0.65–2.54) compared to the No-EVT group in CT-ASPECTS stratum, and 6.15 (2.46–16.3) in DWI-ASPECTS stratum with significant interaction between treatment assignment and mode of imaging study (P=0.002). There were significant interactions in the improvement of the National Institutes of Health Stroke Scale score at 48 hours (CT-ASPECTS stratum: OR, 1.95; DWIASPECTS stratum: OR, 14.5; interaction P=0.035) and mortality at 90 days (CT-ASPECTS stratum: OR, 2.07; DWI-ASPECTS stratum: OR, 0.23; interaction P=0.008). Conclusion Patients with ASPECTS of 3–5 on MRI benefitted more from EVT than those with ASPECTS of 3–5 on CT.

Feedback is an educational activity that occurs in a variety of settings in medical education and has been widely discussed since 2008, when Ridder et al. defined it as "Specific information about the comparison between a trainee's observed performance and a standard, given with the intent to improve the trainee's performance." (Ridder et al., 2008, p.3). Since then, discussions on effective feedback have shifted from a behaviorist, instructor-centered approach to a more multifaceted approach that focuses on relationship and the learner as recipient of feedback, or the learner's potential ability to make use of feedback (self-regulated learning, feedback literacy).

Cardiac metastasis from cervical cancer is rare. We herein present a case involving a 54-year-old woman with cervical cancer who was undergoing radiotherapy for left supraclavicular lymph node metastasis. The patient was admitted to the hospital because of shortness of breath. Transthoracic echocardiography showed a large mass in the right ventricle. To rescue the patient from circulatory collapse, we surgically resected the intracardiac mass via a right ventricular incision parallel to the posterior descending artery and left anterior descending artery. This approach prevented right ventricular outflow tract obstruction and perioperative pulmonary embolization, which could have led to death. The intracardiac mass was diagnosed as squamous cell carcinoma. After hospital discharge, the patient underwent chemotherapy. An echocardiography performed 3 months postoperatively showed recurrence of the cardiac metastasis, and the patient died 5 months later. Cardiac metastasis in the right ventricle can present as pulmonary embolization. Although rare, most cases of metastasis from cervical carcinoma to the heart have an extremely poor prognosis.

Teaching professionalism is one of the most important themes in medical education, but difficulties remain regarding teaching and assessment. From the perspective of professionalism assessment discussions have focused on observable “behaviors” and redefining them as unprofessional behaviors has been growing since around 2000, especially in North America. This paper summarizes the concepts related to classification, assessment, and remediation of unprofessional behavior, including Japanese trends. It also aims to enlighten the public on concepts related to unprofessional behavior and to promote research that is relevant to the Japanese context. Through appropriate management of unprofessional behavior, we hope to foster medical students and doctors who can better withstand the demands of society.

Background: Type 1 diabetes mellitus induced by immune-checkpoint inhibitors (ICI-T1DM) is a rare critical entity. However, the etiology of ICI-T1DM remains unclear. Methods: In order to elucidate risk factors for ICI-T1DM, we evaluated the clinical course and immunological status of patients with ICI-T1DM who had been diagnosed during 2016 to 2021. Results: Seven of 871 (0.8%, six men and one woman) patients developed ICI-T1DM. We revealed that the allele frequencies of human leukocyte antigen (HLA)-DPA1*02:02 and DPB1*05:01 were significantly higher in the patients with ICI-T1DM In comparison to the controls who received ICI (11/14 vs. 10/26, P=0.022; 11/14 vs. 7/26, P=0.0027, respectively). HLA-DRB1*04:05, which has been found to be a T1DM susceptibility allele in Asians, was also observed as a high-risk allele for ICI-T1DM. The significance of the HLA-DPB1*05:01 and DRB1*04:05 alleles was confirmed by an analysis of four additional patients. The absolute/relative neutrophil count, neutrophils-lymphocyte ratio, and neutrophil-eosinophil ratio increased, and the absolute lymphocyte count and absolute/relative eosinophil count decreased at the onset as compared with 6 weeks before. In two patients, alterations in cytokines and chemokines were found at the onset. Conclusion Novel high-risk HLA alleles and haplotypes were identified in ICI-T1DM, and peripheral blood factors may be utilized as biomarkers.