Investigating the perceptions of career development as the Japanese regional quota medical students and graduates in A prefecture.

Background: There are few reports about the perceptions of the regional quota called Chiikiwaku medical students and graduates. Method: Eighty-four medical students and 41 graduates were enrolled in A prefecture. The questionnaire comprised 22 items scored on a 7-point Likert scale, focusing on perceptions of merit and demerit of Chiikiwaku. The data were collected online. Results: Chiikiwaku students scored higher on an item such as 'regional quotas are a solution to the doctor shortage'. Chiikiwaku graduates felt more burdened than Chiikiwaku students. Conclusion: Our results suggested that the perception of Chiikiwaku was different between Chiikiwaku students and graduates.

Engineering CD3/CD137 dual specificity into a DLL3-targeted T-cell engager enhances T-cell infiltration and efficacy against small cell lung cancer.

Small cell lung cancer (SCLC) is an aggressive cancer for which immune checkpoint inhibitors (ICIs) have had only limited success. Bispecific T-cell engagers are promising therapeutic alternatives for ICI-resistant tumors, but not all SCLC patients are responsive. Herein, to integrate CD137 costimulatory function into a T-cell engager format and thereby augment therapeutic efficacy, we generated a CD3/CD137 dual-specific Fab and engineered a DLL3-targeted trispecific antibody (DLL3 trispecific). The CD3/CD137 dual-specific Fab was generated to competitively bind to CD3 and CD137 to prevent DLL3-independent cross-linking of CD3 and CD137, which could lead to systemic T-cell activation. We demonstrated that DLL3 trispecific induced better tumor growth control and a marked increase in the number of intratumoral T cells compared to a conventional DLL3-targeted bispecific T-cell engager. These findings suggest that DLL3 trispecific can exert potent efficacy by inducing concurrent CD137 costimulation and provide a promising therapeutic option for SCLC.

Engineering CD3/CD137 Dual Specificity into a DLL3-Targeted T-Cell Engager Enhances T-Cell Infiltration and Efficacy against Small-Cell Lung Cancer.

Small-cell lung cancer (SCLC) is an aggressive cancer for which immune checkpoint inhibitors (ICI) have had only limited success. Bispecific T-cell engagers are promising therapeutic alternatives for ICI-resistant tumors, but not all patients with SCLC are responsive. Herein, to integrate CD137 costimulatory function into a T-cell engager format and thereby augment therapeutic efficacy, we generated a CD3/CD137 dual-specific Fab and engineered a DLL3-targeted trispecific antibody (DLL3 trispecific). The CD3/CD137 dual-specific Fab was generated to competitively bind to CD3 and CD137 to prevent DLL3-independent cross-linking of CD3 and CD137, which could lead to systemic T-cell activation. We demonstrated that DLL3 trispecific induced better tumor growth control and a marked increase in the number of intratumoral T cells compared with a conventional DLL3-targeted bispecific T-cell engager. These findings suggest that DLL3 trispecific can exert potent efficacy by inducing concurrent CD137 costimulation and provide a promising therapeutic option for SCLC.

Deep Learning-Driven Estimation of Centiloid Scales from Amyloid PET Images with 11C-PiB and 18F-Labeled Tracers in Alzheimer's Disease.

BACKGROUND: Standard methods for deriving Centiloid scales from amyloid PET images are time-consuming and require considerable expert knowledge. We aimed to develop a deep learning method of automating Centiloid scale calculations from amyloid PET images with 11C-Pittsburgh Compound-B (PiB) tracer and assess its applicability to 18F-labeled tracers without retraining. METHODS: We trained models on 231 11C-PiB amyloid PET images using a 50-layer 3D ResNet architecture. The models predicted the Centiloid scale, and accuracy was assessed using mean absolute error (MAE), linear regression analysis, and Bland-Altman plots. RESULTS: The MAEs for Alzheimer's disease (AD) and young controls (YC) were 8.54 and 2.61, respectively, using 11C-PiB, and 8.66 and 3.56, respectively, using 18F-NAV4694. The MAEs for AD and YC were higher with 18F-florbetaben (39.8 and 7.13, respectively) and 18F-florbetapir (40.5 and 12.4, respectively), and the error rate was moderate for 18F-flutemetamol (21.3 and 4.03, respectively). Linear regression yielded a slope of 1.00, intercept of 1.26, and R2 of 0.956, with a mean bias of -1.31 in the Centiloid scale prediction. CONCLUSIONS: We propose a deep learning means of directly predicting the Centiloid scale from amyloid PET images in a native space. Transferring the model trained on 11C-PiB directly to 18F-NAV4694 without retraining was feasible.

Impacts of "Diabetes Theater," a participative educational workshop for health care professionals, on participants: a patient empowerment perspective.

Introduction: Patient empowerment, as part of patient-centered care, is important in the treatment of diabetes. However, this concept is still not well-understood by healthcare professionals, because it differs substantially from traditional approaches. We developed the "Diabetes Theater" workshop to promote a better understanding of patient empowerment. The present study sought to characterize the learning experience and impact of Diabetes Theater on participants' perceptions regarding patient empowerment. Methods: We analyzed the data using mixed methods. Quantitative data were collected using a questionnaire with a five-item, 11-point Likert scale derived from the Diabetes Attitude Scale. The qualitative component asked the question "If you had to tell your colleagues at work two things you felt or learned at the Diabetes Theater, what would they be?" Quantitative data were analyzed using t tests, and free-text responses were analyzed using Steps for Coding and Theorization. Results: We received 131 responses. Nurses were the most numerous respondents, followed by dietitians, physicians, and pharmacists. Scores for the five items after participation increased in the direction of promoting participants' understanding of and attitudes toward patient empowerment compared to pre-participation. Scores for most questions increased significantly, regardless of the participants' occupation. In their answers to the open-ended questions, participants reported that they had learned about patient empowerment. Discussion: Diabetes Theater appears to be a useful method for healthcare professionals to accurately understand the philosophy of patient empowerment in diabetes.

Characterizations of a neutralizing antibody broadly reactive to multiple gluten peptide:HLA-DQ2.5 complexes in the context of celiac disease.

In human celiac disease (CeD) HLA-DQ2.5 presents gluten peptides to antigen-specific CD4+ T cells, thereby instigating immune activation and enteropathy. Targeting HLA-DQ2.5 with neutralizing antibody for treating CeD may be plausible, yet using pan-HLA-DQ antibody risks affecting systemic immunity, while targeting selected gluten peptide:HLA-DQ2.5 complex (pHLA-DQ2.5) may be insufficient. Here we generate a TCR-like, neutralizing antibody (DONQ52) that broadly recognizes more than twenty-five distinct gluten pHLA-DQ2.5 through rabbit immunization with multi-epitope gluten pHLA-DQ2.5 and multidimensional optimization. Structural analyses show that the proline-rich and glutamine-rich motif of gluten epitopes critical for pathogenesis is flexibly recognized by multiple tyrosine residues present in the antibody paratope, implicating the mechanisms for the broad reactivity. In HLA-DQ2.5 transgenic mice, DONQ52 demonstrates favorable pharmacokinetics with high subcutaneous bioavailability, and blocks immunity to gluten while not affecting systemic immunity. Our results thus provide a rationale for clinical testing of DONQ52 in CeD.

[Video-assisted Thoracoscopic Surgery for Mediastinal Tumor and Thoracic Wall Tumor].

"A final conceptual change concerns the appreciation that all major thymoma subtypes can behave in a clinically aggressive fashion and, therefore, should no longer be called benign tumors, irrespective tumor stage. Accordingly, their International Classification of Disease for Oncology( ICD)-O codes now have a /3 suffix, thymomas, for as malignant.1)" This manuscript indicated that almost all mediastinal tumors, which could not be easy to diagnose per-operatively, should be removed. There were two large problems for mediastinal tumors resection with video-assisted thoracoscopic surgery (VATS). First is management or approach for the thymic vein, which have a short distance but large diameter relatively, and individual variation about the position and the number. Some solutions were 1) performance of pre-operative enhanced computed tomograpy( CT) or magnetic resonance imaging( MRI), 2) transcervical approach with Kent retractor, 3) sternal-L shape approach. Second is for the patients, which have thymoma or thymic tumor with myasthenia gravis, to what extent should be removed anterior fatty tissue. For the moment including beneath the innominate vein it should be removed as extent as possible. Liga Sure Impact was useful to remove a large thoracic wall tumor with VATS for resection of thick muscle.

＜Editors' Choice＞ Myelodysplastic syndrome with trisomy 8 presenting periodic fever and multiple MEFV gene variants outside exon 10: a case report.

Myelodysplastic syndrome is associated with the development of autoinflammatory conditions, such as recurrent fever, polymyalgia, arthralgia, and erythema. Trisomy 8 is a common chromosomal abnormality in patients with myelodysplastic syndrome. Myelodysplastic syndrome with trisomy 8 involves autoinflammatory conditions, especially Behçet's disease-like symptoms with intestinal mucosal damage. MEFV variants, particularly those in exon 10, are pathogenic in familial Mediterranean fever, the most common autoinflammatory disease, presenting typical symptoms such as periodic fever and pleuritis/pericarditis/peritonitis. MEFV variants outside exon 10 are common in Japanese patients with familial Mediterranean fever and are associated with atypical symptoms, including myalgia and erythema. MEFV variants in myelodysplastic syndrome with trisomy 8 have rarely been investigated, although myelodysplastic syndrome with trisomy 8 might develop autoinflammatory conditions similar to those in familial Mediterranean fever. We encountered a 67-year-old man who had myelodysplastic syndrome with trisomy 8 and multiple MEFV variants outside exon 10. He presented with periodic fever, as well as chest/abdominal pain, myalgia, and erythema, although the symptoms did not fulfill the diagnostic criteria of familial Mediterranean fever. We discussed the possibility that these symptoms are modified by MEFV variants outside exon 10 in myelodysplastic syndrome with trisomy 8.

Development of an automatic multiplanar reconstruction processing method for head computed tomography.

BACKGROUND: Head computed tomography (CT) is a commonly used imaging modality in radiology facilities. Since multiplanar reconstruction (MPR) processing can produce different results depending on the medical staff in charge, there is a possibility that the antemortem and postmortem images of the same person could be assessed and identified differently. OBJECTIVE: To propose and test a new automatic MPR method in order to address and overcome this limitation. METHODS: Head CT images of 108 cases are used. We employ the standardized transformation of statistical parametric mapping 8. The affine transformation parameters are obtained by standardizing the captured CT images. Automatic MPR processing is performed by using this parameter. The sphenoidal sinus of the orbitomeatal cross section of the automatic MPR processing of this study and the conventional manual MPR processing are cropped with a matrix size of 128×128, and the value of zero mean normalized correlation coefficient is calculated. RESULTS: The computed zero mean normalized cross-correlation coefficient (Rzncc) of≥0.9, 0.8≤Rzncc < 0.9 and 0.7≤Rzncc < 0.8 are achieved in 105 cases (97.2%), 2 cases (1.9%), and 1 case (0.9%), respectively. The average Rzncc was 0.96±0.03. CONCLUSION: Using the proposed new method in this study, MPR processing with guaranteed accuracy is efficiently achieved.

Congenital sideroblastic anemia model due to ALAS2 mutation is susceptible to ferroptosis.

X-linked sideroblastic anemia (XLSA), the most common form of congenital sideroblastic anemia, is caused by a germline mutation in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene. In XLSA, defective heme biosynthesis leads to ring sideroblast formation because of excess mitochondrial iron accumulation. In this study, we introduced ALAS2 missense mutations on human umbilical cord blood-derived erythroblasts; hereafter, we refer to them as XLSA clones. XLSA clones that differentiated into mature erythroblasts showed an increased frequency of ring sideroblast formation with impaired hemoglobin biosynthesis. The expression profiling revealed significant enrichment of genes involved in ferroptosis, which is a form of regulated cell death induced by iron accumulation and lipid peroxidation. Notably, treatment with erastin, a ferroptosis inducer, caused a higher proportion of cell death in XLSA clones. XLSA clones exhibited significantly higher levels of intracellular lipid peroxides and enhanced expression of BACH1, a regulator of iron metabolism and potential accelerator of ferroptosis. In XLSA clones, BACH1 repressed genes involved in iron metabolism and glutathione synthesis. Collectively, defective heme biosynthesis in XLSA clones could confer enhanced BACH1 expression, leading to increased susceptibility to ferroptosis. The results of our study provide important information for the development of novel therapeutic targets for XLSA.

A 2-item version of the Japanese Consultation and Relational Empathy measure: a pilot study using secondary analysis of a cross-sectional survey in primary care.

BACKGROUND: The Consultation and Relational Empathy (CARE) measure is a patient-reported measure of physician empathy which is widely used internationally. The Japanese version of the CARE measure has very high internal reliability, suggesting that a shorter version may have adequate validity and reliability. OBJECTIVE: To investigate a valid shorter version of the Japanese CARE measure. METHODS: We conducted a pilot study using secondary analysis of previous data obtained from 9 general practitioners and 252 patients and used to develop the Japanese CARE measure. All 1,023 possible combinations of the Japanese CARE items (n = 1-10) were candidates for the short measure. The internal consistency (Cronbach's alpha) and the correlations between candidate short questionnaires and the original questionnaire were calculated. After selecting the most valid short questionnaire, inter-rater reliability was determined using generalizability theory, and construct validity (Spearman's rho) was determined using patient satisfaction. RESULTS: Two items were selected for a pilot shorter version: item 6 "Showing care and compassion" and item 9 "Helping you to take control." These showed high internal consistency and correlations with the 10-item measure (Cronbach's alpha = 0.920, correlation = 0.979). Forty-five questionnaires per doctor allowed us to reliably differentiate between practitioners. The construct validity for the pilot short measure was high (Spearman's rho 0.706, P < 0.001). CONCLUSION: We generated a pilot 2-item version of the Japanese CARE measure. This pilot 2-item version provides a basis for future validation studies of short CARE measures in other languages.

Key factors for overcoming psychological insulin resistance: A qualitative study in Japanese people with type 2 diabetes.

AIMS: We report the key factors that motivate reluctant Japanese people with type 2 diabetes (T2D) to initiate insulin treatment. METHODS: Participants were asked questions pertaining to 2 primary areas of exploration in a concurrent mixed methods approach: (a) understanding people's thoughts and perceptions before and after insulin initiation and any related factors; and (b) exploring the reasons behind people's responses. Data were analyzed using Steps for Coding and Theorization. RESULTS: Participant responses broadly related to 3 themes which influence insulin initiation; 1. Advice from a health care provider (HCP) that insulin is an appropriate treatment; 2. Demonstration by HCPs on how to use the insulin pen/needle and the injection process; and 3. Resignation/surrender/acceptance of insulin, where participants felt there was no other choice but to commence insulin. CONCLUSIONS: Based on the 3 identified themes, it is important for HCPs to explain the benefits of insulin and demonstrate and explain the injection procedure to reluctant Japanese people with T2D. We also identified resignation/surrender/acceptance of insulin as a reason for treatment commencement. This study provides important information to assist HCPs in helping reluctant Japanese people with T2D to initiate basal insulin therapy.

Diversity of academic general medicine: A cross-sectional bibliometric study of original English-language research articles in general medicine and cardiology in Japan.

ABSTRACT: Although research in general medicine is diverse, it has not been compared with research in a different medical specialty. The study aim was to understand the characteristics of research produced at Japanese university departments of general medicine and published in English-language journals, via comparison with another academic specialty, cardiology.In this cross-sectional study, a nationwide survey of the official websites of 82 university-affiliated medical schools in Japan was conducted in April 2020 to identify the heads of general medicine departments. We then surveyed the research output of these individuals in terms of original article output and research field diversity for journals listed in the Web of Science Core Collection of journals from 2010 to 2019. A similar survey of cardiology department publications was also conducted to provide a reference for intergroup comparisons and analysis of covariance.The analysis included 128 researchers from 78 general medicine departments and 96 researchers from 81 cardiology departments. The dominant research field of general medicine was general and internal medicine; that of cardiology was cardiac/cardiovascular systems. Data stratification by research field showed that general medicine researchers published significantly more articles than researchers in cardiology, a field that contains relatively few researchers. Furthermore, a comparison of individual researchers with the same number of published articles showed that researchers in general medicine departments published across a significantly wider range of fields than those in cardiology.This is the first study to describe the research characteristics of general medicine university departments in Japan through comparison with research in a different academic specialty. General medicine researchers in Japan comprise a heterogeneous group that mainly publishes research on general and internal medicine. Some general medicine researchers take a multidisciplinary approach to research and publishing.

Problem-Based Learning in Child and Adolescent Psychiatry: A Perspective from Japan.

PURPOSE: Japanese higher education institutions have long been striving for the globalization of medical education. Nagoya University (NU) adopted PBL as a means of enhancing intercultural awareness in globalizing medical education by working with the Norwegian University of Science and Technology (NTNU), Faculty of Medicine and Health Science, under the Trondheim NTNU-Nagoya (TroNa) partnership for mobility and internationalization of child and mental health studies. This study aims to assess students' attitudes towards PBL and to suggest future developments in this form of education by introducing common PBL scenarios experienced at NTNU and NU. METHODS: Two 90-minute PBL sessions were conducted at NU. Ten groups of medical students were formed, each consisting of up to 10 students, and students were asked to fill in a questionnaire developed to assess their understanding of, attitudes to and satisfaction with the classes. We investigated three different groups of questions on: NU medical students' general impressions of PBL; their impressions of PBL in child and adolescent psychiatry (CAP); and their impressions of PBL in specific case scenarios. Correlations between each of the questions from the three groups were evaluated using multivariate analysis. RESULTS: Overall, a majority of the NU medical students were satisfied with PBL, while a small number preferred traditional lecture-style learning (5%). More than half of the students agreed that PBL increased their understanding and interest in CAP (53%), although some male students felt that the amount of time spent was insufficient (20.3%). Correlations were seen for students who thought that PBL enhanced their understanding of and interest in CAP. Regarding case scenarios, most students (82.5%) agreed that PBL helped them to develop clinical problem-solving skills. CONCLUSION: The study found an overall positive attitude towards PBL, PBL in CAP and the specific PBL case scenario presented.

Students' perception of a hybrid interprofessional education course in a clinical diabetes setting: a qualitative study.

OBJECTIVES: To explore what the student participants learned and how they felt about the use of three educational settings, namely, face-to-face workshop setting, asynchronous and synchronous online learning environments and interactions with outpatients in a real-world clinical setting in a hybrid interprofessional education course. METHODS: This qualitative study used semi-structured in-depth interviews with healthcare undergraduate student participants in a course comprising workshops in three educational settings. A total of 15 healthcare undergraduate students, which included four medical, three pharmacy, five nursing and three nutrition students, completed this IPE course. All students agreed to participate in the study. We conducted four focus groups selected using convenient sampling. Focus group transcripts were analysed using the 'Steps for Coding and Theorization' qualitative data analysis method. We investigated the students' perception through the experience of three educational settings in the hybrid interprofessional education course. RESULTS: The students recognised that this course had three types of educational spaces, namely, real, semi-real and unreal. Then, the positive changes in the awareness of students are trained in recognition of the patient perspective, the recognition of the roles discharged by the other professions and the recognition of the functions of their own profession after experiencing the educational spaces designated for this course. CONCLUSIONS: The repeated experience of participants to real, semi-real and unreal educational spaces promoted changes over time in the students' awareness of interprofessional competencies with respect to patient-centred care and ameliorated their readiness to undertake interprofessional tasks.

[Contrivance for Video-assisted Thoracic Surgery Lung Operation Especially Lobectomy with Adhesive and Fissureless Complications].

There were 74 cases (29.5%) with adhesive and fissureless complications in comparison with all 251 cases who had undergone video-assisted thoracic surgery (VATS) lung operations in author's hospital. On lobectomy and segmentectomy adhesive and fissureless effective factors were old age( p=0.012), the difference between %DLco to %DLco/VA( p<0.05), Brinkman index( p=0.043) compared with non-ad- hesive cases, therefore operation times of fissureless group prolonged (p=0.009). The point at issue was in what manner we should perform appropriate division of the bronchus, the pulmonary arteries and the veins on the fissureless lobectomy. Especially it is very important which the apicoposterior artery( rA2b:Asc) on right upper lobectomy and the lingular segmental artery( lA4+5) on left upper lobectomy branch from the major fissure or not. For that purpose the management procedure had been done pulmonary artery (primary upper division: A1+2+A3)→ pulmonary vein → bronchus → residual pulmonary artery (rA2b or lA4+5). On the very severe fissureless cases the management procedure had been done pulmonary vein → bronchus → pulmonary artery. Mobilization of "fissure first, hilum last" and/or "hilum first, fissure last" techniques should be performed for VATS fissureless lobectomy.

Prediction of an oxygen extraction fraction map by convolutional neural network: validation of input data among MR and PET images.

PURPOSE: Oxygen extraction fraction (OEF) is a biomarker for the viability of brain tissue in ischemic stroke. However, acquisition of the OEF map using positron emission tomography (PET) with oxygen-15 gas is uncomfortable for patients because of the long fixation time, invasive arterial sampling, and radiation exposure. We aimed to predict the OEF map from magnetic resonance (MR) and PET images using a deep convolutional neural network (CNN) and to demonstrate which PET and MR images are optimal as inputs for the prediction of OEF maps. METHODS: Cerebral blood flow at rest (CBF) and during stress (sCBF), cerebral blood volume (CBV) maps acquired from oxygen-15 PET, and routine MR images (T1-, T2-, and T2*-weighted images) for 113 patients with steno-occlusive disease were learned with U-Net. MR and PET images acquired from the other 25 patients were used as test data. We compared the predicted OEF maps and intraclass correlation (ICC) with the real OEF values among combinations of MRI, CBF, CBV, and sCBF. RESULTS: Among the combinations of input images, OEF maps predicted by the model learned with MRI, CBF, CBV, and sCBF maps were the most similar to the real OEF maps (ICC: 0.597 ± 0.082). However, the contrast of predicted OEF maps was lower than that of real OEF maps. CONCLUSION: These results suggest that the deep CNN learned useful features from CBF, sCBF, CBV, and MR images and predict qualitatively realistic OEF maps. These findings suggest that the deep CNN model can shorten the fixation time for 15O PET by skipping 15O2 scans. Further training with a larger data set is required to predict accurate OEF maps quantitatively.

Effect of physician attire on patient perceptions of empathy in Japan: a quasi-randomized controlled trial in primary care.

BACKGROUND: There is limited quantitative research on the effect of physician attire on patient-physician relationships. This study aimed to measure the influence of Japanese family physicians' attire on the "human" aspects of medical care in terms of patient-perceived relational empathy. METHODS: This was a multicenter, prospective, controlled trial conducted in primary clinics in Japan. We explored the effects of family physician attire (white coat vs. casual attire) on patient-perceived empathy. Family physicians were allocated to alternate weeks of wearing a white coat or casual attire during consultations. Patients' perceptions of physician empathy were evaluated using the self-rated Japanese Consultation and Relational Empathy (CARE) Measure. We used a linear mixed model to analyze the CARE Measure scores, adjusting for cluster effects of patients nested within doctor, age, and sex of patients, and doctors' sex and years of clinical experience. We used the same method with Bonferroni adjustment to analyze patient sex differences in perceived empathy. RESULTS: A total of 632 patients of seven family physicians were allocated to white coat-wearing consultations (n = 328), and casual attire-wearing consultations (n = 304). There was no difference in CARE Measure scores between white coat and casual primary care consultations overall (p = 0.162). Subgroup analysis of patient sex showed that CARE Measure scores of male patients were significantly higher in the Casual group than in the White coat group (adjusted p-value = 0.044). There was no difference in female patient scores between White coat and Casual groups (adjusted p-value = 1.000). CONCLUSIONS: This study demonstrated that physician attire (white coat or casual attire) in a primary care setting did not affect patient-perceived relational empathy overall. However, male patients of physicians wearing casual attire reported higher physician empathy. Although empathy cannot be reduced to simple variables such as attire, white coats may have a negative effect on patients, depending on the context. Family physicians should choose their attire carefully. TRIAL REGISTRATION: Japanese University Hospital Medical Information Network (UMIN-ICDR). Clinical Trial identifier number UMIN000037687 (Registered August 14, 2019, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000042749 ). The study was prospectively registered.