Correction: Suzuki et al. Cross-Country Student Perceptions about Online Medical Education during the COVID-19 Pandemic. Int. J. Environ. Res. Public Health 2022, 19, 2840.

In the published publication, there was an error regarding the affiliation for "Tomoya Suzuki" [...].

Mutated ZRSR2 and CUL3 accelerate clonal evolution and confer venetoclax resistance via RAS signaling pathway in blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive subtype of myeloid malignancy characterized by skin, lymph node and central nervous system (CNS) involvement. Although various regimens are used, a standard therapeutic strategy for BPDCN has not been established. Recent studies revealed that BPDCN patients frequently have a mutation in ZRSR2, which is a minor spliceosome component. However, the association between the clinical features of BPDCN and ZRSR2 mutational status remains unknown. A 70-year-old man was referred to our hospital with skin rash and enlarged lymph nodes, as well as blasts in the peripheral blood. BPDCN was diagnosed based on the immunophenotype of the blasts derived from bone marrow. Whole exome sequencing revealed that BPDCN cells collected at diagnosis had mutations in ZRSR2, ZBTB33, CUL3, TET2 and NRAS. RNA sequencing analysis indicated that U12-type intron retention occurred in LZTR1, caused by ZRSR2 loss. After seven cycles of venetoclax combined with azacitidine therapy, BPDCN cells appeared in the peripheral blood and infiltrated the CNS. Two KRAS mutated clones appeared at BPDCN recurrence. These findings are important for understanding the pathogenesis of BPDCN, which will inform development of novel therapeutic strategies.

Successful allogeneic hematopoietic stem cell transplantation for myelodysplastic neoplasms complicated with secondary pulmonary alveolar proteinosis and Behçet's disease harboring GATA2 mutation.

Myelodysplastic neoplasms (MDS) are defined by cytopenia and morphologic dysplasia originating from clonal hematopoiesis. They are also frequently complicated with diseases caused by immune dysfunction, such as Behçet's disease (BD) and secondary pulmonary alveolar proteinosis (sPAP). MDS with both BD and sPAP is extremely rare, and their prognosis is poor. In addition, haploinsufficiency of the hematopoietic transcription factor gene GATA2 is recognized as a cause of familial MDS and is frequently complicated by sPAP. Herein, we report a case of MDS combined with both BD and sPAP in association with GATA2 deficiency in a Japanese woman. Because she developed progressive leukopenia and macrocytic anemia during BD treatment at the age of 61, she underwent a bone-marrow examination and was diagnosed with MDS. She subsequently developed sPAP. At the age of 63, she underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Since allo-HSCT, she has maintained complete remission of MDS as well as the symptoms of BD and sPAP. Furthermore, we performed whole exome sequencing and identified the GATA2 Ala164Thr germline mutation. These findings suggest that patients with MDS, BD and sPAP should be considered for early allo-HSCT.

Survival rates of systemic interventions for psoriasis in the Western Japan Psoriasis Registry: A multicenter retrospective study.

Psoriasis affects approximately 0.3% of the Japanese population. Recently, various effective systemic drugs have become available, and the continuation of a given treatment has become critical because of the chronic nature of psoriasis. Factors affecting drug survival (the time until treatment discontinuation) in psoriasis treatment include efficacy, safety, ease of use, and patient preference. In the present study, the authors retrospectively surveyed a multifacility patient registry to determine the real-world evidence of the survival rate of systemic interventions for psoriasis treatment. Patients with psoriasis who visited 20 facilities in the Western Japan area between January 2019 and May 2020 and gave written consent were registered as study participants, and their medical history of systemic interventions for psoriasis (starting from 2010) was retrospectively collected and analyzed. The drugs investigated were adalimumab, infliximab, ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, risankizumab, cyclosporine, and apremilast. When drugs were discontinued, the reasons were also recorded. A total of 1003 patients with psoriasis including 268 with psoriatic arthritis (PsA) were enrolled. In biologics, more recently released drugs such as interleukin 17 inhibitors showed a numerically higher survival rate in the overall (post-2010) analysis. However, in the subset of patients who began treatment after 2017, the difference in the survival rate among the drugs was smaller. The reasons for discontinuing drugs varied, but a loss of efficacy against dermatological or joint symptoms were relatively frequently seen with some biologics and cyclosporine. The stratification of drug survival rates based on patient characteristics such as bio-naive or experienced, normal weight or obese, and with or without PsA, revealed that bio-experienced, obese, and PsA groups had poorer survival rates for most drugs. No notable safety issues were identified in this study. Overall, the present study revealed that the biologics show differences in their tendency to develop a loss of efficacy, and the factors that negatively impact the survival rate of biologics include the previous use of biologics, obesity, and PsA.

Japan's valsartan clinical trials shambles; time for fundamental changes.

Japan's Diovan® /valsartan 'scandal' has received sensational coverage in the nation's media since 2012. Publication of fraudulent research and their subsequent retraction boosted and then curtailed the use of what was a useful therapeutic drug. Some authors of the papers resigned, others disputed the retractions and resorted to legal counsel to protect themselves. One individual, an undeclared Novartis employee involved in the research, was arrested. A complex and virtually unwinnable case was brought against him and Novartis, claiming that data alteration amounted to false advertising, but lengthy criminal court cases resulted in the case failing. Unfortunately, key elements, including conflicts of interest, pharmaceutical company interference in trials of its product, and the role of the institutions involved, have been effectively ignored. The incident also emphasised the fact that Japan's unique society and approach to science does not conform well to international standards. Although the supposed impropriety caused the appearance of a new Clinical Trials Act in 2018, the law has been criticized for being ineffectual and simply increasing clinical trial bureaucracy. This article examines the 'scandal' and identifies where changes must be made to clinical research and the roles of the various stakeholders in Japan to increase public trust in clinical trials and biomedical publications.

Real-world evidence of the impact of obesity on residual teeth in the Japanese population: A cross-sectional study.

BACKGROUND: Tooth loss is associated with nutritional status and significantly affects quality of life, particularly in older individuals. To date, several studies reveal that a high BMI is associated with tooth loss. However, there is a lack of large-scale studies that examined the impact of obesity on residual teeth with respect to age and tooth positions. OBJECTIVE: We assessed the impact of obesity on the number and position of residual teeth by age groups using large scale of Japanese database. METHODS: This was a cross-sectional study of 706150 subjects that were included in the database that combined the data from health insurance claims and health check-up, those lacking information about BMI, HbA1c level, smoking status, and the number of residual teeth were excluded. Thus, a total of 233517 aged 20-74 years were included. Subjects were classified into 4 categories based on BMI, and the number of teeth was compared between age-groups. The percentage of subjects with residual teeth in each position was compared between groups with obesity (BMI ≥25.0 kg/m2) and non-obesity. Logistic regression analysis was performed to clarify whether obesity predicts having <24 teeth. RESULTS: Higher BMI was associated with fewer teeth over 40s (P for trend <0.0001 when <70s). Obesity was associated with the reduction of residual teeth in the maxillary; specifically, the molars were affected over the age 30. Smoking status further affected tooth loss at positions that were not affected by obesity alone. After adjusting for age, sex, smoking status, and HbA1c ≥6.5%, obesity remained an independent predictive factor for having <24 teeth (ORs: 1.35, 95% CIs: 1.30-1.40). CONCLUSIONS: We found that an increase in BMI was associated with a decrease in the number of residual teeth from younger ages independently of smoking status and diabetes in the large scale of Japanese database.

Successful management of unstable angina in a ravulizumab-treated patient with paroxysmal nocturnal hemoglobinuria.

Ravulizumab is an anti-C5 antibody approved for treating paroxysmal nocturnal hemoglobinuria (PNH). In August 2019, a 77-year-old Japanese man with PNH, who had been on ravulizumab treatment for 2 years, was hospitalized for chest discomfort and malaise. Electrocardiography identified a right bundle block, and elevated serum troponin I and d-dimer suggested ischemic heart disease. Cardiac catheterization revealed severe stenosis in the left anterior descending coronary artery, and intracoronary stenting relieved his chest discomfort. The final diagnosis was unstable angina unrelated to ravulizumab, and the patient's ravulizumab treatment was uninterrupted with no significant complications of PNH. This case report highlights the importance of continuing complement inhibition therapy during acute coronary events.

Cross-Country Student Perceptions about Online Medical Education during the COVID-19 Pandemic.

(1) Introduction: Most educational institutions around the world have shifted from traditional face-to-face to online education amid COVID-19. This change may particularly impact medical students, whose education is heavily influenced by clinical learning experiences. Accordingly, we investigated medical students' perceptions about positive and negative aspects of online medical education in Japan and overseas during the COVID-19 pandemic. (2) Methods: In-depth online interviews were conducted among 13 Japanese medical students and five medical students from Slovakia, Norway, and Hungary. Interviews were conducted from 23rd September to 3rd October 2020 using the snowball sampling method. Questions were focused on five main areas: Q1 the type of online education; Q2 advantages and disadvantages of online education; Q3 any changes in the relationship with teachers, friends, and family; Q4 any opinions about further improvements in online education; and Q5 any needs for affiliation with a particular university. Then thematic analysis was conducted. (3) Results: The results of the thematic analysis revealed the following four themes that represent the positive and negative aspects of online medical education; Theme 1: Timesaving and Flexibility; Theme 2: Technical problems and lack of digital skills; Theme 3: Unstandardized teaching skills; Theme 4: Lack of experience beyond medical school lectures. (4) Conclusions: While online education was found useful in terms of saving time and creating a flexible learning environment, many important drawbacks were noted such as internet and computer problems and unstandardized teaching skills, and lack of quality assurance. In addition, experiences outside the classroom such as making relationships with faculty and friends, conducting research and participating in extracurricular activities were missed, which they normally enjoy in college life.

Awareness and Perceptions among Members of a Japanese Cancer Patient Advocacy Group Concerning the Financial Relationships between the Pharmaceutical Industry and Physicians.

OBJECTIVES: Awareness and perceptions of financial conflicts of interest (FCOI) between pharmaceutical companies (Pharma) and healthcare domains remain unclear in Japanese cancer patient communities. This study aimed to assess awareness (RQ1), the influence of FCOI on physician trustworthiness (RQ2), and their perception (RQ3) among the Japanese cancer patient advocacy group members. METHODS: A cross-sectional study using a self-administered survey was conducted with a Japanese cancer patient advocacy group between January and February 2019. The main outcome measures included awareness and perceptions of physician-Pharma interactions, their impact on physician trustworthiness, and attitudes towards FCOI among medical and other professions. Furthermore, we performed thematic analyses on the comments which responders provided in the surveys. RESULTS: Among the 524 contacted members, 96 (18.3%) completed the questionnaire, including 69 (77.5%) cancer patients. In RQ1, most of the respondents were aware of physician-Pharma interactions, although the extent differed based on the nature of the interaction. Furthermore, the respondents mainly considered these interactions influential on clinical practice (RQ2) and agreed to the need for further regulation of physician-Pharma interactions (QR3). In qualitative analyses (n = 56), we identified the 4 following themes: perception towards the FCOI (Theme 1), concerns about the respondent's treatment (Theme 2), reason of physician-Pharma interactions (Theme 3), and possible solutions from the patient perspective (Theme 4). CONCLUSIONS: Most respondents were generally aware of physician-Pharma-associated FCOI and perceived them negatively. Additionally, participants appeared supportive of further FCOI regulation to protect patient-centred care. ABBREVIATIONS: FCOI-financial conflicts of interest; United States-US; Pharma-pharmaceutical companies; RQ-research question.

Glycemic control and number of natural teeth: analysis of cross-sectional Japanese employment-based dental insurance claims and medical check-up data.

AIM: Diabetes mellitus is a well-known risk factor for onset and progression of periodontal disease. However, the continuous relationship between glycemic control and the number of natural teeth has not been well characterized in large-scale studies. We aimed to determine whether the glycated hemoglobin A1c (HbA1c) level and fasting plasma glucose (FPG) are associated with the number of natural teeth. METHODS: A cross-sectional study: A database comprising employment-based health insurance claim and medical check-up data from 706,150 participants between April 2015 and March 2016 in Japan. The exclusion criteria included missing data regarding dental receipts, number of natural teeth, HbA1c, smoking status, and age < 20 years. Ultimately, 233,567 individuals were analyzed. The participants were allocated to five groups according to their HbA1c and three groups according to their FPG, and then the number of natural teeth were compared. RESULTS: Higher HbA1c was associated with fewer teeth in participants ≥ 30 years of age (P for trend < 0.001). Higher FPG was associated with fewer teeth between 30 and 69 years of age (P for trend < 0.001). Participants with impaired fasting glucose was already at risk for fewer teeth between 40 and 69 years of age than those with normal FPG. CONCLUSIONS: Glycemic control is strongly associated with the number of natural teeth in the real-world setting. Furthermore, there are continuous relationships of HbA1c and FPG with number of natural teeth including individual with impaired fasting glucose. These data emphasize the importance of glycemic control and appropriate oral care for the protection against tooth loss. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00533-2.

Weight Loss Intervention before Cord Blood Transplantation in an Obese Patient with Acute Myeloid Leukemia: A Case Study.

BACKGROUND: A severely obese woman (39.8 kg/m2) with relapsed acute myeloid leukemia was admitted to our hospital to undergo salvage chemotherapy followed by cord blood transplantation (CBT). CASE: During the salvage chemotherapy period, a 70-day weight loss program addressing diet and exercise was administered. After the 70-day intervention, the patient's body weight and body fat mass had decreased (8.6% and 15.0%, respectively) without any adverse events. The number of available cord blood units with total nucleated cells per body weight greater than 2 × 107/kg was zero at admission and two after weight loss; therefore, CBT could be performed. DISCUSSION: Considering this case, we suggest that a weight loss program combining exercise and nutrition therapy may help patients scheduled for hematopoietic stem cell transplantation by focusing on risk management.

Financial payments made by pharmaceutical companies to the authors of Japanese hematology clinical practice guidelines between 2016 and 2017.

Financial conflicts of interest (FCOI) between pharmaceutical companies and physicians may negatively impact patient care. This is particularly relevant regarding clinical practice guidelines (CPG), where FCOI may inappropriately influence individual drugs' promotion or use. In a cross-sectional analysis of pharmaceutical company payments, we sought to elucidate the extent of FCOI between Japanese hematologists and drug promotion in CPG. Data collected from two professional medical associations and companies belonging to the Japanese Pharmaceutical Manufacturers Association included the type and amount of company payments, individual financial disclosures, and new drug or indication approvals between 2015 and 2017. Of the 74 hematologists drafting CPG, 70 (94.6 %) received at least one payment during the study period. The cumulative median (interquartile range) value of these payments was $31,553 ($11,449-$74,390). Also, during this period, 26 new drugs or indications were approved and discussed in the CPG. Among the 79 pharmaceutical companies, the 11 (13.9 %) with newly approved and discussed drugs in the CPG made median (interquartile range) payments of $210,388 ($85,141-$292,536), while the remaining 68 (86.1 %) made $0 ($0-$9607) in payments. Disclosure of these payments was inconsistent. Such discrepancies suggest an association between pharmaceutical payments and drug approvals that only greater transparency can clarify. Consequently, a comprehensive overhaul of the current framework to control FCOI that includes legal regulation may be necessary.

How Do Institutional Conflicts of Interest Between Pharmaceutical Companies and the Healthcare Sector Become Corrupt? A Case Study of Scholarship Donations Between Department of Clinical Anesthesiology, Mie University, and Ono Pharmaceutical in Japan.

Institutional conflicts of interest (ICOIs) with pharmaceutical companies can bias internal operation of healthcare organizations. Naturally, a scholarship donation-which is a donation scheme unique to Japan, provided to healthcare organizations and their subunits to encourage educational and academic activities related to the development of new drugs-fall into the ICOI category. While anecdotal evidence exists that scholarship donations have been used as bribes by pharmaceutical companies, there has been little case study research that would illuminate the workings of this "gray area" mechanism. From this perspective, we offer an in-depth analysis of a recent scandal involving the Department of Clinical Anesthesiology, Mie University and Ono Pharmaceutical, where a scholarship donation was used by a pharmaceutical company to increase the prescription of one of its key drugs at a hospital department. Available evidence also suggests that a professor based within the department originally requested a scholarship donation from the company, which became an initial trigger of the scandal. We argue that by scrutinizing scholarship donations we can gain insight into problems specific to ICOIs between the pharmaceutical companies and the healthcare sector in Japan. In addition, scholarship donations can be understood as a form of "gifts" which have been found to underpin certain forms of pharmaceutical companies' promotional activities in Japan but also in other countries. We conclude by highlighting potential institutional remedies, which may alleviate ICOIs and corrupt behavior affecting the healthcare sector.

Assessment of dysplasia in bone marrow smear with convolutional neural network.

In this study, we developed the world's first artificial intelligence (AI) system that assesses the dysplasia of blood cells on bone marrow smears and presents the result of AI prediction for one of the most representative dysplasia-decreased granules (DG). We photographed field images from the bone marrow smears from patients with myelodysplastic syndrome (MDS) or non-MDS diseases and cropped each cell using an originally developed cell detector. Two morphologists labelled each cell. The degree of dysplasia was evaluated on a four-point scale: 0-3 (e.g., neutrophil with severely decreased granules were labelled DG3). We then constructed the classifier from the dataset of labelled images. The detector and classifier were based on a deep neural network pre-trained with natural images. We obtained 1797 labelled images, and the morphologists determined 134 DGs (DG1: 46, DG2: 77, DG3: 11). Subsequently, we performed a five-fold cross-validation to evaluate the performance of the classifier. For DG1-3 labelled by morphologists, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 91.0%, 97.7%, 76.3%, 99.3%, and 97.2%, respectively. When DG1 was excluded in the process, the sensitivity, specificity, PPV, NPV, and accuracy were 85.2%, 98.9%, 80.6%, and 99.2% and 98.2%, respectively.

A Novel Antihypertensive Peptide Identified in Thermolysin-Digested Rice Bran.

SCOPE: Hypertension is a risk factor for arteriosclerosis. In this study, we investigate the antihypertensive effect of protease-digested rice bran in a spontaneously hypertension rat (SHR) model. We also purify a novel antihypertensive peptide from the digest. METHODS AND RESULTS: Thermolysin-digested rice bran (TRB) is administered to SHRs for 4 weeks, and systolic blood pressure (SBP) was measured weekly using the tail-cuff method. TRB shows an antihypertensive effect in a dose-dependent manner. TRB also reduces angiotensin I-converting enzyme (ACE) activity in lung tissue and serum troponin I levels. TRB is fractionated by HPLC and ACE-inhibitory activity in the HPLC fractions is measured. Peptides LRA and YY are identified from the two fractions with the strongest ACE-inhibitory activity. Amino acid sequence of these peptides are found in a vicilin-like seed storage protein, and identified in rice bran protein using the peptide mass fingerprint method. We confirm that LRA and YY are cleaved by thermolysin digestion of a model synthetic peptide. Orally administered LRA (0.25 mg kg-1 ) or YY (0.5 mg kg-1 ) lowers the SBP of SHRs at 4 h after administration. CONCLUSION: We identify a novel, orally active antihypertensive peptide, LRA from the digest of rice bran protein.