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Background: The use of adjuvant osimertinib for epidermal growth factor receptor (EGFR) mutants is expected to expand to earlier stage I in the future, potentially competing with the current standard of care, oral tegafur/uracil (UFT), in Japan. However, the effect of EGFR mutation status on the therapeutic effect of UFT remains unclear. This study was conducted as an exploratory analysis of a retrospective observational study that investigated the real-world data of postoperative adjuvant chemotherapy in Japan (CSPOR-LC03)., Methods: Between 2008 and 2013, 1812 patients with completely resected adenocarcinoma diagnosed as pathologic stage I (T1 > 2 cm, TNM classification, sixth edition) who have maintained organ function, and no history of other cancers were included. The primary endpoint was the 5-year disease-free survival (DFS) rate, and we compared this rate between four groups classified based on the administration of adjuvant UFT and EGFR mutation status., Results: Of the 933 (51%) patients with EGFR mutations, 394 underwent adjuvant UFT therapy. Of the 879 (49%) patients without EGFR mutations, 393 underwent adjuvant UFT therapy. The 5-year DFS of UFT+/EGFR+ and UFT-/EGFR+ patients were 82.0 and 87.1%, respectively, and those of UFT+/EGFR- and UFT-/EGFR- patients were 80.0 and 86.9%, respectively. DFS was significantly worse in the UFT+ group than in the UFT- group (P = 0.015). Adjuvant UFT therapy was not an independent prognostic factor for DFS, regardless of the EGFR mutation status., Conclusion: In pathologic stage I (>2 cm) lung adenocarcinomas with EGFR mutation, the survival benefit of adjuvant UFT was not observed., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Medical interviewing is a critical skill in clinical practice, yet opportunities for practical training are limited in Japanese medical schools, necessitating urgent measures. Given advancements in artificial intelligence (AI) technology, its application in the medical field is expanding. However, reports on its application in medical interviews in medical education are scarce., Objective: This study aimed to investigate whether medical students' interview skills could be improved by engaging with AI-simulated patients using large language models, including the provision of feedback., Methods: This nonrandomized controlled trial was conducted with fourth-year medical students in Japan. A simulation program using large language models was provided to 35 students in the intervention group in 2023, while 110 students from 2022 who did not participate in the intervention were selected as the control group. The primary outcome was the score on the Pre-Clinical Clerkship Objective Structured Clinical Examination (pre-CC OSCE), a national standardized clinical skills examination, in medical interviewing. Secondary outcomes included surveys such as the Simulation-Based Training Quality Assurance Tool (SBT-QA10), administered at the start and end of the study., Results: The AI intervention group showed significantly higher scores on medical interviews than the control group (AI group vs control group: mean 28.1, SD 1.6 vs 27.1, SD 2.2; P=.01). There was a trend of inverse correlation between the SBT-QA10 and pre-CC OSCE scores (regression coefficient -2.0 to -2.1). No significant safety concerns were observed., Conclusions: Education through medical interviews using AI-simulated patients has demonstrated safety and a certain level of educational effectiveness. However, at present, the educational effects of this platform on nonverbal communication skills are limited, suggesting that it should be used as a supplementary tool to traditional simulation education., (©Akira Yamamoto, Masahide Koda, Hiroko Ogawa, Tomoko Miyoshi, Yoshinobu Maeda, Fumio Otsuka, Hideo Ino. Originally published in JMIR Medical Education (https://mededu.jmir.org), 23.09.2024.)

Three Streptococcus suis-like strains positive for Lancefield antigen group A were isolated from human boar bite wounds and the oral cavities of boars in Hashimoto City, Wakayama Prefecture, Japan, and their taxonomic positions were investigated. Application of the VITEK2 system identified all three isolates as S. suis with > 94 % probability. The isolates were assigned to S. suis based on the results of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analysis (Biotyper score of 2.382) but were differentiated according to the characteristic signal peaks (4709 m/z and 9420 m/z) that were not present for S. suis. Sequence analysis of the 16S rRNA and sodA genes determined that the isolates were similar to S. suis; however, these genes appeared on a phylogenetic sub-branch. Phylogenetic analysis of the whole chromosomal DNA showed that the isolate formed a cluster with S. suis but with clear divergence. The average nucleotide index using BLAST between the clinical isolate (PAGU 2482) and a closely related reference strain of S. suis was 94.75 %, which was not clearly conclusive; however, digital DNA-DNA hybridization showed a value of 61.2 %. Biochemical reactions, including those with acid phosphatase, α-chymotrypsin, and tagatose (acidification), distinguished our isolates from S. suis. Thus, based on phylogenetic, genomic, and phenotypic characteristics and MALDI-TOF-MS signal patterns, we propose that the isolate with Lancefield group A positive characteristics be designated as a novel subspecies, Streptococcus suis subsp. hashimotonensis subsp. nov., with the type strain PAGU 2482 T (GTC 18290 T  = CCUG 77434 T )., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Objective: The optimal region of lymph node dissection (LND) during segmentectomy in patients with small peripheral non-small cell lung cancer requires clarification. Through a supplemental analysis of the Japan Clinical Oncology Group (JCOG) 0802/West Japan Oncology Group (WJOG) 4607L, we investigated the associated factors, distribution, and recurrence pattern of lymph node metastases (LNMs) and proposed the optimal LND region., Methods: Of the 1106 patients included in the JCOG0802/WJOG4607L, 1056 patients with LNDs were included in this supplemental analysis. We investigated the distribution and recurrence pattern of LNMs along with the radiologic findings (with ground-glass opacity, part-solid tumor; without ground-grass opacity component, pure-solid tumor)., Results: The radiologic findings were the only significant factor for LNMs. Of 533 patients with part-solid tumors, 8 (1.5%) had LNMs. Further, only 3 (0.5%) patients had pN2 disease, and no patients had interlobar LNMs from nonadjacent segments. Of the 523 patients with pure-solid tumors, 55 (10.5%) had LNMs, and 28 (5.4%) had pN2 disease. Five patients had metastases to nonadjacent interlobar lymph nodes (LNs). Two (2.0%) patients with S6 tumors had upper mediastinal LNMs. In addition, the incidence of mediastinal LN recurrence in patients with S6 lung cancer was greater in those who underwent selective LND than those who underwent systematic LND (P = .0455)., Conclusions: Nonadjacent interlobar and mediastinal LND have little impact on pathologic nodal staging in patients with part-solid tumors. In contrast, selective LND is recommended at least for patients with pure-solid tumors., Competing Interests: Conflict of Interest Statement H.Y. reported honoraria from Eli Lilly, Chugai, Boehringer Ingelheim, Nippon Kayaku, Astra Zeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Ono, Merck Biopharma, Taiho, Otsuka, Takeda, Novartis, Amgen, Nipro Pharma, Kyowa Kirin, and Pfizer (payments were made to the author) and consulting fees from Delta Fly Pharma (payments were made to the author). M.T. reported participation on a Data Safety Monitoring Board or Advisory Board, Chugai Pharmaceutical Co, Ltd. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Age-related changes in left ventricular (LV) structure and function lower the threshold for the onset of heart failure with preserved ejection fraction (HFpEF). LV parameters change also with race; however, the racial differences in age-related changes in LV parameters with and without adjustment for body mass index (BMI), heart rate (HR), and blood pressure (BP) remain unclear., Methods and Results: We performed a subanalysis of the World Alliance Society of Echocardiography Normal Values Study, an international cross-sectional study that examined normal echocardiographic values in 15 countries. The age-related changes in 2-dimensional echocardiographic derived parameters including LV size, systolic function, and mass, were compared between healthy Japanese (n=227) and healthy White (n=98) and Black (n=69) American participants. In men, age-related changes in all parameters did not differ significantly among races. However, compared with Japanese women, White American women had a smaller body surface area (BSA)-indexed LV volume, BSA-indexed LV internal dimension at end-systole, BSA-indexed LV stroke volume, and LV mass index to BSA, and a larger LV ejection fraction with age, even after adjusting for BMI, HR, and BP., Conclusions: Age-related changes in LV structure and function, which are important for the pathophysiology of HFpEF, may differ by race. Therefore, future studies examining echocardiographic reference values for each age group in each race are needed.

Background: We aimed to improve the prognosis, treatment, and management of Staphylococcus aureus bacteremia (SAB) by evaluating the association between adherence to quality indicators (QIs) and clinical outcomes in patients with their clinical outcomes., Methods: We retrospectively collected clinical and microbiological data on hospitalized patients with SAB from 14 hospitals (three with >  600, two with 401-600, five with 201-400, and four with ≤ 200 beds) in Japan from January to December 2022. The SAB management quality was evaluated using the SAB-QI score (ranging from 0 to 13 points), which consists of 13 QIs (grouped into five categories) based on previous literature., Results: Of the 4,448 positive blood culture episodes, 289 patients with SAB (6.5%) were enrolled. The SAB-QI scores ranged from 3 to 13, with a median score of 9 points. The SAB-QI score was highest in middle-sized hospitals with 401-600 beds. Adherence to each of the four QI categories (blood culture, echocardiography, source control, and antibiotic treatment) was significantly higher in survived cases than in fatal cases. Kaplan-Meier curves with log-rank tests demonstrated that higher adherence to SAB-QIs indicated a better prognosis. Logistic regression analysis revealed that age, methicillin resistance, multiple comorbidities (≥ 2), and low SAB-QI score were significantly associated with 30-day mortality in patients with SAB., Conclusions: Our study highlights that greater adherence to the SAB-QIs correlates with improved patient outcomes. Management of patients with SAB should follow these recommended indicators to maintain the quality of care, especially for patients with poor prognosticators., (© 2024. The Author(s).)

Purpose: The volume of surgical services has significantly reduced globally due to the coronavirus disease 2019 (COVID-19) pandemic. This study evaluated the level of recovery in terms of the number of operations performed in Japan in 2021, based on nationwide periodic surveillance., Methods: Information on the weekly and annual volumes of 20 representative procedures in 6 surgical subspecialties in 2021 was extracted from the National Clinical Database. Statistical data for 2018 and 2019 (pre-pandemic era) were compared with those for 2020. Data on waves of infection, peak period, and high-prevalence areas (13 of 47 prefectures) were analyzed individually., Results: The volumes of the 10 procedures, including gastrectomy, hepatectomy, valve replacement and valve plasty, coronary artery bypass grafting, infrarenal abdominal aorta replacement, ventricular septal defect closure, lung lobectomy, inguinal hernia repair (age < 16 years old), and appendectomy (age < 16 years old), did not reach 95% of that in the pre-pandemic era. The most striking decline in the surgical volume of these 10 procedures was observed during the peak period of wave 5 in high-prevalence areas., Conclusion: This near-complete enumeration survey identified the polarization of 20 representative procedures in terms of resumption of surgical service after the pandemic., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Diabetes mellitus (DM) is a major risk and prognostic factor for heart failure (HF). Insulin resistance (IR) is an important component of DM, but the relationship between IR and HF prognosis has not yet been established across a wide variety of HF populations. We retrospectively evaluated the relationship between IR and clinical outcomes of HF patients at our hospital between 2017 and 2021. IR was defined as a homeostatic model assessment of IR (HOMA-IR) index ≥ 2.5, calculated from fasting blood glucose and insulin concentrations. The primary outcome was a composite of all-cause death and hospitalisation for HF (HHF). Among 682 patients included in the analyses, 337 (49.4%) had IR. The median age was 70 [interquartile range (IQR): 59-77] years old, and 66% of the patients were men. Among the patients, 41% had a left ventricular ejection fraction below 40%, and 32% had DM. The median follow-up period was 16.5 [IQR: 4.4-37.3] months. IR was independently associated with the primary outcome (HR: 1.91, 95% CI: 1.39-2.62, p < 0.0001), death (hazard ratio [HR]: 1.86, 95% confidence interval [CI]: 1.28-2.83, p < 0.01), and HHF (HR: 1.91, 95% CI: 1.28-2.83, p < 0.01). HOMA-IR is an independent prognostic factor of HF in a wide variety of HF populations.

We have previously isolated a gram-negative microaerophilic strain, PAGU2000 T from a patient presenting with a fever in Kumamoto Prefecture, Japan. The present study aimed to comprehensively analyze the taxonomy of the isolated strain using a polyphasic approach. The 16S rRNA gene sequence analysis indicated that the strain was a member of enterohepatic Helicobacter. The strain PAGU2000 T shared a 97.5% 16S rRNA gene nucleotide identity with Helicobacter valdiviensis, and this taxonomic position was confirmed by phylogenetic analysis of the GyrA amino acid sequences. The proposed strain PAGU2000 T has a 1.482 Mbp chromosome with a DNA G + C content of 31.3 mol% and encodes 1520 predicted coding sequences. The average nucleotide identity between the strain PAGU2000 T and type strain of H. valdiviensis was 70.3%, which was lower than the recommended threshold of 95% for species delineation. The strain PAGU2000 T was a motile, non-spore-forming, and spiral-shaped bacterium, exhibiting catalase and oxidase activities but not urease and nitrate reduction. This study demonstrates that the isolate represents a novel species within enterohepatic Helicobacter, for which the name Helicobacter higonensis is proposed (type strain: PAGU2000 T  = GTC 16811 T  = LMG 33095 T ). In this study, we describe the phenotypic and morphological features of this strain and propose an emended description of some biochemical traits of H. valdiviensis., (© 2024 The Societies and John Wiley & Sons Australia, Ltd.)

Background: An ambulance traffic crash not only leads to injuries among emergency medical service (EMS) professionals but also injures patients or their companions during transportation. We aimed to describe the incidence of ambulance crashes, seating location, seatbelt use for casualties (ie, both fatal and nonfatal injuries), ambulance safety efforts, and to identify factors affecting the number of ambulance crashes in Japan., Methods: We conducted a nationwide survey of all fire departments in Japan. The survey queried each fire department about the number of ambulance crashes between January 1, 2017, and December 31, 2019, the number of casualties, their locations, and seatbelt usage. Additionally, the survey collected information on fire department characteristics, including the number of ambulance dispatches, and their safety efforts including emergency vehicle operation training and seatbelt policies. We used regression methods including a zero-inflated negative binomial model to identify factors associated with the number of crashes., Results: Among the 726 fire departments in Japan, 553 (76.2%) responded to the survey, reporting a total of 11,901,210 ambulance dispatches with 1,659 ambulance crashes (13.9 for every 100,000 ambulance dispatches) that resulted in a total of 130 casualties during the 3-year study period (1.1 in every 100,000 dispatches). Among the rear cabin occupants, seatbelt use was limited for both EMS professionals ( n  = 3/29, 10.3%) and patients/companions ( n  = 3/26, 11.5%). Only 46.7% of the fire departments had an internal policy regarding seatbelt use. About three-fourths of fire departments (76.3%) conducted emergency vehicle operation training internally. The output of the regression model revealed that fire departments that conduct internal emergency vehicle operation training had fewer ambulance crashes compared to those that do not (odds of being an excessive zero -2.20, 95% CI: -3.6 to -0.8)., Conclusion: Two-thirds of fire departments experienced at least one crash during the study period. The majority of rear cabin occupants who were injured in ambulance crashes were not wearing a seatbelt. Although efforts to ascertain seatbelt compliance were limited, Japanese fire departments have attempted a variety of methods to reduce ambulance crashes including internal emergency vehicle operation training, which was associated with fewer ambulance crashes.

Background: Although remote monitoring (RM) after pacemaker implantation is common, its cost-effectiveness has not been fully investigated. Therefore, we assessed the cost-effectiveness of RM compared with conventional follow-up (CFU) in Japanese patients with pacemakers., Methods: A Markov model was constructed to analyze costs and quality-adjusted life years after pacemaker implantation. The target population was Japanese patients implanted with a dual-chamber pacemaker for bradycardia. Transition probabilities (e.g. atrial fibrillation, stroke, and device trouble) were obtained from literature and expert sources. Additionally, stroke risk was determined according to anticoagulation and CHADS 2 scores. We used a 10-year horizon with sensitivity analyses for significant variables., Results: Compared to CFU, RM was more effective; however, it was also more expensive. When the range of the Japanese willingness-to-pay threshold was considered to be ¥5,000,000, RM was at least cost-neutral relative to the CFU in all elderly patients with pacemakers for bradycardia. The cost-effectiveness of RM relative to CFU could be higher for patients with high CHADS 2 scores, especially in patients with a CHADS 2 score ≥ 3. Scenario analyses changing the interval between visits to an in-office evaluation in the CFU also demonstrated the same conclusions. In particular, when the interval between office visits was 1 year for the CFU, the RM could be more cost-effective., Conclusions: This study demonstrated that RM can be a cost-effective option for Japanese patients, especially those with high CHADS 2 scores and long-term intervals between office visits., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aims: Psychological distress is associated with poor prognosis in patients with cardiovascular disease (CVD). However, factors related to psychological distress in elderly patients with CVD are less understood. We aim to investigate the rate of psychological distress in elderly patients with CVD in comparison with that of patients without CVD and to examine the clinical, socio-economic, and lifestyle factors associated with this condition., Methods and Results: Data from a nationwide population-based study in Japan of patients aged ≥60 years were extracted, and 1:1 propensity score matching was conducted of patients with and without CVD. Psychological distress was assessed using the K6 scale, on which a score ≥6 was defined as psychological distress. Of the 24 388 matched patients, the rate of psychological distress was significantly higher among patients with CVD compared with those without CVD (29.8 vs. 20.5%, P < 0.0001). The multivariate analysis revealed that female sex, comorbidities, except for hypertension, current smoking status, daily sleep duration of <6 vs. ≥8 h, home renter vs. owner, retired status, having a walking disability, and lower monthly household expenditure were independently associated with psychological distress. Walking disability was observed to be in greatest association with psychological distress (odds ratio 2.69, 95% confidence interval 2.46-2.93)., Conclusion: Elderly patients with CVD were more likely to have psychological distress compared with those without CVD. Multiple factors, including clinical, socio-economic, and lifestyle variables, were associated with psychological distress. These analyses may help healthcare providers to identify high-risk patients with psychological distress in a population of older adults with CVD., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Rules and regulations for ambulance operations differ across countries and regions, however, little is known about ambulance crashes outside of the United States. Japan is unique in several aspects, for example, routine use of lights and sirens during response and transport regardless of the urgency of the case and low speed limits for ambulances. The aim of this study was to describe the incidence and characteristics of ambulance crashes in Japan., Methods: We retrospectively analyzed data from the Institute for Traffic Accident Research and Data Analysis (ITARDA) that include all traffic crashes resulting in injury or death in Japan. The study included all ambulance crashes from 2009 to 2018. We compared crashes that occurred during emergency operations with lights and sirens (i.e., when responding to a call or transporting a patient) to those that occurred during non-emergency operations without lights or sirens. We also used data on total number of ambulance dispatches from the Japanese Fire and Disaster Management Agency to calculate ambulance crash risk., Results: During the 10-year period, we identified a total of 486 ambulance crashes out of 59,208,761 ambulance dispatches (0.82 in every 100,000 dispatches or one crash for every 121,829 dispatches) that included two fatal crashes. Among all ambulance crashes, 142 (29.2%) occurred during emergency operations. The incidence of ambulance crashes decreased significantly over the 10-year period. Ambulance crashes at an intersection occurred more frequently during emergency operations than during non-emergency operations (72.5% vs. 58.1%; 14.4% difference, 95% CI 5.0-22.9)., Conclusions: Ambulance crashes occurred infrequently in Japan with crash rates much lower than previously reported crash rates in the United States. Ambulance crashes during emergency operations occurred more frequently at intersections compared to non-emergency operations. Further investigation of the low Japanese ambulance crash rates could provide opportunities to improve ambulance safety in other countries.

Background: Polymyxin E (colistin) is a last-resort antibiotic to treat infections caused by carbapenemase-producing Enterobacteriaceae (CPE). However, reports of CPEs resistant to colistin have been increasing, and the mcr genes are emerging as resistance mechanisms. Among them, plasmid-mediate mcr-9 is known to be associated with colistin resistance, whereas reports on chromosomal mcr-9 and its association with colistin resistance in humans are few., Case Presentation: We identified Enterobacter asburiae harboring mcr-9 and bla IMP-60 in the pleural fluid of a patient with empyema. The long-read sequencing technique revealed that these genes were located on its chromosome. Despite the lack of exposure to colistin, the organism showed microcolonies in the inhibition circle in the E-test and disk diffusion test. Antibiotic susceptibility testing by broth microdilution confirmed its resistance to colistin., Conclusion: Our case report showed that mcr-9 can be present not only on plasmids but also on the chromosome in E. asburiae, and that the presence of mcr-9 on its chromosome may influence its susceptibility to colistin., (© 2022. The Author(s).)

Recent advances in genome editing technology are accompanied by increasing public expectations on its potential clinical application, but there are still scientific, ethical, and social considerations that require resolution. In Japan, discussions pertaining to the clinical use of genome editing in human embryos are underway. However, understanding of the public's sentiment and attitude towards this technology is limited which is important to help guide the debate for prioritizing policies and regulatory necessities. Thus, we conducted a cross-sectional study and administered an online questionnaire across three stakeholder groups: the general public, patients and their families, and health care providers. We received responses from a total of 3,511 individuals, and the attitudes were summarized and compared among the stakeholders. Based on the distribution of responses, health care providers tended to be cautious and reluctant about the clinical use of genome editing, while patients and families appeared supportive and positive. The majority of the participants were against the use of genome editing for enhancement purposes. Participants expressed the view that clinical use may be acceptable when genome editing is the fundamental treatment, the risks are negligible, and the safety of the technology is demonstrated in human embryos. Our findings suggest differences in attitudes toward the clinical use of genome editing across stakeholder groups. Taking into account the diversity of the public's awareness and incorporating the opinion of the population is important. Further information dissemination and educational efforts are needed to support the formation of the public's opinion., (© 2022. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

The 86 th Annual Scientific Meeting of the Japanese Circulation Society was held in a web-based format on March 11-13, 2022. In accordance with the internationalization policy of the JCS, the meeting was held with the Asian Pacific Society of Cardiology Congress 2022. The main theme was "Cardiology Spreading its Wings". The number of patients with heart failure and other cardiovascular diseases is increasing dramatically, and the fields dealt with by cardiovascular medicine are also greatly expanding. This conference was both intellectually satisfying and exciting for all participants, who numbered over 14,900. The meeting was completed with great success, and the enormous amount of cooperation and support from all involved was greatly appreciated.

In this study, metal leaching was investigated in commercially available faucets in Japan to clarify their compliance to Japanese regulations. We purchased 37 faucets from the market and analyzed the leaching of cadmium, mercury, selenium, lead (Pb), arsenic, hexavalent chromium, boron, zinc (Zn), copper, manganese, and nickel. The leaching tests were performed with and without a conditioning treatment, that simulated approximately 1-month intermittent use of faucets on weekdays, and the results were compared to estimate the changes in metal leaching during the use of faucets. The results revealed that metal leaching from most of the faucets complied with Japanese regulations. However, the levels of Pb leaching from several faucets produced by certain manufacturers exceeded the Japanese standard. The conditioning treatment was generally effective in reducing metal leaching. However, the reductions in Pb and Zn leaching tended to be lower than those of the other metals. Nickel is not legally regulated in Japan; although the number of cases where nickel concentration in leachate exceeded the water quality management target value was greater, such cases were limited to faucets primarily made of copper alloys. We believe that these results will be helpful to improve the public health associated with metal leaching from faucets.

Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) has become a serious epidemiologic problem worldwide. In this study, we aimed to investigate recently isolated MRSA types and determine their characteristics., Methods: We collected 164 strains isolated from 13 hospitals located in Tokyo and surrounding prefectures. In addition to drug resistance tests, we sequenced whole genomes of the prevalent MRSA clones and analysed their genomic characteristics, such as drug resistance genes, virulence factor genes, and genome arrangements., Results: Multilocus sequencing typing showed that 51% of the SCCmecⅣ MRSA isolates belonged to clonal complex 1 (CC1). Staphylococcus protein A gene (spa) typing showed that 91% of these CC1 isolates could be categorised as t1784 type. These CC1/t1784 isolates possessed genes encoding erythromycin resistance protein, spectinomycin 9-adenylyltransferase, and staphylococcal enterotoxins (SEA, SEI, SEM), but not the pvl gene encoding Panton-Valentine leukocidin. Complete genomic analysis of nine CC1/t1784 isolates showed that they shared an intact phage, which carried no annotated virulence factor genes except for two encoding a hypothetical membrane protein and a teichoic acid biosynthesis protein. No significant genomic rearrangements were observed among the CC1/t1784 isolates., Conclusion: These data and previous reports indicate that this CC1/t1784 clone has been expanding rapidly in Japan without genomic changes., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Bacterial strain PAGU 2197 T , which was isolated from soil collected from the bottom of a pond in Japan, is characterized in this study. Cells of strain PAGU 2197 T were aerobic, Gram-negative, short rod-shaped, non-motile, flexirubin-producing, oxidase-positive, catalase-positive and lecithinase-negative. A phylogenetic study based on 16S rRNA gene sequences and multilocus sequence analysis ( gyrB , rpoB and rpoD ) indicated that strain PAGU 2197 T belongs to the genus Chryseobacterium and is a member of an independent lineage including Chryseobacterium tructae CCUG 60111 T (sequence similarity, 95.9 %), Chryseobacterium lactis CCUG 60566 T (93.4 %) and Chryseobacterium viscerum CCUG 60103 T (91.6 %). The average nucleotide identity values were 80.83-85.04 %. Because average nucleotide identity values of 95-96 % exceed the 70 % DNA-DNA hybridization cutoff value for species discrimination, strain PAGU 2197 T represents a novel species in the genus Chryseobacterium . The genome of strain PAGU 2197 T was 4 967 738 bp with a G+C content of 35.5 mol%. The sole respiratory quinone of strain PAGU 2197 T was MK-6; the major cellular fatty acids were iso-C 15 : 0 , iso-C 17 : 0 3OH, summed feature 3 (C 16 : 1  ω 7 c and/or C 16 : 1  ω 6 c ) and summed feature 9 (iso-C 17 : 1  ω 9 c and/or C 16 : 0 10-methyl); and the major polar lipids were phosphoglycolipids and phosphatidylethanolamine. These results indicate that strain PAGU 2197 T should be classified as representing a novel species in the genus Chryseobacterium , for which the name Chryseobacterium lecithinasegens sp. nov. is proposed, with strain PAGU 2197 T (=NBRC 114264 T =CCUG 75150 T ) as the type strain.

Clinical isolates of drug-resistant (isoniazid and/or rifampicin-resistant) Mycobacterium tuberculosis were obtained from 254 patients diagnosed with drug-resistant tuberculosis in Japan from April 2015 to March 2017 in National Hospital Organization hospitals. The 254 patients were approximately 32% of all 795 patients who were diagnosed with culture-confirmed drug-resistant tuberculosis from 2015 to 2016 nationwide in Japan. The whole-genome sequences of all the isolates from the 254 patients and the lineages of these isolates were determined, and phylogenetic trees were constructed based on single nucleotide polymorphism concatemers. Of these patients, 202 (79.5%) were born in Japan and 52 (20.5%) were born elsewhere. Of the 254 drug-resistant isolates, 54 (21.3%) were multidrug resistant, being resistant to both isoniazid and rifampicin. The percentages of multidrug-resistant isolates were significantly higher in foreign-born (38.5% [20/52]) than Japanese-born patients (16.8% [34/202]). Of the 54 multidrug-resistant isolates, nine were extensively drug resistant, which were all obtained from Japanese-born patients. Five extensively drug-resistant isolates were obtained from patients with incipient tuberculosis. A significant number of multidrug-resistant M. tuberculosis strains were isolated from foreign-born patients from Asian countries that have a high tuberculosis burden. Foreign-derived isolates affect the nationwide genetic diversity of drug-resistant M. tuberculosis in Japan. Extensively drug-resistant M. tuberculosis isolates were transmitted among the Japanese population. IMPORTANCE The incidence rate of tuberculosis (TB) in Japan was 11.5 per 100,000 of the population in 2019. Of TB patients in Japan, 61.1% were aged >70 years, and 10.7% were born outside Japan, mostly in Asian countries with a high burden of tuberculosis. Of the tuberculosis patients in the present study, 5.4% and 1.0% showed resistance to isoniazid and rifampicin, respectively, and 0.7% were multidrug resistant. The objective of this study was to clarify the molecular epidemiological properties of drug-resistant tuberculosis in Japan. Molecular epidemiology provides several clues to inform potential measures to control drug-resistant tuberculosis in Japan.

Background Arterial stiffness is an important predictor of cardiovascular events; however, indexes for measuring arterial stiffness have not been widely incorporated into routine clinical practice. This study aimed to determine whether the cardio-ankle vascular index (CAVI), based on the blood pressure-independent stiffness parameter β and reflecting arterial stiffness from the origin of the ascending aorta, is a good predictor of cardiovascular events in patients with cardiovascular disease risk factors in a large prospective cohort. Methods and Results This multicenter prospective cohort study, commencing in May 2013, with a 5-year follow-up period, included patients (aged 40‒74 years) with cardiovascular disease risks. The primary outcome was the composite of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction. Among 2932 included patients, 2001 (68.3%) were men; the mean (SD) age at diagnosis was 63 (8) years. During the median follow-up of 4.9 years, 82 participants experienced primary outcomes. The CAVI predicted the primary outcome (hazard ratio, 1.38; 95% CI, 1.16‒1.65; P <0.001). In terms of event subtypes, the CAVI was associated with cardiovascular death and stroke but not with myocardial infarction. When the CAVI was incorporated into a model with known cardiovascular disease risks for predicting cardiovascular events, the global χ 2 value increased from 33.8 to 45.2 ( P <0.001), and the net reclassification index was 0.254 ( P =0.024). Conclusions This large cohort study demonstrated that the CAVI predicted cardiovascular events. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01859897.

Among early-stage lung cancers that show ground-glass nodules on chest computed tomography, the lung cancer surgical study group of the Japan Clinical Oncology Group previously reported that nodules of ≤2 cm with a consolidation/tumor ratio of ≤0.25 were considered radiologically non-invasive cancers with a low risk of metastasis. However, there is no consensus based on high-quality evidence about the optimal timing of surgical intervention for radiologically non-invasive cancers. In June 2020, we launched a multi-institutional, single-arm confirmatory trial to evaluate the efficacy and safety of watchful waiting for patients with radiologically non-invasive lung cancer. It is planned that a total of 720 patients will be enrolled from 49 institutes over a 5-year period. The primary endpoint is 10-year overall survival (OS). The secondary endpoints are 5-year OS, operation-free survival, proportion of extensive lung resection, proportion of unresectable progression, lung cancer-specific survival and adverse events., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Food allergies are often life threatening. In order to establish appropriate food allergy measures in nursery children, it is important to analyze local epidemiological data on the food allergy prevalence in nursery children. However, no such data are currently available for the city of Kawasaki, Japan., Objective: The present study retrospectively evaluated food allergy prevalence among nursery children in Kawasaki city., Methods: Data from children with food allergies requiring food avoidance in the nurseries of Kawasaki city between 2007 and 2016 were evaluated., Results: From 2007 to 2016, the prevalence of food allergies among nursery children in Kawasaki city increased from 2.7% to 5.3%. The increase of food allergy prevalence was higher in 2-5 year-old children than in 0-1 year-old children (2.0% to 4.7% vs. 5.3% to 7.0%, respectively). The top five most common food allergies were hen's egg (73.0%), cow's milk (29.3%), nuts (9.7%), soy (8.9%), and wheat (6.5%). Hen's egg was consistently identified as a causative food of food allergy in more than 70% (73.0-89.1%) of food avoidance cases over the 10 year period. The increase of egg allergy prevalence was higher in 2-5 year-old children than in 0-1 year-old children (1.7% to 3.2% vs. 5.2% to 6.0%, respectively)., Conclusions: Food allergies, to hen's egg in particular, have increased considerably among nursery children in the city of Kawasaki, Japan, and that increase was higher among older children.

The coronavirus disease 2019 (COVID-19) global pandemic has drastically changed how we live and work. Amid the prolonged pandemic, burnout of the frontline healthcare professionals has become a significant concern. We conducted a cross-sectional survey study to provide data about the relationship between the COVID-19 pandemic and the prevalence of burnout in healthcare professionals in Japan. Healthcare workers in a single Japanese national university hospital participated in the survey, including basic demographics, whether a participant engaged in care of COVID-19 patients in the past 2 weeks and the Maslach Burnout Inventory. Of those, 25.4% fully answered the survey; 33.3% were doctors and 63.6% were nurses, and 36.3% engaged in care of COVID-19 patients in the past 2 weeks. Compared to those belonging to General Medicine, those in Emergency Intensive Care Unit were at higher risk of burnout (odds ratio (OR), 6.7; 95% CI, 1.1-42.1; p = 0.031). Of those who engaged in care of COVID-19 patients, 50% reported burnout while 6.1% did not (OR 8.5, 95% CI; 1.3-54.1; p = 0.014). The burnout of healthcare workers is a significant concern amid the pandemic, which needs to be addressed for sustainable healthcare delivery.

Introduction . Streptococcus dysgalactiae subsp. equisimilis We have previously reported the prevalence of Lancefield group A SDSE (GA-SDSE) strains in Japan and have analysed the draft genome sequences of these strains. As GA-SDSE is a rare type of SDSE, only one complete genome has been sequenced to date. Hypothesis/Gap Statement. We have previously reported the prevalence of Lancefield group A SDSE (GA-SDSE) strains in Japan and have analysed the draft genome sequences of these strains. As GA-SDSE is a rare type of SDSE, only one complete genome has been sequenced to date. Aim. The present study is focused on genetic characteristics of GA-SDSE strains. In order to examine molecular characteristics, we also tested growth inhibition of other streptococci by GA-SDSE. Methodology. We determined the complete genome sequences of three GA-SDSE strains by two new generation sequencing systems (short-read and long-read sequencing data). Using the sequences, we also conducted a comparative analysis of GA-SDSE and group C/G SDSE strains. In addition, we tested multiplex and quantitative PCRs targeting the GA-SDSE, group G SDSE, and S. pyogenes . Results. We found a group-specific conserved region in GA-SDSE strains that is composed of genes encoding predicted anti-bacteriocin and streptococcal lantibiotic (Sal) proteins. Multiplex and quantitative PCRs targeting the GA-SDSE-specific region were able to distinguish between GA-SDSE, other SDSE, and S. pyogenes strains. The growth of GA-SDSE was suppressed in the presence of group G SDSE, indicating a possible explanation for the low frequency of isolation of GA-SDSE. Conclusion. The comparative genome analysis shows that the genome of GA-SDSE has a distinct arrangement, enabling the differentiation between S. pyogenes , GA-SDSE, and other SDSE strains using our PCR methods.

Background: Risk stratification of cardiovascular events in patients with type 2 diabetes mellitus (T2DM) has not been established. Coronary artery calcium score (CACS) and non-alcoholic fatty liver disease (NAFLD) are independently associated with cardiovascular events in T2DM patients. This study examined the incremental prognostic value of NAFLD assessed by non-enhanced computed tomography (CT) in addition to CACS and Framingham risk score (FRS) for cardiovascular events in T2DM patients., Methods: This prospective pilot study included 529 T2DM outpatients with no history of cardiovascular disease who underwent CACS measurement because of suspected coronary artery disease. NAFLD was defined on CT images as a liver:spleen attenuation ratio < 1.0. Cardiovascular events were defined as cardiovascular death, nonfatal myocardial infarction, late coronary revascularization, nonfatal stroke, or hospitalization for heart failure., Results: Among 529 patients (61% men, mean age 65 years), NAFLD was identified in 143 (27%). Forty-four cardiovascular events were documented during a median follow-up of 4.4 years. In multivariate Cox regression analysis, NAFLD, CACS, and FRS were associated with cardiovascular events (hazard ratios and 95% confidence intervals 5.43, 2.82-10.44, p < 0.001; 1.56, 1.32-1.86, p < 0.001; 1.23, 1.08-1.39, p = 0.001, respectively). The global χ 2 score for predicting cardiovascular events increased significantly from 27.0 to 49.7 by adding NAFLD to CACS and FRS (p < 0.001). The addition of NAFLD to a model including CACS and FRS significantly increased the C-statistic from 0.71 to 0.80 (p = 0.005). The net reclassification achieved by adding CACS and FRS was 0.551 (p < 0.001)., Conclusions: NAFLD assessed by CT, in addition to CACS and FRS, could be useful for identifying T2DM patients at higher risk of cardiovascular events.

Antimicrobial resistance (AMR) is an urgent global issue. After the AMR action plan was introduced in 2016, a study on antibiotic literacy (i.e., awareness, knowledge, and attitude relating to antimicrobial use) among clinicians and lay people was conducted in Japan. However, no studies have hitherto targeted medical students who are expected to have a high level of antibiotic literacy. The present study was conducted between September 2019 and February 2020, enrolling undergraduate students at Okayama University Medical School. We collected data using a paper-based questionnaire form with 11 questions about antibiotic literacy. The response rate was 93.8% (661/705 students). Overall, 92.6% of the students knew that antibiotics inhibit the growth of bacteria. Student reporting that antibiotics could treat the common cold accounted for 77.0% (Year 1), 50.9% (Year 2), 48.2% (Year 3), 49.1% (Year 4), 23.8% (Year 5), and 26.2% (Year 6). Only 43 (6.5%) had heard about the AMR action plan. The study data suggested that medical students' level of literacy on antimicrobial use should be further enhanced to address AMR and promote antimicrobial stewardship., Competing Interests: Declaration of Competing Interest None to report., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to evaluate the efficacy and safety of transdermal β-blocker patches, which offer stable blood concentration and easy availability during operation, for prevention of perioperative myocardial injury (PMI) in high-risk patients., Methods and results: In this randomized controlled trial, patients aged >60 years with hypertension and high revised cardiac risk index (≥2) undergoing non-cardiac surgery were randomly assigned to a bisoprolol patch or control group. Primary efficacy outcome was incidence of PMI, defined as postoperative high-sensitivity cardiac troponin T (hs-cTnT) >0.014ng/mL and relative hs-cTnT change ≥20%. Secondary efficacy outcomes were number of cardiovascular events and 30-day mortality. From November 2014 to February 2019, 240 patients from 5 hospitals were enrolled in this study. The incidence of PMI was 35.7% in the bisoprolol patch group and 44.5% in the control group (P=0.18). Incidence of major adverse cardiac events including non-critical myocardial infarction, strokes, decompensated heart failure and tachyarrhythmia was similar between the 2 groups. Tachyarrhythmia tended to be higher in the control group. There were no significant differences in safety outcomes including significant hypotension and bradycardia requiring any treatment between the 2 groups., Conclusions: Bisoprolol patches do not influence the incidence of PMI and cardiovascular events in high-risk patients undergoing non-cardiac surgery, but perioperative use of these patches is safe.

Background: Carbapenem-resistant Enterobacteriaceae (CRE) are classified as carbapenemase-producing Enterobacteriaceae (CPE) and non-CPE; the majority of CPE in Japan produce IMP carbapenemase., Objectives: We evaluated the clinico-epidemiological and microbiological information and effects of IMP-type carbapenemase production in CRE., Methods: Patients with isolations of CRE (MICs of meropenem ≥2 mg/L, imipenem ≥2 mg/L or cefmetazole ≥64 mg/L) from August 2016 to March 2018 were included. Microbiological analyses and WGS were conducted and clinical parameters were compared between groups. Independent predictors for the isolation of CPE from patients were identified by logistic regression. For comparing clinical outcomes, a stabilized inverse probability weighting method was used to conduct propensity score-adjusted analysis., Results: Ninety isolates (27 CPE and 63 non-CPE) were collected from 88 patients (25 CPE and 63 non-CPE). All CPE tested positive for IMP carbapenemase. Antibiotic resistance (and the presence of resistance genes) was more frequent in the CPE group than in the non-CPE group. Independent predictors for CPE isolation were residence in a nursing home or long-term care facility, longer prior length of hospital stay (LOS), use of a urinary catheter and/or nasogastric tube, dependent functional status and exposure to carbapenem. Although in-hospital and 30 day mortality rates were similar between the two groups, LOS after CRE isolation was longer in the CPE group., Conclusions: IMP-CPE were associated with prolonged hospital stays and had different clinical and microbiological characteristics compared with non-CPE. Tailored approaches are necessary for the investigational and public health reporting, and clinical and infection prevention perspectives for IMP-CPE and non-CPE., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Streptococcus dysgalactiae subsp. equisimilis (SDSE) causes severe invasive streptococcal infections, especially in elderly people. Between 2013 and 2018, 88 streptococci were isolated from clinical blood culture in a hospital in Toyama prefecture, Japan. The collection included six Group A SDSE (ASD) strains, which are rarely isolated. Multilocus sequence typing categorized five of the six strains into ST128 and the remaining strain into a new type. Maximum-likelihood phylogenetic analysis revealed that the six ASD strains had highly similar genome sequences. Bayesian analysis indicated that the most recent common ancestor of the strains appeared 39 years ago. The ASD strains possessed carbohydrate synthase genes that are conserved in Streptococcus pyogenes strains, whereas one strain featured a different arrangement of the gene cluster. The carbohydrate synthase genes varied by Lancefield type (A, C, and G)., (© 2019 The Societies and John Wiley & Sons Australia, Ltd.)

In order to prevent ischemic stroke, it is important to identify and treat patients with atrial fibrillation (AF) who do not consult a doctor in a medical institution. The aim of this study was to determine the consultation rate at medical institutions for patients with AF in group medical examinations conducted in a city in western Japan. Of 6101 examinees of group medical examinations (40 years of age or older) conducted in Ibara City, Okayama Prefecture, Japan, from 2012 to 2014, 4338 participants (71.1%) who were evaluated by electrocardiogram (ECG) gave written informed consent and responded to surveys in the form of questionnaires through a personal interview conducted by nurses were included in the Ibara-AF study. A cumulative total of 82 subjects were diagnosed as having AF by ECG (prevalence of AF = 1.89%), and 51 individuals had AF during the three-year period.15 (29.4%) of the 51 patients with AF did not regularly visit medical institutions. Among them, 46.7% (n = 7) and 53.3% (n = 8) of the patients were symptomatic and asymptomatic, respectively, and 73.3% of the patients had a CHADS 2 score of more than one point. There were no significant differences in patients' characteristics between regular and non-regular visit groups. In conclusion, about one-third of the patients with AF did not regularly see a doctor in a medical institution and most of them had a CHADS 2 score of more than one point in a Japanese rural area. Educating the public about the risks of AF is required.

Heparin anticoagulant therapy for thromboembolic disorders during pregnancy is problematic due to unexpected adverse bleeding. To avoid bleeding, we have used a less-intensive anticoagulation protocol of unfractionated heparin (UFH). The protocol had a therapeutic activated partial thromboplastin time (APTT) ratio of 1.5-2.0 with the control value, a UFH dose of ≤ 30,000 U/day, and an antithrombin (AT) activity target of ≥ 70%. In the present study, we evaluated this protocol using an anti-Xa assay. We collected UFH-treated plasma samples from ten consecutive pregnant Japanese patients with current or previous thromboembolic disorders. Seven patients remained in the therapeutic APTT ratio range (heparin-sensitive [HS] group). The other three patients had difficulty remaining within the therapeutic range (heparin-resistant [HR] group). In the HR group, two had AT deficiency and one had congenital absence of the inferior vena cava. Of the HS and HR samples, 73% and 31%, respectively, were within the therapeutic anti-Xa activity range 0.3-0.7 U/mL, indicating difficulty for the HR group to remain within the therapeutic range. Neither major bleeding nor symptomatic thromboembolic episodes occurred in either group. These findings suggest that the less-intensive anticoagulation protocol is permissive and may be beneficial in the HS group.

Background: Standardized treatment of fetal tachyarrhythmia has not been established., Objectives: This study sought to evaluate the safety and efficacy of protocol-defined transplacental treatment for fetal supraventricular tachycardia (SVT) and atrial flutter (AFL)., Methods: In this multicenter, single-arm trial, protocol-defined transplacental treatment using digoxin, sotalol, and flecainide was performed for singleton pregnancies from 22 to <37 weeks of gestation with sustained fetal SVT or AFL ≥180 beats/min. The primary endpoint was resolution of fetal tachyarrhythmia. Secondary endpoints were fetal death, pre-term birth, and neonatal arrhythmia. Adverse events (AEs) were also assessed., Results: A total of 50 patients were enrolled at 15 institutions in Japan from 2010 to 2017; short ventriculoatrial (VA) SVT (n = 17), long VA SVT (n = 4), and AFL (n = 29). One patient with AFL was excluded because of withdrawal of consent. Fetal tachyarrhythmia resolved in 89.8% (44 of 49) of cases overall and in 75.0% (3 of 4) of cases of fetal hydrops. Pre-term births occurred in 20.4% (10 of 49) of patients. Maternal AEs were observed in 78.0% (39 of 50) of patients. Serious AEs occurred in 1 mother and 4 fetuses, thus resulting in discontinuation of protocol treatment in 4 patients. Two fetal deaths occurred, mainly caused by heart failure. Neonatal tachyarrhythmia was observed in 31.9% (15 of 47) of neonates within 2 weeks after birth., Conclusions: Protocol-defined transplacental treatment for fetal SVT and AFL was effective and tolerable in 90% of patients. However, it should be kept in mind that serious AEs may take place in fetuses and that tachyarrhythmias may recur within the first 2 weeks after birth., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: We explore the prevalence and characteristics of burnout among Japanese resident physicians and identifies factors associated with burnout., Methods: A cross-sectional study was conducted three times between April 2017 and March 2018 at a Japanese teaching hospital. Resident physicians were invited to answer an online survey that included existing valid instruments related to burnout, depression, and empathy. Demographic, background, occupational, and socioeconomic data were also collected. Participants were prompted to report the average daily work hours and the specialty they wish to pursue., Results: Overall, 39/76 (51%), 27/76 (36%), and 21/76 (28%) resident physicians responded to surveys in April 2017, October 2017, and March 2018, respectively. The percentages of participants with burnout for surveys in April 2017, October 2017, and March 2018 were 7/39 (18%), 6/27 (22%), and 7/21 (33.3%). Emotional exhaustion (EE) was the only burnout component strongly correlated with the severity of depression (r = .615, p < .001; r = .706, p < .001; r = .601, p < .01). EE and depersonalization (DP) had no significant correlation with average daily working hours (β = .156, p = .343 for EE; β = .061, p = .711 for DP)., Conclusions: The results suggest that capping working hours alone may not be effective in reducing burnout in Japanese resident physicians. Medical educators might need to consider not only working hours but also individual job quality and satisfaction to address burnout. Future studies may need to incorporate qualitative methods to explore the characteristics of burnout.

Background: Simulation-based learning plays an important role in contemporary medical education, although there are problems providing tutors. Peer-assisted learning has begun being formally adopted in medical education. Although it is considered useful for simulation-based learning, its effectiveness remains unclear. This study was designed to compare the effect of simulation-based learning with that of traditional lectures conducted by postgraduate-year (PGY)-II residents on PGY-I residents., Methods: This study was conducted at Okayama University Hospital over three years, for one week each year, before residents entered clinical practice. The study enrolled 76 PGY-I residents, who were randomized into two groups: simulation and lecture groups. PGY-II residents volunteered to conduct simulations and lectures. Knowledge evaluation was performed using pre- and post-tests, and self-evaluation of competence and behaviour-change and program evaluations were conducted using questionnaires., Results: In both groups, knowledge test scores were found to improve significantly, and the score difference between pre- and post-tests in both the groups was not significant. Self-evaluation of competence and behaviour-change was found to be higher in the simulation group than the lecture group. The trainees in the simulation group valued the program and the PGY-II residents as teaching staff more than those in the lecture group., Conclusions: The combination of simulation-based learning and peer-assisted learning led by PGY-II residents is potentially more effective in improving the postgraduate education of PGY-I residents than the combination of lecture and peer-assisted learning.

Purpose: The Japan Clinical Oncology Group Study 0201 has proposed radiologic criteria on thin-slice computed tomography to diagnose pathologic less invasive lung adenocarcinoma that could be a candidate for sublobar resection based on the previous tumor, node, metastasis classification system (TNM). The aim of this study was to propose the new radiologic criteria for predicting pathologic less invasive cancer according to the 8th edition TNM., Patients and Methods: We analyzed 744 patients who had peripheral clinical Tis-T1cN0M0 non-small-cell lung cancer of 3 cm or less and underwent complete resection by lobectomy from 2003 to 2011. We defined lung cancer with no nodal involvement and no vessel invasion pathologically as a pathologic less invasive cancer and investigated the radiologic criteria on the basis of the solid component size and by the consolidation-to-tumor (C/T) ratio (calculated with the maximum solid component diameter divided by the maximum tumor diameter) by using preoperative thin-slice computed tomography to predict them with a specificity of 97% or more, and evaluated overall survival., Results: Patients with clinical Tis/T1mi/T1a disease had no pathologic invasive cancer except for one patient (specificity, 99%). From the investigation with the C/T ratio, only the criterion of C/T ratio 0.5 or less met the standard (specificity, 100%). The final specificity after combining these criteria was 99.6%, and they showed excellent prognosis (5-year overall survival rate, 96.2%)., Conclusion: Lung cancer with clinical Tis/T1mi/T1a or a C/T ratio of 0.5 or less can be completely cured by sublobar resection with sufficient margin because of its less invasive nature pathologically., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background/aims: It has been reported that the body mass index shows a U-shaped association with death from cardiovascular disease (CVD) in the Asian population. The relationship between body weight (BW) gain from early adulthood and diabetic nephropathy remains to be elucidated in Japanese patients with type 2 diabetes. Our aim was to investigate the association between BW gain from early adulthood and diabetic nephropathy in Japanese patients with type 2 diabetes., Methods: We assessed the BW of 471 consecutive patients with type 2 diabetes and calculated the change in BW from the age of 20 years to the lifetime maximum (ΔBWmax-20y). We then evaluated the relationship of ΔBWmax-20y with the degree of urinary albumin excretion (UAE), which is a useful marker for CVD., Results: ΔBWmax-20y negatively correlated with the logarithm of UAE (r = -0.160, p = 0.002). Multiple regression analysis demonstrated that ΔBWmax-20y was independently correlated with the logarithm of UAE (β =-0.112, p =0.034)., Conclusions: BW gain from the age of 20 years is correlated with diabetic nephropathy in Japanese patients with type 2 diabetes., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Objective: We attempted to evaluate fetal cardiac activity of congenital heart disease (CHD) and normal heart fetuses by magnetic resonance imaging (MRI)., Methods: We evaluated the fetal cardiac functional assessment and the blood flow of descending aorta at 34 weeks' gestation or more by MRI and compared the results with ultrasonography findings. We measured 6 normal heart fetuses and 14 CHD fetuses., Results: The ejection fraction (EF) and descending aorta blood flow in the CHD group were 76.4% ± 11.9%, 687.5 ± 303.8 mL/min by ultrasonography and 48.3% ± 7.1%, 711.4 ± 273.1 mL/min by MRI; those in the normal group were 66.9% ± 12.2%, 898.1 ± 245.9 mL/min by ultrasonography and 51.3% ± 4.2%, 911.9 ± 223.1 mL/min by MRI., Conclusions: There was no significant difference in descending aorta blood flow measurements between ultrasonography and MRI, but the EF showed a significant between-group difference. In the normal group, the variation of EF and blood flow measured by MRI was significantly smaller compared with those of ultrasonography.

Objective: The objective of our study was to assess the preoperative resectability of pancreatic ductal adenocarcinoma (PDAC) using the National Comprehensive Cancer Network (NCCN) guideline, the general rules of the Japan Pancreas Society (JPS), and both of them combined., Materials and Methods: Eighty-six consecutive patients with PDAC (50 men and 36 women; mean age ± SD, 70.8 ± 9.0 years; age range, 49-86 years) underwent dynamic contrast-enhanced CT. Following the NCCN guideline, the degree of vascular invasion was evaluated to determine the NCCN score: 0 points for absence of vascular invasion, 1 point for tumor contact ≤ 180°, and 2 points for tumor contact > 180°. Direct invasion to adjacent structures was rated according to the general rules of JPS to determine the JPS score: 0 points for absence and 1 point for presence. The NCCN score, JPS score, and sum of the two scores, which we refer to as the "combined score," were compared with histopathologic or intraoperative findings as well as for the differentiation of R0 resection (negative resection margins) from R1 (microscopic tumor infiltration) and R2 (macroscopic residual tumor) using ROC curve analysis., Results: The sensitivities, specificities, and areas under the ROC curves (AUCs) for the differentiation of R0 from R1 and R2 were 100.0%, 40.0%, and 0.725, respectively, with the NCCN score; 63.9%, 84.0%, and 0.824 with the JPS score; and 86.9%, 68.0%, and 0.874 with the combined score. The AUC of the combined score was significantly greater than that of the NCCN score (p = 0.0059)., Conclusion: The assessment of resectability of PDAC based on the combined criteria of the NCCN guideline and general rules of JPS was superior to that based on either criterion alone.

Objectives: Patients with lung cancer and interstitial lung disease (ILD), usual interstitial pneumonia in particular, are known to have a poor outcome. The aim of this study was to evaluate the prognostic impact of ILD in patients with non-small-cell lung cancer., Methods: A total of 2054 consecutive patients underwent complete resection of Stage IA-IIIA non-small-cell lung cancer in our institution between January 2002 and March 2013. The presence of ILD was diagnosed and categorized based on high-resolution computed tomography images. Multivariate analysis was performed to identify the prognostic factors., Results: There were 106 (5%) patients with ILD. There were significantly more patients who developed severe complications (P < 0.01) in the ILD group, with 4 (4%) patients developing acute exacerbation. Although the difference in postoperative mortality rate was marginal between the groups (P = 0.07), the 5-year overall survival and cancer-specific survival rates of the ILD patients were significantly worse than those of the non-ILD group (overall survival: 40.4% vs 72.0%, P < 0.01; cancer-specific survival 55.4% vs 78.6%, P < 0.01). The results of multivariate analysis showed that coexistence of ILD (hazard ratio 1.45; P = 0.01) was an independent, unfavourable prognostic factor., Conclusions: The presence of ILD led to a much poorer survival after complete resection of non-small-cell lung cancer.

Background: The effect of lipid-lowering agents on progression of coronary artery calcification (CAC) remains unclear. We evaluated the effects of pitavastatin 2 mg/day (PIT2), pitavastatin 4 mg/day (PIT4), and PIT2 combined with eicosapentaenoic acid (PIT2+EPA) on CAC progression.Methods and Results:This prospective multicenter study in Japan included patients with an Agatston score of 1-999, hypercholesterolemia, and no evidence of cardiovascular disease. Patients were allocated into PIT2, PIT4, or PIT2+EPA groups. The primary outcome was the annual percent change in Agatston score in all patients. In total, 156 patients who had multi-detector row computed tomography without any artifacts were included in the primary analysis. Pitavastatin did not significantly reduce the annual progression rate of the Agatston score (40%; 95% CI: 19-61%). The annual progression rate of Agatston score in the PIT2 group was not significantly different from that in the PIT4 group (34% vs. 42%, respectively; P=0.88) or the PIT2+EPA group (34% vs. 44%, respectively; P=0.80). On post-hoc analysis the baseline ratio of low- to high-density lipoprotein cholesterol was a significant predictor of non-progression of Agatston score by pitavastatin (OR, 2.17; 95% CI: 1.10-44.12; P=0.02)., Conclusions: Pitavastatin does not attenuate progression of CAC. Intensive pitavastatin treatment and standard treatment with EPA does not reduce progression of CAC compared with standard treatment.

Background: Chronic kidney disease (CKD) and inflammation play critical roles in atherosclerosis. There is limited evidence regarding the relationship between CKD and patients receiving second-generation drug-eluting stents for coronary artery disease., Objective: This study aimed to investigate the effect of CKD on cardiovascular and renal events in patients undergoing percutaneous coronary intervention (PCI) with everolimus-eluting stents (EES)., Methods: We analyzed 504 consecutive patients with stable angina pectoris and significant coronary artery stenosis treated with EES. CKD was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2 before coronary angiography. The primary outcome was the occurrence of major adverse renal and cardiovascular events (MARCE) including cardiac death, revascularization, heart failure, cerebral infarction, worsening renal function > 25% from baseline, and renal replacement therapy at 1 year., Results: Patients were divided into the a MARCE (n = 126) and a non-MARCE (n = 378) group. The incidence of CKD was 51% in all subjects (including those on hemodialysis) and was significantly higher in the MARCE group than in the non-MARCE group (p = 0.00001). Multivariate logistic regression analysis identified that CKD was independently associated with MARCE (adjusted odds ratio 2.03, 95% confidence interval 1.21-3.39, p = 0.007). Patients were divided into four groups based on CKD and C-reactive protein (CRP) level prior to initial coronary angiography. Cox proportional hazards analysis revealed that patients with CKD and high CRP (≥0.3 mg/dL) had the worst prognosis (hazard ratio 4.371, 95% confidence interval 2.634-7.252, p = 0.00001) compared to patients without CKD and with low CRP., Conclusion: CKD combined with CRP predicted more clinical events in patients undergoing PCI with EES., (© 2018 S. Karger AG, Basel.)

Pseudomonas aeruginosa (P. aeruginosa) is one of the most common nosocomial pathogens worldwide. Although the emergence of multidrug-resistant (MDR) P. aeruginosa is a critical problem in medical practice, the key features involved in the emergence and spread of MDR P. aeruginosa remain unknown. This study utilized whole genome sequence (WGS) analyses to define the population structure of 185 P. aeruginosa clinical isolates from several countries. Of these 185 isolates, 136 were categorized into sequence type (ST) 235, one of the most common types worldwide. Phylogenetic analysis showed that these isolates fell within seven subclades. Each subclade harbors characteristic drug resistance genes and a characteristic genetic background confined to a geographic location, suggesting that clonal expansion following antibiotic exposure is the driving force in generating the population structure of MDR P. aeruginosa. WGS analyses also showed that the substitution rate was markedly higher in ST235 MDR P. aeruginosa than in other strains. Notably, almost all ST235 isolates harbor the specific type IV secretion system and very few or none harbor the CRISPR/CAS system. These findings may help explain the mechanism underlying the emergence and spread of ST235 P. aeruginosa as the predominant MDR lineage., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

High diagnostic performance of noninvasive fractional flow reserve computed from CT (FFR-CT) was recently reported in prospective multicenter trials. The aims of this study were to evaluate the diagnostic accuracy of FFR-CT in clinical practice and to examine the lesion characteristics showing a mismatch between FFR-CT and invasive FFR. A total of 20 patients (29 vessels) with suspected coronary artery disease were included. All patients underwent invasive coronary angiography and invasive FFR according to coronary artery CT angiography (CCTA) findings. The same raw data used for CCTA were used to evaluate FFR-CT. Results from FFR-CT were compared with invasively measured FFR. A positive ischemia was defined as FFR <0.80. Analyses from three vessels in two patients were not evaluated because of severe calcification or motion artifacts. The diagnostic accuracy, sensitivity, and specificity of FFR-CT per-vessel basis were 81, 100, and 69 %, respectively. To find the reason for mismatch in positive ischemia, lesion characteristics determined with CCTA were compared between the matched group and the mismatched group. A significant difference in bifurcation lesions with positive remodeling was observed between the matched group and the mismatched group (p < 0.01). The high sensitivity of FFR-CT may provide an additional support to the use of CCTA, although particular attention should be paid when using FFR-CT in bifurcation lesions with positive remodeling.

Objectives: Invasive lepidic predominant adenocarcinoma (LPA) of the lung is thought to progress in a stepwise fashion from adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA). The aim of this study was to investigate the microenvironmental changes during the development from AIS to LPA., Materials and Methods: Clinicopathological characteristics of AIS (n=51), MIA (n=59), LPA smaller than 3cm (LPA-S, n=113), and LPA larger than 3cm (LPA-L, n=47) were analyzed. We then evaluated the expression levels of epithelial-mesenchymal transition (EMT)-related molecules (E-cadherin, S100A4), invasion-related molecules (laminin-5, ezrin), stem-cell-related molecules (ALDH-1), and growth factor receptors (c-Met, EGFR) in cancer cells of each group (n=20). The number of tumor-promoting stromal cells, including podoplanin-positive cancer-associated fibroblasts (PDPN+ CAFs), CD204-positive tumor-associated macrophages (CD204+ TAMs), and CD34+ microvessel cells, were also analyzed., Results: No significant difference in these characteristics was found between LPA-S and LPA-L. Laminin-5 expression in the non-invasive carcinoma component of MIA was significantly higher than that of AIS (p<0.001). During the progression from MIA to LPA-S, the expression level of laminin-5 in the invasive carcinoma component was significantly elevated (p<0.01). Moreover, tumor-promoting stromal cells were more frequently recruited in the invasive area of LPA-S (PDPN+ CAFs; p<0.05, CD204+ TAMs; p<0.001, CD34+ microvessel; p<0.05). Ezrin expression in the invasive carcinoma component of LPA-L was significantly increased (p<0.05) compared to LPA-S; however, the number of tumor-promoting stromal cells were not different between these two groups., Conclusion: Our current results indicated that microenvironmental molecular changes occur during the progression from MIA to LPA-S and suggested that this process may play an important role in disease progression from AIS to LPA., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

A carbapenem-resistant strain of Pseudomonas aeruginosa, NCGM1984, was isolated in 2012 from a hospitalized patient in Japan. Immunochromatographic assay showed that the isolate was positive for IMP-type metallo-β-lactamase. Complete genome sequencing revealed that NCGM1984 harbored two copies of blaIMP-34, located at different sites on the chromosome. Each blaIMP-34 was present in the same structures of the class 1 integrons, tnpA(ISPa7)-intI1-qacG-blaIMP-34-aac(6')-Ib-qacEdelta1-sul1-orf5-tniBdelta-tniA. The isolate belonged to multilocus sequence typing ST235, one of the international high-risk clones. IMP-34, with an amino acid substitution (Glu126Gly) compared with IMP-1, hydrolyzed all β-lactamases tested except aztreonam, and its catalytic activities were similar to IMP-1. This is the first report of a clinical isolate of an IMP-34-producing P. aeruginosa harboring two copies of blaIMP-34 on its chromosome.

The liver micronucleus assay using young adult rats has the potential to detect liver carcinogens by repeated dosing, and could be expected to be integrated into repeated-dose toxicity studies using a hepatocyte isolation method without the traditional in situ collagenase perfusion. In this study, to assess the performance of the repeated-dose liver micronucleus assay, 2,4-dinitrotoluene (DNT), which is a rodent liver carcinogen, was administered orally to male rats at doses of 50, 100 and 200 mg/kg/day once daily for 14 or 28 consecutive days, and the frequencies of micronucleated hepatocytes (MNHEPs) and micronucleated immature erythrocytes (MNIMEs) were examined. Significant increases in the MNHEPs were observed at 50 mg/kg/day or more in the 14-day treatment, and 50 and 100 mg/kg/day in the 28-day treatment. These increases were dependent on both the dose and the number of administrations, which indicates the possibility that the MNHEPs accumulate as a result of repeated dosing. In contrast, no increase in the MNIMEs was observed. In conclusion, the repeated-dose liver micronucleus assay using young adult rats is sufficiently sensitive to detect the genotoxicity of 2,4-DNT at a low dose.

Background: Because there is limited information on fetal bradyarrhythmia associated with congenital heart defects (CHD), we investigated its prognosis and risk factors., Methods and Results: In our previous nationwide survey of fetal bradyarrhythmia from 2002 to 2008, 38 fetuses had associated CHD. Detailed clinical data were collected from secondary questionnaires on 29 fetuses from 18 institutions, and were analyzed. The 29 fetuses included 22 with isomerism, 4 with corrected transposition of the great arteries (TGA) and 3 with critical pulmonary stenosis; 14 had complete atrioventricular block (AVB), 8 had second-degree AVB, and 16 had sick sinus syndrome; 5 died before birth, and 10 died after birth (5 in the neonatal period). Neonatal and overall survival rates for fetal bradyarrhythmia with CHD were 66% and 48%, respectively. Pacemaker implantation was needed in 17 cases (89%). Beta-sympathomimetics were administered in utero in 13 cases and were effective in 6, but were not associated with prognosis. All cases of corrected TGA or ventricular rate ≥70 beats/min survived. A ventricular rate <55 beats/min had significant effects on fetal myocardial dysfunction (P=0.02) and fetal hydrops (P=0.04), resulting in high mortality., Conclusions: The prognosis of fetal bradyarrhythmia with CHD is still poor. The type of CHD, fetal myocardial dysfunction, and fetal hydrops were associated with a poor prognosis, depending on the ventricular rate.

The spread throughout Japan of antibiotic-resistance factors in multidrug-resistant (MDR) Pseudomonas aeruginosa isolates was investigated epidemiologically, using immunochromatographic assays specific for IMP-type metallo-β-lactamases (IMPs) and aminoglycoside 6'-N-acetyltransferase [AAC(6')]-Iae and -Ib. Three hundred MDR P. aeruginosa isolates were obtained during each of two years, 2011 and 2012, from 190 hospitals in 39 prefectures in Japan. The percentage of P. aeruginosa isolates producing IMPs, AAC(6')-Iae or AAC(6')-Ib increased significantly from 170/300 (56.7%) in 2011 to 230/300 (76.7%) in 2012, with 134/170 (78.8%) in 2011 and 179/230 (77.8%) in 2012 producing both IMP and either AAC(6')-Iae or AAC(6')-Ib. The MICs of antibiotics, including cephalosporins and carbapenems, were markedly higher for isolates that did than did not produce these resistance factors. These results indicated that MDR P. aeruginosa producing IMPs, AAC(6')-Iae or AAC(6')-Ib have spread throughout Japan and that these antibiotic-resistance factors are useful markers for monitoring MDR P. aeruginosa in Japan., (Copyright © 2014. Published by Elsevier Ltd.)