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Itsuki Terao,1 Jiro Masuya,1 Chihiro Morishita,1 Motoki Higashiyama,1 Akiyoshi Shimura,1 Yu Tamada,1,2 Takeshi Inoue,1 Yota Fujimura1 1Department of Psychiatry, Tokyo Medical University, Tokyo, Japan; 2Department of Psychiatry, Toranomon Hospital Kajigaya, Kawasaki, Kanagawa, JapanCorrespondence: Chihiro Morishita, Department of Psychiatry, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan, Tel +81 3 3342 6111, Fax +81 3 3340 4499, Email mchihiro@tokyo-med.ac.jpPurpose: Depression poses a substantial burden worldwide. Therefore, elucidating the pathophysiological mechanism of depression is important. Sleep disturbance and sleep reactivity are symptoms of depression and are also known to exacerbate depressive symptoms. On the other hand, it is well known that resilience ameliorates depressive symptoms. To our knowledge, there have been no reports to date regarding the interaction effects among sleep disturbance, sleep reactivity, and resilience on depressive symptoms. We hypothesized that resilience buffers the aggravating effects of sleep disturbance and sleep reactivity on depressive symptoms. To test this hypothesis, we conducted hierarchical multiple regression analyses.Subjects and Methods: A total of 584 Japanese adult volunteers were recruited between April 2017 and April 2018 by convenience sampling. Their demographic characteristics, sleep disturbance, sleep reactivity, resilience, and depressive symptoms were investigated using self-administered questionnaires. The data were analyzed using hierarchical multiple regression analyses.Results: Sleep disturbance and sleep reactivity were significantly positively associated with depressive symptoms, whereas resilience was significantly negatively associated with depressive symptoms. Moreover, there was a significant interaction between sleep disturbance or sleep reactivity and resilience on depressive symptoms. Resilience significantly alleviated the aggravating effect of sleep disturbance and sleep reactivity on depressive symptoms.Conclusion: Our results indicate that people with lower resilience have more severe depressive symptoms that are associated with sleep disturbance and sleep reactivity. Therefore, there is a possibility that the enhancement of resilience will buffer the aggravating effects of sleep disturbance and sleep reactivity on depressive symptoms, and that improving sleep quality might alleviate the negative effect of low resilience on depressive symptoms.Keywords: depression, resilience, sleep disturbance, sleep reactivity, CD-RISC

Shogo Hashimoto,1,* Masahiko Ichiki,2,* Yoshitaka Ishii,2,3 Chihiro Morishita,2 Akiyoshi Shimura,2 Ichiro Kusumi,1 Takeshi Inoue,2 Jiro Masuya2 1Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan; 2Department of Psychiatry, Tokyo Medical University, Tokyo, 160-0023, Japan; 3Fuji Psychosomatic Rehabilitation Institute Hospital, Fujinomiya, Shizuoka, 418-0035, Japan*These authors contributed equally to this workCorrespondence: Takeshi Inoue, Tel +81 3 3342 6111, Fax +81 3 3340 4499, Email tinoue@Tokyo-med.ac.jpBackground: Victimization in childhood profoundly influences the mental health of individuals in adulthood, causing depression, anxiety disorder, suicidality, and self-harm, which leads to productivity loss in the workplace, ie, presenteeism. However, the specific effects of victimization on presenteeism remain unclear. We hypothesized that victimization affects the presenteeism of workers through neuroticism and perceived job stressors and analyzed the association among these factors by path analysis.Methods: A questionnaire survey, including demographic and clinical data, Japanese versions of victimization scale in childhood, Brief Job Stress Questionnaire, and Work Limitations Questionnaire (WLQ), was administered to 443 adult volunteers between April 2017 and April 2018 in Tokyo, Japan. Multiple variables were analyzed by multiple regression analysis and path analysis. The Institutional Review Board of Tokyo Medical University approved this study.Results: Path analysis demonstrated that neuroticism and perceived job stressors had direct effects on presenteeism in the WLQ. Victimization indirectly increased presenteeism via neuroticism and its subsequent effects on perceived job stressors. This model accounted for 18% of the variability of presenteeism (R2 = 0.180).Limitations: There may be possible recall bias owing to the self-administration of the questionnaire. In addition, this study had a cross-sectional design, and hence the causal associations among variables should be validated in a prospective study.Conclusion: The present study indicates that the experience of victimization in childhood is a risk factor of adulthood presenteeism, and this effect is mediated by neuroticism and adverse effects on job stressors. These results suggest that multiple factors, including childhood victimization, neuroticism, and job stressors, should be considered when assessing and preventing presenteeism.Keywords: victimization, neuroticism, job stressor, presenteeism, childhood

Taito Hayashida,1,2 Akiyoshi Shimura,2 Motoki Higashiyama,2 Yota Fujimura,1 Kotaro Ono,2 Takeshi Inoue2 1Department of Psychiatry, Tokyo Medical University Hachioji Medical Center, Hachioji-shi, Tokyo, 193-0998, Japan; 2Department of Psychiatry, Tokyo Medical University, Shinjuku-ku, Tokyo,160-0023, JapanCorrespondence: Akiyoshi ShimuraDepartment of Psychiatry, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, JapanTel +81-3-3342-6111Fax +81-3-3340-4499Email sim@tokyo-med.ac.jpBackground: Presenteeism is the loss of work productivity of workers owing to physical and mental problems, and its socioeconomic effects are greater than those of absenteeism. Presenteeism is caused by psychological and physical dysfunctions. On the other hand, the regularity of mealtimes is an important factor associated with physical and mental health conditions. We hence assessed the association among the irregularity of mealtimes, presenteeism, psychological and physical stress responses, and sleep disturbance in office workers in companies.Methods: From May to December 2017, the data of 2905 participants who had given their consent to use their information for academic purposes, and answered a questionnaire about the survey and their lifestyle were collected. Path analysis was performed to analyze the association between the irregularity of mealtimes, psychosomatic symptoms (Brief Job Stress Questionnaire), sleep disturbance (Pittsburgh Sleep Questionnaire), and presenteeism (Work Limitations Questionnaire).Results: The direct effect of the irregularity of mealtimes on presenteeism was significant but weak. However, the irregularity of mealtimes had a strong effect on presenteeism indirectly through psychological and physical stress responses and sleep disturbance.Conclusion: Psychological and physical stress responses and sleep disturbance were identified as mediating factors of the effects of irregularity of mealtimes on presenteeism.Keywords: presenteeism, Work Limitations Questionnaire, WLQ, mealtimes, sleep disturbance, stress reaction, mediating effect

Tomoteru Seki,1,2 Akiyoshi Shimura,1 Hitoshi Miyama,1 Wataru Furuichi,1 Kotaro Ono,1 Jiro Masuya,1 Yuko Odagiri,3 Shigeru Inoue,3 Takeshi Inoue1 1Department of Psychiatry, Tokyo Medical University, Shinjuku-ku, Tokyo 160-0023, Japan; 2Fuji Psychosomatic Rehabilitation Institute Hospital, Fujinomiya, Shizuoka 418-0035, Japan; 3Department of Preventive Medicine and Public Health, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, JapanCorrespondence: Akiyoshi ShimuraDepartment of Psychiatry, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, JapanTel +81-3-3342-6111Fax +81-3-3340-4499Email sim@tokyo-med.ac.jpBackground: The complex interaction between parenting styles, job stressors, and the stress response has not been clarified to date. We hypothesized that neuroticism acts as a mediator in the effects of parenting quality on perceived job stressors and the psychological and physical stress response (PPSR), and tested this hypothesis using covariance structure analysis.Subjects and Methods: We conducted research between April 2017 and April 2018 on 597 adult from the community, and 69 subjects were excluded owing to missing data or nonworkers. Finally, a total of 528 participants were analyzed using the following self-administered questionnaires: the Parental Bonding Instrument, the shortened Eysenck Personality Questionnaire-Revised, and the Brief Job Stress Questionnaire (BJSQ). The data were analyzed by single regression analyses and covariance structure analyses. Job stress was assessed by the BJSQ and 2 subscales, ie, perceived job stressors and the PPSR. This study was approved by the Ethics Committee of Tokyo Medical University.Results: On covariance structure analysis, high parental overprotection was associated with high neuroticism and high PPSR directly, but had no significant effect on perceived job stressors. High parental overprotection was associated with high-perceived job stressors and the high PPSR indirectly through enhanced neuroticism. High parental overprotection was also associated with the high PPSR indirectly through 2 combined paths of neuroticism and perceived job stressors. This model accounted for 40% of the variability of the PPSR. On the other hand, parental care had opposite effects to parental overprotection, and this model of parental care accounted for 39% of the variability of PPSR. The model fits of the 2 models were good.Conclusion: Our results suggest that the quality of parenting in childhood is associated with perceived job stressors and the PPSR indirectly through neuroticism.Keywords: parental care, parental overprotection, neuroticism, job stress, covariance structure analysis, structural equation model

Hitoshi Miyama,1,2 Akiyoshi Shimura,1 Wataru Furuichi,1 Tomoteru Seki,1 Kotaro Ono,1 Jiro Masuya,1 Yuko Odagiri,3 Shigeru Inoue,3 Takeshi Inoue1 1Department of Psychiatry, Tokyo Medical University, Tokyo 160-0023, Japan; 2Department of Psychiatry, Maruyamasou Hospital, Ishioka, Ibaraki 315-0116, Japan; 3Department of Preventive Medicine and Public Health, Tokyo Medical University, Tokyo 160-8402, JapanCorrespondence: Akiyoshi ShimuraDepartment of Psychiatry, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-Ku, Tokyo 160-0023, JapanTel +81-3-3342-6111Fax +81-3-3340-4499Email sim@tokyo-med.ac.jpBackground: Chronotype, which is a person’s circadian characteristics throughout a day, greatly influences a person’s lifestyle, health, and sleep pattern; however, the association between job stress and chronotype remains unknown to date. Therefore, in this study, we analyzed the effects of chronotype on the job stress response, and the mediating effects of sleep disturbance using path analysis.Methods: A cross-sectional survey was conducted on 535 adult volunteers (239 men and 296 women; average age, 41.2 ± 11.9 years) from the community. Participants were evaluated using the Diurnal Type Scale for chronotype, Pittsburg Sleep Quality Index for sleep disturbance, Brief Job Stress Questionnaire for job stressors, and the psychological and physical stress response (PPSR). To investigate the association between chronotype, sleep disturbance, perceived job stressors, and PPSR, a covariance structure analysis was performed.Results: The eveningness chronotype had a significant weak direct effect on sleep disturbance, perceived job stressors, and PPSR, and had a significant indirect effect through sleep disturbance. The perceived job stressors indirectly increased PPSR through sleep disturbance. Sleep disturbance mediated the effects of the eveningness chronotype and perceived job stressors on PPSR. This model accounted for 37.3% of the variability in PPSR of adult workers.Conclusion: Chronotype affected PPSR through sleep disturbance. Therefore, improving the sleep disturbance of workers with the eveningness chronotype may reduce their stress response.Keywords: eveningness chronotype, sleep disturbance, job stress, Diurnal Type Scale

Wataru Furuichi,1,2 Akiyoshi Shimura,1 Hitoshi Miyama,1 Terutomo Seki,1 Kotaro Ono,1 Jiro Masuya,1 Takeshi Inoue1 1Department of Psychiatry, Tokyo Medical University, Tokyo 160-0023, Japan; 2Department of Psychiatry, Seiwakai Nakayama Hospital, Ichikawa, Chiba, 272-0813, JapanCorrespondence: Akiyoshi Shimura Tel +81-3-3342-6111Fax +81-3-3340-4499Email sim@tokyo-med.ac.jpBackground: Occupational mental health, work environment, sleep health, presenteeism, and loss of work productivity caused by health problems are all public health concerns. Although sleep affects mental health and presenteeism, the associations between sleep disturbance, job stressors, stress responses, and presenteeism have remained unclear. We hypothesized that job stressors affect the presenteeism of office workers through sleep disturbance and analyzed the association among these factors.Subjects and Methods: In 2017, a cross-sectional survey of adult office workers was performed. A total of 2899 subjects who provided written consent were included in the analysis. The survey collected demographic information, as well as the Work Limitation Questionnaire (WLQ), Pittsburgh Sleep Quality Index (PSQI), and Brief Job Stress Questionnaire (BJSQ). Associations between each of the variables were analyzed by path analysis (covariance structure analysis). This study was approved by the Ethics Committee of Tokyo Medical University.Results: The path analysis demonstrated that job stressors, psychological and physical stress response (PPSR) in the BJSQ, and sleep disturbance in the PSQI had direct effects on presenteeism in the WLQ. Both job stressors and social support in the BJSQ indirectly affected presenteeism through effects on sleep disturbance and PPSR. Sleep disturbance indirectly affected presenteeism via PPSR. This model accounted for the variation of presenteeism (R2 = 0.322).Conclusion: In the workplace, job stressors and low social support increase presenteeism through psychological and physical stress responses, as well as sleep disturbance. Evaluating and resolving work problems and sleep disturbance would hence be beneficial from the aspects of public health and socioeconomics.Keywords: job stress, occupational stress, sleep disturbance, presenteeism, work limitation questionnaire, WLQ

Kotaro Ono,1 Yoshikazu Takaesu,1 Yukiei Nakai,2 Akiyoshi Shimura,1 Yasuyuki Ono,1 Akiko Murakoshi,1 Yasunori Matsumoto,1 Hajime Tanabe,3 Ichiro Kusumi,2 Takeshi Inoue1 1Department of Psychiatry, Tokyo Medical University, Tokyo, 2Department of Psychiatry, Hokkaido University Graduate School of Medicine, Hokkaido, 3Department of Clinical Human Sciences, Graduate school of Humanities and Social Sciences, Shizuoka University, Shizuoka, Japan Background: Recent studies have suggested that the interactions among several factors affect the onset, progression, and prognosis of major depressive disorder. This study investigated how childhood abuse, neuroticism, and adult stressful life events interact with one another and affect depressive symptoms in the general adult population. Subjects and methods: A total of 413 participants from the nonclinical general adult population completed the Patient Health Questionnaire-9, the Child Abuse and Trauma Scale, the neuroticism subscale of the shortened Eysenck Personality Questionnaire – Revised, and the Life Experiences Survey, which are self-report scales. Structural equation modeling (Mplus version 7.3) and single and multiple regressions were used to analyze the data. Results: Childhood abuse, neuroticism, and negative evaluation of life events increased the severity of the depressive symptoms directly. Childhood abuse also indirectly increased the negative appraisal of life events and the severity of the depressive symptoms through enhanced neuroticism in the structural equation modeling. Limitations: There was recall bias in this study. The causal relationship was not clear because this study was conducted using a cross-sectional design. Conclusion: This study suggested that neuroticism is the mediating factor for the two effects of childhood abuse on adulthood depressive symptoms and negative evaluation of life events. Childhood abuse directly and indirectly predicted the severity of depressive symptoms. Keywords: childhood abuse, depression, neuroticism, stressful life events, structural equation modeling

Abstract Repeat expansions cause at least 50 hereditary disorders, including Friedreich ataxia and other diseases known to cause mitochondrial dysfunction. We identified a patient with NAXE-related mitochondrial encephalopathy and novel biallelic GGGCC repeat expansion as long as ~200 repeats in the NAXE promoter region using long-read sequencing. In addition to a marked reduction in the RNA and protein, we found a marked reduction in nascent RNA in the promoter using native elongating transcript-cap analysis of gene expression (NET-CAGE), suggesting transcriptional suppression. Accordingly, CpG hypermethylation was observed in the repeat region. Genetic analyses determined that homozygosity in the patient was due to maternal chromosome 1 uniparental disomy (UPD). We assessed short variants within NAXE including the repeat region in the undiagnosed mitochondrial encephalopathy cohort of 242 patients. This study identified the GGGCC repeat expansion causing a mitochondrial disease and suggests that UPD could significantly contribute to homozygosity for rare repeat-expanded alleles.

Abstract Delirium is a multifactorial medical condition of waxing and waning impairment across various domains of mental functioning over time. Importantly, delirium is also one of the greatest risk factors for prolonged hospitalization, morbidity, and mortality. Studying this important condition is challenging due to the difficulty in both objective diagnosis in patients and validation of laboratory models. As a result, there is a lack of protective treatments for delirium. Our recent studies report the efficacy of bispectral electroencephalography (BSEEG) in diagnosing delirium in patients and predicting patient outcomes, advancing the concept that this simple measure could represent an additional vital sign for patients. Here, we applied BSEEG to characterize and validate a novel lipopolysaccharide (LPS) mouse model of infection-related delirium. We then applied this model to evaluate the protective efficacy of three putative therapeutic agents: the conventional antipsychotic medication haloperidol, the neuroprotective compound P7C3-A20, and the antibiotic minocycline. Aged mice were more susceptible than young mice to LPS-induced aberration in BSEEG, reminiscent of the greater vulnerability of older adults to delirium. In both young and old mice, P7C3-A20 and minocycline administration prevented LPS-induced BSEEG abnormality. By contrast, haloperidol did not. P7C3-A20 and minocycline have been shown to limit different aspects of LPS toxicity, and our data offers proof of principle that these agents might help protect patients from developing infection-related delirium. Thus, utilization of BSEEG in a mouse model for infection-related delirium can identify putative therapeutic agents for applications in patient clinical trials.

ABSTRACT Aims/Introduction Chronic kidney disease (CKD) is a very important issue globally because of the risk of its progressing to end‐stage renal disease. We aimed to identify factors contributing to long‐term estimated glomerular filtration rate (eGFR) decline to determine an early diagnosis and prevent CKD progression. Materials and Methods From January 2003 to December 2006, 5,507 individuals underwent health checkups at our hospital's Preventive Medicine Research Center. We ultimately enrolled 2,175 individuals. The eGFR was ≥60 mL/min/1.73 m2 at the start of observation period, which was 20 years. The event onset time was the day that the eGFR became

Abstract Aims The prognosis of colorectal cancer (CRC) has been historically reliant on the Tumor Node Metastasis (TNM) staging system, but there is variability in outcomes among patients at similar stages. Therefore, there is an urgent need for more robust biomarkers. The aim of this study was to assess the clinical feasibility of the recently reported Inflammatory Burden Index (IBI) for predicting short‐ and long‐term outcomes in patients with CRC. Methods This was a retrospective observational study of 555 CRC patients undergoing surgery for primary tumor resection. We determined the prognostic value of preoperative IBI for disease‐free and overall survival, and its predictive value for perioperative risk of infectious complications, including surgical site infection. Results Increased preoperative IBI was significantly associated with advanced disease stage and poor oncological outcome in CRC patients. Higher IBI was independently linked to poorer disease‐free and overall survival. Similar outcomes were observed in a subanalysis focused on high‐risk stage II and stage III CRC patients. Elevated preoperative IBI was significantly correlated with an increased risk of surgical site infection and other postoperative infectious complications. Propensity score‐matching analysis validated the impact of IBI on the prognosis in CRC patients. Conclusion We established preoperative IBI as a valuable predictive biomarker for perioperative risks and oncological outcomes in CRC patients. Preoperative IBI is useful for designing effective perioperative management and postoperative oncological follow‐up.

Introduction: Enfortumab vedotin (EV) is an antibody-drug conjugate combining a monoclonal antibody targeting nectin-4 with a highly potent microtubule disrupting agent. EV is expected to be a candidate for the third-line treatment for urothelial carcinoma previously treated with platinum-based chemotherapy and PD-1/PD-L1 inhibitors. Very few cases of patients experienced hyperglycemia of unknown cause. Case Presentation: We describe a 72-year-old Asian man with mild obesity, type 2 diabetes, hyperlipidemia, hypertension, and chemo-resistant metastatic urothelial carcinoma. He developed hyperglycemia and febrile neutropenia after 3 doses of EV. He had hyperglycemia of 489 mg/dL and was started on continuous intravenous insulin infusion (CVII). The patient’s intravenous insulin requirements peaked at 316 units per day. He also developed febrile neutropenia and consequent sepsis caused acute kidney injury. Continuous hemodialysis filtration (CHDF) together with antibiotics were started to treat the septic condition. The blood glucose level gradually decreased after CHDF treatment and CHDF was continued for 14 days. The timing of liberation from CHDF correlated with the elimination half-life of EV of 3.4 days. CVII was treated for 26 days and the patient was finally released from the intensive care unit. Conclusion: This case indicates that the uncontrollable hyperglycemia induced by EV during metastatic urothelial carcinoma treatment is effectively managed with CVII and CHDF until the elimination of the adverse effect of EV.

Objective: This study was performed to demonstrate the clinical application of duodenum-preserving pancreatic head resection (DPPHR) as a surgical treatment for pancreatic neuroendocrine tumors (PNETs) in terms of both curability and maintenance of postoperative quality of life. Methods: Seven patients diagnosed with PNETs underwent DPPHR from January 2011 to December 2021 at our institution. We investigated the clinical relevance of DPPHR based on the patients’ clinicopathological findings. Results: The median operative time was 492 min, and the median blood loss was 302 g. Postoperative complications were evaluated according to the Clavien–Dindo classification, and postoperative intra-abdominal bleeding was observed in one patient. Pathological examination revealed a World Health Organization classification of G1 in six patients and G2 in one patient. Microvascular invasion was observed in two patients (29%); however, no patients developed lymph node metastasis or recurrence during the follow-up period. A daughter lesion was observed near the primary tumor in one patient. All patients achieved curative resection, and no tumor specimens showed positive margins. Conclusions: DPPHR facilitates anatomical resection of the pancreatic head in patients with PNETs as well as detailed pathological evaluation of the resected specimen. Therefore, this surgical procedure is an acceptable alternative to pancreaticoduodenectomy or enucleation for patients with PNETs.

Abstract Carbonaceous material (CM) undergoes progressive changes that reflect its thermal history. These changes are in general irreversible and provide valuable information for understanding diagenetic and metamorphic processes of crustal rocks. Among various approaches to quantify these changes, the R2 ratio, area ratio of specific peaks in CM Raman spectra, is widely used to estimate the maximum temperature of intermediate- to moderately high-grade metamorphism. The calculation of the R2 ratio requires peak deconvolution of the original spectrum, and the results depend on the details of how this is carried out. However, a clear protocol for selecting appropriate initial conditions has not been established and obtaining a reliable temperature estimate depends at least in part on the experience and skill of the operator. In this study, we developed a Python code that automatically calculates the R2 ratio from CM Raman spectra. Our code produces R2 ratios that are generally in good agreement with those of Aoya et al. (J Metamorph Geol 28:895–914, 2010, https://doi.org/10.1111/j.1525-1314.2010.00896.x ) for the same Raman data, with much less time and effort than was the case in the previous studies. We have confirmed that the code is also applicable to other previous datasets from both contact and regional metamorphic regions. The overall trend of the recalculated data indicates that samples with R2 greater than ~ 0.7 are not sensitive to the changes in CM maturity and thus should not be used for the calibration of an R2-based geothermometer. We propose a modified geothermometer for contact metamorphism that is strictly applicable to samples with R2 from 0.023 to 0.516, with the proviso that a laser with a wavelength of 532 nm should be used. A slight extrapolation of the newly proposed geothermometer up to R2 of 0.57 provides a temperature estimate that is consistent with the geothermometer of Kaneki and Kouketsu (Island Arc 31:e12467, 2022; https://doi.org/10.1111/iar.12467 ); the boundary between the two geothermometers corresponds to a temperature of 391 °C.

Abstract Background It is unclear how primary care physicians manage insomnia after the introduction of novel hypnotics such as orexin receptor antagonists and melatonin receptor agonists. This Web-based questionnaire survey aimed to examine treatment strategies for insomnia in Japanese primary care practice. Methods One-hundred-and-seventeen primary care physicians were surveyed on the familiarity of each management option for insomnia on a binary response scale (0 = “unfamiliar”; 1 = “familiar”) and how they managed insomnia using a nine-point Likert scale (1 = “I never prescribe/perform it”; 9 = “I often prescribe/perform it”). Physicians who were unfamiliar with a management option were deemed to have never prescribed or performed it. Results Regarding medication, most physicians were familiar with novel hypnotics. Suvorexant was the most used hypnotic, followed by lemborexant and ramelteon. These novel hypnotics averaged 4.8–5.4 points and 4.0–4.7 points for sleep onset and sleep maintenance insomnia, respectively. By contrast, most benzodiazepines were seldom used below two points. Regarding psychotherapy, only approximately 40% of the physicians were familiar with cognitive behavioral therapy for insomnia (CBT-I) and they rarely implemented it, at an average of 1.5–1.6 points. More physicians were familiar with single-component psychotherapies (i.e., relaxation, sleep restriction therapy, and stimulus control) compared to CBT-I, and 48–74% of them implemented it slightly more often, with scores ranging from 2.6 to 3.4 points. Conclusion This study suggests that Japanese primary care physicians seldom use CBT-I to treat insomnia. In addition, they use novel sleep medications more frequently than benzodiazepines in terms of pharmacotherapy. The use and availability of CBT-I in Japanese primary care might be facilitated by: educating primary care physicians, implementing brief or digital CBT-I, and/or developing collaborations between primary care physicians and CBT-I specialists.

Background The Direct Oral Anticoagulant (DOAC) Score can predict bleeding risk in patients with atrial fibrillation taking DOACs; however, it lacks external validation. Therefore, this study aimed to assess the association between the DOAC Score and bleeding events in patients with atrial fibrillation who underwent transcatheter aortic valve replacement. Methods and Results This retrospective multicenter cohort study included patients with atrial fibrillation who underwent transcatheter aortic valve replacement, as registered in a Japanese multicenter registry. The primary end point was the incidence of bleeding. Patients were categorized based on their DOAC Score: low and moderate‐ (≤7 points), high‐ (8–9 points), and very high‐risk (≥10 points) groups. Among 1230 patients (mean age 84.6±5.1 years; 457 men), 465 (37.8%) received a vitamin K antagonist, and the remaining patients received DOACs. The low and moderate‐, high‐, and very high‐risk groups included 380 (30.1%), 497 (40.4%), and 353 patients (28.7%), respectively. The 3‐year cumulative incidence of all bleeding events was significantly different among the 3 groups (low and moderate risk: 6.6%, high risk: 6.9%, and very high risk: 14.0%; P

Background: Statins bring favourable effects on the clinical prognosis of patients with atherosclerotic disease partly through their anti-inflammatory properties. However, this effect has not been fully verified in patients with peripheral arterial disease (PAD). We aimed to test whether statins exert different prognostic effects depending on the degrees of inflammation in patients with PAD. Methods: This study was a sub-analysis of a multicenter prospective cohort of 2321 consecutive patients with PAD who received endovascular therapy (EVT). After excluding patients without information on C-reactive protein (CRP) levels at the time of index EVT, 1974 patients (1021 statin users and 953 non-users) were classified into four groups depending on CRP levels: low CRP (1.0 mg/dL). A composite of death, stroke, myocardial infarction, and major amputation as the primary endpoint was compared between statin users and non-users in each CRP category. Results: During the median observation period of 316 days, the primary composite endpoint occurred in 112 (11.0 %) statin users and 178 (18.7 %) non-users (log-rank test, p

Background The Clinical Frailty Scale (CFS) is a useful frailty marker for predicting clinical outcomes in patients undergoing invasive therapy. However, the clinical impact of CFS after transcatheter edge‐to‐edge repair in patients with mitral regurgitation (MR) remains unclear. This study aimed to elucidate the association between the baseline frail status defined by the CFS and clinical outcomes with or without postprocedural MR ≥2+ (post‐MR ≥2+) after transcatheter edge‐to‐edge repair. Methods and Results Based on a Japanese multicenter registry (OCEAN [Optimized Catheter Valvular Intervention]‐Mitral), data from 2078 patients with MR who underwent transcatheter edge‐to‐edge repair were analyzed. The patients were classified into 5 groups: CFS 1 to 3, 4, 5, 6, and ≥7. The procedural and clinical outcomes and post‐MR ≥2+ were compared among the groups. All‐cause mortality for up to 2 years was explored using Cox proportional hazards regression analysis. Although the rates of acute procedural success and post‐MR ≥2+ were similar, all‐cause mortality at 2 years was significantly increased across the 5 CFS categories (15.5%, 23.8%, 27.7%, 34.6%, and 48.8%, respectively, P

Fournier's gangrene is a severe type of necrotizing fasciitis that affects the perineal and genital regions. Because of its rapid progression, Fournier's gangrene is associated with high mortality and morbidity rates. Surgical treatment of Fournier's gangrene requires leaving the wound open and performing multiple debridement procedures. We report a case of Fournier's gangrene caused by Streptococcus anginosus in a 9-year-old boy with severe autism. Because of the patient's condition, surgical treatment included thorough debridement and closure of the initial wound under general anesthesia. This case was successfully treated and the patient was discharged without infection recurrence.

Summary: Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we develop a series of genetically engineered mouse models of treatment-naive and -experienced NTRK1/2/3 fusion-driven gliomas. All tested NTRK fusions are oncogenic in vivo. The NTRK variant, N-terminal fusion partners, and resistance-associated point mutations all influence tumor histology and aggressiveness. Additional tumor suppressor losses greatly enhance tumor aggressiveness. Treatment with TRK kinase inhibitors significantly extends the survival of NTRK fusion-driven glioma mice, but fails to fully eradicate tumors, leading to recurrence upon treatment discontinuation. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools to study therapy resistance of NTRK fusion tumors.

Live imaging of experimental animals is now possible thanks to recent technological advances that overcome the limitations of conventional histological analysis. In contrast to conventional histological microscopy techniques, this intravital approach can reveal previously unknown morphogenetic and functional processes in live tissues. In addition, this approach can capture real-time information on these processes, compared with conventional histological microscopy and other techniques that only provide snapshots in time. We used multi-photon laser-scanning microscopy (MPLSM) for in vivo real-time imaging of intra-abdominal organs, and investigated the intravital microscopic changes in various disease-model mice, referred to as ‘dynamic pathology’. For example, we used this technology to examine bacterial translocation in dextran sodium sulfate (DSS)-induced colitis, thrombus formation in laser-induced endothelial injury, neutrophil extracellular traps, the dynamics of circulating free DNA in a model of DSS-induced colitis, and to obtain a comprehensive understanding of the development and blood flow dynamics of the small intestinal microcirculation in a mouse model of necrotizing enterocolitis. This mini review summarizes the in vivo observation methods that we have developed to observe the dynamic pathology in various disease-model mice using MPLSM.

Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) is the established therapy for refractory metastatic colorectal cancer, but there are concerns regarding the regimen’s complexity and hematotoxic effects, especially for patients with organ dysfunction, comorbidities, or a reduced performance status—groups often excluded from conventional clinical trials. Preliminary studies demonstrated that bi-weekly FTD/TPI + BEV may mitigate these hematotoxic effects compared with the conventional schedule without compromising efficacy. No clinical trials, however, have directly compared these two regimens. Therefore, we initiated the PRABITAS trial, a multicenter, randomized, phase III non-inferiority trial, to evaluate the efficacy and safety of bi-weekly FTD/TPI + BEV compared with conventional FTD/TPI + BEV. This was designed as a pragmatic trial, a novel approach in clinical trials aiming to aid decision-making in daily practice by mimicking real-world clinical settings. The PRABITAS trial incorporates minimal eligibility criteria to include a more representative patient population, allows flexibility in intervention adherence and assessment, and employs streamlined data collection to reduce the burden on both patients and healthcare providers. The primary endpoint is overall survival in the intention-to-treat population. Launched in December 2023, the trial aimed to enroll a total of 890 patients.

Coastal flood damage is primarily the result of extreme sea levels. Climate change is expected to drive an increase in these extremes. While proper estimation of changes in storm surges is essential to estimate changes in extreme sea levels, there remains low confidence in future trends of surge contribution to extreme sea levels. Alerting local populations of imminent extreme sea levels is also critical to protecting coastal populations. Both predicting and projecting extreme sea levels require reliable numerical prediction systems. The SurgeMIP (surge model intercomparison) community has been established to tackle such challenges. Efforts to intercompare storm surge prediction systems and coordinate the community's prediction and projection efforts are introduced. An overview of past and recent advances in storm surge science such as physical processes to consider and the recent development of global forecasting systems are briefly introduced. Selected historical events and drivers behind fast increasing service and knowledge requirements for emergency response to adaptation considerations are also discussed. The community's initial plans and recent progress are introduced. These include the establishment of an intercomparison project, the identification of research and development gaps, and the introduction of efforts to coordinate projections that span multiple climate scenarios.

Abstract Biallelic IGFALS variants lead to acid‒labile subunit (ALS) deficiency characterized by growth hormone resistance with or without delayed puberty. Here, we report a prepubertal boy with a homozygous 2-amino acid deletion within the fourth N-glycosylation motif (c.1103_1108del, p.N368_S370delinsT) associated with parental consanguinity. He showed short stature consistent with ALS deficiency. This case expands the mutation spectrum of IGFALS to include the elimination of only one N-glycosylation motif of ALS.