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Objectives: This retrospective multicenter study aimed to clarify the clinical impact of endotherapy for painless pancreatic duct (PD) stones compared with that in patients who received conservative treatment without endotherapy., Methods: We enrolled 268 patients suffering from chronic pancreatitis with painless PD stones (145 with endotherapy and 123 without endotherapy) and evaluated the impact of endotherapy for painless PD stones on clinical and radiological outcomes., Results: When conservative treatment without endotherapy was set as a reference, complete clearance of the targeted PD stones decreased the relative risk for atrophy of pancreatic parenchyma after inclusion (hazard ratio [HR] 0.42; 95% confidence interval [CI] 0.21-0.84). Incomplete clearance of the targeted PD stones was identified as a risk factor for new-onset or worsening of diabetes (HR 2.08; 95% CI 1.10-3.91) and inducement of pain attack (HR 4.03; 95% CI 1.45-11.19), although complete clearance was not correlated with these outcomes., Conclusion: In chronic pancreatitis patients with painless PD stones, endotherapy with complete stone clearance allows the maintenance of pancreatic parenchymal volume. However, if complete clearance fails, endotherapy could lead to aggravation of glucose tolerance and pain attacks during follow-up., (© 2025 Japan Gastroenterological Endoscopy Society.)

Background: Out-of-hospital cardiac arrest (OHCA) with initial shockable rhythm generally has a favorable prognosis. However, the prognosis worsens when this rhythm transitions to nonshockable rhythm on hospital arrival. This study aimed to investigate the association between no-flow time (NFT), prehospital low-flow time (LFT), and the conversion to nonshockable rhythm on hospital arrival in patients with OHCA initially exhibiting shockable rhythm., Methods: We analyzed adult patients with OHCA from the JAAM-OHCA (Japanese Association for Acute Medicine Out-of-Hospital Cardiac Arrest) registry (June 2014-December 2020) with initial shockable rhythm. The primary outcome was rhythm conversion to nonshockable on hospital arrival. Adjusted odds ratios (aORs) with 95% CIs were calculated using a logistic model to examine the associations between NFT, prehospital LFT, and rhythm conversion., Results: Of 68 110 patients, 3720 patients were included in our analysis. On hospital arrival, 27.9% patients achieved return of spontaneous circulation, 32.8% maintained shockable rhythm, and 39.3% transitioned to nonshockable rhythm (718 to pulseless electrical activity, 744 to asystole). Median NFT was 4 minutes (interquartile range [IQR], 1-9 minutes), and median prehospital LFT was 22 minutes (IQR, 14-31 minutes). Longer NFT and prehospital LFT were associated with higher aORs of rhythm conversion: NFT (5-9 minutes: aOR, 1.38 [95% CI, 1.14-1.67]; ≥10 minutes: aOR, 1.75 [95% CI, 1.44-2.14]); and prehospital LFT (15-19 minutes: aOR, 2.56 [95% CI, 2.00-3.27]; 20-29 minutes, aOR, 4.73 [95% CI, 3.83-5.85]; ≥30 minutes, aOR, 6.85 [95% CI, 5.49-8.56])., Conclusions: Prolonged NFT and prehospital LFT were significantly associated with rhythm conversion to nonshockable on hospital arrival in patients with OHCA with initial shockable rhythm at the scene.

Purpose: To investigate transcriptomic differences between patients with Fuchs endothelial corneal dystrophy (FECD) with and without trinucleotide repeat (TNR) expansion in the transcription factor 4 gene, as the genetic basis for patients with FECD lacking TNR expansion remains unclear., Methods: Bulk RNA sequencing was performed on corneal endothelial cells from 17 subjects: 10 patients with FECD [4 with repeat expansion lengths <50 (RE-) and 6 with expansions of 50 or more (RE+)] and 7 controls. Differential gene expression analysis was conducted using DESeq2. Principal component analysis (PCA), correlation matrix analysis, and heatmap visualization were used to evaluate gene expression patterns. Gene Ontology enrichment analysis was performed on differentially expressed genes (DEGs)., Results: Analysis identified 509 DEGs (281 upregulated, 228 downregulated) between RE- and controls, and 640 DEGs (292 upregulated, 348 downregulated) between RE+ and controls. PCA revealed distinct gene expression patterns in both RE- and RE+ groups compared with controls. Between RE- and RE+ groups, only 10 DEGs were identified: ALDH3A1, ENSG00000286252, RNU6-645P, SNORD113-7, RNU6-429P, SNORA16A, COCH, EGFL6, SEMA3E, and ENSG00000228463. PCA, correlation matrix analysis, and heatmap visualization demonstrated high similarity in overall gene expression patterns between RE- and RE+ groups., Conclusions: Contrary to expectations, gene expression profiles showed remarkable similarity between patients with FECD with and without TNR expansion. Further investigation of the identified DEGs may provide insights into the role of TNR expansion in FECD pathophysiology., Competing Interests: N. Okumura and N. Koizumi are cofounders of ActualEyes Inc, which is currently developing a pharmaceutical therapy for treating Fuchs endothelial corneal dystrophy. The remaining authors have no funding or conflicts of interest to disclose., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The clinical outcomes of percutaneous coronary intervention (PCI) using drug-coated balloons (DCB) for de novo coronary artery lesions with eruptive calcified nodules remain unclear., Methods and Results: This retrospective study analyzed the long-term outcomes of 308 consecutive patients (389 lesions) treated with PCI using DCB under optical coherence tomography guidance for de novo coronary artery lesions between September 2018 and November 2020. Patients were classified into 2 groups: those with an eruptive calcified nodule in the culprit lesion (CN group) and those without (non-CN group). The primary endpoint was major adverse cardiovascular events (MACE), including clinically driven target lesion revascularization (TLR), myocardial infarction (MI), and cardiac death. The median follow-up period was 2.6 years (interquartile range 1.9-3.4 years). The CN group had significantly higher rates of MACE (hazard ratio [HR] 9.2; 95% confidence interval [CI] 4.1-20.2; P<0.0001), TLR (HR 5.0; 95% CI 1.7-15.1; P<0.01), MI (HR 30.5; 95% CI 5.0-184.8; P<0.001), and cardiac death (HR 25.1; 95% CI 8.7-72.6; P<0.0001) than the non-CN group. Results were similar even after adjusting for potential confounding factors using propensity score matching., Conclusions: This study demonstrated that patients with eruptive calcified nodules who underwent PCI with DCB for de novo coronary artery lesions had worse long-term clinical outcomes than patients without such nodules.

The 2024 revised edition of the Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock (J-SSCG 2024) is published by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine. This is the fourth revision since the first edition was published in 2012. The purpose of the guidelines is to assist healthcare providers in making appropriate decisions in the treatment of sepsis and septic shock, leading to improved patient outcomes. We aimed to create guidelines that are easy to understand and use for physicians who recognize sepsis and provide initial management, specialized physicians who take over the treatment, and multidisciplinary healthcare providers, including nurses, physical therapists, clinical engineers, and pharmacists. The J-SSCG 2024 covers the following nine areas: diagnosis of sepsis and source control, antimicrobial therapy, initial resuscitation, blood purification, disseminated intravascular coagulation, adjunctive therapy, post-intensive care syndrome, patient and family care, and pediatrics. In these areas, we extracted 78 important clinical issues. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 42 GRADE-based recommendations, 7 good practice statements, and 22 information-to-background questions were created as responses to clinical questions. We also described 12 future research questions., Competing Interests: All committee members and working group members submitted disclosure forms of financial and academic conflict of interest (COI) prior to being requested to participate in individual activities. All COI were collected according to the guideline by the JSICM and the JAAM. Detailed information of COI and the roles in creating this clinical guideline are summarized in Data S4., (© 2025 The Author(s). Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

Purposes: Postoperative stress hyperglycemia is reported to be associated with increased postoperative complications (PCs) following various surgical procedures. However, most reports of postoperative hyperglycemia are based on conventional, point blood glucose measurements. We sought to clarify trends in post-gastrectomy glucose levels using continuous glucose monitoring (CGM) and investigate the relationship between postoperative hyperglycemia and stress-related factors such as PCs and the degree of surgical invasiveness., Methods: The subjects of this prospective study were 40 patients who underwent gastrectomy between November, 2022 and September, 2023. We recorded their glucose levels by CGM immediately after surgery until discharge (up to 2 weeks postoperatively)., Results: There was no increase in glucose levels caused by open gastrectomy, a strong inflammatory response, or PCs. Hyperglycemia, defined as the percentage of time that the glucose level was > 140 mg/dL, was associated only with the preoperative HbA1c value (P = 0.039). Patients with an HbA1c ≥ 6% had a significantly longer duration of hyper- and hypo-glycemia and greater glycemic variability than those with an HbA1c < 6% (glucose level < 70 mg/dL, P = 0.027; > 140 mg/dL, P = 0.001, coefficient of variation P = 0.024)., Conclusions: No association was observed between stress hyperglycemia during the acute phase following gastrectomy and PCs. Only patients with an elevated HbA1c had high rates of hypo- and hyper-glycemia and large glycemic variability, despite perioperative glucose management., Competing Interests: Declarations. Conflict of interest: We have no conflicts of interest to declare. Ethical approval and consent to participate: This study was designed in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Kyoto Prefectural University of Medicine (ERB-C-2645). All patients were given sufficient explanation about the study and written informed consent was obtained., (© 2025. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

The optimal extent of lymph node dissection in colon cancer surgery is specified in guidelines based on the results of past analyses. However, with advances in surgical techniques and multidisciplinary treatments, the clinical significance of dissecting each lymph node may change. In this study, we re-examined the optimal dissection range in each colon cancer localization. We retrospectively analyzed 788 cases of T1-T4 colon cancer who underwent radical resection between 2008 and 2018 at our hospital, and evaluated the Lymphadenectomy Index. No metastases to the main lymph node were found in T1 cases. In T2 cases, dissection effect to the main lymph node were observed in cases with tumors localized in the ascending colon and left side of the transverse colon. For tumors localized in the cecum, dissection was effective for lymph nodes in nodal station 213, in the right side of the transverse colon in station 211, in the descending colon in station 221, and in the sigmoid colon in station 231. These lymph nodes could have been considered out of scope for dissection if the Japanese guidelines were followed. In these cases, the extent of lymph node dissection should be carefully considered on a case-by-case basis., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics declarations: Informed consent was obtained from all subjects and/or their legal guardians. The study was approved by the institutional review board of the Kyoto Prefectural University of Medicine (Approval Number: ERB-C-1178)., (© 2025. The Author(s).)

Microglia are cerebral immune cells that maintain brain homeostasis; those that are juxtaposed to vessels are sometimes called vessel-associated microglia (VAM). Recent studies have indicated a role for VAM in maintaining blood-brain barrier integrity in different stages of diseases such as ischemic stroke and systemic inflammatory disease. Hypertension is a major cause of cerebral small vessel disease (CSVD) in humans. Recently, several reports reported that microglial activation in hypertensive animal models and our previous report indicated the increase in VAM from the early stage of chronic hypertension. However, the precise involvement of VAM in hypertensive CSVD remains unclear. In the present study, we used a deoxycorticosterone-acetate-salt chronic hypertensive rat model to demonstrate that signaling via CC motif chemokine ligand 2 (CCL2) and its receptor CC chemokine receptor type 2 (CCR2) is crucial for the increase in VAM. This signaling was associated with microglial migration toward vessels at the early disease stage. Moreover, the inhibition of this signaling resulted in reduced VAM numbers and the preservation of astrocytic endfeet in the late disease stage. Overall, CCL2/CCR2 signaling may be a trigger for microglial migration, leading to the development of CSVD, during chronic hypertension. This signaling is therefore a potential target for future preventive treatments., (Copyright © 2025. Published by Elsevier Inc.)

In individuals with a history of renal cell carcinoma (RCC), mediastinal lymphadenopathy is frequently attributed to metastatic recurrence. However, secondary malignancies, despite their rarity, should also be considered. During routine follow-up examinations, a 63-year-old male with a history of renal cell carcinoma demonstrated progressive mediastinal lymphadenopathy. This was initially suspected to be a recurrence of renal cell carcinoma (RCC). The diagnosis of metastatic prostate adenocarcinoma was confirmed by prostate biopsy and elevated prostate-specific antigen (PSA) levels, as determined by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). Treatment with androgen deprivation therapy (ADT) and chemotherapy was initiated after the patient was diagnosed with metastatic prostate cancer. This case underscores the critical role of EBUS-TBNA in the accurate diagnosis of patients with a history of RCC who demonstrate atypical mediastinal lymphadenopathy. The provision of tissue samples for histopathological analysis by EBUS-TBNA facilitated the differentiation between metastatic recurrence and secondary malignancies. Comprehensive diagnostic methods, including tumor marker analysis, immunohistochemistry, and tissue biopsy, are essential for accurate diagnosis. EBUS-TBNA is indispensable for accurate diagnosis, especially in differentiating metastatic recurrence from secondary malignancies, as it provides a minimally invasive method of tissue access for precise evaluation., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2025, Tsuji et al.)

Systemic lupus erythematosus (SLE) is a systemic disease that affects several organs. The diagnosis was performed using the international classification criteria updated in 2019. The significance of antinuclear antibodies (ANAs) with a centromere pattern has not been clearly documented in these criteria. We herein report a patient with ANAs with a centromere pattern and anti-centromere antibodies, without anti-Sm antibodies or anti-dsDNA antibodies, who developed severe lupus nephritis, neuropsychiatric SLE, and lupus pleuritis. The patient was successfully treated with prednisolone, hydroxychloroquine, mycophenolate mofetil, cyclophosphamide, and belimumab, despite several relapses. Anti-centromere antibodies are not regarded as characteristics of SLE but can be detected in SLE patients with severe organ involvement.

Background: Deeper understanding of the mechanisms of postoperative pain is critical for developing more effective pain management strategies. The present animal study explored the function of four p38 mitogen-activated protein kinase (MAPK) subclasses (α, β, γ, and δ) in dorsal root ganglion (DRG) in the development of post-incisional pain hypersensitivity., Methods: The amount of p38 MAPK subclass mRNA in the DRG of male Sprague-Dawley rats was quantified using real-time PCR. Localization of p38 MAPK expression was analyzed by immunohistochemistry using subclass-selective antibodies. The effects of a p38α MAPK inhibitor on plantar incision-induced pain hypersensitivity was assessed using behavioral tests to measure mechanical and thermal sensitivity. The impact of the inhibitor on phosphorylated p38 MAPK expression was also analyzed by immunohistochemistry., Results: Four p38 MAPK subclass mRNA were identified in the DRG, with p38α, β, and γ MAPK showing significant expression. p38α and γ MAPK were identified in the DRG neurons, whereas p38β MAPK was distributed in satellite glial cells. Selective inhibition of p38α MAPK reduced both mechanical and thermal hypersensitivity following plantar incision. Treatment with the p38α MAPK inhibitor decreased the expression of phosphorylated p38 MAPK in the DRG., Conclusion: These results demonstrated the distinct roles of p38 MAPK subclasses in the DRG, with p38α MAPK playing a dominant role in the development of pain hypersensitivity after tissue injury. Targeting p38α MAPK might be a promising therapeutic strategy for managing postoperative pain., Competing Interests: Dr Fumimasa Amaya reports personal fees from Maruishi Pharmaceutical Co.,Ltd., HISAMITSU PHARMACEUTICAL CO.,INC, DAIICHI SANKYO, INC., Nippon Zoki Pharmaceutical Co., Ltd., icu medical, Otsuka Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Kowa Pharmaceuticals, Inc., Sumitomo Dainippon Pharma Co., Ltd, AYUMI Pharmaceutical Corporation., Mundipharma, TSUMURA & CO., ONO PHARMACEUTICAL CO., LTD.; grants from Nobelpharma Co., Ltd., outside the submitted work. All the authors declare they have no other conflicts of interest in relation to this study., (© 2025 Ishikawa et al.)

This is an abridged edition of English version of the Clinical Practice Guidelines for the Management of Atopic Dermatitis 2024. Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. A crucial aspect of AD treatment is the prompt induction of remission via the suppression of existing skin inflammation and pruritus. To achieve this, topical anti-inflammatory drugs such as topical corticosteroids, tacrolimus ointment, delgocitinib ointment, and difamilast ointment have been used. However, the following treatments should be considered in addition to topical therapy for patients with refractory moderate-to-severe AD: oral cyclosporine, subcutaneous injections of biologics (dupilumab, nemolizumab, tralokinumab), oral Janus kinase inhibitors (baricitinib, upadacitinib, abrocitinib), and phototherapy. In the revised guidelines, descriptions of five new drugs, namely, difamilast, nemolizumab, tralokinumab, upadacitinib, and abrocitinib, have been added. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice., (Copyright © 2025 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Objectives: This study aims to identify challenges nurses face in providing care to older patients with rheumatoid arthritis (RA) in Japan., Methods: Nurses certified by the Japan Rheumatism Foundation were requested via mail to describe challenges in providing care to older RA patients. Qualitative content analysis was used., Results: One hundred and eighty-two issues were identified from 152 responses. Twenty categories were grouped into seven components, five of which focused on patients: (1) lack of patient understanding, (2) lack of understanding and support from surrounding people, (3) numerous comorbidities and complications, (4) challenges related to physical strength, and (5) financial issues. Two focused on nurses: (6) lack of knowledge of nurses and (7) inadequate systems and environment in the workplace. Various difficulties, such as polypharmacy due to multimorbidity, lifestyle issues due to aged couples or those living alone, and inadequate decision-making and informed consent due to cognitive decline, were also identified., Conclusions: Nurses experienced numerous medical and nonmedical difficulties in providing care to older RA patients. Assessing patients' comprehension and self-management and grasping their situations at home are necessary. Along with the improvement of nurses' knowledge and skills, support from their workplace and multidisciplinary team care, including families, are crucial., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Purpose: Recently, a novel deep learning (DL)-based technique for reconstructing highly undersampled MR data (DL-Speed, DLS) has been developed, which demonstrated superior performance over compressed sensing. This study aimed to achieve high-resolution double inversion recovery (DIR) imaging using DLS (DLS-DIR) and compare its diagnostic performance in the detection of juxtacortical multiple sclerosis (MS) lesions with that of conventional DIR (C-DIR)., Methods: We retrospectively analyzed MRI data from 25 patients with MS who underwent a comprehensive imaging protocol, including 3D fluid-attenuated inversion recovery (FLAIR), C-DIR, and DLS-DIR. A voxel size of 1.3 × 1.3 × 1.4 mm 3 with a scan duration of 3 mins 55s were used for C-DIR, and isotropic 0.7 mm voxels with a scan time of 4 mins 23s were employed for DLS-DIR. Two neuroradiologists assessed the juxtacortical MS lesions during 2 separate reading sessions (one with C-DIR and the other with DLS-DIR). Lesions were categorized as subcortical white matter lesions, intracortical lesions, or mixed lesions involving both subcortical white and gray matter. The lesion counts per region were compared between the imaging techniques using the Wilcoxon signed-rank test., Results: DLS-DIR detected a significantly higher number of juxtacortical MS lesions compared to C-DIR (Radiologist A: 211 lesions vs. 164 lesions; Radiologist B: 209 lesions vs. 157 lesions, P < 0.05). DLS-DIR also identified more intracortical lesions (Radiologist A: 22 additional lesions, Radiologist B: 34 additional lesions, P < 0.05) and more mixed lesions (Radiologist A: 46 additional lesions, Radiologist B: 42 additional lesions, P < 0.05)., Conclusion: The DLS technology enables high-resolution, whole-brain DLS-DIR imaging within a 5 mins acquisition time, which can be seamlessly incorporated into routine clinical workflows. This approach substantially enhances the detection and evaluation of juxtacortical MS lesions.

Keratinase from Nocardiopsis sp. TOA-1 (NAPase) holds significant potential for industrial and medical applications. Here, we developed a heterologous secretory expression system for NAPase in Bacillus subtilis. The recombinant enzyme exhibited catalytic properties comparable to the native enzyme, demonstrating its suitability for further protein engineering. This work provides a foundation for enhancing NAPase activity and stability, expediting its biotechnological applications., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Sephin1 was discovered as a protein phosphatase inhibitor, and its efficacy against neurodegenerative diseases has been confirmed. There are conflicting reports on whether inhibition of eIF2α dephosphorylation by PP1 holoenzyme with the protein phosphatase 1 regulatory subunit 15 A is the mechanism of action of Sephin1. In the present study, we found that Sephin1 significantly suppressed renal tubular cell death in an animal model of ER stress administered with tunicamycin. CHOP, which plays a central role in the ER stress-induced cell death pathway, requires nuclear translocation to act as a transcription factor to increase the expression of cell death-related genes. Sephin1 markedly suppressed this nuclear translocation of CHOP. To elucidate the molecular mechanism underlying the cell death suppressive effect of Sephin1, we used human renal tubular epithelial cells under ER stress with tunicamycin. Sephin1 reduced intracellular CHOP levels by promoting CHOP phosphorylation at Ser30, which led to protein degradation in UPS. Phosphorylated CHOP is generated by Thr172-phosphorylated activated AMPK, and Sephin1 increased phosphorylated AMPK. Phosphorylated AMPK is inactivated by PP2A through dephosphorylation of its Thr172, and Sephin1 inhibits the formation of the PP2A holoenzyme with the PP2A subunit B isoform delta. These results indicate that inhibition of PP2A holoenzyme formation is the molecular target of Sephin1 in this experimental system., Competing Interests: Competing interests: SG is a Scientific advisor to Remiges Ventures, Inc., and he has a patent related to this work. Ethics: The animal study was reviewed and approved by the Animal Experiment Ethics Committee of Kyoto Prefectural University of Medicine (Approval number, M2022-530)., (© 2025. The Author(s).)

FoxO1, a transcription factor, is upregulated in skeletal muscle during atrophy and inactivation of FoxO1 is a potential strategy to prevent muscle loss. This study identified Rebastinib as a potent suppressor of FoxO1 activity among protein kinase inhibitors. To determine whether Rebastinib inhibits atrophy-related ubiquitin ligases gene expression and mitigates atrophy in mouse skeletal muscle-derived cells, we investigated its protective effects of the compound against dexamethasone (DEX)-induced muscle atrophy using C2C12 myotubes. Rebastinib inhibited the DEX-induced upregulation of atrogin-1 and MuRF-1 mRNA, and atrogin-1 protein. Rebastinib also suppressed protein degradation and increased myotube diameter in DEX-treated C2C12 myotubes. Additionally, Rebastinib ameliorated the DEX- and cachexia-induced reduction in contractile force generation. Although the precise mechanisms underlying the action of Rebastinib against muscle atrophy and its efficacy in vivo remains to be elucidated, this compound shows great potential as a therapeutic agent for muscle atrophy., Competing Interests: Declaration of Competing Interest The authors declare no competing interests directly related to the content of this article., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Hoarseness is often observed in patients with acute central nervous system (CNS) impairment. However, the vocal function is not routinely assessed. The purpose of this prospective study was to reveal the severity of dysphagia and dysphonia simultaneously during a bed side swallowing assessment in patients with CNS disorders., Study Design: Prospective observational cohort study., Methods: The bed side evaluation of swallowing and vocal function was performed in 24 patients (aged 22-96 years; 14 male, 10 female) who were admitted to the Center for Neurology and Medical Science of out institute. They were suspected to have aspiration by a routine screening examination and required a bed side swallowing endoscopic assessment. The swallowing functions were evaluated by videoendoscopic swallowing test and Food Intake Level Scale (FILS). Vocal function was evaluated by bed side stroboscopic examinations with the measurement of vocal fold vibratory amplitude (VFVA) and Bowing Index (BI). Grade Roughness Breathiness Asthenia and Strain scale, aerodynamic and acoustic analyses were also completed. In addition, grip strength, tongue pressure measurements, geriatric nutritional risk index (GNRI), and the respiratory function tests were evaluated., Results: Swallowing and vocal function were impaired in all patients. An overall FILS average was level 4-6 that required alternative nutrition. Vocal fold atrophy was observed in 19 patients with reduced values in both VFVA and BI. Inspiratory function and muscle strength were decreased compared to the average of the healthy elderly, and the overall average of nutrition fell into the category of moderate nutritional impairment., Conclusions: The current study revealed that both swallowing and vocal function were impaired in the patients under acute treatment of CNS disorders. It was suggested that several factors can affect swallowing and vocal disorder in CNS disorder patients, including vocal fold atrophy, poor respiratory function, reduced muscle strength, and poor nutritional status, which should be kept in mind during the treatment or rehabilitation for CNS disorders., 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 © 2025 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

A 45-year-old woman with Basedow's disease, who was later diagnosed with slowly progressive type 1 diabetes mellitus (SPIDDM), developed iron deficiency anemia. Despite normal vitamin B12 levels, the endoscopic findings of the residual fundic glands and severe atrophy predominantly in the body of the stomach and fundus, along with serological tests, confirmed a diagnosis of autoimmune gastritis (AIG). This case highlights the significance of an early AIG diagnosis in non-elderly patients with type 1 diabetes mellitus (T1DM) and autoimmune thyroid disease (AITD) because of the risk of developing pernicious anemia and gastric neoplasms. Key words:slowly progressive type 1 diabetes mellitus (SPIDDM); latent autoimmune diabetes in adults (LADA); Basedow's (Graves) disease; autoimmune gastritis (AIG); thyrogastric disease; autoimmune polyglandular syndrome (APS) type 3.

Aims: Doxorubicin (DOX) is one of the most effective chemotherapeutic agents for various types of cancers. However, DOX often causes cardiotoxicity, which is referred to as DOX-induced cardiomyopathy (DIC). Despite extensive research, only a limited number of effective treatments are currently available. In this study, we aimed to identify a potential therapeutic target for DIC by preventing DOX-induced cell injury in cardiomyocytes., Methods and Results: We performed a kinome-wide CRISPR gene knockout screen in human cardiomyocytes derived from pluripotent stem cells (hPSC-CMs) and identified a member of the STE20 kinase family, thousand and one amino acid protein kinase 1 (TAOK1) as a potential regulator of DOX-induced cardiomyocyte death. Using CRISPR-mediated gene knockout and siRNA-mediated gene knockdown, we demonstrated that TAOK1 suppression improved DOX-induced cardiomyocyte death and dysfunction, including sarcomere disarray, contractile dysfunction, DNA damage, and mitochondrial dysfunction in hPSC-CMs. Transcriptome analysis using RNA-Seq also showed that DOX-induced mitochondrial dysfunction was attenuated by TAOK1 suppression. In contrast to the protective role of TAOK1 against DOX toxicity in cardiomyocytes, TAOK1 suppression did not induce DOX resistance in human cancer cell lines. DOX-induced activation of p38 MAPK was markedly attenuated in TAOK1-knockout hPSC-CMs. Furthermore, DOX-induced cardiomyocyte death and disruption of mitochondrial membrane potential were augmented by TAOK1 overexpression, which was partially attenuated by an inhibitor or knockdown of p38 MAPK or an apoptosis inhibitor. Finally, we demonstrated that TAOK1 suppression using AAV-mediated gene silencing attenuated DOX-induced myocardial damage, including myocardial fibrosis, apoptosis, and cardiomyocyte atrophy, resulting in improved cardiac function in a mouse model of DIC., Conclusion: Our results indicate that TAOK1 suppression is a promising therapeutic approach for treating DIC in patients with cancer and highlight the advantages of hPSC-CMs as a platform to study drug-induced cardiotoxicity., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: To investigate the long-term outcome of surgical intervention for limbal dermoids and to evaluate the safety and efficacy of tectonic lamellar keratoplasty., Methods: This retrospective cohort study included 86 eyes that underwent tectonic lamellar keratoplasty by 5 corneal surgeons at Kyoto Prefectural University of Medicine and Baptist Eye Institute, Kyoto, Japan, from 1992 through 2024. The study subjects were categorized into 2 groups: group A, consisting of 35 eyes that underwent amblyopia treatment, and group B, consisting of 51 eyes that did not., Results: Kaplan-Meier survival analysis revealed 95.3% (82 of 86 eyes) maintained clear tectonic corneal grafts with healthy ocular surfaces postoperatively. Three eyes developed psudopterygium formation, and 1 eye developed a corneal infection. Improvement of 0.2 logarithm of the minimum angle of resolution units or more because of preoperative amblyopia treatment was observed in 48.6% (17 of 35 eyes) in group A. Surgical intervention resulted in an improvement of 0.2 logarithm of the minimum angle of resolution units or more in 25.7% (9 of 35 eyes) in group A, and 15.7% (8 of 51 eyes) in group B. One case of corneal infection resulted in decreased best-corrected visual acuity. No other cases exhibited best-corrected visual acuity deterioration., Conclusions: Tectonic lamellar keratoplasty can be performed safely with very few postoperative complications, maintaining long-term corneal clarity, reasonable visual acuity, and satisfactory cosmetic results., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: We investigated the associations of nocturnal oxygen saturation (SpO 2 ) with prevalence of coronary artery calcification (CAC) and its level of burden, and whether the associations differ by obesity and mediate through diabetes mellitus (DM), dyslipidaemia and hypertension., Design: Observational study., Setting: Kusatsu, Shiga., Participants: We analysed data from 510 Japanese men (aged 46-76 years) with no history of myocardial infarction., Primary and Secondary Outcomes: Mean SpO 2 , minimum SpO 2 and oxygen desaturation index (ODI) were measured using overnight pulse oximetry (primary exposures), while CAC was assessed using CT. Prevalence of CAC (>0) and its burden (CAC 0, >0-100, >100-400 and>400) were evaluated as outcomes. Body mass index≥25.0 kg/m 2 defined as obesity., Results: Mean±SD age was 66.7±7.2 years. The prevalence of CAC was 64.7% (CAC scores>0-100, 31.4%; >100-400, 20.0% and>400, 13.3%). In multivariable binary logistic regression, the OR and 95% CI for the prevalence of CAC were 1.25 (1.02 to 1.53) per 1-SD decrement in mean SpO 2 and 1.25 (1.01 to 1.55) per 1-SD increment in ODI. The associations lost their significance while further adjusted for DM and dyslipidaemia. Similar trends were observed for the level of CAC burden in multivariable ordinal logistic regression. Obesity did not show significant interaction with SpO 2 on CAC. In mediation analysis, the OR (95% CI) for natural indirect effect; percentage mediated through dyslipidaemia in association of 1-SD decrement in mean SpO 2 with prevalence of CAC were 1.06 (1.01 to 1.10); 25.4%. These estimates for mediation through DM and dyslipidaemia for 1-SD increment in ODI in the associations were 1.07 (1.01 to 1.12); 29.6% and 1.04 (1.00 to 1.08); 17.5%, respectively., Conclusions: Lower mean SpO 2 and higher ODI are associated with CAC among Japanese men, independent of age, lifestyle factors and obesity. The associations became non-significant after adjusting for diabetes and dyslipidaemia, but were mediated through these factors., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

A retrospective study of extranodal natural killer/T-cell lymphoma (ENKL) patients diagnosed between 2014 and 2021 in Japan was conducted. Among 351 patients with sufficient data, 116 (33%) were in the advanced stage (5 in stage III and 111 in stage IV) at diagnosis, and were further analyzed. The median age was 60 years (range: 19-90), and 68 (59%) were male. Ninety-four (85%) of stage IV patients had two or more extranodal involvements. The most common first-line regimen was SMILE (steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide; 52%). The 2-year overall survival (OS) for all patients was 38.5%, which was significantly improved after 2017 (25.2% for 2014-2017 vs. 50.7% for 2018-2021; P = 0.008). Patients treated with SMILE showed better OS than those treated with DeVIC or CHOP (2y-OS: 57.1%, 35.8%, and 0%, respectively; P < 0.001). The prognosis was significantly better in patients who received hematopoietic stem cell transplantation (HSCT) than in those who did not (2-year OS: 68.3% vs. 17.6%, P < 0.001). Multivariate analysis showed SMILE and HSCT were significant factors for OS. In conclusion, the prognosis of advanced-stage ENKL has improved in recent years. The L-asparaginase-containing chemotherapy and subsequent HSCT is considered the recommended strategy., Competing Interests: Competing interests: AF received honoraria from Chugai Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Sanofi K.K., and Meiji Seika Pharma Co., Ltd., outside of the submitted work. KM received research grants from Eisai Co., Ltd., Takeda Pharmaceutical Company Limited, Nippon Shinyaku Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Asahi Kasei Pharma Corporation, Sumitomo Pharma Co., Ltd., and Zenyaku Kogyo Co., Ltd., and received honoraria from Chugai Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Limited, Janssen Pharmaceutical K.K., Eisai Co., Ltd., Nippon Shinyaku Co., Ltd., AstraZeneca K.K., Bristol-Myers Squibb K.K., Meiji Seika Pharma Co., Ltd., Abbvie GK, Novartis Pharma K.K., Incyte Corporation, Asahi Kasei Pharma Corporation, Ono Pharmaceutical Co., Ltd., and Genmab A/S, outside of the submitted work. TF received honoraria from Janssen Pharmaceutical K.K., Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Meiji Seika Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, and Nippon Shinyaku Co., Ltd., outside of the submitted work. WM received research grants from Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Genmab A/S, Janssen Pharmaceutical K.K., Kyowa Kirin Co., Ltd., and Nippon Shinyaku Co., Ltd., and received honoraria from Janssen Pharmaceutical K.K., Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K., Mundipharma K.K., Gilead Sciences Inc., MSD K.K., Amgen K.K., Takeda Pharmaceutical Company Limited, Eisai Co., Ltd., Novartis Pharma K.K., AstraZeneca K.K., Genmab A/S, Nippon Shinyaku Co., Ltd., and Abbvie GK, outside of the submitted work. DM received research funding from Ono Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., MSD K.K., Zenyaku Kogyo Co., Ltd., Sanofi K.K., SymBio Pharmaceuticals Limited, Takeda Pharmaceutical Company Limited, Abbvie GK, AstraZeneca K.K., Bristol-Myers Squibb K.K., Genmab A/S, Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Pfizer Japan Inc., and Astellas Pharma Inc., and received honoraria from Ono Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Janssen Pharmaceutical K.K., Mundipharma K.K., Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co. Ltd., MSD K.K., Zenyaku Kogyo Co., Ltd., Sanofi K.K., SymBio Pharmaceuticals Limited, Takeda Pharmaceutical Company Limited, Abbvie GK, AstraZeneca K.K., Bristol-Myers Squibb K.K., Genmab A/S, and Novartis Pharma K.K., outside of the submitted work. TM received honoraria from Bristol-Myers Squibb K.K., Janssen Pharmaceutical K.K., Novartis Pharma K.K., Sanofi K.K., Takeda Pharmaceutical Company Limited, Abbvie GK, Chugai Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Ono Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., and AstraZeneca K.K., outside of the submitted work. JT received scholarship from Kyowa Kirin Co., Ltd., Abbvie GK, and AstraZeneca K.K., received consulting fee from AstraZeneca K.K., Janssen Pharmaceutical K.K., and Abbvie GK, and received honoraria from AstraZeneca K.K., Janssen Pharmaceutical K.K., and Abbvie GK, outside of the submitted work. R Sakai received research grants from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., and Taiho Pharmaceutical Co., Ltd., and received honoraria from Takeda Pharmaceutical Company Limited, Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., SymBio Pharmaceuticals Limited, Janssen Pharmaceutical K.K., CSL Behring K.K., Kyowa Kirin Co., Ltd., Eisai Co., Ltd., Nippon Shinyaku Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Celgene Corporation, Bristol-Myers Squibb K.K., Mundipharma K.K., Meiji Seika Pharma Co., Ltd., and Towa Pharmaceutical Co., Ltd., outside of the submitted work. NF received research grants from Abbvie GK, Chugai Pharmaceutical Co., Ltd., Chordia therapeutics Inc., Genmab A/S, Incyte Corporation, Kyowa Kirin Co., Ltd., Loxo Oncology Inc., and Takeda Pharmaceutical Company Limited, and received honoraria from Abbvie GK, AstraZeneca K.K., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Eisai Co., Ltd., Eli Lilly and Company, Genmab A/S, Janssen Pharmaceutical K.K., Kyowa Kirin Co., Ltd., Nippon Shinyaku Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Sanofi K.K., SymBio Pharmaceuticals Limited, and Takeda Pharmaceutical Company Limited, outside of the submitted work. NA has received honoraria from Takeda Pharmaceutical Company Limited, outside of the submitted work. MY received research funding from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Genmab A/S, Incyte Corporation and Abbvie GK, received consulting fees from Genmab A/S, BeiGene Ltd., and Nihon Servier Co. Ltd., and received honoraria from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Abbvie GK, Bristol-Myers Squibb K.K., Janssen Pharmaceutical K.K., Meiji Seika Pharma Co., Ltd., MSD K.K., Nippon Shinyaku Co., Ltd., SymBio Pharmaceuticals Limited, Takeda Pharmaceutical Company Limited, and Eisai Co., Ltd., outside of the submitted work. R Suzuki received research grants from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Shionogi & Co., Ltd., Taiho Pharmaceutical Co., Ltd., Eisai Co., Ltd., and Otsuka Pharmaceutical Co., Ltd., and received honoraria from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Abbvie GK, Bristol-Myers Squibb K.K., Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., MSD K.K., Janssen Pharmaceutical K.K., Takeda Pharmaceutical Company Limited, Meiji Seika Pharma Co., Ltd., Novartis Pharma K.K., and AstraZeneca K.K., outside of the submitted work. KY, YE, NK, NH, MT, and ST have no financial conflicts of interest to disclose., (© 2025. The Author(s).)

Vitrectomy with silicone oil (SO) endotamponade is an effective treatment for vision-threatening retinal diseases. However, unexplained vision impairment has been reportedly critical side effects. Previously, we reported that the eyes with ocular toxoplasmosis showed retinal ferroptosis with the clinical sign of reduced intravitreal iron (Fe). We also found that total iron levels in sub-silicone oil fluid (SOF) in eyes with SO endotamponade were significantly reduced. We hypothesized that the cause of complications related to SO endotamponade is retinal ferroptosis and that low total iron in SOF is a secondary change that occurs similarly to the changes in ocular toxoplasmosis. In this study, we measured total iron levels in ocular fluid from patients, rabbits with SO endotamponade. Retinal iron taken up from the SOF was evaluated using laser ablation inductively coupled plasma mass spectrometry in human and rabbit eyes. Retinal ferroptosis was confirmed by immunohistochemistry of 4-hydrox-2-nonenal-modified proteins, FeRhoNox-1 staining, western blotting and RT-PCR. We found low total iron levels in the SOF, increased oxidative stress and Fe uptake from the SOF into the retinae of human and rabbit eyes, as well as decreased GPx4 expression, increased FeRhoNox-1 signals and altered Fe-related gene expression in SO-filled rabbit eyes. Of note, the target of ferroptosis was Müller cells. We generated an in vitro silicone oil-filled eye model using MIO-M1 cells (a human Müller cell line). The in vitro SO-filled eye model showed decreased GPx4 expression and increased intracellular catalytic Fe(II), an increase in ferroptosis, prevention of cell death by ferrostatin-1, a ferroptosis inhibitor, and altered Fe-related gene expression. These results indicate that the cause of complications related to SO endotamponade was the induction of retinal (Müller cell) ferroptosis, which can be prevented by ferrostatin-1., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: In patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations, a chemoimmunotherapy regimen of atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) has shown promising outcomes following treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, evidence on whether ABCP provides a survival advantage over platinum-based chemotherapy in real-world clinical settings remains limited. This study aimed to investigate the efficacy and safety of ABCP versus platinum-based chemotherapy in patients with EGFR-mutant NSCLC who underwent EGFR-TKI treatment., Materials and Methods: We retrospectively assessed consecutive patients with EGFR-mutant-NSCLC who received platinum-based chemotherapy or ABCP after EGFR-TKI treatment at 20 institutions in Japan between January 2017 and July 2022., Results: Overall, 408 patients with advanced or recurrent EGFR-mutant NSCLC were analyzed. A total of 306 patients (75.0 %) received chemotherapy (Chemo) or chemotherapy plus bevacizumab (Chemo + BEV), and 102 patients (25.0 %) received ABCP. After propensity score matching, no significant differences were noted in progression-free survival (PFS) and overall survival (OS) between the Chemo or Chemo + BEV and ABCP groups (6.0 months versus 7.2 months, log-rank test; p = 0.44 and 22.5 months versus 21.3 months, p = 0.84, respectively). Limiting to the programmed cell death-ligand 1 (PD-L1) ≥ 50 % cohort, the ABCP group had a significantly longer PFS than did the Chemo or Chemo + BEV group (7.9 months versus 4.8 months, log-rank test; p = 0.02)., Conclusion: In patients with EGFR-mutant NSCLC previously treated with EGFR-TKI, ABCP achieved comparable outcomes to those of platinum-based chemotherapy. Among patients with high PD-L1 expression, ABCP may be a superior treatment option., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tadaaki Yamada received research grants from Ono Pharmaceutical, Janssen, AstraZeneca, and Takeda Pharmaceutical, and has received speaking honoraria from Eli Lilly and Chugai-Roche outside the purview of the submitted work. Hisashi Tanaka received speaking honoraria from Ono Pharmaceutical, Bristol Myers Squibb, AstraZeneca, Chugai Pharmaceutical, Boehringer-Ingelheim, Pfizer, Takeda Pharmaceutical, MSD-Merck, and Amgen. Makoto Hibino received speaking honoraria from Asahi Kasei Pharma Corporation, AstraZeneca, Boehringer Ingelheim, Bristol-Myers, Chugai Pharmaceutical Co. Ltd., and Eli Lilly, and is involved in a collaborative research project with Shionogi & Co., Ltd., outside the submitted work. Koichi Takayama received research grants from Chugai Pharmaceutical Co. Ltd. and Ono Pharmaceutical and personal fees from AstraZeneca, Chugai Pharmaceutical Co. Ltd., MSD-Merck, Eli Lilly, Boehringer Ingelheim, and Daiichi-Sankyo outside the purview of the submitted work. All remaining authors declared no conflict of interest., (Copyright © 2025 Elsevier B.V. All rights reserved.)

A six-year-old boy presented with short stature and gingival fibromatosis (GF). Dysmorphic features included slant optic fissures, a high-arched palate, thick earlobes, and an edematous face. Laboratory tests showed low levels of serum insulin-like growth factor-1 and serum free thyroxine but normal serum thyrotropin levels. Provocative tests suggested growth hormone deficiency, central hypocortisolemia, and hypothalamic hypothyroidism. At 12 years old, hypogonadotropic hypogonadism was observed. Next-generation sequencing revealed a heterozygous missense variant, KCNQ1 p. (P369L), in the proband and mother. The coexistence of multiple pituitary hormone deficiencies and GF helps diagnose KCNQ1-variant dysmorphic syndrome through genetic testing.

Objectives: In an ultra-aged society, the increasing number of elderly individuals requiring nursing care because of complications and disabilities poses a significant challenge for healthcare providers, along with a decline in the quality of life (QoL). Therefore, investigating the underlying causes and establishing effective preventive measures is imperative. Sarcopenia, characterized by a reduction in muscle strength throughout the body, can negatively impact QoL because of declining physical function. This study aimed to elucidate the interrelationship between physical function and health-related quality of life (HRQoL) in elderly individuals requiring long-term care., Methods: The participants (n=67) were elderly individuals (32 men, 35 women) requiring light nursing care. HRQoL was assessed using the EuroQol Group 5-Dimensions 5-Level (EQ-5D-5L) scale. Relationships between the EQ-5D-5L score and age, body mass index, SARC-CalF, and sex were examined. The relationships between the EQ-5D-5L score and the 10-s chair stand test, functional reach test (FRT), grip strength, 10-m walking test, and Timed Up-and-Go (TUG) test were investigated separately for men and women., Results: A correlation was identified between EQ-5D-5L score and sex. In men, a correlation was identified between EQ-5D-5L and TUG test results. In women, a comparable correlation was observed between EQ-5D-5L score and the 10-m walking test, FRT, and TUG test., Conclusions: The findings revealed a correlation between physical functions, including standing and walking, and QoL in elderly individuals requiring light nursing care. Maintaining and enhancing standing and walking abilities among this demographic group should be a high priority., Competing Interests: CONFLICTS OF INTEREST: The authors declare no conflict of interest., (2025 The Japanese Association of Rehabilitation Medicine.)

Objectives: We aimed to assess whether proximal ligation of the pulmonary vein stump (PVS) outside the pericardium reduces postoperative cerebral infarction (PCI) incidence after lobectomy., Methods: A single-institution retrospective review was conducted on 683 patients undergoing lobectomy for lung cancer, metastatic lung tumours, and benign diseases. Associations among PCI within 90 days, ligation of the PVS, and clinicopathological features were analysed. Effects of PVS ligation on PCI were assessed using multivariable regression. PVS length measured on three-dimensional computed tomographic angiography was compared between the non-ligation and ligation groups., Results: The non-ligation and ligation groups included 356 (January 2010 to March 2018) and 327 patients (April 2018 to November 2023), respectively. Seven non-ligation group patients (1.96%) underwent PCI (three in left upper lobectomy [LUL] and left lower lobectomy [LLL] and one in right lower lobectomy); no ligation group patients suffered PCI (p = 0.016). Univariable analysis showed that LUL, LLL, chronic kidney disease (CKD), heart failure, cardiovascular disease, and PVS ligation were significantly associated with PCI. Multivariable analysis demonstrated that PVS ligation (p = 0.034) was correlated with decreased PCI and LUL (p = 0.011), LLL (p = 0.010) and CKD (p = 0.004) with increased PCI. After ligation, PVS length was shortened in each lobe in a subset analysis of 109 patients., Conclusions: Proximal ligation of the PVS outside the pericardium may be an option to prevent PCI in lobectomy. Patients with CKD and those undergoing left-sided lobectomy are at higher risk for PCI and may benefit from more intensive management., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: The opaque nature of artificial intelligence (AI) algorithms has led to distrust in medical contexts, particularly in the treatment and monitoring of atrial fibrillation. Although previous studies in explainable AI have demonstrated potential to address this issue, they often focus solely on electrocardiography graphs and lack real-world field insights., Objective: We addressed this gap by incorporating standardized clinical interpretation of electrocardiography graphs into the system and collaborating with cardiologists to co-design and evaluate this approach using real-world patient cases and data., Methods: We conducted a 3-stage iterative design process with 23 cardiologists to co-design, evaluate, and pilot an explainable AI application. In the first stage, we identified 4 physician personas and 7 explainability strategies, which were reviewed in the second stage. A total of 4 strategies were deemed highly effective and feasible for pilot deployment. On the basis of these strategies, we developed a progressive web application and tested it with cardiologists in the third stage., Results: The final progressive web application prototype received above-average user experience evaluations and effectively motivated physicians to adopt it owing to its ease of use, reliable information, and explainable functionality. In addition, we gathered in-depth field insights from cardiologists who used the system in clinical contexts., Conclusions: Our study identified effective explainability strategies, emphasized the importance of curating actionable features and setting accurate expectations, and suggested that many of these insights could apply to other disease care contexts, paving the way for future real-world clinical evaluations., (©Wan Jou She, Panote Siriaraya, Hibiki Iwakoshi, Noriaki Kuwahara, Keitaro Senoo. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 13.02.2025.)

Objective: The COVID-19 pandemic prompted the widespread adoption of telemedicine as an alternative to in-person care. This systematic scoping review evaluated the effectiveness, cost-efficiency, and challenges of telemedicine for patients with rheumatic diseases., Methods: A comprehensive search of the MEDLINE database was conducted using specific terms related to rheumatoid or juvenile arthritis, and telemedicine. The literature search included studies published up to March, 2024. In this review, we only considered studies assessing telemedicine as an alternative to in-person care., Results: The search, conducted on March 15, 2024, generated 258 references. Eight reports from three randomized controlled trials (RCTs) and three observational studies were included. RCTs have shown that the outcomes of telemedicine intervention are comparable to those of in-person care in terms of disease activity, functional status, and quality of life, while enabling fewer outpatient visits and cost-effectiveness. However, the high dropout rates highlight the importance of patient preferences and comprehensive education. Observational studies revealed similar findings but were limited by a high confounding bias., Conclusion: Telemedicine offers economic advantages and maintains clinical outcomes comparable to those of in-person care. Its success depends on structured patient education and alignment with patient preferences. Further research is required, particularly in the context of healthcare in Japan., (© Japan College of Rheumatology 2025. Published by Oxford University Press.)

Total breast reconstruction using only a latissimus dorsi flap (LDF) often has a problem of insufficient volume. Recently, a fat-augmented LDF has been introduced as a solution to this problem. However, there are still many cases in which augmentation with fat grafting alone is not enough to achieve symmetrical breasts. Here, we discuss a new approach for full breast reconstruction, which we refer to as tribrid reconstruction, that combines the fat-augmented LDF with a breast implant. Depending on the need for a skin island, the LDF or muscle flap is harvested and augmented with fat grafting, either to the flap itself or by injecting fat into the pectoral muscle or the subcutaneous tissue of the chest. In cases in which this does not correct asymmetry, an implant is added to enhance the breast volume. This 3-component reconstruction method was applied in 9 cases, and all achieved sufficient postoperative volume and satisfactory aesthetic results. This technique can be used in a single surgery to reconstruct both moderately sized and larger breasts., Competing Interests: The authors have no financial interest to declare in relation to the content of this article. Funding was from institutional sources only, and there was no funder involvement in writing the article., (Copyright © 2025 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Background: The coronavirus disease 2019 (COVID-19) pandemic restricted the activities of the general population and affected health systems, which adapted medical resources to manage COVID-19 treatment. During the initial lockdown, trauma volumes decreased. However, it is unknown whether trauma volumes changed from 2021 to 2022, the late pandemic period when COVID-19 vaccination began and restrictions were gradually lifted., Methods: The first objective of this study was to investigate changes in the number and types of trauma from 2021 to 2022, the late pandemic period, compared with 2018 to 2019, the pre-pandemic period. The second objective was to investigate the direct impact of COVID-19 on the clinical practice in orthopedic trauma units during the late pandemic period. Records of patients admitted to our institution and diagnosed with at least one fracture were retrospectively reviewed., Results: Patient demographics in the pre-pandemic period (n = 980) and the late pandemic period (n = 1058) were not significantly different for sex (p = 0.89) and age (p = 0.55). The proportion of trauma types was not significantly different between these periods (p = 0.45). The proportion of patients followed up at our hospital after discharge was significantly higher in the late pandemic period (79%) than in the pre-pandemic period (64%) (p < 0.001). During the late pandemic period, the proportion of trauma patients infected with COVID-19 during hospitalization was significantly higher in the second half of the late pandemic, compared with the first half (first half vs. second half: 0.8% vs. 3%) (p = 0.011)., Conclusions: This finding suggested that from 2021 to 2022, one year after the start of the pandemic and when restrictions had been eased, the number of trauma cases returned to pre-pandemic levels. From 2021 to 2022, the medical practice of orthopedic trauma units could be maintained and managed by the efforts of medical staff, despite the increase in the number of infected patients who had to be admitted for surgery and whose discharge had to be postponed. These results are based on observations in Japan and cannot be compared with other countries., Competing Interests: Declarations. Ethical approval: The study obtained institutional Research and Ethics Committee approval. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Rho-associated kinase (ROCK) inhibitors have gained popularity as novel treatment options in the management of glaucoma and corneal endothelial disorders. Among the various ocular side effects, reticular corneal epithelial edema has been most frequently reported, mainly after treatment with netarsudil. To explain the potential mechanisms, we comparatively analyzed the effects of ripasudil and netarsudil on corneal endothelial and epithelial function in vitro. Primary human corneal endothelial and epithelial cells were incubated with netarsudil dihydrochloride and ripasudil hydrochloride dihydrate for up to 7 days. Gene and protein expression analyses were performed by real-time PCR and immunocytochemistry. Functional assays assessed the cell migration, proliferation, viability, Na + /K + -ATPase activity, transcellular electrical resistance, and FITC-dextran permeability. Reticular bullous corneal epithelial edema was observed in a patient following netarsudil 0.02%/latanoprost 0.005% ophthalmic solution (Roclanda ® ) for elevated intraocular pressure. In the subsequent laboratory analyses, both netarsudil and ripasudil were found to improve the corneal endothelial pump and barrier function, but they showed differential effects on corneal epithelial cells. Whereas ripasudil improved the epithelial barrier function by upregulating major components of the tight and adherens junctions and reducing paracellular permeability, netarsudil had no or even adverse effects on the epithelial barrier properties by downregulating the expression levels of cell-junction-associated genes. The expression changes normalized after discontinuation of ROCK inhibitors. The findings support the concept that ROCK inhibitors can act as a double-edged sword by having beneficial effects on corneal endothelial cells and adverse effects on epithelial cells.

Despite growing evidence supporting the efficacy of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for accidental hypothermia (AH), few studies have assessed its real-world application. We aimed to describe the use and outcomes of VA-ECMO in AH patients using data from a multicenter registry. This retrospective study included adult AH patients from the Japanese accidental hypothermia network registry (J-Point registry) between April 2011 and March 2016. We analyzed patient characteristics, in-hospital data, VA-ECMO indications, and clinical outcomes for those who received VA-ECMO. Of the 537 patients in this registry, 22 received VA-ECMO, with a median age of 80 years. Severe AH was present in 18 patients, and 10 experienced cardiac arrest (CA) on hospital arrival. VA-ECMO was indicated for CA on hospital arrival (10 patients), CA after hospital arrival (5), hemodynamic instability (5), and severe hypothermia (1), with 1 case having an unclear indication. Rewarming was successful in 18 patients, and 9 survived. Survival was higher among those with CA on hospital arrival (5/10) compared with those who developed CA after hospital arrival (1/5). This study highlights the clinical application and outcomes of VA-ECMO for AH patients using multicenter registry data. Among the 22 patients who received VA-ECMO, 9 survived. Patients with CA on hospital arrival showed better survival compared with those who developed CA after arrival, emphasizing the importance of timely VA-ECMO initiation. Further research is warranted to refine patient selection, optimize initiation timing, and evaluate long-term outcomes.

Background/Objectives : Postoperative analgesia is important for reducing biologically invasive reactions to surgery. In Japan, postoperative analgesia, including indices of analgesia, has not been adequately addressed. This study aimed to determine the relationship between postoperative pain and postoperative course and the importance of analgesia for early recovery. Methods : Patients who underwent any of seven surgical procedures in gastrointestinal, thoracic, and cardiac surgery were enrolled. The primary endpoint was a median Prince Henry Pain Scale score from postoperative days 1 to 3. Secondary endpoints were the quality of recovery on postoperative day 7 (Quality of Recovery-15 [QoR-15]) and the length of postoperative hospital stay. Results : Median postoperative pain levels among surgeries were 3 on day 1, 2 on days 2 and 3, 1 on day 7, and 1 at discharge. In both univariate and multivariate analyses, the use of postoperative epidural analgesia and intravenous patient-controlled analgesia (IV-PCA) were significant predictors of early postoperative pain. Only early postoperative pain was a significant predictor of QoR-15 score. Regular use of acetaminophen, early postoperative pain, no appetite, and postoperative complications were significant in affecting the length of postoperative hospital stay. In the comparison of early postoperative pain according to whether epidural analgesia and IV-PCA were used, the group that used both methods had the least pain. Conclusions : In Japan, early postoperative pain persists after major surgical procedures and affects postoperative quality of recovery and length of hospital stay. The use of epidural analgesia, IV-PCA, or both appeared to be effective in overcoming early postoperative pain, thereby enhancing early postoperative recovery.

Purpose: To investigate temporal changes in multiparametric MRI (mpMRI) findings following lesion-targeted focal therapy with microwave tissue coagulation (MTC) for localized prostate cancer (PCa)., Methods: This retrospective study included 33 patients (34 procedures) with localized PCa who underwent lesion-targeted focal therapy with MTC between June 2019 and March 2024. Post-treatment mpMRI, including T2-weighted imaging (T2WI), T1-weighted imaging (T1WI), diffusion-weighted imaging (DWI), and dynamic contrast-enhanced MRI (DCE-MRI), was evaluated by three radiologists to analyze signal changes and enhancement patterns in the treated area. Inter-reader agreement for each MRI sequence was also assessed., Results: The median PSA reduction following treatment was 82 % (range, 18 %-99 %). The average post-treatment observation period was 16.5 months (range, 2.8-51.6 months), with a total of 97 post-treatment mpMRI scans conducted. In the early post-treatment period (3-6 months), the treated area exhibited heterogeneous hypointensity with a hypointense rim on T2WI, hyperintensity or isointensity on T1WI, and heterogeneous mixed signal intensity on DWI. Over time, these patterns diminished, with all lesions demonstrating hypointensity on T2WI, T1WI, and DWI by 17, 28, and 22 months, respectively. On DCE-MRI, rim enhancement predominated in the early post-treatment period, while all lesions showed no enhancement during later follow-up., Conclusion: After lesion-targeted focal therapy with MTC for localized PCa, MRI findings in the treated area exhibited dynamic changes during the early post-treatment period, ultimately stabilizing as hypointensity across all sequences and no enhancement during late follow-up., 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 © 2025 Elsevier B.V. All rights reserved.)

Purpose: Cervical spine injuries in the elderly (defined as individuals aged 65 years and older) are increasing, often resulting from falls and minor trauma. Prognosis varies widely, influenced by multiple factors. This study aimed to develop a deep-learning-based predictive model for post-injury outcomes., Methods: This study analyzed a nationwide dataset from the Japan Association of Spine Surgeons with Ambition, comprising 1512 elderly patients (aged 65 years and older) with cervical spine injuries from 2010 to 2020. Deep learning predictive models were constructed for residence, mobility, and the American Spinal Injury Association Impairment Scale (AIS). The model's performance was compared with that of a traditional statistical analysis., Results: The deep-learning model predicted the residence and AIS outcomes with varying accuracies. The highest accuracy was observed in predicting residence one year post-injury. The model also identified that the AIS score at discharge was significantly predicted by upper extremity trauma, mobility, and elbow extension strength. The deep learning model highlighted factors, such as upper extremity trauma, that were not considered significant in the traditional statistical analysis., Conclusion: Our deep learning-based model offers a novel method for predicting outcomes following cervical spine injuries in the elderly population. The model is highly accurate and provides additional insights into potential prognostic factors. Such models can improve patient care and individualize future interventions., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The JCCG ALL-B12 clinical trial aimed to evaluate the effectiveness of unvalidated treatment phases for pediatric ALL and develop a safety-focused treatment framework., Patients and Methods: Patients age 1-19 years with newly diagnosed B-ALL were enrolled in this study. These patients were stratified into standard-risk (SR), intermediate-risk (IR), and high-risk (HR) groups. Randomized comparisons assessed the effectiveness of vincristine (VCR)/dexamethasone pulses in the SR group, evaluated the effects of L-asparaginase (ASP) intensification in the IR group, and compared standard consolidation including block-type treatment with experimental consolidation with high-dose methotrexate (HD-MTX) intensified with VCR and ASP in the HR group., Results: Of 1,936 patients enrolled, 1,804 were eligible for the experimental treatment. The overall 5-year event-free survival and overall survival rates were 85.2% (95% CI, 83.5 to 86.8) and 94.3% (95% CI, 93.1 to 95.3), respectively. The cumulative incidence of relapse and postremission nonrelapse mortality was 13.2% (95% CI, 11.6 to 14.8) and 0.6% (95% CI, 0.3 to 1.0), respectively. Random assignment in the SR group showed no significant benefit from pulse therapy. In the IR group, ASP intensification had limited effects. In the HR group, standard block therapy and HD-MTX yielded equivalent outcomes., Conclusion: The ALL-B12 trial achieved favorable outcomes in a nationwide cohort by stratifying treatment on the basis of risk and balancing treatment intensity. This study not only demonstrated that existing standard of care can be further refined but also indicated that improvement in outcomes with intensified chemotherapy has reached a plateau.

Background: Whether the level of the inferior mesenteric artery ligation affects the incidence of anastomotic leakage remains unclear., Objective: To assess the impact of the level of inferior mesenteric artery ligation on the blood flow to the anastomotic site and the incidence of anastomotic leakage using indocyanine green fluorescence imaging., Design: A post hoc analysis of EssentiAL trial., Settings: This study was conducted at 41 tertiary referral centers in Japan., Patients: 839 rectal cancer patients (<12 cm from the anal verge)., Main Outcome Measures: The incidence of anastomotic leakage and perfusion status were compared between the high and low ligation groups., Results: The median fluorescence time was similar at 25 seconds in both groups (p= 0.74). Although no statistical difference was noted, the high ligation group was more likely to have greater outliers in fluorescence time compared to the low ligation group. The high ligation group demonstrated higher poor perfusion rates than the low ligation group (2.8% vs 1.5%). In the high ligation group, anastomotic leakage occurred in one case of poor perfusion where additional resection was not performed by the surgeon's intraoperative judgment. Additionally, the additional resection rate nearly doubled with the use of indocyanine green fluorescence imaging. After propensity score matching (129 patients per group), the overall anastomotic leakage rate was 13.2% in the high ligation group and 10.9% in the low ligation group (p = 0.57)., Limitations: This study was a post hoc analysis, the sample size was small, and the anastomosis methods varied., Conclusions: The level of inferior mesenteric artery ligation did not affect blood flow at the anastomotic site or the incidence of anastomotic leakage statistically, but assessing bowel perfusion using indocyanine green fluorescence imaging can offer clinical benefits, optimizing patient outcomes. See Video Abstract., Trial Registration: The Japan Registry of Clinical Trials (jRCTs-CRB3180007), the Japanese Clinical Trials Registry (UMIN-CTR000030240). See Video., (Copyright © The ASCRS 2025.)

Background: Post-intensive care syndrome (PICS) affects the quality of life (QOL) of survivors of critical illness. Although PICS persists for a long time, the longitudinal changes in each component and their interrelationships over time both remain unclear. This multicenter prospective study investigated the 2-year trajectory of PICS and its components as well as factors contributing to deterioration or recovery in mechanically ventilated patients with coronavirus disease 2019 (COVID-19), and also attempted to identify possible countermeasures., Methods: Patients who survived COVID-19 requiring mechanical ventilation completed questionnaires on the Barthel index, Short-Memory Questionnaire, Hospital Anxiety and Depression Scale, and EuroQol 5 dimensions 5-level every six months over a two-year period. Scores were weighted to account for dropouts, and the trajectory of each functional impairment was evaluated with alluvial diagrams. The prevalence of PICS and factors impairing or restoring function were examined using generalized estimating equations considering trajectories., Results: Among 334 patients, PICS prevalence rates in the four completed questionnaires were 72.1, 78.5, 77.6, and 82.0%, with cognitive impairment being the most common and lower QOL being noted when multiple impairments coexisted. Physical function and QOL indicated that many patients exhibited consistent trends of either recovery or deterioration. In contrast, cognitive function and mental health revealed considerable variability, with many patients showing fluctuating ratings in the later surveys. Delirium was associated with worse physical and mental health and poor QOL, while prolonged ventilation was associated with poor QOL. Living with family was associated with the recovery of all functions and QOL, while extracorporeal membrane oxygenation (ECMO) was associated with the recovery of cognitive function and mental health., Conclusions: Critically ill patients had PICS for a long period and followed different trajectories for each impairment component. Based on trajectories, known PICS risk factors such as prolonged ventilation and delirium were associated with impaired recovery, while ECMO and the presence of family were associated with recovery from PICS. In critically ill COVID-19 patients, delirium management and family interventions may play an important role in promoting recovery from PICS., Trial Registration Number: UMIN000041276, August 01, 2020., Competing Interests: Declarations. Ethics approval and consent to participate: Approval for the present study was granted by the Institutional Review Board of the National Hospital Organization Tokyo Medical Center (date: November 26, 2020, approval number: R20-133) and the Review Boards of each participating hospital. Informed consent was obtained from all subjects involved in this study. Consent for publication: Not applicable. Competing interests: All authors have disclosed that they do not have any potential conflicts of interest., (© 2025. The Author(s).)

Background: Endometriosis presents as endometrial tissue growths outside the uterine cavity with its major symptoms including dysmenorrhea and infertility. Progestin preparations, such as dienogest, are the first-line therapy for endometriosis symptoms, but may cause abnormal uterine bleeding. A gonadotropin-releasing hormone (GnRH) agonist may also be used to ease symptoms, but may induce flare-ups. Relugolix is a non-peptide GnRH antagonist that does not induce flare-ups. This study aims to compare the efficacy of relugolix with that of dienogest for reducing endometriosis-associated pain, and to evaluate if relugolix, administered prior to dienogest, decreases abnormal uterine bleeding., Methods: A multicenter, open-label, active-controlled, non-inferiority randomized study will be conducted at 11 sites in Japan. A total of 100 premenopausal patients aged ≥ 18 years with endometriosis, a maximum visual analog scale (VAS) score > 30 for endometriosis-associated pain, and dysmenorrhea or pelvic pain of at least moderate severity on the Biberoglu & Behrman (B&B) scale will be randomized in a 1:1 ratio to either a relugolix group or dienogest group. Patients in the relugolix group will receive 40 mg oral relugolix once daily for 16 weeks, followed by 1 mg oral dienogest twice daily for 24 weeks. Patients in the dienogest group will receive oral dienogest 1 mg twice daily for 24 weeks. The primary outcome will be change in maximum VAS score for endometriosis-associated pain from baseline to 13-16 weeks after start of treatment. The secondary outcomes will include VAS score for dyspareunia, B&B score for dysmenorrhea, severity of induration in the pouch of Douglas, restricted uterine mobility, pelvic tenderness, quality of life, analgesic use, and ovarian endometrioma diameter. The safety outcomes will include treatment-emergent adverse events, bone density, bone markers, menstrual status, genital bleeding, and endometrial thickness., Discussion: This study will determine the efficacy of relugolix for improving endometriosis-associated pain and dienogest-induced abnormal uterine bleeding. The results will support treatment decisions regarding endometriosis-associated pain, and the introduction of new treatments to reduce dienogest-induced abnormal uterine bleeding., Trial Registration: Japan Registry of Clinical Trials ID jRCTs061230064. Registered on 29 September 2023., Competing Interests: Declarations. Ethics approval and consent to participate: This study protocol was approved by the Certified Review Board, Tottori University Hospital on 30 January 2024 (version 1.3, approval number: 23C004), and the study is registered in the JRCT ID (registration number: jRCTs061230064, 29 September 2023; https://jrct.niph.go.jp/latest-detail/jRCTs061230064 ). Any changes to the study protocol, informed consent form (see Additional file 1 for an approved informed consent form), or other study-related documents will need to be approved by the Certified Review Board. After receiving approval, the principal investigator will notify investigators at each study site. This study will be conducted in compliance with the Declaration of Helsinki, Clinical Trials Act (Act No. 16, 2017), and Act on the Protection of Personal Information (Act No. 57, 2003). Investigators will explain the study and obtain written informed consent from all participants prior to the start of any study-related procedures. Consent for publication: Not applicable. Competing interests: FT, YO, TH, and JK received honoraria as a speaker and consultant fee from ASKA Pharmaceutical Co., Ltd. The principal investigators will receive research grant from ASKA Pharmaceutical Co., Ltd. MF is an employee of ASKA Pharmaceutical Co., Ltd., (© 2025. The Author(s).)

Background: Out-of-hospital cardiac arrest (OHCA) is a global health burden with low survival rates. The termination of resuscitation (TOR) rule, widely adopted internationally, aims to preserve dignity, optimize resources, and protect healthcare providers. However, prehospital TOR is not implemented in Japan, presenting legal and practical challenges. This study analyzes temporal trends in prehospital and in-hospital interventions for OHCA patients with poor predicted outcomes., Methods: This retrospective study analyzed data from the Japanese Association for Acute Medicine Out-of-Hospital Cardiac Arrest (JAAM-OHCA) registry (June 2014-December 2021). Adult OHCA patients with medical causes were included if they fulfilled all the advanced life support (ALS) TOR rule criteria: unwitnessed arrest, no return of spontaneous circulation, no bystander-initiated cardiopulmonary resuscitation, and no automated external defibrillator use or defibrillation. Prehospital and in-hospital interventions were evaluated., Results: Among 11,334 patients meeting the inclusion criteria, 2,447 received all three ALS interventions (advanced airway management, intravenous access, and epinephrine administration). Over time, in-hospital interventions, including endotracheal intubation (56%) and epinephrine administration (82%), decreased, while advanced therapies, including coronary angiography, extracorporeal membrane oxygenation, and targeted temperature management, remained rare (<1%). The median time to TOR after hospital arrival shortened to 18 min. In contrast, prehospital epinephrine administration increased, while advanced airway management and intravenous access decreased., Conclusions: OHCA patients who met TOR rule showed a decrease in in-hospital interventions. Further efforts are warranted to avoid futile medical treatments and promote patient-centered care., 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 © 2025 Elsevier B.V. All rights reserved.)

We report the development of a redox-responsive system that induces reversible conformational changes in peptides through the design of a seven-membered cyclic α,α-disubstituted α-amino acid with a disulfide bond, 5-amino-1,2-dithiepane-5-carboxylic acid (Dtp). Upon reduction, the disulfide bond in Dtp was cleaved to form thiols, converting Dtp into (2-mercaptoethyl)homocysteine (Mhc), and this process was reversed by oxidation. Dtp-containing peptides predominantly adopted 3 10 -helical conformation in solution, whereas Mhc-containing peptides exhibited a mixture of helical and other conformations. This redox-responsive mechanism allows for precise control over peptide secondary structures, making it a promising approach for designing functional helical peptides capable of acting molecular switches in response to intracellular reductive environments., (© 2025 Wiley-VCH GmbH.)

Stereogenic macrocycles composed of axially chiral binaphthyls and bithiophenes were synthesized. The bis(1,5-cyclooctadiene)nickel(0)-catalyzed coupling of an enantiomeric precursor yielded a cyclic dimer and trimer with doubly-twisted and triply-twisted triangular geometries, respectively. The orientation of the bithiophenes, s-cis, and s-trans in the cyclic compounds significantly altered their macrocyclic structure. Mixing of conformers in the cyclic dimer results in complex chiroptical properties, leading to bisignate-type spectra, which are rarely observed in circularly polarized luminescence., (© 2025 Wiley-VCH GmbH.)

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis; however, advancements in cancer genome profiling using next-generation sequencing have provided new perspectives. KRAS mutations are the most frequently observed genomic alterations in patients with PDAC. However, until recently, it was not considered a viable therapeutic target. Although KRAS G12C mutations for which targeted therapies are already available are infrequent in PDAC, treatments targeting KRAS G12D and pan-KRAS are still under development. Similarly, new treatment methods for KRAS, such as chimeric antigen receptor T-cell therapy, have been developed. Several other potential therapeutic targets have been identified for KRAS wild-type PDAC. For instance, immune checkpoint inhibitors have demonstrated efficacy in PDAC treatment with microsatellite instability-high/deficient mismatch repair and tumor mutation burden-high profiles. However, for other PDAC cases with low immunogenicity, combination therapies that enhance the effectiveness of immune checkpoint inhibitors are being considered. Additionally, homologous recombination repair deficiencies, including BRCA1/2 mutations, are prevalent in PDAC and serve as important biomarkers for therapies involving poly (adenosine diphosphate-ribose) polymerase inhibitors and platinum-based therapies. Currently, olaparib is available for maintenance therapy of BRCA1/2 mutation-positive PDAC. Further therapeutic developments are ongoing for genetic abnormalities involving BRAF V600E and the fusion genes RET, NTRK, NRG, ALK, FGFR2, and ROS1. Overcoming advanced PDAC remains a formidable challenge; however, this review outlines the latest therapeutic strategies that are expected to lead to significant advancements., (© The Author(s) 2025. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Voltage-gated potassium channel subfamily B member 1 (KCNB1) encodes the α-subunit of the Kv2.1 channel and mediates transmembrane potassium transport. The functions and mechanisms underlying KCNB1 activation have been examined in various cancer types; however, its role in esophageal squamous cell carcinoma (ESCC) remains unclear. Therefore, the present study investigated the involvement of KCNB1 in tumor progression and the clinicopathological significance of its expression in ESCC., Methods: Knockdown experiments using KCNB1 small interfering RNA were performed on the human ESCC cell lines, KYSE70 and TE5, and changes in cell proliferation, the cell cycle, apoptosis, migration, and invasion were assessed. Gene expression profiles were examined using a microarray analysis. An immunohistochemical (IHC) analysis was performed on 129 primary tumor samples from ESCC patients who underwent curative esophagectomy., Results: Cell proliferation, G 2 -M phase progression, migration, and invasion were inhibited, and apoptosis was induced in KCNB1-depleted cells. Microarray results showed that KCNB1 gene expression affected Ephrin receptor signaling by suppressing EPHB1, EPHB2, and ERK1/2 gene expression. IHC results revealed a relationship between high KCNB1 expression and a poor prognosis. High KCNB1 expression was extracted as an independent prognostic factor in a multivariate analysis of 5-year relapse-free survival in ESCC patients (p = 0.0197)., Conclusions: Cell proliferation is controlled by KCNB1 through its regulation of ERK1/2 gene expression via ephrin receptor signaling. A relationship was observed between KCNB1 and the prognosis of ESCC patients, indicating its potential as a biomarker for cancer progression and in targeted therapy for ESCC., Competing Interests: Declarations. Conflict of interest: There are no conflicts of interest or financial ties to declare., (© 2025. Japanese Society of Gastroenterology.)

The development of efficient immunosuppressants may bring significant benefits to patients after organ/stem transplantation and those with allergies or autoimmune diseases. MEK inhibitors were originally developed as anticancer reagents, but recent reports have suggested that they may have the potential to be immunosuppressants. Trametinib is a first-in-class MEK inhibitor. Here, we examined the effects of trametinib on the immune system and revealed its mechanism. Trametinib suppressed both CD4 and CD8 T-cell proliferation and activated T cells, which expressed CD25 and TIM3, in a dose-dependent manner in vitro. Trametinib also suppressed T cell-related cytokine secretion in a dose-dependent manner. Notably, trametinib suppressed T cell proliferation through the induction of G1 arrest and apoptosis in stimulated T cells. In addition, trametinib induced regulatory T cells (Tregs). We confirmed that low concentrations of trametinib (1 and 10 nM) were not toxic toward splenic naïve T cells and normal mouse liver cells. In this study, we demonstrated whether trametinib suppressed CD4 and CD8 T cell proliferation by inducing G1 arrest and apoptosis along with suppression of cytokine secretion., (© 2025 Wiley‐VCH GmbH.)

Sonic Hedgehog (Shh), encoding an extracellular signaling molecule, is vital for heart development. Shh null mutants show congenital heart disease due to left-right asymmetry defects stemming from functional anomaly in the midline structure in mice. Shh signaling is also known to affect cardiomyocyte differentiation, endocardium development, and heart morphogenesis, particularly in second heart field (SHF) cardiac progenitor cells that contribute to the right ventricle, outflow tract, and parts of the atrium. Despite extensive studies, our understanding remains incomplete. Notably, Shh signaling is suggested to promote cardiac differentiation, while paradoxically preventing premature differentiation of SHF progenitors. In this study, we elucidate the role of Shh signaling in the earliest phase of cardiac differentiation. Our meta-analysis of single-cell RNA sequencing suggests that cardiogenic nascent mesoderm cells expressing the bHLH transcription factor Mesp1 interact with axial mesoderm via Hh signaling. Activation of Hh signaling using a Smoothened agonist delayed or suppressed the differentiation of primitive streak cells expressing T-box transcription factor T to Mesp1 + nascent mesoderm cells both in vitro and ex vivo. Conversely, inhibition of Hh signaling by cyclopamine facilitated cardiac differentiation. The reduction of Eomes, an inducer of Mesp1, by Hh signaling appears to be the underlying mechanism of this phenomenon. Our data suggest that SHH secreted from axial mesoderm inhibits premature differentiation of T + cells to Mesp1 + nascent mesoderm cells, thereby regulating the pace of cardiac differentiation. These findings enhance our comprehension of Shh signaling in cardiac development, underscoring its crucial role in early cardiac differentiation., (© 2025 The Author(s). Development, Growth & Differentiation published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Developmental Biologists.)

Atopic dermatitis (AD) is a common skin disease. Although AD pathogenesis has been widely researched, inhibitory mechanisms in AD are still unclear. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of receptors recognising sialic acids; most Siglecs work as inhibitory receptors. Among Siglecs, Siglec-E is expressed on dendritic cells (DCs) and eosinophils, important immune cells in AD. Although Siglec-E inhibits Type 1 inflammatory diseases, how it influences AD is unknown. Thus, we investigated the role of Siglec-E in AD mouse model by using Siglec-E knockout (KO) mice. We demonstrated that Siglec-E attenuated AD-like inflammation of mice caused by topical application of MC903 on ear skin (MC903-induced AD). To reveal the role of Siglec-E in MC903-induced AD, we focused on Siglec-E on DCs and eosinophils. We first showed that Sigle-E was expressed on cutaneous DCs and migratory DCs of draining lymph nodes. Moreover, OX40L expression on cutaneous DCs was reduced in the presence of Siglec-E. In vitro experiments using cultured spleen DCs (SpDCs), highly expressing Siglec-E, revealed that IL-33 was involved in the induction of Siglec-E and confirmed that Siglec-E inhibited OX40L expression on SpDCs induced by IL-33. Moreover, CD4 + T cell-SpDC coculture revealed that Siglec-E inhibited Th2 polarisation under IL-33 stimulation. We finally revealed that Siglec-E was expressed on eosinophils and reduced the eosinophils infiltration to the MC903-treated ear skin with the suppression of CD49d, a necessary integrin for eosinophil migration to skin tissue [1], expression on eosinophils. These findings elucidated the inhibitory role of Siglec-E in MC903-induced AD., (© 2025 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)