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The Spontaneously Running Tokushima Shikoku (SPORTS) rat is characterized by hyperactive behavior but is also a potential model for studies of the role of the gut-pancreas axis in the regulation of insulin secretion. We here explored the role of ghrelin, a hormone associated with appetite regulation, in insulin dynamics within the context of streptozotocin (STZ) resistance in SPORTS rats. Comprehensive analyses-including histological examinations, gene expression profiling, and assessment of metabolic parameters-revealed that SPORTS rats are resistant to STZ-induced pancreatic injury and that, in addition to low circulating ghrelin levels, they manifest increased circulating levels of active glucagon-like peptide-1 (GLP-1) and upregulated expression of Pdx1 in the pancreas. Ghrelin administration attenuated the STZ resistance of these rats, with suppression of GLP-1 and downregulation of Pdx1 expression being implicated in this effect. Our results highlight the complex interplay among ghrelin, GLP-1, and insulin dynamics, and they suggest potential new therapeutic targets for diabetes., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

The antihyperglycemic effect of black tea is well-known, and theaflavins (TFs) are considered active compounds. It is, however, unclear whether glucagon-like peptide-1 (GLP-1) is involved in the antihyperglycemic effects of TFs. We demonstrate that TFs suppress postprandial hyperglycemia by stimulating GLP-1 secretion in mice. In STC-1 cells, theaflavin 3'-gallate (TF2B), possessing a galloyl group at the 3'-position, showed the strongest effect on GLP-1 secretion among the four TFs. TF2B activated G protein-coupled receptor 55 (GPR55) and was confirmed to bind to the receptor, notably exhibiting the highest binding affinity. Moreover, GPR55 antagonist canceled TF2B-induced GLP-1 secretion. Downstream, TF2B increased intracellular Ca 2+ levels and activated the Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinases 1/2 (ERK1/2) pathways. Inhibitors of Ca 2+ signaling, CaMKII, and ERK pathways abolished TF2B-stimulated GLP-1 secretion. These findings suggest that TF2B from black tea prevents hyperglycemia through GPR55-dependent stimulation of GLP-1 secretion via Ca 2+ -Ca 2+ /CaMKII and ERK1/2 pathways.

Glucagon-like peptide-1 (GLP-1) is an incretin produced by enteroendocrine preproglucagon (PPG)-expressing cells in response to nutrient ingestion that potentiates insulin secretion. The voltage-gated Ca 2+ channel has been reported previously to be involved in glucose-stimulated GLP-1 secretion; in this study, we show that PPG-cells in upper and lower small intestine substantially express the voltage-gated Ca 2+ channel α 2 δ-1 subunit (Ca V α 2 δ-1). In vitro experiments using NCI-H716 cells demonstrate that inhibition of Ca V α 2 δ-1 by gabapentin (GBP), an inhibitory ligand of the α 2 δ subunit, attenuates glucose-stimulated intracellular calcium elevation and reduces GLP-1 secretion. In addition, systemic administration of gabapentin significantly reduces glucose-stimulated GLP-1 secretion without affecting blood glucose levels in wild-type mice. Furthermore, knockout mice of intestine-specific Cacna2d1 , a gene encoding Ca V α 2 δ-1, exhibit reduced GLP-1 secretion in response to oral glucose administration regardless of sex. These results demonstrate that Ca V α 2 δ-1 expressed in PPG-cells plays an important role in glucose-stimulated GLP-1 secretion and represents a potential target in the treatment of diabetes and obesity. NEW & NOTEWORTHY In this study, we establish high expression of the voltage-gated Ca 2+ channel α 2 δ-1 subunit (Ca V α 2 δ-1) subunit in enteroendocrine glucagon-like peptide-1 (GLP-1) producing cells and elucidate its role in GLP-1 secretion, providing a more detailed understanding of the mechanism of GLP-1 secretion.

Background: Coronary artery calcification (CAC) detected through chest computed tomography (CT) strongly predicts cardiovascular events in asymptomatic individuals undergoing primary prevention. Few studies with limited sample sizes have investigated the predictive value of CAC for cardiovascular complications in COVID-19. This study examined the impact of CAC on cardiovascular complications using a large-scale COVID-19 database., Methods and Results: This multicenter retrospective cohort study used data from the Japan COVID-19 Task Force database. After exclusion based on missing information, 1,109 patients with COVID-19 were included. The Agatston score was used to evaluate CAC, dividing the population into 3 groups based on calcification degree (no, moderate, and severe CAC). The primary outcome was cardiovascular complications; the secondary outcome was critical outcomes. The severe CAC group had a higher rate of cardiovascular complications than the other groups. Multivariable analysis, considering COVID-19 severity factors, identified severe CAC as independently associated with cardiovascular complications but not with critical outcomes. Subgroup analysis revealed that, in patients without hypertension, diabetes, cardiovascular disease, or chronic kidney disease, severe CAC was significantly correlated with cardiovascular complications, whereas this association was not observed in patients with these underlying conditions., Conclusions: Patients with COVID-19 and severe CAC had increased cardiovascular complications, and identifying cardiovascular and pulmonary findings on chest CT is essential. Measuring CAC via non-electrocardiogram-gated CT helps predict patient risk.

Estrogen is synthesized throughout various tissues in the body, and its production is regulated by the rate-limiting enzyme aromatase (encoded by the Cyp19a1 gene). Notably, aromatase is also expressed in central nervous system cells, allowing for localized estrogen synthesis in regions such as the hypothalamus. Estrogens produced within these neurons are referred to as neuroestrogens. In this study, we investigated the role of neuroestrogens in the regulation of appetite through modulation of hypothalamic pathways in OVX, ArKO, and aromatase-restored mice. Estrogen suppresses appetite by influencing the expression of appetite-regulating peptides, including POMC and NPY, via MC4R. We explored the direct effects of neuroestrogens, independent from ovarian estrogen, on appetite suppression and the underlying molecular mechanisms. We monitored body weight and food intake and evaluated the expression of Cyp19a1, Mc4r, and other appetite-related genes. Our findings indicate that OVX and ArKO mice exhibited increased body weight and food consumption, which correlated with altered expression of Mc4r and Cyp19a1. Conversely, restoration of Cyp19a1 expression in a neuron specific manner significantly decreased food intake and increased Mc4r expression in the hypothalamus. Furthermore, neuroestrogens enhanced leptin responsiveness. Our results imply that neuroestrogens likely contribute to appetite regulation and may be relevant for body weight reduction., (© 2025 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Disaster-related deaths can be classified as direct and indirect disaster-related deaths that are becoming more predominant in Japan. To reduce indirect disaster-related deaths, accurate statistics based on medical documentation are essential. However, the definition and reporting of such deaths in Japan present systemic challenges. These deaths are certified and recorded by municipalities at the request of bereaved families seeking condolence grants. This cross-sectional study assessed 755 certified indirect disaster-related deaths after the 2011 Great East Japan Earthquake in the Miyagi Prefecture, Japan, to determine whether medical documents mentioned disaster relevance. Of the 755 cases, 74 (9.8%) death certificates and 145 (19.2%) medical documents described the relevance of disasters. Relevance mentioned only in the self-reported documentation from bereaved families was 536 (71.0%). The median [interquartile range] time from the disaster onset to disaster-related deaths was 21 [7-52] days. The mean age was 79.7-years-old, and 346 (46.7%) of the victims were female. The predominant etiologies of these deaths included circulatory (32.7%) and respiratory (27.7%) diseases. The time periods of the deaths varied among the municipalities, suggesting a lack of consensus among the review committees. Establishing a medical and social consensus for indirect disaster-related deaths and recording them on death certificates is crucial for accurate disaster death data and social resilience., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Objective: Testing with fingertip blood sampling, including HbA1c testing, has been available in community pharmacies in Japan since 2014. In 2016, the Mihara Pharmacy Association in Hiroshima Prefecture, in collaboration with the Mihara municipal government, developed a community programme that utilized the walk-in HbA1c test that could be offered by participating community pharmacies. The aim of this study was to assess whether the new programme could detect undiagnosed DM in the community and to compare groups who had and had not accessed the SHCG programme among SHCG eligible participants., Method: The programme includes pharmacist advice following participants conducted Hba1c testing in the pharmacy, and completing a questionnaire to collect self-reported personal data including lifestyle, demography, height, weight, and blood pressure. All those accessing the programme were included. We analysed data from fiscal years 2016 to 2018, obtained retrospectively from the questionnaires., Key Findings: The participants aged 40-74 years who were the target of a national health check programme represented 73.7% of the 1933 total unique participants. Approximately 40% of these participants did not undergo routine checkups, 23.8% had HbA1c scores ≥5.6%, and 2.7% had HbA1c scores ≥6.5%., Conclusions: The walk-in HbA1c community testing programme provided an opportunity to test the diabetes mellitus risk of residents, especially those who have missed their routine checkups. If the community programme were adopted widely, more undiagnosed populations at risk for diabetes mellitus could be detected in the early stages and the use of community resources such as pharmacists and pharmacies would be utilized., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. 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.)

Certain polyphenols improve glucose tolerance by stimulating glucagon-like peptide-1 (GLP-1) secretion from intestinal L-cells. Ashitaba chalcones, 4-hydroxyderricin (4-HD), and xanthoangelol (XAG) have antihyperglycemic effects, but their molecular mechanism, including whether they promote GLP-1 secretion is unknown. This study investigates the 4-HD-induced GLP-1 secretory mechanisms and its anti-hyperglycemic effects. The secretory mechanisms were examined in STC-1 cells and antihyperglycemic effects in male ICR mice. In STC-1 cells, 4-HD, but not XAG, stimulated GLP-1 secretion through membrane depolarization and intracellular Ca 2+ increase [Ca 2+ ] i , via the L-type Ca 2+ channel (VGCC). Verapamil and nifedipine, blockers of VGCC, and treatment in Ca 2+ -free buffer abolished 4-HD effects on [Ca 2+ ] i and GLP-1 secretion. Moreover, 4-HD activated CaMKII and ERK1/2. Consistently, oral 4-HD suppressed postprandial hyperglycemia in mice and increased plasma GLP-1 and insulin levels, GLUT4 translocation, and activation of LKB-1 and Akt pathways in skeletal muscle. Furthermore, exendin 9-39, a GLP-1R antagonist, and compound C, an AMPK inhibitor, completely canceled the 4-HD-caused anti-hyperglycemic activities. 4-HD stimulated GLP-1 secretion through membrane depolarization coupled with [Ca 2+ ] i increase via VGCC in L-cells and activated AMPK- and insulin-induced GLUT4 translocation in skeletal muscle. Thus, 4-HD possesses dual mechanisms for the prevention of hyperglycemia., (© 2025 Wiley‐VCH GmbH.)

Background: Chest computed tomography (CT) is a valuable tool for diagnosing and predicting the severity of coronavirus disease 2019 (COVID-19) and assessing extrapulmonary organs. Reduced muscle mass and visceral fat accumulation are important features of a body composition phenotype in which obesity and muscle loss coexist, but their relationship with COVID-19 outcomes remains unclear. In this study, we aimed to investigate the association between the erector spinae muscle (ESM) to epicardial adipose tissue (EAT) ratio (ESM/EAT) on chest CT and disease severity in patients with COVID-19., Methods: We analysed data from 1074 COVID-19 patients enrolled in the Japan COVID-19 Task Force database. The primary outcome was the rate of critical outcomes (requiring high-flow oxygen therapy, invasive ventilator support or death). The incidence of critical outcomes was compared between patients with high and low ESM/EAT ratios., Results: The low ESM/EAT group (n = 353) had a higher incidence of critical outcomes (13.3% vs. 5.13%, p < 0.001) and mortality (2.55% vs. 0.69%, p = 0.019) than the high ESM/EAT group (n = 721). In multivariable analysis, the low ESM/EAT ratio was associated with critical outcomes (adjusted odds ratio [aOR] 2.11, 95% confidence interval [CI] 1.22-3.66) independently of the known COVID-19 severity factors including age, sex, body mass index (BMI), smoking history, lifestyle-related comorbidities and pneumonia volume., Conclusion: The low ESM/EAT ratio in COVID-19 patients can be obtained on chest CT and used to predict critical outcomes after disease onset, demonstrating the importance of detailed body composition assessments in COVID-19 practice., (© 2025 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RAs) are widely used as antidiabetic and anti-obesity agents. Although conventional GLP-1 RAs, such as liraglutide and semaglutide, are acylated with fatty acids to delay their degradation by dipeptidyl peptidase-4, the manufacturing process is challenging. We previously developed selectively lipidated GLP-1 peptides at their only tryptophan residue (peptide A having one 8-amino-3,6-dioxaoctanoic acid (miniPEG) linker and peptide B having three miniPEG linkers). In this study, we evaluated their effects on the GLP-1 receptor in vitro and in vivo. Both novel peptides were shown to increase cyclic adenosine monophosphate production and insulin secretion similarly to that by GLP-1(7-37) and liraglutide in vitro. In addition, these novel peptides lowered blood glucose levels by increasing insulin levels after oral administration of glucose and they suppressed gastrointestinal motility as effectively as liraglutide. The effects of peptide A on activation of satiety-promoting neurons in the arcuate nucleus and the consequent suppression of food intake and body weight were also similar to those of liraglutide, while the effects of peptide B were less than those of liraglutide. Under high-fat diet feeding, both long-term administration of peptide A and peptide B improved glucose tolerance and insulin sensitivity similarly to liraglutide. Thus, tryptophan-selective lipidated GLP-1 peptides are as effective as conventional GLP-1 RAs in reducing plasma glucose levels and body weight and may represent a less demanding method of manufacture of GLP-1 RAs.

Time-space network hypertension is a data science approach that connects diverse information related to hypertension within a time-space framework. This field of academic research aims to predict disease onset and direct effective, individualized, optimized treatments by integrating and analyzing the variability of multiple internal biological and external environmental signals as they relate to blood pressure variability across different time phases. By linking time series changes in blood pressure and biological distribution with multi-environmental and physiological information, enabled by advances in digital technology, the time-space network hypertension approach contributes to "digital hypertension" research. This article from Jichi Medical University provides an update on research relating to the time-space network hypertension approach, which is designed to progress hypertension management towards achieving net zero cardiovascular events.

Sex differences exist in the commensal microbiota that impact on multiple physiological processes in the host. Here, we examined the mechanism by which the sex differences are formed. In addition to the epithelial ductal cell, the acinar cell mass in the submandibular gland was associated with androgen-androgen receptor (AR) signaling. Sex differences in the formation of submandibular mucin 10 (MUC10) were identified using SDS-PAGE. Neuraminidase treatment, which hydrolyzes terminal sialic acid, influenced the mobility shift of MUC10. Androgen-AR signaling negatively regulated ST3 β-galactoside α-2,3-sialyltransferase 1 (St3gal1) and St3gal4 in the submandibular gland. There was a trend and significant sex differences in α-diversity (Shannon, P = .09) and β-diversity (unweighted UniFrac) in oral microbiota composition, respectively. Some female-preferring bacteria including Akkermansia muciniphila can assimilate mucin by degrading terminal sialic acids. Our results indicate that androgen-AR signaling suppresses ST3GAL1 and ST3GAL4, which can influence sex differences in commensal microbiota composition., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Background: Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory disease of unknown cause, predominantly affecting teens and young adults. The early diagnosis and management are challenging due to the lack of reliable diagnostic markers and the occasional intractable cases despite conventional anti-inflammatory treatments. Janus kinase (JAK) inhibitors have recently shown potential utility; however, reports on their use for pediatric patients with CNO remain limited, and no established biomarkers exist to monitor disease activity. We aimed to investigate the pathophysiology of CNO and explore the rapid testing methods for accurate diagnosis and also assessing the disease activity., Methods: We assessed intracellular phosphorylation of signal transducer and activator of transcription 1 (pSTAT1) in peripheral blood monocytes or T cells following interferon-gamma (IFNγ) stimulation, using flow cytometry in 9 patients under 15 years old with CNO. The pSTAT1 expression levels were compared with those in patients with STAT1-gain of function (STAT1-GOF) mutations (n = 5), other autoinflammatory diseases (n = 7), and healthy controls. Clinical and immunological data were monitored in 4 patients with intractable CNO treated with adjunctive JAK inhibitors, focusing on scoring scales, imaging data, lymphocyte subsets, cytokine profiles, and pSTAT1 levels., Results: Monocyte pSTAT1 expression after IFNγ stimulation was elevated at diagnosis or during active CNO, similar to levels observed in STAT1-GOF cases. The pSTAT1 levels in CNO patients were significantly higher than those in other autoinflammatory diseases (p = 0.024) or controls (p < 0.001). Notably, pSTAT1 levels in CNO monocytes fluctuated with disease activity, decreasing in 5 patients during clinical remission following conventional therapies (p = 0.016). In four intractable cases, pSTAT1 levels remained high despite conventional treatments but significantly decreased after initiating JAK inhibitors (p = 0.036). This reduction correlated with improved patient pain visual analog scale (p = 0.008), CNO clinical disease activity score (p = 0.029), and better bone and joint imaging, though cytokine levels remained unchanged., Conclusions: The monocyte pSTAT1 levels after IFNγ stimulation reflect the activity of CNO, indicating the diagnostic utility as well as the monitoring effect of disease control. Adjunctive JAK inhibitors successfully controlled inflammation in treatment-resistant cases. Rapid pSTAT1 testing may help reduce osteo-articular complications, although the long-term adverse effects and resistance should be further investigated., Competing Interests: Declarations. Ethics approval and consent to participate: The research protocols were approved by Kyushu University Hospital Ethics Committee and informed written consent was obtained from a subject or a parent or guardian, participating in the study. Consent for publication: Written informed consent was obtained from a subject or a parent or guardian for the publication. Competing interests: The authors declare that they have no competing interests., (© 2025. The Author(s).)

Background: Although randomized controlled trials (RCT) have demonstrated the efficacy of mepolizumab for asthma, they have excluded certain patient subgroups. To bridge the gap between RCT and real-world practice, the effectiveness of mepolizumab in a diverse population, including those potentially excluded from RCT, was assessed. Its effects on imaging findings and symptoms of chronic rhinosinusitis (CRS) with asthma were also assessed., Methods: This retrospective observational study of patients in Japan (J-Real-Mepo: UMIN000045021) evaluated multiple endpoints and analyzed the relationship between clinical background and treatment outcomes., Results: Mepolizumab significantly reduced exacerbations, improved Asthma Control Test (ACT) scores, and forced expiratory volume in 1 s, and reduced oral corticosteroid (OCS) dose, regardless of patient characteristics, including age, body mass index, smoking history, and comorbidities. Regarding RCT exclusion criteria, 29.4 % of patients had no history of exacerbations. Although 25.4 % of these patients required continuous OCS, the OCS dose was reduced similar to those with a history of exacerbations. Disease control and mepolizumab effectiveness in patients with a smoking history ≥10 pack-years was similar to that of never-smokers. Patients with eosinophil counts <150/μL had lower ACT scores and higher OCS use compared with patients with eosinophilia and comparable effectiveness regarding exacerbation and OCS reduction. Significant improvements in Lund-Mackay scores and CRS symptoms were observed., Conclusions: Mepolizumab effectiveness was demonstrated in a broad range of patients including those with RCT exclusion criteria, who had significant disease or OCS burden. These findings may explain the consistent results between RCT and real-world studies of mepolizumab., Competing Interests: Conflict of interest HN reports grants from GSK and Kyorin and personal fees from AstraZeneca, GSK, Kyorin, Novartis, and Sanofi. Kkob reports personal fees from AstraZeneca and GSK. MS reports grants from AstraZeneca, Daiichi Sankyo, GSK, Kyorin, Kyowa Kirin, Sanofi, and Shionogi, and personal fees from AstraZeneca, GSK, Novartis, and Sanofi, and participated in advisory board for AstraZeneca. NH reports personal fees from AstraZeneca, GSK, Kyorin, Novartis, and Sanofi; and grants from AstraZeneca, Daikin, Sanofi. KMa reports personal fees from AstraZeneca, GSK, Kyorin, Novartis, Sanofi, and Viatris. JTH reports personal fees from GSK. KMi reports personal fees from AstraZeneca, GSK, Boehringer Ingelheim, and Novartis. TK reports personal fees from AstraZeneca, GSK, Sanofi, and Novartis. NS reports personal fees from AstraZeneca, GSK, and Sanofi. NI reports personal fees from AstraZeneca and GSK. MH reports personal fees from AstraZeneca, GSK and Sanofi. ET reports personal fees from Sanofi, AstraZeneca, Kyorin, and GSK. AT reports personal fees from AstraZeneca, GSK and Sanofi. KF reports grants from Boehringer Ingelheim, Taiho, and Sanofi, and personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, GSK, and Sanofi. YG reports grants from AstraZeneca, GSK, and Novartis and personal fees from AstraZeneca, GSK, and Sanofi. The rest of the authors have no conflict of interest., (Copyright © 2025 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background: Asthma involves variable airflow limitation and persistent airway inflammation. Eosinophilic asthma, characterized by cytokine-mediated type 2 inflammation, is generally treated with inhaled corticosteroids. However, patients with severe asthma may require biologics, such as mepolizumab, which targets IL-5 and can manage uncontrolled eosinophilic asthma., Objective: We investigated the relationship between serum mepolizumab concentrations and treatment response in patients with severe asthma., Methods: Patients with mepolizumab-treated severe asthma were enrolled onto this prospective cohort study. Baseline assessments were conducted and repeated at 3, 6, and 12 months. Those with response were categorized on the basis of improvements in asthma control test score, lung function, and asthma exacerbations. We quantified the serum concentration of mepolizumab at 3, 6, and 12 months after treatment by liquid chromatography coupled with tandem mass spectrometry., Results: Twenty-five adult patients aged 20 years and older with severe asthma were included in the analysis. Serum mepolizumab concentrations significantly increased at 6 and 12 months compared with those at 3 months, particularly in those with disease that responded to therapy. Furthermore, the relative change in mepolizumab concentration was significantly higher in those with response than in those with no response. Body size parameters were negatively correlated with mepolizumab concentration. In those with response, there were inverse correlations between mepolizumab concentration and baseline body size parameters., Conclusions: The study observed a yearlong increase in mepolizumab concentrations, particularly in those with response, indicating a potential mepolizumab surplus. Correlations between mepolizumab concentrations and baseline characteristics suggested differing mepolizumab requirements between those with response and those with no response. Further research is needed to validate these findings and optimize treatment strategies for patients with severe asthma., Competing Interests: Supported in part by 10.13039/501100001691Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (grant 20K08549) and by a Grant-in-Aid for Special Research in Subsidies for ordinary expenses of private schools from the 10.13039/501100012359Promotion and Mutual Aid Corporation for Private Schools of Japan to the Atopy (Allergy) Research Center. Disclosure of potential conflict of interest: N. Harada reports personal fees from AstraZeneca, GlaxoSmithKline, Kyorin, Novartis, and Sanofi; and grants from AstraZeneca, Daikin, Kao, Sanofi, and TOSOH outside the submitted work. S. Yagishita reports personal fees from LSI Medience outside the submitted work. A. Hamada reports grants from CIMIC Pharma Science, TOSOH, Chordia Therapeutics, LSI Medience, Chugai, Eli Lilly, Sysmex, Healios, Konica Minolta, Boehringer Inhelheim, Eisai, Daiichi Sankyo, AstraZeneca, Mitsubishi Tanabe Pharma, and Novartis outside the submitted work. K. Takahashi reports grants from Asahi Kasei Pharma Corporation, Bayer Yakuhin, Chugai, Daiichi Sankyo, Eli Lilly, Kyorin, Kyowa, Nippon Boehringer Ingelheim, Nippon Kayaku, Nippon Shinyaku, Nipro, Novartis, Ono, Pfizer, Sanofi, Shionogi, Taiho, Takeda, Teijin, and Tsumura; and personal fees from Abbott Japan, AstraZeneca, Bristol-Myers, Chugai, Eli Lilly, Janssen, Kyorin, Meiji Seika, Merck, MSD, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis, Ono, Pfizer, Sumitomo Dainippon Pharma, Taiho, Takeda, Thermo Fisher Scientific, and Viatris outside the submitted work. Furthermore, K. Takahashi has a patent (P6840330) for detecting cells, managed by Juntendo University in Japan. The rest of the authors declare that they have no relevant conflicts of interest., (© 2025 The Author(s).)

Ultrasound (US) imaging is a widely used tool in oncology because of its noninvasiveness and real-time performance. However, its diagnostic accuracy can be limited by the skills of the examiner when performing manual scanning and by the presence of acoustic shadows that degrade image quality. Artificial intelligence (AI) technologies can support examiners in cancer screening and diagnosis by addressing these limitations. Here, we examine recent advances in AI research and development for US imaging in oncology. Breast cancer has been the most extensively studied cancer, with research predominantly focusing on tumor detection, differentiation between benign and malignant lesions, and prediction of lymph node metastasis. The American College of Radiology developed a medical imaging reporting and data system for various cancers that is often used to evaluate the accuracy of AI models. We will also explore the application of AI in clinical settings for US imaging in oncology. Despite progress, the number of approved AI-equipped software as medical devices for US imaging remains limited in Japan, the United States, and Europe. Practical issues that need to be addressed for clinical application include domain shifts, black boxes, and acoustic shadows. To address these issues, advances in image quality control, AI explainability, and preprocessing of acoustic shadows are essential., Competing Interests: None, (Copyright © Japan Medical Association.)

Diffuse interstitial lung diseases (ILD) include conditions with identifiable causes such as chronic eosinophilic pneumonia (CEP), sarcoidosis (SAR), chronic hypersensitivity pneumonitis (CHP), and connective tissue disease-associated interstitial pneumonia (CTD), as well as idiopathic interstitial pneumonia (IIP) of unknown origin. In non-IIP diffuse lung diseases, bronchoalveolar lavage (BAL) fluid appearance is diagnostic. This study examines lymphocyte subsets in BAL fluid and peripheral blood of 56 patients with diffuse ILD, excluding idiopathic pulmonary fibrosis (IPF), who underwent BAL for diagnostic purposes. Patients were classified into CEP, SAR, CHP, CTD, and IIP groups, and clinical data, BAL cell analysis, and peripheral blood mononuclear cell analysis were compared. Eosinophils and type 3 innate lymphocytes (ILC3s) were significantly increased in the BAL fluid of the CEP group. Receiver operating characteristic curve analysis identified eosinophils ≥ 8% in BAL cells and ILC3s ≥ 0.0176% in the BAL lymphocyte fraction as thresholds distinguishing CEP. SAR patients exhibited significantly elevated CD4/CD8 ratios in the BAL fluid, with a ratio of 3.95 or higher and type 1 innate lymphoid cell frequency ≥ 0.254% as differentiation markers. High Th1 cell frequency (≥17.4%) in BAL lymphocytes in IIP, elevated serum KL-6 (≥2081 U/mL) and SP-D (≥261 ng/mL) in CHP, and increased BAL neutrophils (≥2.0%) or a low CD4/CD8 ratio (≤1.2) in CTD serve as distinguishing markers for each ILD. Excluding CEP and SAR, CD4 + T cell frequencies, including Th1, Th17, and Treg cells in peripheral blood, may differentiate IIP, CHP, and CTD.

This study evaluates the potential of using pond water eDNA to reflect the surrounding terrestrial plant communities, aiming to develop a sustainable, large-scale, and long-term monitoring method for plant diversity in forest ecosystems. Water samples were collected four times from two ponds with different vegetation types during the late spring to autumn seasons in Japan. eDNA was extracted from dissolved particles fractionated by sequential filtration through pore sizes of 200 µm, 5 µm, and 0.45 µm, followed by high-throughput amplicon sequencing targeting the plant rbcL gene. By comparing field surveys with the eDNA data, we identified 79% and 63% of plant families and genera, respectively, suggesting that pond water eDNA may reflect the surrounding terrestrial plant ecosystem. Additionally, different trends were observed in the seasonal variation of plant taxa and their composition detected in eDNA, based on particle size. This study highlights the potential of pond water eDNA to provide valuable insights into forest plant richness and seasonal dynamics, offering a novel approach for ecological monitoring.

Background: The therapeutic effectiveness of dupilumab for severe asthma in real-world settings is yet to be prospectively investigated across multiple institutions, and uncertainties persist regarding predictive factors for its effectiveness. We aimed to assess the effectiveness of dupilumab and identify predictors of its effectiveness in real-world settings using two type-2 biomarkers: FeNO concentration and blood eosinophil count., Methods: This prospective multicenter study included 103 patients with severe asthma. Exacerbations and respiratory functions were monitored for 24 weeks. Asthma control was evaluated using the Asthma Control Questionnaire-5. Clinical symptoms and their impact on cough and sputum were assessed using the Cough and Sputum Assessment Questionnaire (CASA-Q). Subgroup analyses of type-2 biomarkers were conducted based on FeNO levels and blood eosinophil counts at baseline., Results: Treatment with dupilumab led to a reduction in exacerbations and enhancement in asthma control, FEV 1 , and CASA-Q scores. FEV 1 improvement was correlated with enhancement in the sputum domain of the CASA-Q. Patients exhibiting elevated FeNO levels and blood eosinophil counts demonstrated more significant enhancements in FEV 1 . CASA-Q sputum domain scores were significantly higher in the group with elevated eosinophil counts. Regression analysis revealed that FeNO levels and blood eosinophil counts are significant predictors of FEV 1 improvement, with blood eosinophil counts also predicting sputum improvement in patients treated with dupilumab., Conclusions: Type-2 biomarkers may act as indicators of improvement in FEV 1 and sputum outcomes among patients with severe asthma undergoing dupilumab treatment in real-world settings., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

This rapid communication highlights the correlation between protein kinase B alpha (AKT1)-phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)- phosphatase and tensin homolog (PTEN) alterations and clinicopathological factors in Japanese patients with metastatic recurrent breast cancer (mBC). This study analyzed 1967 patients with luminal-type breast cancer who underwent cancer gene panel testing. The results demonstrated that AKT pathway alterations, including PI3K/AKT/PTEN, occurred in 1038 (52.8%) cases. Patients with AKT pathway mutations were older (p = 0.002) and had a higher rate of invasive lobular carcinoma (ILC) histology (p = 0.001), progesterone receptor (PgR) positivity (p = 0.006), and bone metastases (p = 0.001), and a lower rate of germline BRCA2 (p < 0.001). Comprehensive genomic profile results demonstrated a higher tumor mutational burden (TMB) (< 0.001) and lower tumor BRCA1/2 expression (< 0.001) in patients with mutations in the AKT pathway. These results are crucial for characterizing candidates for AKT pathway-targeted molecular therapies and conceptualizing optimal treatment strategies. Clinical trial registration: This study is an observational study and is therefore not registered with the clinical trials registration., Competing Interests: Declarations. Conflict of interest: Payment or honoraria for lectures—HT: Chugai, Daiichi Sankyo, Pfizer, Eli Lilly, Eisai AstraZeneca, MSD, Takeda, and Kyowa Kirin; MM: Chugai, Pfizer, Eli Lilly, MSD, Eisai, Taiho and AstraZeneca; NH: Chugai, Daiichi Sankyo, Pfizer, Eli Lilly, Takeda, Novartis, Eisai, AstraZeneca, MSD and Kyowa Kirin; AE: Kyowa Kirin; TI: Chugai, Daiichi Sankyo, Pfizer, Eli Lilly; YH, MS, TM, MY, TK and AS have no conflicts of interest to declare. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards., (© 2024. The Author(s).)

Although the top-down and bottom-up concept in microbial food-webs has been a primary interest in ecology, less is still known about it in soil ecosystems. Protists are the primary top-down predators of bacterial communities, altering their compositions, while the bottom-up resources are the primary factors limiting bacterial growth. Here, we hypothesized that the top-down predators modulate soil bacterial community composition, while the bottom-up nutrients control the bacterial growth and population. To precisely control nutrient levels, we used an inert soil substitute consisting of a combination of calcined clay and sand. Nutrients equivalent to the reference paddy field soil were added to microcosms as a control treatment. To investigate the effects of C, N, and P, six additional bottom-up treatments in the absence and double amounts of the nutrients were prepared. Four top-down treatments (no protist addition, Acanthamoeba castellanii, Vermamoeba vermiformis, and Heteromita globosa) were set up for each bottom-up treatment. A total of 252 microcosms under 28 treatments were incubated. Bacterial communities were analyzed using high-throughput sequencing and real-time PCR in the 1st, 3rd, and 5th weeks. The results revealed that the top-down predators significantly altered the bacterial community composition, and the bacterial population was predominantly controlled by the bottom-up nutrients. Analysis of absolute abundance data demonstrated that both top-down and bottom-up factors shaped the bacterial community structure (community composition and population). Random forest analysis classified the amplicon sequence variants associated with the treatments, showing that mostly similar families were affected by both bottom-up and top-down factors. In conclusion, the results of this study fully supported our hypothesis that top-down predators alter community composition, while bottom-up factors influence bacterial population dynamics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The three-vessel view (3VV) is a standardized transverse scanning plane used in fetal cardiac ultrasound screening to measure the absolute and relative diameters of the pulmonary artery (PA), ascending aorta (Ao), and superior vena cava, as required. The PA/Ao ratio is used to support the diagnosis of congenital heart disease (CHD). However, vascular diameters are measured manually by examiners, which causes intra- and interobserver variability in clinical practice. In the present study, we aimed to develop an artificial intelligence-based method for the standardized and quantitative evaluation of 3VV. In total, 315 cases and 20 examiners were included in this study. We used the object-detection software YOLOv7 for the automated extraction of 3VV images and compared three segmentation algorithms: DeepLabv3+, UNet3+, and SegFormer. Using the PA/Ao ratios based on vascular segmentation, YOLOv7 plus UNet3+ yielded the most appropriate classification for normal fetuses and those with CHD. Furthermore, YOLOv7 plus UNet3+ achieved an arithmetic mean value of 0.883 for the area under the receiver operating characteristic curve, which was higher than 0.749 for residents and 0.808 for fellows. Our automated method may support unskilled examiners in performing quantitative and objective assessments of 3VV images during fetal cardiac ultrasound screening.

Background: Biologics are integral in the management of severe asthma. As the effectiveness of the anti-IL-5 receptor antibody benralizumab in Japan remains elusive, this study aimed to assess its real-world effectiveness in Japanese patients with severe asthma., Methods: This prospective, interventional, single-arm clinical trial was conducted across ten facilities in Japan between September 2020 and July 2022. Adult patients with severe eosinophilic asthma (peripheral blood eosinophil count ≥150 cells/μl) were enrolled and treated with benralizumab. The primary endpoint was the change in ACQ-5 score from baseline to week 24., Results: Of 103 patients, 98 (mean age: 62.1 years, women: 55.1 %, regular oral corticosteroids [OCS] treatment: 20.4 %) were included in the analysis. From baseline to week 24, benralizumab significantly improved ACQ-5 (-0.67, 95 % CI: -0.94 to -0.39) and AQLQ (0.71, 95 % CI: 0.46 to 0.96) scores with an increase in FEV1 (87 ml, 95 % CI: 15-159 ml). The maintenance OCS dose and the percentage of OCS users decreased from 13.9 mg/day to 6.0 mg/day and from 20.4 % to 9.2 %, respectively. Multivariable analysis identified baseline blood eosinophil count (≥400 cells/μl) and fractional exhaled nitric oxide (≥22 ppb) as independent predictors of therapeutic response to benralizumab. Benralizumab treatment was discontinued due to nonserious adverse events and patient choice in four and three patients, respectively., Conclusions: In a real-world setting in Japan, patients with severe eosinophilic asthma treated with benralizumab demonstrated substantial improvements in asthma control, quality of life, and respiratory function with reduced OCS usage., Trial Registration: Japan Registry of Clinical Trials (jRCTs031190237)., Competing Interests: Conflict of interest KM, MS, NH, YM, ET, MH, HN, HKab, JM, KF received honoraria for lectures from AstraZeneca. HN has received fee for advisory board from AstraZeneca. The rest of the authors have no conflict of interest., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

There are several physiological and pharmacological actions of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide for the regulation of blood glucose and bodyweight., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Although the mental health burden of diabetes has received substantial attention, there is limited evidence on whether the risk of suicide-a severe consequence of mental health problems-increases among individuals with diabetes. Therefore, this study investigated the association between diabetes and suicide in Japan., Methods: This nationwide longitudinal cohort study included adults aged 18-74 years, who were enrolled in the Japan Health Insurance Association's health insurance programme between 2015 and 2022. Individuals newly diagnosed with diabetes were matched in a 1:1 ratio with those without diabetes, based on age and sex. We employed multivariable Cox proportional hazard models to estimate the hazard ratios for suicide in relation to the diagnosis of diabetes, adjusting for potential confounders, such as sociodemographic characteristics, history of psychiatric disorders, physical measurements, health behaviours and laboratory data., Results: Among 4 210 272 individuals in the matched-pair cohort, we observed 337 deaths by suicide among those with diabetes and 250 deaths by suicide among those without diabetes. After conditioning on potential confounders, diabetes diagnosis was linked to an increased risk of suicide (HR (95% CI) = 1.25 (1.06 to 1.47)). The association tended to be larger among those aged younger than 40 years and among women (among those aged 18-39 years, HR=1.69 (95% CI 1.05 to 2.73); among women, HR=1.56 (95% CI 0.92 to 2.64))., Conclusion: Diabetes diagnosis may increase suicide risk among the working-age population, even after conditioning on potential confounders. Our findings underscore the importance of psychosocial support following a diagnosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We examined shifts in labor productivity and their economic ramifications among adult patients with long COVID in Japan., Methods: A total of 396 patients were categorized into three groups based on symptom progression: non-long COVID, long COVID recovered, and long COVID persistent. Patient-reported outcomes were assessed at three time intervals: 3, 6, and 12 months after COVID-19 diagnosis. Labor productivity was gauged through presenteeism and absenteeism, measured using the World Health Organization Health and Work Performance Questionnaire., Results: Long COVID was observed in 52.7% of patients, and 29.3% of all the patients continued to experience long COVID symptoms 1 year after diagnosis. At all three time points (3, 6, and 12 months after diagnosis), the long COVID persistent group showed a statistically significant difference in absolute presenteeism compared with the non-long COVID and long COVID recovered groups ( P <0.01). Economic loss owing to decrease in labor productivity was calculated as $21,659 per year in the long COVID persistent group and $9008 per year in the long COVID recovered group ( P <0.01)., Conclusion: The study's results revealed a notable decline in labor productivity over time, underscoring the importance of early detection and intervention to mitigate the socio-economic repercussions of long COVID, in addition to its health implications., Competing Interests: The authors have no competing interests to declare., (© 2024 The Author(s).)

Introduction: The COVID-19 pandemic precipitated substantial disruptions in healthcare utilization globally. In Japan, reduced healthcare utilization during the pandemic's early phases had been documented previously. However, few studies have investigated the impact of the pandemic's later stages (2022-2023) on healthcare utilization rates, particularly in the Japanese context., Methods: We employed a quasi-Poisson regression model, adapted from the FluMOMO framework, to analyze temporal trends in Japanese healthcare utilization throughout the pandemic until November 2023. We estimated inpatient and outpatient volumes and hospital length of stay by bed type (general and psychiatric)., Results: In general hospital beds, inpatient volumes remained significantly below pre-pandemic levels for every month until November 2023, with a reduction of 7.8 percent in 2023 compared to pre-pandemic levels. Psychiatric inpatient volumes, which had been declining before the pandemic, continued this downward trend, with the average occupancy rate decreasing by approximately 5.3% to 81.3% in 2023 compared to pre-pandemic levels. Significantly reduced outpatient volumes for both general and psychiatric care, in addition to prolonged lengths of hospital stay for psychiatric beds, were observed sporadically for several months in 2022 and 2023, persisting beyond the cessation of state of emergency and quasi-state of emergency declarations., Conclusion: The COVID-19 pandemic fundamentally altered healthcare utilization patterns in Japan. We observed a sustained reduction in general and psychiatric inpatient volumes relative to pre-pandemic baselines nationwide. The prolonged impact on healthcare utilization patterns, persisting beyond emergency measures, warrants continued monitoring of service delivery.

Purpose: Omalizumab, the anti-IgE monoclonal antibody used to treat severe asthma, reduces asthma exacerbations, hospitalizations, and corticosteroid use. Although allergic asthma is a therapeutic target of omalizumab, omalizumab is not effective in all patients with severe allergic asthma and is not always available for long-term use. We retrospectively investigated factors related to long-term (≥2 years) use of omalizumab for severe asthma., Patients and Methods: Of the 116 patients treated with omalizumab for severe asthma at our hospital between 2009 and 2017, 82 were included in this retrospective analysis. Thirty-four were excluded because of adverse events, financial difficulties, or hospital transfers. The number of asthma exacerbations, unscheduled visits, corticosteroid doses, asthma control test scores, pulmonary function test results, and fractional exhaled nitric oxide levels were evaluated., Results: The median age of the study population was 58 years, with 66% female and 26% taking regular oral corticosteroids. After 2 years of treatment, 52 responders were identified using the global evaluation of treatment effectiveness (GETE) score. Improvements in asthma control test scores, airflow limitation, exacerbations, and oral corticosteroid use were observed in the responders. Multivariate analysis revealed that a peripheral blood eosinophil count of ≥200 or a perennial antigen-specific IgE antibody positivity of ≥2 predicted a response at the 2-year mark. However, Kaplan-Meier analysis demonstrated that neither high eosinophil counts nor perennial antigen-specific IgE positivity influenced the prolongation of treatment beyond 2 years, and responders at 2 years underwent omalizumab treatment for a significantly longer period than non-responders (HR = 9.89, p < 0.001), with GETE at 2 years being the only predictor of long-term omalizumab use., Conclusion: In this retrospective study the GETE after 2 years of omalizumab therapy emerged as the most meaningful predictor of the long-term effectiveness of omalizumab treatment in patients with severe asthma, highlighting the benefits of prolonged therapy in certain populations. These findings may guide future therapeutic strategies for severe asthma., Competing Interests: NH reports personal fees from AstraZeneca, GlaxoSmithKline, Kyorin, Novartis, and Sanofi and grants from AstraZeneca, Daikin, Kao Corporation, Sanofi, and TOSOH outside the submitted work. KT reports grants from Asahi Kasei Pharma Corporation, Bayer Yakuhin, Chugai, Daiichi Sankyo, Eli Lilly, Kyorin, Kyowa Kirin, Nippon Boehringer Ingelheim, Nippon Kayaku, Nippon Shinyaku, Nipro, Novartis, Ono, Pfizer, Sanofi, Shionogi, Taiho, Takeda, Teijin, and Tsumura; and personal fees from Abbott Japan, AstraZeneca, Bristol-Myers, Chugai, Eli Lilly, Janssen, Kyorin, Meiji Seika, Merck, MSD, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis, Ono, Pfizer, Sumitomo Dainippon Pharma, Taiho, Takeda, Thermo Fisher Scientific, and Viatris outside the submitted work. Furthermore, KT has a patent (P6840330) on the method of detecting cells, managed by Juntendo University in Japan. He is also part of the Board of Directors of The Japan Lung Cancer Society and The Japanese Respiratory Society. All other authors declare that they have no conflicts of interest in this work., (© 2024 Goto et al.)

Background: Examining human coding and non-coding RNAs present in skin surface lipids (SSL-RNAs) offers a promising approach to understanding the physiological state of the skin. Benralizumab treatment can reduce exacerbations and improve symptom control and quality of life in patients with severe eosinophilic asthma. Although this treatment effectively depletes peripheral blood eosinophils, the impact of benralizumab on SSL-RNA remains completely unknown., Objective: To investigate the effects of benralizumab treatment on SSL-RNA profiles in patients with severe asthma., Methods: Skin samples were non-invasively collected from patients before and after one year of benralizumab treatment. Sixteen patients were enrolled, but the SSL-RNA analysis was only feasible for five patients due to collection challenges, mainly in female participants., Results: Following benralizumab treatment, asthma symptoms, exacerbation rates, and lung function parameters improved. Peripheral blood eosinophils were completely depleted and serum eotaxin-1 levels increased. SSL-RNA analysis revealed differential expression of 134 genes, with significant downregulation of immune-related pathways and genes associated with neutrophilic inflammation., Conclusion: These findings suggest a suppression of both type 2 and non-type 2 inflammation in response to benralizumab treatment, with potential implications for asthma management. However, the limitations of the study include a small sample size and challenges in sebum collection, particularly among female participants. Although the noninvasive nature of this sampling method makes it attractive for both research and clinical applications, additional studies are needed to fully investigate the potential of SSL-RNA analysis as a noninvasive biomarker to assess treatment response in asthma., Competing Interests: NH reports personal fees from AstraZeneca, GlaxoSmithKline, Kyorin, Novartis, and Sanofi; and grants from AstraZeneca, Daikin, Sanofi, and TOSOH outside the submitted work. Furthermore, NH has supported in part by Kao Corporation in this study. KT reports grants from Asahi Kasei Pharma Corporation, Bayer Yakuhin, Chugai, Daiichi Sankyo, Eli Lilly, Kyorin, Kyowa, Nippon Boehringer Ingelheim, Nippon Kayaku, Nippon Shinyaku, Nipro, Novartis, Ono, Pfizer, Sanofi, Shionogi, Taiho, Takeda, Teijin, and Tsumura; and personal fees from Abbott Japan, AstraZeneca, Bristol-Myers, Chugai, Eli Lilly, Janssen, Kyorin, Meiji Seika, Merck, MSD, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis, Ono, Pfizer, Sumitomo Dainippon Pharma, Taiho, Takeda, Thermo Fisher Scientific, and Viatris outside the submitted work. Furthermore, KT has a patent (P6840330) on the method of detecting cells managed by Juntendo University in Japan. A patent application related to this work has been filed (No. PCT/JP2017/021040: method for preparing nucleic acid sample). Status: patent granted (DE, FR, GB, KR, CN, JP), patent pending (US). Inventors: TI and AH patent applicant: Kao Corporation). The rest of the authors have no competing interests to declare in this work., (© 2024 Harada et al.)

Epstein-Barr virus (EBV) reactivation in COVID-19 patients has been reported, but studies on its clinical significance are lacking. We herein report the occurrence of infectious mononucleosis (IM) due to EBV reactivation in a 60-year-old man with rheumatoid arthritis being treated with methotrexate and tocilizumab. The patient presented with a fever and tested positive for COVID-19. Laboratory findings revealed an increased atypical lymphocyte count, decreased platelet count, and elevated liver enzyme levels. Flow cytometry showed predominant expansion of reactive T cells. EBV reactivation was confirmed using real-time polymerase chain reaction. The patient was treated with remdesivir, and clinical improvement was observed after 10 days of treatment. Follow-up showed a gradual decrease in the EBV-DNA load with no recurrence of atypical lymphocytes. These findings suggest that COVID-19 in immunocompromised patients may lead to unexpected EBV reactivation and IM, even for patients outside the age at which IM is likely to occur., Competing Interests: Declaration of competing interest All authors declare no competing financial interests., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

TQS-168, a first-in-class small-molecule inducer of peroxisome proliferator-activated receptor gamma coactivator 1-alpha gene expression, is in development for the treatment of amyotrophic lateral sclerosis. A single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study of TQS-168 was carried out in healthy male subjects to investigate safety, tolerability, pharmacokinetics (PK), food effect, and preliminary pharmacodynamic effects (PD). Since solubility enhancement could be beneficial, assessment of three formulations was incorporated into the study using an integrated rapid manufacturing and clinical testing approach. Dosing in the SAD part was initiated with a crystalline methylcellulose (MC) suspension, and then spray-dried dispersion (SDD) and hot-melt extrusion (HME) suspensions were evaluated. The HME and SDD formulations showed two and fourfold higher exposure than the MC suspension, respectively, and the SDD formulation was selected for progression to subsequent SAD and MAD cohorts, in which there was further investigation of the food effect on exposure in addition to assessments of safety, tolerability, PK, and PD. C max and AUC plasma exposures of TQS-168 were supra-proportional at higher doses, irrespective of formulation. Median T max for TQS-168 occurred between 0.5 and 4.0 h post-dose and occurred later with higher doses. Geometric mean half-lives (T 1/2 ) for TQS-168 were independent of formulation and food, ranging from 3.2 to 10.5 h following single doses and 4.1 to 7.3 h following multiple doses. Food blunted TQS-168 C max but had minimal impact on AUC. TQS-168 was considered to be safe and generally well tolerated following single and multiple oral doses. The SDD formulation was selected for future patient studies., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Sensitization to Aspergillus, mucus plugs, and bacterial colonization may coexist and relate to a refractory phenotype during follow-up in asthma with bronchiectasis and allergic bronchopulmonary aspergillosis (ABPA)., Objective: This study aimed to clarify the features of Aspergillus -sensitized refractory asthma with bronchiectasis and determine the refractory phenotype in this population and ABPA., Methods: This study included cases of the oldest available Aspergillus fumigatus -specific IgE data and chest computed tomography images from a nationwide survey of refractory asthma with bronchiectasis. The characteristics of the A fumigatus -IgE positive ( Af sIgE + ) group were investigated and compared with its nonsensitized counterpart ( Af sIgE - ) and ABPA group. Cluster analysis was conducted to determine the refractory phenotype., Results: The Af sIgE + group (n = 35) demonstrated type 2 inflammation levels intermediate between the ABPA (n = 42) and Af sIgE - (n = 38) groups while exhibiting higher blood monocyte counts than the Af sIgE - group. Cluster analysis conducted in patients with ABPA and Af sIgE + newly determined 2 clusters: one was characterized by a younger age of asthma onset with fungal detection in sputum, and the other was characterized by mucus plugs and inflammation with eosinophils and monocytes, which was significantly related to mucus plugs, airflow limitation, and trend to show exacerbation. In the latter cluster, mucus plugs persisted, and 30% yielded Pseudomonas aeruginosa in the sputum <5 years later., Conclusion: The refractory phenotype with persistent mucus plugs was identified in Aspergillus -sensitized refractory asthma with bronchiectasis and ABPA. Mucus plug prevention is warranted., Competing Interests: Supported by the Scientific Assembly of Allergy, Immunology & Inflammation, 10.13039/501100009098Japanese Respiratory Society, 10.13039/100030831Novartis Japan, and the 10.13039/100009619Japan Agency for Medical Research and Development (research grant 24ek0410097 for Allergic Disease and Immunology). Disclosure of potential conflict of interest: K. Asano received lecturer fees from Sanofi, AstraZeneca, and Boehringer Ingelheim outside this work; and received a research grant on Allergic Disease and Immunology from the Japan Agency for Medical Research and Development. K. Fukunaga received lecturer fees from Sanofi, AstraZeneca, GlaxoSmithKline, Kyorin Pharmaceutical, Boehringer Ingelheim, and Novartis Pharma outside this work; and received grants from Boehringer Ingelheim and Chugai Pharmaceutical outside this work. N. Harada received lecturer fees from Sanofi, AstraZeneca, GlaxoSmithKline, Kyorin Pharmaceutical, and Novartis Pharma outside this work; and royalties from Sanofi, AstraZeneca, Daikin Investment, and TOSOH. T. Hirai received lecturer fees from AstraZeneca, Kyorin Pharmaceutical, and Boehringer Ingelheim outside this work. N. Hattori received lecturer fees from Sanofi, AstraZeneca, GlaxoSmithKline, Kyorin Pharmaceutical, Ono Pharmaceutical, MSD, and Pfizer Japan outside this work. T. Kimura received lecture fees from Sanofi, AstraZeneca, GlaxoSmithKline, Eli Lilly Japan, Chugai Phamaceutical, Novartis Pharma, Brsitol Myers Squibb, Meiji Seika Pharma, DAIICHI SANKYO, and MSD outside this work. H. Matsumoto received lecturer fees from Sanofi, AstraZeneca, GlaxoSmithKline, Kyorin Pharmaceutical, and Boehringer Ingelheim; received grants from Kyorin Pharmaceutical, Boehringer Ingelheim, and Teijin Pharma outside this work; and received support from the Japanese Respiratory Society and a research grant from Novartis Japan. O. Matsuno received lecturer fees from Sanofi, AstraZeneca, and GlaxoSmithKline. T. Sakagami received lecturer fees from AstraZeneca, GlaxoSmithKline, Novartis Pharma, and Boehringer Ingelheim outside this work. H. Sugiura received lecturer fees from Sanofi, AstraZeneca, GlaxoSmithKline, Novartis Pharma, and Boehringer Ingelheim outside this work. H. Sunadome reports grants from Philips Japan, ResMed, Fukuda Denshi, and Fukuda Lifetec Keiji outside this work. N. Tanabe received research grants from Daiichi Sankyo and FUJIFILM outside this work. K. Tomii received lecturer fees from Sanofi, AstraZeneca, GlaxoSmithKline, and Novartis Pharma outside this work. A. Yokoyama received lecturer fees from Sanofi, AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim outside this work. The rest of the authors declare that they have no relevant conflicts of interest., (© 2024 The Author(s).)

Background: There are approximately 872 certified nurse practitioners (NPs) in Japan as of April 2024. However, research on the results of their specific activities is still scarce., Purpose: This study aimed to compare health care outcomes before (i.e., 2019) and after (i.e., 2021) employing NPs in cardiovascular hospitals in Japan., Methodology: We conducted a retrospective chart review and analyzed 114 patients who underwent cardiac surgery in Hospital A and 381 patients who received pacemaker implantation/replacement in Hospital B. Hospital A hired one NP for cardiac surgery service, and Hospital B hired one NP for pacemaker device service. The NPs assisted in the surgical procedures and provided postsurgical management., Results: In Hospital A, the median length of hospitalization and intubation were shorter in 2021 than in 2019 ( p = .02 and .01, respectively). In Hospital B, medical fee reimbursement was lower in 2021 ( p < .001) than in 2019, and the median procedure duration was shorter ( p = .01), which remained statistically significant after controlling for age, comorbidities, and device types. Some outcomes improved following the employment of NPs, whereas others remained unchanged., Conclusions: Nurse practitioners managed surgical patients well and contributed to the quality care of cardiovascular medicine., Implications: The employment of NPs in Japan is encouraged because even a single NP can have a positive, although not large, impact on patients and organizations., Competing Interests: Competing interests: The authors report no conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Association of Nurse Practitioners.)

Steroid-resistant asthma is a common cause of refractory asthma. Type 2 inflammation is the main inflammatory response in asthma, and the mechanism underlying the steroid-resistance of type 2 inflammation has not been completely elucidated. Tumor-necrosis-factor-like apoptosis-inducing factor (TWEAK) and transforming growth factor (TGF)-β1 are involved in epithelial-mesenchymal transition (EMT) and the production of thymic stromal lymphopoietin (TSLP) and C-C motif chemokine ligand 5 (CCL5). We herein hypothesize that the combined exposure to TWEAK and TGF-β1 may result in the development of steroid resistance in bronchial epithelial cells. The bronchial epithelial cell line BEAS-2B was cultured with or without TGF-β1 or TWEAK, in the presence or absence of dexamethasone (DEX). The roles of Smad-independent pathways and MAP kinase phosphatase 1 (MKP-1) were also explored. Co-stimulation of TWEAK and TGF-β1 induced E-cadherin reduction, N-cadherin upregulation, and TSLP and CCL5 production, which were not suppressed by DEX. Inhibition of the nuclear factor kappa beta (NF-κB) and mitogen-activated protein kinase pathways downregulated steroid-unresponsive TSLP and CCL5 production, whereas knockdown of MKP-1 improved steroid-unresponsive TSLP production, induced by co-stimulation with TWEAK and TGF-β1. Therefore, co-stimulation with TWEAK and TGF-β1 can induce the steroid-insensitive production of TSLP and CCL5 in the bronchial epithelium and may contribute to airway inflammation.

Cyclic adenosine monophosphate-response element-binding protein-1-regulated transcription coactivator-1 (CRTC1), a cytoplasmic coactivator that translocates to the nucleus in response to cAMP, is associated with obesity. We previously reported that CRTC1 deficiency in melanocortin-4 receptor (MC4R)-expressing neurons, which regulate appetite and energy metabolism in the brain, causes hyperphagia and obesity under a high-fat diet (HFD). HFD is preferred for mice, and the dietary fat in HFD is the main factor contributing to its palatability. These findings, along with our previous results, suggest that CRTC1 regulates the appetite for dietary fat. Therefore, in this study, we aimed to investigate the dietary fat intake behavior and energy metabolism of MC4R neuron-specific CRTC1 knockout mice fed soybean oil or lard. CRTC1 deficiency increased the intake of soybean oil and significantly increased body weight gain. Furthermore, obesity induced by soybean oil intake was partially due to leptin resistance. No significant changes in soybean oil intake were observed between young CRTC1 -deficient and wild-type mice; however, soybean oil intake increased with age. Moreover, lard intake did not significantly affect the body weight. Overall, our findings highlighted the crucial role of CRTC1 in the regulation of spontaneous dietary fat intake. Furthermore, the role of CRTC1 becomes increasingly significant with age., Competing Interests: The authors declare no conflicts of interest. All co‐authors have read the manuscript and approved the content. The authors have no financial interests to declare., (©2024 The Author(s) FASEB BioAdvances published by The Federation of American Societies for Experimental Biology.)

Localization to the endoplasmic reticulum (ER) and subsequent disulfide bond formation are crucial processes governing the biogenesis of secretory pathway proteins in eukaryotes. Hence, comprehending the mechanisms underlying these processes is important. Here, we have engineered firefly luciferase (FLuc) as a tool to detect deficiencies in these processes within mammalian cells. To achieve this, we introduced multiple cysteine substitutions into FLuc and targeted it to the ER. The reporter exhibited FLuc activity in response to defects in protein localization or disulfide bond formation within the ER. Notably, this system exhibited outstanding sensitivity, reproducibility, and convenience in detecting abnormalities in these processes. We applied this system to observe a protein translocation defect induced by an inhibitor of HIV receptor biogenesis. Moreover, utilizing the system, we showed that modulating LMF1 levels dramatically impacted the ER's redox environment, confirming that LMF1 plays some critical role in the redox control of the ER., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

The analysis of skin surface lipid-RNAs (SSL-RNAs) provides a non-invasive method for understanding the molecular pathology of atopic dermatitis (AD), but its relevance to asthma remains uncertain. Although dupilumab, a biologic drug approved for both asthma and AD, has shown efficacy in improving symptoms for both conditions, its impact on SSL-RNAs is unclear. This study aimed to investigate the impact of dupilumab treatment on SSL-RNA profiles in patients with severe asthma. An SSL-RNA analysis was performed before and after administering dupilumab to asthma patients requiring this intervention. Skin samples were collected non-invasively from patients before and after one year of dupilumab treatment. Although 26 patients were enrolled, an SSL-RNA analysis was feasible in only 7 due to collection challenges. After dupilumab treatment, improvements were observed in asthma symptoms, exacerbation rates, and lung function parameters. Serum levels of total IgE and periostin decreased. The SSL-RNA analysis revealed the differential expression of 218 genes, indicating significant down-regulation of immune responses, particularly those associated with type 2 inflammation, suggesting potential improvement in epithelial barrier function. Dupilumab treatment may not only impact type 2 inflammation but also facilitate the normalization of the skin. Further studies are necessary to fully explore the potential of SSL-RNA analysis as a non-invasive biomarker for evaluating treatment response in asthma.

Introduction: Contrast-enhanced computed tomography (CE-CT) has been gaining attention as an initial investigation in the management of colonic diverticular bleeding (CDB), yet the role of CE-CT other than its diagnostic yield has not been adequately clarified. We aimed to determine whether the use of urgent CE-CT improves identification of stigmata of recent hemorrhage (SRH) in subsequently performed early colonoscopy (≤24 h of arrival) or other clinical outcomes of CDB., Methods: We conducted a randomized, open-label, controlled trial at 23 institutions in Japan. Outpatients with suspected CDB were randomly assigned to undergo either urgent CE-CT followed by early colonoscopy (urgent-CE-CT + early-colonoscopy group) or early colonoscopy alone (early-colonoscopy group). The primary outcome was SRH identification. Secondary outcomes included successful endoscopic hemostasis, early (<30 days) and late (<1 year) rebleeding, length of hospital stay, and transfusion requirements., Results: In total, 240 patients, mostly in a hemodynamically stable condition, were randomized. A contrast extravasation on CE-CT was observed in 20 of 115 patients (17.4%) in the urgent-CE-CT + early-colonoscopy group. SRH was identified in 23 of 115 patients (20.0%) in the urgent-CE-CT + early-colonoscopy group and 21 of 118 patients (17.8%) in the early-colonoscopy group (difference, 2.2; 95% confidence interval [CI], -7.9 to 12.3; p = 0.739). Successful endoscopic hemostasis was achieved in 21 patients in each group (18.3% and 17.8%, respectively) (difference, 0.5; 95% CI, -9.4 to 10.4; p = 1.000). There were also no significant differences between groups in early and late rebleeding, length of hospital stay, and transfusion requirements., Conclusion: The use of urgent CE-CT before early colonoscopy did not improve SRH identification or other clinical outcomes in patients with suspected CDB in a hemodynamically stable condition. The routine use of urgent CE-CT as an initial investigation is not recommended in this population, also considering the low rate of extravasation-positive cases (UMIN registry number, UMIN000026865)., (© 2024 S. Karger AG, Basel.)

Background: A key measure of the effectiveness of end-of-life care is the place of death. The coronavirus disease 2019 (COVID-19) pandemic affected end-of-life care and the circumstances of patients with dementia., Methods: This observational, retrospective cohort study used Japanese national data to examine the numbers and locations of reported deaths among patients with dementia older than 65 years during the COVID-19 pandemic. Locations were grouped as medical institutions, nursing facilities, homes, or all settings. The quasi-Poisson regression model known as the Farrington algorithm was employed., Results: Between December 30, 2019, and January 29, 2023, 279,703 patients who died of causes related to dementia were reported in Japan. A decline was seen in early 2020, followed by increased numbers of deaths in homes, medical facilities, and nursing homes beginning in October 2020, December 2020, and March 2021, respectively. In 2021, the percentage of excess deaths at home peaked at 35.2%, while in 2022, those in medical facilities and nursing homes peaked at 18.8% and 16.6%, respectively. In 2022, the percentage of excess deaths in nursing homes exceeded that of other locations., Conclusion: The results suggest a change in the preferred place of death, along with pandemic-related visitation restrictions among healthcare facilities. Excess deaths also suggest strained medical resources and limited access to care. Methodological limitations include data from a limited period (2017 onwards) and post-2020 data used to estimate data after 2021, albeit with weighting. Considering these findings, physicians should reconfirm preferred places of death among older patients with dementia.

Background: The aim of the present study was to conduct a prospective observational study to explore the effects of imeglimin on systemic energy metabolism/body composition and to identify potential mitochondria-related biomarkers of the efficacy of the drug in clinical settings., Methods: In this prospective observational study, 16 participants with type 2 diabetes mellitus in the diabetes clinic of Kyoto University Hospital were enrolled. Individuals were started on imeglimin as monotherapy or add-on therapy., Results: After 3 months under imeglimin treatment, there was no significant change in basal metabolism or body composition. However, serum levels of growth differentiation factor 15 (GDF15) were higher while those of serum fibroblast growth factor 21 and urine 8-hydroxy-2'-deoxyguanosine were not changed. Additional in vitro examination revealed that imeglimin induces GDF15 protein release from human hepatocytes., Conclusions: Three-month imeglimin treatment increased serum GDF15 levels in clinical type 2 diabetes mellitus patients along with little change in basal metabolism or body composition, suggesting GDF15 as a potential marker for the efficacy of imeglimin., Competing Interests: None to declare., (Copyright 2024, Wada et al.)

Vaccine-induced T cells and neutralizing antibodies are essential for protection against SARS-CoV-2. Previously, we demonstrated that an antigen delivery system, pullulan nanogel (PNG), delivers vaccine antigen to lymph node medullary macrophages and thereby enhances the induction of specific CD8 + T cells. In this study, we revealed that medullary macrophage-selective delivery by PNG depends on its binding to a C-type lectin SIGN-R1. In a K18-hACE2 mouse model of SARS-CoV-2 infection, vaccination with a PNG-encapsulated receptor-binding domain of spike protein decreased the viral load and prolonged the survival in the CD8 + T cell- and B cell-dependent manners. T cell receptor repertoire analysis revealed that although the vaccine induced T cells at various frequencies, low-frequency specific T cells mainly promoted virus clearance. Thus, the induction of specific CD8 + T cells that respond quickly to viral infection, even at low frequencies, is important for vaccine efficacy and can be achieved by SIGN-R1 + medullary macrophage-targeted antigen delivery., (© 2024. The Author(s).)

Background: Oscillometry devices (also termed forced oscillation technique) devices such as MasterScreen-IOS® (Jaeger, Hochberg, Germany) and MostGraph-01® (Chest, Tokyo, Japan) are useful for obtaining physiological assessments in patients with obstructive lung diseases, including asthma. However, as oscillometry measurements have not been fully compared between MasterScreen-IOS® and MostGraph-01® in patients with asthma, it is unknown whether there are differences in the measurements between the devices. This study aimed to determine whether there is any difference in oscillometry measurements obtained using the two devices in patients with asthma., Methods: Oscillometry measurements obtained using MasterScreen-IOS® and MostGraph-01® were retrospectively evaluated in 95 patients with asthma at Juntendo University Hospital between October 2009 and November 2009., Results: There was a strong positive correlation in the measurements between the two devices. However, the values of R5, R20, ALX and Fres were lower when measured with MostGraph-01® than with MasterScreen-IOS®, and vice versa for the values of X5. The results were used in correction equations to convert oscillometry parameters measured using MasterScreen-IOS® to those measured using MostGraph-01®., Conclusions: To our knowledge, this is the first report to compare MostGraph-01® and MasterScreen-IOS® devices using practical clinical data obtained in patients with asthma. The values obtained by both devices can be interpreted in a similar way, although there is slight variation. The conversion equations produced in this study may assist to compare the oscillometry measurements obtained by each of the two devices., Competing Interests: The authors have read the journal’s policy and have the following competing interests: NH reports personal fees from AstraZeneca, GlaxoSmithKline, Kyorin, Novartis, and Sanofi; and grants from AstraZeneca, Daikin, Sanofi, and TOSOH outside the submitted work. KT reports grants from Asahi Kasei Pharma Corporation, Bayer Yakuhin, Chugai, Daiichi Sankyo, Eli Lilly, Kyorin, Kyowa Kirin, Nippon Boehringer Ingelheim, Nippon Kayaku, Nippon Shinyaku, Nipro, Novartis, Ono, Pfizer, Sanofi, Shionogi, Taiho, Takeda, Teijin, and Tsumura; and personal fees from Abbott Japan, AstraZeneca, Bristol-Myers, Chugai, Eli Lilly, Janssen, Kyorin, Meiji Seika, Merck, MSD, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis, Ono, Pfizer, Sumitomo Dainippon Pharma, Taiho, Takeda, Thermo Fisher Scientific, and Viatris outside the submitted work. KT has a patent (P6840330) on the method of detecting cells managed by Juntendo University in Japan. HK is one of the holders of the patent related to MostGraph-01®. The royalties are paid to Tohoku University, not to individuals. Lecture fees were paid to HK from Chest Co. Ltd. All other authors have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no additional patents, products in development or marketed products associated with this research to declare., (Copyright: © 2024 Harada et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This algorithm was issued for the appropriate use of drugs for the treatment of type 2 diabetes mellitus in Japan. The revisions include safety considerations, fatty liver disease as a comorbidity to be taken into account and the position of tirzepatide., (© 2024 The Japan Diabetes Society. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Fatty acid synthase (FASN) catalyzes the rate-limiting step of cellular lipogenesis. FASN expression is upregulated in various types of cancer cells, implying that FASN is a potential target for cancer therapy. 2-Deoxy-D-glucose (2-DG) specifically targets cancer cells by inhibiting glycolysis and glucose metabolism, resulting in multiple anticancer effects. However, whether the effects of 2-DG involve lipogenic metabolism remains to be elucidated. We investigated the effect of 2-DG administration on FASN expression in HeLa human cervical cancer cells. 2-DG treatment for 24 h decreased FASN mRNA and protein levels and suppressed the activity of an exogenous rat Fasn promoter. The use of a chemical activator or inhibitors or of a mammalian expression plasmid showed that neither AMPK nor the Sp1 transcription factor is responsible for the inhibitory effect of 2-DG on FASN expression. Administration of thapsigargin, an endoplasmic reticulum (ER) stress inducer, or 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF), a site 1 protease inhibitor, mimicked the inhibitory effect of 2-DG on FASN expression. 2-DG did not further decrease FASN expression in the presence of thapsigargin or AEBSF. Site 1 protease mediates activation of ATF6, an ER stress mediator, as well as sterol regulatory element-binding protein 1 (SREBP1), a robust transcription factor for FASN. Administration of 2-DG or thapsigargin for 24 h suppressed activation of ATF6 and SREBP1, as did AEBSF. We speculated that these effects of 2-DG or thapsigargin are due to feedback inhibition via increased GRP78 expression following ER stress. Supporting this, exogenous overexpression of GRP78 in HeLa cells suppressed SREBP1 activation and Fasn promoter activity. These results suggest that 2-DG suppresses FASN expression via an ER stress-dependent pathway, providing new insight into the molecular basis of FASN regulation in cancer., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Purpose: In recent years, new systemic therapies have been developed for hepatocellular carcinoma (HCC). The aim of this study was to evaluate the prognosis of patients with unresectable HCC treated with R0 hepatectomy after systemic therapy., Methods: Data from 27 patients who underwent hepatectomy for HCC after systemic therapy at six facilities were analyzed retrospectively. Cancer-specific survival (CSS) and recurrence-free survival (RFS) after hepatectomy were investigated using Kaplan-Meier curves. We examined the prognostic value of the oncological criteria of resectability for HCC reported by the Japanese Expert Consensus 2023., Results: R0 resection was performed in 24 of the 27 patients. Using the Response Evaluation Criteria in Solid Tumors, 0 patient had a complete response, 16 had a partial response, 6 had stable disease, and 2 had progressive disease. Median CSS was not evaluated, but the median RFS was 17.8 months. Patients with resectable and borderline resectable (BR) 1 cancers had a better prognosis than those with BR2 cancers. The group whose oncological criteria were improved by systemic therapy had a lower recurrence rate than the group whose oncological criteria were maintained, but no difference was observed in CSS., Conclusions: The findings of this study suggest that hepatectomy after systemic therapy may improve the prognosis of HCC patients., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: Ehlers-Danlos syndrome (EDS) is a rare inherited connective tissue disease characterized by hyperextensibility of the skin and joints and tissue fragility of the skin and blood vessels, Vascular EDS is the most severe form of EDS, with abnormal arterial fragility. There have been no reports of breast cancer occurring in patients with vascular EDS. Here, we report here a very rare case of breast cancer in a patient with vascular EDS., Case Presentation: A 46-year-old woman with vascular EDS underwent partial left mastectomy and sentinel lymph node biopsy for left breast cancer (cStage 0) detected by medical examination. The final pathological diagnosis was invasive ductal carcinoma of the breast (pStage IA) [hormone receptor-positive, HER2 score 2 equivocal (FISH-positive), Ki-67LI 18%, luminal-HER2 type]. BluePrint was submitted as an aid in determining the postoperative treatment strategy, BluePrint Molecular Subtype HER2-type. However, the 10-year breast cancer mortality risk using Predict was low (5%). After consultation with the patient, the decision was made to administer postoperative radiation to the preserved breast along with hormone therapy only. There was no delay in postoperative wound healing, and the patient was free of metastatic recurrence for 9 months after surgery., Conclusion: We performed surgery, postoperative radiotherapy, and hormonal therapy in a breast cancer patient with vascular EDS without major complications., (© 2024. The Author(s).)