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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. There was a sex difference in the formation of submandibular mucin 10 (MUC10) in 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=0.09) 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.)

The plant-microbe interactions, which is crucial for plant health and productivity, mainly occur in rhizosphere: a narrow zone of soil surrounding roots of living plants. The rhizosphere hosts one of the most intense habitats for microbial prey-predator interactions, especially between predatory protists and bacteria. Here, based on two key facts, microbial predators modulate rhizobacterial community composition, and the rhizobacterial community is the primary source of root microbiome, endophytes; we hypothesized that predation upon rhizobacteria would modulate the community composition of endophytic bacteria. The effects of three taxonomically distinct axenic protist species (Acanthamoeba castellanii, Vermamoeba vermiformis, and Heteromita globosa) were tested in this study. To examine the robustness of the hypotheses, the experiments were conducted in three soil types characterized by distinct bacterial communities and physicochemical properties. The bacterial community compositions were analyzed with high throughput sequencing. Bacterial gene abundances were estimated with a real-time-PCR method. The results showed that protists modulated endophytic communities, which originated in the rhizosphere soil. The modulation of endophytic communities by protists showed chaotic patterns rather than a deterministic effect under different soil types. The observed chaotic dynamics were further confirmed with an additional experiment, in which chaos was triggered by changes in the dilution rates of soil nutrients. Furthermore, the presence of predators enhanced the root colonization of endophytes. Our findings identify a key mechanism for the modulation of root endophytes and enhance understanding of underground plant-microbe interactions, which can lead to open new avenues for modulating the root microbiome to enhance crop production., (© The Author(s) [2024]. Published by Oxford University Press on behalf of the International Society for Microbial Ecology.)

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., (Copyright © 2024. Published by Elsevier B.V.)

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.)

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.)

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.)

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.

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., (© 2024. The Author(s).)

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.)

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.)

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: 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.)

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).)

Glycogen storage disease type 1a (GSD-1a) is a rare congenital disease. Recently, life expectancy with GSD-1a has been improved by its early diagnosis and management. Complications of diabetes with GSD-1a are extremely rare. The optimal treatment for glucose control using this disease combination remains unclear. The existence of GSD-1a and diabetes can cause both hypoglycemia and hyperglycemia, making glucose control especially problematic. In the present report, α-glucosidase inhibitor (α-GI) and dipeptidyl peptidase-4 (DPP-4) inhibitors improved hyperglycemia without symptoms of hypoglycemia in a patient with diabetes and GSD-1a using intermittent continuous glucose monitoring (isCGM).

The twenty-three Fanconi anemia (FA) proteins cooperate in the FA/BRCA pathway to repair DNA interstrand cross-links (ICLs). The cell division cycle and apoptosis regulator 1 (CCAR1) protein is also a regulator of ICL repair, though its possible function in the FA/BRCA pathway remains unknown. Here, we demonstrate that CCAR1 plays a unique upstream role in the FA/BRCA pathway and is required for FANCA protein expression in human cells. Interestingly, CCAR1 co-immunoprecipitates with FANCA pre-mRNA and is required for FANCA mRNA processing. Loss of CCAR1 results in retention of a poison exon in the FANCA transcript, thereby leading to reduced FANCA protein expression. A unique domain of CCAR1, the EF hand domain, is required for interaction with the U2AF heterodimer of the spliceosome and for excision of the poison exon. Taken together, CCAR1 is a splicing modulator required for normal splicing of the FANCA mRNA and other mRNAs involved in various cellular pathways., Competing Interests: Declaration of interests A.D.D. reports consulting for AbbVie, Deerfield Management Company, Impact Therapeutics, Moderna Therapeutics, PrimeFour Therapeutics, Schrödinger Inc., Servier BioInnovation LLC, and Tango Therapeutics; is a Scientific Advisory Board Member and Stockholder for Impact Therapeutics and Covant Therapeutics. K.A. is a member of the Advisory Board of Molecular Cell, the SAB of CAMP4 Therapeutics, consults for Syros Pharmaceuticals and Odyssey Therapeutics, and received research funding from Novartis not related to this work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether diffusion tensor image (DTI) parameters and regional cerebral blood flow (rCBF) serve to preoperatively predict postoperative motor outcomes in patients with brain tumors., Methods: We included 81 patients with brain tumors who underwent surgical treatment. Motor function was assessed using the manual muscle test in the upper and lower limbs at admission and discharge. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and their ratios (rFA, rMD, rAD, and rRD) were measured at the corona radiata, internal capsule, and cerebral peduncle of the corticospinal tract (CST). In addition, DTI and single photon emission computed tomography (SPECT) were synthesized to measure rCBF at the CST., Result: Both DTI parameters and rCBF at the CST in the preoperative motor weakness group significantly differed from those of the preoperative normal function group. rFA at the cerebral peduncle and the internal capsule was considerably higher in those showing postoperative motor recovery than in those postoperative unchanged or with deteriorated motor function (P < 0.05). Moreover, there was significantly lower rMD and rRD at the internal capsule in the motor recovery group (P < 0.05, P < 0.01). Furthermore, rCBF was higher at all the cerebral peduncle, internal capsule, and corona radiate in the motor recovery group than in the unchanged and deteriorated motor function group (P < 0.05, P < 0.01, P < 0.01)., Conclusion: The analysis of DTI parameters and rCBF is useful in predicting postoperative motor outcomes in patients with brain tumors., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Ethics Committee of Toho University Omori Hospital issued approval No. M22111. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. 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 © 2024, Matsuura et al.)

Liver transplantation is the definitive treatment for advanced liver cirrhosis with portal hypertension. In Japan, the scarcity of deceased donors leads to reliance on living donors, often resulting in smaller grafts. Managing portal venous pressure (PVP) is critical to prevent fatal posttransplant complications. This study explored the possibility of predicting intraoperative PVP. We analyzed 475 living donor liver transplant cases from 2006 to 2023, excluding those with acute liver failure or prior splenectomy or splenic artery embolization. Patients were divided into a training group (n = 425) and a test group (n = 50). We evaluated the correlation between preoperative factors and PVP at laparotomy to predict PVP at laparotomy and closure. The predictive model was validated with the test group data. PVP at laparotomy could be predicted using correlated preoperative factors: prothrombin time ( p < 0.001), predicted splenic volume ( p < 0.001), and presence of a portosystemic shunt ( p = 0.002), as follows: predicted PVP at laparotomy (mm Hg)=25.818 - 0.077 × (prothrombin time [%]) + 0.004 × (predicted splenic volume [mL]) - 2.067 × (1: with a portosystemic shunt) ( p < 0.001; R = 0.346). In addition, PVP at closure could be predicted using correlated operative factors, including measured PVP at laparotomy, as follows: predicted PVP at closure (mm Hg)=14.268 + 0.149 × (measured PVP at laparotomy [mm Hg]) - 0.040 × (GV/SLV [%]) - 0.862 × (1: splenectomy [if yes]) - 3.511 × (1: splenic artery ligation without splenectomy [if yes]) ( p < 0.001; R = 0.339). This study demonstrated the feasibility of predicting intraoperative PVP using preoperative factors in patients with decompensated cirrhosis undergoing liver transplant. This predictive approach could refine surgical planning, potentially improving patient outcomes., (Copyright © 2024 American Association for the Study of Liver Diseases.)

The Japan Diabetes Society (JDS) adopted a sweeping decision to release consensus statements on relevant issues in diabetes management that require updating from time to time and launched a "JDS Committee on Consensus Statement Development." In March 2020, the committee's first consensus statement on "Medical Nutrition Therapy and Dietary Counseling for People with Diabetes" was published. In September 2022, a second consensus "algorithm for pharmacotherapy in people with type 2 diabetes" was proposed. In developing an algorithm for diabetes pharmacotherapy in people with type 2 diabetes, the working concept was that priority should be given to selecting such medications as would appropriately address the diabetes pathology in each patient while simultaneously weighing the available evidence for these medications and the prescribing patterns in clinical practice in Japan. These consensus statements are intended to present the committee's take on diabetes management in Japan, based on the evidence currently available for each of the issues addressed. It is thus hoped that practicing diabetologists will not fail to consult these statements to provide the best available practice in their respective clinical settings. Given that the persistent dual GIP/GLP-1 receptor agonist tirzepatide was approved in April 2023, these consensus statements have been revised 1) . In this revision, specifically, tirzepatide was added to the end of [likely involving insulin resistance] of "Obese patients" in Step 1: "Select medications to address the diabetes pathology involved" in Fig. 2. While the sentence, "Insulin insufficiency and resistance can be assessed by referring to the various indices listed in the JDS 'Guide to Diabetes Management.' was mentioned in the previous edition as well, "While insulin resistance is analogized based on BMI, abdominal obesity, and visceral fat accumulation, an assessment of indicators (e.g., HOMA-IR) is desirable" was added as information in order to more accurately recognize the pathology. Regarding Step 2: "Give due consideration to safety," "For renal excretion" was added to the "Rule of thumb 2: Avoid glinides in patients with renal impairment." The order of the medications in "rule of thumb 3: Avoid thiazolidinediones and biguanides in patients with heart failure (in whom they are contraindicated)." to thiazolidinediones then biguanides. In the description of the lowest part of Fig. 2, for each patient failing to achieve his/her HbA1c control goal, "while reverting to step 1" was changed to "while reverting to the opening" and "including reassessment if the patient is indicated for insulin therapy" was added. In the separate table, the column for tirzepatides was added, while the two items, "Characteristic side effects" and "Persistence of effect" were added to the area of interest. The revision also carried additional descriptions of the figure and table such as tirzepatides and "Characteristic side effects" in the statement, and while not mentioned in the proposed algorithm figure, nonalcoholic fatty liver disease (NAFLD) is covered from this revision for patients with comorbidities calling for medical attention. Moreover, detailed information was added to the relative/absolute indication for insulin therapy, the Kumamoto Declaration 2013 for glycemic targets, and glycemic targets for older people with diabetes. Again, in this revision, it is hoped that the algorithm presented here will not only contribute to improved diabetes management in Japan, but will continue to evolve into a better algorithm over time, reflecting new evidence as it becomes available., Competing Interests: Conflict of interestRyotaro Bouchi: Honoraria (Sumitomo Pharma; AstraZeneca; Novo Nordisk Pharma), and Research funding (Sumitomo Pharma) Yasuharu Ohta: Research funding (Manpei Suzuki Diabetes Foundation), and Subsidies or Donations (Sumitomo Pharma; Nippon Boehringer Ingelheim; Novo Nordisk Pharma). Daisuke Yabe: Honoraria (Novo Nordisk Pharma; Nippon Boehringer Ingelheim; Eli Lilly Japan; Sanofi; Kyowa Kirin; Sumitomo Pharma), and Research funding (Terumo Corporation; Nippon Boehringer Ingelheim), and Endowed departments by commercial entities (Novo Nordisk Pharma; Taisho Pharmaceutical; ARKRAY). Rimei Nishimura: Honoraria (Sanofi; Medtronic; Nippon Boehringer Ingelheim; KISSEI PHARMACEUTICAL; Eli Lilly Japan; Novo Nordisk Pharma; Astellas Pharma; Abbott Japan; Sumitomo Pharma; AstraZeneca; KOWA; ONO PHARMACEUTICAL; Taisho Pharmaceutical), and Research funding (Mitsubishi Electric), and Subsidies or Donations (Taisho Pharmaceutical; Nippon Boehringer Ingelheim; Abbott Japan; Sumitomo Pharma; Eli Lilly Japan; Arkley). Norio Harada: Research funding (Mitsubishi Tanabe Pharma; Eli Lilly Japan; Nippon Boehringer Ingelheim; ONO PHARMACEUTICAL). Hideki Kamiya: Honoraria (Novo Nordisk Pharma; Sanofi; Sumitomo Pharma; Eli Lilly Japan; Nippon Boehringer Ingelheim; DAIICHI SANKYO; AstraZeneca; ONO PHARMACEUTICAL; KISSEI PHARMACEUTICAL; Mitsubishi Tanabe Pharma; KOWA; Novartis Pharma; MSD; SANWA KAGAKU KENKYUSHO; Otsuka Pharmaceutical), and Research funding (ONO PHARMACEUTICAL; Eli Lilly Japan; KISSEI PHARMACEUTICAL), and Subsidies or Donations (ONO PHARMACEUTICAL; Taisho Pharmaceutical; Sumitomo Pharma; Takeda Pharmaceutical; Mitsubishi Tanabe Pharma; JAPAN TOBACCO; Novo Nordisk Pharma). Ryo Suzuki: Honoraria (Novo Nordisk Pharma; Sanofi; Sumitomo Pharma; Astellas Pharma; KOWA; MSD; Eli Lilly Japan; Mitsubishi Tanabe Pharma; TEIJIN PHARMA), and Research funding (Sumitomo Pharma), and Subsidies or Donations (Nippon Boehringer Ingelheim). Toshimasa Yamauchi: Honoraria (ONO PHARMACEUTICAL; Takeda Pharmaceutical; Sumitomo Pharma; TEIJIN PHARMA; Nippon Boehringer Ingelheim; Novo Nordisk Pharma), and Research funding (KOWA; Minophagen Pharmaceutical; NIPRO CORPORATION; Kyowa Kirin), and Subsidies or Donations (Novo Nordisk Pharma; Mitsubishi Tanabe Pharma; Kyowa Kirin; Takeda Pharmaceutical; ONO PHARMACEUTICAL; Sumitomo Pharma), and Endowed departments by commercial entities (ONO PHARMACEUTICAL; Mitsubishi Tanabe Pharma; Novo Nordisk Pharma; Nippon Boehringer Ingelheim; KOWA; NITTO BOSEKI; Asahi Mutual Life Insurance Company). Dr Daisuke Yabe, Dr Norio Harada, Dr Hideki Kamiya, Dr Toshimasa Yamauchi are Editorial Board members of Journal of Diabetes Investigation and a co-author of this article. To minimize bias, they were excluded from all editorial decision-making related to the acceptance of this article for publication., (© The Japan Diabetes Society 2024.)

Living-donor liver transplantation (LDLT) is an established treatment for patients with end-stage liver disease or acute liver failure, and outflow reconstruction is considered one of the most vital techniques in LDLT. To date, many strategies have been reported to prevent outflow obstruction, which can be refractory to liver dysfunction and can cause life-threatening graft loss or mortality. In addition, in this era of laparoscopic hepatectomy in donor surgery, especially LDLT using a left liver graft, it has been predicted that cutting the hepatic vein with automatic linear staplers will lead to more outflow-related problems than with conventional open hepatectomy because of the short neck of the anastomosis orifice. We herein review 10 cases of venoplasty performed with a novel venous cuff system using a donor's round ligament around the hepatic vein in LDLT with a left lobe graft, which makes anastomosis of the hepatic vein sterically easy for postoperative venous patency., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Purpose: To evaluate the short term-outcomes of venous reconstruction using a round ligament-covered prosthetic vascular graft and assess its effectiveness in the prevention of prosthetic vascular graft migration in right‑lobe living donor liver transplantation (LDLT)., Methods and Results: Thirty patients underwent reconstruction of the middle hepatic vein (MHV) tributaries during right lobe LDLT between January, 2021 and October, 2022. These patients were divided into the autologous vascular graft group (A group, n = 24) and the round ligament-covered prosthetic vascular graft group (RP group, n = 6). The computed tomography (CT) density ratio of the drainage area in the posterior segment of patent grafts was significantly higher in the RP group than in the A group (0.91 vs. 1.06, p = 0.0025). However, the patency rates of reconstructed MHV tributaries in the A and RP groups were 61% and 67%, respectively, with no significant difference between the groups (p = 0.72). Prosthetic vascular graft migration did not occur in the RP group., Conclusion: Venous reconstruction using round ligament-covered prosthetic vascular grafts is a feasible and simple method to prevent prosthetic vascular graft migration in right-lobe LDLT., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: The consensus that portal venous pressure modulation, including splenectomy (Spx), prevents portal hypertension-related complications after living-donor liver transplantation (LDLT) has been established. However, little evidence about the risk factors for graft loss after simultaneous Spx during LDLT is available. This study aimed to identify the independent predictors of graft loss after simultaneous Spx during LDLT., Methods: Data of 655 recipients who underwent LDLT between 1997 and 2021 were collected and separated into the simultaneous Spx group (n = 461) and no-Spx group (n = 194)., Results: The simultaneous Spx group had significantly lower serum total bilirubin levels, drained ascites volumes, and prothrombin time-international normalized ratios on postoperative day 14 than the no-Spx group ( P  < 0.001 for each). Incidences of small-for-size graft syndrome ( P  < 0.001), acute cellular rejection ( P  = 0.002), and sepsis ( P  = 0.007) were significantly lower in the Spx group. Graft survival of the Spx group was significantly better than that of the no-Spx group ( P  < 0.001; hazard ratio [HR], 1.788; 95% confidence interval, 1.214-2.431). A multivariate analysis revealed that 3 variables, platelet count ≤4.0 × 10 4 /mm 3 ( P  = 0.029; HR, 2.873), donor age ≥60 y old ( P  = 0.013; HR, 6.693), and portal venous pressure at closure ≥20 mm Hg ( P  = 0.010; HR, 3.891), were independent predictors of graft loss within 6 mo after simultaneous Spx during LDLT., Conclusions: Spx is a safe inflow modulation procedure with a positive impact on both postoperative complications and prognosis for most patients. However, patients with the 3 aforementioned independent factors could experience graft loss after LDLT., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The low vertebral bone computed tomography (CT) Hounsfield unit values measured on CT scans reflect low bone mineral density (BMD) and are known as diagnostic indicators for osteoporosis. The potential prognostic significance of low BMD defined by vertebral bone CT values for the coronavirus disease 2019 (COVID-19) remains unclear. This study aimed to assess the impact of BMD on the clinical outcome in Japanese patients with COVID-19 and evaluate the association between BMD and critical outcomes, such as high-flow nasal cannula, non-invasive and invasive positive pressure ventilation, extracorporeal membrane oxygenation, or death. We examined the effects of COVID-19 severity on the change of BMD over time. This multicenter retrospective cohort study enrolled 1132 inpatients with COVID-19 from the Japan COVID-19 Task Force database between February 2020 and September 2022. The bone CT values of the 4th, 7th, and 10th thoracic vertebrae were measured from chest CT images. The average of these values was defined as BMD. Furthermore, a comparative analysis was conducted between the BMD on admission and its value 3 months later. The low BMD group had a higher proportion of critical outcomes than did the high BMD group. In a subanalysis stratifying patients by epidemic wave according to onset time, critical outcomes were higher in the low BMD group in the 1st-4th waves. Multivariable logistic analysis of previously reported factors associated with COVID-19 severity revealed that low BMD, chronic kidney disease, and diabetes were independently associated with critical outcomes. At 3 months post-infection, patients with oxygen demand during hospitalization showed markedly decreased BMD than did those on admission. Low BMD in patients with COVID-19 may help predict severe disease after the disease onset. BMD may decrease over time in patients with severe COVID-19, and the impact on sequelae symptoms should be investigated in the future., 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 Inc. All rights reserved.)

Introduction: Incretin-based drugs are extensively utilized in the treatment of type 2 diabetes (T2D), with remarkable clinical efficacy. These drugs were developed based on findings that the incretin effect is reduced in T2D. The incretin effect in East Asians, whose pancreatic β-cell function is more vulnerable than that in Caucasians, however, has not been fully examined. In this study, we investigated the effects of incretin in Japanese subjects., Methods: A total of 28 Japanese subjects (14 with normal glucose tolerance [NGT], 6 with impaired glucose tolerance, and 8 with T2D) were enrolled. Isoglycemic oral (75 g glucose tolerance test) and intravenous glucose were administered. The numerical incretin effect and gastrointestinally-mediated glucose disposal (GIGD) were calculated by measuring the plasma glucose and entero-pancreatic hormone concentrations., Results and Discussion: The difference in the numerical incretin effect among the groups was relatively small. The numerical incretin effect significantly negatively correlated with the body mass index (BMI). GIGD was significantly lower in participants with T2D than in those with NGT, and significantly negatively correlated with the area under the curve (AUC)-glucose, BMI, and AUC-glucagon. Incretin concentrations did not differ significantly among the groups. We demonstrate that in Japanese subjects, obesity has a greater effect than glucose tolerance on the numerical incretin effect, whereas GIGD is diminished in individuals with both glucose intolerance and obesity. These findings indicate variances as well as commonalities between East Asians and Caucasians in the manifestation of incretin effects on pancreatic β-cell function and the integrated capacity to handle glucose., Competing Interests: NI received clinical commissioned/joint research grants from Terumo, Asken, and Drawbridge Health Inc.; speaker honoraria from MSD, Astellas Pharma, Novo Nordisk Pharma, Ono Pharmaceutical, Nippon Boehringer Ingelheim, Takeda, Eli Lilly Japan, Sumitomo Dainippon Pharma, and Mitsubishi Tanabe Pharma, Kyowa Kirin, Sanofi; and scholarship grants from Kissei Pharmaceutical, Sanofi, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Takeda, Japan Tobacco, Kyowa Kirin, Sumitomo Dainippon Pharma, Astellas Pharma, MSD, Eli Lilly Japan, Ono Pharmaceutical, Sanwa Kagaku Kenkyusho, Nippon Boehringer Ingelheim, Novo Nordisk Pharma, Novartis Pharma, Kowa and Life Scan Japan. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hamasaki, Harada, Muraoka, Yamane, Joo, Suzuki and Inagaki.)

Pancreatic β-cell mass is a critical determinant of insulin secretion. Severe endoplasmic reticulum (ER) stress causes β-cell apoptosis; however, the mechanisms of progression and suppression are not yet fully understood. Here, we report that the autocrine/paracrine function of insulin reduces ER stress-induced β-cell apoptosis. Insulin reduced the ER-stress inducer tunicamycin- and thapsigargin-induced cell viability loss due to apoptosis in INS-1 β-cells. Moreover, the effect of insulin was greater than that of insulin-like growth factor-1 at physiologically relevant concentrations. Insulin did not attenuate the ER stress-induced increase in unfolded protein response genes. ER stress did not induce cytochrome c release from mitochondria. Mitochondrial hyperpolarization was induced by ER stress and prevented by insulin. The protonophore/mitochondrial oxidative phosphorylation uncoupler, but not the antioxidants N-acetylcysteine and α-tocopherol, exhibited potential cytoprotection during ER stress. Both procaspase-12 and cleaved caspase-12 levels increased under ER stress. The caspase-12 inhibitor Z-ATAD-FMK decreased ER stress-induced apoptosis. Caspase-12 overexpression reduced cell viability, which was diminished in the presence of insulin. Insulin decreased caspase-12 levels at the post-translational stages. These results demonstrate that insulin protects against ER stress-induced β-cell apoptosis in this cell line. Furthermore, mitochondrial hyperpolarization and increased caspase-12 levels are involved in ER stress-induced and insulin-suppressed β-cell apoptosis., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Aim: To investigate the distribution of nurse practitioners (NPs) across Japan and their perceived facilitators and barriers to NP implementation in Japan., Background: NP certification examinations have been conducted in Japan since 2011, and by 2020, there were 487 NPs in the country. The momentum of NP implementation is slower in Japan compared with other countries., Methods: A cross-sectional descriptive study, following the STROBE guidelines, was conducted. Web-based survey questionnaires, developed by the authors, were administered to 248 NPs whose email addresses were maintained by the certification management body., Results: Valid responses were obtained from 101 NPs (response rate: 40.7%), of which 34% were male. The respondents had more than 12 years of registered nurse experience on an average before enrolling in the graduate NP program. 53% were employed as NPs from the beginning, while 25% were initially employed as registered nurses and later advanced to NPs, and 11% still worked as RNs. A majority worked in hospitals with beds. Many NPs perceived the lack of NP national licensure and reimbursement benefits as barriers to NP implementation, whereas recognition from superiors and organizations was considered facilitators., Conclusions: Despite their small numbers in Japan, NPs take on crucial tasks and contribute to the appropriate distribution of medical resources. The NP licensure system and recognition from superiors and organizations may be necessary to promote NP roles in Japan., Implications for Nursing and Health Policy: Some certified NPs still work as registered nurses. Recognition from nursing and organization administrators is critical to implementing NPs. To this end, a reimbursement system benefiting the organizations and a legislation facilitating NP employment are required., (© 2022 The Authors. International Nursing Review published by John Wiley & Sons Ltd on behalf of International Council of Nurses.)

Wang et al. report that clinical dipeptidyl peptidase-4 (DPP-4) inhibitors show little effect on microbial DPP-4 produced by Bacteroides genus. Furthermore, oral administration of microbial DPP-4 to high-fat diet-fed mice was found to reduce plasma active glucagon-like peptide-1 levels through an increase in extraluminal intestinal tissular DPP-4 activity, resulting in reduced glucose-induced insulin levels and exacerbated glucose tolerance., (© 2024 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Myelodysplastic syndrome (MDS) is well known to be complicated by systemic inflammatory autoimmune disease (SIADs). However, it remains unclear how the prognosis after allogenic hematopoietic stem cell transplantation (allo-HSCT) in patients with MDS is impacted by SIADs that occur before allo-HSCT. Therefore, we hypothesized that SIADs before allo-HSCT may be a risk factor for negative outcomes after allo-HSCT in patients with MDS. We conducted a single-center, retrospective, observational study of sixty-nine patients with MDS or chronic myelomonocytic leukemia who underwent their first allo-HCT. Fourteen of the patients had SIADs before allo-HSCT. In multivariate analysis, the presence of SIADs before allo-HSCT was an independent risk factor for overall survival (HR, 3.36, 95% confidence interval: 1.34-8.42, p = 0.009). Endothelial dysfunction syndrome was identified in five of 14 patients with SIADs who required immunosuppressive therapy or intensive chemotherapy, and notably, all patients with uncontrollable SIADs at allo-HSCT developed serious endothelial dysfunction syndrome and died in the early phase after allo-HSCT. The development of SIADs in the context of MDS is thought to reflect the degree of dysfunction of hematopoietic cells in MDS and suggests a higher risk of disease progression. In addition, MDS patients with SIADs before allo-HSCT are considered to be at higher risk of endothelial dysfunction syndrome because of preexisting vascular endothelial dysfunction due to SIADs. In conclusion, SIADs before allo-HSCT constitute an independent risk factor for death in MDS patients undergoing allo-HSCT., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Stereocilia are unidirectional F-actin-based cylindrical protrusions on the apical surface of inner ear hair cells and function as biological mechanosensors of sound and acceleration. Development of functional stereocilia requires motor activities of unconventional myosins to transport proteins necessary for elongating the F-actin cores and to assemble the mechanoelectrical transduction (MET) channel complex. However, how each myosin localizes in stereocilia using the energy from ATP hydrolysis is only partially understood. In this study, we develop a methodology for live-cell single-molecule fluorescence microscopy of organelles protruding from the apical surface using a dual-view light-sheet microscope, diSPIM. We demonstrate that MYO7A, a component of the MET machinery, traffics as a dimer in stereocilia. Movements of MYO7A are restricted when scaffolded by the plasma membrane and F-actin as mediated by MYO7A's interacting partners. Here, we discuss the technical details of our methodology and its future applications including analyses of cargo transportation in various organelles., Competing Interests: Declaration of interests The authors declare no conflict of interest associated with this manuscript.

BACKGROUND Fulminant type 1 diabetes is characterized by a low prevalence of autoantibodies, and was originally described as a nonautoimmune subtype of type 1 diabetes. Herein, we report a case in which we observed the process of extremely rapid onset of diabetes and early decline in anti-glutamic acid decarboxylase (GAD) antibody titers during the inpatient stay. CASE REPORT A 61-year-old man was brought to our hospital with marked hyperglycemia (1327 mg/dL), ketonemia (3-hydroxybutyrate: 14 012 µmol/L), and moderately elevated HbA1c (7.2%) and glycoalbumin (22.3%). C-peptide levels were undetectable. He had suffered from thirst, polyuria, and fatigue for 2 days. Abrupt onset was proven by the clinical data when he visited the hospital with respiratory symptoms 6 days before his admission; plasma glucose, glycoalbumin, C-peptide, and insulin levels were 117 mg/dL, 13.0%, 5.07 ng/mL, and 24.4 µIU/mL, respectively. The anti-GAD antibody titer measured by enzyme-linked immunosorbent assay was 111 U/mL at admission, 22.8 U/mL 2 weeks after admission, and negative 1 year later. He had a susceptible haplotype DRB1*09: 01-DQB1*03: 03, which is significantly more common in anti-GAD antibody-positive patients with fulminant type 1 diabetes. CONCLUSIONS The early decline of anti-GAD antibody titer likely reflected rapid and complete beta cell loss. The sequential metabolic and immunological observation in this case may provide insight into the pathogenesis of fulminant type 1 diabetes.

Purpose: To elucidate how precisely microvascular invasion (MVI) in hepatocellular carcinoma (HCC) can be predicted using multiparametric assessment of gadoxetic acid-enhanced MRI., Methods: In this retrospective single-center study, patients who underwent liver resection or transplantation of HCC were evaluated. Data obtained in patients who underwent liver resection were used as the training set. Nine kinds of MR findings for predicting MVI were compared between HCCs with and without MVI by univariate analysis, followed by multiple logistic regression analysis. Using significant findings, a predictive formula for diagnosing MVI was obtained. The diagnostic performance of the formula was investigated in patients who underwent liver resection (validation set 1) and in patients who underwent liver transplantation (validation set 2) using a receiver operating characteristic curve analysis. The area under the curves (AUCs) of these three groups were compared., Results: A total of 345 patients with 356 HCCs were selected for analysis. Tumor diameter (D) (P = 0.021), tumor washout (TW) (P < 0.01), and peritumoral hypointensity in the hepatobiliary phase (PHH) (P < 0.01) were significantly associated with MVI after multivariate analysis. The AUCs for predicting MVI of the predictive formula were as follows: training set, 0.88 (95% confidence interval (CI) 0.82,0.93); validation set 1, 0.81 (95% CI 0.73,0.87); validation set 2, 0.67 (95% CI 0.51,0.80). The AUCs were not significantly different among three groups (training set vs validation set 1; P = 0.15, training set vs validation set 2; P = 0.09, validation set 1 vs validation set 2; P = 0.29, respectively)., Conclusion: Our multiparametric assessment of gadoxetic acid-enhanced MRI performed quite precisely and with good reproducibility for predicting MVI., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: This study aimed to investigate the utility of CT quantification of lung volume for predicting critical outcomes in COVID-19 patients., Methods: This retrospective cohort study included 1200 hospitalised patients with COVID-19 from 4 hospitals. Lung fields were extracted using artificial intelligence-based segmentation, and the percentage of the predicted (%pred) total lung volume (TLC (%pred)) was calculated. The incidence of critical outcomes and posthospitalisation complications was compared between patients with low and high CT lung volumes classified based on the median percentage of predicted TLC ct (n=600 for each). Prognostic factors for residual lung volume loss were investigated in 208 patients with COVID-19 via a follow-up CT after 3 months., Results: The incidence of critical outcomes was higher in the low TLC ct (%pred) group than in the high TLC ct (%pred) group (14.2% vs 3.3%, p<0.0001). Multivariable analysis of previously reported factors (age, sex, body mass index and comorbidities) demonstrated that CT-derived lung volume was significantly associated with critical outcomes. The low TLC ct (%pred) group exhibited a higher incidence of bacterial infection, heart failure, thromboembolism, liver dysfunction and renal dysfunction than the high TLC ct (%pred) group. TLC ct (%pred) at 3 months was similarly divided into two groups at the median (71.8%). Among patients with follow-up CT scans, lung volumes showed a recovery trend from the time of admission to 3 months but remained lower in critical cases at 3 months., Conclusion: Lower CT lung volume was associated with critical outcomes, posthospitalisation complications and slower improvement of clinical conditions in COVID-19 patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Bronchial thermoplasty (BT) improves clinical outcomes and quality of life for patients with severe asthma and has shown sustained reductions in airway narrowing and air trapping in previous CT studies. However, there is a lack of a comprehensive analysis, including CT evaluation, of clinical outcomes in Japanese patients who have undergone BT for severe asthma. This study aimed to evaluate the impact of BT in Japanese asthma patients, with a focus on the CT metric "WA at Pi10" to assess airway disease., Methods: Twelve patients with severe persistent asthma who underwent BT were assessed using ACQ6, AQLQ, pulmonary function tests, FeNO measurement, blood sampling, and chest CT before BT and one year after the third procedure for the upper lobes., Results: The median age of the patient was 62.0 years, 7/12 (58.3%) were male, 4/12 (33.3%) used regular oral corticosteroids, and 8/12 (66.7%) received biologics. Median FEV 1 % was 73.6%, and median peripheral eosinophil count was 163.8/μL. After one year of BT, ACQ6 scores improved from 2.4 to 0.8 points ( p = 0.007), and AQLQ scores improved from 4.3 to 5.8 points ( p < 0.001). Significant improvements were also observed in asthma exacerbations, unscheduled visits due to exacerbations, FeNO, and √WA at Pi10 ( p < 0.05). The baseline mucus score on the CT findings was negatively correlated with FEV 1 (r = -0.688, p = 0.013) and with the maximum mid-expiratory flow rate (r = -0.631, p = 0.028), and positively correlated with the peripheral blood eosinophil count (r = -0.719, p = 0.008). Changes in √WA at Pi10 after one year were positively correlated with changes in the mucus score (r = 0.742, p = 0.007)., Conclusion: This study has limitations, including its single-arm observational design and the small sample size. However, BT led to a symptomatic improvement in patients with severe asthma. The validated "√WA at Pi10" metric on CT effectively evaluated the therapeutic response in Japanese asthma patients after BT., Competing Interests: NH reports personal fees from AstraZeneca, GlaxoSmithKline, Kyorin, Novartis, and Sanofi; and grants from AstraZeneca, Daikin, and TOSOH, outside of the submitted work. KTa reports grants and personal fees from Chugai Pharmaceutical Co., Ltd.; and grants from Nippon Boehringer Ingelheim Co., Ltd., Bristol-Myers K.K., Eli Lilly Japan K.K., KYORIN Pharmaceutical Co., Ltd., MSD K.K., ONO PHARMACEUTICAL CO., LTD., Sanofi K.K., TEIJIN PHARMA LIMITED, and TAIHO PHARMACEUTICAL CO., LTD.; and personal fees from AstraZeneca, outside of the submitted work. All other authors declare that they have no conflicts of interest., (© 2024 Abe et al.)

Background: Invasive lobular carcinoma (ILC) is distinct from invasive ductal carcinoma (IDC) in terms of their hormonal microenvironments that may require different therapeutic strategies. We previously reported that selective estrogen receptor modulator (SERM) function requires F-box protein 22 (Fbxo22). Here, we investigated the role of Fbxo22 as a potential biomarker contributing to the resistance to endocrine therapy in ILC., Methods: A total of 302 breast cancer (BC) patients including 150 ILC were recruited in the study. Fbxo22 expression and clinical information were analyzed to elucidate whether Fbxo22 negativity could be a prognostic factor or there were any correlations among clinical variables and SERM efficacy., Results: Fbxo22 negativity was significantly higher in ILC compared with IDC (58.0% vs. 27.0%, P < 0.001) and higher in postmenopausal patients than premenopausal patients (64.1% vs. 48.2%, P = 0.041). In the ILC cohort, Fbxo22-negative patients had poorer overall survival (OS) than Fbxo22-positive patients, with 10-year OS rates of 77.4% vs. 93.6% (P = 0.055). All patients treated with SERMs, Fbxo22 negativity resulted in a poorer outcome, with 10-year OS rates of 81.3% vs. 92.3% (P = 0.032). In multivariate analysis regarding recurrence-free survival (RFS) in ILC patients, Fbxo22 status was independently predictive of survival as well as lymph node metastasis., Conclusion: Fbxo22 negativity significantly impacts on survival in BC patients with IDC and ILC, and the disadvantage was enhanced among ILC postmenopausal women or patients treated with SERMs. The findings suggest that different therapeutic strategies might be needed according to the different histopathological types when considering adjuvant endocrine therapy., (© 2024. The Author(s).)

This study offers an in-depth analysis of Japan's suicide trends three years after the COVID-19 outbreak. Using data from the National Police Agency (January 2010-May 2023), we examined suicide rates across genders and age groups. Employing the quasi-Poisson regression, we predicted monthly death counts. Findings indicate a steady rise in female suicides from April 2020 to January 2023. Notably, male cohorts aged 50-59 and over 80 in 2022 displayed heightened death rates. While these trends may reflect the impacts of the pandemic, it is essential to consider other factors, including socio-economic changes, to fully understand the context of Japan's suicide patterns., 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 Author(s). Published by Elsevier B.V. All rights reserved.)