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Over a decade has passed since the development of the Hi-C method for genome-wide analysis of 3D genome organization. Hi-C utilizes next-generation sequencing (NGS) technology to generate large-scale chromatin interaction data, which has accumulated across a diverse range of species and cell types, particularly in eukaryotes. There is thus a growing need to streamline the process of Hi-C data analysis to utilize these data sets effectively. Hi-C generates data that are much larger compared to other NGS techniques such as chromatin immunoprecipitation sequencing (ChIP-seq) or RNA-seq, making the data reanalysis process computationally expensive. In an effort to bridge this resource gap, the 4D Nucleome (4DN) Data Portal has reanalyzed approximately 600 Hi-C data sets, allowing users to access and utilize the analyzed data. In this chapter, we provide detailed instructions for the implementation of the common workflow language (CWL)-based Hi-C analysis pipeline adopted by the 4DN Data Portal ecosystem. This reproducible and portable pipeline generates standard Hi-C contact matrices in formats such as .hic or .mcool from FASTQ files. It enables users to output their own Hi-C data in the same format as those registered in the 4DN Data portal, facilitating comparative analysis using data registered in the portal. Our custom-made scripts are available on GitHub at https://github.com/kuzobuta/4dn_cwl_pipeline ., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Ferroptosis is a type of programmed cell death owed to an intracellular accumulation of iron resulting in the generation reactive oxygen species, which in turn can cause peroxidation of plasma membrane lipids and ultimately result in cell death. We investigated the potential involvement of VPS13A deficiency in ferroptosis. The VPS13A gene encodes for chorein, and its deficiency is a molecular cause of chorea-acanthocytosis (ChAc), a Huntington-like disease with neurodegeneration in the striatum. In our previous study, we found male infertility characterized by increased malondialdehyde staining of the spermatozoa in the testes of the ChAc model mice. Thus, in this study we performed metabolome analysis of sperm extracted from the epididymis of the ChAc model mice, which revealed decreased cystine levels, suggesting an association between chorein deficiency and ferroptosis. We then investigated the role of chorein in ferroptosis using VPS13A knockdown (VPS13A-KD) HEK293 cells. We found that VPS13A-KD cells displayed a significantly diminished resistance to tert-Butyl hydroperoxide (tBHP)-induced lipid peroxidation and cell death compared to control cells, which could be rescued by treatment with ferrostatin-1. Moreover, VPS13A-KD cells showed Fe(II) accumulation, suggesting an impaired capacity for divalent iron removal. In the cytosolic fraction of VPS13A-KD cells, the protein level of glutathione peroxidase 4 (GPX4) was significantly reduced, suggesting that dysfunction of chorein impairs GPX4 transport, thereby facilitating ferroptosis. These results suggest that ferroptosis may contribute to neurodegeneration in ChAc caused by loss of chorein function., (© 2024 The Author(s). FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Serotonin-transporter-linked polymorphic region (5-HTTLPR), a variable number of tandem repeats in the promoter region of serotonin transporter gene, is classified into short (S) and long (L) alleles. Initial case-control association studies claiming the risks of the S allele in depression and anxiety were not completely supported by recent studies. However, most studies, especially those on East Asian populations, have overlooked the complexity of 5-HTTLPR, which involves multiple different alleles with distinct functional properties. To address this issue, distinguishing multiple 5-HTTLPR alleles is essential. Here, using the 5-HTTLPR genotypes previously determined by exhaustive Sanger sequencing of approximately 1,500 Japanese subjects and their comprehensive SNP data, we constructed a method for 5-HTTLPR genotype imputation. We identified 28 tag SNPs for the imputation of four major 5-HTTLPR alleles, which collectively account for 97.6% of 5-HTTLPR alleles in the Japanese population. Our imputation method, achieved an accuracy of 0.872 in cross-validation, will contribute to association analysis of 5-HTTLPR in the Japanese subjects., Competing Interests: Competing interests: Some of the authors declared financial and non-financial relationships and activities, and conflicts of interest regarding this manuscript as indicated in the supplementary materials. The sponsor had no role in study design, data collection, data analysis, data interpretation or writing of the report., (© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Bone morphogenetic protein 3b (BMP3b), also known as growth differentiation factor 10 (GDF10), is a non-osteogenic BMP highly expressed in the skeleton. Although in vitro studies have shown that BMP3b suppresses osteoblast differentiation, the physiological role of BMP3b in regulating bone mass in vivo remains unknown. Here, we show that BMP3b deletion in mice leads to a high bone mass phenotype via an unexpected novel mechanism involving de-repression of canonical BMP/Smad signaling. BMP3b null mice were viable, and exhibited no significant difference in body size compared to wildtype control. Trabecular bone parameters assessed by histomorphometry and μCT, revealed a significant increase in bone volume and bone mineral density. Expression of osteoblast-differentiation genes were elevated in bone tissue of BMP3b null mice, whereas expression of osteoclast-related genes remained unchanged. Consistent with this, Bmp3b was highly expressed in osteoblasts relative to osteoclast cells. Ex-vivo culture of primary bone marrow mesenchymal stem cells (BMSCs) and primary bone marrow-derived osteoclasts revealed that inactivation of BMP3b enhances osteogenesis without affecting osteoclastogenesis. Mechanistically, we found that BMP3b suppressed BMP4-induced Smad1/5 phosphorylation and inhibited the activity of a BMP4-driven Id-1 luciferase reporter. Protein-protein interaction assays revealed that BMP3b competitively interfered with the association of BMP4 and BMP type I receptors. These findings suggest that BMP3b regulates bone mass by acting as a BMP receptor antagonist. Thus, maintenance of bone mass involves antagonism of canonical BMP/Smad signaling by a member of the BMP family., Competing Interests: Declaration of competing interest The authors declare that this article and related all data are original, is not under consideration by any other journals. The authors also declare that we will not submit this manuscript to any other journals during the review period of Bone. The authors also confirm that data from previously published papers have not been used in this manuscript and agree to provide information about any relevant publications., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cytochrome c oxidase (CcO) is the terminal enzyme in the electron transfer chain in mitochondria. It catalyzes the four-electron reduction of O 2 to H 2 O and harnesses the redox energy to drive unidirectional proton translocation against a proton electrochemical gradient. A great deal of research has been conducted to comprehend the molecular properties of CcO. However, the mechanism by which the oxygen reduction reaction is coupled to proton translocation remains poorly understood. Here, we review the chemical properties of a variety of key oxygen intermediates of bovine CcO (bCcO) revealed by time-resolved resonance Raman spectroscopy and the structural features of the enzyme uncovered by serial femtosecond crystallography, an innovative technique that allows structural determination at room temperature without radiation damage. The implications of these data on the proton translocation mechanism are discussed., 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.)

The Response Time Concealed Information Test can reveal that a person recognizes a relevant item (probe, e.g., a murder weapon) among other, irrelevant items (controls), based on slower responses to the probe compared to the controls. A previous study (Lukács, 2022, JARMAC) analyzed the data of 14 experiments and demonstrated that classification accuracy is increased by increased test length (i.e., increased number of trials included in the analysis). However, that study left the important question open whether prior practice (whose trials are not included in the analysis) influences the classification accuracy of subsequent testing (i.e., subsequent trials included in the analysis). Reanalyzing the same data from the 14 experiments (comprising 2223 individual tests), we show that different sections of the test (each with the same number of trials), such as the first and second half of each examined test, do not differ substantially in their classification accuracy. The main implications for real-life application are that, at least up to about 600 trials, prior practice does not affect subsequent tests' results, and the number of examined relevant items or their order of presentation may be freely chosen without compromising the method's validity., (© 2024 American Academy of Forensic Sciences.)

Child malnutrition is a major health problem in Sub-Saharan Africa. Complementary foods made from African indigenous and locally available raw materials are often low in protein and nutrients. It is, therefore, important to supply complementary foods that are nutritious and affordable, and with an acceptable consistency and taste. The objective of this study was to develop, on a pilot scale, food-to-food fortified, convenient, canned complementary porridges based on blends of African indigenous crops, i.e., orange fleshed sweet potato (OFSP) flour, and leguminous (i.e., cowpea, and Bambara groundnut) and cereal flours (i.e., teff, finger millet, maize, and amaranth), and milk powder. Plant-based, African complementary foods are often lacking in vitamin A, zinc, iron, and energy. Porridge with OFSP on a 32% dry weight (dw) basis achieved recommended levels of vitamin A (530 µg per 100 g dw). Satisfactory energy (431 Kcal per 100 g dw) was obtained by supplementation of vegetable oil. A nutritious, low-cost porridge (costing 0.15 € per 100 g can) that fulfills consistency constraints was obtained by including supplements of zinc and iron salts as ingredients. The solids content and thus protein/energy could be significantly increased using protein fractionated or germinated cowpea flours without compromising on viscosity. The sensory profile was characterised by more intense vegetable, leguminous, and malty flavours as compared to traditional reference porridges., (© 2024 The Author(s). Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

Background & Aims: The xenobiotic efflux pump P-glycoprotein is highly expressed on the apical membrane of the gastrointestinal tract, where it regulates the levels of intracellular substrates. P-glycoprotein is altered in disease, but the mechanisms that regulate the levels of P-glycoprotein are still being explored. The molecular motor myosin Vb (Myo5b) traffics diverse cargo to the apical membrane of intestinal epithelial cells. We hypothesized that Myo5b was responsible for the delivery of P-glycoprotein to the apical membrane of enterocytes., Methods: We used multiple murine models that lack functional Myo5b or the myosin binding partner Rab11a to analyze P-glycoprotein localization. Pig and human tissue were analyzed to determine P-glycoprotein localization in the setting of MYO5B mutations. Intestinal organoids were used to examine P-glycoprotein trafficking and to assay P-glycoprotein function when MYO5 is inhibited., Results: In mice lacking Myo5b or the binding partner Rab11a, P-glycoprotein was improperly trafficked and had decreased presence in the brush border of enterocytes. Immunostaining of a pig model lacking functional Myo5b and human biopsies from a patient with an inactivating mutation in Myo5b also showed altered localization of intestinal P-glycoprotein. Human intestinal organoids expressing the motorless MYO5B tail domain had colocalization with P-glycoprotein, confirming that P-glycoprotein was trafficked by MYO5B in human enterocytes. Inhibition of MYO5 in human intestinal cell lines and organoids resulted in decreased P-glycoprotein capacity. Additionally, inhibition of MYO5 in human colon cancer cells diminished P-glycoprotein activity and increased cell death in response to a chemotherapeutic drug., Conclusions: Collectively, these data demonstrate that Myo5b is necessary for the apical delivery of P-glycoprotein., (Copyright © 2025 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Mainland Japanese have been recognized as having dual ancestry, originating from indigenous Jomon people and immigrants from continental East Eurasia. Although migration from the continent to the Japanese Archipelago continued from the Yayoi to the Kofun period, our understanding of these immigrants, particularly their origins, remains insufficient due to the lack of high-quality genome samples from the Yayoi period, complicating predictions about the admixture process. To address this, we sequenced the whole nuclear genome of a Yayoi individual from the Doigahama site in Yamaguchi prefecture, Japan. A comprehensive population genetic analysis of the Doigahama Yayoi individual, along with ancient and modern populations in East Asia and Northeastern Eurasia, revealed that the Doigahama Yayoi individual, similar to Kofun individuals and modern Mainland Japanese, had three distinct genetic ancestries: Jomon-related, East Asian-related, and Northeastern Siberian-related. Among non-Japanese populations, the Korean population, possessing both East Asian-related and Northeastern Siberian-related ancestries, exhibited the highest degree of genetic similarity to the Doigahama Yayoi individual. The analysis of admixture modeling for Yayoi individuals, Kofun individuals, and modern Japanese respectively supported a two-way admixture model assuming Jomon-related and Korean-related ancestries. These results suggest that between the Yayoi and Kofun periods, the majority of immigrants to the Japanese Archipelago originated primarily from the Korean Peninsula., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Ménière's disease (MD) is characterized by loss of balance and hearing disorders. Although there is known to be endolymphatic hydrops involved in the pathological process, the pathogenesis of the disease is still largely unclear. Approximately half of patients with MD suffer from depressive symptoms and high levels of several stress hormones were observed in MD and depression, simultaneously. Recently, gut microbes have been shown to influence the function of the central nervous system in humans through their metabolites. We studied the intestinal microbiota of 10 patients with MD and 11 healthy donors (HD). Significant negative correlations were found between disease duration and alpha diversity indexes of gut microbes in patients with MD. The relative abundance of the species Butyricicoccus ambiguous taxa was increased in patients with MD compared with that of HD. In contrast, Oscillospiraceae UCG-002/UCG-005 ambiguous taxa and Anaerovoracaceae (Eubacterium) brachy group uncultured bacterium were increased in the relative abundance of HD than that of patients with MD. The relative abundance of the Butyricicoccus species was positively correlated with disease duration. Thus, these compositional alterations of gut microbes in patients with MD are associated with inner ear pathologies, such as endolymphatic hydrops, by changing the metabolite profiles in the intestine., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Altered gut microbiota is linked to systemic lupus erythematosus (SLE), but its association with disease development, disease activity, and post-intervention changes remains unclear. We compared new-onset SLE (NOSLE, n = 25), SLE in remission (RemSLE, n = 30), and healthy controls (HC, n = 30) cross-sectionally and conducted the first longitudinal analysis of NOSLE patients (n = 22) from pre-intervention to remission over 12 months. Significant β-diversity differences were observed in both NOSLE and RemSLE compared to HC, but not between NOSLE and RemSLE. Only four operational taxonomic units (OTUs) were enriched in NOSLE versus HC. However, 26 OTUs, including butyrate-producing bacteria (BPB), were depleted, and seven (including five BPBs) remained depleted in RemSLE compared to HC. OTUs positively and negatively correlated with disease activity were also identified. Longitudinal analysis revealed a reversal of several OTUs altered at onset and an increase in Streptococci, unrelated to the disease. Significant β-diversity differences were observed in patients with anti-SSA or anti-RNP antibodies and those with complement reduction compared to their counterparts. Our study identified gut microbiota alterations, including BPB depletion, in SLE regardless of onset or remission status, bacteria linked to disease activity, and a reversal of disease-associated bacteria along with the enrichment of Streptococci through intervention., Competing Interests: Declarations. Competing interests: EW received a grant from GSK plc. All other authors declare no competing interests., (© 2024. The Author(s).)

Sotos syndrome is a genetic disorder characterized by distinct facial features, intellectual disability, and overgrowth. In this case, a patient with Sotos syndrome presented with severe intellectual disability, for which general anesthesia was initially considered. However, at the request of the patient's guardian, the treatment was performed under intravenous sedation. Due to the patient's severe intellectual disability and microtia, administering intravenous sedation was anticipated to be challenging. Nevertheless, the dental treatment was successfully and safely completed by employing multiple strategies. These included using risperidone as premedication, applying a local anesthetic cream, securing the peripheral venous route after nitrous oxide inhalation, and monitoring respiratory status with a capnometer to adjust sedation levels. This report aims to demonstrate the successful management of intravenous sedation in a patient with Sotos syndrome, focusing on the strategies employed to address the unique challenges posed by severe intellectual disability, behavioral difficulties, and anatomical considerations. By highlighting these approaches, we aim to contribute to the limited literature on sedation management for patients with complex medical and behavioral needs., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kuroda et al.)

Background: Home-based rehabilitation involves professional rehabilitation care and guidance offered by physical, occupational, and speech therapists to patients in their homes to help them recuperate in a familiar living environment. The effects on the patient's motor function and activities of daily living (ADLs), and caregiver burden for community-dwelling patients are well-documented; however, little is known about the immediate benefits in patients discharged from the hospital. Therefore, we examined the effects of continuous home-based rehabilitation immediately after discharge to patients who received intensive rehabilitation during hospitalization., Methods: We retrospectively reviewed 150 patients [mean (standard deviation, SD) = 81 (9) years] discharged from the convalescent rehabilitation and community-based integrated care wards undergoing tailored home-based rehabilitation for 6 months (provided by physical or occupational therapists: 1-2 sessions of 40-60 min each per week). The outcome measures at baseline and after 3 and 6 months were compared., Results: The participants included in this study had orthopedic (n = 76), cerebrovascular (n = 50), neuromuscular (n = 11), cardiovascular (n = 5), respiratory (n = 3), cancer (n = 3) and other diseases (n = 2). The mean (SD) time from discharge to the start of rehabilitation was 4 (4) days. One-way analysis of variance and post-hoc comparisons showed significant improvements at 3 months from baseline in grip strength (p = 0.002), 5-repetition sit-to-stand test (p < 0.001), Standing test for Imbalance and Disequilibrium test (p = 0.025), Functional Independence Measure (p < 0.001), modified Frenchay Activities Index (p < 0.001). Additionally, a statistically significant improvement was observed in the Japanese Zarit Caregiver Burden Interview score at 6 months from baseline (p < 0.001)., Conclusions: Home-based rehabilitation improves motor function, ADLs, and instrumental ADLs even after intensive inpatient rehabilitation and decreases the burden of the caregiver in the long term. Hence, tailored home-based rehabilitation should be continuously implemented after the completion of intensive inpatient rehabilitation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sato 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.)

Background: Socially assistive robots introduced in nursing care settings have multidimensional psychological impacts on care recipients and caregivers. This study aims to explore the longitudinal changes induced by socially assistive robots, focusing on a chain of human behaviors., Methods: In this qualitative study, nine participants from two nursing homes who had experience in manipulating socially assistive robots were interviewed in a semi-structured focus group using a topic guide to explore the changes in care recipients and caregivers. Following the framework analysis method, the transcripts were coded using the International Classification of Functioning, Disability, and Health (ICF). The identified codes were charted for each side-care recipients and caregivers sides- using a causal loop diagram, a tool used to visualize nonlinear dynamics in complex systems., Results: Three and seven kinds of codes in the domains of "body functions" and "activities and participation", respectively, were identified on the care recipients' side; whereas on the caregivers' side, one and five kinds of codes in the domains of "body functions" and "activities and participation", respectively, were found. The codes obtained from the facility with longer experience were represented graphically as a reinforcing feedback loop, in which favorable changes were amplified in a chain of events. Robot use directly changed the mental functions of care recipients, and the caregivers' perceptions of these positive changes led to their own emotional and behavioral changes, which would reduce the burden of care. Moreover, the findings suggest that sharing information regarding these changes and objectively recognizing the effectiveness of robots among staff members can be the key to continuous robot use in nursing care settings. Conversely, the figure obtained from the novice facility shows fragmented chain relationships of the codes, indicating that all the effects of robot use are recognizable and form a chain reaction after continuous robot use for more than several months., Conclusions: This study revealed important aspects regarding the longitudinal effects of socially assistive robots in nursing care settings. These implications should be broadly implemented for effective robot use and reduction of the burden of care in nursing care settings., Clinical Trial Number: Not applicable., Competing Interests: Declarations. Ethics approval and consent to participate: The study protocol was approved by the Ethics Committees of the Kanagawa Prefectural Institute of Industrial Science and Technology and the Ethics Committee of the National Center for Geriatrics and Gerontology (approval number 22TB20). All participants provided written informed consent before participation. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

In oncology drug development, overall response rate (ORR) is commonly used as an early endpoint to assess the clinical benefits of new interventions; however, ORR benefit may not always translate into a long-term clinical benefit such as overall survival (OS). Most of the work on developing endpoints based on tumor growth dynamics relies on empirical validation, leading to a lack of generalizability of the endpoints across indications and therapeutic modalities. Additionally, many of these metrics are model-based and do not use data from all the patients. The objective of this work is to use longitudinal tumor size data and new lesion information (that is, the same information used by the ORR) to develop novel endpoints that can improve early clinical decision-making compared to the ORR. We investigate in this work multiple candidate novel endpoints based on tumor size ratio that utilize longitudinal tumor size data from all the patients regardless of their follow-up, rely only on tumor size and new lesion information, and are model-free. An extensive simulation study is conducted, exploring a wide spectrum of tumor size data and overall survival outcomes by modulating a variety of trial characteristics such as slow vs fast tumor growth, high vs low drug efficacy rates, variability in patients' responses, variations in the number of patients, follow-up periods, new lesion rates and survival curve shapes. The proposed novel endpoints based on tumor size ratio consistently outperform the ORR by having a comparable or higher correlation with the OS. Further, the novel endpoints exhibit superior accuracy compared to the ORR in predicting the long-term OS benefit. Retrospective empirical validation on BMS clinical trials confirms our simulation findings. These findings suggest that the tumor size ratio-based endpoints could replace ORR for early clinical decision-making in oncology drug development., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: This study aimed to develop and validate a Japanese version of the Public Attitudes Toward Epilepsy (PATE-J) Scale to measure attitudes towards epilepsy among the general Japanese population., Methods: The study employed a cross-sectional design using an online survey of 537 participants from the general public in Japan, with follow-up surveys at 2 weeks and 3 months. The PATE Scale was translated following standard guidelines and validated by conducting confirmatory factor analysis (CFA) on the complete data set to assess the original two-factor structure of the PATE Scale. Internal consistency assessment, and convergent validity testing with the Modified Epilepsy Stigma Scale (M-ESS), Perceived Devaluation Discrimination Scale (PDDS), and Epilepsy Knowledge Scale (EKS) were carried out., Results: CFA confirmed the two-factor structure of the PATE-J, comprising "Personal Domain" and "General Domain." The model showed acceptable fit indices ( χ ²(76) = 607.974, comparative fit index = 0.849, Tucker-Lewis index = 0.820, root-mean-square error of approximation = 0.114, standardized root-mean-square residual = 0.078) and high reliability (Cronbach's α  = 0.87 for Personal Domain and 0.75 for General Domain). Strong correlations with the M-ESS ( r  = 0.713, p  < 0.001), and weaker correlations with the PDDS, along with a negative correlation with the EKS ( r  = -0.306, p  < 0.001), highlighted the PATE-J's distinctiveness. No significant associations were found between demographic factors and PATE-J scores., Conclusion: The PATE-J demonstrates strong psychometric properties and cultural relevance for measuring public attitudes toward epilepsy in Japan. Its validated two-factor structure supports cross-cultural comparisons and provides a reliable tool for assessing public attitudes, informing interventions, and guiding education campaigns., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Granulomatous interstitial nephritis (GIN) has been reported in <0.5% of patients with inflammatory bowel disease, and most cases of GIN are drug-induced. A 13-year-old boy was referred for the evaluation of abdominal pain, diarrhea, and weight loss. The patient was diagnosed with non-drug-induced GIN and Crohn's disease based on total colonoscopy and a biopsy of the colon and kidney. Both tissues contained macrophages and increased epithelial expression of IκBζ, a protein involved in the NF-κB pathway. There may be more patients with GIN complicated by Crohn's disease than expected, and macrophages may be involved in the pathogenesis.

Delta-like 1 homolog (DLK1), a non-canonical Notch ligand, is highly expressed in various malignant tumors, especially in hepatocellular carcinoma (HCC). CBA-1205 is an afucosylated humanized antibody against DLK1 with enhanced antibody-dependent cellular cytotoxicity (ADCC). The binding characteristics of CBA-1205 were analyzed by enzyme-linked immunosorbent assay and fluorescence-activated cell sorting assay. The ADCC activity of CBA-1205 was assessed. The anti-tumor efficacy of CBA-1205 was evaluated in xenograft mouse models, and toxicity and toxicokinetic profiles of CBA-1205 were evaluated in cynomolgus monkeys. CBA-1205 selectively bound to DLK1 among the Notch ligands and only to monkey and human DLK1. The binding epitope was between epidermal growth factor-like domains 1 and 2 of DLK1, which are not involved in any known physiological functions. The ADCC activity of CBA-1205 was confirmed using human peripheral blood mononuclear cells as effector cells. CBA-1205 as a single agent and in combination with lenvatinib demonstrated long-lasting anti-tumor efficacy, including tumor regression, in two liver cancer xenograft models. The toxicity and toxicokinetic profiles of CBA-1205 in cynomolgus monkeys were favorable. These findings suggest that CBA-1205 has the potential to be a useful therapeutic option for drug treatment in HCC. A phase 1 study is ongoing in patients with advanced cancers (jRCT2080225288, NCT06636435).

Originally developed as a specific form of exhaustive intermittent training involving 6-8 X 20-seconds of supramaximal-intensity cycling exercises with 10-seconds of recovery for athletes, Tabata training has become universally recognized around the world. The purpose of this review article is to provide a perspective on Tabata training and discuss how this popular style of intermittent training has evolved and been applied over the last ~30 years. The article will review the original motivation behind Tabata training with relevance to concepts such as maximal accumulated oxygen deficit (MAOD) and maximal oxygen uptake (V̇o2max) and discuss how Tabata training has been adapted to involve resistance exercise, cross training, and sport-specific training. Studies of Tabata training on physiological responses and adaptations in muscle, blood vessels, bone, and brain across different populations will be reviewed. Finally, research on how Tabata-style training was applied to counteract inactivity during the COVID19 pandemic will be discussed. Evolving from the study of athletes, Tabata training represents an example of how high intensity intermittent/interval training can be adapted and applied in various settings to enhance performance and health.

Context: In most cases of non-islet cell tumor hypoglycemia (NICTH), high molecular weight forms of insulin-like growth factor II, commonly referred to as big IGF-II, cause hypoglycemia. MicroRNA-483 (miR-483), encoded within an intron of IGF2 gene, has been suggested to be co-expressed with IGF-II., Objective: The aim of this study is to demonstrate the utility and reliability of circulating miR-483 as a biomarker for diagnosis and therapeutic outcome of NICTH., Methods: Sera from 145 cases of suspected NICTH, and postoperative sera from 25 surgical cases of confirmed NICTH were subjected to Western blot analysis and ELISA for IGF-II and quantitative PCR analysis for miR-483-5p and -3p. Tissue miR-483 expression levels were compared between resected solitary fibrous tumors (SFTs) and their surrounding margins from 11 surgical cases., Results: NICTH was confirmed in 100 out of 145 cases based on the detection of big IGF-II in their sera. Receiver operating characteristic curve analysis revealed that serum miR-483-5p had a better diagnostic ability for NICTH than serum IGF-II or the classical diagnostic marker IGF-II to IGF-I ratio. Notably, serum miR-483-5p levels decreased significantly with the disappearance of big IGF-II after surgical tumor resection. Tissue miRNA-483-5p and -3p expression levels were significantly higher in resected SFT tissues compared to their surgical margins., Conclusion: Circulating miR-483-5p, derived from IGF-II-producing tumors, appears to be a more reliable biomarker for diagnosis and therapeutic outcome of NICTH compared to IGF-II or IGF-II to IGF-I ratio. These findings highlight the clinical utility of miR-483-5p in the management of NICTH., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Intake of branched-chain amino acids (BCAA) has been suggested to have a prophylactic effect against carcinogenesis in colorectal cancer (CRC). However, the possible effect of plasma BCAA concentration has not been fully evaluated., Methods: We conducted a prospective case-control study within a cohort of four public health center areas for which blood sample and questionnaire data from a 5-year follow-up survey were available. We identified 360 newly diagnosed CRC cases during the follow-up period and selected two matched controls for each case. We estimated odds ratio (OR) and 95% confidence intervals (CI) for CRC using conditional logistic regression models adjusted for potential confounding factors., Results: Increased plasma concentrations of BCAAs were not inversely associated with CRC risk after adjustment for potential confounders. Compared with the lowest quartile, ORs in the highest quartile of leucine, isoleucine, valine, and total BCAA were 0.74 (95% CI, 0.49-1.12), 0.85 (0.56-1.29), 0.75 (0.50-1.13), and 0.70 (0.47-1.05), respectively. After excluding cases diagnosed within the first 6 years of follow-up, total BCAA and leucine were significantly related to a decreased risk of CRC, with ORs in the highest quartile of total BCAA and leucine of 0.58 (0.35-0.96) and 0.56 (0.33-0.93), respectively., Conclusions: We found no statistically significant inverse association between plasma BCAA concentrations and CRC risk in overall analyses, whereas on 6-year exclusion, total BCAA and leucine were associated with decreased CRC risk. Plasma BCAA concentrations may play a prophylactic role in colorectal carcinogenesis, and further investigation is warranted., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Silicone breast implants (SBIs) are commonly used for breast reconstruction and cosmetic surgery. However, long-term complications associated with SBI, such as rupture and infection, require careful monitoring. Here, we report a case in which coronavirus disease 2019 infection led to immunosuppression and secondary bacterial infection, resulting in skin ulceration and eventual removal of the SBI. This case highlights the potential complications of long-term use of SBI and the need for careful postoperative monitoring., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Nagata et al.)

Objective: Self-stigma means internalizing negative beliefs and attitudes associated with stigmatized identity. This study aimed to translate and validate the Malay and Chinese versions of the Epilepsy Self-Stigma Scale (ESSS)., Methods: The Epilepsy Self-Stigma Scale was translated into the Malay (ESSS-M) and Chinese versions (ESSS-C) according to standard principles and were tested in 100 Malay and 100 Chinese-speaking people with epilepsy (PWE) respectively. Psychometric evaluations were done based on equal item variance, convergent and discriminant validity, construct validity and reliability. Correlation analyses were carried out between the ESSS and the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and Generalized Anxiety Disorder-7 (GAD-7)., Results: For the ESSS-M, 100 Malay-speaking PWE with a mean age of 42.25 years (±15.18) were recruited. Exploratory factor analysis identified eight items loaded on three factors: "Internalization of stigma", "Societal incomprehension", and "Confidentiality". However, item 1 was loaded under a different component from the initial paper, conceptualized as confidentiality. For the ESSS-C, 100 Chinese-speaking participants with a mean age of 41.07 years (±15.57). Exploratory factor analysis identified three loading factors similar to the original scale: "Internalization of stigma", "Societal incomprehension", and "Confidentiality". Both ESSS-M and ESSS-C scales showed significant correlations with NDDI-E and GAD-7 scores, showcasing substantial construct validity. The Cronbach's alpha values were α = 0.822 for the ESSS-M and α = 0.831 for the ESSS-C., Conclusion: Both the ESSS-M and ESSS-C were reliable and valid for measuring epilepsy self-stigma among the Malay- and Chinese-speaking PWE in Malaysia., 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: Stigma toward epilepsy is widespread not only among the general population but also among healthcare professionals. Therefore, the necessity of providing educational opportunities for epilepsy from an early stage in student education has been emphasized. Recently, problem-based learning (PBL) has gained importance in higher education, with reports indicating that it not only enhances knowledge but also reduces stigma., Objective: This study aimed to evaluate the effects of an epilepsy-related problem-based learning (E-PBL) program on medical students' stigma toward epilepsy. Additionally, we assessed whether the E-PBL program improved medical students' knowledge of epilepsy., Materials and Methods: Participants were fourth-year medical students. The E-PBL program was conducted over 5 days, from July 3, 2023 to July 7, 2023. The outcomes included the Japanese version of the Public Attitudes Toward Epilepsy (PATE-J) scale, which was used to assess stigma toward epilepsy before and after the E-PBL program. We also administered a short, structured questionnaire to assess participants' knowledge of epilepsy., Results: In total, 112 students were examined. The total PATE-J score was significantly lower after E-PBL (median: 18; interquartile range [IQR]: 14-20) than before PBL (median: 19; IQR: 16-23) (p = 0.013). Additionally, the number of correct responses to the short, structured questionnaire after the E-PBL program was significantly higher than before the program (p < 0.001)., Conclusions: E-PBL programs have the potential to decrease stigma toward epilepsy while enhancing knowledge about epilepsy among medical students. E-PBL represents a novel educational approach for medical students in the context of epilepsy education., 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.)

Calphostin C (Cal-C) is a protein kinase C (PKC) inhibitor that binds to its C1 domain. The aim of the present study was to elucidate the action of Cal-C in addition to PKC inhibition. First, we confirmed that Cal-C at low concentrations (<200 nM) inhibit phorbol ester-induced PKC translocation and G-protein-coupled receptor (GPCR)-mediated PKC activation. Cal-C at higher concentrations (>2 μM) increased intracellular calcium ion concentrations ([Ca 2+ ] i ) in a concentration-dependent manner. The origin of this increase is the mobilization of the endoplasmic reticulum (ER), which does not involve GPCR or ryanodine receptors. Cal-C at high concentrations also cause structural changes in the ER, such as the formation of vacuoles and aggregates, and calcium leakage from the ER. At 2 μM, Cal-C translocated a calcium-sensitive PKCα. Studies using a C-kinase activity reporter and a myristoylated alanine-rich protein kinase C substrate fused with green fluorescent protein (GFP) have also revealed that Cal-C at high concentrations activate PKC in living cells. Additionally, the PKC-activating effects of Cal-C were light-dependent. Finally, studies using Si-DMA, an indicator of singlet oxygen, showed that Cal-C at high concentrations generated singlet oxygen, causing structural changes in the ER and leakage of calcium into the cytosol, which triggered PKC activation. This study confirms the novel action of Cal-C, solely considered a PKC inhibitor. Cal-C acted as a PKC inhibitor at low concentrations and a PKC activator at high concentrations by generating singlet oxygen in a light-dependent manner, suggesting that Cal-C can be used in photodynamic therapy., Competing Interests: Declaration of competing interest The authors have no conflicts of interest regarding this study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cancer patients residing in rural areas experience substantial barriers to care and suboptimal care coordination. To date, there is a paucity of interventions to improve care coordination for rural cancer patients. In this study, we conducted a pilot trial to assess the feasibility and efficacy of a remote, tablet-based patient video education intervention focused on cancer care coordination among rural patients in Hawaii. The pilot trial utilized a single-arm, pre-post intervention design. Our TED-talk style video education intervention included talks on cancer basics, care coordination, and self-advocacy. Eligible participants were rural patients newly diagnosed with early-stage cancer receiving adjuvant therapy. Validated instruments were administered at baseline and post-intervention to assess patients' perceptions of care coordination and self-advocacy. Acceptability and satisfaction were assessed using semi-structured interviews. Descriptive statistics were used to describe study outcomes. From January 2022 to December 2022, 19 patients enrolled on the study; the mean age was 52.2. Participants were racially diverse. A total of 71.4% of eligible patients completed all assessments. No changes were observed in the overall perceptions of care coordination. However, improved scores were observed for the care coordination instrument communication domain (Cohen's d =  - 0.76, 95% CI: - 1.45, - 0.03). There was a trend for improved scores on navigation and self-advocacy. All participants reported high satisfaction with the intervention. Results support the feasibility, satisfaction, and acceptability of this intervention among rural cancer patients in Hawaii. Further study is needed to evaluate the intervention in other rural areas. Clinical Trial Registration: NCT05162404.Registration Date: 12/17/2021., (© 2024. The Author(s).)

Objective Masticatory muscle tendon-aponeurosis hyperplasia (MMTAH) is a recently identified condition characterized by restricted mouth opening due to hyperplasia of the temporalis muscle tendon and masseter muscle aponeurosis. This study examines the treatment and clinical course of patients with MMTAH who underwent surgery at our hospital. Subjects and methods The study included 14 patients (four males and 10 females; mean age: 33.9 years; age range: 17-50 years) who were clinically diagnosed with MMTAH at our hospital between 2008 and 2020. The surgical procedure, as well as the preoperative, intraoperative, and postoperative mouth opening range of each patient, were examined. Results In all cases, the mouth opening range significantly improved postoperatively. Patients who underwent mandibular anglectomy showed a significantly greater mouth opening range both preoperatively and postoperatively compared to those who did not undergo the procedure. Additionally, mandibular anglectomy was effective in maintaining the mouth opening range at six months in patients who underwent the procedure, in contrast to those who did not. Conclusions Mandibular anglectomy appears to be effective in maintaining the mouth opening range in patients with MMTAH. While additional case studies are needed to confirm our findings, we believe that mandibular anglectomy is a valuable treatment option for MMTAH., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. The Kyushu Dental University Hospital Ethics Committee issued approval 23-28. 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, Yoshiga et al.)

Background: Sodium polystyrene sulfonate (SPS) is a cation-exchange resin used to treat hyperkalemia. Although colorectal ulcers are known side effects of long-term SPS use, few studies have reported SPS-associated gastric ulcers. Herein, we report a case of repeated gastric ulcers during SPS administration., Case Presentation: The patient was a 55-year-old man who was on SPS treatment of hyperkalemia since the initiation of hemodialysis (HD) at the age of 51 years. At the age of 54 years, he started taking vonoprazan fumarate after developing a bleeding duodenal ulcer. The patient underwent laparoscopic pylorus-preserving gastrectomy for four recurrent bleeding gastric ulcers. The resected specimen showed an ulcerative lesion in the pyloric curvature of the stomach, and pathological findings showed deposition of a basophilic crystalline substance resembling a cation-exchange resin at the base of the ulcer., Conclusion: In this case, various factors, including diabetic gastroenteropathy, use of multiple calcium channel blockers and phosphate binders, obesity, and lifestyle, contributed to decreased gastrointestinal peristalsis. This may have promoted SPS deposition in the stomach, potentially leading to ulceration., Competing Interests: Declarations. Ethics approval and consent to participate: This study is a case report and does not qualify as a clinical trial. Therefore, clinical trial registration is not applicable. Consent for publication: Informed consent was obtained from the patient for publication of this Case report and any accompanying images. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Functional loss of the motor protein myosin Vb (MYO5B) induces various defects in intestinal epithelial function and causes a congenital diarrheal disorder, namely, microvillus inclusion disease (MVID). Utilizing the MVID model mice Vil1-Cre ERT2 ;Myo5b flox/flox (MYO5BΔIEC) and Vil1-Cre ERT2 ;Myo5b flox/G519R [MYO5B(G519R)], we previously reported that functional MYO5B loss disrupts progenitor cell differentiation and enterocyte maturation that result in villus blunting and deadly malabsorption symptoms. In this study, we determined that both absence and a point mutation of MYO5B impair lipid metabolism and alter mitochondrial structure, which may underlie the progenitor cell malfunction observed in the MVID intestine. Along with a decrease in fatty acid oxidation, the lipogenesis pathway was enhanced in the MYO5BΔIEC small intestine. Consistent with these observations in vivo, RNA sequencing of enteroids generated from the two MVID mouse strains showed similar downregulation of energy metabolic enzymes, including mitochondrial oxidative phosphorylation genes. In our previous studies, we reported that lysophosphatidic acid (LPA) signaling ameliorated epithelial cell defects in MYO5BΔIEC tissues and enteroids. The present study demonstrated that the highly soluble LPA receptor (LPAR)5-preferred agonist Compound-1 improved sodium transporter localization and absorptive function and tuft cell differentiation in patient-modeled MVID animals that carry independent mutations in MYO5B. Body weight loss in male MYO5B(G519R) mice was ameliorated by Compound-1. These observations suggest that Compound-1 treatment has a trophic effect on the intestine with MYO5B functional loss through epithelial cell-autonomous pathways that can accelerate the differentiation of progenitor cells and the maturation of enterocytes. Targeting LPAR5 may represent an effective therapeutic approach for the treatment of MVID symptoms induced by different point mutations in MYO5B. NEW & NOTEWORTHY This study demonstrates the importance of MYO5B for cellular lipid metabolism and mitochondria in intestinal epithelial cells, previously unexplored functions of MYO5B. The alterations may underlie the progenitor cell malfunction observed in microvillus inclusion disease (MVID) intestines. To examine the therapeutic potential of progenitor-targeted treatments, the effects of the LPAR5-preferred agonist Compound-1 were investigated utilizing several MVID model mice and enteroids. Our observations suggest that Compound-1 may provide a therapeutic approach for treating MVID.

Objective: The Epilepsy Self-Stigma Scale (ESSS) has been developed in Japan for patients with epilepsy (PWE). We aimed to validate the scale in Spanish and examine its validity and reliability., Methods: The transcultural adaptation of the ESSS was conducted using translation and back-translation, along with pilot testing and an expert panel review. An online questionnaire was used to assess construct validity, criterion validity, and internal consistency., Results: A total of 260 out of 628 participants completed the questionnaires. We found a two-factor structure that explained 61.3% of the total variance: factor 1 "self-perceived discrimination" with a Cronbach's alpha of 0.80, and factor 2 "social isolation" with a Cronbach's alpha of 0.75. The reliability of overall ESSS-S 8-item scores was high (Cronbach's alpha = 0.74). Convergent validity was tested and demonstrated a significant correlation. P. Self-perceived discrimination scores were associated with higher anxiety and depression scores (r = 0.53/0.54; p < 0.001), lower self-esteem (-0.53; p < 0.001), and lower quality of life (r = -0.66; p < 0.001). Social isolation scores were associated with higher anxiety and depression scores (r = 0.41/0.33; p < 0.001), lower self-esteem (-0.34; p < 0.001), and lower quality of life (r = -0.35; p < 0.001). Temporal reliability was also tested, showing a test-retest ICC of 0.87. The mean self-stigma score in the Spanish population was 17.68 ± 5.45 out of 32 points. Invariance across gender and age groups indicated that there are no systematic response biases by gender or age, so stratified scores could be related to other constructs., Significance: The Spanish version of ESSS (ESSS-S) is a valid and reliable tool for the assessment of self-stigma in PWE among Spanish speakers., Plain Language Summary: This study aimed to validate the Epilepsy Self-Stigma Scale (ESSS) for Spanish speakers (ESSS-S). We conducted transcultural adaptation of the scale. ESSS-S showed high reliability and strong validity, correlating with higher anxiety and depression, lower self-esteem, and quality of life. ESSS-S is a reliable and valid tool for assessing self-stigma in Spanish-speaking people with epilepsy., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The transposition of the great arteries (TGA) associated with a complete atrioventricular septal defect is a rare and serious congenital cardiac anomaly. In this report, we describe the successful biventricular repair of a TGA with a complete atrioventricular septal defect in an infant. Due to the low body weight of the patient and a complex coronary pattern anomaly, an arterial switch operation was executed, with the Mee procedure and pulmonary arterial banding as initial palliative measures when the infant was 22 days old and weighed 2.5 kg. Subsequently, atrioventricular septal defect repair using the modified one-patch method was performed when the patient was 1.3 years old and weighed 8.8 kg. Remarkably, the postoperative course of the patient demonstrated no notable incidents. To our knowledge, this is the first time a two-stage strategy was applied to repair these complex defects, presenting a promising approach for managing similar cases in future medical practice., (© 2023. The Author(s).)

Objective: Epilepsy is a neurological disorder characterized by recurrent seizures, exhibiting variance in prevalence and treatment availability across diverse geopolitical contexts and cultural milieus. The stigma associated with epilepsy is a significant global issue affecting the quality of life (QOL) of people with epilepsy (PWE). This study aims to examine the relationship between self-stigma and depressive symptoms in PWE, with a particular emphasis on understanding the manifestations of these across different cultural contexts. We aim to enhance the provision of customized care to diverse cultural settings, fostering the adoption of healthier lifestyles for PWE., Methods: We recruited PWE who received treatment at specialized medical facilities for epilepsy in Japan, Malaysia (Chinese, Malay), and Turkey from February to October 2023. The Epilepsy Self-Stigma Scales (ESSS), Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), and Generalized Anxiety Disorder 7 (GAD-7) in local languages were used to assess self-stigma, depressive symptoms, and anxiety., Results: The ESSS total scores were significantly higher among the Turkish and Japanese cohorts (F [3, 406] = 6.57, p < 0.001, η 2  = 0.05). In addition, the self-stigma observed moderate positive correlations for depressive symptoms (rs = 0.41-0.50, Ps < 0.001) and anxiety (rs = 0.42-0.44, Ps < 0.001). The ANCOVA findings suggested that the notable variations in self-stigma, as found in the one-way ANOVA conducted across four cultures, were reduced when taking into consideration depressed symptoms. Our finding highlights the potential influence of mental health factors over cultural factors concerning self-stigma., Significance: The manifestation of self-stigmatization within epilepsy exhibits distinctions across diverse cultural cohorts, regardless of the demographic and clinical variation, yet demonstrates a significant correlation with psychological factors. In subsequent research endeavors, we should comprehensively investigate these subtle differences, their potential impact on patient care, and the development of supportive approaches., Plain Language Summary: This cross-cultural study reveals significant variations in self-stigma among people with epilepsy across different cultural contexts, with Turkish and Japanese cohorts showing higher levels. Self-stigma demonstrated moderate positive correlations with depressive symptoms and anxiety across all cultures. Notably, differences in self-stigma were reduced when accounting for depressive symptoms, suggesting that mental health factors may have a stronger influence than cultural factors. These findings underscore the importance of considering both cultural and psychological aspects in developing targeted interventions to address self-stigma in epilepsy care., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

A population pharmacokinetic (PopPK) analysis was conducted using data from 215 Japanese administered oral sirolimus (tablet and granule) including healthy subjects and patients with intractable vascular anomalies and other diseases. The analysis included neonates, infants, and adults, and identified covariates that influence sirolimus pharmacokinetics (PK). The final model was used to predict sirolimus trough concentrations for various dosing regimens and covariates of interest. The results showed that sirolimus trough concentrations were predicted to increase with higher levels of hemoglobin, and that the granule formulation had a 1.23-fold higher exposure than the tablet formulation. Coadministration of CYP3A4 inducers was found to decrease trough concentrations by 54 %. The PK simulations showed that administration of the granule formulation at doses of 0.02, 0.04, 0.06, and 0.08 mg/kg/day in ages <3 months, 3 to <6 months, 6 to <12 months, and ≥1 year, respectively, resulted in >70 % target attainment within the therapeutic trough concentration range (5-15 ng/mL). In conclusion, incorporation of time-varying covariates (body weight and age) into the PopPK model appropriately predicted sirolimus concentrations in Japanese subjects from infants to adult sub-populations. This PopPK model would therefore be able to provide a reference for clinical individualization of sirolimus dosing., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Restenosis after carotid artery stenting (CAS) is associated with the risk of developing ischemic stroke. We aimed to evaluate the inhibitory effect of cilostazol addition on in-stent restenosis (ISR) in patients treated with CAS., Methods: In a randomized, open-label, blind-end point trial, patients with symptomatic and asymptomatic carotid artery stenosis and scheduled for CAS were randomly assigned to adding cilostazol (50 or 100 mg, twice per day) on other antiplatelets from 3 days before CAS or not adding cilostazol. Concomitant use of other antiplatelets was unrestricted. ISR was diagnosed by a peak systolic velocity of at least 1.75 m/s on duplex ultrasonography. The primary outcome was incidence of ISR within 2 years after CAS. Secondary outcomes included occurrences of cardiovascular events or any death and hemorrhagic events., Results: Participants were recruited from December 2010 to September 2015. Although the sample size was initially set to be 900 (450 in each group), 631 patients (mean age 69.9 years, 558 men, 325 in the cilostazol, and 306 in the noncilostazol group) were included in the primary analysis. Within 2 years' follow-up, ISR occurred in 31 of 325 patients (cumulative incidence 10.8%) in the cilostazol group and 46 of 306 patients (19.6%) in the noncilostazol group (hazard ratio, 0.64 [95% CI, 0.41-1.0]; P =0.056). In the exploratory analysis, incidence of ISR beyond 30 days after CAS was lower in the cilostazol group than in the noncilostazol group (10.3% versus 19.3%; P =0.040). Incidences of cardiovascular events or any death and hemorrhagic events were similar between the groups (6.2% versus 6.7% and 2.3% versus 1.4%, respectively)., Conclusions: The addition of cilostazol to other antiplatelet agents could contribute to the reduction of ISR in the chronic stage of patients who underwent CAS, the authenticity of which depends on further studies with sufficient statistical power., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01261234., Competing Interests: Otsuka Pharmaceutical provided funding for this study to the Translational Research Center for Medical Innovation, but was not involved in the planning, management, or discussion of the results of the study. Dr Yamagami reports a research grant from Bristol-Myers Squibb; lecturer’s fees from Stryker, Medtronic, Johnson & Johnson, Medico’s Hirata, Bristol-Myers Squibb, Diichi-Sankyo, Boston Scientific, and Otsuka Pharmaceutical. Dr Matsumaru reports research grants, travel support, and data and safety monitoring fees from Philips; lecturer’s fees from Diichi-Sankyo, Bayer, Stryker, Jimro, Johnson & Johnson, Terumo, Kaneka, Medtronic, and Philips. Dr Yoshimura reports lecturer’s fees from Idorsia, Bristol-Myers Squibb, Terumo, Daiichi Sankyo, Kaneka, Johnson & Johnson, Bayer, Medtronic, Boehringer Ingelheim and Stryker. Dr Matsumoto reports lecturer’s fees from Kaneka medics, Medico’s Hirata, Fuji systems, GE Healthcare, Otsuka Pharmaceutical, Takeda Pharmaceutical Limited, Medtronic, Century Medical, Stryker, Medtronic and Terumo; and royalties from Sumitomo Bakelite. Dr N. Sakai reports a research grant from Biomedical Solutions, Medtronic, Terumo and TG Medical; lecturer’s fees from Asahi-Intec, Biomedical Solutions, Daiichi Sankyo, Kaneka, Medtronic, Otsuka Pharmaceutical and Terumo; and membership on the advisory boards for Johnson & Johnson, Medtronic, and Terumo outside the submitted work. The other authors report no conflicts.

Tryptophan dioxygenase (TDO) and indoleamine 2,3 dioxygenase (IDO) belong to a unique class of heme-based enzymes that insert dioxygen into the essential amino acid, L-tryptophan (Trp), to generate N-formylkynurenine (NFK), a critical metabolite in the kynurenine pathway. Recently, the two dioxygenases were recognized as pivotal cancer immunotherapeutic drug targets, which triggered a great deal of drug discovery targeting them. The advancement of the field is however hampered by the poor understanding of the structural properties of the two enzymes and the mechanisms by which the structures dictate their functions. In this review, we summarize recent findings centered on the structure, function, and dynamics of the human isoforms of the two enzymes., 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.)

Objective: The aim of the study is to clarify the association of job stressor score (A score), psychological and physical stress response score (B score), and social support (C score), with the incidence of ≥10% weight gain., Methods: This study included 10,036 university employees who completed the Brief Job Stress Questionnaire (BJSQ) and annual health checkups between 2016 and 2021. The incidence of ≥10% weight gain from baseline weight was measured. Participants were classified into four categories based on their BJSQ dimension scores., Results: B score was significantly associated with the incidence of weight gain, whereas A and C scores were not. Participants of Q 75-89 , and Q 90-100 categories of B score were at significantly high risk of the incidence of ≥10% weight gain., Conclusions: Psychological and physical stress response had an increasing risk of weight gain., Competing Interests: Conflict of interest: K.N. received funding from the Smoking Research Foundation and has no relationships, conditions, or circumstances that present a potential conflict of interest to this research., (Copyright © 2024 American College of Occupational and Environmental Medicine.)

A satisfactory treatment for the dissemination of duodenal cancer has not yet been established. We describe a case of peritoneal dissemination and malignant ascites in duodenal cancer that was successfully treated with adoptive cell therapy with no adverse effects. A 72-year-old Japanese male patient with primary duodenal cancer with distal lymph node metastases received chemotherapy with S-1, an oral pyrimidine fluoride - derived agent, and oxaliplatin after gastrojejunal bypass, which resulted in tumor shrinkage; however, peritoneal dissemination developed. Despite the administration of a second-line chemotherapy regimen comprising irinotecan, peritoneal dissemination, malignant ascites, and cachexia continued to progress, ultimately resulting in the failure of chemotherapy. He then received adoptive cell therapy with Wilms' tumor 1 (WT1)- and mucin 1 (MUC1) peptide-pulsed dendritic cells (WT1/MUC1-DC) and CD3-activated T lymphocytes (CAT). Following the administration of this treatment eight times per week, the patient's symptoms and malignant ascites surrounding his cancer disappeared. He developed no adverse effects from this treatment and was able to resume his usual activities without any symptoms. He has continued this treatment every few months as maintenance therapy and has been free of relapse for 54 months. This case suggests a possible beneficial effect of adoptive cell therapy with WT1/MUC1-DC and CAT for peritoneal dissemination and malignant ascites in duodenal cancer., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Bio-Thera Clinic Authorized Committee for Regenerative Medicine issued approval NB3140004. This study was conducted in accordance with the basic principles of the Declaration of Helsinki. Following the opinion of an Accredited Committee for Regenerative Medicine, etc. accredited by the Regional Health and Welfare Bureau (Bio-Thera Clinic Authorized Committee for Regenerative Medicine: NB3140004), a regenerative medicine provision plan was submitted to the Minister of Health, Labor and Welfare. The approved plan and facilities providing regenerative medicine include cancer vaccine therapy using tumor antigen-labeled dendritic cell vaccine (PC3150005) and activated lymphocyte therapy (PC3150004). 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, Yagawa et al.)

Getah virus (GETV), belonging to the genus Alphavirus within the family Togaviridae, is a mosquito-borne virus that causes fever, rash, and edema in horses and fatalities and pregnancy disorders in pigs. It has caused occasional outbreaks in horse populations in Japan, China, and India, and endemic areas are gradually expanding, particularly in Asia and Oceania. In this study, we isolated a new GETV strain from Culex tritaeniorhynchus mosquitoes collected from Nagasaki Prefecture, Japan in 2022. Phylogenetic analysis revealed that this new strain, 22IH8, is more closely related to previous Chinese strains than to the strains prevalent in Japan in the 2010s. Furthermore, some amino acid substitutions in the viral proteins of strain 22IH8 were found to be common with those in previous Chinese strains. These results suggest that 22IH8 strain may have recently invaded the Japanese archipelago from mainland Asia. The antiserum against the current vaccine strain, MI-110, showed high neutralization activity against the 22IH8 strain indicating the efficiency of the current vaccine for horses in Japan.

We started a registry for cases of immunoglobulin (Ig)G4-related disease (IgG4-RD) in December 2019 to clarify the clinical profile of IgG4-RD. In this study, clinical information from 854 cases registered by February 16, 2024 was analyzed from multiple perspectives. Diagnosis of IgG4-RD was made in 808 cases, comprising 638 definite, 38 probable, and 132 possible. The mean ± SD age at time of enrollment of the 808 cases was 67.9 ± 11.3 years, with 68.8% being male. The pancreas was the most frequently affected organ (49.8%), followed by the submandibular glands (46.2%) and lacrimal glands (30.6%). This study reconfirmed the pancreas and head-and-neck region as major affected areas in IgG4-RD. Clinically, submandibular adenitis and autoimmune pancreatitis often occur together in the same patient, but no association between the two organs was observed in our analysis. Regarding diagnosis, the comprehensive diagnostic criteria were most commonly used (63.6%). Storiform fibrosis and phlebitis obliterans were detected at different frequencies in different organs. In summary, this registry study identified clinical, imaging, hematologic, and pathologic findings in 808 Japanese patients with IgG4-RD. The frequency of affected organs and their characteristic pathological findings will be particularly useful for future practice.

The psychological states of wives and husbands are thought to influence each other to varying degrees. However, relatively little is known from a longitudinal observation about the effects of spouses' psychological distress and well-being on their mental health. To address this question, we analyzed the TWIN Study II dataset using a three-wave annual survey of the psychological distress and happiness of 379 dual-income families. A group-based trajectory modeling analysis was conducted to identify psychological distress patterns and happiness over time, while estimating the effects of spouses' psychological distress and happiness and their own job demands, control, and support as time-varying covariates. The two- or three-group trajectory model best fit husbands' and wives' psychological distress and happiness trajectories. Husbands' trajectories of psychological distress and happiness were significantly influenced by wives' happiness as well as their own job demands and/or support, whereas wives' happiness and psychological distress were not.

Background and Objectives: All 4 previous nationwide surveys of multiple sclerosis (MS) in Japan were conducted before the discovery of anti-aquaporin-4 (AQP4) antibodies; thus, neuromyelitis optica spectrum disorder (NMOSD) was included in MS, as optic-spinal MS. We aimed to clarify the epidemiologic features and trends of MS and NMOSD in Japan separately using a fifth nationwide survey., Methods: The primary survey, in which a questionnaire was sent to 3,799 selected departments (including neurology/internal medicine, pediatrics, and ophthalmology), explored the estimated number and prevalence of patients with MS or NMOSD in 2017, and the secondary survey collected detailed characteristics of the patients using a second questionnaire., Results: The response rates for the primary and secondary surveys were 60.1% and 53.9%, respectively. The estimated total number of patients with MS or NMOSD was 24,800, 2.5-fold higher than that in the fourth survey in 2003. The crude prevalence was 19.6 per 100,000 patients (14.2 for MS and 5.4 for NMOSD), compared with 7.7 per 100,000 patients in the fourth survey. Patients with MS showed milder disability (median Expanded Disability Status Scale [EDSS] score: 2.0 [interquartile range 1.0-4.5] vs 2.5 [1.0-6.0]), decreased secondary progression (8.5% vs 15.2%), and increased usage of disease-modifying drugs (63.7% vs 37.2%) compared with those with conventional MS in the fourth survey. The proportions of oligoclonal bands and Barkhof criteria fulfillment on MRI, which are features of classical MS, increased with advancing year of birth. Patients with NMOSD also showed less disability and shorter disease duration than patients with optic-spinal MS in the fourth survey (EDSS score: 3.5 [2.0-5.5] vs 3.8 [2.0-6.0]; disease duration: 8.0 [3.9-14.8] vs 10.0 [5.0-16.0]). Among patients with NMOSD, disability was exacerbated by a history of longitudinally extensive spinal cord lesions and anti-AQP4 antibody positivity, which both decreased with advancing year of birth., Discussion: The prevalences of MS (particularly with classical features) and NMOSD have been increasing in Japan, suggesting the contribution of environmental factors. However, disabilities in patients with MS and NMOSD have been mitigated. Extensive usage of various disease-modifying drugs could be a factor contributing to this disability mitigation in MS.

Aim: Assessing symptoms and daily functioning in patients with major depressive disorder (MDD) can be challenging, as their limited self-monitoring abilities may result in behavior observed during structured interviews not accurately reflecting their daily lives. This study aimed to determine if specific occupational behaviors could distinguish individuals with MDD from healthy individuals., Methods: Baseline data were collected from medical records and activity programs. Three occupational therapists conducted content analysis to assess occupational performance characteristics. Chi-squared tests compared the prevalence of these characteristics between patients with MDD and healthy controls. Multivariable logistic regression controlled for potential confounders, with independent variables selected based on clinical relevance and sample size ( p  < 0.01). Discriminant analysis was used to enhance group differentiation, assessing prediction rates using area under the curve (AUC) values., Results: A total of 69 occupational performance characteristics were identified, with 12 showing significant differences between 27 patients with MDD and 43 healthy controls. Key discriminators included "Ask questions and consult" ( p  < 0.001, odds ratio [OR] = 0.051, 95% confidence interval [CI] = 0.009-0.283), "Concentrate on work" ( p  = 0.003, OR = 0.078, 95% CI = 0.015-0.416), "Choose simple work" ( p  = 0.004, OR = 17.803, 95% CI = 2.446-129.597), and "Punctual" ( p  = 0.017, OR = 0.030, 95% CI = 0.002-0.530). Discriminant analysis using these variables yielded a Wilks' λ of 0.493 ( p  < 0.001), achieving an 88.6% accuracy rate. The receiver operating characteristic curve's AUC value was 0.911 (sensitivity = 95.3%, specificity = 77.8%)., Conclusion: This study highlights the importance of occupational performance characteristics in tailoring treatment strategies for MDD, providing insights beyond traditional assessment methods., Competing Interests: Dr. Tomonari Hayasaka, Dr. Izumi Nagashima, Ms. Miku Hoshino, Dr. Koji Teruya, Dr. Taku Maruki, Dr. Masako Watanabe, Dr. Takeshi Katagiri, Dr. Yayoi Imamura, Ms. Mariko Kurihara, and Mr. Yuki Oe have nothing to declare. Dr. Masami Murao received honorariums from Sumitomo Pharma and Yoshitomiyakuhin. Dr. Yasuyuki Matumoto received grants from the Japan Society for the Promotion of Science and honorariums from Sumitomo Pharma, Janssen Pharmaceutical, and Meiji Seika Pharma. Dr. Takaesu has received lecture fees from Takeda Pharmaceutical, Sumitomo Dainippon Pharma, Otsuka Pharmaceutical, Meiji Seika Pharma, Kyowa Pharmaceutical, Eisai, MSD, Yoshitomi, and research funding from Otsuka Pharmaceutical, Meiji Seika Pharma, MSD, and Eisai. Dr. Takashi Tsuboi received grants from the Japan Society for the Promotion of Science and honorariums from Takeda Pharmaceutical, Otsuka Pharmaceutical, Meiji Seika Pharma, Shionogi Pharma, Yoshitomiyakuhin, Sumitomo Pharma, Kyowa Pharmaceutical, MSD, Nippon Boehringer lngelheim, Mylan EPD, Mitsubishi Tanabe Pharma, Viatris, Mochida Pharmaceutical, Janssen Pharmaceutical, TEIJIN PHARMA, and Lundbeck Japan. Dr. Koichiro Watanabe is a consultant of Boehringer Ingelheim, Daiichi Sankyo, Eisai, Eli Lily, Janssen Pharmaceutical, Kyowa Pharmaceutical, Lundbeck Japan, Luye Pharma, Mitsubishi Tanabe Pharma, Otsuka Pharmaceutical, Lundbeck Japan, Luye Pharma, Mitsubishi Tanabe Pharma, Otsuka Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, Taisho Pharmaceutical, and Takeda Pharmaceutical. Dr. Hitoshi Sakurai received grants from the Japan Society for the Promotion of Science, Japan Research Foundation Clinical Pharmacology, and Takeda Science Foundation, and honorariums from Eisai, Takeda Pharmaceutical, Otsuka Pharmaceutical, Meiji Seika Pharma, Shionogi Pharma, Yoshitomiyakuhin, Sumitomo Pharma, Kyowa Pharmaceutical, MSD, Viatris, and Lundbeck Japan., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Background: Previous research has raised concerns regarding inconsistencies between reported and pre-specified outcomes in randomized controlled trials (RCTs) across various biomedical disciplines. However, studies examining whether similar discrepancies exist in RCTs focusing on gastrointestinal and liver diseases are limited. This study aimed to assess the extent of discrepancies between registered and published primary outcomes in RCTs featured in journals specializing in gastroenterology and hepatology., Methods: We retrospectively retrieved RCTs published between January 1, 2017 and December 31, 2021 in the top three journals from each quartile ranking of the 2020 Journal Citation Reports within the "Gastroenterology and Hepatology" subcategory. We extracted data on trial characteristics, registration details, and pre-specified versus published primary outcomes. Pre-specified primary outcomes were retrieved from the World Health Organization's International Clinical Trials Registry Platform. Only trials reporting specific primary outcomes were included in analyzing primary outcome discrepancies. We also assessed whether there was a potential reporting bias that deemed to favor statistically significant outcomes. Statistical analyses included chi-square tests, Fisher's exact tests, univariate analyses, and logistic regression., Results: Of 362 articles identified, 312 (86.2%) were registered, and 79.8% of the registrations (249 out of 312) were prospective. Among the 285 trials reporting primary outcomes, 76 (26.7%) exhibited at least one discrepancy between registered and published primary outcomes. The most common discrepancies included different assessment times for the primary outcome (n = 32, 42.1%), omitting the registered primary outcome in publications (n = 21, 27.6%), and reporting the registered secondary outcomes as primary outcomes (n = 13, 17.1%). Univariate analyses revealed that primary outcome discrepancies were lower in the publication year 2020 compared to year 2021 (OR = 0.267, 95% CI: 0.101, 0.706, p = 0.008). Among the 76 studies with primary outcome discrepancies, 20 (26.3%) studies were retrospectively registered, and 32 (57.1%) of the prospectively registered trials with primary outcome discrepancies showed statistically significant results. However, no significant differences were found between journal quartiles regarding primary outcome consistency and potential reporting bias (p = 0.14 and p = 0.28, respectively)., Conclusions: This study highlights the disparities between registered and published primary outcomes in RCTs within gastroenterology and hepatology journals. Attention to factors such as the timing of primary outcome assessments in published trials and the consistency between registered and published primary outcomes is crucial. Enhanced scrutiny from journal editors and peer reviewers during the review process is necessary to ensure the reliability of gastrointestinal and hepatic trials., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Adriano R. Tonelli plays as an advisory board for Janssen and Merck and received grant from Janssen; Szymon Bialka is the secretary of the Silesian Branch of the Polish Society of Anesthesiology and Intensive Care from 2021 till now, the president of the Section of Regional Anesthesia and Pain Therapy and Polish Society of Anesthesiology and Intensive Care from 2021 til now, continued Treasurer of the Polish Society of Regional Anesthesia and Pain Therapy from 2023 till now, a co-creator patent device for isolating a patient with suspected infectious disease (exclusive right number: Pat.243051)., (Copyright: © 2024 Shang 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.)

Objective: The genus Veillonella is one of the major and important constitutions of the oral microbiome. A novel anaerobic, Gram-negative coccus belonging to the genus Veillonella was isolated from the saliva of a child. In the present study, the characterization of strain S12025-13 T , is described with the comparison to established species of the genus Veillonella and a novel oral species of the genus Veillonella is proposed., Methods: Strain S12025-13 T was conclusively identified using phenotypic, phylogenetic, genomic and biochemical approach. In phylogenetic analysis, multi-locus species trees (MLST) analysis was also conducted in this study., Results: The strain S12025-13 T showed typical phenotypic characteristics of members of the genus Veillonella. Under anaerobic conditions, the strain produced acetic acid and propionic acid as metabolic end products in a trypticase-yeast extract-heamin medium containing 1 % (w/v) glucose, 1 % (w/v) fructose and 1 % (v/v) sodium lactate. Sequencing of their 16S rRNA genes confirmed that it belongs to the genus Veillonella. Comparative analysis of the 16S rRNA, dnaK and rpoB gene sequences indicated that phylogenetically the strain comprised a distinct novel branch within the genus Veillonella. The novel strain showed 99.77, 97.29, and 99.02 % similarity to partial 16S rRNA, dnaK and rpoB gene sequencing, respectively, to the type strains of the most closely related species. In MLST (selected 79 genes) analysis, strain S12025-13 T formed a distinct taxon with robust bootstrap support (100 %) within the genus Veillonella. Furthermore, strain S12025-13 T shared the highest average nucleotide identity (ANI) value (95.97 %) with the type strain of the most closely related species, "Veillonella faecalis" which is not validly published under the International Code of Nomenclature of Prokaryotes (ICNP). Likewise, strain S12025-13 T showed the highest digital DNA-DNA hybridization (dDDH) value (65.00 %) with the type strain of "V. faecalis". In addition, strain S12025-13 T formed a distinct branch in this clade with a bootstrap value of 72 % with Veillonella nakazawae and 51 % with "V. faecalis" related species of the genus Veillonella in the genome based phylogenetic tree., Conclusion: The novel strain could be discriminated from previously reported species of the genus Veillonella based on partial dnaK gene sequencing, MLST analysis, ANI and dDDH values, and genome-based phylogeny. Based on these observations, this strain represents a novel species, for which the name Veillonella orientalis sp., nov. is proposed. The type strain is S12025-13 T (= JCM 33967 T  = CCUG 74596 T )., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Opantimycin A, a rare antimycin-class antibiotic without the macrolide core, was isolated from Streptomyces sp. RK88-1355 in 2017. In this study, we explored the total synthesis and stereochemical assignment of opantimycin A. The synthesis of all potential diastereomers has been accomplished via traceless Staudinger ligation. A comparison of the spectroscopic data of the synthesized compounds with that reported for the natural product confirmed that the absolute configuration of the natural product was (14 S ,17 R ,21 R ). Two analogous compounds were prepared, where the Dhb (( Z )-dehydrobutyrine) moiety was replaced with Dha (dehydroalanine) or ΔVal moieties, respectively. The inhibitory activities of these synthetic compounds against the production of the anti-inflammatory cytokine IL-6 were evaluated, and two potential candidates for further development as anti-inflammatory agents were identified.

Activins, multifunctional cytokines of the transforming growth factor-beta superfamily, play critical roles in the regulation of growth and differentiation in multiple biological systems. Activin activity is finely regulated by the endogenous antagonist follistatin. Early studies reported that activins are involved in renal organogenesis, but subsequent research demonstrated that activins also play a significant role in kidney regeneration following injury. The results of more recent studies suggest activins play roles in both inflammatory kidney diseases and renal fibrosis, conditions that often culminate in end-stage renal disease. Given these findings, the inhibition of activin activity represents a promising therapeutic approach for treating a range of kidney disorders. This review discusses the latest discoveries concerning the role of the activin-follistatin system in renal development and pathophysiology and explores the potential therapeutic implications of targeting this system in the management of kidney diseases., 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 Ltd. All rights reserved.)

Since sarcopenic obesity (SO) impacts negatively on our health, early detection of SO is essential. However, prevalence of SO in an apparently healthy population has not been well examined. This study aimed to elucidate the prevalence and related factors of SO in middle-aged women, and to investigate useful diagnostic criteria for SO. Body component analyses were conducted on 432 female Osaka University employees aged 30-59 during their health checkups. Healthy (H) and SO groups were defined using cutoff values of 5.7 kg/m 2 for skeletal muscle mass index and 30% for percent body fat. Serum myostatin and insulin levels were additionally measured. Among 432 participants, the prevalence of SO was 6.3%. Grip strength (P < 0.0001) was lower and triglyceride (P = 0.0004) and low-density lipoprotein cholesterol (P = 0.0105) levels, and Homeostatic Model Assessment of Insulin Resistance (P = 0.0262) were higher in the SO group than in the H group. Serum myostatin levels in the SO group were lower than in the H group (3,107 pg/mL vs. 3,957 pg/mL, P = 0.0003). Myostatin levels may be suppressed in individuals with SO without any pre-existing conditions. Our diagnostic criteria for SO could reveal the risks for metabolic-related diseases and may be useful for the early detection of SO., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Microglia are the immune cells in the central nervous system (CNS) and become pro-inflammatory/activated in Alzheimer's disease (AD). Cell surface glycosylation plays an important role in immune cells; however, the N-glycosylation and glycosphingolipid (GSL) signatures of activated microglia are poorly understood. Here, we study comprehensive combined transcriptomic and glycomic profiles using human induced pluripotent stem cells-derived microglia (hiMG). Distinct changes in N-glycosylation patterns in amyloid-β oligomer (AβO) and LPS-treated hiMG were observed. In AβO-treated cells, the relative abundance of bisecting N-acetylglucosamine (GlcNAc) N-glycans decreased, corresponding with a downregulation of MGAT3. The sialylation of N-glycans increased in response to AβO, accompanied by an upregulation of genes involved in N-glycan sialylation (ST3GAL4 and 6). Unlike AβO-induced hiMG, LPS-induced hiMG exhibited a decreased abundance of complex-type N-glycans, aligned with downregulation of mannosidase genes (MAN1A1, MAN2A2, and MAN1C1) and upregulation of ER degradation related-mannosidases (EDEM1-3). Fucosylation increased in LPS-induced hiMG, aligned with upregulated fucosyltransferase 4 (FUT4) and downregulated alpha-L-fucosidase 1 (FUCA1) gene expression, while sialofucosylation decreased, aligned with upregulated neuraminidase 4 (NEU4). Inhibition of sialyation and fucosylation in AβO- and LPS-induced hiMG alleviated pro-inflammatory responses. However, the GSL profile did not exhibit significant changes in response to AβO or LPS activation. AβO- and LPS- specific glycosylation changes could contribute to impaired microglia function, highlighting glycosylation pathways as potential therapeutic targets for AD., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. Additional Declarations: No competing interests reported.

Objective: This study aimed to investigate the relationship between falls and cognitive and balance problems in patients., Methods: This retrospective observational study analyzed the medical records of 1010 older patients admitted to a convalescent rehabilitation ward. The primary endpoint was fall occurrence during ward stays. The main outcomes were the Mini-Mental State Examination (MMSE) and Standing Test for Imbalance and Disequilibrium (SIDE), with patients divided into groups of MMSE ≥28 and <28 and SIDE ≥2b and <2b., Results: During ward stays, 220 patients (22%) fell. Estimating the fall risk of the MMSE ≥28 + SIDE ≥2b group compared to that of other groups revealed that only the MMSE <28 + SIDE <2b group had a significantly higher fall risk, with a hazard ratio [95% confidence interval] of 3.13 [1.51-6.46]., Conclusion: Combined MMSE and SIDE assessment at ward admission facilitated the easy identification of individuals at high fall risk., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.