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

In African American adults, the strongest genetic predictor of pneumonia appears to be the A allele of rs334, a variant in the β-globin gene, which in homozygous form causes sickle cell disease (SCD). No comparable studies have been done in African American children. We performed genome-wide association analyses of 482 African American children with documented pneumonia and 2,048 African American control individuals using genotypes imputed from two reference panels: 1000 Genomes (1KG) (which contains rs334) and TOPMed (does not contain rs334). Using 1KG imputed genotypes, the most significant variant was rs334 (A allele; odds ratio [OR] = 2.76; 95% CI, 2.21-3.74; p = 5.9 × 10 -19 ); using TOPMed imputed genotypes the most significant variant was rs2226952, found in the β-globin locus control region (G allele; OR = 2.14; 95% CI, 1.78-2.57; p = 5.1 × 10 -16 ). After conditioning on rs334, the most strongly associated variant in the β-globin locus, rs33930165 (T allele, 1KG: OR = 4.09; 95% CI, 2.29-7.29; p = 1.7 × 10 -6 ; TOPMed: OR = 3.58; 95% CI, 2.18-5.90; p = 4.7 × 10 -7 ), which as a compound heterozygote with rs334 A allele, can cause SCD. To compare the power of different sample sets we developed a way to estimate the power of sample sets with different sample sizes, genotype arrays, and imputation platforms. Our results suggest that, in African American children, the strongest genetic determinants of pneumonia are those that increase the risk of SCD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Precise control of assembled structures of quantum dots (QDs) is crucial for realizing the desired photophysical properties, but this remains challenging. Especially, the one-dimensional (1D) control is rare due to the nearly isotropic nature of QDs. Herein, we propose a novel strategy for controlling the 1D-arrangement range of cubic perovskite QDs in solution based on the morphological modification of a supramolecular polymer (SP) template. The original template with a short and tangled fibrous structure is prepared in a low-polarity solvent mixture via self-assembly of a naphthalenediimide-functionalized cholesterol derivative with an adhesion group for QDs. Mixing this template with QDs leads to the co-aggregation into short-range 1D-arrays of QDs on the templates. Notably, subsequent heating and cooling of the co-aggregate solution forms longer-range 1D-arrays of QDs with lateral growth, where arranged QDs are sandwiched between reconstructed SP templates. Furthermore, the longer-range 1D-array of QDs is achieved via an alternative route involving the pre-organization of templates into longer and dispersed fibers by heating and cooling of the original template, succeeded by co-assembly with QDs. Finally, we reveal continuous fluorescence resonance energy transfer between 1D-arranged QDs by an in-depth analysis of the photoluminescence decay curves., (© 2025 Wiley‐VCH GmbH.)

Genome-wide association studies have identified approximately 200 genetic risk loci for breast cancer, but the causal variants and target genes are mostly unknown. We sought to fine-map all known breast cancer risk loci using genome-wide association study data from 172,737 female breast cancer cases and 242,009 controls of African, Asian and European ancestry. We identified 332 independent association signals for breast cancer risk, including 131 signals not reported previously, and for 50 of them, we narrowed the credible causal variants down to a single variant. Analyses integrating functional genomics data identified 195 putative susceptibility genes, enriched in PI3K/AKT, TNF/NF-κB, p53 and Wnt/β-catenin pathways. Single-cell RNA sequencing or in vitro experiment data provided additional functional evidence for 105 genes. Our study uncovered large numbers of association signals and candidate susceptibility genes for breast cancer, uncovered breast cancer genetics and biology, and supported the value of including multi-ancestry data in fine-mapping analyses., Competing Interests: Competing interests: O.I.O is co-founder at CancerIQ, serves as Scientific Advisor at Tempus and is on the Board of 54gene. The other authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The prevalence of wild-type transthyretin (ATTR) amyloidosis is increasing with advancements in diagnostic techniques and growing awareness of the disease worldwide. 99m Tc-labeled pyrophosphate ( 99m Tc-PYP) scintigraphy exhibits high performance in diagnosing ATTR cardiac amyloidosis. This study aimed to validate the characteristics of patients with positive 99m Tc-PYP scintigraphy results in a multicenter setting to provide more accurate case selection criteria., Methods and Results: In total, 180 patients with suspected ATTR amyloidosis underwent 99m Tc-PYP scintigraphy in participating institutions in Japan between January 2018 and July 2022. Of 135 patients included in the analysis, 62 were 99m Tc-PYP-positive. Logistic regression analysis was performed, and the following five factors were adopted to create a scoring system, with each weighted according to its odds ratio value; 1 point was scored for the absence of hypertension, existence of peripheral entrapment neuropathy (carpal tunnel syndrome or spinal canal stenosis), conduction disturbance (the presence of QRS complex ≥120 ms, first-degree atrioventricular block, higher degree of atrioventricular block, or presence of pacemaker implantation), and left ventricular hypertrophy and 2 points for troponin I/T ≥ 0.06 ng/mL. 99m Tc-PYP scintigraphy positivity rate in the 0-point group was 0 %, whereas that in the 6-point group was 100 %. The area under the curve of the criteria was 0.820 (95 % confidence interval, 0.752-0.888; P < 0.001)., Conclusions: The combination of clinical information, which is easily available in local clinics, can provide accurate pretest prediction of positive 99m Tc-PYP scintigraphy results. This will help clinicians to make an early diagnosis of ATTR amyloidosis., Competing Interests: Declaration of competing interest Yuya Matsue received an honorarium from Otsuka Pharmaceutical Co., Novartis Pharma K.K., Bayer Inc., and AstraZeneca, and a collaborative research grant from Pfizer Japan Inc., Otsuka Pharmaceutical Co., EN Otsuka Pharmaceutical Co., Ltd., and Nippon Boehringer Ingelheim Co., Ltd. Hidekazu Tanaka received remuneration from AstraZeneca plc, Ono Pharmaceutical Company, Limited. Pfizer Inc., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Boehringer Ingelheim GmbH, Abbott Japan LLC, and Novartis International AG., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Emerging evidence suggests a link between salivary metabolite changes and neurodegenerative dementia, with antimicrobial peptides (AMPs) implicated in its pathogenesis., Objective: We investigated the effects of a clinical oral rehabilitation programme tailored for dementia patients on salivary flow rate, AMP levels and oral health-related quality of life (OHRQoL)., Methods: Eligible patients were randomly assigned to either the experimental group (EG; n = 28) or the control group (CG; n = 27). Both groups received a leaflet on oral health. In addition, the EG received an oral care intervention that included individual lessons on oral muscle exercises and oral self-care practices. Saliva samples and OHRQoL data were collected at baseline and follow-up visits. Generalised estimating equation models were used to analyse the changes over time., Results: At the 3-month follow-up, EG showed significantly lower histatin 5 (HTN-5) levels (β = -0.08; effect size [ES] = 0.72) than CG. At 6 months, EG exhibited improved salivary flow rate (β = 0.89; ES = 0.89) and OHRQoL (β = 6.99; ES = 1.31) compared to CG. Changes in salivary flow rate (β = 4.03), HTN-5 level (β = -0.78) and beta-defensin 2 level (BD-2) (β = -0.91) at 3 months predicted improved OHRQoL at 6 months (all p < 0.05)., Conclusions: Our clinical oral rehabilitation programme reduced the level of salivary HTN-5, increased salivary flow rate and enhanced OHRQoL in dementia patients. Furthermore, changes in salivary flow rate, HTN-5 level and BD-2 level were associated with improvements in patients' OHRQoL., (© 2024 John Wiley & Sons Ltd.)

The absolute value of small dense low-density lipoprotein (sd-LDL) including small LDL (s-LDL) and very small LDL (vs-LDL) has been shown to be associated with increased incidence of atherosclerosis. However, the impact of short-timeframe increases in sd-LDL on arteriosclerosis has not yet been elucidated. Therefore, we investigated the clinical roles of ex-vivo induced sd-LDL in acute coronary syndrome (ACS) using a novel method. This is a prospective, single-blind, and observational study that screened patients who underwent coronary angiography (CAG) for the treatment of ACS or investigation of heart-failure etiology between June 2020 and April 2022 (n = 247). After excluding patients with known diabetes mellitus and advanced renal disease, the patients were further divided into the ACS (n = 34) and control (non-obstructive coronary artery, n = 34) groups. The proportion of sd-LDL (s-LDL + vs-LDL) in total lipoproteins was observed before and after 2-h incubation at 37 ℃ (to approximate physiologic conditions) using 3% polyacrylamide gel electrophoresis. The coronary plaque burden was quantified upon CAG in the ACS group. There were no significant differences between the ACS and control groups in terms of clinical coronary risk factors. The baseline of large, medium, small, and very small LDL were comparable between the two groups. Following a 2-h incubation period, significant increases were observed in the ratios of s-LDL and vs-LDL in both the ACS and control groups (ACS, p = 0.01*; control, p = 0.01*). Notably, the magnitude of increase in sd-LDL was more pronounced in the ACS group compared to the control group, with s-LDL showing a significant difference (p = 0.03*) and vs-LDL showing a tread toward significance (p = 0.08). In addition, in both groups, there was a decrease in IDL and L-LDL, while M-LDL remained unchanged. The plaque burden index and rate of short-timeframe changes in both s-LDL (p = 0.01*) and vs-LDL (p = 0.04*) before and after incubation were significantly correlated in the ACS group. The enhanced production rate of sd-LDL induced under short-term physiologic culture in an ex-vivo model was greater in patients with ACS than in the control group. The increase in sd-LDL is positively correlated with coronary plaque burden. Short-timeframe changes in sd-LDL may serve as markers for the severity of coronary artery disease., Competing Interests: Declarations. Conflict of interest: The authors declare that they do not have any conflict of interest. Ethical approval: This study was approved by the Clinical Research Appropriate Promotion Center at Saitama Medical University International Medical Center (No. 19-307), and written informed consent was obtained from all participants., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

Neoantigen-reactive CD4 + T cells play a key role in the anti-tumor immune response. However, the majority of epithelial tumors are negative for HLA class II (HLA-II) surface expression, and less is known about the processing of HLA-II antigens. Here, we directly identified naturally presented HLA-II neoantigens in HLA-II negative colorectal cancer (CRC) tissue using a proteogenomic approach. The neoantigens were immunogenic and induced patient CD4 + T cells with a Th1-like memory phenotype that produced IFN-γ, IL2 and TNF-α. Multiplex immunohistochemistry (IHC) demonstrated an interaction between Th cells and HLA-II-positive antigen-presenting cells (APCs) at the invasive margin and within the tertiary lymphoid structures (TLS). In our CRC cohort, the density of stromal APCs was associated with HLA-II antigen presentation in the tumor microenvironment (TME), and the number of TLS was positively correlated with the number of somatic mutations in the tumors. These results demonstrate the presence of neoantigen-specific CD4 + surveillance in HLA-II-negative CRC and suggest a potential role for macrophages and dendritic cells (DCs) at the invasive margin and in TLS for antigen presentation. Stromal APCs in the TME can potentially be used as a source for HLA-II neoantigen identification.

"Wound, Pressure Ulcer, and Burn Guidelines-5: Guidelines for the management of lower leg ulcers and varicose veins, second edition" is revised from the first edition, which was published in the Japanese Journal of Dermatology in 2011. The guidelines were drafted by the Wound, Pressure Ulcer, and Burn Guidelines Drafting Committee delegated by the Japanese Dermatological Association and intend to facilitate physicians' clinical decisions in preventing, diagnosing and management of lower leg ulcers and varicose veins. We updated all sections by collecting documents published since the publication of the first edition. In particular, we added clinical question 8 (CQ8), which addresses endovenous laser ablation for varicose veins, a procedure that became covered by the Japanese national health insurance after the writing of the first edition, and endovenous radiofrequency ablation, which became covered by national health insurance in 2014. We also rearranged the subsequent clinical question (CQs) for easier reading. While the addition of these new techniques has increased the number of options available within the treatment algorithm, differences have arisen in the indication for surgery depending on the facility performing the treatment. Therefore, these have been abbreviated., (© 2024 Japanese Dermatological Association.)

A patient with behavioral variant frontotemporal dementia presented with stereotypic speech. The 85-year-old right-handed man had progressive language disorder over 2 years, with changes in eating behavior. His verbal output consisted mainly of the stereotypic speech; his articulation was mildly distorted, but his speech was intelligible. Spontaneous speech was rare, but there was no evidence of difficulty in initiating speech or effort. MRI of the head showed atrophy of the left frontal lobe, mainly in the superior, middle, and inferior frontal gyrus. Cerebral blood flow SPECT showed decreased cerebral blood flow in the same areas and in the left basal ganglia. We diagnosed behavioral variant frontotemporal dementia based on the symptoms, progression, and lesions. The stereotypic speech was judged to be non-meaningful recurrent utterance.

Alkaline-earth metal oxides with the rocksalt structure, which are simple ionic solids, have attracted attention in attempts to gain fundamental insights into the properties of metal oxides. The surfaces of alkaline-earth metal oxides are considered promising catalysts for the oxidative coupling of methane (OCM); however, the development of such catalysts remains a central research topic. In this paper, we performed first-principles calculations to investigate the ability of four alkaline-earth metal oxides (MgO, CaO, SrO, and BaO) to catalyze the OCM. We adopted five types of surfaces of rocksalt phases as research targets: the (100), (110), stepped (100), oxygen-terminated octopolar (111), and metal-terminated octopolar (111) surfaces. We found that the formation energy of surface O vacancies is a good descriptor for the adsorption energy of a H atom and a methyl radical. The energies related to the OCM mechanism show that, compared with the most stable surface, the minor surfaces better promote the C - H bond cleavage of methane. However, as the trade-off for this advantage, the minor surfaces exhibit increased affinity for the methyl radical. On the basis of this trade-off relationship between properties, we identified several surfaces that we expect to be promising OCM catalysts. Our investigation of the temperature dependence of the Gibbs free energy indicated that, at higher temperatures, the step (100) surface exhibits properties that might benefit the OCM mechanism., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by National Institute for Materials Science in partnership with Taylor & Francis Group.)

Background: There are scarce data on risk factors for epithelial ovarian cancer (EOC) in Asian populations. Our goal was to advance knowledge on reproductive -related risk factors for EOC in a large population of Asian women., Methods: This study used pooled individual data from baseline questionnaires in 11 prospective cohorts (baseline years, 1958-2015) in the Asia Cohort Consortium. A Cox proportional hazards regression model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusting for age, parity and cohort., Results: After a mean = 17.0 years (SD = 6.3) of follow-up, 674 incident invasive EOC cases were identified among 325,626 women. In multivariable adjusted models we observed an inverse association with parity (5+ children vs. 0, HR = 0.44, 95% CI = 0.28-0.68, Ptrend < 0.001), and a positive association with increasing menopausal age (55+ years vs. <45, HR = 1.77, 95% CI = 1.05-3.01, Ptrend = 0.02) for risk of all EOC., Conclusions: In this large study of Asian women we identified an inverse association with parity and a positive association with higher menopausal age in relation to EOC risk. Further work is needed to understand EOC risk factors for rare histologic subtypes that occur more frequently in Asian populations., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The institutional review board of the National Cancer Center Japan approved the analysis in the Asia Cohort Consortium (ACC) (number 2014-041) and each cohort study included in ACC received ethical approval by their respective institutional ethical committees. Written or oral consent was provided by all subjects who participated in the study. The authors certify that the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments. Consent for publication: This is an observational study involving the analysis of secondary data only. All data were deidentified. There was no direct interaction with human subjects for this study., (© 2024. The Author(s).)

Purpose: Using a magnetic resonance (MR) image generation technique with deep learning, we elucidated whether changing the training data patterns affected image generation accuracy., Methods: The pix2pix training model generated T1-weighted images from T2-weighted images or FLAIR images. Head MR images obtained at our hospital were used in this study. We prepared 300 cases for each model and four training data patterns for each model (a: 150 cases for one MR system, b: 300 cases for one MR system, c: 150 cases and augmentation data for one MR system, and d: 300 cases for two MR systems). The extension data were images of 150 cases rotated in the XY plane. The similarity between the images generated by the training and evaluation data in each group was evaluated using the peak signal-to-noise ratio (PSNR) and structural similarity (SSIM)., Results: For both MR systems, the PSNR and SSIM were higher for training dataset b than training dataset a. The PSNR and SSIM were lower for training dataset d., Conclusion: MR image generation accuracy varied among training data patterns.

Background: Although vancomycin is commonly used to treat methicillin-resistant coagulase-negative staphylococci (MRCoNS) infections, there are no clear guidelines for the optimal 24 h AUC24/MIC ratio. This study aimed to determine the target AUC24/MIC ratio associated with vancomycin-treated MRCoNS infection outcomes., Methods: This multicentre retrospective cohort study included adult patients who received vancomycin for ≥5 days for bloodstream infections caused by MRCoNS between January 2018 and December 2023. Primary outcome was treatment success, defined as a composite of survival beyond 30 days, clinical success and microbiological eradication. Secondary outcomes included 30-day mortality, clinical success, microbiological eradication and nephrotoxicity. Receiver operating characteristic (ROC) curve analysis was used to identify the AUC24/MIC cut-off for treatment success. Multivariate regression analysis was used to determine the association between AUC24/MIC and outcomes., Results: This study included 147 patients. ROC analysis identified a target AUC24/MIC ≥373 for treatment success. The overall treatment success rate (70.1%) was significantly higher in the above-average AUC24/MIC cut-off group (83.1%) than that in the below AUC24/MIC cut-off group (57.9%). Multivariate analysis confirmed that AUC24/MIC ≥373 was an independent predictor (adjusted OR = 10.227; 95% CI = 3.585-29.171). The 30-day mortality and microbiological eradication rates differed significantly between the below- and above-cut-off groups, whereas nephrotoxicity rates were comparable among the groups., Conclusions: In treating MRCoNS infections, vancomycin AUC24/MIC ratio ≥373 was independently associated with favourable treatment outcomes. However, further prospective studies are required to confirm this target owing to the retrospective nature of this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Reverse genetics systems for rotaviruses (RV) facilitate the generation of genetically engineered RVs by transfection of 11 plasmids encoding 11 genomic viral RNA segments. In addition to viral genome expression, overexpression of NSP2 and NSP5 has been used to increase the rescue efficiency of recombinant RVs. Here, we showed that the overexpression of nucleotide sequence-modified NSP2 and NSP5 enabled the rapid and efficient production of recombinant RVs. Using improved reverse genetics, we established a reverse genetics system for human and bovine RV clinical isolates, as well as laboratory strains of bovine RV (NCDV and UK) and porcine RV (Gottfried). In addition, we rescued low-replicating recombinant RVs carrying a mutant NSP4 lacking the double-layered particle-binding domain, which was deficient in the efficient production of mature virions. These advancements in reverse genetics enabled the generation of molecular clones of RV clinical isolates and recombinant RVs harboring critical amino acid mutations, offering a versatile platform for investigating RV biology and pathogenesis.IMPORTANCERecombinant rotavirus (RV) synthesis via reverse genetics relies on both the viral propagation capacity and the efficiency of the experimental system. Since the establishment of our reverse genetics system, several enhancements have been implemented to augment the rescue efficiency. Nevertheless, challenges persist in generating RV clinical strains and recombinant viruses with low replication capacities. Notably, this improved reverse genetics system successfully facilitated the establishment of molecular clones of human and bovine RV clinical isolates. Fecal samples from patients with RV typically harbor quasi-species or, occasionally, multiple genotypes of RV. In the present study, we performed the genetic sequencing of clinical viral strains during the early propagation stages in cultured cells. Subsequently, infectious viruses were synthesized, allowing the characterization of circulating viruses in nature. This approach provides valuable insights into the genetic diversity and dynamics of RV populations and contributes to a more comprehensive understanding of viral pathogenesis and evolution., Competing Interests: The authors declare no conflict of interest.

Wilms' Tumor (WT1) mRNA is a non-specific marker of measurable residual disease in acute myeloid leukemia (AML). Few studies have focused on the prognostic value of WT1 mRNA after initial remission induction of patients with AML who have received transplant treatments. Thus, we retrospectively analyzed the clinical features and prognostic impact of WT1 mRNA reduction in patients with AML after initial remission induction at our hospital. We classified the reduction in WT1 mRNA levels using logarithmic stratification, with particular focus on the prognostic impact of a 3-log reduction after initial remission induction. This single-center, retrospective, observational study included 71 consecutive patients with AML who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) between April 2013 and June 2023 and had WT1 mRNA quantified. Patients were grouped based on whether a 3-log reduction was observed during follow-up (N=30) or not (N=41). Among patients who did not achieve a 3-log reduction, European Leukemia Net (ELN) 2022 adverse risk was more common, and fewer patients showed complete hematological responses at transplantation. Patients who reached a 3-log reduction in WT1 mRNA after the initial remission induction had significantly longer overall survival (OS) and progression-free survival (PFS) and a lower relapse rate than patients who had not reached a 3-log reduction (2-year OS: 79.7% vs. 27.5%, 2-year PFS: 83.1% vs. 11.7% and 2-year cumulative relapse rate: 5.9% vs. 81.2%). In multivariate analysis, a 3-log reduction in WT1 mRNA after initial remission induction and ELN 2022 adverse risk by genetics were significantly associated with OS and PFS. We identified that patients with AML undergoing HSCT with an early and deep 3-log reduction in WT1 mRNA after initial remission induction were associated with low relapse rates and better long-term prognosis. Our data highlight the importance of WT1 mRNA reduction after initial remission induction., (Copyright © 2025. Published by Elsevier Inc.)

A 38-year-old woman with a history of systemic lupus erythematosus presented at our university hospital with fever, fatigue, and oral pain and was urgently admitted based on a diagnosis of septic shock. Initially, dental infection was suspected based on the symptoms and clinical presentation of purpura accompanied by severe tenderness along the marginal gingiva in the maxilla and mandible. However, subsequent investigations, including an oral examination, radiographic studies, and blood cultures, ruled out dental infection as the cause of the septic shock. The patient received antibiotic therapy and was discharged on Day 16 after admission, with no definitive source of the infection yet being identified. The gingiva around where the purpura was observed on Day 1 gradually necrosed and detached, leading to ulcer formation by Day 8 and gingival recession by Day 15. Gingival necrosis was attributed to septic shock-induced neutropenia and circulatory disturbances, indicating the severity of the systemic conditions. Follow-up after discharge revealed no recurrence. This case underscores the importance of recognising oral symptoms as potential precursors to severe systemic conditions such as septic shock. Timely intervention and interdisciplinary collaboration are essential in effectively managing such cases. Further research is warranted to elucidate the relationship between oral health and systemic diseases to enable clinicians to provide optimal patient care.

Tumor-reactive CD4+ T cells often accumulate in the tumor microenvironment (TME) in human cancer, but their functions and roles in antitumor responses remain elusive. Here, we investigated the immunopeptidome of HLA class II-positive (HLA-II+) endometrial cancer with an inflamed TME using a proteogenomic approach. We identified HLA-II neoantigens, one of which induced polyclonal CD4+ tumor-infiltrating lymphocyte (TIL) responses. We then experimentally demonstrated that neoantigen-specific CD4+ TILs lyse target cells in an HLA-II-dependent manner. Single cell transcriptomic analysis of the TME coupled with T-cell receptor (TCR) sequencing revealed the presence of CD4+ T-cell clusters characterized by CXCL13 expression. The CXCL13+ clusters contained two subclusters with distinct cytotoxic gene expression patterns. The identified neoantigen-specific CD4+ T cells were found exclusively in one of the CXCL13+ subclusters characterized by granzyme B and CCL5 expression. These results demonstrate the involvement of tumor-reactive CD4+ T cells with cytotoxic function in immune surveillance of endometrial cancer and reveal their transcriptomic signature.

Objectives: The deterioration of oral function to a state of oral hypofunction (OHF) has been associated with malnutrition and frailty. This cross-sectional pilot study investigated for differences in OHF prevalence and its category measures across age groups and sex, as well as their associations with physical function., Methods: A total of 155 healthy adults (median age: 55 years, range: 22-89 years) participated in this study after providing informed consent. The cohort was age and sex matched. Seven oral function measures based on the concept of OHF were assessed: oral hygiene (Hygiene), oral dryness, maximum occlusal force (MOF), lip-tongue motor function (LTMF), maximum tongue pressure (MTP), masticatory function, and swallowing function. Hand grip strength (HGS) was also measured. The participants were divided into the young (20-39 years), middle (40-64 years), and old (≥ 65 years) age groups for linear regression analysis of differences in oral and physical function. Differences in OHF prevalence were tested by the chi-square test., Results: The prevalence of OHF was significantly higher in the old group than in the young and middle groups. Such OHF measures as Hygiene, MTP, LTMF, and MOF were significantly worse in the old group as well. The measures of Hygiene and LTMF showed a moderate correlation with age in the multiple regression model (standardized partial regression coefficient, β = 0.24 and -0.19, respectively). HGS was significantly associated with MTP (β = 0.58, p < 0.001) and LTMF (β = 0.38, p = 0.002) in both male and female participants., Conclusions: Our findings suggest that OHF prevalence increases with age, especially after 65 years old. However, the pathological route may vary among OHF categories., Competing Interests: Declarations. Ethics approval and consent to participate: This study’s protocol was approved by the Institutional Review Board of Tokyo Medical and Dental University (Approval ID: D2022-053–01). Informed consent was obtained from all participants involved in the study. Consent for publication: Not applicable. Competing interests: A grant aid from GC Corporation., (© 2024. The Author(s).)

Purpose: Younger age and steep posterior tibial slope (PTS) have been reported as risk factors for graft failure after anterior cruciate ligament reconstruction (ACLR). Few studies have evaluated these risk factors simultaneously in a large cohort of patients undergoing double-bundle ACLR (DB-ACLR). Therefore, this retrospective study aimed to simultaneously investigate known risk factors such as PTS and age in DB-ACLR, determine their thresholds and calculate odds ratios (ORs)., Methods: We investigated 482 knees that underwent DB-ACLR with a follow-up period of at least 2 years. Receiver operating characteristic analysis determined cut-off values for age and PTS for graft failure. Subsequently, logistic regression analysis was conducted to evaluate the effects of age, sex, height, weight, laterality, surgical waiting period, pre-operative sport type and level, meniscal injury, hyperextension, general joint laxity and PTS on graft failure., Results: Graft failure was observed in 33 out of 482 knees (6.8%). Notably, the graft failure group was significantly younger (18.0 ± 5.0 years [standard deviation] vs. 30.4 ± 13.1 years, p  < 0.01) and had a steeper PTS (11.9 ± 2.3° [standard deviation] vs. 9.6 ± 2.9°, p  < 0.01) than the group with no graft failure. The cut-off values were 20.0 years for age (specificity, 64.6%; sensitivity, 87.9% and area under the curve, 0.808) and 12.0° for PTS (specificity, 70.9%; sensitivity, 69.7% and area under the curve, 0.734). Logistic regression analysis identified an age of <20 years (OR = 10.1; p  < 0.01), PTS of ≥12° (OR = 5.6; p  < 0.01) and pre-operative participation in pivoting sports (OR = 6.0; p  < 0.01) as significant risk factors for graft failure., Conclusion: We identified an age of <20 years, PTS of ≥12° and pre-operative participation in pivoting sports as significant risk factors for graft failure after DB-ACLR., Level of Evidence: Level III., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Purpose: To clarify indications for treating incidental obturator hernia (IOH) detected during laparoscopic groin hernia repair by comparing features of IOH with obturator hernia (OH) complicated by incarceration., Methods: Twenty patients who underwent laparoscopic OH repair between January 2017 and July 2024 were included in this retrospective study. They were divided into groups with incarceration or a past history of incarceration (the OH group) or without incarceration (the IOH group). Univariate analysis was performed, and ROC curves were constructed with the cut-off values representing indications for treating IOH., Results: Thirteen patients comprised the IOH group (bilateral in one), while seven comprised the OH group (all unilateral). Univariate analysis selected high age, low body mass index (BMI), and a large orifice as risk factors for incarceration. Cut-off values of these variables were age 89 years (area under curve, 0.816), BMI 17.7 kg/m 2 (0.939), and orifice diameter 12 mm (0.796). Age of at least 89 years and BMI of 18 or less were more common in the incarceration group (P = 0.004, P = 0.007), and all patients in the incarceration group had orifices at least 12 mm in diameter. Assigning the 3 variables 1 point each, the OH group had significantly higher scores of at least 2 points (P < 0.001)., Conclusion: High age, low BMI, and large orifice diameter may be considered useful indicators for treating IOH. Two or more of these factors could place a patient at high risk for incarceration and show need for treatment of IOH., Competing Interests: Declarations. Conflict of interest: We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied criteria for authorship but are not listed. We further confirm that all authors have approved the order in which they are listed at the beginning of the manuscript. All authors declare that they have no conflicts of interest. Ethical standards: Since this study is a retrospective, noninvasive observational study, we applied for and received approval from the Institutional Ethics Committee at Showa University (notice of approval number, 2023-067-B) using the opt-out method. The investigation was conducted in compliance with the Declaration of Helsinki of 1975., (© 2024. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Aims: Paclitaxel and nanoparticle albumin-bound (nab)-paclitaxel can cause early, extremely severe neutropenia, occasionally leading to fatal outcomes. As paclitaxel is a substrate of P-glycoprotein, this study aimed to investigate the impact of ABCB1 single-nucleotide variants, which encode P-glycoprotein, on early, extremely severe neutropenia in patients receiving paclitaxel/nab-paclitaxel plus ramucirumab as second-line therapy for unresectable advanced/recurrent gastric cancer., Methods: We analysed patients treated at Aichi Cancer Center Hospital from January 2018 to August 2023, with DNA samples stored in the Cancer BioBank Aichi. The impact of ABCB1 variants T1236C (rs1128503), G2677T/A (rs2032582) and C3435T (rs1045642) on early, extremely severe neutropenia was examined. Neutropenia was defined as a decline in neutrophil count to <100/μL within 28 days of therapy initiation. Firth's logistic regression evaluated the association between the ABCB1 C3435T (rs1045642) TT genotype and early, extremely severe neutropenia, adjusted for age, sex, baseline neutrophil count, and serum albumin and aspartate aminotransferase levels., Results: Of the 203 eligible patients, 5 (2%) experienced neutropenia with neutrophil counts of <100/μL. The odds ratio for neutrophil counts of <100/μL was 28.1 (95% confidence interval 2.8-283.3) in patients with the ABCB1 C3435T (rs1045642) TT genotype., Conclusion: The ABCB1 C3435T (rs1045642) TT genotype was significantly associated with early, extremely severe neutropenia in patients receiving paclitaxel/nab-paclitaxel. Evaluating this genotype status may help predict those at increased risk for early, extremely severe neutropenia., (© 2024 British Pharmacological Society.)

The objective of this study was to reveal the effectiveness of repetitive transcranial magnetic stimulation (rTMS) for Japanese patients with treatment-resistant depression (TRD) in clinical practice, based on real-world data from a nationwide multicenter observational study in Japan. Clinical data of patients with TRD treated with rTMS (NeuroStar TMS treatment system) under public insurance coverage were retrospectively collected from 21 institutes nationwide between June 2019 and December 2023. Depression severity was assessed by the 17-item Hamilton Depression Rating Scale (HAMD-17). Response and remission were defined as ≥50 % reduction from baseline and ≤7 points on the HAMD-17, respectively. The primary outcome was the changes in the HAMD-17 score from baseline to the endpoint following rTMS. Data from 497 patients with TRD were candidates for this study. The HAMD-17 scores (mean (SD)) improved significantly from 18.9 (5.3) to 9.7 (6.6), respectively. The response and remission rates at the end of rTMS therapy as assessed by the HAMD-17 were 53.5 % and 42.8 %, respectively. The dropout rate due to adverse effects was 4.2 %, and the treatment was generally well tolerated. No convulsive seizures or manic changes were observed. These results indicate that conventional rTMS is effective and safe in Japanese patients with TRD., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest in relation to this study., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Psychotropic drugs have been reported to cause urinary retention (UR) via anticholinergic and other mechanisms. However, UR has not received much attention because of its non-fatal symptoms. We investigated the occurrence of UR associated with psychotropic drugs using the Japanese Adverse Drug Event Report (JADER) database., Methods: Using the JADER database, we calculated reporting odds ratios for UR for 74 psychotropic drugs. Multivariate logistic regression analysis was used to adjust for the effects of sex, underlying disease, and age on UR. Variable selection included forced entry for sex, age, benign prostatic hyperplasia (BPH), depression, and backward-forward stepwise selection for each drug., Results: A total of 887,704 cases were reported, of which 4653 (0.52%) had UR. In terms of sex, 0.79% (3401/429,372 cases) and 0.43% (1797/415,358 cases) of male and female patients had UR. In terms of age, 0.31% (892/288,676 cases) and 0.68% (3463/506,907 cases) of patients aged < 60 years and 60 years or older had UR. Among the underlying diseases, 8.22% (930/11,316 cases) and 0.43% (3723/876,388 cases) of patients with BPH and without BPH had UR, respectively. Further, 1.99% (337/16,959 cases) and 0.50% (4316/870,745 cases) of patients with depression and without depression had UR, respectively. Overall, 38 psychotropic drugs met the criteria for signal detection. In logistic regression, a total of 783,083 patients of discernible age and sex were included. The selected variables were sex, age, BPH, depression, and 23 drugs, including quetiapine [adjusted reporting odds ratio (ROR) 95% confidence interval (CI): 1.46-2.81], chlorpromazine (adjusted ROR 95%CI: 1.29-3.13), etizolam (adjusted ROR 95%CI: 1.47-3.09), maprotiline (adjusted ROR 95%CI: 1.99-8.34), mirtazapine (adjusted ROR 95%CI: 1.37-2.88), and duloxetine (adjusted ROR 95%CI: 2.15-4.21)., Conclusions: Many psychotropic drugs induce UR, which may be owing to their pharmacological effects. Appropriate monitoring is needed, especially in patients with other risk factors for UR., Competing Interests: Declarations. Statement of Ethics: This study analyzed a publicly available database; therefore, it did not require ethical approval. Conflict of Interest Statement: The authors have no conflicts of interest to declare. Funding Sources: There are no funding sources for this study. Author Contributions: K.K., T.Y., and K.M. conceived and designed the study; S.U., K.M., Y.H., and Y.O. analyzed the data; S.U. and K.M. wrote the manuscript. All authors read and approved the final version. Data Availability Statement: The data that support the findings of this study are not publicly available because the dataset is too large but are available from S.U. (shuusuke.uekusa@phar.toho-u.ac.jp) upon reasonable request., (© 2024. The Author(s).)

Objective: To examine the association between adjuvant chemotherapy and survival outcomes in patients with stage I uterine leiomyosarcoma (uLMS)., Methods: This comprehensive systematic review and meta-analysis through December 31, 2023 (PROSPERO registration number: CRD42024504776) investigated studies that examined survival outcomes in patients with stage I uLMS using 4 public search engines (PubMed, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials). Two investigators searched the studies independently, and survival outcomes (overall survival [OS] and disease-free survival [DFS]) were compared between the adjuvant chemotherapy and observation groups. Utilization rate of adjuvant chemotherapy and the regimens used were also assessed. Kaplan-Meier survival curves in the two treatment groups were evaluated using ImageJ software., Results: From 1988 to 2022, 16 eligible studies including a total of 5690 patients met the inclusion criteria and evaluated the effect of adjuvant chemotherapy on survival outcomes in patients with stage I uLMS. Adjuvant chemotherapy was utilized in 38.5 % of patients (range, 14.8 % to 70.0 %). Eight studies from 2017 to 2022 compared the survival outcomes between adjuvant chemotherapy and observation. OS was comparable between the two groups in both unadjusted (n = 6, hazard ratio [HR] 1.02, 95 % confidence interval [CI] 0.77-1.35, P = 0.88) and adjusted (n = 4, HR 0.90, 95 %CI 0.56-1.43, P = 0.65) pooled analyses. DFS was also similar between adjuvant chemotherapy and observation in both unadjusted (n = 4, HR 0.78, 95 %CI 0.53-1.13, P = 0.18) and adjusted (n = 2, HR 1.14, 95 %CI 0.67-1.94, P = 0.64) pooled analyses. Adjuvant chemotherapy regimens utilized included doxorubicin, ifosfamide, cisplatin, gemcitabine, and docetaxel as monotherapies or combination therapies., Conclusions: In this contemporaneous systematic review and meta-analysis, less than 40 % of patients received adjuvant chemotherapy for stage I uLMS and adjuvant chemotherapy which was not associated with improved survival. These results support the current National Comprehensive Cancer Network clinical practice guidelines that recommends de-escalating adjuvant chemotherapy in stage I uLMS after complete resection., Competing Interests: Declaration of competing interest Research funding, MSD (S.M.); consultant, Cardiff Oncology, Nutcracker, participation in the Steering Committee for the Global Coalition of Adaptive Research (L.D.R.); consultant, research grant, Merck, royalties, UpToDate, honorarium, American College of Obstetrics and Gynecology (J.D.W.); none for others., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The iPocc trial, a randomized, global phase 3 study that compared intraperitoneal (IP) and intravenous (IV) carboplatin with dose-dense paclitaxel chemotherapy in epithelial ovarian cancer (EOC) patients, demonstrated improved progression-free survival in patients who received IP chemotherapy. The present study aimed to investigate the role of preexisting tumor immunity in the clinical outcomes of patients receiving IP chemotherapy., Methods: This study involved analyzing patient data from the iPocc trial, selectively of those whose tumor specimens were preserved at the time of primary surgery. A total of 116 cases ((IP; n = 59), (IV; n = 57)) were subjected to microarray analysis. Single-sample gene set enrichment analyses were performed to evaluate the tumor immune microenvironment., Results: Patients with enhanced tumor infiltration of T cells, natural killer (NK) cells, and cytotoxic lymphocytes in the IP group had a longer overall survival (OS) than those in the IV group, but not in the group with low infiltration. IP therapy improved the OS of patients with high expression of immune-related genes such as CD8A and FOXP3. In patients' subdivided into "immune Hot" and "immune Cold" groups based on hierarchical clustering analysis using four parameters representing "Innate immunity," "T cells," "IFNG response" and "Inhibitory molecules," IP therapy significantly improved prognosis in the "immune Hot" group, but not in the "immune Cold" group compared to that of IV therapy., Conclusions: IP chemotherapy enhances the survival rates of patients with EOC with an immune-Hot phenotype in the tumor microenvironment prior to treatment. (Japan Registry of Clinical Trials number, jRCTs031180141.)., 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.)

Objectives: To evaluate changes in the age at menarche in Asian populations., Study Design: Retrospective cohort study., Methods: We included 548,830 women from six countries in Asia. The data were sourced from 20 cohorts participating in the Asia Cohort Consortium (ACC) and two additional cohort studies: Japan Multi-institutional Collaborative Cohorts (J-MICC), and Japan Nurse Health Study (JNHS) with data on age at menarche. Joinpoint regression was used to evaluate changes in age at menarche by birth year and by country., Results: The study includes data from cohorts in six Asian countries namely, China, Iran, Japan, Korea, Malaysia and Singapore. Birth cohorts ranged from 1873 to 1995. The mean age of menarche was 14.0 years with a standard deviation (SD) of 1.4 years, ranged from 12.6 to 15.5 years. Over 100 years age at menarche showed an overall decrease in all six countries. China showed a mixed pattern of decrease, increase, and subsequent decrease from 1926 to 1960. Iran and Malaysia experienced a sharp decline between about 1985 and 1990, with APC values of -4.48 and -1.24, respectively, while Japan, South Korea, and Singapore exhibited a nearly linear decline since the 1980s, notably with an APC of -3.41 in Singapore from 1993 to 1995., Conclusions: Overall, we observed a declining age at menarche, while the pace of the change differed by country. Additional long-term observation is needed to examine the contributing factors of differences in trend across Asian countries. The study could serve as a tool to strengthen global health campaigns., (Copyright © 2024 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Competing Interests: The authors declare that they have no conflict of interest.

Objective: The increasing use of fertility-preserving treatments in reproductive-aged patients with early-stage endometrial cancer necessitates robust evidence on the effectiveness of oral progestins and levonorgestrel-releasing intrauterine device. We conducted a systematic review and meta-analysis to examine the outcomes following these 2 primary progestin-based therapies in reproductive-aged patients with early-stage endometrial cancer., Data Sources: We conducted a systematic review of observational studies and randomized controlled trials following the Cochrane Handbook guidance. We conducted a literature search of 5 databases and 1 trial registry from inception of the study to April 16, 2024., Study Eligibility Criteria: Studies reporting complete response within 1 year in reproductive-aged patients with clinical stage IA endometrioid cancer undergoing progestin therapy treatment were included. We used data from both observational and randomized controlled studies., Study Appraisal and Synthesis Methods: The primary exposure assessed was the type of progestational treatment (oral progestins or LNG-IUD). The primary outcome was the pooled proportion of the best complete response (CR) within 1 year of primary progestational treatment. We performed a proportional meta-analysis to estimate the treatment response. Sensitivity analyses were performed by removing studies with extreme effect sizes or removing grade 2 tumors. The risk of bias was assessed in each study using the Joanna Briggs Institute critical appraisal checklist., Results: Our analysis involved 754 reproductive-aged patients diagnosed with endometrial cancer, with 490 receiving oral progestin and 264 receiving levonorgestrel-releasing intrauterine device as their primary progestational treatment. The pooled proportion of the best complete response within 12 months of oral progestin and levonorgestrel-releasing intrauterine device treatment were 66% (95% CI, 55-76) and 86% (95% CI, 69-95), respectively. After removing outlier studies, the pooled proportion was 66% (95% CI, 57-73) for the oral progestin group and 89% (95% CI, 75-96) for the levonorgestrel-releasing intrauterine device group, showing reduced heterogeneity. Specifically, among studies including grade 1 tumors, the pooled proportions were 66% (95% CI, 54-77) for the oral progestin group and 83% (95% CI, 50-96) for the levonorgestrel-releasing intrauterine device group. The pooled pregnancy rate was 58% (95% CI, 37-76) after oral progestin treatment and 44% (95% CI, 6-90) after levonorgestrel-releasing intrauterine device treatment., Conclusion: This meta-analysis provides valuable insights into the effectiveness of oral progestins and levonorgestrel-releasing intrauterine device treatment within a 12-month timeframe for patients with early-stage endometrial cancer who desire to preserve fertility. These findings have the potential to assist in personalized treatment decision-making for patients., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are triggered by α-synuclein aggregation, triggering progressive neurodegeneration. However, the intracellular α-synuclein aggregation mechanism remains unclear. Herein, we demonstrate that RNA G-quadruplex assembly forms scaffolds for α-synuclein aggregation, contributing to neurodegeneration. Purified α-synuclein binds RNA G-quadruplexes directly through the N terminus. RNA G-quadruplexes undergo Ca 2+ -induced phase separation and assembly, accelerating α-synuclein sol-gel phase transition. In α-synuclein preformed fibril-treated neurons, RNA G-quadruplex assembly comprising synaptic mRNAs co-aggregates with α-synuclein upon excess cytoplasmic Ca 2+ influx, eliciting synaptic dysfunction. Forced RNA G-quadruplex assembly using an optogenetic approach evokes α-synuclein aggregation, causing neuronal dysfunction and neurodegeneration. The administration of 5-aminolevulinic acid, a protoporphyrin IX prodrug, prevents RNA G-quadruplex phase separation, thereby attenuating α-synuclein aggregation, neurodegeneration, and progressive motor deficits in α-synuclein preformed fibril-injected synucleinopathic mice. Therefore, Ca 2+ influx-induced RNA G-quadruplex assembly accelerates α-synuclein phase transition and aggregation, potentially contributing to synucleinopathies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

We assessed the association between a genome-wide polygenic risk score (PRS) developed for lung adenocarcinoma (LUAD) risk and mutation on the epidermal growth factor receptor (EGFR) gene in 998 East Asian never-smoking female LUAD cases (518 EGFR-positive; 480 EGFR-negative) and 4,544 never-smoking controls using case-case and multinomial regression analyses. We found that the PRS was more strongly associated with EGFR-positive LUAD compared to EGFR-negative LUAD, where the association between the fourth quartile of the PRS and EGFR-positive LUAD (OR=8.63, 95% CI:5.67, 13.14) was significantly higher than the association between the fourth quartile of the PRS with EGFR-negative LUAD (OR=3.50, 95% CI: 2.44, 5.00) (p-heterogeneity=3.66x10 -3 ). Our findings suggest that germline genetic susceptibility may be differentially associated with LUAD in never-smoking female East Asian patients depending on the cancer's mutation status, which may have important public health and clinical implications., (Copyright © 2024. Published by Elsevier Inc.)

Aims: Lenvatinib mesylate (LEN) is an orally administered tyrosine kinase inhibitor used to treat various cancers, including hepatocellular carcinoma (HCC). LEN therapy for HCC is associated with a high incidence of adverse events, including hypertension (HTN). However, the risk factors associated with LEN therapy remain unclear. This study investigated the incidence of LEN-induced HTN (LENiHTN), and the relationship between HTN incidence and patient demographics in patients with HCC receiving LEN therapy., Methods: This was a single-centre, retrospective study of patients with HCC who received LEN therapy between 19 April 2018 and 30 September 2020. The observation period was from 1 week before the start to 1 month after the end of LEN administration., Results: Seventy-five patients with HCC were enrolled. Any grade LENiHTN was found in 74.7% of patients. Among patients with LENiHTN, the use of 2 or more antihypertensive agents before starting LEN was less common (P = .007); serum potassium (K) and albumin-bilirubin score (ALBI) were lower (P = .013 and 0.038, respectively); and albumin (Alb) was higher (P = .025). The cut-off values of K, Alb and ALBI for HTN were estimated at 4.1 mEq L -1 , 3.1 g dL -1 and -1.736, respectively. In the multivariable analysis, low K (adjusted HR: 2.078) and low ALBI (adjusted HR: 2.845) were independent risk factors for LENiHTN., Conclusion: Low K, high Alb and low ALBI were independent risk factors for LENiHTN. Systematic evaluation of HTN risk and early intervention for HTN prevention among high-risk patients can markedly enhance LEN therapy efficacy and use., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Purpose: To assess national trends, characteristics, and delivery outcomes associated with gestational carriers (GC) pregnancies., Methods: This cross-sectional study queried the Healthcare Cost and Utilization Project's National Inpatient Sample. The study population was 14,312,619 deliveries between 2017 and 2020. Obstetric characteristics and outcomes associated with GC pregnancies were assessed with inverse probability of treatment weighting propensity score., Results: There were 1965 GCs (13.7 per 100,000) included for national estimates. The prevalence rate of GC pregnancies increased by 55.0% over a 4-year period from 11.8 to 18.2 per 100,000 deliveries (P-trend < .001). In the weighted model, GCs were more likely to have a multiple gestation pregnancy (14.7% vs 1.8%, adjusted odds ratio [aOR] 7.83, 95% confidence interval [CI] 6.54-9.38, P < .001), placental abruption (3.5% vs 1.1%, aOR 2.98, 95%CI 2.12-4.19), and low-lying placenta (1.6% vs 0.2%, aOR 5.14, 95%CI 3.10-8.52). Among singleton delivery, odds of late-preterm (10.8% vs 6.4%, aOR 1.79, 95%CI 1.44-2.23) and periviable (1.1% vs 0.4%, aOR 2.54, 95%CI 1.32-4.89) deliveries and postpartum hemorrhage (12.2% vs 4.1%, aOR 3.27, 95%CI 2.67-4.00) were increased for GC compared to non-GCs whereas odds of cesarean delivery (23.6% vs 31.6%, aOR 0.59, 95%CI 0.51-0.69) were decreased. These associations were less robust in multi-fetal gestations., Conclusion: The results of the current nationwide assessment suggest that GC pregnancies are rare but gradually increasing in the United States. This study shows that GC pregnancies have usually favorable pre-pregnancy patient characteristics compared to non-GC pregnancies, with mixed obstetric outcomes including increased odds of preterm delivery, placental abnormalities, and postpartum hemorrhage and decreased odds of cesarean delivery in singleton pregnancies., Competing Interests: Declarations. Details of ethics approval: University of Southern California Institutional Review Board (HS-16–00481). Attestation statements: The manuscript’s corresponding authors affirm that the manuscript is an honest, accurate, and transparent account of the study being reported, that no important aspects of the study have been omitted, and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. The National Inpatient Sample is developed for the Healthcare Cost and Utilization Project that is sponsored by the Agency for Healthcare Research and Quality, and the program is the source of the de-identified data used; race/ethnicity was grouped by the program; and the program has not verified and is not responsible for the statistical validity of the data analysis or the conclusions derived by the study team. Declaration of AI and AI-assisted technologies in the writing process: Not applicable. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Stable planar dithienoarsinines were synthesized and structurally characterized. These compounds exhibit monomeric structures in the solution and solid states, avoiding dimerization, even in the absence of steric protection. They exhibited high global aromaticity with 14 or 22π-electron systems. In the solid state, intermolecular interactions through arsenic atoms were observed, and As⋯As interactions resulted in aggregation-induced emission enhancement properties with a significant bathochromic shift. The W(CO) 5 complex displayed a significantly distorted coordination geometry owing to arsenic cooperative stacking and hydrogen interactions, resulting in a 1D alignment of the complex. Additionally, despite their aromatic nature, dithienoarsinines undergo reactions with alkynes or benzynes to form the corresponding [4 + 2] cycloadducts. Oxygen molecules oxidize the p -position of arsinine, leading to the formation of σ-dimerized compounds while retaining the aromaticity of the arsinine ring. In contrast, oxygen attacks the phosphorus atom in phosphinine, resulting in the formation of phosphinic acid with a loss of aromaticity., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Introduction: In oral maxillofacial surgery, the nasal tracheal tube is mostly used to provide a better surgical field for oral, head and neck operations. Postoperative sore throat and hoarseness are common following tracheal intubation, with an incidence of 11-55%. Then, we previously reported advantage technique of fiberoptic scope to decrease the risk which the tip of the tube is visualized as the tube is advanced which helps avoid impingement of the tube. However, the extent to which this technique causes postoperative complications is unknown compared to traditional technique. The aim of this study was retrospectively to determine the effect of postoperative sore throat following nasotracheal intubation by tip of the tube is visualized by fiberoptic scope., Method: Anesthesia records of the adult patients with nasotracheal intubation were checked. Patients underwent oral maxillofacial surgery from January 2021 until March 2023. Facilitated with rocuronium, nasotracheal intubation was performed using the traditional or observative method by fiberoptic scope with a 4.8 mm outer diameter. Intubation was performed with a cuffed 6.5-8.0 mm ID nasotracheal tube. The following variables were recorded: gender, age, height, weight, ASA classification, anesthesia time, duration of intubation, tube size, intubation attempts, fentanyl and remifentanil. The postoperative sore throat and the incidence of hoarseness were recorded at operative day and at the day after operative day, and the time to recovery., Result: A total of 104 cases (traditional fiberoptic intubation n = 51, observative fiberoptic intubation n = 53) were enrolled in this retrospective study. There were no significant differences in clinical characteristics and anesthetic data. There was not significant difference in incidence of postoperative sore throat, hoarseness and recovery between the two groups (P = 0.61, 0.44, 0.90). For subjects reporting postoperative sore throat (n = 30), there was not a significant difference in VAS means at operative day and at the day after operative day between the two groups (P = 0.81, 0.91)., Conclusion: We found that postoperative sore throat and recovery were not influenced by observative fiberoptic scope for nasotracheal intubation., Competing Interests: Declarations Ethics approval and consent to participate The need for informed consent was waived by Kyushu University Institutional Review Board for Clinical Research. Consent for publication Not Applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: It has been suggested that the association between body mass index and breast cancer risk differs between Asian women and Western women. We aimed to assess the associations between body mass index and breast cancer incidence in East Asian women., Methods: Pooled analyses were performed using individual participant data of 319,189 women from 13 cohort studies in Japan, Korea, and China. Participants' height and weight were obtained by measurement or self-reports at cohort baseline. Breast cancer was defined as code C50.0-C50.9 according to the International Classification. Using a Cox proportional hazards model, hazard ratios of breast cancer were estimated for each body mass index category, with the reference group set as the group with a body mass index of 21 to < 23 kg/m 2 . The hazard ratio for a 5 kg/m 2 increase in body mass index was also calculated., Results: During a mean 16.6 years of follow-up, 4819 women developed breast cancer. Similar to Westerners, a steady increase in breast cancer risk with increasing body mass index was observed in postmenopausal women, but the slope of the risk increase appeared to slow at a body mass index of 26-28 kg/m 2 . In premenopausal women, the inverse association seen in Westerners was not observed. The risk of developing breast cancer after 50 years of age increased slightly with increasing body mass index, which was more pronounced in the older birth cohort. There was no significant association between body mass index and the risk of developing breast cancer before 50 years of age, but the risk estimates changed from positive to negative as the birth cohort got younger., Conclusions: In East Asia, the role of body mass index in breast cancer in premenopausal women may be changing along with the increase in obesity and breast cancer. The increased risk of postmenopausal breast cancer with a higher body mass index was as robust as that of Western women., Competing Interests: Declarations Ethics approval and consent to participate This study was performed in accordance with the Declaration of Helsinki. Each participating study was approved by the relevant institutional ethical review boards. The protocol for the ACC analysis was approved by the institutional review board of the National Cancer Center, Japan. The requirement for consent from several cohort studies was waived due to the justification for lack of consent at the time of the survey, the difficulty in obtaining new consent, and the public necessity of the research. Consent for publication All authors reviewed and approved the final version for submission. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

In the central nervous system (CNS), neuronal function and dysfunction are critically dependent on mitochondrial integrity and activity. In damaged or diseased brains, mitochondrial dysfunction reduces adenosine triphosphate (ATP) levels and impairs ATP-dependent neural firing and neurotransmitter dynamics. Restoring mitochondrial capacity to generate ATP may be fundamental in restoring neuronal function. Recent studies in animals and humans have demonstrated that endogenous mitochondria may be released into the extracellular environment and transported or exchanged between cells in the CNS. Under pathological conditions in the CNS, intercellular mitochondria transfer contributes to new classes of signaling and multifunctional cellular activities, thereby triggering deleterious effects or promoting beneficial responses. Therefore, to take full advantage of the beneficial effects of mitochondria, it may be useful to transplant healthy and viable mitochondria into damaged tissues. In this review, we describe recent findings on the mechanisms of mitochondria transfer and provide an overview of experimental methodologies, including tissue sourcing, mitochondrial isolation, storage, and modification, aimed at optimizing mitochondria transplantation therapy for CNS disorders. Additionally, we examine the clinical relevance and potential strategies for the therapeutic application of mitochondria transplantation., 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.

Aim: We examined the association between dairy intake and all-cause, cancer, and cardiovascular disease mortality in a cohort of the general population followed up for 12 years across Japan., Methods: We conducted a longitudinal cohort study of 79,715 participants from the Japan Multi-Institutional Collaborative Cohort study (57.2% women, mean age 54.7 years old). The amount of dairy (milk and yogurt) intake was determined using a validated short-food frequency questionnaire. The hazard ratio for mortality according to sex-specific tertile of dairy intake was calculated using Cox proportional hazards regression models with adjustment for potential confounding factors and dietary factors by sex., Results: During the follow-up period (932,738 person-years), 3,723 participants died, including 2,088 cancer and 530 cardiovascular disease deaths. The highest tertile of total dairy intake (versus the lowest tertile) was associated with a 19% lower all-cause mortality risk (hazard ratio=0.81, 95% confidence interval: 0.70-0.92; P for trend=0.001) in women. Similarly, we observed inverse associations between milk intake and all-cause and cancer mortality risk in women, yogurt intake and cardiovascular disease risk in women, and yogurt intake and all-cause mortality risk in both sexes., Conclusion: A higher total dairy and milk intakes in women and yogurt intake in both sexes were associated with a reduced risk of all-cause mortality in the general population across Japan during the 12-year follow-up period.

S100A8 is a protein that is abundant in neutrophils and macrophages (MΦ), but its role in inflammation remains unclear. This study aimed to assess the immunological role(s) of S100A8 in acute intestinal inflammation in rats and its role in MΦ. Rat recombinant S100A8 (rr-S100A8, 1.0 mg/kg) was intraperitoneally administered daily to rats with 3% dextran sulfate sodium (DSS) (DSS + A8 group)-induced experimental acute colitis. The histological severity score (6.50 ± 0.51, p = 0.038) in the DSS + A8 group rats remained lower than that (9.75 ± 1.48) of the rats without S100A8 (DSS group) administration. The tumor necrosis factor-alpha (TNF-α) production in the colon tissues of the rats in the DSS + A8 group (4.76 ± 0.90 pg/mL/g, p = 0.042) was significantly suppressed, compared with that of the DSS group (10.45 ± 2.04 pg/mL/g). To stimulate rat peritoneal MΦ, rr-S100A8, the anti-rat S100A8 antibody, and a lipopolysaccharide (LPS) were used in the in vitro experiments. In the MΦ stimulated with rr-S100A8 for 2 h, the mRNA level of intracellular S100A8 (47.41 ± 24.44, p = 0.002) increased in an autocrine manner, whereas that of S100A9 (0.24 ± 0.43, p = 0.782) was not significant. The TNF-α mRNA level in the MΦ treated with LPS and the anti-rat S100A8 antibody significantly increased (102.26 ± 18.60, p = 0.001) compared to that with LPS alone (16.9 ± 8.56). These results indicate that S100A8 can serve as an anti-inflammatory protein in acute inflammation by negatively regulating S100A9 and TNF-α production through inflammatory signaling pathways in MΦ.

Polygenic risk scores (PRSs) are promising for risk stratification but have mainly been developed in European populations. This study developed single- and multi-ancestry PRSs for lung adenocarcinoma (LUAD) in East Asian (EAS) never-smokers using genome-wide association study summary statistics from EAS (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. A multi-ancestry PRS, developed using CT-SLEB, was strongly associated with LUAD risk (odds ratio=1.71, 95% confidence interval (CI):1.61,1.82), with an area under the receiver operating curve value of 0.640 (95% CI:0.629,0.653). Individuals in the highest 20% of the PRS had nearly four times the risk compared to the lowest 20%. Individuals in the 95 th percentile of the PRS had an estimated 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41. Our study underscores the potential of multi-ancestry PRS approaches to enhance LUAD risk stratification in EAS never-smokers.

Tau aggregation is a defining feature of neurodegenerative tauopathies, including Alzheimer's disease, corticobasal degeneration, and frontotemporal dementia. This aggregation involves the liquid-liquid phase separation (LLPS) of Tau, followed by its sol-gel phase transition, representing a crucial step in aggregate formation both in vitro and in vivo. However, the precise cofactors influencing Tau phase transition and aggregation under physiological conditions (e.g., ion concentration and temperature) remain unclear. In this study, we unveil that nucleic acid secondary structures, specifically RNA G-quadruplexes (rG4s), and calcium ions (Ca 2+ ) synergistically facilitated the sol-gel phase transition of human Tau under mimic intracellular ion conditions (140 mM KCl, 15 mM NaCl, and 10 mM MgCl 2 ) at 37 °C in vitro. In the presence of molecular crowding reagents, Tau formed stable liquid droplets through LLPS, maintaining fluidity for 24 h under physiological conditions. Notably, cell-derived RNA promoted Tau sol-gel phase transition, with rG4s emerging as a crucial factor. Surprisingly, polyanion heparin did not elicit a similar response, indicating a distinct mechanism not rooted in electrostatic interactions. Further exploration underscored the significance of Ca 2+ , which accumulate intracellularly during neurodegeneration, as additional cofactors in promoting Tau phase transition after 24 h. Importantly, our findings demonstrate that rG4s and Ca 2+ synergistically enhance Tau phase transition within 1 h when introduced to Tau droplets. Moreover, rG4-Tau aggregates showed seeding ability in cells. In conclusion, our study illuminates the pivotal roles of rG4s and Ca 2+ in promoting Tau aggregation under physiological conditions in vitro, offering insights into potential triggers for tauopathy., Competing Interests: Conflict of interests The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Genetic epidemiological evidence for the kidney function traits in East Asian populations, including Japanese, remain still relatively unclarified. Especially, the number of genome-wide association studies (GWASs) for kidney traits reported still remains limited, and the sample size of each independent study is relatively small. Given the genetic variability between ancestries/ethnicities, implementation of GWAS with sufficiently large sample sizes in specific population of Japanese is considered meaningful., Methods: We conducted the GWAS meta-analyses of kidney traits by leveraging the GWAS summary data of the representative large genome cohort studies with about 200,000 Japanese participants (n = 202,406 for estimated glomerular filtration rate [eGFR] and n = 200,845 for serum creatinine [SCr])., Results: In the present GWAS meta-analysis, we identified 110 loci with 169 variants significantly associated with eGFR (on chromosomes 1-13 and 15-22; P < 5 × 10 -8 ), whereas we also identified 112 loci with 176 variants significantly associated with SCr (on chromosomes 1-22; P < 5 × 10 -8 ), of which one locus (more than 1 Mb distant from known loci) with one variant (CD36 rs146148222 on chromosome 7) for SCr was considered as the truly novel finding., Conclusion: The present GWAS meta-analysis of the largest genome cohort studies in Japanese subjects provided some original genomic loci associated with kidney function, which may contribute to the possible development of personalized prevention of kidney diseases based on genomic information in the near future.

Background/aim: Trastuzumab (TRA) is a key drug in human epidermal growth factor receptor type 2 (HER2)-positive breast cancer treatment. Infusion reactions (IR) with TRA are frequently observed in practice. Although the efficacy of premedication has been previously reported, it remains uncommon. The probability of severe IR due to TRA is low; however, when it does occur, it is associated with patient discomfort and expenditure of medical resources. This study aimed to analyze the factors associated with the occurrence of IR in patients with breast cancer who received TRA., Patients and Methods: We retrospectively studied 204 patients who underwent TRA for breast cancer treatment between September 2008 and June 2023, identifying factors influencing the occurrence of IR at the time of TRA administration., Results: A total of 182 patients were included in this study, and the incidence of IR was 25.8% (47/182 patients). Multiple logistic regression analysis showed that pertuzumab (PER) use, high alkaline phosphatase (ALP), and low high-density lipoprotein (HDL) cholesterol levels were associated with IR., Conclusion: IR should be considered when PER is combined with TRA. ALP and HDL cholesterol levels may be predictive markers of TRA-induced IR in patients with breast cancer., Competing Interests: The Authors declare no conflicts of interest in relation to this study., (©2024 The Author(s). Published by the International Institute of Anticancer Research.)