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The therapeutic potential of suppressing polypyrimidine tract-binding protein 1 (Ptbp1) messenger RNA by viral transduction in a post-stroke dementia mouse model has not yet been examined. In this study, 3 days after cerebral ischemia, we injected a viral vector cocktail containing adeno-associated virus (AAV)-pGFAP-mCherry and AAV-pGFAP-CasRx (control vector) or a cocktail of AAV-pGFAP-mCherry and AAV-pGFAP-CasRx-SgRNA-(Ptbp1) (1:5, 1.0 × 10 11 viral genomes) into post-stroke mice via the tail vein. We observed new mCherry/NeuN double-positive neuron-like cells in the hippocampus 56 days after cerebral ischemia. A portion of mCherry/GFAP double-positive astrocyte-like glia could have been converted into new mCherry/NeuN double-positive neuron-like cells with morphological changes. The new neuronal cells integrated into the dentate gyrus and recognition memory was significantly ameliorated. These results demonstrated that the in vivo conversion of hippocampal astrocyte-like glia into functional new neurons by the suppression of Ptbp1 might be a therapeutic strategy for post-stroke dementia., (© 2024. The Author(s).)

Background: There are few reports on conversion surgery (CS) after chemotherapy plus nivolumab as a first-line treatment in patients with unresectable advanced or recurrent gastric cancer (GC). This multicenter study was conducted to analyze real-world data on CS after chemotherapy plus nivolumab as a first-line treatment and to identify predictive biomarkers., Methods: This multicenter study included 104 patients who received chemotherapy plus nivolumab as primary treatment for unresectable advanced recurrent GC from 12 institutes. We investigated and analyzed patient characteristics and blood test data in the presence or absence of CS, the relationship between the Gustave Roussy Immune Score (GRIm-s) and CS, and the characteristics of CS cases., Results: CS was performed in 12 patients (11.5%). Eastern Cooperative Oncology Group Performance Status (ECOG-PS) was significantly better in patients who underwent CS (p < 0.0001). There were no CS cases with high-risk GRIm-s (0%), however there were 22 non-CS cases (23.9%). No high-risk GRIm-s cases were converted to CS. Minimally invasive surgery was performed in 50.0% of the cases, with R0 resection in all cases and only one case of urinary retention (Grade II) as a postoperative complication, indicating a good postoperative short-term outcome. There were two cases of postoperative recurrence (16.7%), both of which were grade 1b., Conclusions: The short-term postoperative results of CS after chemotherapy plus nivolumab as the first-line treatment for GC were acceptable in this study. There were no high-risk GRIm-s cases among those who underwent CS, suggesting that the GRIm-s may be a predictor of CS., (© 2024. Society of Surgical Oncology.)

Background/aim: The predictive role of hematological markers in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) treated with pembrolizumab remains unclear., Patients and Methods: We conducted a multicenter retrospective cohort study to investigate the predictive impact of the pre-treatment hematological markers neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), CRP-albumin-lymphocyte (CALLY) index, and the modified Glasgow prognostic score (mGPS) on overall survival (OS) and progression-free survival (PFS) in patients with R/M SCCHN treated with pembrolizumab. From December 2019 to February 2022, 119 and 28 patients were treated with pembrolizumab alone and pembrolizumab plus chemotherapy, respectively. The optimal cut-off point of dichotomized hematological markers was calculated using the area under the receiver operating characteristic curve. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) were estimated using Cox proportional hazard models with adjustment for potential confounders., Results: In the pembrolizumab monotherapy group, patients with higher NLR, PLR, and mGPS and a lower CALLY index showed significantly shorter OS after adjustment for potential confounders. In addition, all hematological markers examined in this study tended to be associated with clinical response, such as overall response rate or disease control rate (DCR); in particular, a lower CALLY index and higher mGPS were significantly associated with poor DCR. In the pembrolizumab with chemotherapy group, these hematological markers had a similar association with OS but not with clinical response., Conclusion: Pre-treatment NLR, PLR, CALLY index, and mGPS might be predictive markers of survival in patients with R/M SCCHN treated with pembrolizumab., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A case of death due to combined use of multiple drugs is reported, and the pharmacokinetic interactions are discussed. A woman in her thirties was found dead in her home. A medico-legal autopsy found no findings suggestive of injury or natural disease. Toxicological analysis using liquid chromatography tandem mass spectrometry (LC-MS/MS) identified a toxic level of fluvoxamine (0.947 µg/mL), and concentrations greater than the therapeutic levels of levomepromazine (0.238 µg/mL) and trihexyphenidyl (0.225 µg/mL) were present, while bromazepam, haloperidol, sulpiride, and 7-aminoflunitrazepam were within or below their therapeutic ranges. Fluvoxamine is mainly metabolized by cytochrome P450 2D6 (CYP2D6), and levomepromazine is a potent CYP2D6 inhibitor. A high concentration of levomepromazine may increase the blood fluvoxamine level. Since the combined use of levomepromazine and fluvoxamine induces seizures, it may have been involved in causing the subject's death. In addition, combined use of trihexyphenidyl may potentiate anticholinergic effects of fluvoxamine overdose, including convulsions and coma. It was concluded that the cause of the subject's death was the interaction of multiple drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: In the global phase 3 DESTINY-Breast04 study (NCT03734029), the anti-human epidermal growth factor 2 (HER2) antibody-drug conjugate trastuzumab deruxtecan (T-DXd) demonstrated a statistically significant improvement in progression-free survival (PFS) and overall survival (OS), with manageable safety compared with treatment of physician's choice (TPC) in patients with HER2-low metastatic breast cancer (mBC) who had received 1-2 prior lines of chemotherapy., Methods: This subgroup analysis examined the efficacy and safety of T-DXd versus TPC in 213 patients from Asian countries and regions who were enrolled in the DESTINY-Breast04 trial and randomized to T-DXd (n = 147) or TPC (n = 66)., Results: Median PFS with T-DXd and TPC was 10.9 and 5.3 months, respectively, in Asian patients with hormone receptor-positive mBC, and 10.9 and 4.6 months, respectively, in the overall Asian population. In both populations, median OS was not reached with T-DXd and was 19.9 months with TPC. The objective response rate was higher with T-DXd versus TPC in all Asian patients. Median treatment duration was 8.4 months with T-DXd and 3.5 months with TPC. The most common grade ≥ 3 drug-related treatment-emergent adverse events in Asian patients treated with T-DXd were neutropenia (16.3%), anemia (12.9%), and leukopenia (11.6%); the incidences of neutropenia and leukopenia were higher with TPC versus T-DXd. Adjudicated drug-related interstitial lung disease or pneumonitis with T-DXd was 14.3%; the majority of events were grade 1-2., Conclusions: T-DXd demonstrated clinically meaningful survival benefits versus TPC in Asian HER2-low mBC patients, regardless of hormone receptor status, with no new safety signals., Clinical Trial Registration Number: ClinicalTrials.gov, NCT03734029., (© 2024. The Author(s).)

Background:  We evaluated the pharmacokinetics (PK) of low-dose (15 mg) edoxaban in very elderly patients (≥80 years) with nonvalvular atrial fibrillation (NVAF) and high bleeding risk., Methods:  This subanalysis of the phase 3, randomized, double-blind, placebo-controlled, multicenter ELDERCARE-AF study evaluated edoxaban plasma concentrations and compared them with the Japanese population of the ENGAGE AF-TIMI 48 and Japanese severe renal impairment (SRI) studies., Results:  The PK analysis population included 451 patients, 53.8% of whom concomitantly used antiplatelet drugs, 41.0% had SRI, and 38.0% had low body weight. Edoxaban plasma concentrations at trough and 1 to 3 hours post-dose in ELDERCARE-AF were 17.3 ± 13.9 ( n  = 427) and 93.3 ± 57.8 ng/mL ( n  = 447), respectively. These values were slightly higher than the 15 mg group in ENGAGE AF-TIMI 48 ( n  = 79; 12.4 ± 12.1 and n  = 115; 78.7 ± 45.0 ng/mL, respectively), lower than the ENGAGE AF-TIMI 48 high-dose reduced to 30 mg group ( n  = 83; 25.1 ± 36.6 and n  = 111; 150 ± 91.6 ng/mL, respectively), but similar to the Japanese SRI study ( n  = 39; 18.4 ± 11.2 and n  = 40; 96.8 ± 48.3 ng/mL, respectively). ELDERCARE-AF patients with SRI and low body weight (≤45 kg) had higher concentrations than those without, and those taking antiplatelet drugs had lower concentrations than those who were not., Conclusion:  PK data support edoxaban 15 mg once daily for very elderly NVAF patients with high bleeding risk, with caution for patients with SRI and/or low body weight., Competing Interests: T.Y. received personal fees from Daiichi Sankyo Co., Ltd. during the conduct of the study; grants and personal fees from Daiichi Sankyo Co., Ltd., Bayer Yakuhin, Ltd., and Bristol Myers Squibb K.K.; personal fees from Pfizer Japan Inc., Nippon Boehringer Ingelheim Co., Ltd., Ono Pharmaceutical Co., Ltd., Toa Eiyo Ltd., Novartis Pharma K.K., and Otsuka Pharmaceutical Co., Ltd. outside the submitted work. Y.I., M.F., and T.H. are employees of Daiichi Sankyo Co., Ltd. S.H. is an employee of Certara, Inc. K.O. received grants and personal fees from Daiichi Sankyo Co., Ltd. during the conduct of the study; personal fees from Daiichi Sankyo Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Bristol-Myers Squibb K.K., Medtronic Japan Co., Ltd., Johnson and Johnson K.K., and Bayer Yakuhin, Ltd. outside the submitted work., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Competing Interests: Conflicts of interest Drs Fukasawa and Yoshizaki belong to the Social Cooperation Program, Department of Clinical Cannabinoid Research, supported by the Japan Cosmetic Association and the Japan Federation of Medium ＆ Small Enterprise Organizations. Drs Enomoto, Yamashita, Miyagawa, Sato, and Yoshizaki Johnson have no conflicts of interest to declare.

In recent years, rapid advances in research methods have made single cell analysis possible. Systemic sclerosis (SSc), a disease characterized by the triad of immune abnormalities, fibrosis, and vasculopathy, has also been the subject of various analyses. To summarize the results of single cell analysis in SSc accumulated to date and to deepen our understanding of SSc. Four databases were used to perform a database search on 23rd June 2023. Assessed Grading of Recommendations Assessment, Development and Evaluation certainty of evidence were performed according to PRISMA guidelines. The analysis was completed on July 2023. 17 studies with 358 SSc patients were included. Three studies used PBMCs, six used skin, nine used lung with SSc-interstitial lung diseases (ILDs), and one used lung with SSc-pulmonary arterial hypertension (PAH). The cells studied included immune cells such as T cells, natural killer cells, monocytes, macrophages, and dendritic cells, as well as endothelial cells, fibroblasts, keratinocytes, alveolar type I cells, basal epithelial cells, smooth muscle cells, mesothelial cells, etc. This systematic review revealed the results of single cell analysis, suggesting that PBMCs, skin, SSc-ILD, and SSc-PAH show activation and dysfunction of cells associated with immune-abnormalities, fibrosis, and vasculopathy, respectively.

Purpose: Alpelisib plus fulvestrant demonstrated a significant progression-free survival benefit versus fulvestrant in patients with PIK3CA-mutated HR+ /HER2- advanced breast cancer (ABC) (SOLAR-1). Hyperglycemia, an on-target adverse effect of PI3Kα inhibition, can lead to dose modifications, potentially impacting alpelisib efficacy. We report data from preclinical models and two clinical trials (SOLAR-1 and BYLieve) on Sodium glucose cotransporter 2 inhibitor (SGLT2i) use to improve PI3Kα inhibitor-associated hyperglycemia., Methods: Healthy Brown Norway (BN), mild diabetic Zucker diabetic fatty (ZDF), and Rat1-myr-p110α/HBRX3077 tumor-bearing nude rats treated with alpelisib were analyzed for glucose and insulin control with metformin and dapagliflozin (SGLT2i) and alpelisib efficacy. Hyperglycemia adverse events (AEs) were compared between patients receiving SGLT2i with alpelisib (n = 19) and a propensity score-matched cohort not receiving SGLT2i (n = 74) in both trials., Results: Dapagliflozin and metformin in BN and ZDF rats treated with alpelisib normalized blood glucose and reduced insulin levels. No signs of ketosis or drug-drug interaction were observed when metformin and dapagliflozin was administered with alpelisib. Alpelisib antitumor efficacy was maintained when used with dapagliflozin in tumor-bearing rats. Compared with a matched set of patients without SGLT2i, patients receiving SGLT2i had 4.9 and 6.4 times lower rates of grade ≥ 3 hyperglycemia AEs and hyperglycemia AEs resulting in alpelisib dose adjustments, interruptions, or withdrawals, respectively, and a relative reduction in risk of experiencing these AEs (70.6% and 35.7%)., Conclusion: These data suggest adding an SGLT2i can effectively manage hyperglycemia, resulting in fewer alpelisib dose modifications and discontinuations in patients with PIK3CA-mutated HR+ /HER2- ABC (SOLAR-1: NCT02437318; BYLieve: NCT03056755)., (© 2024. The Author(s).)

The 88 th Annual Scientific Meeting of the Japanese Circulation Society (JCS2024) was held from Friday, March 8 th to Sunday, March 10 th in Kobe, Japan. The main theme of this 3-day meeting was "The Future of Cardiology: Challenges in Overcoming Cardiovascular Disease". As COVID-19 has been finally conquered, with revision of its categorization under the Infectious Disease Control Law and relaxation of infection prevention measures, it was once again possible to have face-to-face presentations and lively discussion. JCS2024 was a major success, with 19,209 participants and attendees, thanks to the greatly appreciated cooperation and support from all affiliates.

We developed a novel hepatitis B virus (HBV) infection-monitoring system using a luminescent, 11-amino acid reporter (HiBiT). We performed high-throughput antiviral screening using this system to identify anti-HBV compounds. After the infection of primary human hepatocytes with the recombinant virus HiBiT-HBV, which contains HiBiT at its preS1, 1262 compounds were tested in a first screening using extracellular HiBiT activity as an indicator of viral infection. Following a second screening, we focused on the compound skimmianine, which showed a potent antiviral effect. When skimmianine was added at the same time as HiBiT-HBV infection, skimmianine inhibited HiBiT activity with EC 50 of 0.36 pM, CC 50 of 1.67 μM and a selectivity index (CC 50 :EC 50 ratio) of 5,100,000. When skimmianine was added 72 h after HiBiT-HBV infection, the EC 50 , CC 50 and selectivity index were 0.19 μM, 1.87 μM and 8.79, respectively. Time-lapse fluorescence imaging analysis using another recombinant virus, ReAsH-TC155HBV, with the insertion of tetra-cysteine within viral capsid, revealed that skimmianine inhibited the accumulation of the capsid into hepatocytes. Furthermore, skimmianine did not inhibit either attachment or internalization. These results imply that skimmianine inhibits the retrograde trafficking of the virus after internalization. This study demonstrates the usefulness of the recombinant virus, HiBiT-HBV, for high-throughput screening to identify anti-HBV compounds.

Background: A streamlined and effective renal biopsy technique is essential for all nephrologists, particularly those who are less experienced, such as residents. Herein, we report the efficacy of a Straightforward and Immediate ultrasound-guided kidney biopsy using a Guide Needle (SIGN) technique, which allows operators to insert a biopsy gun through a guide needle placed into the fascia of the posterior abdominal wall., Methods: A retrospective cross-sectional study was conducted at a nephrology training institution to compare the time spent on the procedure and the number of glomeruli obtained between a group using the SIGN (n = 81) and a group using the conventional ultrasound-guided kidney biopsy technique with a needle guide device (n = 143)., Results: The median procedure time in the SIGN group (2 min, interquartile range [IQR]: 1-3 min) was significantly shorter than that in the conventional group (3 min, IQR: 2-4 min) (P < 0.001). Multivariable linear regression and logistic regression analyses adjusted for covariates, including operators (board-certificated nephrologists or nephrology residents), showed that the use of the SIGN technique was independently associated with a high number of glomeruli obtained and a procedure time above 2 min as the median value (odds ratio: 0.17, 95% confidence interval CI 0.09-0.34). The prevalence of complications was comparable between the two groups (P = 0.681)., Conclusion: The SIGN technique reduces the procedure time and obtains adequate biopsy tissue regardless of the operator's experience. SIGN can be applied in nephrology training programs and used as a standard biopsy technique., (© 2024. The Author(s).)

Background: The structures around the navicular bones, which constitute the medial longitudinal arch, develop by 10 years of age. While navicular bone height is often emphasized in the assessment of flatfoot, three-dimensional (3D) evaluations, including those of structural parameters during inversion, have rarely been investigated. If the development of flatfoot during the growth process could be predicted, appropriate interventions could be implemented. Therefore, in this longitudinal cohort study, we developed a system, utilizing smartphones, to measure the 3D structure of the foot, performed a longitudinal analysis of changes in midfoot structures in 124 children aged 9-12 years, and identified factors influencing the height of the navicular bone. The foot skeletal structure was measured using a 3D system., Results: Over 2 years, foot length and instep height increased during development, while navicular height decreased. The 25th percentile of the instep height ratio and navicular height ratio at ages 9-10 years did not exceed those at ages 11-12 years, with percentages of 17.9% and 71.6%, respectively, for boys, and 15.8% and 49.1%, respectively, for girls. As the quartiles of the second toe-heel-navicular angle (SHN angle) increased at ages 9-10 years, the axis of the bone distance (ABD) and SHN angles at ages 11-12 years also increased, resulting in a decrease in the navicular height ratio. A significant inverse correlation was found between changes in SHN angle and navicular height ratio. These findings indicate that the navicular bone rotation of the midfoot is a predictor of the descent of the navicular bone., Conclusions: This study revealed that some children exhibit decreases in navicular bone height with growth. As a distinct feature, the inversion of the navicular bone promotes flattening of the midfoot. Thus, this study provides insights into changes in midfoot development in children and provides an effective evaluation index., (© 2024. The Author(s).)

Multiple hereditary infundibulocystic basal cell carcinoma syndrome (MHIBCC), an autosomal dominant disorder caused by variants in SUFU, is characterized by numerous infundibulocystic basal cell carcinomas (IBCCs). In this report, we present a possible case of mosaic MHIBCC. A 57-year-old woman underwent the removal of four papules on her face, which were diagnosed as IBCCs. Exome sequencing revealed a SUFU c.1022+1G>A mutation within the skin tumor. The same mutation was detected in her blood but at a lower allele frequency. TA cloning revealed that the allele frequency of the mutation in the blood was 0.07. Additionally, tumor assessment revealed loss of heterozygosity (LOH) in chromosome 10, including the SUFU locus. These results indicate the patient had mosaicism for the SUFU mutation in normal tissues, aligning with the mosaic MHIBCC diagnosis. This, combined with LOH, likely contributed to IBCC development. Mosaic MHIBCC may present with milder symptoms. However, it may still increase the risk of developing brain tumors and more aggressive basal cell carcinoma. The possibility of mosaicism should be investigated in mild MHIBCC cases, where standard genetic tests fail to detect SUFU germline variants., (© 2024 Japanese Dermatological Association.)

In sludge dewatering of most wastewater treatment plants (WWTPs), the dose of polymer flocculant is manually adjusted through direct visual inspection of the flocs without the aid of any instruments. Although there is a demand for the development of automatic control of flocculant dosing, this has been challenging owing to the lack of a reliable flocculation sensor. To address this issue, this study developed a novel image sensor for measuring the degree of flocculation (DF) based on deep learning. Two types of sludge samples were used in the laboratory-scale flocculation tests: excess sludge and mixtures of excess sludge and raw wastewater. To search for a deep learning regression model suitable for DF inference, ten models, including convolutional neural networks, vision transformers, and a multilayer perceptron MLP mixer, were comparatively analysed. The ConvNeXt and MLP mixer models showed the highest accuracies with coefficients of determination (R 2 ) greater than 0.9. The region contributing to the DF inference in the flocculation images was visualised using a modulus-weighted, gradient-weighted regression activation map. A prototype of the flocculation sensor was constructed using an inexpensive EdgeAI device. This device comprises a single-board computer and an integrated graphical processing unit (GPU) and is equipped with a quantised ConvNeXt model. The maximum inference speed of the sensor was 12.8 frames per second (FPS). The flocculation control tests showed that the sensor could control the DF to the target value by adjusting the polymer flocculant dose. Therefore, the flocculation sensor can provide a data-driven approach to the management of the flocculation process, thereby facilitating the automation of WWTPs., 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. Published by Elsevier Ltd.)

The autoxidation of tea catechins by dissolved oxygen proceeds in pH-neutral aqueous solutions, and the major products are oligomers. However, the reaction mechanisms have not been clarified. In this study, the autoxidation of (-)-epigallocatechin-3-O-gallate (1) was examined. The autoxidation with β-cyclodextrin, which includes the A-ring of 1, significantly suppressed oligomer production and increased the formation of products generated by the oxidative cleavage of the B-ring, indicating the participation of the A-ring in the oligomerization. Further, the autoxidation of 1 in the presence of phloroglucinol, a mimic of the catechin A-ring, yielded products via the nucleophilic addition of phloroglucinol to the B-ring quinone of 1. These results indicated that the oxidative A-B ring couplings accounted for the major oligomerization mechanism., 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.)

Purpose: Inter-structural release (ISR) procedure to skeletal muscles is believed to attenuate adhesion between neighboring muscles and alleviate subjective symptoms, including perceived stiffness and associated pain. However, objective evidence about the effect of ISR on the mechanical properties of the muscles is limited. The purpose of this study was to test the acute effect of ISR on the shear modulus of adjacent muscles. It was hypothesized that ISR applied to the border between synergistic muscles would acutely reduce the resting shear modulus of the involved muscle., Methods: To assess the effect of ISR, the shear modulus of the resting peroneus longus (PL) and soleus (SOL) muscles was measured at various ankle joint positions (inversion/eversion) before and after interventions in nine non-symptomatic male individuals (age: 21.9 ± 1.4 years, height: 170 ± 6.6 cm, body mass: 64.3 ± 4.0 kg). Potential muscle activity during the measurement was assessed by recording surface electromyogram from these muscles. The interventions were ISR to the lower leg between the deep fascia of the PL and SOL and sham (massage)., Results: As the ankle joint position was passively varied toward inversion, the shear modulus increased substantially in PL and decreased moderately in SOL. Shear modulus of the proximal PL in the most inverted position increased acutely after ISR (by 11.4 ± 5.8%, P < 0.001), but not after the sham, without any change in the amplitude of electromyogram., Conclusions: These results provide objective evidence that the ISR procedure can acutely alter shear modulus, at least in a specific site in a resting muscle., Competing Interests: Conflict of Interest and Funding Source: This study was partly supported by JSPS KAKENHI Grant-in-Aid for Scientific Research (B) (Grant Number JP23H03297). The authors declare that they have no conflict of interest related to the subject matter or materials discussed in this article., (Copyright © 2024 by the American College of Sports Medicine.)

Scorpions, a seemingly primitive, stinging arthropod taxa, are known to exhibit marked diversity in their venom components. These venoms are known for their human pathology, but they are also important as models for therapeutic and drug development applications. In this study, we report a high-quality genome assembly and annotation of the striped bark scorpion, Centruroides vittatus, created with several shotgun libraries. The final assembly is 760 Mb in size, with a BUSCO score of 97.8%, a 30.85% GC, and an N50 of 2.35 Mb. We estimated 36,189 proteins with 37.32% assigned to Gene Ontology (GO) terms in our GO annotation analysis. We mapped venom toxin genes to 18 contigs and 2 scaffolds. We were also able to identify expression differences between venom gland (telson) and body tissue (carapace) with 19 sodium toxin and 14 potassium toxin genes to 18 contigs and 2 scaffolds. This assembly, along with our transcriptomic data, provides further data to investigate scorpion venom genomics., Competing Interests: Conflicts of interest The author(s) declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

The presence of high-density emboli in the pulmonary artery on non-enhanced computed tomography (CT) has high diagnostic performance for acute central pulmonary thromboembolism. Acute pulmonary thromboembolism is usually diagnosed by contrast-enhanced CT. However, it may be possible to achieve early diagnosis by identifying characteristic findings on non-enhanced CT., Competing Interests: None declared., (© 2024 The Author(s). Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.)

Background: The Tohoku Medical Megabank Project (TMM) was established to realize personalized healthcare and medicine using genomic and omics data. This study evaluated the validity and reproducibility of food group intakes derived from a self-administered food frequency questionnaire (TMM-FFQ) that included the response option "constitutionally unable to eat/drink it" among community-dwelling Japanese adults., Methods: Participants comprised 89 men and 124 women aged ≥20 years from Miyagi Prefecture. Participants completed weighed food records (WFRs) for 3 consecutive days per season as reference intake and FFQs in 2019 (FFQ1) and 2021 (FFQ3). Spearman's rank correlation coefficients (CCs) were calculated for correlations between food group intakes estimated from the 12-day WFR and FFQ3 (validity), and for correlations between those estimated from the FFQ1 and FFQ3 (reproducibility). Cross-classification according to quintiles using FFQ and WFR data was also performed., Results: The percentage of participants who chose the "constitutionally unable to eat/drink it" option was non-negligible for some food groups. In the validity analysis, CCs were >0.40 for many food groups; the median across 21 food groups was 0.49 in men and 0.45 in women. The median percentages of cross-classification into exact plus adjacent quintiles were 73.0% in men and 66.9% in women. In the reproducibility analysis, CCs were >0.50 for many food groups; the median across 21 food groups was 0.60 in men and 0.51 in women., Conclusions: The validity of the TMM-FFQ compared with 12-day WFR and the reproducibility of the TMM-FFQ were reasonable for food groups in the TMM cohort studies.

Objective: Organ preservation is a goal of head and neck squamous cell cancer (HNSCC) treatment. chemoradiotherapy remains one of the main treatment options and is widely recognized as a method with organ-preserving potential and outcomes comparable to those of surgery. However, few studies have investigated the quality of life (QOL) of patients with HNSCC treated using chemoradiotherapy, therefore, we aimed to retrospectively evaluate how QOL changes pre and post-chemoradiotherapy., Methods: We evaluated QOL outcomes in patients who underwent initial radical chemoradiotherapy for HNSCC at the Department of Otolaryngology and Head and Neck Surgery Kitasato University Hospital from 2018 to 2021. We used the Cancer Fatigue Scale (CFS) and the combined European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-H&N35 questionnaires at pre-treatment, three months and six months post-treatment., Results: We obtained 37 and 29 responses from the CFS and EORTC QLQ-C30/H&N35 questionnaire, respectively. From the CFS, the physical fatigue score at three months post-treatment deteriorated more than that at pre-treatment, and significantly improved by six months post-treatment. The total score worsened significantly at three months and there was a trend toward improvement at six months. In the EORTC QLQ-C30, physical and social functioning declined in three months and did not improve within six months. Fatigue was substantially worse at three months and significantly improved at six months but did not reach the same level as that before treatment. Appetite loss was also significantly worse at three months. In the QLQ-H&N35 questionnaire, sensory issues, trouble with social contact, and dry mouth were significantly worse at three months and did not improve within six months. Sticky saliva also worsened at three months and significantly improved at six months., Conclusion: There were some problems associated with chemoradiotherapy. Some patients showed an improvement, while others continued to have challenges. In Japan, chemoradiotherapy was shown to have a long-term impact on the patient's life., Competing Interests: Conflict of interest We declare no conflicts of interest associated with this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background and Objectives: Advancing automation technologies are replacing certain occupations such as those involving simple food preparation more than occupations such as those in STEM fields (e.g., engineering and health care). Older workers generally face higher job automation risks in part due to their lower levels of digital skills. A better understanding of the associations between job automation risk, digital skills, and type of occupation (e.g., STEM vs non-STEM) can facilitate preparations for job automation and workforce population aging., Research Design and Methods: We analyzed a nationally representative sample (N = 1,560) of middle-aged and older U.S. workers aged 50-74 years from the 2012/2014/2017 Program for International Assessment of Adult Competencies (PIAAC) restricted-use file. The estimated job automation risks (i.e., percentage of jobs to be automated in the next decades) were derived from the previous studies. PIAAC digital problem-solving skills proficiency (measured on a scale of 0-500 points) was assessed based on a series of practical digital tasks (e.g., finding a job research website that does not require registration)., Results: Linear regression analysis showed that greater digital skill proficiency (b = -0.04, p < .05) and STEM occupations (b = -17.78, p < .001) each were associated with lower job automation risks, even after adjusting for a series of demographic, socioeconomic, and civic engagement characteristics., Discussion and Implications: Education and labor policy interventions to promote digital skills among older workers and non-STEM workers may better prepare an aging workforce for the dynamic labor market needs in the United States., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. 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.)

Osteotomy is often necessary for the repair of post-traumatic nasal bone deformities. Typically, tools such as chisels are used for osteotomies; however, we performed osteotomies using Kirschner wires without making a skin incision. Between April 2011 and July 2022, we performed rhinoplasty with external perforated osteotomy using Kirschner wires in 13 patients with post-traumatic nasal bone deformities (9 males and 4 females; mean age, 34 years, range 12-51 years), all of whom exhibited improvement, with only one case showing mild residual cosmetic deformity. None of the patients requested further revision, and all were satisfied with their functional results. The non-incisional external perforated technique is a reasonable method that allows for bone osteotomies along the fracture line and is well-controlled, predictable, and reproducible., (Copyright © 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

The proto-oncogene MYCN expression marked a cancer stem-like cell population in hepatocellular carcinoma (HCC) and served as a therapeutic target of acyclic retinoid (ACR), an orally administered vitamin A derivative that has demonstrated promising efficacy and safety in reducing HCC recurrence. This study investigated the role of MYCN as a predictive biomarker for therapeutic response to ACR and prognosis of HCC. MYCN gene expression in HCC was analyzed in the Cancer Genome Atlas and a Taiwanese cohort (N = 118). Serum MYCN protein levels were assessed in healthy controls (N = 15), patients with HCC (N = 116), pre- and post-surgical patients with HCC (N = 20), and a subset of patients from a phase 3 clinical trial of ACR (N = 68, NCT01640808). The results showed increased MYCN gene expression in HCC tumors, which positively correlated with HCC recurrence in non-cirrhotic or single-tumor patients. Serum MYCN protein levels were higher in patients with HCC, decreased after surgical resection of HCC, and were associated with liver functional reserve and fibrosis markers, as well as long-term HCC prognosis (>4 years). Subgroup analysis of a phase 3 clinical trial of ACR identified serum MYCN as the risk factor most strongly associated with HCC recurrence. Patients with HCC with higher serum MYCN levels after a 4-week treatment of ACR exhibited a significantly higher risk of recurrence (hazard ratio 3.27; p = .022). In conclusion, serum MYCN holds promise for biomarker-based precision medicine for the prevention of HCC, long-term prognosis of early-stage HCC, and identification of high-response subgroups for ACR-based treatment., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

We examined the inhibitory effects of α-linolenic acid (ALA) on the contractions of pig coronary arteries. ALA concentration-dependently inhibited the contractions elicited by U46619 and prostaglandin F 2α without affecting those elicited by 80 mM KCl, histamine, acetylcholine, and serotonin. ALA rightward shifted the concentration-response curve of U46619, and Schild plot analysis revealed that ALA competitively antagonized U46619. Furthermore, ALA inhibited the increase in intracellular Ca 2+ concentration caused by TP receptor stimulation but not that caused by FP receptor stimulation. These results suggest that ALA behaves as a selective antagonist of TP receptors in coronary arteries., Competing Interests: Declaration of competing interest The authors indicated no potential conflicts of interest., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER + ) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (n = 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER + human epidermal growth factor receptor-negative (HER2 - ) metastatic breast cancer (mBC). The primary objectives of assessing the safety and tolerability and determining the recommended dose for expansion of PF-07248144, as monotherapy and in combination with fulvestrant, were met. Secondary endpoints included characterization of PK and evaluation of antitumor activity, including objective response rate (ORR) and progression-free survival (PFS). Common treatment-related adverse events (any grade; grades 3-4) included dysgeusia (83.2%, 0%), neutropenia (59.8%, 35.5%) and anemia (48.6%, 13.1%). Exposure was approximately dose proportional. Antitumor activity was observed as monotherapy. For the PF-07248144-fulvestrant combination (n = 43), the ORR (95% confidence interval (CI)) was 30.2% (95% CI = 17.2-46.1%) and the median PFS was 10.7 (5.3-not evaluable) months. PF-07248144 demonstrated a tolerable safety profile and durable antitumor activity in heavily pretreated ER + HER2 - mBC. These findings establish KAT6A and KAT6B as druggable cancer targets, provide clinical proof of concept and reveal a potential avenue to treat mBC. clinicaltrial.gov registration: NCT04606446 ., (© 2024. The Author(s).)

Kikuchi-Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenitis, is a rare condition characterized by benign localized lymphadenopathy and clinical symptoms such as fever, sore throat, odynophagia, and leukopenia. Though the etiology of KFD is unknown, this condition is similar to viral infection, including increased infiltration of activated plasmacytoid dendritic cells. KFD exhibits three histological phases that reflect its progression status: proliferative, necrotic, and xanthomatous lesions. The expression loss of pan T-cell markers, such as CD2, CD5, and CD7, of infiltrating T-cells is observed in KFD cases, complicating the distinction from T-cell lymphoma. However, reports on the loss of their expression in KFD have been limited. Furthermore, the precise population of the T-cell subset in KFD is still unclear. Here, we focused on surface markers and transcription factors for T-cell differentiation and analyzed them immunohistochemically in 46 KFD cases. We observed diminished CD5 expression of CD8-positive (CD5 dim CD8+) T-cells in the proliferative lesion of KFD cases. Furthermore, these CD5 dim CD8+ T-cells expressed T-BET, a master regulator of type 1 helper T-cells. The upregulation of T-BET and downregulation of CD5 in CD8+ T-cells causes dysregulated activation and proliferation of CD8+ T-cells, potentially contributing to the unique histopathological features of KFD. Recognizing the frequent infiltration of T-BET-positive CD5 dim CD8+ T-cells in KFD is important for distinguishing it from mature T-cell lymphoma. Our findings suggest that the immune response in KFD shares similarities with viral infections and highlight the importance of characterizing T-BET-positive CD5 dim CD8+ T-cell populations for understanding KFD pathogenesis.

Purpose: To investigate the relationship between the fundus sex index obtained from fundus photographs and body height or axial length in the Kumejima population., Study Design: Prospective cross-sectional observational population study., Methods: Using color fundus photographs obtained from the Kumejima population, 1,653 healthy right eyes with reliable fundus parameter measurements were included in this study. The tessellation fundus index was calculated as R/(R + G + B) using the mean value of the red-green-blue intensity in the eight locations around the optic disc and foveal region. The optic disc ovality ratio, papillomacular angle, and retinal vessel angle were quantified as previously described. The masculine or feminine fundus was quantified using machine learning (L2 regularized binominal logistic regression and leave one out cross validation), with the range of 0-1 as the predictive value, and defined as the fundus sex index. The relationship between the fundus sex index and body height or axial length was investigated using Spearman's correlation., Results: The mean age of the 838 men and 815 women included in this study was 52.8 and 54.0 years, respectively. The correlation coefficient between fundus sex index and body height was - 0.40 (p < 0.001) in all, 0.01 (p = 0.89) in men, and - 0.04 (p = 0.30) in women, and that between fundus sex index and axial length was - 0.23 (p < 0.001) in all, - 0.12 (p < 0.001) in men, and - 0.13 (p < 0.001) in women., Conclusion: This study shows that a larger number of masculine fundi tend to have longer axial lengths in each sex group. However, sex index was not significantly related with body height either in men or in women., (© 2024. The Author(s).)

Mechanical stress significantly affects the physiological functions of cells, including tissue homeostasis, cytoskeletal alterations, and intracellular transport. As a major cytoskeletal component, microtubules respond to mechanical stimulation by altering their alignment and polymerization dynamics. Previously, we reported that microtubules may modulate cargo transport by one of the microtubule-associated motor proteins, dynein, under compressive mechanical stress. Despite the critical role of tensile stress in many biological functions, how tensile stress on microtubules regulates cargo transport is yet to be unveiled. The present study demonstrates that the low-level tensile stress-induced microtubule deformation facilitates dynein-driven transport. We validate our experimental findings using all-atom molecular dynamics simulation. Our study may provide important implications for developing new therapies for diseases that involve impaired intracellular transport.

CHCHD2 and CHCHD10, linked to Parkinson's disease and amyotrophic lateral sclerosis-frontotemporal dementia (ALS), respectively, are mitochondrial intermembrane proteins that form a heterodimer. This study aimed to investigate the impact of the CHCHD2 P14L variant, implicated in ALS, on mitochondrial function and its subsequent effects on cellular homeostasis. The missense variant of CHCHD2, P14L, found in a cohort of patients with ALS, mislocalized CHCHD2 to the cytoplasm, leaving CHCHD10 in the mitochondria. Drosophila lacking the CHCHD2 ortholog exhibited mitochondrial degeneration. In contrast, human CHCHD2 P14L, but not wild-type human CHCHD2, failed to suppress this degeneration, suggesting that P14L is a pathogenic variant. The mitochondrial Ca 2+ buffering capacity was reduced in Drosophila neurons expressing human CHCHD2 P14L. The altered Ca 2+ -buffering phenotype was also observed in cultured human neuroblastoma SH-SY5Y cells expressing CHCHD2 P14L. In these cells, transient elevation of cytoplasmic Ca 2+ facilitated the activation of calpain and caspase-3, accompanied by the processing and insolubilization of TDP-43. These observations suggest that CHCHD2 P14L causes abnormal Ca 2+ dynamics and TDP-43 aggregation, reflecting the pathophysiology of ALS., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

Introduction: Previous studies have suggested that the prolonged or highly fractionated electrograms during atrial fibrillation (AF) are closely related to the reentrant driver regions. We hypothesized that exploration and ablation of these critical complex atrial fractionated electrograms (CFAE) may improve the outcome of persistent AF (PeAF) refractory to conventional PVI., Methods: A total of 73 PeAF patients with residual inducibility or failed cardioversions of AF after PVI were enrolled and underwent number-of-fractionation mapping (NFM) by counting the number of fractionations in 2.5 s at each of the points using the CARTO3 (ICL mode) and EnSite (fractionation map) systems. After NFM, selective CFAE ablation (NFM-CA) targeting the sites of the upper 40% of the counted fraction number (NF40) was performed as an additional procedure for refractory PeAF. We investigated the prognosis of these patients within 24 months after the index ablation procedure and the relationship between changes in activation patterns during the ablation procedure and their prognosis. We also performed a propensity score-matched analysis comparing these patients with historical controls (HC) to identify the optimal indications for NFM-CA., Results: The AF/AT free survival rate was 79.1% at 12 months and 56.7% at 24 months. Patients with AF termination or AF cycle length prolongation > 21 ms during the procedure had significantly better AF/AT-free survival rates than those without notable activation changes (87.7% vs. 69.0%, logrank p = 0.028). After propensity-matched analysis, AF/AT-free survival showed comparable results between the two groups (1 year; NFM 72.1% vs. HC 77.1%, logrank p = 0.649)., Conclusions: NFM-CA is a versatile and less invasive adjunctive procedure for patients with PVI-refractory PeAF who showed a comparable prognosis to patients with PVI-compliant PeAF. In particular, remarkable activation changes during the procedure (AFCL prolongation > 21 ms or acute termination) suggest a favorable prognosis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Large population-based registries, such as the Surveillance, Epidemiology and End Results (SEER) Registry, help in the study of rare tumors, including medullary thyroid cancer (MTC), but lack data to understand the natural history of the disease. The Medullary Thyroid Cancer Collaborative Registry (MTCCoRe) is an exhaustive multi-institutional collection of demographic, clinical, and pathological data. To determine the extent to which MTCCoRe represents the real-world MTC population, we compared the characteristics of patients enrolled in MTCCoRe with patients enrolled in population-based cancer registries. Methods: Comparison of demographic and clinical characteristics of MTC patients who were enrolled in MTCCoRe, Texas Cancer Registry (TCR), California Cancer Registry (CCR), and SEER between 1995 and 2018. Results: A total of 1416 patients were identified in MTCCoRe, 329 in TCR, 2105 in CCR, and 3820 in SEER. Percentages of patients 20-54 years in MTCCoRe were 58.0%, 50.2% in TCR, 47.2% in CCR, and 44.8% in SEER ( p < 0.0001). About half of the patients were female (55.9% in MTCCoRe, 61.4% in TCR, 59% in CCR, and 57.5% in SEER ( p = 0.3). Percentages of Hispanic and Black patients differed among cohorts (10.1% and 3.8% for MTCCoRe, 23.7% and 8.2% for TCR, 24.8% and 4.9% in CCR, and 15.9% and 8.2% for SEER, respectively; p < 0.001). MTCCoRe patients presented with more advanced T and N classifications than patients in the other registries (MTCCoRe, 28.6% T3-4 and 49.4% N1; TCR, 12.7% and 32.2%; CCR, 18.6% and 32.4%; and SEER, 24% and 37.8%; p < 0.0001). Prevalence of M1 disease was 10% in MTCCoRe, 11.9% in TCR, 14.1% in CCR, and 9.5% in SEER ( p < 0.0001). In the MTCCoRe, 11.4% underwent systemic therapy (compared with 0.3% in TCR and 5.6% in CCR). Conclusions: The clinicodemographic profile of patients with MTC enrolled in a multi-institutional registry differs from those enrolled in population-based databases, with lower proportions of Hispanic and Black patients but additive data on treatment modalities. Moving forward, MTCCoRe and other registry and clinical trial enrollment efforts should intentionally include underrepresented groups via community engagement techniques, patient stakeholder involvement, and inclusion of languages other than English in study materials to yield more generalizable results and conclusions.

Background: To investigate the relationship between changes in the optic disc size and color, cup-to-disc (C/D) ratio, and axial elongation in schoolchildren., Methods: A prospective cohort study was performed in 75 right eyes of elementary school students for six years (from 8.5 to 14.5 years old). In the first and last year, all participants underwent optical axial length measurement and color fundus photography. The optic disc color was calculated by dividing the intensity of red by the sum of the intensity of red, green, and blue. The optic disc area was calculated by modifying the number of pixels according to Bennett's formula. The C/D ratio was calculated by dividing the vertical cup diameter by vertical optic disc diameter. Wilcoxon signed rank test was used to compare these optic disc parameters and axial length in the first and last year., Results: Mean axial length in the last year (24.82 mm) was significantly longer than that in the first year (23.34 mm). Likewise, the mean optic disc size was significantly smaller in the last year (41,946 pixels) than that in the first year (46,144 pixels). The mean optic disc color in the last year (0.49) was significantly more reddish than that in the first year (0.46), while the mean C/D ratio in last year (0.50) was significantly smaller than that in first year (0.52)., Conclusions: During the period from 8.5 years to 14.5 years of age, both the optic disc size and C/D ratio became smaller, while the color became more red., (© 2024. The Author(s).)

Background: The All Nippon Atrial Fibrillation In the Elderly Registry provides real-world insights into non-valvular atrial fibrillation (NVAF) in >30,000 elderly Japanese patients (aged ≥75 years), including >2,000 nonagenarians. We aimed to investigate outcomes in these patients by age and oral anticoagulant (OAC) type., Methods and Results: This prospective, multicenter, observational, cohort, 2-year follow-up study included elderly patients with NVAF who were able to attend hospital visits. The incidences of stroke/systemic embolic events (SEE), major bleeding, intracranial hemorrhage (ICH), cardiovascular death, all-cause death, and major adverse cardiovascular or neurological events (MACNE) were evaluated by age. Incidence rates increased significantly with age. Stroke/SEE, major bleeding, and ICH incidences plateaued in patients aged ≥90 years. Direct OACs (DOACs) yielded a numerically lower event incidence vs. warfarin in all age groups and endpoints, except for major bleeding in patients aged ≥90 years. DOACs (vs. warfarin) were significantly associated with a lower risk of stroke/SEE, major bleeding, and ICH in the ≥80-<85 years group, and reduced cardiovascular and all-cause death in the ≥75-<80 years group. In the ≥90 years subgroup, major bleeding history was a risk factor for all-cause death., Conclusions: Although DOAC vs. warfarin offers potential benefits for stroke prevention, limitations occurred in reducing major bleeding among those aged ≥90 years, indicating a potential benefit of very-low-dose DOAC for this demographic., Competing Interests: S.S. received research funding from Daiichi Sankyo, and remuneration from Bristol-Myers Squibb and Daiichi Sankyo. T. Yamashita received research funding from Bristol-Myers Squibb, Bayer, and Daiichi Sankyo, manuscript fees from Daiichi Sankyo and Bristol-Myers Squibb, and remuneration from Daiichi Sankyo, Bayer, Pfizer Japan, and Bristol-Myers Squibb. M.A. received research funding from Bayer and Daiichi Sankyo, and remuneration from Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Bayer, and Daiichi Sankyo. H.A. received remuneration from Daiichi Sankyo. T.I. received research funding from Daiichi Sankyo, and remuneration from Daiichi Sankyo, Pfizer Japan, and Bayer. Y.K. received remuneration from Daiichi Sankyo, Bristol-Myers Squibb, and Nippon Boehringer Ingelheim. K.O. received remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, and Medtronic. W.S. received research funding from Daiichi Sankyo, and Nippon Boehringer Ingelheim, and remuneration from Daiichi Sankyo, Pfizer Japan, Bristol-Myers Squibb, Bayer, and Nippon Boehringer Ingelheim. H.T. received research funding from Daiichi Sankyo and Nippon Boehringer Ingelheim, remuneration from Daiichi Sankyo, Bayer, Nippon Boehringer Ingelheim, and Pfizer Japan, scholarship funding from Daiichi Sankyo, and consultancy fees from Pfizer Japan, Bayer, and Nippon Boehringer Ingelheim. K.T. received remuneration from Daiichi Sankyo, Bayer, Bristol-Myers Squibb, Otsuka, and Novartis. A.H. participated in a course endowed by Boston Scientific Japan, has received research funding from Daiichi Sankyo and Bayer, and remuneration from Bayer, Daiichi Sankyo, Bristol-Myers Squibb, and Nippon Boehringer Ingelheim. M.Y. received research funding from Nippon Boehringer Ingelheim, and remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Bayer, Bristol-Myers Squibb, and Pfizer Japan. T. Yamaguchi acted as an advisory board member for Daiichi Sankyo and has received remuneration from Daiichi Sankyo and Bristol-Myers Squibb. S.T. received research funding from Nippon Boehringer Ingelheim and remuneration from Daiichi Sankyo, Sanofi, Takeda, Chugai Pharmaceutical, Solasia Pharma, Bayer, Sysmex, Nipro, NapaJen Pharma, Gunze, and Atworking. M.F., Y.M., and A.T. are employees of Daiichi Sankyo. H.I. received remuneration and consultancy fees from Daiichi Sankyo. T. Yamashita, T.I., W.S, and H.T. are Associate Editors for Circulation Journal. A.H. was a member of Circulation Reports’ Editorial Team., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)

Background: Thoracoscopic esophagectomy (TE) with carbon dioxide (CO 2 )   insufflation is increasingly performed for esophageal cancer; however, there is limited evidence of the long-term outcomes of CO 2 insufflation on postoperative survival., Objectives: We investigated the long-term outcomes of TE with or without CO 2 insufflation., Methods: We enrolled 182 patients who underwent TE for esophageal cancer between January 2003 and October 2013 and categorized them into two groups: with and without CO 2 insufflation. The primary endpoint was five-year overall survival (5y-OS). Secondary endpoints included long-term outcomes, such as five-year relapse-free survival (5y-RFS) and five-year cancer-specific survival (5y-CSS), and short-term outcomes, such as surgical and non-surgical complications and reoperation within 30 days., Results: Follow-up until death or the five-year postoperative period was 98.9% (median follow-up duration was six years in survivors). After adjusting for age, sex, and yield pathologic tumor, node, and metastasis (TNM) stage, we found no significant differences in 5y-OS (HR 1.12, 95% CI 0.66-1.91), 5y-RFS (HR 1.12, 95% CI 0.67-1.83), or 5y-CSS rates (HR 1.00, 95% CI 0.57-1.75). For short-term outcomes, significant intergroup differences in operation time (p=0.02), blood loss (p<0.001), postoperative length of stay (p<0.001), and incidence of atelectasis (p=0.004) were observed. The results of the sensitivity analysis were similar to the main results., Conclusions: In thoracoscopic procedures, CO 2 insufflation significantly improved short-term outcomes, and it appears that the recurrence risk of esophageal cancer may not impact the long-term prognosis. While the influence of CO 2 insufflation in thoracoscopic esophageal surgery remains unclear, our study suggests that the long-term prognosis is not compromised in other thoracic surgeries., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Review Board of Showa University School of Medicine issued approval 2256. 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, Otsuka et al.)

Background: Hip fracture and depression are important public health issues among older adults, but how pre-fracture depression impacts recovery after hip fracture is unknown, especially among males who often experience greater depression severity. Days at home (DAH), or the days spent outside a hospital or healthcare facility, is a novel, patient-centered outcome that can capture meaningful aspects of fracture recovery. How pre-fracture depression impacts DAH after fracture, and related sex differences, remains unclear., Methods: Participants included 63,618 Medicare fee-for-service beneficiaries aged 65+ years, with a hospitalization claim for hip fracture surgery between 2010 and 2017. The primary exposure was a diagnosis of depression at hospital admission, and the primary outcome was total DAH over 12 months post-discharge. Longitudinal associations between pre-fracture depression and the count of DAH among beneficiaries were estimated using Poisson regression models after adjustment for covariates; sex-by-depression interactions were also assessed. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) reflecting relative differences were estimated from these models., Results: Overall, beneficiaries with depression were younger, White females, and spent 11 fewer average DAH compared to counterparts without depression when demographic factors (age and sex) (IRR = 0.91; 95% CI = 0.90, 0.92; p < 0.0001) and social determinants of health (race, Medicaid dual eligibility, and poverty) were adjusted for (IRR = 0.92; 95% CI = 0.91, 0.93; p < 0.0001), but this association attenuated after adjusting for medical complexities (IRR = 0.99; 95% CI = 0.98, 1.01; p = 0.41) and facility and geographical factors (IRR = 1.0037; 95% CI = 0.99, 1.02; p = 0.66). There was no evidence of effect modification by sex., Conclusions: The comorbidity burden of preexisting depression may impact DAH among both male and female Medicare beneficiaries with hip fracture. Results suggest a holistic health approach and secondary prevention of depressive symptoms after hip fracture., (© 2024 The American Geriatrics Society.)

Flow-injection spin-trapping electron paramagnetic resonance (FI-EPR) methods that involve the use of 5,5-dimethyl-pyrroline- N -oxide (DMPO) as a spin-trapping reagent have been developed for the kinetic study of the O 2 •- radical scavenging reactions occurring in the presence of various plant-derived and synthetic phenolic antioxidants (Aox), such as flavonoid, pyrogallol, catechol, hydroquinone, resorcinol, and phenol derivatives in aqueous media (pH 7.4 at 25 °C). The systematically estimated second-order rate constants ( k s ) of these phenolic compounds span a wide range (from 4.5 × 10 to 1.0 × 10 6 M -1 s -1 ). The semilogarithm plots presenting the relationship between k s values and oxidation peak potential ( E p ) values of phenolic Aox are divided into three groups (A1, A2, and B). The k s - E p plots of phenolic Aox bearing two or three OH moieties, such as pyrogallol, catechol, and hydroquinone derivatives, belonged to Groups A1 and A2. These molecules are potent O 2 •- radical scavengers with k s values above 3.8 × 10 4 (M -1 s -1 ). The k s - E p plots of all phenol and resorcinol derivatives, and a few catechol and hydroquinone derivatives containing carboxyl groups adjacent to the OH groups, were categorized into the group poor scavengers ( k s < 1.6 × 10 3 M -1 s -1 ). The k s values of each group correlated negatively with E p values, supporting the hypothesis that the O 2 •- radical scavenging reaction proceeds via one-electron and two-proton processes. The processes were accompanied by the production of hydrogen peroxide at pH 7.4. Furthermore, the correlation between the plots of k s and the OH proton dissociation constant (p K a • ) of the intermediate aroxyl radicals ( k s -p K a • plots) revealed that the second proton transfer process could potentially be the rate-determining step of the O 2 •- radical scavenging reaction of phenolic compounds. The k s - E p plots provide practical information to predict the O 2 •- radical scavenging activity of plant-derived phenolic compounds based on those molecular structures.

Background: The causative genes for over 60% of inherited peripheral neuropathy (IPN) remain unidentified. This study endeavours to enhance the genetic diagnostic rate in IPN cases by conducting screenings focused on non-coding repeat expansions., Methods: We gathered data from 2424 unrelated Japanese patients diagnosed with IPN, among whom 1555 cases with unidentified genetic causes, as determined through comprehensive prescreening analyses, were selected for the study. Screening for CGG non-coding repeat expansions in LRP12 , GIPC1 and RILPL1 genes was conducted using PCR and long-read sequencing technologies., Results: We identified CGG repeat expansions in LRP12 from 44 cases, establishing it as the fourth most common aetiology in Japanese IPN. Most cases (29/37) exhibited distal limb weakness, without ptosis, ophthalmoplegia, facial muscle weakness or bulbar palsy. Neurogenic changes were frequently observed in both needle electromyography (97%) and skeletal muscle tissue (100%). In nerve conduction studies, 28 cases primarily showed impairment in motor nerves without concurrent involvement of sensory nerves, consistent with the phenotype of hereditary motor neuropathy. In seven cases, both motor and sensory nerves were affected, resembling the Charcot-Marie-Tooth (CMT) phenotype. Importantly, the mean CGG repeat number detected in the present patients was significantly shorter than that of patients with LRP12 -oculopharyngodistal myopathy (p<0.0001). Additionally, GIPC1 and RILPL1 repeat expansions were absent in our IPN cases., Conclusion: We initially elucidate LRP12 repeat expansions as a prevalent cause of CMT, highlighting the necessity for an adapted screening strategy in clinical practice, particularly when addressing patients with IPN., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Epigenetic modifications affect cell differentiation via transcriptional regulation. G9a/EHMT2 is an important epigenetic modifier that catalyzes the methylation of histone 3 lysine 9 (H3K9) and interacts with various nuclear proteins. In this study, we investigated the role of G9a in osteoclast differentiation. When we deleted G9a by infection of Cre-expressing adenovirus into bone marrow macrophages (BMMs) from G9a fl/fl (Ehmt2 fl/fl ) and induced osteoclastic differentiation by the addition of macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL), the number of TRAP-positive multinucleated osteoclasts significantly increased compared with control. Furthermore, the mRNA expression of osteoclast markers, TRAP, and cathepsin K, and to a lesser extent, NFATc1, a critical transcription factor, increased in G9a KO cells. Infection of wild-type (WT) G9a-expressing adenovirus in G9a KO cells restored the number of TRAP-positive multinucleated cells. In G9a KO cells, increased nuclear accumulation of NFATc1 protein and decreased H3K9me2 accumulation were observed. Furthermore, ChIP experiments revealed that NFATc1 binding to its target, Ctsk promoter, was enhanced by G9a deletion. For in vivo experiments, we created G9a conditional knock-out (cKO) mice by crossing G9a fl/fl mice with Rank Cre/+ (Tnfrsf11a Cre/+ ) mice, in which G9a is deleted in osteoclast lineage cells. The trabecular bone volume was significantly reduced in female G9a cKO mice. The serum concentration of the C-terminal telopeptide of type I collagen (CTX), a bone-resorbing indicator, was higher in G9a cKO mice. In addition, osteoclasts differentiated from G9a cKO BMMs exhibited greater bone-resorbing activity. Our findings suggest that G9a plays a repressive role in osteoclastogenesis by modulating NFATc1 function., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Objective: This study aims to fill the knowledge gap regarding the effects of high frequency facial neuromuscular electrical stimulation (fNMES) on facial aging, using a device equipped with CERTEC (Cell Energy Regeneration Technology) operating between 40 and 190 kHz., Methods: This prospective split-face study was conducted at Tokyo University Hospital between March and May 2023 with 24 healthy adult women aged 30-59. The intervention group used the fNMES device along with basic skin care on one side of the face, and basic skin care alone on the other side for 8 weeks. Evaluations included changes in skin wrinkles, sagging, and blood flow., Results: This study found significant improvements in skin elasticity and degree of wrinkles in the areas intervened with fNMES (p < 0.05, respectively). In addition, the intervention resulted in significant improvements in jawline angle (p < 0.01), submental volume (p < 0.05), cheek volume (p < 0.05), maximum nasolabial fold depth (p = 0.03), and total volume of the nasolabial folds (p = 0.03). The fNMES intervention also showed improvement in blood flow (p < 0.05). These improvements were also subjectively assessed by the participants in subject questionnaires at 8 weeks after the intervention (p < 0.05)., Conclusion: This study suggests that high frequency fNMES effectively improves facial skin elasticity, reduces wrinkles and sagging, promotes blood flow, and contributes to overall facial appearance rejuvenation. Although further studies are needed, high frequency fNMES appeared promising as a noninvasive anti-aging therapy., (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

The global phase 3 DESTINY-Breast03 study (ClinicalTrials.gov; NCT03529110) showed statistically significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) with trastuzumab deruxtecan (T-DXd) over trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. Here, we report a subgroup analysis of Asian patients enrolled in DESTINY-Breast03. In total, 309 patients (149 in the T-DXd arm and 160 in the T-DM1 arm) from Asian countries and regions were randomized. At data cutoff (July 25, 2022), the median duration of follow-up in the Asian subpopulation was 29.0 months with T-DXd and 26.0 months with T-DM1. The PFS (determined by blinded independent central review) hazard ratio was 0.30 (95% confidence interval 0.22-0.41) favoring T-DXd over T-DM1 (median PFS 25.1 vs. 5.4 months). Median OS was not reached in the T-DXd arm and was 37.7 months in the T-DM1 arm. The median treatment duration was 15.4 months with T-DXd and 5.5 months with T-DM1. The incidence of grade ≥3 drug-related treatment-emergent adverse events was similar between both treatment arms (49.0% vs. 46.5%) and was consistent with the overall DESTINY-Breast03 population. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 12.9% of patients treated with T-DXd and 2.5% treated with T-DM1, with a higher incidence in Japanese patients; none of these were grade ≥4 events. These efficacy and safety data reinforce the favorable benefit-risk profile of T-DXd in HER2-positive mBC, including in the Asian subgroup., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objectives: We aim to assess the early use of contrast-enhanced computed tomography (CECT) of patients with severe acute pancreatitis (SAP) using the computed tomography severity index (CTSI) in prognosis prediction. The CTSI combines quantification of pancreatic and extrapancreatic inflammation with the extent of pancreatic necrosis., Methods: Post-hoc retrospective analysis of a large, multicentric database (44 institutions) of SAP patients in Japan. The area under the curve (AUC) of the CTSI for predicting mortality and the odds ratio (OR) of the extent of pancreatic inflammation and necrosis were calculated using multivariable analysis., Results: In total, 1097 patients were included. The AUC of the CTSI for mortality was 0.65 (95 % confidence interval [CI:] [0.59-0.70]; p < 0.001). In multivariable analysis, necrosis 30-50 % and >50 % in low-enhanced pancreatic parenchyma (LEPP) was independently associated with a significant increase in mortality, with OR 2.04 and 95 % CI 1.01-4.12 (P < 0.05) and OR 3.88 and 95 % CI 2.04-7.40 (P < 0.001), respectively. However, the extent of pancreatic inflammation was not associated with mortality, regardless of severity., Conclusions: The degree of necrosis in LEPP assessed using early CECT of SAP was a better predictor of mortality than the extent of pancreatic inflammation., Competing Interests: Declaration of competing interest All authors have no conflicts of interests relevant to this article to disclose., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Objective: Rarefaction of blood and lymphatic vessels in the skin has been reported in systemic sclerosis (SSc) (scleroderma). E26 transformation-specific-related factor (ERG) and Friend leukemia virus-induced erythroleukemia 1 (FLI-1) are important regulators of angiogenesis, but their role in lymphatic vasculature is lesser known. The goal of this study was to determine the role of ERG and FLI-1 in postnatal lymphangiogenesis and SSc lymphatic system defects., Methods: Immunofluorescence was used to detect ERG and FLI-1 in skin biopsy samples from patients with SSc and healthy controls. Transcriptional analysis of ERG or FLI-1-silenced human dermal lymphatic endothelial cells (LECs) was performed using microarrays. Effects of ERG and FLI-1 deficiency on in vitro tubulogenesis in human dermal LECs were examined using a Matrigel assay. ERG and FLI-1 endothelial-specific knockouts and ERG lymphatic-specific knockouts were generated to examine vessel regeneration in mice., Results: ERG and FLI-1 protein levels were reduced in the blood and lymphatic vasculature in SSc skin biopsy samples. ERG levels were shown to regulate genes involved in lymphatic vessel specification, including vascular endothelial growth factor receptor 3/FLT-4, lymphatic vessel endothelial hyaluronan receptor 1, SOX-18, and prospero homeobox 1 (PROX-1), whereas FLI-1 enhanced the function of ERG. The ERG-FLT-4 pathway regulated in vitro tubulogenesis in human LECs. Deficiency of ERG or FLI-1 similarly impaired the function of blood vessels in mice. However, only ERG deficiency affected the regeneration of lymphatic vessels during wound healing., Conclusion: ERG and FLI-1 are essential regulators of blood and lymphatic vessel regeneration. Deficiency of ERG and FLI-1 in SSc endothelial cells may contribute to the impairment of blood and lymphatic vasculature in patients with SSc., (© 2024 American College of Rheumatology.)

We herein report a 47-year-old man who presented with progressive paraparesis. Imaging revealed a right upper pulmonary nodule, massive bilateral adrenal metastases, thoracolumbar vertebral osteolysis, and subcutaneous nodules. A biopsy of the right buttock nodule revealed a poorly differentiated metastatic carcinoma with high programmed cell death-ligand 1 expression and extensive chromosomal rearrangements. The patient died 10 days after the initiation of pembrolizumab treatment. Autopsy findings confirmed pulmonary pleomorphic carcinoma with extensive metastases. Quantification of chromosomal rearrangements revealed a jump-up mutation from the normal karyotype, followed by a further incremental increase in the degree of deviation.

A pleiotropic immunoregulatory cytokine, TGF-β, signals via the receptor-regulated SMADs: SMAD2 and SMAD3, which are constitutively expressed in normal cells. Here, we show that selective repression of SMAD3 induces cDC differentiation from the CD115 + common DC progenitor (CDP). SMAD3 was expressed in haematopoietic cells including the macrophage DC progenitor. However, SMAD3 was specifically down-regulated in CD115 + CDPs, SiglecH - pre-DCs, and cDCs, whereas SMAD2 remained constitutive. SMAD3-deficient mice showed a significant increase in cDCs, SiglecH - pre-DCs, and CD115 + CDPs compared with the littermate control. SMAD3 repressed the mRNA expression of FLT3 and the cDC-related genes: IRF4 and ID2. We found that one of the SMAD transcriptional corepressors, c-SKI, cooperated with phosphorylated STAT3 at Y705 and S727 to repress the transcription of SMAD3 to induce cDC differentiation. These data indicate that STAT3 and c-Ski induce cDC differentiation by repressing SMAD3: the repressor of the cDC-related genes during the developmental stage between the macrophage DC progenitor and CD115 + CDP., (© 2024 Yoon et al.)

Immunoglobulin A (IgA) is notable for its broad specificity toward multiple bacteria. Phosphorylcholine (PC) plays a role in the infection of pathogenic bacteria carrying PC and in the induction of IgA responses in the host immune system. The commercially available mouse monoclonal IgA, TEPC15-IgA, is a distinctive antibody with specificity for PC, warranting further exploration of its response to PC-bearing enteric bacteria. In this study, using 17 different enteric bacteria, including 3 aerobic and 14 anerobic bacteria that could be cultured in vitro, we confirmed that TEPC15-IgA recognizes 4 bacterial species: Lactobacillus taiwanensis, Limosilactobacillus frumenti, Streptococcus infantis, and Escherichia coli, although reactivity varied. Interestingly, TEPC15-IgA did not react with four of six Lactobacillus species used. Moreover, distinct target molecules associated with PC in L. taiwanensis and L. frumenti were evident, differing in molecular weight. These findings suggest that the natural generation of PC-specific IgA could prevent PC-mediated infections and potentially facilitate the formation of a microflora rich in indigenous bacteria with PC, particularly in the gastrointestinal tract.

Introduction: The enduring COVID-19 pandemic has had persistent, intermittent socioeconomic impacts on migrants. This raises the concern that many Vietnamese migrants in Japan may have developed mental health issues due to the socioeconomic impact. The study aimed to examine changes in the socio-economic and mental health status of Vietnamese migrants in Japan and factors affecting mental health status during the early to mid-COVID-19 period., Methods: We conducted a prospective cohort study among Vietnamese migrants in Japan from September to October 2021 (baseline) and from May to June 2022 (follow-up) using an online questionnaire. Multiple linear regression analyses were conducted to examine the association between changes in socioeconomic status and alterations in symptoms of depression and anxiety within this demographic., Results: The mean age of the 159 participants was 26.1 ± 4.9 years, with a mean length of residency in Japan of 4.0 ± 4.1 years. The mean PHQ-9 score exhibited a significant decrease from 7.89 (SD = 6.34) to 6.62 (SD = 5.87) (p = 0.01). Variables associated with changes in depression and anxiety included subjective socioeconomic status (unstandardized partial regression coefficient (UPRC): 1.901, 95% confidence interval (CI) 0.30 to 3.50, p = 0.02) and (UPRC: 2.060, 95% CI 0.80 to 3.32, p = 0.002), as well as changes in having someone with whom to discuss one's health (UPRC: 2.689, 95% CI 0.89 to 4.49, p = 0.004) and (UPRC: 1.955, 95% CI 0.54 to 3.38, p = 0.007)., Conclusions: In this prospective cohort study of depression and anxiety, depressive symptoms among Vietnamese migrants decreased from 2021 to 2022. Key findings underscore the importance of socioeconomic status improvement and having someone to discuss to about their health as protective factors against mental health challenges. Employment and social support have emerged as crucial determinants of mental health among Vietnamese migrants in Japan, emphasizing the necessity for comprehensive support strategies addressing both economic vulnerabilities and social connectedness., (© 2024. The Author(s).)

Serum laminin-γ2 monomer (Lm-γ2m) is a potent predictive biomarker for hepatocellular carcinoma (HCC) onset in patients with hepatitis C infection who achieve a sustained virologic response with liver cirrhosis (LC) and for the onset of extrahepatic metastases in early-stage HCC. Although Lm-γ2m involvement in late-stage cancer progression has been well investigated, its precise roles in HCC onset remain to be systematically investigated. Therefore, we analyzed an HCC model, human hepatocytes and cholangiocytes, and surgically resected liver tissues from patients with HCC to understand the roles of Lm-γ2m in HCC onset. Ck-19- and EpCAM-positive hepatic progenitor cells (HPCs) in the liver of pdgf-c transgenic HCC mouse model with ductular reaction showed ectopic expression of Lm-γ2m. Forced expression of Lm-γ2m in hepatocytes adjacent to HPCs resulted in enhanced tumorigenicity, cell proliferation, and migration in immortalized hepatocytes, but not in cholangiocytes in vitro. Further, pharmacological inhibition of epidermal growth factor receptor (EGFR) and c-Jun activator JNK suppressed Lm-γ2m-induced hepatocyte transformation, suggesting the involvement of EGFR/c-Jun signaling in the transformation, leading to HCC development. Finally, immunohistochemical staining of HCC tissues revealed a high level of Lm-γ2 expression in the HPCs of the liver with ductular reaction in normal liver adjacent to HCC tissues. Overall, HPC-derived Lm-γ2m in normal liver with ductular reaction acts as a paracrine growth factor on surrounding hepatocytes and promotes their cellular transformation through the EGFR/c-Jun signaling pathway. Furthermore, this is the first report on Lm-γ2m expression detected in the normal liver with ductular reaction, a human precancerous lesion of HCC., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: We have investigated the absorption dynamics of petroleum fuel components from the analytical results of autopsy samples., Methods: Post-mortem samples of the severely burned case, including femoral blood, intratracheal contents (mucus) and intratracheal gas-phase samples were collected, and analysed by gas chromatography-mass spectrometer with head-space solid-phase microextraction., Results: The composition of flammable substances in the tracheal gas phase differed slightly from that in mucus., Conclusion: High-boiling point components are retained in the trachea, whereas relatively lower-boiling point components are detected predominantly in the tracheal gas phase and blood., (© 2024. The Author(s).)