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Kazuhiro Sakaguchi,1 Masanori Yoshikawa,1 Yukio Fujita,1 Yoshifumi Yamamoto,1 Takahiro Ibaraki,1 Nobuhiro Fujioka,1 Takao Osa,1 Motoo Yamauchi,1 Hiroshi Ichikawa,2 Shigeo Muro1 1Department of Respiratory Medicine, Nara Medical University, Kashihara, Nara, Japan; 2Major of Medical Life Systems, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, JapanCorrespondence: Masanori Yoshikawa, Department of Respiratory Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan, Tel +81-744-22-3051, Fax +81-744-29-0907, Email noriy@naramed-u.ac.jpBackground: Oxidative stress is an important mechanism for the development and progression of chronic obstructive pulmonary disease (COPD). It may also contribute to systemic manifestation in patients with COPD. Reactive oxygen species (ROS) including free radicals play a crucial role in oxidative stress in COPD. The aims of this study were to determine serum scavenging capacity profile against multiple free radicals and to evaluate its correlation with pathophysiology, exacerbations, and prognosis in patients with COPD.Methods: Serum scavenging capacity profile against multiple free radicals comprising hydroxyl radical (•OH), superoxide radical (O2−•), alkoxy radical (RO•), methyl radical (•CH3), alkylperoxyl radical (ROO•), and singlet oxygen (1O2) was assessed using the multiple free-radical scavenging method in 37 patients with COPD (mean age, 71 years; mean forced expiratory volume in 1 s, 55.2% predicted). The severity of emphysema was evaluated by Goddard classification on chest computed tomography. Exacerbations were recorded prospectively for 1 year and the overall mortality was assessed 5 years after the initial assessment.Results: •OH scavenging capacity was significantly decreased (p < 0.05) and O2−• and •CH3 scavenging capacity tended to decrease in patients with COPD compared to that in healthy controls. On the other hand, ROO• scavenging capacity tended to increase. In addition, RO• scavenging capacity was associated with severity of emphysema (p < 0.05) and exacerbation frequency (p < 0.02). There was a difference in the profile of the scavenging capacity between survived and deceased patients with COPD for 5 years after initial assessment.Conclusion: Characteristic profile of free radical scavenging capacity can provide insight into the pathophysiology and prognosis of patients with COPD.Keywords: oxidative stress, free radicals, the multiple free-radical scavenging method, pathophysiology, exacerbations, prognosis

Regional climate modeling addresses our need to understand and simulate climatic processes and phenomena unresolved in global models. This paper highlights examples of current approaches to and innovative uses of regional climate modeling that deepen understanding of the climate system. High-resolution models are generally more skillful in simulating extremes, such as heavy precipitation, strong winds, and severe storms. In addition, research has shown that finescale features such as mountains, coastlines, lakes, irrigation, land use, and urban heat islands can substantially influence a region's climate and its response to changing forcings. Regional climate simulations explicitly simulating convection are now being performed, providing an opportunity to illuminate new physical behavior that previously was represented by parameterizations with large uncertainties. Regional and global models are both advancing toward higher resolution, as computational capacity increases. However, the resolution and ensemble size necessary to produce a sufficient statistical sample of these processes in global models has proven too costly for contemporary supercomputing systems. Regional climate models are thus indispensable tools that complement global models for understanding physical processes governing regional climate variability and change. The deeper understanding of regional climate processes also benefits stakeholders and policymakers who need physically robust, high-resolution climate information to guide societal responses to changing climate. Key scientific questions that will continue to require regional climate models, and opportunities are emerging for addressing those questions.

Silent inactivation (SI) of L-asparaginase (ASP) is a phenomenon by which a neutralizing antibody for ASP (AAA) decreases ASP activity (ASA) in patients without a clinical allergy to ASP. Acute lymphoblastic leukemia (ALL) has a poor prognosis in patients with SI. Therefore, measurement of ASA levels, not AAA levels, is needed to identify patients with SI. We herein report the results of the prospective clinical trial ALL-ASP19, the first study in Japan to measure ASA and AAA to identify patients with SI. A total of 110 newly diagnosed ALL patients were enrolled, and ASA levels were measured three times during ALL treatment. Besides the 12 patients who discontinued the study, 32 were excluded due to inappropriate frequency and timing of ASA measurements and inappropriate ASP dosing. The remaining 66 patients were analyzed, and 3 patients with SI (4.5%) were identified. The incidence of SI is lower in Japan than in other countries. AAA was detected in all patients with SI, but four of the seven patients with AAA did not develop SI. Clinical characteristics did not significantly differ between patients with and without SI. Therefore, ASA levels must be measured to identify patients receiving insufficient ASP treatment., Competing Interests: Declarations. Conflict of interest: None of the authors have any conflict of interest to disclose., (© 2024. Japanese Society of Hematology.)

Numerical weather, climate, or Earth system models involve the coupling of components. At a broad level, these components can be classified as the resolved fluid dynamics, unresolved fluid dynamical aspects (i.e., those represented by physical parameterizations such as subgrid-scale mixing), and nonfluid dynamical aspects such as radiation and microphysical processes. Typically, each component is developed, at least initially, independently.Once development ismature, the components are coupled to deliver a model of the required complexity. The implementation of the coupling can have a significant impact on the model.As the error associated with each component decreases, the errors introduced by the coupling will eventually dominate. Hence, any improvement in one of the components is unlikely to improve the performance of the overall system. The challenges associated with combining the components to create a coherentmodel are here termed physics-dynamics coupling. The issue goes beyond the coupling between the parameterizations and the resolved fluid dynamics. This paper highlights recent progress and some of the current challenges. It focuses on three objectives: to illustrate the phenomenology of the coupling problemwith references to examples in the literature, to show howthe problem can be analyzed, and to create awareness of the issue across the disciplines and specializations. The topics addressed are different ways of advancing full models in time, approaches to understanding the role of the coupling and evaluation of approaches, coupling ocean and atmosphere models, thermodynamic compatibility between model components, and emerging issues such as those that arise as model resolutions increase and/ormodels use variable resolutions.

Background: Through a retrospective analysis of existing FDG PET-MRI images, we recently demonstrated that metformin increases the accumulation of FDG in the intestinal lumen, suggesting that metformin stimulates glucose excretion into the intestine. However, the details of this phenomenon remain unclear. We here investigate the detailed dynamics of intestinal glucose excretion, including the rate of excretion and the metabolism of excreted glucose, in both the presence and absence of metformin., Methods: We quantified intestinal glucose excretion using newly developed FDG PET-MRI-based bioimaging in individuals with type 2 diabetes, both treated and untreated with metformin. The metabolism of excreted glucose was analyzed through mass spectrometry of fecal samples from mice intravenously injected with 13 C-labeled glucose., Results: Continuous FDG PET/MRI image taking reveals that FDG is initially observed in the jejunum, suggesting its involvement in FDG excretion. Metformin-treated individuals excrete a significant amount of glucose (~1.65 g h -1 per body) into the intestinal lumen. In individuals not receiving metformin, a certain amount of glucose (~0.41 g h -1 per body) is also excreted into the intestinal lumen, indicating its physiological importance. Intravenous injection of 13 C-labeled glucose in mice increases the content of 13 C in short-chain fatty acids (SCFAs) extracted from feces, and metformin increased the incorporation of 13 C into SCFAs., Conclusions: A previously unrecognized, substantial flux of glucose from the circulation to the intestinal lumen exists, which likely contributes to the symbiosis between gut microbiota and the host. This flux represents a potential target of metformin's action in humans., Competing Interests: Competing interests: The authors declare the following competing interests: W.O. has received research support and lecture fees from Sumitomo Pharma and Teijin Pharma. K. Sakaguchi and Y. Hirota have received research support from Sumitomo Pharma. All other authors declare no competing interests., (© 2025. The Author(s).)

Purpose: The optimal neoadjuvant regimen before radical prostatectomy (RP) in patients with high-risk (HR) prostate cancer (PCa) remains to be determined. This retrospective multicenter cohort study assessed the effectiveness and safety of neoadjuvant chemohormonal therapy (NCHT) in patients with HR-PCa undergoing robot-assisted laparoscopic radical prostatectomy (RALP)., Methods: We reviewed the datasets of 1023 subjects who underwent RALP at nine Japanese facilities between September 2012 and October 2023. The enrolled patients were divided into two groups using propensity score matching: a RALP-alone group and those who underwent NCHT followed by RALP (NCHT group). The NCHT regimen consisted of a luteinizing hormone-releasing hormone antagonist and tegafur-uracil for at least 3 months before RALP. The primary endpoint was biochemical recurrence (BCR) after RALP. The secondary endpoint was the surgical specimen pathology findings., Results: Propensity score matching identified 139 individuals for each group. Median follow-up was 18.2 months. During follow-up, BCR was observed in 41 patients (29.5%) in the RALP-alone group and 22 patients (15.8%) in the NCHT group (p = 0.010). Pathological results showed significantly more organ-confined PCa and significantly fewer positive surgical margins or lymphovascular invasion in the NCHT group than in the RALP-alone group. The 2-yr biochemical recurrence-free survival (BRFS) was 72.7% and 74.7% in the RALP-alone and NCHT groups, respectively (p = 0.086). Two patients (1.4%) experienced grade 3 liver disorder as an NCHT-related adverse event., Conclusion: The results suggest that NCHT can safely treat HR-PCa and may reduce the incidence of BCR when combined with RALP., Competing Interests: Declarations. Conflict of interest: The authors have no relevant financial or non-financial interests to disclose. Ethical approval: This retrospective study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Institutional Review Board of Gifu University approved this study (Approval No.: 2021-A050). Consent to participate: Retrospective study, no consent required. Consent for publication: Taken from the Institute., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: In Japan, despite 5 years since CGP tests were covered by insurance in 2019, low drug accessibility rates remain a critical issue. We evaluated drug accessibility in 3776 breast cancer from the C-CAT database using two criteria: the proportion first linked to PMDA-approved drugs with phase III trial evidence for breast cancer through CGP tests but not existing Companion diagnostics [CDx] (*), and the proportion first linked to PMDA-approved drugs including based on phase I and II trial evidence (**). Additionally, cases linked to investigational drugs for non-PMDA-approved drugs were counted., Methods: We identified the top 100 genetic alterations in Japanese breast cancer via CGP tests, listing corresponding drugs from C-CAT reports. Drug accessibility was re-evaluated through simulations with updated evidence levels by a member of the expert panel at Osaka University (EP-EL in OUH)., Results: Results showed the proportion improved to 28.4% under the newest EP-EL in OUH, including 3.4% for HER2-negative cases eligible for HER2-targeted therapy due to ERBB2 amplification and 25.0% for ER-positive, HER2-negative cases eligible for capivasertib-fulvestrant therapy due to PIK3CA, AKT1, and PTEN alterations (*). However, in part, initial false negatives for HER2 status and practical difficulties in using CGP tests as a CDx for capivasertib exist. Including mutations like TMB-H, MSI-H, BRAF V600E mutation, and NTRK fusions raised the proportion to 37.9% (**), but lacking drugs with phase III trials evidence., Conclusion: These findings highlight the ongoing difficulties in demonstrating clear clinical utility of CGP tests in Japan, emphasizing the need for broad discussions on its future direction., Competing Interests: Declarations. Conflict of interest: Koichi Takayama received grants from Chugai Pharmaceutical and Ono Pharmaceutical, and personal fees from AstraZeneca, Chugai Pharmaceutical, MSD, Eli Lilly, Boehringer Ingelheim, and Daiichi Sankyo. Yasuto Naoi has received research funding from Sysmex, ONO, Daiichi-Sankyo and AstraZeneca, and honoraria from AstraZeneca, Pfizer, Eli Lilly, ONO, Daiichi-Sankyo and Chugai outside the submitted work; he holds joint patents with Sysmex including Curebest™ 95GC Breast (JP.5725274.B2). The other authors declare that there are no conflicts of interest. Ethical approval: Approval of the research protocol by the Ethics Review Committee of Kyoto Prefectural University of Medicine (ERB-C-2860) and by the review board of C-CAT (CDU2023-025N). Consent for publication: Not applicable., (© 2024. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Objective: To evaluate the effect of body posture on occlusal contact., Methods: A total of 30 healthy subjects were evaluated. T-Scan™ III was used to analyze the center of occlusal force (COF) and occlusal force distribution while subjects remained supine (SP), upright sitting with the head fixed (UP-HFI), upright sitting with the head free (UP-HFR), and natural standing (NS)., Results: The total trajectory length of COF was significantly longer in NS than in SP, UP-HFI, and UP-HFR. The COF area was significantly larger in UP-HFR than in SP and UP-HFI and also significantly larger in NS than in SP, UP-HFI, and UP-HFR. The anteroposterior occlusal force distribution (AOD) in NS shifted significantly forward, compared to SP, UP-HFI, and UP-HFR. AOD in UP-HFI and UP-HFR shifted significantly forward, compared to the SP position., Conclusion: Changes in body posture affect the stability and anteroposterior balance of occlusal contacts.

In cattle, the culture temperature used for the in vitro growth (IVG) of immature oocytes is generally 38.5 or 39.0 °C, which is close to the normal temperature in the vagina or rectum. However, the temperature in the in vivo ovarian tissue is approximately 1 °C lower (37.5 °C) than that in the vagina or rectum. Therefore, the generally accepted culture temperature may not be optimal for the IVG of bovine oocytes. Herein, we investigated the effects of culture temperature on the IVG of oocyte-cumulus granulosa complexes (OCGCs) derived from early antral follicles (0.5-1 mm in diameter). OCGCs were subjected to 12 days of IVG at temperatures of 37.5, 38.5, and 39.0 °C. OCGC viability and antrum formation were evaluated every 4 days. Estradiol-17β (E 2 ) and progesterone (P 4 ) production from OCGCs during the 1st, 2nd, and 3rd 4-day periods was evaluated by enzyme immunoassay. Viable OCGCs after IVG were subjected to in vitro maturation (IVM), in vitro fertilization, and embryo culture. Then, the nuclear status and diameter of oocytes after IVM, rates of cleavage and blastocysts, and cell number in blastocysts were evaluated. In addition, the mRNA expression of heat shock proteins (HSPs) in the granulosa cells and reduced glutathione (GSH) levels in oocytes after IVG were measured. The viability of OCGCs did not differ among the groups, whereas the rate of antrum formation on day 12 of IVG culture was highest in the 37.5 °C group (P < 0.05). P 4 production did not differ among the groups; however, E 2 production during days 8-12 tended to be higher in the 37.5 °C group than in the other two groups combined (P < 0.1). The mRNA expression of HSP70 and 90, and the GSH levels of oocytes, did not differ among the groups. The oocyte diameter after culture was larger in the 37.5 °C group than in the 39.0 °C group (P < 0.05), and that in the 38.5 °C group was intermediate between the other two groups. The rates of nuclear maturation and cleavage did not differ among the groups. However, the blastocyst rate was higher in the 37.5 and 38.5 °C groups than in the 39.0 °C group (P < 0.05). The cell number in the blastocysts in the 38.5 °C group was smaller than the in vivo-grown oocytes, while that in the 37.5 °C group and the in vivo-grown oocytes did not differ. In summary, OCGCs in the 37.5 °C group showed healthy morphology and steroidogenesis, as well as better growth and developmental competence of oocytes. Therefore, culture conditions close to the in vivo ovarian tissue temperature would be optimal for the IVG of immature bovine oocytes., 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 © 2025 Elsevier Inc. All rights reserved.)

Due to the strong demand for embryo production from young and genotyped superior animals using ovum-pick up (OPU) combined with in vitro fertilization (IVF), the number of in vitro-produced embryos has exceeded that of in vivo-derived embryos globally since 2016. One of the merits of OPU-IVF is that the administration of follicle-stimulating hormone (FSH) is not essential, while FSH treatment prior to OPU promotes oocyte developmental competence. Thus, investigations are needed to optimize OPU-IVF protocols with and without FSH. In addition, OPU enables oocyte collection from antral follicles in living animals. However, there are numerous immature oocytes in follicles at earlier stages, which are potentially destined to degenerate in ovaries. The technology used to foster acquisition of maturational and developmental competences in these immature oocytes is called in vitro growth (IVG). IVG is expected to contribute to assisted reproductive technologies for livestock, humans, and endangered species. However, no offspring from preantral follicles has been reported using IVG in animals other than in mice. Furthermore, IVG can be used to investigate factors affecting the fertility and developmental competence of oocytes by reconstituting follicle growth at each stage in vitro, which cannot be evaluated in vivo. Here, the technological progress of the optimization of immature bovine oocyte utilization is reviewed alongside findings from a variety of other ruminants.

Objective: Type A insulin resistance syndrome (IRS), characterized by impaired insulin receptor function due to variants of the insulin receptor gene, manifests as severe insulin-resistant diabetes. Differentiation of type A IRS from type 2 diabetes on the basis of hyperinsulinemia can be challenging. Given the association between insulin receptor dysfunction and reduced insulin clearance, we evaluated the potential of the circulating C-peptide reactivity (CPR)/immunoreactive insulin (IRI) molar ratio, a marker of insulin clearance, for distinguishing type A IRS from type 2 diabetes., Methods: We retrospectively analyzed CPR and IRI levels measured during a 75-g oral glucose tolerance test (OGTT) in 18 individuals with type A IRS and 126 with type 2 diabetes. Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic performance of the CPR/IRI molar ratio and IRI levels., Results: IRI levels were significantly higher and the CPR/IRI molar ratio significantly lower in individuals with type A IRS compared with those with type 2 diabetes. The area under the ROC curve for the CPR/IRI molar ratio at baseline, 1 hour, and 2 hours after OGTT initiation was 0.997 (sensitivity 100%, specificity 99.2%), 0.999 (sensitivity 100%, specificity 97.6%), and 0.997 (sensitivity 100%, specificity 95.1%), respectively. The CPR/IRI molar ratio demonstrated robust diagnostic performance regardless of body mass index or hyperinsulinemia severity., Conclusions: The CPR/IRI molar ratio, both at baseline and during OGTT, exhibited higher sensitivity and specificity than IRI levels alone for distinguishing type A IRS from type 2 diabetes. This ratio may serve as a reliable clinical marker for early and accurate diagnosis of type A IRS., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Pheophytin-a derivatives possessing plastoquinone and phylloquinone analogs in the peripheral 3-substituent were prepared by Friedel-Crafts reactions of a 3-hydroxymethyl-chlorin as one of the chlorophyll-a derivatives with benzo- and naphthohydroquinones, respectively, and successive oxidation of the 1,4-dihydroxy-aryl groups in the resulting dehydration products. The 3-quinonylmethyl-chlorins exhibited ultraviolet-visible absorption and circular dichroism spectra in acetonitrile, which were composed of those of the starting 3-hydroxymethyl-chlorin and the corresponding methylated benzo- and naphthoquinones. No intramolecular interaction between the chlorin and quinone π-systems was observed in the solution owing to the methylene spacer. The first reduction potentials of the quinone moieties in the synthetic conjugates were determined by cyclic voltammetry and shifted positively from those of the reference quinones. The former quinonyl groups were reduced more readily by approximately 0.1 V than the latter quinones, which was ascribable to the stabilization of the quinonyl anion radical by the nearby macrocyclic chlorin π-chromophore. This observation implied that the reduction potentials of quinones were regulated by the close pheophytin-a derivative by through-space interaction. Considering the charge shift from pheophytin-a anion radical to plastoquinone and phylloquinone in reaction centers of photosystems II and I, respectively, the reduction potentials of these quinones as a determinant factor of the rapid electron transfer process would be dependent on the pheophytin-a in the photosynthetic reaction centers of oxygenic phototrophs as well as on the neighboring peptides., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s).)

Tumor initiation represents the first step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Capturing this process as it occurs in vivo, however, remains elusive. Here we employ spatiotemporally controlled oncogene activation and tumor suppressor inhibition together with multiomics to unveil the processes underlying oral epithelial progenitor cell reprogramming into tumor initiating cells at single cell resolution. Tumor initiating cells displayed a distinct stem-like state, defined by aberrant proliferative, hypoxic, squamous differentiation, and partial epithelial to mesenchymal invasive gene programs. YAP-mediated tumor initiating cell programs included activation of oncogenic transcriptional networks and mTOR signaling, and recruitment of myeloid cells to the invasive front contributing to tumor infiltration. Tumor initiating cell transcriptional programs are conserved in human head and neck cancer and associated with poor patient survival. These findings illuminate processes underlying cancer initiation at single cell resolution, and identify candidate targets for early cancer detection and prevention., Competing Interests: Competing interests: J.S.G. has received other commercial research support from Kura Oncology, Mavupharma, Dracen, Verastem, and SpringWorks Therapeutics, and is a consultant/advisory board member for Domain Therapeutics, Pangea Therapeutics, and io9, and founder of Kadima Pharmaceuticals. The remaining authors declare no competing interests., (© 2025. The Author(s).)

Purpose: To investigate patients with primary aldosteronism (PA) and the prevalence of normal-tension glaucoma (NTG)., Design: Cross-sectional study., Methods: Newly diagnosed PA patients were evaluated in this cross-sectional study, with ophthalmic examinations such as intraocular pressure measurements by a Goldmann applanation tonometer, central corneal thickness, slit-lamp biomicroscopic examination, gonioscopy, ophthalmoscopy, fundus photography, visual field test with a Humphrey Field Analyzer 24-2 SITA Standard program, and optical coherence tomography of the peripapillary retinal nerve fiber layer, performed in each of the subjects. Optic disc appearance, perimetric results, optical coherence tomography results, and other ocular findings were all used for determining the glaucoma diagnosis. The primary outcome was shown the prevalence of NTG in patients with PA., Results: NTG prevalence in the 212 PA patients was 11.8% (95% confidence interval [CI], 4.7%-20.7%). As compared to the hypertensive patients without PA, the hypertensive patients with PA exhibited a significantly increased NTG prevalence (odds ratio; 4.019, 95% CI, 1.223-13.205; P = .022). Increased NTG prevalence was associated with age, ranging from 8.8% (95% CI, 2.1%-15.6%) for those aged 40 to 49 years, to 37.5% (95% CI, 13.8%-61.2%) for those aged 70 years and older. In 72 hypertensive patients without PA, who were used as the controls, NTG prevalence was 5.2%, with a 95% CI ranging from 0.5% to 14.4%., Conclusions: There was an 11.8% prevalence of NTG in PA patients, with these patients at an elevated risk of NTG, which was not mediated by blood pressure., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To investigate the effect of visualizing blood glucose variability by intermittently scanned continuous glucose monitoring (isCGM) on weight reduction in overweight individuals with impaired glucose tolerance (IGT) or mild type 2 diabetes mellitus (T2DM)., Materials and Methods: Forty overweight (BMI, ≥25 kg/m2) individuals with IGT or T2DM (drug naïve; HbA1c, ≤7.0 %) were included in this 24-week randomized controlled trial. Participants were randomly assigned to the control group (diet and exercise therapy) or the isCGM group (diet and exercise therapy plus isCGM). The primary endpoint was the change in body weight during the 24-week intervention period., Results: One participant in the isCGM group withdrew consent. We therefore analyzed 19 individuals in the isCGM group and 20 in the control group. Baseline BMI was significantly higher in the isCGM group (35.2 ± 5.7 kg/m²) compared to the control group (31.6 ± 6.8 kg/m²). Weight change in the isCGM and control groups (-1.8 and -2.2 kg) did not differ. However, the change in coefficient of variation (-0.9 and 2.9 %) of sensor glucose differed significantly between the two groups. isCGM scan frequency was positively correlated with time above range (TAR) during the first month, positively correlated with the change in protein intake, and negatively correlated with that in TAR., Conclusion: While isCGM use in overweight individuals with IGT or mild T2DM did not reduce body weight, it might have influence dietary behavior. The negative correlation between scan frequency and TAR, and the positive correlation between scan frequency and protein intake suggest that self-awareness of glucose fluctuations contributed to behavioral change., Competing Interests: Declaration of Competing Interest Y.H. has received lecture fees from Eli Lilly Japan K.K., Sanofi Aventis, Abbott Japan, Terumo Co., and Sumitomo Pharma Co. Ltd.; research funding from Sumitomo Pharma Co. Ltd., Medtronic Japan Co. Ltd., and Kyowa Kirin Co. Ltd.; and a donation from Abbott Japan. K.S. has received lecture fees from Eli Lilly Japan K.K., Sanofi Aventis, Novo Nordisk Pharma Ltd., Sumitomo Pharma Co. Ltd.; research funding from Sumitomo Pharma Co. Ltd. W.O. has received lecture fees from Sumitomo Pharma Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Abbott Japan, and Novo Nordisk Pharma Ltd.; research grants from Noster Inc., Nippon Boehringer Ingelheim Co. Ltd., Eli Lilly Japan K.K., Abbott Diabetes Care UK Ltd., Sumitomo Pharma Co. Ltd., and Teijin Pharma Ltd.; and donations from Kowa Co. Ltd., Novo Nordisk Pharma Ltd., Sumitomo Pharma Co. Ltd., Takeda Pharmaceutical Co. Ltd., and Teijin Pharma Ltd. All remaining authors declare that they have no conflict of interest., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Repetitive pitching causes immediate changes in the medial elbow joint. However, the recovery process from these changes is not clear., Purpose/hypothesis: The purpose of this study was to investigate the recovery of the medial elbow joint in the 24-hour period after pitching. The hypothesis was that while some recovery will occur at 24 hours after repetitive pitching, this would not be a complete return to baseline., Study Design: Controlled laboratory study., Methods: A total of 26 high school baseball pitchers participated (mean age, 16.0 ± 0.5 years). Participants threw 100 pitches (5 sets of 20 pitches). Medial elbow joint width as well as strain ratios of the ulnar collateral ligament (UCL) and forearm flexor-pronator muscles (FPMs) were measured and followed for 24 hours after pitching. The data before pitching and at each time point after pitching were compared. The standard error of measurement (SEM) and minimal detectable change with 95% confidence interval (MDC 95 ) were calculated using measurements before pitching., Results: The medial elbow joint width significantly increased by 0.84 mm immediately after pitching ( P < .05), but this was not maintained at 24 hours. The UCL strain ratio significantly decreased by 1.64 immediately after pitching ( P < .05), but this was not maintained at 18 hours after pitching. The strain ratio of the FPMs significantly decreased by 0.09 immediately after pitching ( P < .05) but significantly increased by 0.13 at 24 hours ( P < .05). The SEM for medial elbow joint width was 0.06 mm, and the MDC 95 was 0.18 mm (maximum change: 0.84 mm immediately after pitching). The SEM for UCL strain ratio was 0.85, and the MDC 95 was 2.35 (maximum change: 1.64 immediately after pitching). The SEM for strain ratio of the FPMs was 0.08, and the MDC 95 was 0.22 (maximum change: 0.13 at 24 hours)., Conclusion: After 100 pitches, stability against elbow valgus laxity recovered within 24 hours. UCL and FPMs showed statistical characteristic changes, but those changes were within the minimal detectable change., Clinical Relevance: Pitchers' medial elbow joint tissue recovered to baseline at 24 hours after pitching. This suggests that it may be acceptable to resume low-intensity throwing after a 24-hour rest period after 100 repetitive pitches while also considering the condition of the rest of the body., Competing Interests: The authors declared that they have no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Purpose: There are no definitive prognostic factors for patients with pathological Grade Group 5 (pGG 5) prostate cancer (PCa) undergoing robot-associated radical prostatectomy (RARP). This study aimed to explore the prognostic factors among patients with pGG 5 PCa in a large Japanese cohort (MSUG94)., Methods: This retrospective, multi-institutional cohort study was conducted between 2012 and 2021 at ten centers in Japan and included 3195 patients. Patients with clinically metastatic PCa (cN1 or cM1) and those receiving neoadjuvant and/or adjuvant therapy were excluded. Finally, 217 patients with pGG5 PCa were analyzed., Results: The median follow-up period was 28.0 months. The 3- and 5-year biochemical recurrence-free survival (BCRFS) rates of the overall population were 66.1% and 57.7%, respectively. The optimal threshold value (47.2%) for the percentage of positive cancer cores (PPCC) with any GG by systematic biopsy was chosen based on receiver operating characteristic curve analysis. Univariate analysis revealed that the prostate-specific antigen level at diagnosis, pT, pN, positive surgical margins (PSMs), lymphovascular invasion, and PPCC were independent prognostic factors for BCRFS. A multivariate analysis revealed that PSMs and PPCC were independent prognostic factors for BCRFS. Using these two predictors, we stratified BCRFS, metastasis-free survival (MFS), and castration-resistant PCa-free survival (CRPC-FS) among patients with pGG 5 PCa., Conclusion: The combination of PSMs and PPCC may be an important predictor of BCRFS, MFS, and CRPC-FS in patients with pGG 5 PCa undergoing RARP., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: Declarations. Conflict of interest: Michito Murayama, Suguru Ishizaka, Keita Sakaguchi, Rion Ando, Hisao Nishino, Sanae Kaga, and Toshihisa Anzai declare that they have no conflict of interest. Informed consent: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent was obtained from the patient for being included in the study.

To establish a sustainable cultured meat technology, a low-cost culture medium must be developed without expensive biological materials such as serum and coating substances. However, even adhering bovine myogenic cells to uncoated culture dishes in the serum-free medium is challenging. We found that serum-free culture medium conditioned by HepG2 and NIH/3T3 cells not only accomplished the cell adhesion on uncoated culture dishes (the serum-containing medium : the serum-free medium : the conditioned medium = 6722 ± 1500 : 2210 ± 319 : 5985 ± 1558 cells/cm 2 ), but also induced proliferation comparable to that observed in a serum-containing medium (the serum-containing medium : the serum-free medium : the conditioned medium = 10,050 ± 2814 : 2200 ± 707 : 8998 ± 3890 cells/cm 2 ). Interestingly, although the nutrient composition of the developed medium differed significantly from that of the serum-containing medium, it tended to coordinate the expression of cell adhesion, proliferation, and myogenic differentiation markers as serum-containing medium. Component analysis and validation experiments suggested that pyridoxamine, asparagine, and glutamic acid contributed to the acquisition of the culture function of the developed medium. Our study paves the way to realize a low-cost and sustainable cultured meat technology., Competing Interests: Competing interests: T.M., K.S., R.T., A.Y., H.T., and K.I. declare no financial or non-financial competing interests. With T.S. as the principal investigator, Tokyo Women’s Medical University was receiving research funds from IntegriCulture Inc., (© 2024. The Author(s).)

Objective: To elucidate the mechanisms underlying diabetic osteoporosis, we conducted a comprehensive histological examination of the femora of Spontaneously Diabetic Torii-Lepr fa (SDT-fa/fa) rats, an established model of obesity-related type 2 diabetes., Materials and Methods: Femora from 12 30-week-old male SDT-fa/fa rats and age-matched Sprague-Dawley (SD) rats (controls) were used for detailed histochemical analyses, including tartrate-resistant acid phosphatase (TRAP), cathepsin K, alkaline phosphatase (ALP), phosphoethanolamine/ phosphocholine phosphatase 1 (PHOSPHO1), dentin matrix protein (DMP)-1, matrix extracellular phosphoglycoprotein (MEPE), sclerostin, osteocalcin staining, silver impregnation, von Kossa staining, and micro-computed tomography (CT)., Results: Micro-CT and hematoxylin-eosin staining demonstrated significantly reduced trabecular bone volume in the femoral metaphyses of SDT-fa/fa rats. Although the number of TRAP-positive osteoclasts per bone surface remained comparable between both groups, SDT-fa/fa rats exhibited reduced areas of ALP-positive and PHOSPHO1-reactive mature osteoblasts/BS. Silver impregnation revealed a well-organized osteocytic lacunar-canalicular system in both groups. However, immunostaining identified aberrant DMP-1 and MEPE expression localized predominantly in the lacunae in SDT-fa/fa rats and in the lacunae and canaliculi of SD rats. Additionally, intense osteocalcin and sclerostin immunoreactivity was detected in osteocytes, along with a higher proportion of osteocalcin-positive osteocytes in SDT-fa/fa rats, distinguishing them from controls., Conclusion: SDT-fa/fa rats displayed a significant decline in osteoblastic function and distinctive distribution patterns of osteocyte-derived peptides, suggesting that this diabetic model may manifest alterations in osteoblastic activity and the osteocytic lacunar-canalicular network., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Hospital wastewater is a reservoir for the environmental spread of clinically relevant antimicrobial-resistant bacteria and resistance genes. The aim of this study was to quantify total Escherichia coli, extended-spectrum β-lactamase (ESBL)-producing E. coli, and carbapenemase-producing organisms (CPOs) and perform whole-genome sequencing-based characterization of these bacterial isolates in hospital wastewater samples collected bimonthly in Japan from January to November 2021. Total E. coli counts were 8.1 × 10 3 -8.8 × 10 4 colony-forming units (CFU)/mL. ESBL-producing E. coli were detected in the sampling months of January, March, May, and July, with the ratio of ESBL-producing E. coli to total E. coli being remarkably highest (95 %) in July. In contrast, DHA-1 Ambler class C β-lactamase (AmpC)-producing E. coli was detected in September and November, accounting for 28 % and 3 % of total E. coli counts, respectively. All 140 ESBL-producing E. coli isolates harbored the bla CTX-M genes, with bla CTX-M-14 being the most common genotype (94.3 %), the vast majority of which were associated with the human virulent B2-O25b: H4-ST131-fimH30R/non-Rx. In September, E. coli clade I-O8:H33-ST3910-fimH1074 was primarily associated with bla DHA-1 . Among 26 representative CPO isolates, Aeromonas caviae (34.6 %) and A. hydrophila subsp. hydrophila (30.8 %) were dominant. The most frequently detected carbapenemase gene was bla IMP-1 (57.7 %), followed by bla GES-24 (34.6 %) and bla GES-4 (7.7 %). Estimated bacterial counts of CPOs ranged from 4.0 × 10 -1 to 4.7 × 10 3  CFU/mL over the six sampling months. bla IMP-1 -positive A. hydrophila subsp. hydrophila ST860, which was repeatedly detected over the five sampling months, accounted for the highest total number of this bacterial clone (79 %). Overall, this study provides insights into the overwhelming presence and persistence of E. coli B2-O25b:H4-ST131-H30R/non-Rx with bla CTX-M-14 and Aeromonas spp. with bla IMP-1 in hospital wastewater, and the change in the dynamics of resistance gene prevalence from bla CTX-M -positive E. coli to bla DHA-1 -positive E. coli., 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.)

Purpose: In this study, we evaluated serial changes in shoulder muscle volume and computed tomography (CT) density of the transverse force couple (i.e., subscapularis (Ssc) vs. infraspinatus and teres minor (Isp+TM) muscles) after Bankart repair surgery in patients with anterior shoulder instability (ASI)., Methods: Four consecutive CT scans (obtained preoperatively and postoperatively at 1 month, 6 months, and 12 months) of 24 shoulders from 24 patients who underwent arthroscopic rotator cuff repair were examined. To generate muscle models, the Ssc and Isp+TM muscles were segmented. The reconstructed models were separated by the Y-view plane, and the planes were situated 2.5 cm and 5 cm medial to the Y-view plane. Balance was evaluated using volume ratio (VR Ssc/Isp+TM ) and computed tomography-density ratio (CT-DR Ssc/Isp+TM ) in each section of both groups, employing a three-dimensional sectional approach. Changes in these values were correlated with the preoperative background factors., Results: Shoulder muscle volume and CT density were decreased in the early postoperative period compared with the preoperative period but recovered through the late postoperative period. The mean VR Ssc/Isp+TM decreased in all sections in the early postoperative period but increased thereafter, whereas the mean CT-DR Ssc/Isp+TM in all sections remained mostly unchanged throughout the perioperative period. Furthermore, the perioperative differences in muscle volume were correlated with sex, work and sports activity level, Hill-Sachs lesion, and range of motion. Perioperative differences in CT density were not correlated with most items, except for sulcus signs., Conclusion: Serial changes in the VR Ssc/Isp+TM group were significantly different and had clinical implications, whereas changes in the CT-DR Ssc/Isp+TM group were not significantly different. This method may provide a potential indicator for evaluating muscle balance and recovery after Bankart repair surgery for ASI., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. The Research Ethics Committee of Saitama Medical University Hospital issued approval 2022-072. All experiments were conducted in accordance with the relevant guidelines and regulations. The requirement for informed consent was waived due to the retrospective nature of the study. 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, Nagawa et al.)

The prognosis of HER2-positive breast cancer (BC) has improved with the development of anti-HER2 therapies; however, the problem remains that there are still cases where anti-HER2 therapies do not respond well. We found that the expression of SREBF2, a master transcriptional factor in the mevalonate pathway, was correlated with ERBB2 (HER2) expression and a poor prognosis in HER2-positive BC. The target gene expressions of SREBF2 were associated with higher expression of ERBB2 in HER2-positive BC cells. Statins, anti-hypercholesterolemia drugs that inhibit the mevalonate pathway, enhanced the efficacy of HER2-targeting agents with inducing apoptosis in a geranylgeranylation-dependent manner. Mechanistically, statins specifically inhibited membrane localization of Rac1, a target protein of geranylgeranylation, and suppressed the activation of HER2 downstreams AKT and ERK pathways. Consistently, retrospective analysis showed a longer recurrence-free survival in Rac1-high/HER2-positive BC patients treated with HER2-targeting agents with statins than without statins. Our findings thus suggest that Rac1 expression could be used as a biomarker to stratify HER2-positive BC patients that could benefit from dual blockade, i.e., targeting HER2 with inhibition of geranylgeranylation of Rac1 using statins, thereby opening avenues for precision medicine in a new subset of Rac1-high/HER2-positive BC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Isao Yokota reports a relationship with KAKENHI that includes: funding grants. Isao Yokota reports a relationship with Japan Agency for Medical Research and Development (AMED) that includes: funding grants. Isao Yokota reports a relationship with Government of Japan Ministry of Health Labour and Welfare Policy Research Grants that includes: funding grants. Isao Yokota reports a relationship with Nihon Medi-Physics Co., Ltd. that includes: funding grants. Isao Yokota reports a relationship with Chugai Pharmaceutical Co., Ltd. that includes: speaking and lecture fees. Isao Yokota reports a relationship with AstraZeneca K.K. that includes: speaking and lecture fees. Isao Yokota reports a relationship with Pfizer K.K. that includes: speaking and lecture fees. Shogen Boku reports a relationship with Amgen Inc. that includes: funding grants. Shogen Boku reports a relationship with Ono Pharmaceutical Co., Ltd. that includes: funding grants. Shogen Boku reports a relationship with Taiho Pharmaceutical Co., Ltd. that includes: funding grants and speaking and lecture fees. Shogen Boku reports a relationship with AstraZeneca K.K. that includes: funding grants. Shogen Boku reports a relationship with Kyo-diagnostics Co., Ltd. that includes: funding grants. Shogen Boku reports a relationship with Nippon Kayaku Co., Ltd. that includes: speaking and lecture fees. Shogen Boku reports a relationship with MSD K.K. that includes: speaking and lecture fees. Shogen Boku reports a relationship with BMS K.K. that includes: speaking and lecture fees. Shogen Boku reports a relationship with Eisai Co., Ltd. that includes: speaking and lecture fees. Shogen Boku reports a relationship with Chugai Pharmaceutical Co., Ltd. that includes: speaking and lecture fees. Yasuto Naoi reports a relationship with Sysmex Corp that includes: speaking and lecture fees. Yasuto Naoi reports a relationship with Ono Pharmaceutical Co., Ltd. that includes: funding grants and speaking and lecture fees. Yasuto Naoi reports a relationship with Daiichi Sankyo Co., Ltd. that includes: funding grants and speaking and lecture fees. Yasuto Naoi reports a relationship with AstraZeneca K.K. that includes: funding grants and speaking and lecture fees. Yasuto Naoi reports a relationship with Pfizer K.K. that includes: speaking and lecture fees. Yasuto Naoi reports a relationship with Eli Lilly K.K. that includes: speaking and lecture fees. Yasuto Naoi reports a relationship with Chugai Pharmaceutical Co., Ltd. that includes: speaking and lecture fees. Yasuto Naoi has patent #Curebest™ 95GC Breast (JP.5725274.B2) licensed to Sysmex Corp. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

A 14-year-old spayed female mixed-breed cat weighing 3.4 kg was admitted to the Tokyo University of Agriculture and Technology Animal Medical Center for syncope after vomiting. Echocardiography, electrocardiography, and thoracic radiography revealed no abnormalities. Holter electrocardiography showed a paroxysmal high-grade atrioventricular block coinciding with the vomiting. Based on these findings, the cat was diagnosed as having situational syncope with paroxysmal high-grade atrioventricular block triggered by vomiting, which improved with antiemetic treatment alone. The cat subsequently died of chronic kidney disease approximately 3 years and 4 months after the initial diagnosis. This is the first reported case of situational syncope triggered by vomiting in a cat.

Structural adhesives are currently applied in the assembly of automobiles, aircraft, and buildings. In particular, epoxy adhesives are widely used due to their excellent mechanical strength and durability. However, cured epoxy resins are typically rigid and inflexible; thus, they have low peel and impact strength. In this study, tough cured epoxy adhesives were developed by mixing a liquid epoxy prepolymer (EP) and polystyrene- b -polyisoprene- b -polystyrene (SIS). SIS is a block polymer-based thermoplastic elastomer (TPE) composed of polystyrene (S) soluble in liquid EP and polyisoprene (I) insoluble in liquid EP, where S and I have a glass transition temperature that is higher and lower than room temperature, respectively. In addition, cured adhesives tougher than the cured adhesives containing SIS were prepared by mixing liquid EP and SIS with hydrogen-bonding groups in the I block (h-SIS). Transmission electron microscopy (TEM) observations revealed mixed S/cured EP domains, with a d -spacing of several tens of nanometers, and cured EP domains, with diameters of one hundred to several hundred nanometers, that were macroscopically dispersed in the I or hydrogen-bonded I matrix of the cured adhesive containing SIS or h-SIS. The lap shear, peel, and impact strength of cured neat EP (EP*) were 23 MPa, 45 N/25 mm, and 0.62 kN/m, respectively. Meanwhile, the cured adhesive containing 16.5 wt % SIS exhibited the slightly lower lap shear strength of 17 MPa compared to that of cured EP*, whereas the peel and impact strength of the cured adhesive with SIS were 61 N/25 mm and 7.1 kN/m, respectively, both higher than those of EP*. Furthermore, the lap shear strength of the cured adhesive containing 15.5 wt % h-SIS was 21 MPa, which was similar to that of cured EP*. The cured adhesive with h-SIS also exhibited an excellent peel strength of 97 N/25 mm and an impact strength of 14 kN/m which was 22 times higher than that of cured EP*. Therefore, mixing liquid EP and SIS improved the cured adhesive properties and flexibility of the cured epoxy adhesives compared to the cured adhesive composed of neat EP, and further enhancement of the adhesive properties was achieved by mixing liquid EP and h-SIS with hydrogen-bonding groups instead of mixing with SIS.

Mesenchymal stem cells such as adipose-derived stem cells (ADSCs) are known to secrete factors that stimulate cell division and promote regeneration in neighboring cells. While conditioned medium from stem cells has been used in blastocyst production, no studies have examined the use of cell lysates. In this study we investigated the effects of adding ADSC lysate to in vitro culture (IVC) medium. ADSCs and fibroblasts were isolated from bovine adipose tissue and auricular tissue, respectively, and their lysates were prepared by freeze-thaw disruption. ADSC lysate was added to synthetic oviductal fluid medium. The effects on cleavage, blastocyst development rates, cell numbers, cryotolerance, gene expression (POU5F1, BAX, IGF1R, IGF2R, SOD2), lipid content, and membrane integrity were evaluated according to the experimental design. In Expt. 1, the comparison involved adding ADSC or fibroblast lysate alongside the control group. The total blastocyst rate increased when ADSC lysate was introduced (ADSCs: 40.1 %, fibroblasts: 33.1 %, control: 27.3 %). However, there were no significant differences in the number of trophoblast cells or in the inner cell mass. Experiment 2 confirmed that this increase in blastocyst development was not due to the solvent, PBS(-). In Expt. 3, addition of 10 % fetal calf serum (FCS) or ADSC lysate increased the total blastocyst rate compared to the control (control, 26.2 %; 10 % FCS, 43.4 %; 1 % ADSC lysate, 34.2 %; 10 % ADSC lysate, 48.1 %). After freezing and thawing, the survival and hatching rates of embryos with FCS were significantly lower than those of the control as well as those with added ADSC lysate. In Expt. 4, the addition of ADSC lysate or FCS had no significant effect on gene expression in blastocysts compared to control. However, the addition of FCS significantly increased the gray intensity, indicating higher lipid content compared to the control, with a significant increase in the number of dead cells in the blastocyst. These results indicate that the addition of ADSC lysate to the IVC medium accelerates bovine blastocyst development and that its 10 % addition, corresponding to 1 × 10 5  cells/mL, is as effective as 10 % FCS without a decrease in cryotolerance due to the increased lipid content., Competing Interests: Declaration of competing interest Tokunori Yamamoto is President of Meis Technology, Inc., which possesses a patent related to this work (Japan Patent No. 6970853). The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Understanding the metastatic patterns is crucial for the treatment of malignancies. This study aimed to identify the characteristic organ metastases of primary malignancies, including rare malignancies, and classify them according to their metastatic patterns., Methods: We extracted data on primary malignancies and organ metastases from the Annual of Pathological Autopsy Cases in Japan recorded in 1993-2021. Autopsy findings of the primary and metastatic organs in patients with malignancy were recorded on an organ-by-organ basis. The metastatic frequency (number of metastases per autopsy) and the proportion (percentage of organs with metastases out of the total in a primary malignancy) for 48 organ metastasis sites across 76 primary malignancies were calculated. Metastatic patterns were classified into hierarchical and nonhierarchical clustering classifications based on the standard proportion of organ metastases., Results: A total of 332,195 autopsy cases and 810,206 organ metastases were analyzed. The metastatic frequency of all malignancies was 2.44. Malignancies of the placenta, eye, and ovary showed a higher propensity for metastasis, whereas central nervous system malignancies showed a lower tendency. Metastasis site was a characteristic of each malignancy, with a particularly high proportion of lung metastasis in parathyroid malignancy and bone metastasis in prostate malignancy. In the hierarchical and nonhierarchical cluster methods, brain, lung, liver, bone, peritoneum, and hematolymphoid organ were key metastatic sites, and this factor divided primary malignancies into seven categories. The unweighted kappa coefficient comparing the two classification methods was 0.84 (95% confidence interval: 0.75-0.93). The proportion of metastatic organs was influenced by anatomical location and/or organ specificity of the primary malignancies., Conclusion: Our study provides a comprehensive overview of the patterns and frequencies of metastatic organ sites associated with 76 primary malignancies. Our findings will provide useful information for future research and clinical practice., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background : In recent years, implant-assisted removable partial dentures (IARPDs) have been used clinically. However, the extent to which additional implants reduce the burden of supporting tissues is unclear. The aim of this study was therefore to investigate the influence of implanted IARPDs on stress sharing among supporting tissues, using finite element (FE) analysis. Methods : FE models were constructed based on the computed tomography (CT) of a patient with a unilateral defect of the mandibular premolars and molars and the surface data of an RPD with cuspids as abutments, designed using computer-aided design software. A titanium implant was placed in the area equivalent to the first premolar, second premolar, or first molar (IARPD4, IARPD5, and IARPD6, respectively). FE analysis was performed for laterally symmetrical models, i.e., bilateral distal free-end IARPDs. A vertical load of 200 N was applied to the central fossa of the artificial premolars or molars (L4, L5, or L6). Results : Equivalent stress in the alveolar mucosa and vertical displacement of the denture was smaller, with IARPDs under L5 and L6 loads, compared to RPDs. However, abutment teeth were displaced upward under an L6 load in the IARPD5 model. Conclusions : Within the limitations of this study, the area corresponding to the first molar was recommended as the location for an implant under the denture base of bilateral distal free-end IARPDs. Implants located in the area corresponding to the second premolar may apply non-physiological extrusion force on abutment teeth under the load on the artificial second molar.

In patients with anterior shoulder instability (ASI), a chronic imbalance might exist between the anterior and posterior shoulder muscles (i.e., subscapular [Ssc] vs. infraspinatus and teres minor [Isp + TM]). The balance could be evaluated as the ratio of volume (VR Ssc/Isp+TM ) and computed tomography density (CT-DR Ssc/Isp+TM ) using a 3D sectional approach. A total of 28 CT images (19 patients) of non-pathological shoulders (clavicular fracture [CF]) and 17 CT images (17 patients) of ASI were used. Segmentation of Ssc and Isp + TM muscles was performed; the reconstructed models were separated by the Y-view plane and the planes situated 2.5 cm and 5 cm medial to the Y-view plane to generate muscle models. VR Ssc/Isp+TM and CT-DR Ssc/Isp+TM were measured in each section of both the groups, as well as in whole muscle measurements in the CF group. VR Ssc/Isp+TM and CT-DR Ssc/Isp+TM obtained through a 3D sectional approach in the CF group were comparable to the whole muscle measurements, with a value of 1.06 for both. In the ASI group, the VR Ssc/Isp+TM was higher, whereas the CT-DR Ssc/Isp+TM was lower than those in the CF group. The VR Ssc/Isp+TM and CT-DR Ssc/Isp+TM appeared to be balanced in the CF group. However an imbalance was observed in the ASI group. Our 3D sectional measurement approach has the potential to assess the balance between the anterior and posterior shoulder muscles in ASI., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: The extreme male brain (EMB) theory, a major causal hypothesis of autism (ASD: autism spectrum disorder), attributes excess androgens during early development as one of the causes. While studies have generally followed the EMB theory in females at birth, the co-occurrence of ASD in males at birth has been observed in conditions that are assumed to be associated with reduced androgen action during early development, including Klinefelter syndrome (KS) and sexual minorities. ASD is also associated with atypical sensory sensitivity, synesthesia, and savant syndrome., Methods: In the present study, we examined adult KS individuals ( n  = 22), sexual minorities assigned male at birth ( n  = 66), and control males matched for age and educational background to those with KS [Exploratory analysis (control 1st): n  = 36; Reanalysis (control 2nd): n  = 583]. Participants completed a self-report questionnaire assessing sensory hypersensitivity/hyposensitivity, savant tendency (developed for the present study), synesthesia, and sexual aspects, including gender identity and sexual orientation., Results: The results of the exploratory analysis suggested that individuals with KS exhibited a higher tendency toward sensory hypersensitivity/hyposensitivity than the tendency exhibited by the controls. In the Reanalysis, sexual minorities were more likely to be synesthetes, and in both analyses sexual minorities exhibited a higher savant tendency and sensory hypersensitivity/hyposensitivity than the controls. Moreover, the gender dysphoric state was associated with phenotypes observed in individuals with ASD, such as synesthesia, savant tendency, and sensory hypersensitivity/hyposensitivity., Discussion: These results suggest a common physiological background among gender dysphoria, synesthesia, savant tendency, and atypical sensory sensitivity. Thus, androgynous features (reduced effects of sex steroids during early development) in males at birth may be partially related to the phenotype commonly observed in individuals with ASD. Based on the present results, we propose that the reduction of sex steroids during early development may lead to atypical neurodevelopment and be involved in the atypicality of external and internal sensory perception, and thus in the atypicality of self-concept integration, through the disruption of oxytocin and the gamma-aminobutyric acid system modulating the neural excitation/inhibition balance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Tawata, Sakaguchi and Saito.)

The Japan Children's Cancer Group Relapsed Acute Lymphoblastic Leukemia (ALL) Committee conducted a prospective observational study (ALL-R14) to explore promising reinduction therapy regimens for relapsed ALL to investigate in future trials. In Japan, clofarabine- and bortezomib-based regimens were of interest since they were newly introduced for ALL in the study period (2015-2018). Seventy-five pediatric patients were enrolled in total. The 2-year event-free/overall survival rates in patients with first (n = 59) or second (n = 11) relapse were 40.1% (95% confidence interval [CI]: 25.5-52.3%)/66.3% (95% CI 52.3-77.0%) and 34.1% (95% CI 9.1-61.6%)/62.3% (95% CI 27.7-84.0%), respectively. Clofarabine- or bortezomib-based regimens were used only in patients with high-risk disease. The first reinduction therapy used in the 41 patients with early or multiple relapsed B-cell precursor ALL was clofarabine in 7 patients and bortezomib in 9 patients. The odds ratio for reinduction failure risk with a clofarabine- or bortezomib-based regimen compared with other regimens was 9.0 (95% CI 0.9-86.4, P = 0.057) or 1.9 (95% CI 0.4-8.7, P = 0.42), respectively. Thus, clofarabine- or bortezomib-based regimens had no obvious advantage as reinduction therapy for relapsed ALL in children., (© 2024. Japanese Society of Hematology.)

This study aimed to identify the independent predictors of postacute stroke dysphagia at discharge using sarcopenia-related parameters. This single-center prospective observational study assessed consecutive inpatients diagnosed with cerebral infarction or cerebral hemorrhage upon admission to the stroke unit. Tongue pressure, grip strength, and body composition were evaluated within 48 h. Dysphagia was defined by a functional oral intake scale of ≤ 5. Patient characteristics were compared between non-dysphagia and dysphagia groups using Mann-Whitney or chi-squared tests. Logistic regression analysis was performed using age, sex, tongue pressure, grip strength, skeletal muscle mass index (SMI), and National Institutes of Health Stroke Scale (NIHSS) scores as explanatory variables, with dysphagia at discharge as the objective variable. A total of 302 patients (mean age: 69.4 ± 13.8 years, 67.5% male) were analyzed, with 64 having dysphagia at discharge (21.2%). The dysphagia group was significantly older (p<0.001), had higher NIHSS scores on admission (p<0.001), lower SMI (p = 0.002), lower grip strength (p<0.001), and lower tongue pressure (p<0.001) than the non-dysphagia group. Logistic regression revealed that age (OR: 1.042, p = 0.018), tongue pressure (OR: 0.954, p = 0.010), and grip strength (OR: 0.943, p = 0.048) on admission were independent predictors of dysphagia at discharge, while NIHSS scores (OR: 1.403, p = 0.106), sex, and SMI (OR: 1.403, p = 0.150) were not. Older age, reduced tongue pressure, and reduced grip strength are strong predictors of persistent poststroke dysphagia at discharge. Thus, muscle strength is a more valuable parameter than muscle mass in predicting persistent poststroke dysphagia., (© 2024. The Author(s).)

Tumor initiation represents the first step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Capturing this process as it occurs in vivo, however, remains elusive. Here we employ spatiotemporally controlled oncogene activation and tumor suppressor inhibition together with multiomics to unveil the processes underlying oral epithelial progenitor cell reprogramming into tumor initiating cells (TIC) at single cell resolution. TIC displayed a distinct stem-like state, defined by aberrant proliferative, hypoxic, squamous differentiation, and partial epithelial to mesenchymal (pEMT) invasive gene programs. YAP-mediated TIC programs included the activation of oncogenic transcriptional networks and mTOR signaling, and the recruitment of myeloid cells to the invasive front contributing to tumor infiltration. TIC transcriptional programs are conserved in human head and neck cancer and associated with poor patient survival. These findings illuminate processes underlying cancer initiation at single cell resolution, and identify candidate targets for early cancer detection and prevention.

Aim: The chronic lack of obstetrics-gynecology (Ob/Gyn) doctors is a serious problem to be tackled in Japan. To address this issue, it is necessary for medical students to be interested in working as an Ob/Gyn doctor and more junior residents need to specialize in Ob/Gyn. This study aims to identify the preferences concerning working conditions among students and discusses what information should be provided and what conditions should be changed., Methods: A questionnaire survey was conducted among participants in the Summer School 2023 of the Japanese Society of Obstetrics and Gynecology. The respondents were medical students and junior residents interested in Ob/Gyn. Ob/Gyn specialists contributing to the summer school were also asked the same questions for comparison. The resulting data focused on important working conditions, concerns about future work, and expected future working conditions., Results: Responses from 132 medical students (97.8%, N = 135), 122 residents (99.2%, N = 123), and 76 specialists (95.0%, N = 80) were obtained. There were three main findings. First, large gaps between students/residents and specialists were observed in terms of preferences. Second, differences between male and female students/residents were not negligible, although the difference was relatively small in specialists. Third, students/residents were more concerned about risks related to medical malpractice than specialists., Conclusions: Gaps in preferences and perceptions regarding working conditions between students/residents and specialists should be narrowed through sufficient information provision. Working conditions should become gender-inclusive rather than focus on female persons., (© 2024 Japan Society of Obstetrics and Gynecology.)

Factors that determine clinical responses to vonoprazan remain unknown. This study aimed to characterize plasma vonoprazan and CYP3A activity using its endogenous marker and genetic variants in patients with digestive system disorders. Fifty-three patients who were receiving vonoprazan for at least 3 days were enrolled. Blood samples for determination of plasma vonoprazan and its metabolite (ODA-VP) were obtained. Plasma 4β-hydroxycholesterol (4β-OHC), CYP3A5 and ABCB1 genotypes, and plasma gastrin were determined. CYP3A recognition for vonoprazan was evaluated using recombinant CYP3A proteins. Plasma vonoprazan levels exhibited a large interindividual variation. The absolute plasma concentration of vonoprazan was correlated with its dose-normalized value, and had a positive correlation with the inverse value of its metabolic ratio. A negative correlation was observed between plasma vonoprazan and 4β-OHC levels. The metabolic ratio of vonoprazan was positively correlated with the plasma 4β-OHC level. Genetic variants of CYP3A5 and ABCB1 were not associated with the plasma concentration of vonoprazan and its metabolic ratio. Possible saturated metabolism of vonoprazan to its major metabolite was observed at a therapeutic dose. Although the CYP3A5 genotype did not alter plasma vonoprazan, CYP3A activity based on plasma 4β-OHC partially explained the variation in plasma vonoprazan in patients with digestive system disorders., (Copyright © 2024 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Background: Food protein-induced enterocolitis syndrome caused by solid foods (Solid-FPIES) is a non-immunoglobulin E-mediated allergic disease characterized by delayed gastrointestinal symptoms. An oral food challenge (OFC) test, although necessary, can be inconclusive in cases with mild symptoms. Moreover, limited diagnostic marker availability highlights the need for novel surrogate markers. We aimed to examine the efficacy of fecal hemoglobin (FHb), lactoferrin (FLf), and calprotectin (FCp) over time in evaluating gastrointestinal inflammation degree in Solid-FPIES., Methods: This observational study included 40 patients and 42 episodes at Juntendo University Hospital and affiliated hospitals between October 2020 and March 2024 categorized into FPIES (12 patients with 11 egg yolk, 1 fish, and 1 soybean episodes), control (14 patients with 15 episodes), and remission (14 patients). Fecal tests were performed for 7 days following antigen exposure. The ratios of each value were divided by the baseline value and analyzed over time course., Results: The FPIES group had significantly higher peak ratios of all fecal markers than the control group (p < 0.01). The median FHb, FLf, and FCp ratios were 3.25, 9.09, and 9.79 in the FPIES group and 1.08, 1.29, and 1.49 in the control group, respectively. In the remission group, several patients had fluctuating fecal markers despite negative OFC, and one patient was diagnosed with FPIES by OFC with increased load. Receiver operating characteristic curve analyses revealed high diagnostic performance for each fecal marker in FPIES., Conclusions: Sequential fecal marker examination proved valuable in diagnosing Solid-FPIES and evaluating the degree of gastrointestinal inflammation., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Aim: This study aimed to elucidate the parental involvement process regarding childhood cancer survivors' (CCSs') independence while balancing their health management and social lives from adolescence to adulthood to obtain suggestions for long-term support for CCSs and their parents., Methods: Semi-structured interviews were conducted with 19 parents of Japanese CCSs aged 16-25 years. The data were then qualitatively analyzed using the modified grounded theory approach., Results: Three "categories" and 20 "concepts" were generated. The connections among these categories and concepts revealed the parental involvement process regarding CCSs' independence while balancing their health management and social lives. The first phase in this process is to "support careful behaviors," mainly during CCSs' treatment in the outpatient clinic or shortly after discharge. As CCSs recover after cancer treatment, parents "watch over, but feel conflicted," with "conflicts between protecting their sons/daughters and giving them independence." Then, parents reach a phase in which they "acknowledge and entrust," which includes "acknowledgment of development and efforts" of their sons/daughters, and develop an "attitude to entrust medical checkups to their sons/daughters, along with their preparation." The influencing factors of the three phases include "ongoing anxieties about the late effects of therapy and recurrence" and an "expectation for their sons/daughters to acquire abilities for living independently.", Conclusions: These findings suggest that nurses need to accept parents' feelings and thoughts regarding conflicts with CCSs, recognition of CCSs' development, and values. These processes may help nurses and health-care professionals support parents from a comprehensive perspective., (© 2023 Japan Academy of Nursing Science.)

Background: The head plays an important role in the postural control. Chewing co-activates jaw and neck muscles leading to coordinated jaw and head-neck movements. Therefore, to examine effect of masticatory movements on head and trunk sways, and sitting and foot pressure distributions during mastication is helpful in the attempt to understand the interrelationship between stomatognathic function and posture control system in the sitting position., Objectives: The purpose of this study was to test the hypothesis in healthy subjects that masticatory movements affect head and trunk sways and sitting and foot pressure distributions during sitting position., Methods: A total of 30 healthy male subjects with an average age of 25.3  years (range, 22-32  years) were evaluated. The CONFORMat™ and MatScan™ system were used to analyse changes in sitting pressure distribution center of sitting pressure (COSP) and changes in foot pressure distribution center of foot pressure (COFP), respectively, and the three-dimensional motion analysis system was used to analyse changes in head and trunk postures while subjects remained sitting position with rest position, centric occlusion and chewing. The total trajectory length of COSP/COFP, COSP/COFP area, and head and trunk sway values were compared between the three conditions to evaluate whether masticatory movement affected the stability of head and trunk sways and sitting and foot pressure distributions., Results: Total trajectory length of COSP and COSP area during chewing were significantly shorter and smaller respectively than it was in rest position and centric occlusion (p  ⟨  .016). Head sway value during chewing was significantly larger than it was in rest position and centric occlusion (p  ⟨  .016)., Conclusion: Masticatory movements affect sitting pressure distribution and head movements during sitting position., (© 2023 John Wiley & Sons Ltd.)

Katsuhiko Nakatsukasa,1 Hiroshi Koyama,2 Yoshimi Ouchi,1 Kouichi Sakaguchi,1 Yoshifumi Fujita,1 Takayuki Matsuda,3 Makoto Kato,4 Eiichi Konishi,5 Tetsuya Taguchi1 1Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan; 2Department of Breast Surgery, Nara City Hospital, Nara, Japan; 3Department of Breast Surgery, Saiseikai Kyoto Hospital, Kyoto, Japan; 4Department of Breast Surgery, Kato Breast Surgery Clinic, Kyoto, Japan; 5Department of Surgical Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan Background: The aim of the study was to conduct subgroup analyses of therapeutic effects of 12-month denosumab therapy on the percentage change in bone mineral density (BMD) from baseline in the lumber spine and femoral neck. Materials and methods: We prospectively evaluated the BMD of the lumbar spine and femoral neck of 100 hormone receptor-positive, clinical stage I–IIIA postoperative postmenopausal breast cancer patients, for whom treatment with aromatase inhibitors (AIs) as adjuvant endocrine therapy was scheduled. The primary endpoint was the percent change in lumbar spine BMD from baseline to 12 months. Patient subgroups were analyzed according to baseline variables that are known risk factors for bone loss, including previous AI therapy, age, time since menopause, baseline body mass index (BMI), and baseline BMD T-score. Results: At 12 months, lumbar spine BMD increased by 4.7%; the patients who were administered AI therapy prior to denosumab (n=70) demonstrated a 4.7% increase in BMD, and the patients who received denosumab at the start of AI therapy (n=30) demonstrated a 4.5% increase in BMD (p=0.8385). Additionally, 2.4% and 1.4% increases in BMD of the right and left femoral neck, respectively, were observed. Initiation of AI (with denosumab, before denosumab), type of AI (non-steroidal, steroidal), age (5 years), BMI (-1.0) of the right femoral neck were as follows: (2.2%, 2.5%, p=0.7773), (2.6%, 0.9%, p=0.1726), (2.5%, 2.3%, p=0.7594), (2.1%, 2.4%, p=0.2034), (2.1%, 2.9%, p=0.2034), and (2.3%, 2.7%, p=0.6823), respectively. Initiation of AI (with denosumab, before denosumab), type of AI (non-steroidal, steroidal), age (5 years), BMI (-1.0) of the left femoral neck were as follows: (1.0%, 1.5%, p=0.1972), (1.2%, 2.7%, p=0.2931), (1.4%, 1.3%, p=0.8817), (-0.1%, 1.6%, p=0.1766), (1.3%, 1.9%, p=0.6465), and (1.5%, 1.1%, p=0.6573), respectively. Conclusion: Twice-yearly treatment with denosumab was associated with increased BMD among Japanese women receiving adjuvant AI therapy, regardless of the baseline characteristics or skeletal site. Keywords: aromatase inhibitor, denosumab