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This study undertook the analysis of tissue cadmium (Cd) distribution using in-air micro-particle-induced X-ray emission (PIXE) and the examination of the involvement of metal ions in parenteral Cd toxicity. A mouse was injected intraperitoneally with 3 mg/kg body weight of CdCl2 thrice weekly. After 27 wk, the liver and kidney were excised and fixed in 10% formalin solution for 4 h and then embedded in paraffin. Thin paraffin sections were used to analyze trace elements with in-air micro-PIXE and to examine metallothionein protein and histological changes. Cd distribution was determined by micro-PIXE in the liver and renal cortex of the Cd-exposed mouse, and the net Cd count was higher in the liver than in the renal cortex. The net iron (Fe) count was higher in the liver of the Cd-exposed mouse compared to the control, and an opposite tendency was observed in the renal cortex. Wide cellular Cd distribution was demonstrated in the liver and renal cortex of the chronic Cd-exposed mouse compared to the control. Metallothionein staining was increased by chronic exposure to Cd both in the liver and kidney, and nephrotoxicity was more apparent than hepatotoxicity. The modification of tissue Fe and calcium distribution by an intraperitoneal injection of Cd might be involved in Cd-induced toxicity. [ABSTRACT FROM AUTHOR]

We consider the initial value problems of the Kadomtsev-Petviashvili (KP) equation for symmetric V-shape initial waves consisting of two semi-infinite line solitons with the same amplitude. Those are particularly important for studies of large amplitude waves such as tsunami in shallow water. Numerical simulations show that the solutions of the initial value problem approach asymptotically to certain exact solutions of the KP equation found recently in [1]. We then use a chord diagram to explain the asymptotic result. This provides an analytical method to study asymptotic behavior for the initial value problem of the KP equation. We also demonstrate a real experiment of shallow water waves which may represent the solution discussed in this communication. [ABSTRACT FROM AUTHOR]

Brown adipocytes are characterized by a high abundance of mitochondria, allowing them to consume fatty acids for heat production. Increasing the number of brown adipocytes is considered a promising strategy for combating obesity. However, the molecular mechanisms underlying their differentiation remain poorly understood. In this study, we demonstrate that etomoxir, an inhibitor of Carnitine Palmitoyltransferase 1 (CPT1), inhibits their differentiation through mechanisms independent of β-oxidation inhibition. In the presence of etomoxir during brown adipocyte differentiation, reduced expression of the thermogenic gene UCP1 and decreased lipid droplets formation were observed. Furthermore, a transient reduction in the expression of PPARγ2, a critical factor in adipocyte differentiation, was also observed in the presence of etomoxir. These findings suggest the presence of a regulatory mechanism that specifically enhances PPARγ2 expression during brown adipocyte differentiation, thereby modulating thermogenic gene expression., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In many countries, including Brazil, time-based blood donation deferral policies for gay, bisexual, and other men who have sex with men (gbMSM) have been replaced by individual donor assessment (IDA). We examined HIV prevalence and incidence among first-time (FTD) and repeat donors (RD), comparing data from ~3.5 years before and after the IDA policy implementation in 2020., Study Design and Methods: The Recipient Epidemiology and Donor Evaluation Study-IV-Pediatric (REDS-IV-P) Brazil component collects blood donor screening data from five public centers. From January 2017 to December 2023, we report frequencies, rates, and 95% confidence interval (CI) of confirmed HIV-positive donations among FTD, HIV NAT-yield rates for FTD and RD, and the incidence of confirmed HIV among RD before and after the policy change. We also report multivariable regression analysis results., Results: Confirmed HIV prevalence in FTD was 79 per 100,000 (95% CI 72-87) before and 100 per 100,000 (95% CI 90-109) after the policy change, with differences between centers. HIV NAT-yield rates decreased for RD (p = .0025), with no change for FTD (p = .3). HIV incidence in RD did not increase (12.4 [95% CI: 11.1-13.9] vs. 10.3 [95% CI: 9-11.7] per 100,000 person-years)., Discussion: Our findings showed no significant difference in HIV incidence among RD. Although HIV prevalence among FTD increased, there was no rise in HIV NAT-yield donations. The analysis highlights challenges in interpreting changes within specific groups and blood centers, underscoring the importance of multicenter monitoring of transfusion-transmitted infections., (© 2025 The Author(s). Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

A synthesis of the C14-C35 segment of the macrolide ring model of poecillastrin C has been achieved. The C14-C23 segment was synthesized by the stereoselective Mukaiyama aldol reaction between ketene silyl N , O -acetal possessing chiral oxazolidinone auxiliary and O -acetyl lactol prepared by the stereoselective conjugate addition followed by iodolactonization. The C24-C35 segment was constructed by three stereoselective vinylogous Mukaiyama aldol reactions. Both segments were coupled by the aldol reaction followed by diisobutylaluminium hydride (DIBALH) reduction to produce the C14-C35 moiety of the macrocyclic model.

Chagas disease (ChD) remains a significant public health concern in the Americas, with challenges to accurately assessing its mortality burden due to under-reporting and misclassification. This study aimed to analyze mortality patterns of two cohorts of individuals with ChD-one comprising asymptomatic individuals with positive serology (REDS) and another with patients showing Chagas cardiomyopathy (SaMi-Trop)-to propose a method for estimating the potential under-registration of Chagas-related deaths and to find the factors influencing the identification of ChD as the underlying cause of death. We carried out a retrospective analysis of mortality data from these cohorts together with data on the Brazilian Mortality Information System. Causes of death were classified according to ICD-10 codes, and an expert review was used to find possible Chagas-related deaths. Logistic regression was used to explore predictors of ChD identification considering demographic and clinical variables. Of 2,488 patients, 381 died, 28.9% attributed to ChD, predominantly chronic ChD with cardiac involvement (B57.2). Using our method, we estimated a 53.8% potential under-registration rate for possible Chagas deaths. Males were negatively associated with Chagas disease identification, with an odds ratio of 0.52 (95%CI 0.24-1.1). No other significant associations were found, and the overall significance of the model was low. Our findings provide a potential measurement of under-registration, indicating that it may be substantial. These results underscore the need for improved identification and accurate reporting on death certificates. Strengthening the quality of mortality data is essential to understand Chagas-related mortality and guide public health strategies to reduce its impact.

During gestation, the choroid plexus (ChP) produces protein-rich cerebrospinal fluid and matures prior to brain development. It is assumed that ChP dysfunction has a profound effect on developmental neuropsychiatric disorders, such as autism spectrum disorder (ASD). However, the mechanisms linking immature ChP to the onset of ASD remain unclear. Here, we find that ChP-specific CAMDI-knockout mice develop an immature ChP alongside decreased multiciliogenesis and expression of differentiation marker genes following disruption of the cerebrospinal fluid barrier. These mice exhibit ASD-like behaviors, including anxiety and impaired socialization. Additionally, the administration of metformin, an FDA-approved drug, before the social critical period achieves ChP maturation and restores social behaviors. Furthermore, both the ASD model mice and organoids derived from patients with ASD developed an immature ChP. These results propose the involvement of an immature ChP in the pathogenesis of ASD and suggest the targeting of functional maturation of the ChP as a therapeutic strategy for ASD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Long-term blood pressure (BP) variability (BPV) is associated with adverse prognosis in patients with heart failure. However, the clinical significance of very short-term (beat-to-beat) BPV is unclear. We collected data on nighttime pulse transit time-based continuous beat-to-beat BP measurement in patients with heart failure (n = 366, median age 72.0, male sex 53.3%). Coefficient of variation (CoV) of pulse transit time-based BP was considered as very short-term BPV. The primary outcome was a composite of heart failure hospitalization or cardiac death. Median values (25th and 75th percentiles) of systolic and diastolic BP CoV were 3.6% (2.8%, 4.5%) and 5.1% (3.8%, 6.5%), respectively. During a median follow-up period of 1084 days after BPV evaluation, 71 patients experienced the primary outcome. When the patients were divided into tertiles based on the systolic and diastolic BPV, the primary outcome occurred most frequently in the highest tertile of BPV. Multivariable Cox proportional hazard analysis revealed that systolic and diastolic BPV, as continuous variables, were independently associated with the primary outcome (hazard ratio 1.199 and 1.101, respectively). In conclusion, high nighttime very short-term BPV was associated with adverse prognosis in patients with heart failure., Competing Interests: Compliance with ethical standards. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Use of solubilization carriers for poorly soluble drugs may disturb transmembrane absorption by lowering the activity of drug molecules, which is known as the solubility-permeability interplay. However, although many in vitro studies have indicated the negative impacts of use of solubilization carriers for oral absorption, in vivo studies that showed the interplay effect are limited. This study provides systematic in vitro, in situ, and in vivo investigation of the interplay effect of cyclodextrin using dexamethasone as a model drug. The evaluation methods included permeation through polymeric, artificial lipid, cell, and intestinal closed-loop membranes. Then, the results were compared with oral administration studies in mice and dogs. Although the interplay effect was clearly observed in the in vitro studies, no obvious interplay was found in the in vivo studies, suggesting that the interplay effect is more prominent in the in vitro permeation studies. Absence of in vivo interplay was attributed to the dilution effect in the gastrointestinal tract, interaction of the drug with living components, and clearance of the drug after membrane permeation. Overall, this investigation clearly demonstrated the applicability and limitations of in vitro permeation studies for predicting the interplay effects of solubilizers after the oral administration., 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 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Background: Lung cancer represents a significant global health concern and constitutes the primary cause of cancer-related mortality. Complete surgical resection with curative intent remains the most efficacious treatment modality for improving the survival rate of patients with localized lung cancer. Average life expectancy has increased in many countries, and the number of older patients undergoing surgery has increased. We aimed to evaluate the change in health-related quality of life (HRQOL) during perioperative lung resection and the association between HRQOL and perioperative physical function (PF) in older patients with lung cancer., Methods: This prospective observational study was conducted in a single tertiary university hospital. Patients aged ≥70 years who underwent lung resection between 1 April 2013 and 31 December 2020 were included. HRQOL was assessed utilizing the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) preoperatively and at 1, 3, and 6 months postoperatively. PF was evaluated using the handgrip, quadriceps force, and 6-minute walking distance (6MWD) tests preoperatively and 1 week after surgery. We analyzed a model for total HRQOL and each domain of HRQOL scores at different time points using a mixed-effects model for repeated measures. A multiple regression analysis was performed to estimate the associations between changes in total HRQOL scores following surgery and clinically relevant factors., Results: In total, 260 patients (172 with stage IA disease, 162 men; median age, 75 years) were included in the analysis. The median preoperative total HRQOL score was 90.1 points, while the scores at postoperative 1, 3, and 6 months were 81.5, 87.5, and 87.4 points, respectively. The total HRQOL score at baseline and the decline in postoperative 6MWD were significant predictors of the total HRQOL score at each time point., Conclusions: HRQOL recovered to preoperative levels 3 months after surgery; the 6MWD decrease before and after surgery was associated with HRQOL recovery than other clinically relevant factors. These results suggest the importance of active early mobilization in preventing functional decline during hospitalization and continuing exercise training after discharge., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1265/coif). T.M. serves as an unpaid editorial board member of Journal of Thoracic Disease from October 2024 to September 2026. The other authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Background: The effects of myocarditis after mRNA COVID-19 vaccination (mCV) on myocardial tissue, and the association between cardiomyocyte injury and clinical presentation, are not fully understood., Methods and Results: We retrospectively registered patients clinically diagnosed with myocarditis after the first or second mCV who underwent endomyocardial biopsy or autopsy from 42 participating centers in Japan. We investigated the histological features and their association with clinical presentation based on cardiomyocyte injury. Forty patients who underwent endomyocardial biopsy were included in the study. Of these, 19 (47.5%) showed mild lymphocytic infiltration and interstitial edema without cardiomyocyte injury. The remaining 21 (52.5%) patients showed cardiomyocyte injury accompanied by infiltrating inflammatory cells: 11 with lymphocytic infiltration, 7 with eosinophilic infiltration, and 3 with myocarditis with both lymphocyte and eosinophil infiltration. Compared with patients without cardiomyocyte injury, those with cardiomyocyte injury were clinically characterized by older age, a balanced sex distribution, less frequent chest pain, and a lower left ventricular ejection fraction. Fifteen of 21 (71.4%) patients with cardiomyocyte injury developed fulminant myocarditis, with 13 (86.7%) requiring mechanical circulatory support; in contrast, none of those without cardiomyocyte injury developed fulminant myocarditis (P<0.001)., Conclusions: Our histological examination of patients with myocarditis after mCV revealed varying degrees of cardiomyocyte injury, ranging from pronounced to absent, along with various types of myocarditis. Cardiomyocyte injury was strongly associated with the severity of myocarditis.

We present the case of a 54-year-old woman who was diagnosed with intraductal papillary neoplasm of the bile duct (IPNB) in the remnant intrapancreatic bile duct, 37 years after surgery for congenital biliary dilatation. Endoscopic ultrasonography revealed a papillary, low-echoic mass in the intrapancreatic bile duct, and peroral cholangioscopy revealed a papillary mucosa. A pancreaticoduodenectomy was performed, and the patient was pathologically diagnosed with type 1 pancreatobiliary-type IPNB with associated invasive carcinoma. As a similar atypical epithelium was identified in the pancreatic duct, it was suggested that the IPNB extended longitudinally to the pancreatic duct through the common channel.

Purpose: Cardiac dysfunction as a result of anthracycline treatment is a major concern regarding the management of patient life after therapy. The aim of the present study was to determine the clinical characteristics of cancer patients at high risk of developing cancer therapy-related cardiac dysfunction (CTRCD), in order to improve the risk management for the appropriate treatment., Methods: This is a single-center, retrospective study of patients with breast cancer who underwent anthracycline treatment and had regular consultations with cardiologists. To investigate the incidence of CTRCD and the risk factors related to its occurrence, left ventricular ejection fraction (LVEF), cardiac troponin I (TnI), and brain natriuretic peptide (BNP) were assessed in 177 patients at the start of anthracycline treatment, and again at 3, 6, 9, and 12 months., Results: Eight patients (4.5%) developed CTRCD (CTRCD group). The comparisons between the CTRCD group and those without CTRCD (non-CTRCD group) showed significant differences in pre-treatment cancer stage and neutrophil/lymphocyte ratio (NLR). Multivariate analysis showed a strong association between pre-treatment cancer stage, NLR, and type of anthracycline administered (epirubicin or doxorubicin)., Conclusion: High NLR, the more advanced stages of cancer, and doxorubicin administration were suggested as possible risk factors for the development of CTRCD. Special attention should be warranted for patients with any of these risk factors., Competing Interests: Declarations. Ethics approval: All the procedures performed in studies involving human participants were carried out in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required. Consent to participate: For this type of study, formal consent is not required. Consent for publication: Not applicable. Competing interests: MO, ES and YT have nothing to declare. JK has received honoraria from Chugai, Astellas, Ono Pharma, Bristol-Myers Squibb, Daiichi Sankyo, Taiho, Terumo, Eli Lill, and Nipponkayaku. ET has received honoraria from Pfizer., Sanofi, MSD, Eisai, Chugai, TAIHO, Johnson & Johnson, and AstraZeneca. KT has received grants and/or and contracted clinical trials from Chugai, Eisai, Taiho, Takeda, MSD, Daiichi Sankyo, Eli Lill, Asahi Kasei, Nipponkayaku, Kyowa Kirin, Asteras, and Maruho; honoraria from Chugai, Astra Zeneca, Pfizer, Eisai, Daiichi Sankyo, Eli Lill, Novartis, MSD, Nipponkayaku, Hisamitsu, Kyowa Kirin, Asahi Kasei, Taiho, and PDR Pharma. TO has received grants and/or contracted clinical trials from Chugai, Eisai, Taiho, Takeda, Asahi Kasei, Daiichi Sankyo, Eli Lilly, Nipponkayaku, Kyowa Kirin; honoraria from Chugai, Pfizer, Astra Zeneca, Eisai, Daiichi Sankyo, Eli Lilly, Kyowa Kirin, Novartis, FUJIFIRM Toyama Chemical, Johnson & Johnson, Asahi Kasei, Exact Sciences, Otsuka, and MSD. SS has received grants and/or contracted clinical trials from Taiho, Eisai, Chugai, Takeda, MSD, Astra Zeneca, Daiichi Sankyo, Gilead, Eli Lilly, and Sanofi; honoraria from Chugai, Kyowa Kirin, MSD, Novartis, Eisai, Takeda, Daiichi Sankyo, Eli Lilly, Astra Zeneca, Pfizer, Taiho, Ono, Nipponkayaku, Gilead, and Exact Sciences; participation on a data safety monitoring board or advisory board for Chugai/Roche, Astra Zeneca, Eli Lilly, Pfizer, Kyowa Kirin, Daiichi Sankyo, and MSD; and executive board membership of Japan Breast Cancer Research Group, Japan Breast Cancer Society, Japanese Society of Medical Oncology, and Breast International Group., (© 2024. The Author(s).)

Thallium (Tl) is one of the most toxic heavy metals, associated with accidental poisoning and homicide. It causes acute and chronic systemic diseases, including gastrointestinal and cardiovascular diseases and kidney failure. However, few studies have investigated the mechanism by which Tl induces acute kidney injury (AKI). This study investigated the toxic effects of Tl on the histology and function of rat kidneys using biochemical and histopathological assays after intraperitoneal thallium sulfate administration (30 mg/kg). Five days post-administration, rats exhibited severely compromised kidney function. Low-vacuum scanning electron microscopy revealed excessive calcium (Ca) deposition in the outer medulla of Tl-loaded rats, particularly in the medullary thick ascending limb (mTAL) of the loop of Henle. Tl accumulated in the mTAL, accompanied by mitochondrial dysfunction in this segment. Tl-loaded rats showed reduced expression of kidney transporters and channels responsible for Ca 2+ reabsorption in the mTAL. Pre-administration of the Na-K-Cl cotransporter 2 (NKCC2) inhibitor furosemide alleviated Tl accumulation and mitochondrial abnormalities in the mTAL. These findings suggest that Tl nephrotoxicity is associated with preferential Tl reabsorption in the mTAL via NKCC2, leading to mTAL mitochondrial dysfunction and disrupted Ca 2+ reabsorption, culminating in mTAL-predominant Ca crystal deposition and AKI. These findings on the mechanism of Tl nephrotoxicity may contribute to the development of novel therapeutic approaches to counter Tl poisoning. Moreover, the observation of characteristic Ca crystal deposition in the outer medulla provides new insights into diagnostic challenges in Tl intoxication., (© 2024. The Author(s).)

Expansion of economically viable turbot (Scophthalmus maximus) aquaculture depends on access to brackish-cold ground water sources in various parts of the world. Since brackish water sources can adversely affect the physiology and zoo technical performance of fish due to the burden of osmoregulation, dietary salt inclusion can alleviate the negative impacts of low-saline waters in several aquaculture species. This study investigated the effects of increasing dietary salt levels on the growth, feed utilization, body composition, and tissue fatty acid composition of juvenile turbot (initial live weight 120.3 ± 0.03 g/fish). Fish were fed five experimental diets supplemented with varying levels of sodium chloride (1.8-6.4%) or a control diet without salt. Each diet was tested in triplicate tanks for 9 weeks. Results showed that increasing dietary salt intake negatively impacted turbot performance, with significant reductions in weight gain, specific growth rate, and feed conversion ratio. Dry matter and ash content in the whole body and filet increased quadratically with increasing salt levels, whereas gill moisture and protein content decreased linearly. Furthermore, the nitrogen, lipid, and energy utilization efficiencies decreased with their respective intake and gain levels. Dietary salt significantly influenced the fatty acid profiles of gill, liver, and filet tissues. In the gill, monounsaturated fatty acids (16:1n-7, ΣMUFA) and n-6 PUFA (20:2n-6) increased, whereas EPA and DHA decreased. Liver ΣSFA (16:0, 18:0) increased, and n-3 PUFA (18:3n-3, 20:5n-3) decreased with increasing dietary salt. Filet saturated fatty acids (14:0, 15:0, 17:0) and n-6 PUFA (20:2n-6, 20:4n-6) increased, while n-3 PUFA (18:3n-3, EPA) decreased with dietary salt. DHA levels in filets showed a quadratic increase. Overall, this study shows that increasing dietary salt negatively impacts turbot growth, feed utilization, and tissue fatty acid composition in brackish water, highlighting the need for further studies on salinity management strategies for turbot aquaculture., Competing Interests: Declarations Ethics approval Handling and sampling of fish during the study were performed following the guidelines for the care and welfare of the principles of the European Directive (2010/63/EU) and the recommendations of the ARRIVE guidelines (Kilkenny et al. 2010). Consent for publication Not applicable. Conflict of interest The authors declare no competing interests., (© 2024. The Author(s).)

Artificial urinary sphincters (AUS) are an effective treatment for male stress urinary incontinence (SUI). However, infection, erosion, mechanical failure, atrophy, and balloon deterioration cause device malfunction in approximately half of patients by 10 years after implantation. Many patients desire to regain urinary continence and require revision surgery (RS), including device removal and simultaneous or delayed implantation. Patients for whom RS is considered should be examined physically and by interview for signs of infection. Urethral erosion should be assessed using cystoscopy. If there is infection or erosion, all devices should be removed first, and a new device should be implanted several months later. During the RS, after strong adhesion around the urethra, transcorporal cuff implantation is a safe choice. Device removal and simultaneous implantation can be performed in the absence of infection or erosion. If a long time has passed since device implantation, the entire device should be replaced due to device aging and deterioration; however, if the time is short, only the defective component need be replaced. Intraoperative assessment of urethral health is necessary for device removal and implantation. If the urethra is healthy, a new cuff can be placed in the same position as the old cuff was removed from; however, if the urethra is unhealthy, the cuff can be implanted in a more proximal/distal position, or a transcorporal cuff implant may be chosen. This article reviews the literature on diagnostic and treatment strategies for recurrent SUI in male patients with AUS and proposes a flowchart for AUS revision., (© 2024 The Japanese Urological Association.)

Aims: The bicarbonate (HCO 3 - ) buffer system is crucial for maintaining acid-base homeostasis and blood pH. Recent studies showed that elevated serum HCO 3 - levels serve as an indicator of the beneficial effects of acetazolamide in improving decongestion in acute heart failure. In this study, we sought to clarify the clinical relevance and prognostic impact of HCO 3 - in chronic heart failure (CHF)., Methods: This cohort study enrolled 694 hospitalized patients with CHF (mean age 68.6 ± 14.6, 62% male) who underwent arterial blood sampling and exhibited neutral pH ranging from 7.35 to 7.45. We characterized the patients based on HCO 3 - levels and followed them to register cardiac events., Results: Among the patients, 17.3% (120 patients) had HCO 3 - levels exceeding 26 mmol/L. Patients presenting HCO 3 -  > 26 mmol/L were more likely to use loop diuretics and had higher serum sodium and lower potassium levels, but left ventricular ejection fraction did not differ compared with those with HCO 3 - between 22 and 26 (379 patients) or those with HCO 3 -  < 22 mmol/L (195 patients). During a median follow-up period of 1950 days, Kaplan-Meier analysis revealed that patients with HCO 3 -  > 26 mmol/L had the lowest event-free survival rate from either cardiac deaths or heart failure-related rehospitalization (P < 0.01 and 0.03, respectively). In the multivariable Cox model, the presence of HCO 3 -  > 26 mmol/L independently predicted increased risks of each cardiac event with a hazard ratio of 2.31 and 1.69 (P < 0.01 and 0.02, respectively), while HCO 3 -  < 22 mmol/L was not associated with these events (hazard ratios, 0.99 and 1.19; P = 0.98 and 0.43, respectively)., Conclusions: Elevated blood HCO 3 - levels may signify enhanced proximal nephron activation and loop diuretic resistance, leading to long-term adverse outcomes in patients with CHF, even within a normal pH range., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background and study aims Because more than a few patients have intraductal papillary mucinous neoplasms of the pancreas (IPMNs) with mural nodules (MNs) that are benign, clinical plans should be determined by using histocytological specimens especially, for patients with high risk for surgery or with a small MN. Patients and methods This study included 27 patients to evaluate the efficacy of peroral pancreatoscopy using a SpyGlass DS system (POPS-DS) for patients with MN-positive IPMN, mainly focusing on the ability of POPS-DS to detect malignancy. Results Biopsy specimens obtained under POPS-DS guidance could be used for histological evaluation of all patients with MNs in the main pancreatic duct and 67% of the patients with MNs in the branch ducts, whereas fluid specimens collected during POPS-DS could be used for histocytological evaluation for all patients. For the 13 patients who underwent surgery just after POPS-DS, the sensitivity, specificity, and accuracy of POPS-DS to detect malignancy were 89%, 100%, and 92%, respectively. For the 12 patients who underwent surveillance without surgery, the cumulative 3-year progression rates for nine benign IPMNs and three malignant ones determined using POPS-DS were 0% and 100%, respectively. However, the sensitivity of POPS to detect IPMN epithelium in the resection margin was 20%. Only one patient developed procedure-related pancreatitis (mild). Conclusions POPS-DS could be used to accurately detect malignancy in patients with MN-positive IPMN. Therefore, histocytological evaluation using POPS-DS can contribute to selection of patients for whom surgery would be appropriate., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Angiosarcoma (AS) is a malignant vascular neoplasm comprising neoplastic endothelial cells accounting for 1%-4% of soft tissue sarcomas. While lymphedema-associated and post-irradiation ASs are almost always driven by a high-level amplification of MYC (8q24), sporadic ASs, including those of breast parenchymal origin, typically lack MYC amplification. Here, we report a case of sporadic breast MYC-amplified AS in a 19-year-old female with no history of lymphedema or irradiation, who was referred to our hospital for an enlarging right breast mass. After needle biopsy, the patient underwent right mastectomy and axillary lymphadenectomy. Microscopically, atypical endothelial cells proliferated and formed well-defined or slit-like vascular channels that invaded and dissected the breast parenchymal fat, ducts, and lobules. In a limited area, the tumor cells showed solid sheet-like proliferation with increased mitotic figures of 40 per 2 mm 2 with a small area of necrosis. Immunohistochemical analysis revealed strong positivity for c-Myc. Fluorescence in situ hybridization (FISH) with MYC break-apart probes showed a high-level 5' single signal amplification. The patient was disease-free 16 months post-surgery. Nanopore sequencing successfully detected not only a high-level amplification of the 8q24 region, including MYC, but also multiple structural variants of the 8q24 region. In-depth analysis revealed extrachromosomal circular DNA amplification including the MYC protein-coding region and upstream region but not the downstream region. We also performed methylation classification using nanopore-based methylation data to successfully categorize the tumor as AS. This case report highlights the potential utility of nanopore sequencing in the diagnosis of sarcomas., (© 2024 Wiley Periodicals LLC.)

Background: Pulmonary hypertension leads to right ventricular failure, which is a major determinant of prognosis. Circulating biomarkers for right ventricular function are poorly explored in pulmonary hypertension. This study aimed to clarify the significance of collagen triple helix repeat-containing protein 1 (CTHRC1) as a biomarker of right ventricular failure in pulmonary hypertension., Methods: A monocrotaline-induced pulmonary hypertension rat model was used to evaluate right ventricular CTHRC1 expression and its relationship with fibrosis. Next, human plasma CTHRC1 levels were measured in controls (n = 20), pulmonary arterial hypertension (n = 46), and patients with chronic thromboembolic pulmonary hypertension (CTEPH) (n = 64) before the first and after the final balloon pulmonary angioplasty., Results: CTHRC1 expression was higher in the right ventricles of rats with monocrotaline-induced pulmonary hypertension than in those of controls. CTHRC1 was colocalized with vimentin and associated with fibrosis in the right ventricles. Plasma CTHRC1 levels were higher in human patients with pulmonary arterial hypertension (P = 0.006) and CTEPH (P = 0.011) than in controls. Plasma CTHRC levels were correlated with B-type natriuretic peptide (R = 0.355, P < 0.001), tricuspid lateral annular peak systolic velocity (R = -0.213, P = 0.029), and right ventricular fractional area change (R = -0.225, P = 0.017). Finally, plasma CTHRC1 levels were decreased after the final balloon pulmonary angioplasty (P < 0.001) in CTEPH., Conclusions: CTHRC1 can be a circulating biomarker associated with right ventricular function and fibrosis in pulmonary hypertension and might reflect the therapeutic efficacy of balloon pulmonary angioplasty in CTEPH., (Copyright © 2024 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Competing Interests: There are no conflicts of declaration.

Purpose: The importance of tumor markers is well established; yet little is known about their prognostic value for patients with obstructive colorectal cancer (OCRC). We investigated the clinical significance of carcinoembryonic antigen (CEA) and CA 19-9 levels in patients with non-metastatic OCRC, who underwent insertion of a self-expandable metallic stent and curative surgery., Methods: Clinical data on 91 patients with OCRC were analyzed retrospectively to evaluate the associations of preoperative serum values of tumor makers with short- and long-term outcomes., Results: The 91 patients comprised 53 men and 38 women, with a median age of 71 years. Twelve patients had an elevated preoperative CA 19-9 level. Multivariate analyses revealed that an elevated CA 19-9 level was independently associated with poor disease-free survival (DFS) [hazard ratio (HR) = 4.57, 95% confidence interval (CI) 2.06-10.14, P < 0.001] and overall survival (HR = 4.06, 95% CI 1.46-11.24, P = 0.007). A CEA level > 5 ng/ml had no prognostic value, whereas a CEA level > 10.8 ng/ml was significantly associated with worse DFS (P = 0.032)., Conclusion: Measuring the CA 19-9 level concomitantly with the CEA level for patients with advanced CRC, including OCRC, may provide a valuable means to improve prognostication., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Myxoid liposarcoma (MLPS) is a rare sarcoma, typically arising in deep soft tissues during the fourth to fifth decades of life. Histologically, MLPS is composed of uniform oval cells within a background of myxoid stroma and chicken-wire capillaries. Genetically, MLPS is characterized by the FUS/EWSR1::DDIT3 fusion gene, which generally results from balanced interchromosomal translocation and is detectable via DDIT3 break-apart fluorescence in situ hybridization (FISH). Here, we report an unusual intra-articular MLPS case, negative for DDIT3 break-apart FISH but positive for EWSR1::DDIT3. An 18-year-old female was referred to our hospital complaining of an intra-articular mass in the right knee joint. Histologically, the tumor was mainly composed of mature adipocytes, brown fat-like cells, and lipoblasts. Nanopore sequencing detected DNA rearrangements between EWSR1 and DDIT3 and clustered complex rearrangements involving multiple chromosomes, suggesting chromoplexy. Methylation classification using random forest, t-distributed stochastic neighbor embedding, and unsupervised hierarchical clustering correctly classified the tumor as MLPS. The copy number was almost flat. The TERT promoter C-124T was also detected. This report highlights, for the first time, the potential value of a fast and low-cost nanopore sequencer for diagnosing sarcomas., (© 2024 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Through strengthened biobank governance, broad consent has been widely accepted as a means to replace donors' discretion based on the information of individual research protocols. Trust and other ethical and social notions, such as reciprocity and solidarity, are key concepts that support biobank governance. The types of allowed broad consent are several; however, they remain unclear, and whether these ethical and social notions are associated with public attitudes toward the consent model is not fully understood. This quantitative study examined two hypotheses: narrower and limited broad consent are more accepted by the public, and acceptance rates for broad consent increase with established measures related to biobank governance. This analysis supported both hypotheses, implying that the limited type of broad consent should be considered an important option, and that a specific type of governance is critical in promoting trust, reciprocity, and solidarity between biobanks and the public., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Brain death has been used to decide whether to keep sustained care and treatment. It can facilitate tissue, organ, and body donation for several purposes, such as transplantation and medical education and research. In Japan, brain death has strict diagnostic criteria and family consent is crucial, but it has been a challenging concept for the public since its introduction, including knowledge and communication issues., Objective: We analyzed data across YouTube and Twitter in Japan to uncover actors and assess the quality of brain death communication, providing recommendations to communicate new medical technologies., Methods: Using the keyword "" (brain death), we collected recent data from YouTube and Twitter, classifying the data into 5 dimensions: time, individuality (type of users), place, activity, and relations (hyperlinks). We employed a scale to evaluate brain death information quality. We divided YouTube videos into 3 groups and assessed their differences through statistical analysis. We also provided a text-based analysis of brain death-related narratives., Results: Most videos (20/61, 33%) were uploaded in 2019, while 10,892 tweets peaked between July 3 and 9, 2023, and June 12 and 18, 2023. Videos about brain death were mostly uploaded by citizens (18/61, 27%), followed by media (13/61, 20%) and unknown actors (10/61, 15%). On the other hand, most identified users in a random sample of 100 tweets were citizens (73/100, 73%), and the top 10 retweeted and liked tweets were also mostly authored by citizens (75/100, 75%). No specific information on location was uncovered. Information videos contained guides for accreditation of the National Nursing Exam and religious points of view, while misinformation videos mostly contained promotions by spirituality actors and webtoon artists. Some tweets involved heart transplantation and patient narratives. Most hyperlinks pointed to YouTube and Twitter., Conclusions: Brain death has become a common topic in everyday life, with some actors disseminating high-quality information, others disseminating no medical information, and others disseminating misinformation. Recommendations include partnering with interested actors, discussing medical information in detail, and teaching people to recognize pseudoscience., (©Xanat Vargas Meza, Masanori Oikawa. Originally published in JMIR Formative Research (https://formative.jmir.org), 18.09.2024.)

Blood pressure (BP) variability (BPV) is associated with an increased risk of cardiovascular events, independent of absolute BP values. However, the predictive significance of very short-term BPV, occurring within seconds or minutes, in patients with ischemic heart disease (IHD) has yet to be established. This prospective study involved 206 consecutive hospitalized patients with IHD (mean age 67.6 years, 78.2% male) who underwent pulse transit time (PTT)-based continuous BP recording during the night-time. Very short-term BPV was assessed by standard deviation (SD), coefficient of variation (CV), and variation independent of mean (VIM) of PTT-BP. Clinical outcome data were collected. When the patients were categorized into two groups according to the median value of very short-term BPV, Kaplan-Meier analysis revealed that patients with elevated SD, CV, and VIM of systolic and diastolic PTT-BP were associated with lower event-free survival rates from the composite cardiovascular events including cardiac deaths, worsening heart failure cases, nonfatal myocardial infarctions, unplanned revascularizations, and strokes over a median follow-up of 797 days. In a multivariate Cox proportional hazards analysis adjusting for confounding variables, each parameter as a continuous variable was independently associated with adverse events. Incorporating very short-term BPV into basic models had a significant impact on risk reclassification and integrated discrimination for cardiovascular outcomes. In conclusion, the identification of patients with elevated very short-term BPV during the night-time through a PTT-driven approach helps stratify the future risk in IHD patients., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Exercise intolerance in heart failure arises from multifactorial pathophysiological mechanisms. Hepatokines, liver-synthesized molecules, regulate systemic metabolisms in peripheral tissues. We previously identified the hepatokine fetuin-A as being linked to liver hypoperfusion in heart failure. Here, we investigated the role of fetuin-A in connecting cardiac-hepatic-peripheral interaction., Methods and Results: We conducted a prospective study involving 202 consecutive hospitalized patients (mean age, 56.8 years; 76.2% men) with heart failure who underwent cardiopulmonary exercise testing. We measured the serum concentration of fetuin-A by ELISA. Correlation analysis revealed a negative association between fetuin-A levels and the ratio of minimum minute ventilation to carbon dioxide production, its slope, and a tendency toward a positive correlation with peak oxygen uptake. Patients with impaired exercise tolerance exhibited lower fetuin-A levels. During a median follow-up of 1045 days, 18.3% experienced cardiac events, including 4 cardiac deaths and 33 cases of worsening heart failure. Classification and regression tree analysis identified a high-risk subgroup with lower fetuin-A (<24.3 mg/L) and impaired exercise tolerance (peak oxygen uptake<14.2 mL/kg per min). Kaplan-Meier analysis revealed that this subgroup had the highest risk of cardiac events. In a multivariable Cox proportional hazard model, the combination of lower fetuin-A and exercise intolerance was independently associated with increased risks of cardiac events., Conclusions: Reduced circulating fetuin-A levels were associated with exercise intolerance in heart failure patients. Fetuin-A could emerge as a target implicated in exercise capacity connecting cardiac-hepatic-peripheral interaction and as a valuable biomarker for predicting prognosis when combined with peak oxygen uptake.

Malnutrition is classified into marasmus and kwashiorkor in children. However, the clinical significance of these aspects is unclear in adult patients with heart failure (HF). We divided 2308 adult patients with HF into four groups according to marasmus type (body mass index < 18.5 kg/m 2 ) and kwashiorkor type (serum albumin < 3.4 g/dL) malnutrition: Group C (no malnutrition, n = 1511, 65.5%), Group M (marasmus type malnutrition, n = 133, 5.8%), Group K (kwashiorkor type malnutrition, n = 554, 24.0%) and Group MK (marasmic-kwashiorkor type malnutrition, n = 110, 4.8%). Group M showed the lowest blood pressure. Groups K and MK showed higher levels of B-type natriuretic peptide. Right atrial pressure was lowest in Groups M and MK. Kaplan-Meir analysis demonstrated that Group MK had the lowest event-free rate of all-cause death and cardiac death. In the multivariable Cox proportional hazard analysis, Groups M, K, and MK were associated with all-cause death (hazard ratio 1.790, 1.657 and 2.313, respectively) and cardiac death (hazard ratio 2.053, 1.855 and 3.001, respectively) compared to Group C as a reference. Marasmus type and kwashiorkor type malnutrition are associated with distinct profiles and high mortality, and marasmic-kwashiorkor type malnutrition has the poorest prognosis., (© 2024. The Author(s).)

Background: Cardiovascular risk factors are associated with increased risk of future cancer. However, the relationship between quantitative parameters of atherosclerosis and future cancer risk is unclear., Methods and Results: A total of 1,057 consecutive patients with coronary artery disease was divided into 2 groups according to the cutoff value of the cardio-ankle vascular index (CAVI) derived by receiver operating characteristic curve analysis: low CAVI group (CAVI <8.82; n=487), and high CAVI group (CAVI ≥8.82; n=570). Patients in the high CAVI group were older and had a higher prevalence of diabetes, chronic kidney disease, anemia and history of stroke compared with patients in the low CAVI group. There were 141 new cancers during the follow-up period. The cumulative incidence of new cancer was significantly higher in the high CAVI group than in the low CAVI group (P=0.001). In a multivariate Cox proportional hazard analysis, high CAVI was found to be an independent predictor of new cancer diagnosis (hazard ratio 1.62; 95% confidence interval 1.11-2.36; P=0.012). In the analysis of individual cancer types, high CAVI was associated with lung cancer (hazard ratio 2.85; 95% confidence interval 1.01-8.07; P=0.049)., Conclusions: High CAVI was associated with the risk of future cancer in patients with coronary artery disease., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)

Background: The Rapid Autopsy Program (RAP) is a valuable procedure for studying human biology and diseases such as cancer. However, implementing the RAP in Japan necessitates a thorough understanding of concepts such as good death and the integration of sociocultural aspects. By revising perceptions of organ donation on social media, we bring attention to the challenges associated with implementing new medical research procedures such as the RAP., Objective: This study aims to examine YouTube and Twitter/X to identify stakeholders, evaluate the quality of organ donation communication, and analyze sociocultural aspects associated with organ donation. Based on our findings, we propose recommendations for the implementation of new medical research procedures., Methods: Using the term "" (organ donation), we collected data from YouTube and Twitter/X, categorizing them into 5 dimensions: time, individuality, place, activity, and relationships. We utilized a scale to evaluate the quality of organ donation information and categorized YouTube videos into 3 groups to analyze their differences using statistical methods. Additionally, we conducted a text-based analysis to explore narratives associated with organ donation., Results: Most YouTube videos were uploaded in 2021 (189/638, 29.6%) and 2022 (165/638, 25.9%), while tweets about organ donation peaked between 2019 and 2022. Citizens (184/770, 23.9%), media (170/770, 22.0%), and unknown actors (121/770, 15.7%) were the primary uploaders of videos on organ donation. In a sample of average retweeted and liked tweets, citizens accounted for the majority of identified users (64/91, 70%, and 65/95, 68%, respectively). Regarding Japanese regions, there were numerous information videos about organ donation in Hokkaido (F2.46,147.74=-5.28, P=.005) and Kyushu and Okinawa (F2.46,147.74=-5.28, P=.005). On Twitter/X, Japan and China were the most frequently mentioned countries in relation to organ donation discussions. Information videos often focused on themes such as borrowed life and calls to register as donors, whereas videos categorized as no information and misinformation frequently included accusations of organ trafficking, often propagated by Chinese-American media. Tweets primarily centered around statements of donation intention and discussions about family consent. The majority of video hyperlinks directed users to YouTube and Twitter/X platforms, while Twitter/X hyperlinks predominantly led to news reports from Japanese media outlets., Conclusions: There is significant potential to implement new medical research procedures such as the RAP in Japan. Recommendations include conceptualizing research data as borrowed data, implementing horizontally diversified management of donation programs, and addressing issues related to science misinformation and popular culture trends., (©Xanat Vargas Meza, Masanori Oikawa. Originally published in JMIR Formative Research (https://formative.jmir.org), 19.07.2024.)

An aneurysmal bone cyst (ABC) is a benign bone neoplasm that typically occurs during the first and second decades of life. ABC usually presents as a rapidly growing intramedullary expansile mass with multiple blood-filled cysts in the metaphysis of the long tubular bones. Here, we report a case of a periosteal solid ABC that was initially diagnosed as a high-grade surface osteosarcoma. A 10-year-old male was referred to our hospital for swelling and tenderness of the left upper arm. Radiography revealed periosteal mass without fluid-fluid levels. On performing open biopsy, the tumor showed hypercellular proliferation of uniform spindle to epithelioid cells with brisk mitotic activity (up to 12/2 mm 2 ) and lace-like osteoid formation, which was diagnosed as a high-grade surface osteosarcoma. After one course of chemotherapy using adriamycin and cisplatin, peripheral sclerosis was conspicuous, which led to pathological review and revision of diagnosis as "possibly osteoblastoma." The patient was disease-free for 4 years after marginal resection and curettage. Retrospective nanopore DNA sequencing unexpectedly detected a PAFAH1B1::USP6 rearrangement. The fusion gene was further validated using reverse transcription-polymerase chain reaction and the diagnosis was revised to ABC. Chromothripsis involving chromosome 17 has also been identified. Methylation analysis classified the present tumor as an ABC or non-ossifying fibroma using t-distributed stochastic neighbor embedding and unsupervised hierarchical clustering. This case report highlights the utility of nanopore DNA sequencing for soft tissue and bone tumor diagnosis., (© 2024 Wiley Periodicals LLC.)

Purpose: Sarcopenia influences the short- and long-term outcomes of various medical conditions including malignancy. Ishii's screening test estimates the probability of sarcopenia based on a score calculated by three simple variables: age, grip strength, and calf circumference. We investigated the clinical significance of Ishii's score for patients with non-metastatic obstructive colorectal cancer (OCRC) who underwent curative surgery after intraluminal decompression., Methods: Ishii's score was calculated in 79 patients with OCRC. Muscle volume loss and decreased muscle quality were evaluated by computed tomography (CT) images as skeletal muscle index (SMI) and intramuscular adipose tissue content (IMAC), respectively., Results: There were 46 men and 33 women, with a median age of 70 years old. The cutoff value for Ishii's score was 155.1 and 15 patients were in the high-score group. The high-score group was significantly associated with worse time to recurrence (TTR) and overall survival (OS), and a high Ishii's score was an independent negative prognostic factor for TTR (hazard ratio = 2.93, P = 0.015). A high Ishii's score was significantly associated with a low SMI value but not with the IMAC value., Conclusion: A high Ishii's score was independently associated with poorer TTR in patients with non-metastatic OCRC., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Absolute configuration at 12 stereocenters in the 36-membered macrocyclic ring portion of poecillastrin C ( 1 ) was disclosed by chemical degradation and NMR analyses of 1 , chemical synthesis, and molecular modeling techniques.

Copper (Cu) is a critical element for cancer cell proliferation and considerably accumulates in the nucleus. 64 Cu 2+ is an anticancer radiopharmaceutical that targets the copper requirement of cancer cells. However, intravenously injected 64 Cu 2+ ions primarily accumulate in the liver. Ligand complexation of 64 Cu 2+ may be a promising method for increasing tumor delivery by reducing liver uptake. In this study, we used three tripodal amine ligands [tris(2-aminoethyl)amine (Tren), diethylenetriamine (Dien), and tris(2-pyridylmethyl)amine (TPMA)] to enclose 64 Cu 2+ ions and compared their in vivo tumor and liver uptakes using a tumor-bearing xenograft mouse model of the extrahepatic bile duct carcinoma cell line TFK-1. We examined intracellular Cu distribution using microparticle-induced X-ray emission (micro-PIXE) analysis of these compounds. 64 Cu 2+ -Tren and 64 Cu 2+ -Dien showed higher tumor uptake than 64 Cu 2+ -TPMA and 64 Cu 2+ ions in TFK-1 tumors. Among the three 64 Cu 2+ complexes and 64 Cu 2+ ions, liver uptake was inversely correlated with tumor uptake. Micro-PIXE analysis showed that in vitro cellular uptake was similar to in vivo tumor uptake, and nuclear delivery was the highest for 64 Cu 2+ -Tren. Conclusively, an inverse correlation between tumor and liver uptake was observed using three 64 Cu 2+ complexes of tripodal amine ligands and 64 Cu 2+ ions. These results provide useful information for the future development of anticancer 64 Cu radiopharmaceuticals.

Background: Designing competency-based education (CBE) programmes is a priority in global nursing education for better nursing care for the population. In the Democratic Republic of the Congo (DRC), object-based education (OBE) remains mainstream in pre-service nursing education programmes. Recently, the Ministry of Health developed a self-assessment tool and quantitatively compared the clinical competency of CBE- and OBE-trained nurses. This study aimed to qualitatively triangulate the results of self-evaluation by exploring perception of supervisors, incumbent CBE-, and OBE-trained nurses in comparison with the competence of the two types of nurses, and to identify influential factors or barriers to their competence in clinical settings., Methods: A qualitative descriptive approach with conventional content analysis was applied. Twenty interviews with clinical supervisors who oversaw both CBE- and OBE-trained nurses, 22 focus group discussions (FGDs) with CBE-trained nurses, and 21 FGDs with OBA-trained nurses currently working in health facilities were conducted. Participants of the FGDs were selected from the participants of the DRC self-assessment competency comparison study where there was no statistically significance between CBE- and OBE-trained nurses in the demographic characteristics. Data were analysed in terms of the competencies identified by the Ministry of Health., Results: The supervisors recognised that the CBE-trained nurses had stronger competencies in professional communication, making decisions about health problems, and engaging in professional development, but were weak in clinical skills. This study identified challenges for supervisors in assuring standardised care in health facilities with OBE- and CBE-trained nurses, as well as barriers for CBE-trained nurses as a minority in the workplace in demonstrating their competencies., Conclusions: The study results support the Ministry of Health's policy to expand CBE in pre-service education programmes but reveal that its slow implementation impedes full utilisation of the acquired competencies at health facilities. Implementation could be accelerated by strengthening cooperation among the Ministry of Health's three human resource departments, and developing and implementing a well-planned, legally binding, long-term CBE reform strategy, including an approach to the Continuing Professional Development system., (© 2024. The Author(s).)

Background: The immune systems and chronic inflammation are implicated in the pathogenesis of dilated cardiomyopathy (DCM) and heart failure. However, the significance of neutrophil extracellular traps (NETs) in heart failure remains to be elucidated., Methods: We enrolled consecutive 62 patients with heart failure with idiopathic DCM who underwent endomyocardial biopsy. Biopsy specimens were subjected to fluorescent immunostaining to detect NETs, and clinical and outcome data were collected. Ex vivo and in vivo experiments were conducted., Results: The numbers of NETs per myocardial tissue area and the proportion of NETs per neutrophil were significantly higher in patients with DCM compared with non-DCM control subjects without heart failure, and the numbers of NETs were negatively correlated with left ventricular ejection fraction. Patients with DCM with NETs (n=32) showed lower left ventricular ejection fraction and higher BNP (B-type natriuretic peptide) than those without NETs (n=30). In a multivariable Cox proportional hazard model, the presence of NETs was independently associated with an increased risk of adverse cardiac events in patients with DCM. To understand specific underlying mechanisms, extracellular flux analysis in ex vivo revealed that NETs-containing conditioned medium from wild-type neutrophils or purified NET components led to impaired mitochondrial oxygen consumption of cardiomyocytes, while these effects were abolished when PAD4 (peptidyl arginine deiminase 4) in neutrophils was genetically ablated. In a murine model of pressure overload, NETs in myocardial tissue were predominantly detected in the acute phase and persisted throughout the ongoing stress. Four weeks after transverse aortic constriction, left ventricular ejection fraction was reduced in wild-type mice, whereas PAD4-deficient mice displayed preserved left ventricular ejection fraction without inducing NET formation., Conclusions: NETs in myocardial tissue contribute to cardiac dysfunction and adverse outcomes in patients with heart failure with DCM, potentially through mitochondrial dysfunction of cardiomyocytes., Competing Interests: Disclosures Drs Misaka and Kobayashi belong to a department supported by Minamisoma City. The other authors report no conflicts.

Dermatofibroma (DF) is a benign tumor that forms pedunculated lesions ranging in size from a few millimeters to 2 cm, usually affecting the extremities and trunks of young adults. Histopathologically, DF is characterized by the storiform proliferation of monomorphic fibroblast-like spindle cells. In addition to neoplastic cells, secondary elements such as foamy histiocytes, Touton-type giant cells, lymphoplasmacytes, and epidermal hyperplasia are characteristic histological features. Several histological variants, including atypical, cellular, aneurysmal, and lipidized variants, have been reported; cases with variant histologies are sometimes misdiagnosed as sarcomas. We present a case of metastasizing aneurysmal DF that was initially diagnosed as an angiosarcoma on biopsy. A 26-year-old woman was referred to our hospital with a gradually enlarging subcutaneous mass in her lower left leg. Positron emission tomography-computed tomography revealed high fluorodeoxyglucose uptake not only in the tumor but also in the left inguinal region. On biopsy, ERG and CD31-positive atypical spindle cells proliferated in slit-like spaces with extravasation, leading to the diagnosis of angiosarcoma. Histology of the wide-resection specimen was consistent with DF, and lymph node metastasis was also observed. Nanopore DNA sequencing detected CD63::PRKCD fusion and copy number gain, although CD63 was not included in the target region of adaptive sampling. This report highlights the importance of recognizing the unusual clinical, radiological, and pathological features of DF to avoid misdiagnosis, and the potential diagnostic utility of nanopore sequencer., (© 2024 Wiley Periodicals LLC.)

Background: The relationship between liver fibrosis and left atrial (LA) remodeling in atrial fibrillation (AF) remains uncertain. We examined the associations between the fibrosis-4 (FIB4) index, an indicator of liver fibrosis, and both LA low-voltage areas (LVAs) on electroanatomic mapping and AF recurrence postablation., Methods: We recruited 343 patients who underwent radiofrequency catheter ablation (RFCA) or cryoballoon ablation (CBA) for AF. First, the association between the FIB4 index and LA LVAs (<0.5 mV) was evaluated in RFCA using electroanatomic mapping ( n  = 214). Next, the utility of a FIB4 index ≥1.3, recommended cut-off value of liver fibrosis, was verified to assess the risk for AF recurrence in CBA without additional LVA ablation ( n  = 129)., Results: Patients with a FIB4 index ≥1.3 had a higher prevalence of LA LVAs (>5 cm 2 ) compared to those without. Additionally, the quantitative size of LVAs showed a positive correlation with the FIB4 index ( R  = .642, p  < .001). In multivariate logistic models, a FIB4 index ≥1.3 was related to the presence of LVAs after adjusting for LA diameter, right atrial end-systolic area, and nonparoxysmal AF (odds ratio 2.508; p  = 0.039). In CBA, AF recurrence rate was 13.1% during 3-12 months postablation. In multivariate Cox models, a FIB4 index ≥1.3 was an important predictor of AF recurrence (hazard ratio 3.796; p  = .037), suggesting that LVAs might be associated with AF recurrence after CBA., Conclusion: The FIB4 index was a novel predictor of the existence of LA LVAs on electroanatomic mapping and AF recurrence after CBA., Competing Interests: S.Y. and T.I. work for the Department of Arrhythmia and Cardiac Pacing, which is funded by Abbott Medical Japan LLC, Biotronik Japan, Inc, and Nihon Kohden Corporation. These companies are unrelated to the study's content. None of the other authors disclose any conflicts of interest., (© 2024 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Purpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not., Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes., Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine ( P =0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06)., Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Chen et al.)

Aims: We aimed to elucidate the association between malnutrition and the occurrence of bleeding events in patients with heart failure., Methods and Results: We evaluated the nutritional status of patients with heart failure [n = 2044, median (inter-quartile range) age 69.0 (59.0-78.0) years, 1209 (59.1%) males] using the Geriatric Nutritional Risk Index (GNRI). The primary endpoint was a composite of bleeding events such as haemorrhagic stroke or gastrointestinal bleeding. According to the survival classification and regression tree analysis, the accurate cut-off point of GNRI for predicting the primary endpoint was 106.2. We divided the patients into two groups based on GNRI levels: high GNRI group (GNRI ≥ 106.2, n = 606, 29.6%) and low GNRI group (GNRI < 106.2, n = 1438, 70.4%). We compared the patients' characteristics and prognosis between the two groups. The low GNRI group was older [72.0 (63.0-79.0) vs. 63.0 (53.0-73.0) years, P < 0.001] and had a lower prevalence of male sex (56.9% vs. 64.5%, P = 0.001). There were no differences in the use of antiplatelet agents and anticoagulants between the two groups. Levels of B-type natriuretic peptide were higher [321.1 (123.3-667.4) vs. 111.6 (42.6-235.4) pg/mL, P < 0.001] and levels of haemoglobin were lower [12.4 (10.8-13.7) vs. 14.2 (12.9-15.4) g/dL, P < 0.001] in the low GNRI group. The Kaplan-Meier analysis demonstrated that bleeding event rates were higher in the low GNRI group (log-rank P < 0.001). The multivariable Cox proportional hazard analysis revealed that low GNRI (hazard ratio 1.952, 95% confidence interval 1.002-3.805, P = 0.049) was associated with bleeding events., Conclusions: Heart failure patients with poor nutritional status, determined by GNRI under 106.2, experienced high bleeding event rates. Comprehensive management is required to avoid bleeding event in those populations., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

EWSR1::NFATC2 sarcoma, a rare round cell sarcoma constituting the majority of EWSR1::non-ETS sarcomas, has recently been defined in the latest WHO classification. To date, the cytological findings of EWSR1::NFATC2 sarcoma remain undocumented. We present the case of a 25-year-old man with a history of polyostotic fibrous dysplasia in the right leg, referred to our hospital with left thigh pain. Cytological findings included metachromasia, minimally pleomorphic round cells, and eosinophilic infiltration. There was no precursor fibrous dysplasia and the initial diagnosis was undifferentiated pleomorphic sarcoma. Following histologic review, we successfully performed immunocytochemistry and fluorescence in situ hybridization (FISH) on archival cytology specimens. The tumor cells were positive for NKX2-2, NKX3-1, and PAX7 and showed amplified 5' single signals of EWSR1 gene. Reverse transcriptase-polymerase chain reaction revealed an in-frame fusion of EWSR1 and NFATC2. This report describes the cytological features of EWSR1::NFATC2 sarcoma and highlights the diagnostic utility of archival cytology specimens., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This study analyzes the role of education in the outcomes of the reform of the Japanese annual health checkup program. In April 2008, the annual checkup was redesigned to address concerns about metabolic syndrome. As the checkup is mandatory only for salaried workers, their participation rate is significantly higher than other workers; thus, they were most affected by the reform. Using institutional information, a difference-in-differences estimation was conducted with salaried workers as the treatment group and self-employed workers as the control group. We found that the reform caused significant changes in health behaviors and outcomes only among university graduates who were at a relatively high risk of metabolic syndrome. This highly educated group increased their physical activity, brought energy intake close to an ideal level, and achieved significant weight loss and BMI reduction to levels that minimize all-cause mortality among middle-aged Japanese. A secondary analysis implies that the difference in cognitive functioning test scores may be a critical factor in explaining the heterogeneous responses to the reform, suggesting that thoroughly well-articulated recommendations for healthy behaviors are needed in order to improve reform uptake., (© 2023. The Author(s).)

Background : This study investigated the feasibility of using a quantitative diagnostic method based on 99m Tc-pyrophosphate scintigraphy (PYP) lateral planar images to differentiate between PYP-positive (myocardial uptake) and false-positive (blood pool uptake) scans. Methods : The study included 93 consecutive patients with suspected transthyretin amyloid cardiomyopathy (ATTR-CM) who underwent PYP between April 2022 and December 2023. Patients were categorized using planar anterior PYP images according to the Perugini visual grading system; patients with grades ≥ 2 were analyzed. Whether the uptake of the ventricle was in the blood pool or the myocardium was confirmed by transaxial single-photon emission tomography (SPECT). The heart-to-mediastinum ratios (H/M ratio) of the left lateral planar images at 1- and 3-h were calculated by placing a circular region of interest in the heart and cephalodorsal side of the heart to determine optimal cut-off values. Results : Among the PYP images, the study analyzed 15 positives diagnosed as ATTR-CM and 10 false positives. Significant differences were observed in the H/M ratio at 1- and 3-h (both p <0.01), with 100% sensitivity and specificity using cut-off values of 1.22 and 1.21 at 1- and 3-h, respectively. The interclass correlation coefficients (2, 1) between the two readers were 0.919 and 0.958 for the 1- and 3-h H/M ratios, respectively. Conclusions : Lateral planar PYP imaging can exclude PYP false-positive cases caused by blood pools in a simple and quantitative manner using only a 1-h planar image, possibly obviating the need for SPECT imaging., Competing Interests: None., (© The Japanese Society of Nuclear Cardiology 2024.)

In vitro induction of primordial germ cell like-cells (PGCLCs) from pluripotent stem cells (PSCs) is a robust method that will contribute to understanding the fundamentals of cell fate decisions, animal breeding, and future reproductive medicine. Here, we introduce this system established in the rat model. We describe a stepwise protocol to induce epiblast-like cells and subsequent PGCLCs by forming spherical aggregates from rat PSCs. We also describe a protocol to mature these PGCLCs from specified/migratory to the gonadal stage by aggregation with female gonadal somatic cells., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The aim of the study was to explore the association between urate-lowering agents and reduced response to erythropoietin-stimulating agents in patients suffering from chronic kidney disease G5., Methods: We conducted a cross-sectional, multicenter study in Japan between April and June 2013, enrolling patients aged 20 years or older with an estimated glomerular filtration rate of ≤15 mL/min/1.73 m2. Exclusion criteria encompassed patients with a history of hemodialysis, peritoneal dialysis, or organ transplantation. The patients were categorized into four groups based on the use of urate-lowering drugs: high-dose allopurinol (&gt;50 mg/day), low-dose allopurinol (≤50 mg/day), febuxostat, and no-treatment groups. We used a multivariable logistic regression model, adjusted for covariates, to determine the odds ratio (OR) for erythropoietin hyporesponsiveness, defined by an erythropoietin resistance index (ERI) of ≥10, associated with urate-lowering drugs., Results: A total of 542 patients were included in the analysis, with 105, 36, 165, and 236 patients in the high-dose allopurinol, low-dose allopurinol, febuxostat, and no-treatment groups, respectively. The median and quartiles of ERIs were 6.3 (0, 12.2), 3.8 (0, 11.2), 3.4 (0, 9.8), and 4.8 (0, 11.2) in the high-dose allopurinol, low-dose allopurinol, febuxostat, and no-treatment groups, respectively. The multivariate regression model showed a statistically significant association between the high-dose allopurinol group and erythropoietin hyporesponsiveness, compared to the no-treatment group (OR = 1.98, 95% confidence interval: 1.10-3.57)., Conclusions: Our study suggests that the use of high-dose allopurinol exceeding the optimal dose may lead to hyporesponsiveness to erythropoiesis-stimulating agents., (© 2024 S. Karger AG, Basel.)

It has been reported that high levels of calcium-phosphorus (Ca-P) product are an indicator of coronary calcification and mortality risk in patients undergoing chronic hemodialysis. In the present study, we aimed to evaluate the significance of Ca-P product to predict the prognosis of patients with heart failure (HF) and chronic kidney disease (CKD). We conducted a prospective observational study of 793 patients with decompensated HF and CKD, and measured the value of Ca-P product. The cut-off value was obtained from the survival classification and regression tree (CART) analysis to predict post-discharge all-cause mortality and/or worsening HF, and the patients were divided into 2 groups: a high group (Ca-P product > 28, n = 594) and a low group (Ca-P product ≤ 28, n = 199). We compared the patient baseline characteristics and post-discharge prognosis between the 2 groups. The age as well as the prevalence of male sex, ischemic etiology, and anemia were significantly higher in the low group than in the high group. In contrast, there was no difference in echocardiographic parameters between the 2 groups. In the Kaplan-Meier analysis (mean follow-up 1089 days), all-cause mortality and/or worsening HF event rates were higher in the low group than in the high group (log-rank P = 0.001). In the multivariable Cox proportional hazard analysis, lower Ca-P product was found to be an independent predictor of all-cause mortality and/or worsening HF (hazard ratio 0.981, P = 0.031). Lower Ca-P product predicts adverse prognosis in patients with HF and CKD.

Purpose : We aimed to clarify the clinical characteristics of global and regional myocardial perfusion in patients with transthyretin type of cardiac amyloidosis (ATTR) using dual single-photon emission computed tomography (SPECT) with 99m Tc pyrophosphate (PYP) and 201 TL (TL). Methods : Consecutive 178 (mean age 78±12, male 79) patients known or suspect of ATTR who underwent PYP-TL dual SPECT were retrospectively enrolled. Patients were categorized according to the visual grading for planar PYP uptake using Perugini grading, and the patients with grade greater than or equal to 2 were analyzed. In planar analysis, the heart/contralateral ratio (H/CL) for PYP, and heart/lung ratio (H/L) for TL were obtained to evaluate global myocardial uptake. In TL-SPECT polar map analysis, the heterogeneity of myocardial uptake was evaluated using segmental mean %uptake. Cardiac function and left ventricular function and end-diastolic ventricular mass (LVmass) were measured by echocardiography. Results : Among 178 patients, 39 patients showed PYP uptake with grade 2 or 3 and H/CL >1.3 (81±5 ys, male 28). Of those, 4 patients showed significant perfusion defect in TL scan. Among 35 patients without perfusion defect, H/L showed a significant inverse correlation to H/CL, and LVmass (r=-0.3, p=0.02; r=-0.4, p=0.03. 95% confidence interval -0.4 to 0.2, and -0.7 to -0.04 for H/CL and LVmass). Polar map analysis demonstrated significantly lower mean %uptake for TL in septum compared to lateral (79.4±8.4 vs. 84.3±6.2, p=0.006 for TL in septum vs. lateral, respectively). Conclusion : In ATTR, TL uptake surrogated the reduction of global myocardial perfusion. A significant regional heterogeneity was observed with a notable reduction in septum despite the diffuse hypertrophy., Competing Interests: None., (© The Japanese Society of Nuclear Cardiology 2024.)