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Fusion among normal cells is tightly regulated and required for the developmental processes of an organism. Cancer cell fusion appears relatively rare but is associated with generating new hybrid cancer cells with aggressive properties. However, it remains unclear how cancer cells acquire aggressiveness via cell fusion. Here, we report changes in cell proliferative capacity, cell motility, anticancer drug resistance, and gene expression profiles when fusing human MCF-7 breast cancer cells and mesenchymal stem cells (MSCs). The fused cells were established using envelopes of a hemagglutinating virus of Japan, which increased cell proliferation, motility, and drug resistance. Comprehensive gene expression profile analysis revealed that the fused cells expressed higher levels of glycolysis-related genes than their parental cells. In fact, the fused cells relied more on glycolysis for ATP production (Warburg effect). HIF1A, which induces the expression of glycolysis-related genes, was upregulated in fused cells compared to MCF-7 cells. Allele-specific expression analysis of the fused cells indicated that MSC allele-derived HIF1A efficiently induces the expression of glycolysis-related genes in the MCF-7 allele. These findings indicate that the reorganization of gene expression by combining MSCs and MCF-7 alleles resulted in the predominant expression of glycolysis-related genes and increased malignancy in the fused cells., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Multiple microRNAs encapsulated in extracellular vesicles (EVs) including exosomes, unique subtypes of EVs, differ in healthy and cancer groups of people, and they represent a warning sign for various cancer scenarios. Since all EVs in blood cannot be transferred from donor to recipient cells during a single blood circulation, kidney filtration could pass some untransferred EVs from blood to urine. Previously, we reported on the ability of zinc oxide nanowires to capture EVs based on surface charge and hydrogen bonding; these nanowires extracted massive numbers of microRNAs in urine, seeking cancer-related microRNAs through statistical analysis. Here, we report on the scalability of the nanowire performance capability to comprehensively capture EVs, including exosomes, in urine, extract microRNAs from the captured EVs in situ , and identify multiple microRNAs in the extracted microRNAs differing in noncancer and lung cancer subjects through machine learning-based analysis. The nanowire-based extraction allowed the presence of about 2500 species of urinary microRNAs to be confirmed, meaning that urine includes almost all human microRNA species. The machine learning-based analysis identified multiple microRNAs from the extracted microRNA species. The ensembles could classify cancer and noncancer subjects with the area under the receiver operating characteristic curve of 0.99, even though the former were staged early.

Background: The skin barrier function is an important predictor of neonatal barrier defects. This study aimed to investigate the daily changes in skin barrier function and the impact of bathing on skin barrier function in neonates., Methods: We assessed the transepidermal water loss (TEWL) and stratum corneum hydration (SCH) on the forehead, cheek, volar forearm, and chest from days 2 to 7 and at 1 month after birth. Additionally, we measured the values after bathing and compared them with the pre-bathing values., Results: Sixty-six neonates were involved in the assessment, and each value at the four sites showed significant correlations. TEWL remained stable between days 2 and 7, but SCH significantly increased at most sites. Both significantly increased by 1.5-2 times in 1 month. After bathing, TEWL increased by more than 20% but decreased again after 3 h., Conclusions: TEWL did not change significantly with age during the first week of life. To minimize the effects of bathing, TEWL should be measured at least 3 h after bathing., (© 2024 Wiley Periodicals LLC.)

Head and neck squamous cell carcinoma (HNSCC) is diagnosed in more than 71,000 patients each year in the United States, with nearly 16,000 associated deaths. One significant hurdle in the treatment of HNSCC is acquired and intrinsic resistance to existing therapeutic agents. Over the past several decades, the University of Wisconsin has formed a multidisciplinary team to move basic scientific discovery along the translational spectrum to impact the lives of HNSCC patients. In this review, we outline key discoveries made throughout the years at the University of Wisconsin to deepen our understanding of therapeutic resistance in HNSCC and how a strong, interdisciplinary team can make significant advances toward improving the lives of these patients by combatting resistance to established therapeutic modalities. We are profoundly grateful to the many scientific teams worldwide whose groundbreaking discoveries, alongside evolving clinical paradigms in head and neck oncology, have been instrumental in making our work possible.

Estuaries exhibit high physicochemical variability and the properties of estuaries and the constituent segments are not yet systematically understood. This study aims to reveal the spatial heterogeneity of predominant organic sources using carbon and nitrogen stable isotope ratios (δ 13 C and δ 15 N, respectively) of Japanese eels (Anguilla japonica), one of the ideal natural samplers. In the Miyakoda River, Japan, our study site, the effectiveness of eel δ 13 C and δ 15 N values as standard indices of predominant organic sources was tested by employing the River Continuum Concept. This study then extended the application of these indices to the estuary, i.e., the Hamana Lake system, into which the Miyakoda River flows. Once in the upper estuary, eel δ 13 C and δ 15 N values became high, with the latter peaking in this river-estuary continuum, indicating that artificial labile subsidies (nutrients and organic matter) with high δ 15 N values were rapidly assimilated into the food web. Eel δ 15 N values decreased again in the middle estuary. Nevertheless, the influence of terrestrial organic subsidies extended into this segment, as evidenced by the low δ 13 C values of eels. These results suggest that refractory organic matter with low δ 15 N values, such as plant-derived ones, is slowly assimilated into the food web in the downstream estuarine segments. The higher δ 13 C values in the lower estuary suggested that the contribution of eelgrass or macroalgae occurred in addition to benthic microalgae. Thus, our results emphasize the need to consider the multiple energy flows to understand the estuary as a continuum., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Promoting access to and excellence in hematopoietic cell transplantation (HCT) by collecting and disseminating data on global HCT activities is one of the principal activities of the Worldwide Network for Blood and Marrow Transplantation, a non-governmental organization in working relations with the World Health Organization. HCT activities are recorded annually by member societies, national registries and individual centers including indication, donor type (allogeneic/autologous), donor match and stem cell source (bone marrow/peripheral blood stem cells/cord blood). In 2018, 1,768 HCT teams in 89 countries (6 World Health Organization regions) reported 93,105 (48,680 autologous and 44,425 allogeneic) HCT. Major indications were plasma cell disorders and lymphoma for autologous, and acute leukemias and MDS/MPN for allogeneic HCT. HCT numbers increased from 48,709 in 2007. Notable increases were seen for autoimmune diseases in autologous and hemoglobinopathies in allogeneic HCT. The number of allogeneic HCT more than doubled with significant changes in donor match. While HCT from HLA-identical siblings has seen only limited growth, HCT from non-identical related donors showed significant increase worldwide. Strongest correlation between economic growth indicator of gross national income/capita and HCT activity/10 million population was observed for autologous HCT (correlation coefficient [r]=0.79). HCT from unrelated donors showed strong correlation (r=0.68), but only moderate correlation was detected from related donors (r=0.48 for HLA-identical sibling; r=0.45 for other). The use of HCT doubled in about a decade worldwide at different speed and with significant changes regarding donor match as a sign of improved access to HCT worldwide. Although narrowing, significant gaps remain between developing and non-developing countries.

Objectives: Area under the concentration-time curve (AUC)-guided dosing of vancomycin was introduced in a clinical setting; however, the target range of non-steady-state AUCs, such as Day 1 AUC and Day 2 AUC, remains controversial. Therefore, we sought to determine pharmacokinetic parameter thresholds and identify independent risk factors associated with acute kidney injury (AKI) to establish a safe initial dosing design for vancomycin administration., Methods: A single-centre, retrospective, cohort study of hospitalized patients treated with vancomycin was conducted to determine the threshold of both non-steady-state AUCs (Day 1 and 2 AUCs) and trough levels at the first blood sampling point (therapeutic drug monitoring, TDM). In addition, independent risk factors associated with AKI were evaluated using univariate and multivariate logistic regression analyses., Results: The thresholds for predicting AKI were estimated as 456.6 mg·h/L for AUC0-24h, 554.8 mg·h/L for AUC24-48h, 1080.8 mg·h/L for AUC0-48h and 14.0 μg/mL for measured trough levels, respectively. In a multivariate analysis, Day 2 AUC ≥ 554.8 mg·h/L [adjusted odds ratio (OR), 57.16; 95% confidence interval (CI), 11.95-504.05], piperacillin/tazobactam (adjusted OR, 15.84; 95% CI, 2.73-127.70) and diuretics (adjusted OR, 4.72; 95% CI, 1.13-21.01) were identified as risk factors for AKI., Conclusions: We identified thresholds for both AUCs in the non-steady-state and trough levels at the first TDM. Our results highlight the importance of monitoring not only the AUC but also trough levels during vancomycin treatment to reduce the likelihood of AKI., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

In the current environment whereby new sources of proteins are extracted from plant material, it is also important to study the potential use of the resulting side streams. Although a number of studies have been conducted on various polysaccharides extracted from plant raw material, a polysaccharide fraction extracted from lupin bean is yet to be explored, in spite of the emerging interest in this crop as a source of food ingredients. In this work lupin soluble polysaccharide (LuPS) was obtained with a recovery as high as 46 % by extraction at pH 8, 120 °C, for 90 min. This fraction, named LuPS-8, was composed of a mostly linear pectic polysaccharide with a weight average molecular mass of 6608 kg/mol, and containing 71.0 % galactose, with minor amounts of arabinose (16.0 %), glucuronic acid 4.6 %, and galacturonic acid 4.1 %. When added to an acid milk dispersion, LuPS-8 improved its dispersibility, providing storage stability against sedimentation over a wider pH range than a HM-pectin reference, between 3.6-4.4. This research demonstrated the potential for upcycling of a side stream of lupin protein production, by the creation of value-added novel functional polysaccharide., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Prof. Nakamura has a joint appointment with Fuji Oil Holdings, Japan., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Infectious complications (ICs) have been reported as major causes of postoperative mortality in patients with cancer. However, to the best of our knowledge, the impact of ICs after gastrectomy on non-gastric cancer-related deaths (NGCDs) remains unexplored. The present study aimed to identify the impact of ICs after gastrectomy on NGCDs. A retrospective analysis of 712 patients with gastric cancer who underwent curative gastrectomy was conducted. The participants were categorized into IC and non-IC groups based on the incidence of postoperative IC. Clinicopathological factors and non-gastric cancer-related survival (NGCS) rates were compared between groups. Further NGCD and associated risk factor analyses were performed in a background factor-adjusted cohort using multivariate analysis. Among the 712 patients, 112 developed ICs (Clavien-Dindo classification grade ≥II). In the entire cohort, the IC group had a significantly worse 5-year cumulative incidence of NGCD (17.8 vs. 10.6%; Gray's P=0.021) compared with the non-IC group. Although a number of clinicopathological factors differed between the groups, including patient background, operative factors and tumor factors, the risk factors for NGCD identified in the multivariate analysis were older age, low prognostic nutritional index, low skeletal muscle index and Charlson comorbidity index ≥1, excluding IC incidents. The IC group exhibited more background factors contributing to NGCDs, suggesting a potential increase in NGCD regardless of IC incidence., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Nakashima et al.)

Objective: This study aimed to investigate the performance of generative pre-trained transformer-4 (GPT-4) on the Certification Test for Mental Health Management and whether tuned prompts could improve its performance., Methods: This study used a 3 × 2 factorial design to examine the performance according to test difficulty (courses) and prompt conditions. We prepared 200 multiple-choice questions (600 questions overall) for each course using the Certification Test for Mental Health Management (levels I-III) and essay questions from the level I test for the previous four examinations. Two conditions were used: a simple prompt condition using the questions as prompts and tuned prompt condition using techniques to obtain better answers. GPT-4 (gpt-4-0613) was adopted and implemented using the OpenAI API., Results: The simple prompt condition scores were 74.5, 71.5, and 64.0 for levels III, II, and I, respectively. The tuned and simple prompt condition scores had no significant differences (OR = 1.03, 95% CI; 0.65-1.62, p = 0.908). Incorrect answers were observed in the simple prompt condition because of the inability to make choices, whereas no incorrect answers were observed in the tuned prompt condition. The average score for the essay questions under the simple prompt condition was 22.5 out of 50 points (45.0%)., Conclusion: GPT-4 had a sufficient knowledge network for occupational mental health, surpassing the criteria for levels II and III tests. For the level I test, which required the ability to describe more advanced knowledge accurately, GPT-4 did not meet the criteria. External information may be needed when using GPT-4 at this level. Although the tuned prompts did not significantly improve the performance, they were promising in avoiding unintended outputs and organizing output formats. UMIN trial registration: UMIN-CTR ID = UMIN000053582.

Background: Heated tobacco products (HTPs) have gained global popularity, but their health risks remain unclear. Therefore, the current study aimed to identify plasma metabolites associated with smoking and HTP use in a large Japanese population to improve health risk assessment., Methods: Metabolomics data from 9,922 baseline participants of the Tsuruoka Metabolomics Cohort Study (TMCS) were analyzed to determine the association between smoking habits and plasma metabolites. Moreover, alterations in smoking-related metabolites among HTP users were examined based on data obtained from 3,334 participants involved from April 2018 to June 2019 in a follow-up survey., Results: Our study revealed that cigarette smokers had metabolomics profiles distinct from never smokers, with 22 polar metabolites identified as candidate biomarkers for smoking. These biomarker profiles of HTP users were closer to those of cigarette smokers than those of never smokers. The concentration of glutamate was higher in cigarette smokers, and biomarkers involved in glutamate metabolism were also associated with cigarette smoking and HTP use. Network pathway analysis showed that smoking was associated with the glutamate pathway, which could lead to endothelial dysfunction and atherosclerosis of the vessels., Conclusion: Our study showed that the glutamate pathway is affected by habitual smoking. These changes in the glutamate pathway may partly explain the mechanism by which cigarette smoking causes cardiovascular disease. HTP use was also associated with glutamate metabolism, indicating that HTP use may contribute to the development of cardiovascular disease through mechanisms similar to those in cigarette use.

Purpose: While nirmatrelvir/ritonavir (NMV-r) has been positioned as a first-line treatment for mild to moderate COVID-19, it has multiple and significant drug-drug interactions (DDIs). The use of NMV-r in Japan has been limited compared to the United States. This study aimed to describe the distribution of DDIs with NMV-r and their management in patients with COVID-19 under the control of a management system for the appropriate use of NMV-r., Methods: A retrospective observational study was conducted at a Japanese university hospital. The management system included a flowchart for selecting antivirals and a list for reviewing DDI management, based on the National Institutes of Health guidelines and the guidance of the Japanese Society of Pharmaceutical Health Care and Sciences. Patients with mild to moderate COVID-19 and prescribed NMV-r or molnupiravir (MOV) were included. The primary outcome was DDI management practices, including the selected COVID-19 medications. The secondary outcome included the distribution of DDI classification and the 30-day all-cause mortality., Results: This study included 241 patients (median age of 60 years, 112 [46.5%] females), of whom 126 and 115 received NMV-r and MOV, respectively. Of the 241 patients, 145 (60.2%) received concomitant medications that have DDIs with NMV-r. All 30 patients with severe renal impairment or insufficient details on concomitant medications received MOV. Forty-nine patients with concomitant medications required alternative COVID-19 therapy consideration due to DDIs, of whom 42 (85.7%) patients received MOV. Eighty-one patients had concomitant medications requiring temporary adjustment, of whom 44 (54.3%) patients received NMV-r, and 42 of these patients temporarily adjusted these concomitant medications. Five patients with concomitant medications that can continued by monitoring the effects/adverse effects, of whom 4 (80.0%) patients received NMV-r. Seventy-six patients without concomitant medications requiring DDI management, of whom 71 (93.4%) patients received NMV-r. The 30-day all-cause mortality for eligible patients was 0.9% [95% confidence interval, 0.1-3.1]., Conclusions: Most patients received appropriate antivirals according to the classification of DDIs, and most patients with concomitant medications requiring temporary adjustment received the recommended DDI management. Our management system is effective in promoting the use of NMV-r in the appropriate patients and managing problematic DDIs., (© 2024. The Author(s).)

Background: During the COVID-19 pandemic, health care professionals experienced high levels of depression. However, extant research has not highlighted effective internet-based psychological interventions to improve the mental health in this population during the pandemic. It remains unclear whether self-guided, internet-based cognitive behavioral therapy (iCBT) programs are effective in improving the mental health of health care workers during the COVID-19 pandemic., Objective: The aim of this study was to evaluate the effectiveness of a smartphone-based iCBT stress management program for reducing the depression experienced by nurses in Vietnam and Thailand., Methods: From March to April 2022, a 2-arm, parallel-group randomized controlled trial was implemented. One arm offered a 7-week self-guided iCBT program, and the other offered treatment as usual as a control arm. Full-time nurses were recruited from 6 hospitals: 2 hospitals in Vietnam and 4 hospitals in Thailand. The primary outcome of this program was the severity of depression measured by the Depression Anxiety Stress Scale-21 items. Follow-up surveys were conducted to measure the change in depression severity at 3 months (July-August 2022) and at 6 months (October-November 2022) after baseline. Mixed modeling for repeated measures was used to test the effects of the intervention compared with the control for the follow-up., Results: A total of 1203 nurses were included in this study: 602 in the intervention group and 601 in the control group. The follow-up rate at 3 and 6 months ranged from 85.7% (515/601) to 87.5% (527/602). The completion rate for the program was 68.1% (410/602). The group difference in depression was significant at the 3-month follow-up (coefficient=-0.92, 95% CI -1.66 to -0.18; P=.02) and nonsignificant at the 6-month follow-up (coefficient=-0.33, 95% CI -1.11 to 0.45; P=.41). The estimated effect sizes were -0.15 and -0.06 at the 3- and 6-month follow-ups, respectively., Conclusions: Our study shows that the smartphone-based iCBT program was effective in reducing depression at the 3-month follow-up among hospital nurses in Vietnam and Thailand during the COVID-19 pandemic. However, the effect size was small, and therefore, these results may not be clinically meaningful., Trial Registration: UMIN Clinical Trials Registry UMIN000044145; https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000050128., International Registered Report Identifier (irrid): RR2-10.20944/preprints202303.0450.v1., (©Kazuhiro Watanabe, Thuy Thi Thu Tran, Narisara Sripo, Asuka Sakuraya, Kotaro Imamura, Plernpit Boonyamalik, Natsu Sasaki, Thanate Tienthong, Hiroki Asaoka, Mako Iida, Quynh Thuy Nguyen, Nga Thi Nguyen, Son Thai Vu, Thuy Thi Ngo, Tham Thi Luyen, Long Duc Nguyen, Nga Thi Viet Nguyen, Binh Thanh Nguyen, Yutaka Matsuyama, Yukie Takemura, Daisuke Nishi, Akizumi Tsutsumi, Huong Thanh Nguyen, Orawan Kaewboonchoo, Norito Kawakami. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 30.08.2024.)

Objectives　Although self-reported questionnaires are widely used to collect information on medication use in epidemiological studies, their validity for studies involving older adults has not been sufficiently assessed. This study evaluated the validity of self-reported medication use using questionnaires in comparison with drug notebooks.Methods　The study enrolled 370 older community dwellers who participated in an aging sub-study survey of the Tsuruoka Metabolomics Cohort Study between April 2019 and March 2021. Medication use was assessed by comparing self-reported questionnaire data with drug notebook records. We analyzed medications used for hypertension, dyslipidemia, myocardial infarction, angina, diabetes, rheumatism, osteoporosis/metabolic bone disease, constipation, anxiety/depression, dementia, asthma, allergy, thrombosis, and thyroid disease. Moreover, gastrointestinal (GI) medications, steroids, and antipyretic analgesics were assessed, and data on injectable medications for osteoporosis/metabolic bone disease was collected. Using drug notebook records, we identified regular medication users by assessing whether they had received oral medication prescriptions covering over 28 days and took the medication within the 90 days preceding the day of their survey. To define medication categories, we used Anatomical Therapeutic Chemical (ATC) classification codes. Sensitivity, specificity, and kappa statistics were calculated for each medication using drug notebooks as standards. Those who did not bring their drug notebooks on the day of the survey were defined as non-medication users.Results　The mean age (standard deviation) of the 370 participants (146 men and 224 women) was 73.3 (4.0) years. The sensitivity and specificity for each medication were as follows: hypertension (0.97, 0.97), dyslipidemia (0.93, 0.98), myocardial infarction (0.24, 0.99), diabetes (0.94, 1.00), rheumatism (1.00, 1.00), osteoporosis/metabolic bone disease (0.82, 0.99), constipation (0.71, 0.98), GI conditions (0.63, 0.97), anxiety/depression (0.36, 1.00), dementia (0.67, 1.00), asthma (0.67, 0.98), allergy (0.57, 0.99), thrombosis (0.88, 0.98), steroids (0.80, 0.99), thyroid disease (1.00, 1.00) and antipyretic analgesics (0.75, 0.96).Conclusions　Although sensitivity and specificity differed by medication categories, the results of our population-based cohort study suggested that self-reported questionnaires on medication use among older adults are valid, especially for medications with high sensitivity (≥ 0.8).

The present monograph discusses the possibility of BCS-based biowaivers for immediate release pharmaceutical products containing raltegravir potassium, which is used to treat human immunodeficiency virus (HIV) infections. Raltegravir potassium can be assigned to BCS class II or IV since this compound has low solubility and uncertain permeability. Therefore, according to the ICH M9 guideline, it is not recommended to apply BCS-based biowaiver to approval of immediate release solid dosage forms of raltegravir potassium, either for new generic versions or when moderate to major changes in composition and/or the manufacturing method of the product are made., Competing Interests: Conflict of Interest This article is a part of the project of the Focus Group BCS & Biowaiver. The contents of this monograph are based on the data available in the literature and represent the scientific opinion of the authors but not necessarily the policies of regulatory authorities., (Copyright © 2024 American Pharmacists Association. All rights reserved.)

We investigated the single particle kinetics of the molecular release processes from two types of microcapsules used as drug delivery systems (DDS): biodegradable poly(lactic- co -glycolic) acid (PLGA) and a light-triggered-degradable liposome encapsulating gold nanospheres (liposome-GNP). To optimize the design of DDS capsules, it is highly desirable to develop a method for real-time monitoring of the release process. Using a combination of optical tweezers and confocal fluorescence microspectroscopy we successfully analyzed a single optically trapped PLGA particle and liposome-GNPs in solution. From temporal decay profiles of the fluorescence intensity, we determined the time constant τ of the release processes. We demonstrated that the release rate of spontaneously degradable microcapsules (PLGA) decreased with increasing size, while conversely, the release rate of external stimuli-degradable microcapsules (liposome-GNPs) increased in proportion to their size. This result is explained by the differences in the disruption mechanisms of the capsules, with PLGA undergoing hydrolysis and the GNPs in the liposome-GNP undergoing a photoacoustic effect under nanosecond pulsed laser irradiation. The present approach offers a way forward to an alternative microanalysis system for single drug delivery nanocarriers.

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35-74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study uses an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants, and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability and functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women's health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

Purpose: Hypertension (HT), dyslipidemia (DL), and diabetes mellitus (DM) are major risk factors for cardiovascular diseases. Despite the wide availability of medications to reduce this risk, poor adherence to medications remains an issue. The aim of this study is to evaluate medication adherence of prevalent users in these disease medications (HT, DL, DM) using claims data. Factors associated with non-adherence were also examined., Methods: Of 7538 participants of the Tsuruoka Metabolomics Cohort Study, 3693 (HT: 2702, DL: 2112, DM: 661) were identified as prevalent users of these disease medications. Information on lifestyle was collected through a questionnaire. Adherence was assessed by a proportion of days covered (PDC) and participants with PDC ≥0.8 were defined as adherent. Predictors of non-adherence were determined by performing multivariable logistic regression., Results: Medication adherence differed by treatment status. Among those without comorbidities, those with HT-only showed the highest adherence (90.2%), followed by those with DM-only (81.2%) and those with DL-only (80.8%). Factors associated with non-adherence in each medication group were skipping breakfast and poor understanding of medications among those with HT medications, females, having comorbidities, having a history of heart disease, and drinking habit among those with DL medications, and good sleep quality and skipping breakfast among those with DM medications., Conclusion: While participants showed high medication adherence, differences were observed across medication groups. The identified predictors of non-adherence could help target those in need of adherence support., (© 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Aim: A new treatment interval for nivolumab administration at 480 mg every 4 weeks, in addition to 240 mg every 2 weeks, was approved in Japan in 2020. Using model-based evaluation, it was speculated that the effects or safety of nivolumab do not differ between the two treatment intervals; however, real-world data on nivolumab efficacy, safety, and economic impact are lacking. Accordingly, we aimed to examine the effects of nivolumab treatment intervals (2 weeks vs. 4 weeks) in terms of efficacy, safety, and economic impact in Japanese patients with cancer., Methods: We retrospectively analyzed 126 patients treated with nivolumab. The patients were divided into two groups depending on whether they received nivolumab at 240 mg every 2 weeks (2-week group) or 480 mg every 4 weeks (4-week group)., Results: Efficacy results found no significant difference between the 4- and 2-week groups considering median overall survival (p = 0.70) and median progression-free survival (p = 0.57). The incidence of any grade and ≥  grade 3 immune-related adverse events did not differ between the 4-week and 2-week groups (any grade, p = 0.13; ≥  grade 3, p = 0.36). Excluding drug costs, the 4-week group had significantly lower medical costs than the 2-week group (2-week vs. 4-week: mean, 94,659 JPY [679.0 USD] vs. 58,737 JPY [421.3 USD]; p < 0.05)., Conclusion: Collectively, our findings suggest that nivolumab 480 mg every 4 weeks may be more effective than nivolumab 240 mg every 2 weeks in terms of economic impact., (© 2024 John Wiley & Sons Australia, Ltd.)

Background: Combination therapy can offer greater efficacy on medical treatments. However, the discovery of synergistic drug combinations is challenging. We propose a novel computational method, SyndrumNET, to predict synergistic drug combinations by network propagation with trans-omics analyses., Methods: The prediction is based on the topological relationship, network-based proximity, and transcriptional correlation between diseases and drugs. SyndrumNET was applied to analyzing six diseases including asthma, diabetes, hypertension, colorectal cancer, acute myeloid leukemia (AML), and chronic myeloid leukemia (CML)., Results: Here we show that SyndrumNET outperforms the previous methods in terms of high accuracy. We perform in vitro cell survival assays to validate our prediction for CML. Of the top 17 predicted drug pairs, 14 drug pairs successfully exhibits synergistic anticancer effects. Our mode-of-action analysis also reveals that the drug synergy of the top predicted combination of capsaicin and mitoxantrone is due to the complementary regulation of 12 pathways, including the Rap1 signaling pathway., Conclusions: The proposed method is expected to be useful for discovering synergistic drug combinations for various complex diseases., (© 2024. The Author(s).)

The optimal treatment strategy for neoadjuvant chemotherapy in elderly patients with pancreatic cancer (PC) remains unclear. Hence, this study was aimed at evaluating the safety and feasibility of neoadjuvant-modified FOLFIRINOX (mFOLFIRINOX) in elderly patients with PC. We retrospectively collected data from 62 patients who received neoadjuvant mFOLFIRINOX between May 2015 and October 2023 and comparatively analyzed the clinicopathological data and outcomes between the non-elderly group (age: <75 years) and elderly group (age: >75 years). The non-elderly and elderly groups comprised 39 and 23 patients, respectively. Although elevated levels of aspartate aminotransferase ( p = 0.0173) and alanine aminotransferase ( p = 0.0378) and nausea ( p = 0.0177) were more frequent in the elderly group, the incidence of severe adverse events was similar between the groups. Intergroup differences in resection rate ( p = 0.3381), postoperative severe complication rates ( p = 0.2450), and postoperative hospital stay ( p = 0.3496) were not significant. Furthermore, no significant intergroup differences were found in survival in either the whole or the resection cohorts. The perioperative and postoperative outcomes of elderly patients treated with neoadjuvant mFOLFIRINOX were comparable with those of non-elderly patients. Neoadjuvant mFOLFIRINOX should be considered a feasible option for elderly patients with PC.

Background/aim: Cancer cachexia is associated with poor prognosis in patients with metastatic urothelial carcinoma (mUC). The objective of the study was to assess the cachexia index (CXI), which is a new indicator assessing the status of cancer cachexia, as a prognostic indicator for mUC patients treated with gemcitabine plus cisplatin (GC) chemotherapy., Patients and Methods: The study included 55 patients with mUC who underwent GC chemotherapy between 2008 and 2022 as first-line chemotherapy. The CXI at the start of chemotherapy was determined as follows: CXI=(serum albumin × skeletal muscle mass index)/ (neutrophil count/lymphocyte count). Patients were categorized into two groups based on a median CXI value (CXI-high and CXI low). We used Kaplan-Meier curves and multivariate Cox proportional hazards regression models to assess the association between the CXI and overall survival (OS)., Results: At the start of GC chemotherapy, significant differences were not found in patients' characteristics. The median OS was significantly shorter in the CXI-low group [10.0 months (95% confidence interval (CI)=5.1-12.8)] than in the CXI-high group [22.3 months (95% CI=13.6-NA), p<0.05]. Multivariate analysis revealed that low CXI was a predictor of a poor prognosis [hazard ratio (HR)=2.25, 95% CI=1.12-4.52, p<0.05]., Conclusion: CXI might be useful as a prognostic indicator for patients with mUC undergoing first-line GC chemotherapy., Competing Interests: The Authors wish to declare that they have no conflicts of interest., (Copyright 2024, International Institute of Anticancer Research.)

The eighth workshop of the Worldwide Network for Blood and Marrow Transplantation (WBMT) was held in Islamabad, Pakistan, from September 22 to 23, 2022, aiming to foster hematopoietic stem cell transplant (HSCT) activity in the World Health Organization (WHO) Eastern Mediterranean Region (EMRO). Participating countries, including Pakistan, Oman, Iran, and Saudi Arabia, reported increased HSCT in the last few years, whereas others from the EMRO and beyond, including Qatar, United Arab Emirates, Nepal, and Bangladesh, started HSCT recently and have developed HSCT programs with excellent results. During educational sessions and open dialog, participating teams and international experts from the WBMT shared their experience and discussed minimum essential requirements for establishing and expanding HSCT in emerging countries, indications for HSCT training and dissemination of knowledge, stem cell donor selection and safety, quality assurance in transplant centers, and the value and importance of transplant outcome databases. International support, collaboration, and local engagement, including government participation and WHO assistance, are valuable in increasing HSCT access worldwide., (Copyright © 2024 Hematology/Oncology and Stem Cell Therapy.)

Concurrent direct and indirect inguinal, femoral, and obturator hernias are rare. This case report describes a rare case treated using the laparoscopic approach. A 68-year-old female patient presented with a moving left inguinal lump and pain. Physical examination and abdominal computed tomography scan revealed the coexistence of a left inguinal hernia or Nuck canal hydrocele and a left femoral hernia. The patient underwent laparoscopic transabdominal preperitoneal repair, and all four orifices were covered with one mesh. The patient was discharged on the second postoperative day without any complications. The concurrent presence of four hernias on the same side is rare and has not been previously reported. The laparoscopic approach is useful in such cases because it allows visualization of multiple hernia orifices from the intra-abdominal cavity., (© 2024 Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Aim: To evaluate the effectiveness of an individualized nutritional education program in promoting adequate nutrient intake in pregnant women., Methods: A stratified randomized controlled trial was conducted. Participants were stratified by factors affecting the primary outcome and randomly assigned to the intervention or control groups. Intervention group participants received an individualized 30-min booklet-based education program in their 2nd and 3rd trimesters; the control group received usual care. The primary outcome was protein intake after the intervention, which was compared between the intervention and control groups. Secondary outcomes included comparing the amount of increase of protein before and after the intervention. Nutrient intake was measured using a self-administered short dietary history questionnaire, and analyses of covariance and t tests were performed., Results: Of the 130 participants, 66 were assigned to the intervention group and 64 to the control group. There was no difference in protein intake between the two groups after the intervention (p = .051, 95% CI [-0.021, 12.4]). Comparing the increase in protein intake before and after intervention, the intervention group was 7.4 g/day higher than that of the control group (p = .040; F = 4.31; effect size = 0.36)., Conclusions: The primary outcome, a comparison of protein intake between the groups after the program, revealed no significant differences. However, on comparing the amount of protein increase before and after the intervention, the intervention group's increase was significantly higher than that of the control group. Results indicate the potential for individualized face-to-face interventions for pregnant women in Japan., (© 2024 Japan Academy of Nursing Science.)

Aims: Nonalcoholic fatty liver disease (NAFLD) is known to be associated with atherosclerosis. This study focused on upstream changes in the process by which NAFLD leads to atherosclerosis. The study aimed to confirm the association between NAFLD and the cardio-ankle vascular index (CAVI), an indicator of subclinical atherosclerosis, and explore metabolites involved in both by assessing 94 plasma polar metabolites., Methods: A total of 928 Japanese community-dwellers (306 men and 622 women) were included in this study. The association between NAFLD and CAVI was examined using a multivariable regression model adjusted for confounders. Metabolites commonly associated with NAFLD and CAVI were investigated using linear mixed-effects models in which batch numbers of metabolite measurements were used as a random-effects variable, and false discovery rate-adjusted p-values were calculated. To determine the extent to which these metabolites mediated the association between NAFLD and CAVI, mediation analysis was conducted., Results: NAFLD was positively associated with CAVI (coefficients [95% Confidence intervals (CI)]=0.23 [0.09-0.37]; p=0.001). A total of 10 metabolites were involved in NAFLD and CAVI, namely, branched-chain amino acids (BCAAs; valine, leucine, and isoleucine), aromatic amino acids (AAAs; tyrosine and tryptophan), alanine, proline, glutamic acid, glycerophosphorylcholine, and 4-methyl-2-oxopentanoate. Mediation analysis showed that BCAAs mediated more than 20% of the total effect in the association between NAFLD and CAVI., Conclusions: NAFLD was associated with a marker of atherosclerosis, and several metabolites related to insulin resistance, including BCAAs and AAAs, could be involved in the process by which NAFLD leads to atherosclerosis.

Purpose: To assess the effects of intraocular lens (IOL) decentration and tilt, as well as age, on postoperative visual function (corrected distance visual acuity [CDVA] and contrast sensitivity) by comparing an extended depth-of-focus IOL using higher order aspheric optics against a monofocal IOL from the same platform., Methods: This retrospective observational study targeted patients without other eye diseases who underwent surgery to implant the Tecnis Eyhance OptiBlue or the monofocal IOL Tecnis OptiBlue 1-Piece (J&J Vision) during cataract surgery from November 2021 to December 2022. The effects of age, axial length, IOL decentration, tilt, and corneal higher order aberrations (HOAs) on the postoperative 5 m CDVA and area under log contrast sensitivity function (AULCSF) under photopic and scotopic conditions were evaluated within 3 months of surgery., Results: No significant difference was found in postoperative CDVA between the Tecnis Eyhance OptiBlue group (n = 61 eyes) and the Tecnis OptiBlue 1-Piece group (n = 35 eyes), but AULCSF was significantly better in the Tecnis Eyhance OptiBlue group for photopic (1.58 ± 0.13 vs 1.46 ± 0.18; P = .002) and scotopic (1.71 ± 0.11 vs 1.59 ± 0.19; P = .002) eyes. Multivariate analysis showed a negative correlation between AULCSF and IOL decentration and age in the Tecnis Eyhance OptiBlue group ( P < .01), with no significant correlation with tilt, axial length, and corneal HOAs., Conclusions: The Tecnis Eyhance OptiBlue yielded significantly better contrast sensitivity under photopic and scotopic conditions than the Tecnis OptiBlue 1-Piece. However, it is important to consider the effects of IOL decentration and age when evaluating the contrast sensitivity of the Tecnis Eyhance OptiBlue. [ J Refract Surg . 2024;40(7):e499-e505.] .

Background/aim: We evaluated the usefulness of prophylactic mini-tracheostomy (PMT) and perioperative administration of tazobactam/piperacillin (TAZ/PIPC) in high-risk patients after esophagectomy., Patients and Methods: We retrospectively studied 89 consecutive high-risk patients who underwent esophagectomy for esophageal cancer between January 2013 and December 2021. We defined patients with two or more of the following factors as high risk: age ≥70 years, performance status ≥1, respiratory dysfunction, liver dysfunction, cardiac dysfunction, renal dysfunction, diabetes mellitus, albumin <3.5 g/dl, and Brinkman index >600. Standard management was administered to the first 50 patients (standard group). PMT and TAZ/PIPC were administered to the next 39 patients (combination group). Patient characteristics and short-term outcomes were compared before and after propensity-score matching., Results: Before propensity-score matching, 24-hour urine creatinine clearance, retrosternal route, 3-field lymph node dissection, and open abdominal approach were more common, postoperative pneumonia (13% vs. 36%, p=0.045) and complications of grade ≥3b (2.6% vs. 22%, p=0.01) were less frequent, and the postoperative hospital stay was shorter (median: 23 vs. 28 days, p=0.022) in the combination group than in the standard group. In propensity-score matching, patient characteristics, except for 24-h creatinine clearance and reconstructive route, were matched for 23 paired patients. Postoperative pneumonia (8.7% vs. 39%, p=0.035) and complications of grade ≥3b (0% vs. 26%, p=0.022) were less frequent and postoperative hospital stay was shorter (median: 22 vs. 25 days, p=0.021) in the combination group than in the standard group., Conclusion: PMT with TAZ/PIPC can potentially prevent postoperative pneumonia in high-risk patients after esophagectomy., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Competing Interests: Dr. Hironori Kuga is an Editorial Board member of Psychiatry and Clinical Neurosciences Reports and a co‐author of this article. To minimize bias, he was excluded from all editorial decision‐making related to the acceptance of this article for publication.

The present study aimed to identify preoperative and perioperative risk factors for postoperative infectious complications in older patients with gastric cancer. The present retrospective study included 504 patients with gastric cancer aged >65 years who underwent radical gastrectomy. After determining the cutoff values for various perioperative factors in the receiver operating characteristic curve analysis, preoperative and perioperative risk factors for the development of infectious complications after gastrectomy were examined using logistic regression analysis. Of the 504 patients who underwent gastrectomy, 95 (18.8%) developed infectious complications of grade II-V based on the Clavien-Dindo classification. In an analysis restricted to preoperative factors, male sex, low prognostic nutritional index, high visceral fat area and total gastrectomy were independent risk factors for infectious complications after gastrectomy. Among all perioperative factors, a low prognostic nutritional index and long operative duration were identified as independent risk factors for infectious complications after gastrectomy. The patients were divided into five groups according to the number of positive preoperative risk factors for infectious complications, and the incidence of infectious complications differed among the five groups (0 factors, 6.7%; 1 factor, 10.4%; 2 factors, 18.9%; 3 factors, 27.8%; and 4 factors, 47.6%; P<0.001). Older patients with gastric cancer who have a number of preoperative risk factors require careful consideration of the indication for gastrectomy and a shorter operative time to reduce infectious complications., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Iida et al.)

Extracellular vesicles (EVs) contain a subset of proteins, lipids, and nucleic acids that maintain the characteristics of the parent cell. Immunotherapy using EVs has become a focus of research due to their unique features and bioinspired applications in cancer treatment. Unlike conventional immunotherapy using tumor fragments, EVs can be easily obtained from bodily fluids without invasive actions. We previously fabricated nanowire devices that were specialized for EV collection, but they were not suitable for cell culturing. In this study, we fabricated a ZnO/Al 2 O 3 core-shell nanowire platform that could collect more than 60% of the EVs from the cell supernatant. Additionally, we could continue to culture dendritic cells (DCs) on the platform as an artificial lymph node to investigate cell maturation into antigen-presenting cells. Finally, using this platform, we reproduced a series of on-site immune processes that are among the pivotal immune functions of DCs and include such processes as antigen uptake, antigen presentation, and endocytosis of cancer-derived EVs. This platform provides a new ex vivo tool for EV-DC-mediated immunotherapies.

Semi-natural grasslands on steep slopes often show high plant species diversity. These grasslands were traditionally maintained through mowing and/or grazing. The traditional management practices help to maintain species diversity, whereas land abandonment reduces diversity by increasing competition from dominant species and reducing seedling recruitment. The reintroduction of management can reverse species diversity declines, but suitable grassland restoration programs are scarce in Japan. To study the effect of short-term abandonment on seedling ecology, we monitored the vegetation of a Susogari grassland that had been abandoned for 3 years; the grassland occupies a steep slope (ca. 50°) on a hillside above paddy fields, and was traditionally mown. We monitored the vegetation before abandonment, in the 3rd year of abandonment, and in the 1st and 2nd years after restoration of mowing management. Emergence and survival of seedlings was monitored for 18 months after reintroduction of management. We monitored 1,183 seedlings of grassland species and non-target annuals in ten 1-m 2 plots. After mowing was reintroduced, most grassland species reappeared or increased in the first and second years. Few seedlings of perennial plants and no seedlings of annuals flowered. An exotic species, Solidago altissima , had a lower survival rate (10%) than grassland species (>30%), and all but two grassland species survived over the 18-month period. Although vegetation composition was not fully recovered, our findings suggest that a steep slope acts as a strong filter that inhibits the establishment of non-target species while enhancing persistence of target grassland species., Competing Interests: The authors declare there are no competing interests., (©2024 Yamada et al.)

Hematopoietic cell transplantation (HCT) was developed more than 65 years ago to treat malignant blood disorders and irreversible bone marrow failures, with the aim of replacing a diseased hematopoietic system with a healthy one (allogeneic HCT). Decades later, the procedure was adapted to apply maximal chemotherapy or radiotherapy, which would result in bone marrow failure, but could be remedied by an infusion of a patient's own cryopreserved bone marrow (autologous HCT). Both treatments are high-risk and complex, especially during the initial phases. However, concerted efforts, vision, and collaboration between physicians and centers worldwide have resulted in HCT becoming a standard of care for many hematological disorders with progressive improvements in outcomes. Registries and the collaboration of societies worldwide have enabled the delivery of this curative therapy to many patients with fatal hematological diseases. More than 1.5 million HCT were performed between 1957 and 2019, and activity is continuously increasing worldwide., Competing Interests: Declaration of cometing interest NH reports advisory board honoraria from Janssen, Novartis, Takeda, Abbvie, Roche, Astellas and Bigene. YA reports consulting fees from JCR Pharmaceuticals Co., Ltd. and Kyowa Kirin Co., Ltd., lecture fees from Otsuka Pharmaceutical Co., Ltd, Chugai Pharmaceutical Co., Ltd., Novartis Pharma KK, AbbVie GK, and honorarium from Meiji Seika Pharma Co., Ltd. MI is affiliated with the Department of Promotion for Blood and Marrow Transplantation at the Aichi Medical University School of Medicine, and the department is endowed by AIR WATER INC., Clinigen K.K., and JCR Pharmaceuticals Co., Ltd. CF reports support for attending meetings from Casa Bollar and support for attending meetings and travel from Diaz Gill Lab and Prosalud. LG reports consulting fees from Sanofi, Janssen Pharmaceutical, Bristol Myers Squibb, and GlaxoSmithKline Pharmaceuticals and support for attending meetings and travel from Pfizer and Sanofi. KK reports honoraria from Pierre Fabre, Medac, and Novartis. J Snowden reports consulting fees from Jazz Pharmaceuticals, Medac Pharma, Vertex Pharmaceuticals, and participation in a Data Safety Monitoring Board in Kiadis Pharma. NW reports consulting and speakers fees from BMS Celgene, Kite Gilead, Miltenyi BioTec, Novartis, Piere Fabre and Therakos Mallinckrodt. The other authors report no conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier Ltd.)

The efficacy of convolutional neural network (CNN)-enhanced electrocardiography (ECG) in detecting hypertrophic cardiomyopathy (HCM) and dilated HCM (dHCM) remains uncertain in real-world applications. This retrospective study analyzed data from 19,170 patients (including 140 HCM or dHCM) in the Shinken Database (2010-2017). We evaluated the sensitivity, positive predictive rate (PPR), and F1 score of CNN-enhanced ECG in a ''basic diagnosis'' model (total disease label) and a ''comprehensive diagnosis'' model (including disease subtypes). Using all-lead ECG in the "basic diagnosis" model, we observed a sensitivity of 76%, PPR of 2.9%, and F1 score of 0.056. These metrics improved in cases with a diagnostic probability of ≥ 0.9 and left ventricular hypertrophy (LVH) on ECG: 100% sensitivity, 8.6% PPR, and 0.158 F1 score. The ''comprehensive diagnosis'' model further enhanced these figures to 100%, 13.0%, and 0.230, respectively. Performance was broadly consistent across CNN models using different lead configurations, particularly when including leads viewing the lateral walls. While the precision of CNN models in detecting HCM or dHCM in real-world settings is initially low, it improves by targeting specific patient groups and integrating disease subtype models. The use of ECGs with fewer leads, especially those involving the lateral walls, appears comparably effective., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

Purpose: To explore lens capsule pathological characteristics in intraocular lens (IOL) dislocation after cataract surgery in patients with atopic dermatitis (AD)., Setting: University hospital department of ophthalmology., Design: Case series with clinicopathological correlations., Methods: Lens capsules and surrounding tissues excised during surgery from eyes with AD (AD group) and eyes without AD (non-AD group) with IOL dislocation were histologically evaluated. Hematoxylin and eosin staining was used to assess abnormal changes in lens epithelial cells (LECs). Masson trichrome staining distinguished the fibrous metaplasia around the lens capsule into high-density and low-density fibrosis. Capsular splitting (thinning) was identified in both stained preparations., Results: The IOL dislocation morphology in the AD group (10 eyes of 10 patients) included 7 cases of capsular bag dislocation (CBD) and 3 cases of dead bag syndrome (DBS), with an average duration to IOL dislocation of 11.5 ± 5.6 years. All patients in the non-AD group (12 eyes of 12 patients) had CBD, averaging 10.2 ± 5.7 years to dislocation. Abnormal LECs, low-density fibrosis, and capsular splitting were observed in 9 (90), 9 (90), and 6 (60) of the patients in the AD group compared with 6 (50), 3 (25), and 2 (18), respectively, in the non-AD group (total n [%])., Conclusions: Compared with the non-AD group, the AD group exhibited higher frequencies of morphological changes in LECs, low-density fibrosis around the lens capsule, and capsular splitting characteristics of DBS. These results suggest LEC degeneration and increased lens capsule fragility occurred in patients with AD., (Copyright © 2024 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

Pericardial effusion (PE) presentation varies from an incidental finding to a life-threatening situation; thus, its etiology and clinical course remain unknown. The aim of the present study was to retrospectively investigate these factors.We analyzed 171 patients (0.4%) who presented with PE among 34,873 patients who underwent echocardiography between 2011 and 2021 at our hospital. Clinical and prognostic information was retrieved from electronic medical records. The primary endpoints were all-cause death, hospitalization due to heart failure (HF), and other cardiovascular events such as cardiovascular death, acute coronary syndrome, elective percutaneous coronary intervention, and stroke.The etiologies of PE were as follows: idiopathic (32%), HF-related (18%), iatrogenic (11%), cardiac surgery-related (10%), radiation therapy-related (9%), malignancy (8%), pericarditis/myocarditis (8%), myocardial infarction-related (2%), and acute aortic dissection (2%). Patients with idiopathic/HF etiology were more likely to be older than the others.During a mean follow-up period of 2.5 years, all-cause death occurred in 21 patients (12.3%), cardiovascular events in 10 patients (5.8%), and hospitalization for HF in 24 patients (14.0%). All-cause death was frequently observed in patients with malignancy (44% per person-year). Cardiovascular events were mostly observed in patients with radiation therapy-related and malignancy (8.6% and 7.3% per person-year, respectively).The annual incidence of hospitalization for HF was the highest in patients with HF-related (25.1% per person-year), followed by radiation therapy-related (10.4% per person-year).This retrospective study is the first, to the best of our knowledge, to reveal the contemporary prevalence of PE, its cause, and outcome in patients who visited a cardiovascular hospital in an urban area of Japan.

Glucagon-like peptide-1 (GLP-1) is an incretin released into the gastrointestinal tract after food ingestion, and stimulates insulin secretion from the beta cells of the pancreatic islets. Incretins have recently been reported to have extrapancreatic actions, and they are anticipated to have potential efficacy for conditions such as male infertility as well as diabetes. However, the effects of incretins on male reproductive function remain unclear. In this study, GLP-1 receptor expression and the effects of GLP-1 on spermatogenesis-associated genes were investigated using mouse testes and testis-derived cultured cell lines. Glp1r mRNA and GLP-1 protein were expressed in mouse testes at levels comparable to or greater than those in positive control adipose tissue, and the liver and intestine, and also in a Sertoli cell line (TM4) and a Leydig cell line (MA-10) as well as the GC-1 spg and GC-2 spd (ts) germ cell lines. TM4 cells treated with the GLP-1 receptor agonist exenatide showed transiently and significantly upregulated Kitl, Pdgfa, and Glp1r mRNA expression. Furthermore, at 1 hr post-exenatide administration to male mice, Kitl and Glp1r mRNA expression levels were significantly increased, and Pdgfa mRNA expression level also showed a tendency toward increase. TM4 cells were treated with various cell-activating agents, and bucladesine elicited significantly increased Glp1r mRNA expression. We suggest that GLP-1 provides acute stimulation of Sertoli cells in the mouse testis and has a stimulatory effect on the expression of spermatogenesis-related genes.

Triple-negative breast cancer (TNBC) is characterized by the absence of the estrogen receptor, progesterone receptor, and receptor tyrosine kinase HER2 expression. Due to the limited number of FDA-approved targeted therapies for TNBC, there is an ongoing need to understand the molecular underpinnings of TNBC for the development of novel combinatorial treatment strategies. This study evaluated the role of the MerTK receptor tyrosine kinase on proliferation and invasion/metastatic potential in TNBC. Immunohistochemical analysis demonstrated MerTK expression in 58% of patient-derived TNBC xenografts. The stable overexpression of MerTK in human TNBC cell lines induced an increase in proliferation rates, robust in vivo tumor growth, heightened migration/invasion potential, and enhanced lung metastases. NanoString nCounter analysis of MerTK-overexpressing SUM102 cells (SUM102-MerTK) revealed upregulation of several signaling pathways, which ultimately drive cell cycle progression, reduce apoptosis, and enhance cell survival. Proteomic profiling indicated increased endoglin (ENG) production in SUM102-MerTK clones, suggesting that MerTK creates a conducive environment for increased proliferative and metastatic activity via elevated ENG expression. To determine ENG's role in increasing proliferation and/or metastatic potential, we knocked out ENG in a SUM102-MerTK clone with CRISPR technology. Although this ENG knockout clone exhibited similar in vivo growth to the parental SUM102-MerTK clone, lung metastasis numbers were significantly decreased ~4-fold, indicating that MerTK enhances invasion and metastasis through ENG. Our data suggest that MerTK regulates a unique proliferative signature in TNBC, promoting robust tumor growth and increased metastatic potential through ENG upregulation. Targeting MerTK and ENG simultaneously may provide a novel therapeutic approach for TNBC patients.

Objective: To evaluate the impact of daily fraction doses on late genitourinary (GU) toxicity after salvage radiotherapy (SRT) for prostate cancer., Methods: This multi-institutional retrospective study included 212 patients who underwent SRT between 2008 and 2018. All patients received image-guided intensity-modulated SRT at a median dose of 67.2 Gy in 1.8-2.3 Gy/fraction. The cumulative rates of late grade ≥2 GU and gastrointestinal (GI) toxicities were compared using Gray test, stratified by the ≤2.0 Gy/fraction (n = 137) and ≥2.1 Gy/fraction groups (n = 75), followed by multivariate analyses. The total dose was represented as an equivalent dose in 2-Gy fractions (EQD2) with α/β = 3 Gy., Results: After a median follow-up of 63 months, the cumulative rates of 5-year late grade ≥2 GU and GI toxicities were 14% and 2.5%, respectively. The cumulative rates of 5-year late grade ≥2 GU toxicity in the ≥2.1 Gy/fraction and ≤2.0 Gy/fraction groups were 22% and 10%, respectively (P = .020). In the multivariate analysis, ≥2.1 Gy/fraction was still associated with an increased risk of late grade ≥2 GU toxicity (hazard ratio, 2.37; 95% confidence interval, 1.12-4.99; P = .023), while the total dose was not significant., Conclusion: The present results showed that ≥2.1 Gy/fraction resulted in a higher incidence of late grade ≥2 GU toxicity in SRT., Advances in Knowledge: The impact of fraction doses on late GU toxicity after SRT remains unknown. The results suggest that higher fraction doses may increase the risk of late GU toxicity in SRT., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background/aim: Recent research has increasingly demonstrated an association between proton pump inhibitors (PPIs) and serious adverse events. This study aimed to evaluate the association between PPI and rhabdomyolysis (RM), examining its time-to-onset profiles using the Japanese Adverse Drug Event Report (JADER) database., Patients and Methods: Data spanning from April 2004 to March 2022 were used. The association between PPIs and RM was evaluated using the reporting odds ratio (ROR), adjusted for sex and age. Subsequent analyses were conducted after excluding cases involving concomitant use of statins or fibrates. Furthermore, the onset time of RM and Weibull distribution parameters were calculated to evaluate the expression profile of RM, and the outcomes were examined., Results: RM was associated with the use of esomeprazole, omeprazole, and rabeprazole, even in the absence of concomitant statin or fibrate use. The median time to RM onset varied among PPIs, ranging from 6.5 to 127 d. The Weibull distribution parameters indicated that the hazard types of nearly all orally administered PPIs were classified as early failure or close to random failure. Regarding outcomes, cases of death were reported for all PPIs except vonoprazan., Conclusion: The findings suggest the need for vigilant monitoring of RM during PPI administration, particularly in the early stages, considering the varying onset times., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

We compared survival outcomes of high-dose concomitant boost radiotherapy (HDCBRT) and conventional dose radiotherapy (CRT) for newly diagnosed glioblastoma (GB). Patients treated with intensity-modulated radiation therapy for newly diagnosed GB were included. In HDCBRT, specific targets received 69, 60, and 51 Gy in 30 fractions, while 60 Gy in 30 fractions was administered with a standard radiotherapy method in CRT. Overall survival (OS) and progression-free survival (PFS) were compared using the Log-rank test, followed by multivariate Cox analysis. The inverse probability of treatment weighting (IPTW) method was also applied to each analysis. Among 102 eligible patients, 45 received HDCBRT and 57 received CRT. With a median follow-up of 16 months, the median survival times of OS and PFS were 21 and 9 months, respectively. No significant differences were observed in OS or PFS in the Kaplan-Meier analyses. In the multivariate analysis, HDCBRT correlated with improved OS (hazard ratio, 0.49; 95% confidence interval, 0.27-0.90; P = 0.021), and this result remained consistent after IPTW adjustments (P = 0.028). Conversely, dose suppression due to the proximity of normal tissues and IMRT field correlated with worse OS and PFS (P = 0.008 and 0.049, respectively). A prospective study with a stricter protocol is warranted to validate the efficacy of HDCBRT for GB., (© 2024. The Author(s).)

Background: The potential of utilizing artificial intelligence with electrocardiography (ECG) for initial screening of aortic dissection (AD) is promising. However, achieving a high positive predictive rate (PPR) remains challenging., Methods and Results: This retrospective analysis of a single-center, prospective cohort study (Shinken Database 2010-2017, N = 19,170) used digital 12-lead ECGs from initial patient visits. We assessed a convolutional neural network (CNN) model's performance for AD detection with eight-lead (I, II, and V1-6), single-lead, and double-lead (I, II) ECGs via five-fold cross-validation. The mean age was 63.5 ± 12.5 years for the AD group (n = 147) and 58.1 ± 15.7 years for the non-AD group (n = 19,023). The CNN model achieved an area under the curve (AUC) of 0.936 (standard deviation [SD]: 0.023) for AD detection with eight-lead ECGs. In the entire cohort, the PPR was 7 %, with 126 out of 147 AD cases correctly diagnosed (sensitivity 86 %). When applied to patients with D-dimer levels ≥1 μg/dL and a history of hypertension, the PPR increased to 35 %, with 113 AD cases correctly identified (sensitivity 86 %). The single V1 lead displayed the highest diagnostic performance (AUC: 0.933, SD: 0.03), with PPR improvement from 8 % to 38 % within the same population., Conclusions: Our CNN model using ECG data for AD detection achieved an over 30% PPR when applied to patients with elevated D-dimer levels and hypertension history while maintaining sensitivity. A similar level of performance was observed with a single-lead V1 ECG in the CNN model., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Suzuki has received lecture fees from Daiichi Sankyo and Bristol-Myers Squibb. Dr. Yamashita has received research funding and/or lecture fees from Daiichi Sankyo, Bayer Yakuhin, Bristol-Myers Squibb, Pfizer, Nippon Boehringer Ingelheim, Ono Pharmaceutical, and Toa Eiyo. J Motogi, T Umemoto, W Matsuzawa, T Takayanagi, A Hyodo, and K Satoh are employee at Nihon Kohden Corporation., (© 2024 The Authors.)

Aim: The Mental Health Supporter Training Program is a national project conducted in Japan. This study aimed to determine the effects on mental health-related stigma, mental health literacy, and knowledge about mental health difficulties and support techniques among program participants., Methods: The target population was local residents of a wide range of generations in Japan. Outcomes were assessed at baseline (T1), immediately postintervention (T2), and at the 6-month follow-up (T3). A mixed model for repeated-measures conditional growth model analyses were employed to examine the effects of the intervention over time (T1, T2, T3). We also calculated effect sizes using Cohen's d ., Results: The program had a significantly favorable pooled effect on the Japanese version of the Reported and Intended Behaviour Scale score after adjusting for covariates (reported behavior [ t  = 3.20, p  = 0.001]; intended behavior [ t  = 8.04, p  < 0.001]). However, when compared at each time point, only intended behavior from T1 to T2 showed a significant difference ( t  = 8.37, p  < 0.001). Significant pooled effects were found for mental health literacy (knowledge: t  = 19.85, p  < 0.001; attitude: t  = 15.02, p  < 0.001), knowledge of mental health ( t  = 28.04, p  < 0.001), and psychological distress ( t  = -2.41, p  = 0.016)., Conclusion: The results suggest that the program might be effective for improving intended, but not reported, behavior in the short term and for improving mental health literacy, knowledge of mental health, and psychological distress., Competing Interests: Dr Hironori Kuga is an Editorial Board member of Psychiatry and Clinical Neurosciences Reports and a co‐author of this article. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication., (© 2024 The Authors. Psychiatry and Clinical Neurosciences Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Purpose: Removing transparent vitreous tissues, such as a residual vitreous cortex (VC) or proliferative membrane, without damaging the retina is often problematic in vitrectomy. We examined the feasibility of an injectable in situ cross-linking hyaluronan hydrogel (XL-HA) for vitrectomy., Study Design: Experiments using ex vivo and in vivo animal models., Methods: HA-dibenzocyclooctyne and HA-azidoethylamine solutions were mixed to form XL-HA, which then gradually formed a hydrogel. We tested the function of XL-HA in ex vivo porcine eyes. We then examined the performance of XL-HA in in vivo rabbit models of posterior vitreous detachment, posterior VC removal, and proliferative vitreoretinopathy., Results: The ex vivo study showed that XL-HA rapidly embedded triamcinolone acetonide, mimicking VC attached to the retina, and became hard enough to be pinched with tweezers within 3 minutes, allowing us to remove only the triamcinolone acetonide without impairing the internal limiting membrane. In the in vivo rabbit models, XL-HA injection improved posterior vitreous detachment, and the thin and fragile posterior VC or fibrous proliferative membrane was readily peeled off without any damage to the underlying retina as compared with untreated controls. A short-term intraocular biocompatibility test demonstrated that the intraocular pressure remained normal with XL-HA injected into the eye. In addition, transmission electron microscopy showed no obvious abnormalities in the cornea or in the inner and outer retina., Conclusion: The results indicate that XL-HA is a potential adjunctive device to help make vitrectomy safe, effective, and successful., (© 2024. Japanese Ophthalmological Society.)