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Background and Objective: Pooled analyses of previous randomized controlled trials reported that antifibrotics improved survival in patients with idiopathic pulmonary fibrosis (IPF), but the results were only based on short-term outcome data from selected patients who met strict criteria. Observational studies/meta-analyses also suggested that antifibrotics improve survival, but these studies failed to control for immortal time bias that considerably exaggerates drug effects. Therefore, whether antifibrotics truly improve long-term survival in patients with IPF in the real world remains undetermined and requires external validity., Methods: We used data from the Japanese National Claims Database to estimate the intention-to-treat effect of antifibrotics on mortality. To address immortal time bias, we employed models treating antifibrotic initiation as a time-dependent covariate and target trial emulation (TTE), both incorporating new-user designs for antifibrotics and treating lung transplantation as a competing event., Results: Of 30,154 patients with IPF, 14,525 received antifibrotics. Multivariate Fine-Gray models with antifibrotic initiation as a time-dependent covariate revealed that compared with no treatment, nintedanib (adjusted hazard ratio [aHR], 0.85; 95% confidence interval [CI], 0.81-0.89) and pirfenidone (aHR, 0.89; 95% CI, 0.86-0.93) were associated with reduced mortality. The TTE model also replicated the associations of nintedanib (aHR, 0.69; 95% CI, 0.65-0.74) and pirfenidone (aHR, 0.81; 95% CI, 0.78-0.85) with reduced mortality. Subgroup analyses confirmed this association regardless of age, sex, and comorbidities, excluding certain subpopulations., Conclusions: The results of this large-scale real-world analysis support the generalizability of the association between antifibrotics and improved survival in various IPF populations., (© 2024. The Author(s).)

Introduction: The higher scaffold thrombosis rates observed with the first-generation bioresorbable scaffolds (BRSs) compared to conventional drug-eluting stents were likely due in part to bioresorbable polymers having insufficient radial strength, necessitating larger strut profiles. Meta-analysis of the long-term outcomes from the first-generation Absorb bioresorbable vascular scaffold (BVS) showed that this period of excess risk ended at 3 years. Therefore, current attention has been focused on improving early outcomes by increasing the scaffold's tensile strength and reducing strut thickness., Areas Covered: This review summaries the lessons learned from the first-generation BRS. It updates the long-term clinical outcomes of trials evaluating the ABSORB BVS and metallic alloy-based BRS. In addition, it reviews the next-generation BRSs manufactured in Asia., Expert Opinion: Critical areas to improve the performance and safety of biodegradable scaffolds include further development in material science, surface modification, delivery systems, and long-term follow-up studies.

Background: Coronary artery lumen volume (V) to myocardial mass (M) ratio (V/M) can show the mismatch between epicardial coronary arteries and the underlying myocardium., Methods: The V, M and V/M were obtained from the coronary computed tomography angiography (CCTA) of patients in the FAST-TRACK CABG study, the first-in-human trial of coronary artery bypass grafting (CABG) guided solely by CCTA and fractional flow reserve derived from CCTA (FFR CT ) in patients with complex coronary artery disease (CAD). The correlations between V/M ratios and baseline characteristics were determined and compared with those from the ADVANCE registry, an unselected cohort of historical controls with chronic CAD., Results: The V/M ratio was obtained in 106 of the 114 pre-CABG CCTAs. Mean age was 65.6 years and 87% of them were male. The anatomical SYNTAX score from CCTA was significantly higher than the functional SYNTAX score derived using FFR CT [43.1 (15.2) vs 41.1 (16.5), p ​< ​0.001]. Mean V, M, and V/M were 2204 ​mm 3 , 137 ​g, and 16.5 ​mm 3 /g, respectively. There were weak negative correlations between V and anatomical and functional SYNTAX scores (Pearson's r ​= ​-0.26 and -0.34). V and V/M had a strong correlation (r ​= ​0.82). The V/M ratio in the current study was significantly lower than that in the ADVANCE registry (median 16.1 vs. 24.8 [1st quartile 20.1])., Conclusion: Systematically smaller V/M ratios were found in this population with severe CAD requiring CABG compared to an unselected cohort with chronic CAD. The V/M ratio could provide additional non-invasive assessment of CAD especially when combined with FFR CT ., Competing Interests: Declaration of competing interest Dr Serruys has received consultancy fees from Philips/Volcano, SMT, Novartis, Xeltis, Merillife. Dr Garg receives consulting fee from Biosensors. Dr Puskas reports consulting fees from Medtronic, Atricure, Medistim, Edwards Life Science, and royalty payments from Scanlan. Dr Gupta reports an institutional grant from Siemens Health Solutions. Dr Garg reported consulting fees from Biosensors. Dr Taylor and Dr Rogers are employees of HeatFlow Inc. including salary and equity. Dr Thomsen is an employee of GE HealthCare. Dr Pontone reports grants and consultant fees from GE HealthCare, Bracco, and HeartFlow, Payment honoraria from GE HealthCare and HeartFlow, and payment for expert testimony from GE HealthCare. All other authors have no conflict of interest to declare. All other authors have no conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The ability of NaCl-type binary transition metal nitrides (incorporating La, Ce, Y, Zr or Hf) to act as catalytic supports facilitating ammonia decomposition was examined. The effect of nitrogen vacancies formed on nitrides can be understood in terms of the ionic radii of the metal cations. A clear correlation between the N 2 desorption temperature and catalytic activity was found.

The aim of this study was to evaluate the preventive role and underlying mechanisms of fucoxanthin (Fx) on lipopolysaccharide (LPS)-induced intestinal barrier injury in mice. Our results demonstrated that the oral administration of Fx (50 and 200 mg per kg body weight per day) for consecutive 7 days significantly alleviated the severity of LPS-induced intestinal barrier injury in mice, as evidenced by attenuating body weight loss, improving intestinal permeability, and ameliorating intestinal morphological damage such as reduction in the ratio of the villus length to the crypt depth ( V / C ), intestinal epithelium distortion, goblet cell depletion, and low mucin 2 (MUC2) expression. Fx also significantly mitigated LPS-induced excessive apoptosis of intestinal epithelial cells (IECs) and curbed the decrease of tight junction proteins including claudin-1, occludin, and zonula occludens-1 in the ileum and colon. Additionally, Fx effectively alleviated LPS-induced extensive infiltration of macrophages and neutrophils into the intestinal mucosa, the overproduction of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin 1beta (IL-1β) and IL-6, and gasdermin D (GSDMD)-mediated pyroptosis of IECs. The underlying mechanisms might be associated with inhibiting the activation of nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases (MAPKs) and nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling pathways. Moreover, Fx also notably restrained intestinal reactive oxygen species (ROS), malondialdehyde and protein carbonylation levels in LPS-treated mice, and it might be mediated by activating the nuclear factor-erythroid 2 related factor 2 (Nrf2) signaling pathway. Overall, these findings indicated that Fx might be developed as a potential effective dietary supplement to prevent intestinal barrier injury.

Although the frequency of community-acquired infections caused by Klebsiella pneumoniae subsp. ozaenae (K. ozaenae) is low, they are often detected in sputum specimens. In addition, lung abscesses, necrotizing pneumonia, and urinary tract infections caused by K. ozaenae have also been reported. We herein report the first detection of K. ozaenae as an etiological agent of bacterial meningitis in Japan. Cases of K. ozaenae meningitis complicated by diabetes mellitus and sinusitis have been reported elsewhere. When Klebsiella pneumoniae is detected in such cases, it is important to use other detection methods in addition to mass spectrometry for correct identification.

Objectives: This study aimed to elucidate the status of business continuity plan (BCP) formulation in businesses, focusing on different industries. It examined their preparation for natural disasters, such as earthquakes and tsunamis, and crisis events, such as emerging infectious diseases., Methods: A total of 1,583 businesses in Wakayama Prefecture, Japan, were randomly selected from the Wakayama Occupational Health Support Center workplace list. Anonymous self-administered questionnaires were distributed by mail. The questionnaire comprised questions on the business, awareness and formulation status of BCP, and business continuity capabilities in preparation for natural disasters and crisis events. It also explored reasons for the lack of progress in BCP formulation. Businesses were categorized into three groups based on the type of industry: manufacturing (114 companies), lifeline (66 companies), and others (207 companies)., Results: Questionnaires were collected from 412 businesses, and 387 of those that responded to the type of industry were analyzed (valid response rate: 24.3%). More than 50% of businesses in all industries were aware of BCP. Regarding the status of BCP formulation, 39.5% of the manufacturing, 34.8% of the lifeline, and 41.5% of others had already formulated or were formulating a BCP. Many lifeline businesses had not taken any measures to prepare facilities and allocate funds for emergencies. Additionally, 49% were at high risk of being forced to close down due to disasters. As the background to the lack of progress in formulating a BCP, 60.9% of lifeline businesses did not know what to develop or how to consider it. In addition, 44.2% of others had to secure the time and human resources necessary for formulation., Conclusions: Although awareness of BCPs is increasing, their formulation has not progressed significantly. In particular, BCP formulation has been delayed in lifeline industries, resulting in low business continuity capabilities. Given that many businesses do not know the contents or methods of formulating BCPs, it is suggested that educating relevant parties about using templates is necessary. This approach can reduce the time required for formulation and enable the creation of a BCP even without detailed human resources.

Annotating genomic sequence alterations is sometimes a difficult decision, particularly in missense variants with uncertain pathogenic significance and also in those presumed as germline pathogenic variants. We here suggest that mutation spectrum may also be useful for judging them. From the public databases, 982 BRCA1/1861 BRCA2 germline missense variants and 294 BRCA1/420 BRCA2 somatic missense variants were obtained. We then compared their mutation spectra, i.e., the frequencies of two transition- and four transversion-type mutations, in each category. Intriguingly, in BRCA1 variants, A:T to C:G transversion, which was relatively frequent in the germline, was extremely rare in somatic, particularly breast cancer, cells (p = .03). Conversely, A:T to T:A transversion was most infrequent in the germline, but not rare in somatic cells. Thus, BRCA1 variants with A:T to T:A transversion may be suspected as somatic, and those with A:T to C:G as being in the germline. These tendencies of mutation spectrum may also suggest the biological and chemical origins of the base alterations. On the other hand, unfortunately, variants of uncertain significance (VUS) were not distinguishable by mutation spectrum. Our findings warrant further and more detailed studies., (© 2024 The Author(s). Environmental and Molecular Mutagenesis published by Wiley Periodicals LLC on behalf of Environmental Mutagenesis and Genomics Society.)

Retroperitoneal leiomyosarcoma (RPLMS) is rare and usually presents as a large abdominal mass with poor clinical symptoms. Radiological findings of an RPLMS arising in the pelvis of a woman resemble those of adnexal tumors. Herein, we present a case of RPLMS mimicking an adnexal tumor which was differentiated from having an ovarian origin as the right ovarian vein was passing through the tumor but there was no direct vascular connection with the tumor. Therefore, it is important to identify the ovarian vein to distinguish between these tumors., (© 2024 The Authors.)

Introduction: ACE cleaves angiotensin I (Ang I) to angiotensin II (Ang II) inducing vasoconstriction via Ang II type 1 (AT1) receptor, while ACE2 cleaves Ang II to Ang (1-7) causing vasodilatation by acting on the Mas receptor. In diabetic kidney disease (DKD), it is still unclear whether plasma or urine ACE2 levels predict renal outcomes or not., Research Design and Methods: Among 777 participants with diabetes enrolled in the Urinary biomarker for Continuous And Rapid progression of diabetic nEphropathy study, the 296 patients followed up for 9 years were investigated. Plasma and urinary ACE2 levels were measured by the ELISA. The primary end point was a composite of a decrease of estimated glomerular filtration rate (eGFR) by at least 30% from baseline or initiation of hemodialysis or peritoneal dialysis. The secondary end points were a 30% increase or a 30% decrease in albumin-to-creatinine ratio from baseline to 1 year., Results: The cumulative incidence of the renal composite outcome was significantly higher in group 1 with lowest tertile of plasma ACE2 (p=0.040). Group 2 with middle and highest tertile was associated with better renal outcomes in the crude Cox regression model adjusted by age and sex (HR 0.56, 95% CI 0.31 to 0.99, p=0.047). Plasma ACE2 levels demonstrated a significant association with 30% decrease in ACR (OR 1.46, 95% CI 1.044 to 2.035, p=0.027) after adjusting for age, sex, systolic blood pressure, hemoglobin A1c, and eGFR., Conclusions: Higher baseline plasma ACE2 levels in DKD were protective for development and progression of albuminuria and associated with fewer renal end points, suggesting plasma ACE2 may be used as a prognosis marker of DKD., Trial Registration Number: UMIN000011525., Competing Interests: Competing interests: JW receives speaker honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Kyowa Kirin, Novo Nordisk, and Mitsubishi Tanabe, and receives grant support from Bayer, Chugai, Kyowa Kirin, Otsuka, Shionogi, Sumitomo, and Mitsubishi Tanabe., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Microvascular resistance reserve (MRR) can characterize coronary microvascular dysfunction (CMD); however, its prognostic impact in ST-segment elevation myocardial infarction (STEMI) patients remains undefined., Objectives: This study sought to investigate the prevalence of CMD in STEMI patients and to elucidate the prognostic performance of MRR., Methods: This prospective cohort study enrolled 210 STEMI patients with multivessel disease who underwent successful revascularization and returned at 3 months for coronary physiology assessments with bolus thermodilution. The prevalence of CMD (MRR <3) and the association between MRR and major adverse cardiovascular and cerebrovascular events (MACCEs) at 12 months were investigated., Results: The median age of patients was 65 years, and 59.5% were men. At the 3-month follow-up, 56 patients (27%) had CMD (MRR <3.0). The number of MACCEs at 12 months was higher in patients with vs without CMD (48.2% vs 11.0%; P < 0.001). MRR was independently associated with 12-month MACCEs (HR: 0.45 per unit increase; 95% CI: 0.31-0.67; P < 0.001) and with stroke, heart failure, and poorer recovery in left ventricular systolic function. The areas under the receiver-operating characteristic curves for predicting MACCEs at 12 months with fractional flow reserve, coronary flow reserve (CFR), the index of microvascular resistance (IMR), and MRR were 0.609, 0.762, 0.781, and 0.743, respectively. The prognostic performance of CFR, IMR, and MRR were all comparable., Conclusions: The novel parameter MRR is a prognostic marker of MACCEs in STEMI patients with a comparable performance to CFR and IMR. (Impact of TMAO Serum Levels on Hyperemic IMR in STEMI Patients [TAMIR]; NCT05406297)., Competing Interests: Funding Support and Author Disclosures The study was sponsored by the Lithuanian University of Health Sciences. Dr Aldujeli recently held shares in Pfizer Inc. Dr Unikas is the President of the National Interventional Cardiology Association of Lithuania. Dr Tobe has received research grants from the Fukuda Foundation for Medical Technology. Dr Miyashita has received research grants from OrbusNeich Medical K.K. outside the submitted work. Dr Sharif has received grants from SFI Infrastructure 17/RI/5353. Dr Garg has received consulting fees from Biosensors outside the submitted work. Dr Serruys has received consulting fees from SMT, Novartis, Xeltis, Merillife, and Philips outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: There are different definitions of periprocedural myocardial infarction (PPMI) both in terms of thresholds for cardiac biomarkers and the ancillary criteria for myocardial ischemia. Cardiac Troponin I (cTnI) and cardiac Troponin T (cTnT) are used interchangeably to diagnose PPMI., Objectives: This study evaluated the frequency of periprocedural myocardial injury and infarction as defined by the Society of Cardiovascular Angiography & Interventions (SCAI), the Academic Research Consortium-2 (ARC-2), and the 4th Universal definition of MI (4UDMI) stratified using cTnT versus cTnI, among patients with chronic coronary syndrome (CCS) and unstable angina., Results: Among 830 patients, PPMI rates according to the SCAI, ARC2 and 4UDMI criteria were 4.34 %, 2.05 %, and 4.94 % respectively, with higher rates seen for all definitions when using cTnI versus cTnT (SCAI: 9.84 % vs. 1.91 %, p < 0.001; ARC 2: 3.15 % vs. 1.56 %, p = 0.136; and 4UDMI 5.91 % vs. 4.51 %, p = 0.391). Minor and major periprocedural myocardial injury was respectively observed in 58.31 % and 27.10 % of patients, with rates of both significantly higher when using cTnI versus cTnT (Minor: 69.29 % vs. 53.47 %, p < 0.001, Major: 49.21 % vs. 17.36 %, p < 0.001)., Conclusions: Among patients with CCS and unstable angina, PPMIs defined by SCAI occurred more frequently when using cTnI as opposed to cTnT, whereas the type of troponin had no impact on the incidence of PPMIs according to the ARC-2 and 4UDMI., Competing Interests: Declaration of competing interest Dr. Ninomiya reports a grant from Abbott Medical Japan outside the submitted work. Dr. Kotoku has received a grant for studying overseas from Fukuda Foundation for Medical Technology. Dr. Serruys reports institutional grants from Sinomedical Sciences Technology, SMT (Sahajanand Medical technologies), Meril Life sciences, Philips/Volcano, Xeltis, and HeartFlow, outside the submitted work. Dr. Onuma reports institutional grants from Sinomedical Sciences Technology, SMT (Sahajanand Medical technologies), Meril Life sciences, Philips/Volcano, Xeltis, and HeartFlow, outside the submitted work. Dr. Sabate is a consultant for Abbott vascular and iVascular outside the submitted work. Dr. Mollmann is a consultant for Abbott vascular, Boston Scientific, Medtronic and SMT outside the submitted work., (Copyright © 2024. Published by Elsevier Inc.)

Acoustic methods are often used for fisheries resource surveys to investigate fish stocks in a wide area. Commercial fisheries echo sounders, which are installed on most small fishing vessels, are used to record a large amount of data during fishing trips. Therefore, it can be used to collect the basic information necessary for stock assessment for a wide area and frequently. To carry out the quantification for the fisheries echo sounder, we devised a simple method using the backscattering strength of the seabed to perform calibration periodically and easily. In this study, seabed secondary reflections were used instead of primary reflection because the fisheries echo sounders were not equipped with a time-varied gain (TVG) function, and the primary backscattering strength of the seabed was saturated. It was also necessary to use standard values of seabed backscattering strength averaged over a certain area for calibration to eliminate some of the effects of differences in seabed sediment and vessel motions. By using standard values of the seabed secondary reflections, the fisheries echo sounder was calibrated accurately. Our study can provide a reliable framework to calibrate commercial fisheries echo sounders, to improve the estimation and management of fishery resources., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Zhu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Backgrounds: The impact of quantitative assessment to differentiate total occlusions (TOs) from severe stenoses on coronary computed tomography angiography (CCTA) remains unknown., Objective: This study investigated whether quantitative characteristics assessed on CCTA could help differentiate a TO from a severe stenosis on invasive coronary angiography (ICA)., Methods: This study is a sub-analysis of the FASTTRACK CABG (NCT04142021) in which both CCTA and ICA were routinely performed. Quantitative analysis was performed with semi-automated CCTA plaque-analysis software. Blinded analysts compared TOs on CCTA, defined as a complete lack of contrast opacification within the coronary occlusion, with corresponding ICA., Results: Eighty-four TOs were seen on CCTA in 59 of the 114 patients enrolled in the trial. The concordance in diagnosing a TO between ICA and CCTA was 56.0% (n ​= ​47). Compared to severe stenoses, TOs had a significantly longer lesion length (25.1 ​± ​23.0 ​mm vs 9.4 ​± ​11.2 ​mm, P ​< ​0.001). The best cut-off value to differentiate a TO from severe stenosis was a lesion length of 5.5 ​mm (area under the curve 0.77, 95% CI: 0.66-0.87), with a 91.1% sensitivity and 61.1% specificity. Dense calcium percentage atheroma volume (PAV) was significantly higher in TOs compared to severe stenoses (18.7 ​± ​19.6% vs. 6.6 ​± ​13.0%, P ​< ​0.001), whilst the opposite was seen for fibro-fatty PAV (31.3 ​± ​14.2% vs. 19.5 ​± ​10.5%, P ​< ​0.001). On a multivariable logistic regression analysis, lesion length (>5.5 ​mm) was the only parameter associated with differentiating a TO from a severe stenosis., Conclusion: In quantitative CCTA analysis, a lesion length >5.5 ​mm was the only independent predictor differentiating a TO from a severe stenosis., Nct Registration Number: NCT04142021., Competing Interests: Declaration of competing interest Dr. Masuda received a grant from TERUMO corporation outside the submitted work. Dr. Miyashita received research grants from OrbusNeich Medical K.K., outside the submitted work. Dr. Tobe received a grant from the Fukuda foundation for medical technology. Dr. Scot received consultancy fees from Biosensors. Dr. P.W.S. reported consulting fees from SMT, Novartis, Meril Life, Philips, and Xeltis. All other authors have nothing to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Immune checkpoint inhibitor (ICI)-related type 1 diabetes is an immune-related adverse event (irAE), occurring in slightly less than 1% of patients undergoing ICI therapy. Most cases develop during ICI treatment, with occurrences long after discontinuation being extremely rare. A 76-year-old woman, with no history of glucose tolerance issues, was diagnosed with lung adenocarcinoma with pleural invasion and underwent chemotherapy, including atezolizumab, an anti-programmed death-ligand 1 antibody. This treatment was discontinued due to disease progression, although she continued with other chemotherapy regimens. Approximately 5.5 months (166 days) after her last atezolizumab dose, she developed diabetic ketoacidosis, fulfilling the diagnostic criteria for fulminant type 1 diabetes. Anti-glutamic acid decarboxylase antibodies were positive. The patient carried susceptibility human leukocyte antigen (HLA) haplotypes, which are associated with type 1 diabetes. To date, including our patient, only nine cases of ICI-related type 1 diabetes developed after ICI discontinuation have been precisely reported. Eight cases originated from East Asia, with six exhibiting fulminant type 1 diabetes, and seven tested negative for islet-related autoantibodies. The reported cases were independent of ICI types, cycle number, or HLA haplotypes. Median time from the last ICI administration to diabetes onset was 4 months (range: 2-7 months). Although reports of cases occurring after ICI discontinuation are currently limited, their frequency may increase with the wider use of ICIs and improved survival rates of patients post-treatment. Therefore, it is crucial to remain vigilant for the development of ICI-related type 1 diabetes, not only during ICI administration, but also long after discontinuation., Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-024-00719-4., Competing Interests: Conflict of interestThe authors declare that they have no conflicts of interest., (© The Japan Diabetes Society 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

To support in vivo and in vitro studies of intravascular triglyceride metabolism in mice, we created rat monoclonal antibodies (mAbs) against mouse LPL. Two mAbs, mAbs 23A1 and 31A5, were used to develop a sandwich ELISA for mouse LPL. The detection of mouse LPL by the ELISA was linear in concentrations ranging from 0.31 ng/ml to 20 ng/ml. The sensitivity of the ELISA made it possible to quantify LPL in serum and in both pre-heparin and post-heparin plasma samples (including in grossly lipemic samples). LPL mass and activity levels in the post-heparin plasma were lower in Gpihbp1 -/- mice than in wild-type mice. In both groups of mice, LPL mass and activity levels were positively correlated. Our mAb-based sandwich ELISA for mouse LPL will be useful for any investigator who uses mouse models to study LPL-mediated intravascular lipolysis., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The plasma membrane is enriched for receptors and signaling proteins that are accessible from the extracellular space for pharmacological intervention. Here we conducted a series of CRISPR screens using human cell surface proteome and integrin family libraries in multiple cancer models. Our results identified ITGAV (integrin αV) and its heterodimer partner ITGB5 (integrin β5) as the essential integrin α/β pair for cancer cell expansion. High-density CRISPR gene tiling further pinpointed the integral pocket within the β-propeller domain of ITGAV for integrin αVβ5 dimerization. Combined with in silico compound docking, we developed a CRISPR-Tiling-Instructed Computer-Aided (CRISPR-TICA) pipeline for drug discovery and identified Cpd&#95;AV2 as a lead inhibitor targeting the β-propeller central pocket of ITGAV. Cpd&#95;AV2 treatment led to rapid uncoupling of integrin αVβ5 and cellular apoptosis, providing a unique class of therapeutic action that eliminates the integrin signaling via heterodimer dissociation. We also foresee the CRISPR-TICA approach to be an accessible method for future drug discovery studies., (© 2024. The Author(s).)

The spot urinary sodium-to-potassium (Na/K) ratio is a simple measure of salt loading and has been shown to be associated with elevated blood pressure (BP) in middle-aged and older adults. This study aimed to evaluate the association between the spot urinary Na/K ratio and BP in 457 healthy adolescents aged 12-15 years in a school-based setting. The mean urinary Na/K ratio was 4.99 ± 2.76, and no significant difference was found between the boys and girls. When the participants were stratified based on urinary Na/K ratio quartile, age- and sex-adjusted systolic and diastolic BP gradually increased as Na/K ratio increased (systolic BP: 106.1, 106.9, 108.2, and 111.5 mmHg, P trend  < 0.001; diastolic BP: 62.0, 62.4, 63.1, 64.3 mmHg, P trend  = 0.022). The systolic and diastolic BP were more closely associated with urinary Na/K ratio than with Na and K levels, as well as estimated daily salt intake. In the multiple regression analysis, the urinary Na/K ratio was significantly associated with systolic BP (β = 0.144, P < 0.001) and diastolic BP (β = 0.114, P = 0.015) independent of potential confounding factors. An additional subgroup analysis revealed that the BP of the group with both high salt intake (≥8.5 g/day) and high Na/K ratio (≥6.60) was significantly higher than that of the group with high salt intake alone (systolic BP, 115.0 vs. 109.1 mmHg, P < 0.001; diastolic BP, 66.0 vs. 62.5 mmHg, P = 0.017). These results suggest that the urinary Na/K ratio is associated with BP levels in healthy adolescents and may be useful for assessing salt loading and its effects on BP elevation., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

The purpose of this study was to evaluate the preventive role and underlying mechanisms of fucoxanthin (Fx) on dextran sulfate sodium (DSS)-induced colitis in mice. The present data demonstrated that oral administration of Fx (50 and 200 mg/kg body weight/day) for 36 days significantly alleviated the severity of colitis in DSS-treated mice, as evidenced by attenuating body weight loss, bloody stool, diarrhea, shortened colon length, colonic epithelium distortion, a thin mucus layer, goblet cell depletion, damaged crypts, and extensive infiltration of inflammatory cells in the colonic mucosa. Additionally, Fx notably relieved DSS-induced intestinal epithelial barrier dysfunction via maintaining the tight junction function and preventing excessive apoptosis of colonic epithelial cells. Moreover, Fx effectively diminished colonic inflammation and oxidative stress in DSS-treated mice, and its mechanisms might be due to blunting the activation of NF-κB and NLRP3 inflammasome signaling pathways. Furthermore, Fx also modulates DSS-induced gut microbiota dysbiosis via recovering the richness and diversity of gut microbiota and reshaping the structure of gut microbiota, such as increasing the Firmicutes and Bacteroidota (F/B) ratio and elevating the relative abundance of some potential beneficial bacteria, including Lactobacillaceae and Lachnospiraceae . Overall, Fx might be developed as a promising functional ingredient to prevent colitis and maintain intestinal homeostasis.

Background: COVID-19 patients with preexisting interstitial lung disease (ILD) were reported to have a high mortality rate; however, this was based on data from the early stages of the pandemic. It is uncertain how their mortality rates have changed with the emergence of new variants of concern as well as the development of COVID-19 vaccines and treatments. It is also unclear whether having ILD still poses a risk factor for mortality. As COVID-19 continues to be a major concern, further research on COVID-19 patients with preexisting ILD is necessary., Methods: We extracted data on COVID-19 patients between January 2020-August 2021 from a Japanese nationwide insurance claims database and divided them into those with and without preexisting ILD. We investigated all-cause mortality of COVID-19 patients with preexisting ILD in wild-type-, alpha-, and delta-predominant waves, to determine whether preexisting ILD was associated with increased mortality., Results: Of the 937,758 adult COVID-19 patients, 7,333 (0.8%) had preexisting ILD. The proportion of all COVID-19 patients who had preexisting ILD in the wild-type-, alpha-, and delta-predominant waves was 1.2%, 0.8%, and 0.3%, respectively, and their 60-day mortality was 16.0%, 14.6%, and 7.5%, respectively. The 60-day mortality significantly decreased from the alpha-predominant to delta-predominant waves (difference - 7.1%, 95% confidence intervals (CI) - 9.3% to - 4.9%). In multivariable analysis, preexisting ILD was independently associated with increased mortality in all waves with the wild-type-predominant, odds ratio (OR) 2.10, 95% CI 1.91-2.30, the alpha-predominant wave, OR 2.14, 95% CI 1.84-2.50, and the delta-predominant wave, OR 2.10, 95%CI 1.66-2.66., Conclusions: All-cause mortality rates for COVID-19 patients with preexisting ILD decreased from the wild-type- to the more recent delta-predominant waves. However, these patients were consistently at higher mortality risk than those without preexisting ILD. We emphasize that careful attention should be given to patients with preexisting ILD despite the change in the COVID-19 environment., (© 2024. The Author(s).)

Eelgrass beds provide a habitat for many high-value fishery resources, and provisioning services, one of the ecosystem services, need to be quantified. However, few examples have been evaluated spatially. We determined the distribution of eelgrass beds in Lake Notoro, a marine lagoon in Hokkaido, Japan, and quantified the provisioning services by the eelgrass beds in relation to Pandalus latirostris, a fishery resource. Acoustic measurement surveys of the eelgrass beds and catch surveys of the shrimp were conducted in July and August 2015. The relationship between catch per unit effort (CPUE) of shrimp and the distribution of eelgrass beds was shown. The estimated distribution area of eelgrass beds was 7.07 km 2 . Shrimp was frequently caught at water depths of 3-5 m, approximately 200 m from the edge of the eelgrass beds. The expected catch of shrimp in the fishing area of Lake Notoro in 2015 was 25.37 tons and US$ 463.6 thousand. Eelgrass beds were found to affect the fisheries production not only on the inside but also at the edge and outside. The entire coastal space should be evaluated, while considering the effect of the distribution of eelgrass beds, to quantify the provisioning services., (© 2024. The Author(s).)

Abstract: Klippel-Trenaunay syndrome (KTS) is characterized by port-wine stains, mixed vascular malformations, and soft tissue and bone hypertrophy. Klippel-Trenaunay syndrome is occasionally complicated by chyluria, for which there is no effective treatment currently. We report a case of KTS complicated by intractable chyluria and hematuria due to a lymphatic-ureteral fistula. The patient was successfully treated with multiple lymphaticovenular anastomoses (LVAs).A 66-year-old woman with an enlarged left lower extremity since childhood was diagnosed with KTS. At 60 years of age, she developed chyluria (urine albumin, 2224 μg/mL) and hematuria. Lymphoscintigraphy showed a lymphatic-ureteral fistula near the ureterovesical junction. Conservative treatment was ineffective. She also developed left lower extremity lymphedema, which gradually worsened. Leg cellulitis and purulent pericarditis developed because of hypoalbuminemia (minimum serum albumin level, 1.3 g/dL).We performed 14 LVAs in 2 surgeries to reduce lymphatic fluid flow through the lymphatic-ureteral fistula. The chyluria and hematuria resolved soon after the second operation, and the urine albumin level decreased (3 μg/mL). After 28 months, she had no chyluria or hematuria recurrence and her serum albumin level improved (3.9 g/dL). Multiple LVAs can definitively treat chyluria caused by a lymphatic-ureteral fistula in patients with KTS., Competing Interests: Conflicts of interest and sources of funding: The authors received no grants for the research, authorship, and/or publication of this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: This study aimed to evaluate the changes in glycemic control and diabetic complications over time in Japanese patients with juvenile-onset type 1 diabetes mellitus and to clarify the factors associated with the progression of diabetic complications., Methods: We tracked 129 patients with type 1 diabetes mellitus (21.8 ± 4.1 years old [mean ± SD] with a diabetes duration of 12.6 ± 5.7 years) for up to 19 years and analyzed data on glycated hemoglobin (HbA1c) and indicators related to the severity of diabetic complications (estimated glomerular filtration rate [eGFR], urinary albumin excretion rate [UAE], carotid intima-media thickness [CIMT], and brachial-ankle pulse wave velocity [baPWV]) using linear mixed model and decision tree analysis., Results: Although the HbA1c and UAE levels improved over time, the eGFR, CIMT, and baPWV worsened. Decision tree analysis showed that HbA1c and the glycoalbumin/HbA1c ratio for eGFR; HbA1c and systolic blood pressure for UAE; low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio, glycoalbumin/HbA1c ratio, and body mass index (BMI) for CIMT; and HbA1c for baPWV were associated factors., Conclusions: In this retrospective observational study, glycemic control and albuminuria improved; however, renal function and arteriosclerosis worsened over time. HbA1c levels, glycemic excursion, and blood pressure are associated with nephropathy progression. HbA1c levels, glycemic excursion, lipid levels, and BMI are associated with the progression of atherosclerosis., (© 2023 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

We have developed a series of 2-monoaryl-5-diarylmethylene analogs of the green fluorescent protein chromophore to study their viscosity-induced emission (VIE) properties. The analogs were synthesized by a condensation with methyl imidate and N-(diarylmethylene)glycinate. Among the analogs, the N-methylpyrrol-2-yl-substituted analog 1h induced the most remarkable VIE behavior in triglyceride and lipid bilayers probably due to the high π-electron-rich property of the pyrrole ring. The pyrrole substituent in imidazolone analogs can be expected to become a common template for introducing VIE behavior.

Murray law-based quantitative flow ratio (µQFR) assesses fractional flow reserve (FFR) in bifurcation lesions using a single angiographic view, enhancing the feasibility of analysis; however, accuracy may be compromised in suboptimal angiographic projections. FFR CT is a well-validated non-invasive method measuring FFR from coronary computed tomographic angiography (CCTA). We evaluated the feasibility of µQFR in left main (LM) bifurcations, the impact of the optimal/suboptimal fluoroscopic view with respect to CCTA, and its diagnostic concordance with FFR CT . In 300 patients with three-vessel disease, the values of FFR CT and µQFR were compared at distal LM, proximal left anterior descending artery (pLAD) and circumflex artery (pLCX). The optimal viewing angle of LM bifurcation was defined on CCTA by 3-dimensional coordinates and converted into a 2-dimensional fluoroscopic view. The best fluoroscopic projection was considered the closest angulation to the optimal viewing angle on CCTA. µQFR was successfully computed in 805 projections. In the best projections, µQFR sensitivity was 88.2% (95% CI 76.1-95.6) and 84.8% (71.1-93.7), and specificity was 96.8% (93.8-98.6) and 97.2% (94.4-98.9), in pLAD and pLCX, respectively, with regard to FFR CT . The AUC of µQFR for predicting FFR CT  ≤ 0.80 tended to be improved using the best versus suboptimal projections (0.94 vs. 0.89 [p = 0.048] in pLAD; 0.94 vs. 0.88 [p = 0.075] in pLCX). Computation of µQFR in LM bifurcations using a single angiographic view showed high feasibility from post-hoc analysis of coronary angiograms obtained for clinical purposes. The fluoroscopic viewing angle influences the diagnostic performance of physiological assessment using a single angiographic view., (© 2023. The Author(s).)

Background: Even with intracoronary imaging-guided stent optimisation, suboptimal haemodynamic outcomes post-percutaneous coronary intervention (PCI) can be related to residual lesions in non-stented segments. Preprocedural assessment of pathophysiological coronary artery disease (CAD) patterns could help predict the physiological response to PCI., Aims: The aim of this study was to assess the relationship between preprocedural pathophysiological haemodynamic patterns and intracoronary imaging findings, as well as their association with physiological outcomes immediately post-PCI., Methods: Data from 206 patients with chronic coronary syndrome enrolled in the ASET-JAPAN study were analysed. Pathophysiological CAD patterns were characterised using Murray law-based quantitative flow ratio (μQFR)-derived indices acquired from pre-PCI angiograms. The diffuseness of CAD was defined by the pullback pressure gradient (PPG) index. Intracoronary imaging in stented segments after stent optimisation was also analysed., Results: In the multivariable analysis, diffuse disease - defined by the pre-PCI μQFR-PPG index - was an independent factor for predicting a post-PCI μQFR <0.91 (per 0.1 decrease of PPG index, odds ratio 1.57, 95% confidence interval: 1.07-2.34; p=0.022), whereas the stent expansion index (EI) was not associated with a suboptimal post-PCI μQFR. Among vessels with an EI ≥80% and post-PCI μQFR <0.91, 84.0% of those vessels had a diffuse pattern preprocedure. There was no significant difference in EI between vessels with diffuse disease and those with focal disease. The average plaque burden in the stented segment was significantly larger in vessels with a preprocedural diffuse CAD pattern., Conclusions: A physiological diffuse pattern preprocedure was an independent factor in predicting unfavourable immediate haemodynamic outcomes post-PCI, even after stent optimisation using intracoronary imaging. Preprocedural assessment of CAD patterns could identify patients who are likely to exhibit superior immediate haemodynamic outcomes following PCI.

Objective: During the coronavirus disease pandemic in Japan, all patients with respiratory symptoms were initially tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study describes the respiratory pathogens detected from patients who tested negative for SARS-CoV-2 at the Saitama Institute of Public Health from January to December 2020., Methods: We performed pathogen retrieval using multiplex real-time polymerase chain reaction on samples from patients with acute respiratory diseases who tested negative for SARS-CoV-2 in Saitama in 2020 and analysed the results by age and symptoms., Results: There were 1530 patients aged 0-104 years (1727 samples), with 14 pathogens detected from 213 patients (245 samples). Most pathogens were human metapneumovirus (25.4%, 54 cases), rhinovirus (16.4%, 35 cases) and Mycoplasma pneumoniae (13.1%, 23 cases). Human metapneumovirus, human coronavirus (but not NL63) and M. pneumoniae were detected in almost all age groups without any significant bias. Seasonal human coronaviruses, human metapneumovirus, M. pneumoniae and several other pathogens were detected until April 2020., Discussion: Multiple respiratory pathogens were circulating during 2020 in Saitama, including SARS-CoV-2 and influenza viruses. We suggest introducing a system that can comprehensively monitor the regional prevalence of all viruses that cause acute respiratory infections., Competing Interests: The authors have no conflicts of interest to declare., ((c) 2023 The authors; licensee World Health Organization.)

The coronavirus disease 2019 (COVID-19) pandemic has dramatically changed because of virus mutations, vaccine dissemination, treatment development and policies, among other factors. These factors have a dynamic and complex effect on the characteristics and outcomes of patients. Therefore, there is an urgent need to understand those changes and update the evidence. We used a large-scale real-world data set of 937,758 patients with COVID-19 from a nationwide claims database that included outpatients and inpatients in Japan to investigate the changes in their characteristics, outcomes and risk factors for severity/mortality from the early pandemic to the delta variant-predominant waves. The severity of COVID-19 was defined according to the modified World Health Organization clinical-progression ordinal scale. With changing waves, mean patient age decreased, and proportion of patients with comorbidities decreased. The incidences of "severe COVID-19 or death (i.e. ≥severe COVID-19)" and "death" markedly declined (5.0% and 2.9%, wild-type-predominant; 4.6% and 2.2%, alpha variant-predominant and 1.4% and 0.4%, delta variant-predominant waves, respectively). Across the wave shift, risk factors for ≥ severe COVID-19 and death, including older age, male, malignancy, congestive heart failure and chronic obstructive pulmonary disease, were largely consistent. The significance of some factors, such as liver disease, varied as per the wave. This study, one of the largest population-based studies on COVID-19, showed that patient characteristics and outcomes changed during the waves. Risk factors for severity/mortality were similar across all waves, but some factors were inconsistent. These data suggest that the clinical status of COVID-19 will change further with the coming epidemic wave.

Objectives: Medical device-related pressure ulcer (MDRPU) is a skin or subcutaneous tissue injury caused by medical devices. Skin protectants have been used to prevent MDRPU in other fields. In endoscopic sinonasal surgery (ESNS), rigid endoscopes and forceps can cause MDRPU; however, detailed investigations have not been conducted. This study aimed to investigate the frequency of MDRPU in ESNS and the preventive effects of skin protectants METHODS: Thirty-nine patients who received ESNS and consented to study participation were randomly assigned to the "protective agent" (n = 18) or "control" (n = 21) group. MDRPU presence around the nostril was evaluated for up to 7 days post-surgically based on physical findings and subjective symptoms. The occurrence ratio and severity of MDRPU were statistically compared between the groups to evaluate the efficacy of skin protective agents., Results: Stage 1 MDRPU, according to the National Pressure Ulcer Advisory Panel classification, was seen in 20.5% (8/39) of the patients, and no patient had more high-grade ulceration. On postoperative days 2 and 3, skin erythema was predominantly observed on the nasal floor, with a comparatively lower incidence in the protective agent group. Significant pain reduction was observed in the nostril's floor on postoperative days 2 and 3 in the protective agent group., Conclusions: MDRPU occurred with a relatively high frequency around the nostrils after ESNS. Protective agent use in the external nostrils was effective especially in reducing post-operative pain on the nasal floor, where tissue damage can easily occur due to device-related friction., Competing Interests: Declaration of competing interest The Authors declare that there is no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background/aim: Fucoxanthin (Fx), a dietary marine xanthophyll, exerts potent anticancer effects in various colorectal cancer (CRC) animal models. However, therapeutic effects of Fx in human cancer tissues remain unclear. A patient-derived xenograft (PDX) mouse model transplanted with cancer tissues from patients is widely accepted as the best preclinical model for evaluating the anticancer potential of drug candidates., Materials and Methods: Herein, we investigated the anticancer effects of Fx in PDX mice transplanted with cancer tissues derived from a patient with CRC (CRC-PDX) using LC-MS/MS- and western blot-based proteome analysis., Results: The tumor in the patient with CRC was a primary adenocarcinoma (T3N0M0, stage II) showing mutations of certain genes that were tumor protein p53 (TP53), AT-rich interaction domain 1A (ARID1A), neuroblastoma RAS viral oncogene homolog (NRAS), and PMS1 homolog 2 (PMS2). Administration of Fx significantly suppressed the tumor growth (0.6-fold) and tended to induce differentiation in CRC-PDX mice. Fx up-regulated glycanated-decorin (Gc-DCN) expression, and down-regulated Kinetochore-associated protein DSN1 homolog (DSN1), phospho(p) focal adhesion kinase (pFAK)(Tyr 397 ), pPaxillin(Tyr 31 ), and c-MYC involved in growth, adhesion, and/or cell cycle, in the tumors of CRC-PDX mice than in control mice. Alterations in the five proteins were consistent with those in human CRC HT-29 and HCT116 cells treated with fucoxanthinol (FxOH, a major metabolite of Fx)., Conclusion: Fx suppresses development of human-like CRC tissues, especially through growth, adhesion, and cell cycle signals., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Chronic rhinosinusitis (CRS) is a common chronic inflammatory disease and is subdivided into eosinophilic and noneosinophilic forms. There are few reports investigating the nasal microbiome and its pathological functions in patients with CRS., Objective: We sought to analyze factors contributing to variations of the nasal microbiome in CRS, and on the basis of these factors, to elucidate whether the bacterial metabolites were related to the pathogenesis., Methods: Nasal swabs were collected, and the V3 to V4 variable region of the 16S ribosomal RNA gene was amplified and sequenced. Factors contributing to variations of the nasal microbiome in patients with CRS were compared. The most influential factor was whether CRS was eosinophilic, and we compared α- and β-diversity, bacterial species, and predictive bacterial functions between the 2 patient groups. In addition, the metabolites of the key bacteria were extracted, and we evaluated the predicted bacterial functions in airway epithelial cells., Results: In total, 110 patients with CRS and 33 control subjects were enrolled. On the basis of the factors of variation, it was found that patients with eosinophilic CRS (n = 65) had different microbiomes with weighted UniFrac β-diversity and lower α-diversity compared with those with noneosinophilic CRS (n = 45). A higher abundance of Fusobacterium nucleatum and an increased LPS pathway were observed in patients with noneosinophilic CRS compared with those with eosinophilic CRS. In airway epithelial cells, LPS derived from F nucleatum suppressed the expression levels of ALOX15 induced by T H 2 cytokines., Conclusions: The differences in the nasal microbiome may play a key role in the pathophysiology of CRS., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Why apolipoprotein AV (APOA5) deficiency causes hypertriglyceridemia has remained unclear, but we have suspected that the underlying cause is reduced amounts of lipoprotein lipase (LPL) in capillaries. By routine immunohistochemistry, we observed reduced LPL staining of heart and brown adipose tissue (BAT) capillaries in Apoa5-/- mice. Also, after an intravenous injection of LPL-, CD31-, and GPIHBP1-specific mAbs, the binding of LPL Abs to heart and BAT capillaries (relative to CD31 or GPIHBP1 Abs) was reduced in Apoa5-/- mice. LPL levels in the postheparin plasma were also lower in Apoa5-/- mice. We suspected that a recent biochemical observation - that APOA5 binds to the ANGPTL3/8 complex and suppresses its capacity to inhibit LPL catalytic activity - could be related to the low intracapillary LPL levels in Apoa5-/- mice. We showed that an ANGPTL3/8-specific mAb (IBA490) and APOA5 normalized plasma triglyceride (TG) levels and intracapillary LPL levels in Apoa5-/- mice. We also showed that ANGPTL3/8 detached LPL from heparan sulfate proteoglycans and GPIHBP1 on the surface of cells and that the LPL detachment was blocked by IBA490 and APOA5. Our studies explain the hypertriglyceridemia in Apoa5-/- mice and further illuminate the molecular mechanisms that regulate plasma TG metabolism.

Objectives: The "Guidelines for Ensuring the Safety and Health of Older Workers (hereafter referred to as "Guidelines")," formulated in 2021, require employers to implement measures that proactively prevent occupational accidents among older workers. This study aimed to clarify the status of awareness of the Guidelines and workplace improvement efforts with consideration of older workers, focusing on company size., Methods: Overall, 780 businesses in Wakayama Prefecture, Japan, were randomly selected from a Wakayama Occupational Health Support Center workplace list. Anonymous self-administered questionnaires were distributed by mail. The questionnaires comprised questions about the workplace, status of awareness of the Guidelines, comprehensive management of safety and health, considerations for working conditions, workers, workload reduction, work posture, work environment, and safety and health., Results: One hundred and seventy-one businesses (effective response rate: 21.9%) provided questionnaires with complete responses. For the Guidelines, 39.0% of small-sized (less than 50 employees) businesses answered, "never even heard of the name," while many medium-sized (50-99 employees) and large-sized (100 or more employees) businesses answered that they had heard of the name but did not exactly know about it (33.3% of medium-sized businesses and 47.8% of large-sized businesses). Regarding the system that subsidizes the expenses required for the improvement of a working environment for older workers to work safely and securely (hereinafter referred to as the subsidy system), many businesses of all sizes answered that they had "never even heard of the name." In the comprehensive management of safety and health, half of the businesses of all sizes had developed a system that made it easy to consult about the risk against occupational accidents of older workers. Regardless of size, more than half of businesses were able to consider working conditions and workers. However, there were only a few items where more than half of the businesses considered workload reduction, work posture, work environment, and safety and health, regardless of business size. It became clear that workplace improvement had not progressed very much., Conclusions: These results suggest that to promote workplace improvement that considers older workers, it is necessary to disseminate the Guidelines and proactively take on workplace improvement by utilizing the subsidy system.

Lipoprotein lipase (LPL), the enzyme that carries out the lipolytic processing of triglyceride-rich lipoproteins (TRLs), is synthesized by adipocytes and myocytes and secreted into the interstitial spaces. The LPL is then bound by GPIHBP1, a GPI-anchored protein of endothelial cells (ECs), and transported across ECs to the capillary lumen. The assumption has been that the LPL that is moved into capillaries remains attached to GPIHBP1 and that GPIHBP1 serves as a platform for TRL processing. In the current studies, we examined the validity of that assumption. We found that an LPL-specific monoclonal antibody (mAb), 88B8, which lacks the ability to detect GPIHBP1-bound LPL, binds avidly to LPL within capillaries. We further demonstrated, by confocal microscopy, immunogold electron microscopy, and nanoscale secondary ion mass spectrometry analyses, that the LPL detected by mAb 88B8 is located within the EC glycocalyx, distant from the GPIHBP1 on the EC plasma membrane. The LPL within the glycocalyx mediates the margination of TRLs along capillaries and is active in TRL processing, resulting in the delivery of lipoprotein-derived lipids to immediately adjacent parenchymal cells. Thus, the LPL that GPIHBP1 transports into capillaries can detach and move into the EC glycocalyx, where it functions in the intravascular processing of TRLs.

We herein report a Japanese patient with myotonic dystrophy type 2 (DM2), which is rare in Japan. A 64-year-oldman had proximal muscle weakness and grip myotonia. Electromyography showed myotonic discharges, but dystrophia-myotonica protein kinase (DMPK) was negative for CTG repeats. A muscle biopsy revealed increased central nuclei, pyknotic nuclear clumps and muscle fiber atrophy, mainly in type 2 fibers, raising the possibility of DM2. The diagnosis was genetically confirmed by the abnormal CCTG repeat size in cellular nucleic acid-binding protein (CNBP) on repeat-primed polymerase chain reaction, which was estimated to be around 4,500 repeats by Southern blotting.

To develop novel drugs for treating T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) which are highly malignant hematological tumors, a series of analogs having a polyenylpyrrole structure of natural compounds (rumbrin and auxarconjugatin B) were synthesized and investigated their structure-activity relationships (SAR) of in vitro anti-T-ALL and anti-AML activities. We obtained three findings: (1) introduction of a methyl group at the conjugated polyene terminus enhanced anti-T-ALL activity, (2) analogs with a 3-chloropyrrole moiety had even higher selectivity for T-ALL cells, and (3) some analogs were effective against AML-derived cells. Among the studied compounds, 3-chloro-2-(8-ethoxycarbonylnona-1,3,5,7-tetraenyl) pyrrole 4e was the most promising candidate of T-ALL- and AML-treating drug. This study provides useful structural information for designing novel drugs treating T-ALL and AML., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: T. Higashi, C. Y., Y. H., C. N., A. T., T. Y., K. M., T. Hara, and S. M. have Japanese patents pending (2021–004230). N. K., R. O., and T. Hirano 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 © 2023 Elsevier Ltd. All rights reserved.)

Ocimum aristatum, commonly known as O. stamineus, has been widely studied for its potential as an herbal medicine candidate. This research aims to compare the efficacy of water and 100% ethanolic extracts of O. stamineus as α-glucosidase inhibitors and antioxidants, as well as toxicity against zebrafish embryos. Based on the study findings, water extract of O. stamineus leaves exhibited superior inhibition activity against α-glucosidase, ABTS, and DPPH, with IC 50 values of approximately 43.623 ± 0.039 µg/mL, 27.556 ± 0.125 µg/mL, and 95.047 ± 1.587 µg/mL, respectively. The major active compounds identified in the extract include fatty acid groups and their derivates such as linoleic acid, α-eleostearic acid, stearic acid, oleanolic acid, and corchorifatty acid F. Phenolic groups such as caffeic acid, rosmarinic acid, 3,4-Dihydroxybenzaldehyde, norfenefrine, caftaric acid, and 2-hydroxyphenylalanine and flavonoids and their derivates including 5,7-Dihydroxychromone, 5,7-Dihydroxy-2,6-dimethyl-4H-chromen-4-one, eupatorin, and others were also identified in the extract. Carboxylic acid groups and triterpenoids such as azelaic acid and asiatic acid were also present. This study found that the water extract of O. stamineus is non-toxic to zebrafish embryos and does not affect the development of zebrafish larvae at concentrations lower than 500 µg/mL. These findings highlight the potential of the water extract of O. stamineus as a valuable herbal medicine candidate, particularly for its potent α-glucosidase inhibition and antioxidant properties, and affirm its safety in zebrafish embryos at tested concentrations., (© 2023. Springer Nature Limited.)

T-cell acute lymphoblastic leukemia (T-ALL) is one of the most frequently occurring cancers in children and is associated with a poor prognosis. Here, we performed large-scale screening of natural compound libraries to identify potential drugs against T-ALL. We identified three low-molecular-weight compounds (auxarconjugatin-B, rumbrin, and lavendamycin) that inhibited the proliferation of the T-ALL cell line CCRF-CEM, but not that of the B lymphoma cell line Raji in a low concentration range. Among them, auxarconjugatin-B and rumbrin commonly contained a polyenyl 3-chloropyrrol in their chemical structure, therefore we chose auxarconjugatin-B for further analyses. Auxarconjugatin-B suppressed the in vitro growth of five human T-ALL cell lines and two T-ALL patient-derived cells, but not that of adult T-cell leukemia patient-derived cells. Cultured normal T cells were several-fold resistant to auxarconjugatin-B. Auxarconjugatin-B and its synthetic analogue Ra#37 depolarized the mitochondrial membrane potential of CCRF-CEM cells within 3 h of treatment. These compounds are promising seeds for developing novel anti-T-ALL drugs., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objective: The treatment of nasal foreign bodies involves safe and reliable removal. Few reports have investigated the relationship between equipment and the incidence of complications., Methods: This retrospective study included 300 patients with nasal foreign bodies (average: 3.28 years, interquartile range: 2-4 years). Patients' background, characteristics of nasal foreign body, equipment to remove the nasal foreign body, and complications were obtained from medical records. Statistical analysis was performed using Pearson's chi-square test for associated factors and the incidence of epistaxis among the complications., Results: Nasal foreign bodies were found and removed in 256 patients. Forceps, hooks, suction, modified paper clips, and cotton swabs were mainly used to remove the nasal foreign bodies. Epistaxis due to the removal procedure was observed in 26 patients. The occurrence of epistaxis differed depending on the equipment (p = 0.077) and was less frequent in suction and paper clips than in forceps (p < 0.05 and p = 0.077). Epistaxis was not observed when a cotton swab was used. Aspiration and septal perforation were not observed. A statistical relationship was not detected between the hardness of foreign bodies and the occurrence of epistaxis (p = 0.251). The incidence of epistaxis was higher in cases nasal foreign bodies remained for 1 day and over than in cases foreign bodies were removed within 1 day (p < 0.05)., Conclusions: This study revealed that suction, modified paper clips, and cotton swabs could be beneficial options for minimizing complications in the removal of nasal foreign bodies., Level of Evidence: 4 Laryngoscope, 133:2553-2557, 2023., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

To investigate the regulation of soluble very low-density lipoprotein receptor (sVLDL-R), which is cleaved mostly from the extracellular domain of VLDL-R II, we generated two rat monoclonal antibodies (mAbs) against human sVLDL-R, and used them to develop a sandwich enzyme-linked immunosorbent assay (ELISA) to measure sVLDL-R levels in human serum or plasma. The ELISA had a linear range from 0.20 ng/mL to 13.02 ng/mL and allowed for the quantification of sVLDL-R in serum and culture cell medium. The coefficient of variation (CV) was less than 10% for both the intra- and inter-assays. The bililubin F, and C, triglyceride (TG), and hemoglobin levels did not affect assay precision. The sVLDL-R concentration was negatively associated with body fat percentage, TG, and HbA1c, suggesting the possibility of obesity and diabetes in middle-aged Japanese women., Competing Interests: 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., (© 2023 The Authors.)

The NAM, ATAF1/2, and CUC2 (NAC) domain transcription factor VND-INTERACTING2 (VNI2) negatively regulates xylem vessel formation by interacting with another NAC domain transcription factor, VASCULAR-RELATED NAC-DOMAIN7 (VND7), a master regulator of xylem vessel formation. Here, we screened interacting proteins with VNI2 using yeast two-hybrid assay and isolated two NAC domain transcription factors, Arabidopsis thaliana ACTIVATION FACTOR 2 (ATAF2) and NAC DOMAIN CONTAINING PROTEIN 102 (ANAC102). A transient gene expression assay showed that ATAF2 upregulates the expression of genes involved in leaf senescence, and VNI2 effectively inhibits the transcriptional activation activity of ATAF2. vni2 mutants accelerate leaf senescence, whereas ataf2 mutants delay leaf senescence. In addition, the accelerated leaf senescence phenotype of the vni2 mutant is recovered by simultaneous mutation of ATAF2 . Our findings strongly suggest that VNI2 interacts with and inhibits ATAF2, resulting in negatively regulating leaf senescence., Competing Interests: The authors declare that they have no known competing interests that could have appeared to influence this work., (© 2023 The Authors. Plant Direct published by American Society of Plant Biologists and the Society for Experimental Biology and John Wiley & Sons Ltd.)

Lecithin-cholesterol acyltransferase (LCAT) plays a significant role in the progression from premature to mature high-density lipoprotein (HDL) in circulation. Consequently, primary or secondary LCAT deletion or reduction naturally results in low serum HDL cholesterol levels. Recently, rare cases of acquired HDL deficiency with LCAT autoantibodies have been reported, mainly from Japan, where LCAT autoantibodies of immunoglobulin G (IgG) caused the HDL deficiency. Here to our knowledge, we report for the first time two cases of acquired HDL deficiency caused by IgG4 linked LCAT autoantibodies with or without a high serum IgG4 level. Furthermore, these cases can extend to a new concept of "IgG4 autoimmune disease" from the viewpoint of verifying the serum autoantibody and/or renal histopathology.

Rapid reperfusion by primary percutaneous coronary intervention (pPCI) is an established strategy for the treatment of patients with ST-segment elevation myocardial infarction (STEMI). Pre-hospital electrocardiogram (PH-ECG) transmission by the emergency medical services (EMS) facilitates timely reperfusion in these patients. However, evidence regarding the clinical benefits of PH-ECG in individual hospitals is limited.This retrospective, observational study investigated the clinical efficacy of PH-ECG in STEMI patients who underwent pPCI. Of a total of 382 consecutive STEMI patients, 237 were enrolled in the study and divided into 2 groups: a PH-ECG group (n = 77) and non-PH-ECG group (n = 160). Door-to-balloon time (D2BT) was significantly shorter in the PH-ECG group (66 [52-80] min), compared to the non-PH-ECG group (70 [57-88] minutes, P = 0.01). The 30-day all-cause mortality rate was 6% in the PH-ECG group, which was significantly lower than that in the non-PH-ECG group (16%) (P = 0.037, hazard ratio [HR]: 0.38, 95% CI: 0.15-0.98). This trend was particularly evident in severely ill patients when stratified by GRACE score.The use of PH-ECG improved the survival rate of STEMI patients undergoing pPCI due to the improved pre-arrival preparation based on the EMS information. Coordination between EMS and PCI-capable institutes is essential for the management of PH-ECG.

To explore the mechanism by which intermittent fasting (IF) exerts prolonged effects after discontinuation, we examined mice that had been subjected to 4 cycles of fasting for 72 hours and ad libitum feeding for 96 hours per week (72hIF), followed by 4 weeks of ad libitum feeding, focusing on expression of genes for lipid metabolism in the skeletal muscle and histone acetylation in the promoter region. The 72hIF regimen resulted in metabolic remodeling, characterized by enhanced lipid utilization and mitochondrial activation in the muscle. This long-term IF (72hIF) caused stronger metabolic effects than alternate day fasting (24hIF) wherein fasting and refeeding are repeated every 24 hours. Upregulation of lipid oxidation genes and an increase in oxygen utilization were sustained even at 4 weeks after discontinuation of 72hIF, associated with histone hyperacetylation of the promoter region of uncoupling protein 3 ( Ucp3 ) and carnitine palmitoyl transferase 1b ( Cpt1b ) genes. An increase in leucine owing to fasting-induced muscle degradation was suggested to lead to the histone acetylation. These findings support the previously unappreciated notion that sustainable promotion of histone acetylation in lipid oxidation genes of the muscle and adipose tissues during and after IF may contribute to sustained metabolic effects of IF., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Despite advances in multidisciplinary treatment, the prognosis of pancreatic cancer remains poor. Since distant metastasis defines prognosis, elucidation of the mechanism of metastasis is important for improving survival. Exosomes are extracellular secretory vesicles and are responsible for intercellular communication. In this study, we investigated whether exosomes secreted by human pancreatic cancer cells are involved in promoting distant metastasis of cancer and the mechanism that underlies the promotion of metastasis., Methods: Exosomes were isolated from ascites of a patient with pancreatic cancer and a patient with liver cirrhosis as a control. Three days after the administration of exosomes to nude mice, GFP-labeled human pancreatic cancer cells were injected via the spleen or tail vein, and then the liver and lungs were histologically analyzed. To elucidate the mechanism, vascular permeability was estimated using FITC-dextran in place of pancreatic cancer cells in vivo and human umbilical vascular endothelial cells (HUVECs) were used to analyze vascular permeability and the induction of endothelial-mesenchymal transition (EndMT) in vitro., Results: Distant metastasis and vascular permeability were significantly enhanced in mice treated with exosomes from pancreatic cancer patients in comparison to exosomes from a control patient in vivo. In addition, exosomes from pancreatic cancer patients significantly enhanced vascular permeability and the induction of EndMT in HUVECs in vitro., Conclusion: Exosomes derived from pancreatic cancer cells form a pre-metastatic niche and promote the extravasation and colonization of pancreatic cancer cells to remote organs, partially through endothelial-mesenchymal transition., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in association with the present study., (Copyright © 2023 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Purpose: The purpose of this study was to analyze the patterns of failure in patients with glioblastoma multiforme (GBM) treated using chemoradiotherapy in the Standard radiotherapy (60 Gy/30 fractions; Standard) or Short course (40 Gy/15 fractions: Short)., Materials and Methods: Ninety-three consecutive patients with newly diagnosed glioblastoma treated at our hospital between April 2007 and December 2016, and 68 patients who could be followed up were included. All patients underwent surgical resection followed by radiotherapy with concurrent temozolomide. We retrospectively analyzed treatment outcomes and recurrence patterns., Results: The median follow-up period of the surviving patients was 82.8 months (range: 46.0-158.9 months). Of the 68 patients, 58 patients (85%) had recurrences, 34 underwent the Standard and 24 Short course. The Standard course was seen in younger age groups and had a better Karnofsky performance status (KPS) than the Short course. The median survival time (MST) was 25.8 months for the Standard and 15.4 months with the Short in all cases. Standard course had significantly longer MST than the Short (p = 0.001) course. For recurrent cases only, there was no significant difference between Standard and Short courses in OS (p = 0.06). The recurrences occurred at the radiation fields alone (Standard/Short: 85%/83%), only at distant sites (Standard/Short: 12%/13%), and at both the radiation fields and distant sites (Standard/Short: 3%/4%). There was no significant difference in recurrence pattern and frequency between the two protocols (p = 0.11)., Conclusions: Standard course tended to be significant in younger age groups and have a better KPS than the Short course; therefore, the Standard course has a longer OS, but the recurrence pattern of the Short course is similar to that of the Standard treatment., (© 2023. The Author(s) under exclusive licence to Japan Radiological Society.)

Epigenetic dysregulation is reported in multiple cancers including Ewing sarcoma (EwS). However, the epigenetic networks underlying the maintenance of oncogenic signaling and therapeutic response remain unclear. Using a series of epigenetics- and complex-focused CRISPR screens, RUVBL1, the ATPase component of NuA4 histone acetyltransferase complex, is identified to be essential for EwS tumor progression. Suppression of RUVBL1 leads to attenuated tumor growth, loss of histone H4 acetylation, and ablated MYC signaling. Mechanistically, RUVBL1 controls MYC chromatin binding and modulates the MYC-driven EEF1A1 expression and thus protein synthesis. High-density CRISPR gene body scan pinpoints the critical MYC interacting residue in RUVBL1. Finally, this study reveals the synergism between RUVBL1 suppression and pharmacological inhibition of MYC in EwS xenografts and patient-derived samples. These results indicate that the dynamic interplay between chromatin remodelers, oncogenic transcription factors, and protein translation machinery can provide novel opportunities for combination cancer therapy., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)