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Objectives: This study aimed to investigate the association between falls and social frailty and its components among older Japanese adults., Methods: This is a cross-sectional study. Participants were categorized into 3 groups based on the number of falls in the past year: no fall (none), a single fall (occasional), and more than one fall (recurrent). The participants who met 2 or more of the following criteria were defined as socially frail: living alone, going out less frequently compared with the previous year, rarely visiting friends, feeling unhelpful to friends or family, and not talking with someone daily., Results: A total of 4,495 older Japanese adults living in a community analyzed in this study (51.0% women). Of the participants in this study, 3,851 (85.7%) were categorized as none, 443 (9.9%) as occasional, and 201 (4.5%) as recurrent. The proportion of participants considered socially frail was 11.5% in this study. Recurrent falls were associated with social frailty, even after adjusting for covariates (odds ratio [OR]: 1.49; 95% confidence interval [CI]: 1.01-2.19). The experience of recurrent falls was associated with the following components: "feeling unhelpful to friends and family" (OR: 1.62; 95% CI: 1.14-2.31) and "going outside less frequently compared with last year" (OR: 1.57; 95% CI: 1.06-2.31)., Discussion: Among older Japanese adults, recurrent falls were associated with social frailty and with 2 of its components in particular: social roles and social participation. Future longitudinal studies should be conducted to gain insight into any causal relationships between these variables., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: This study evaluates the safety/efficacy of sabatolimab plus spartalizumab in patients with melanoma or non-small cell lung cancer (NSCLC)., Design, Setting and Participants: This is a phase 1-1b/2, open-label, multinational, multicentre study of patients with advanced/metastatic melanoma or NSCLC with ≥1 measurable lesion., Interventions: Patients were given sabatolimab 800 mg every 4 weeks plus spartalizumab 400 mg every 4 weeks until unacceptable toxicity, disease progression and/or treatment discontinuation., Outcome Measures: The phase 2 primary outcome measure was overall response rate and secondary objectives included evaluation of the safety, tolerability, efficacy and pharmacokinetics of sabatolimab in combination with spartalizumab., Results: 33 patients (melanoma n=16, NSCLC n=17) received sabatolimab plus spartalizumab. 31 (94%) experienced ≥1 adverse event (AE); 15 (46%) experienced grade 3/4 events. The most frequent grade ≥3 AEs for NSCLC were anaemia, dyspnoea and pneumonia (each n=2, 12%); for patients with melanoma, the most frequent grade ≥3 AEs were physical health deterioration, hypokalaemia, hypophosphataemia, pathological fracture and tumour invasion (each n=1; 6%). One (3%) patient discontinued treatment due to AE. Stable disease was seen in three patients with melanoma (19%) and six patients with NSCLC (35%). Median progression-free survival was 1.8 (90% CI 1.7 to 1.9) and 1.7 (90% CI 1.1 to 3.4) months for patients with melanoma and NSCLC, respectively. Patients with stable disease had higher expression levels of CD8, LAG3, programmed death-ligand 1 and anti-T-cell immunoglobulin and mucin-domain containing-3 at baseline. The pharmacokinetics profile of sabatolimab was consistent with the phase 1 study., Conclusions: Sabatolimab plus spartalizumab was well tolerated in patients with advanced/metastatic melanoma or NSCLC who had progressed following antiprogrammed death-1/antiprogrammed death-ligand 1 treatment. Limited antitumour activity was observed. The tolerability of sabatolimab administration supports the potential to explore treatment with sabatolimab in various combination regimens and across a spectrum of tumour types., Trial Registration Number: NCT02608268., Competing Interests: Competing interests: NM is the founder of and owns shares in MaxiVAX SA and is the CSO at MaxiVAX. C-CL reports an advisory role for AbbVie, Bayer, Blueprint Medicines, Bristol Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, Novartis and PharmaEngine; honoraria from Lilly, Novartis and Roche; and travel support from BeiGene, Daiichi Sankyo and Lilly. GC reports research funding from Merck and fees for advisory board from BMS, Merck, AstraZeneca, Novartis, Lilly, Pfizer, Roche, Exact Science, Daiichi Sankyo, GSK, Sanofi and Seagen. AS reports serving on an advisory board for BMS, Servier, Gilead, Pfizer, Eisai, Bayer and MSD (Merck Sharp & Dohme); consultancy for Arqule, Sanofi and Incyte; and participating in speaker’s bureaus for Takeda, BMS, Roche, AbbVie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, Arqule, Lilly, Sandoz, Eisai, Novartis, Bayer and MSD. D-WK reports research funding to his institution from Alpha Biopharma, Amgen, AstraZeneca/Medimmune, Boehringer-Ingelheim, Daiichi-Sankyo, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Chong Keun Dang, Bridge BioTherapeutics, and GSK; and travel and accommodation support for advisory board meeting attendance from Amgen and Daiichi-Sankyo. DT reports payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events from Ipsen, Eisai and BMS; and consulting fees from Novartis, BMS and MSD. FSH reports receiving personal fees for serving on an advisory board for Surface, Compass Therapeutics, Apricity, Pionyr, 7 Hills Pharma, Torque, Bicara, Checkpoint Therapeutics, Bioentre, Iovance, Trillium, Amgen and Rheos; consultancy for Bristol-Myers Squibb, Merck, EMD Serono, Novartis, Sanofi, Pieris, Genentech/Roche, Catalym, Immunocore, Kairos, Eisai and Zumutor; serving as an advisor consultant for Aduro; and receiving other personal fees from Gossamer. FSH reports receiving grant support to institution from Bristol-Myers Squibb and Novartis; and having equity in Apricity, Pionyr, Torque, Bicara and Checkpoint Therapeutics. FSH holds issued patents #7250291, #9402905, #10279021 and #10106611 and pending patents #20100111973 (with royalties), #20170248603, #20160340407, #20160046716, #20140004112, #20170022275, #20170008962 and #20170343552, as well as a pending patent for Methods of Using Pembrolizumab and Trebananib. SW reports serving on an advisory board for Eisai, Bristol-Myers Squibb and Pierre Fabre (paid to institution). TD reports receiving grant support to institution from Lilly, MSD, Daiichi-Sankyo, Sumitomo Dainippon, Taiho, Novartis, Merck Biopharma, Janssen Pharma, Pfizer, BMS, AbbVie, Eisai, IQVIA, Chugai Pharma; consulting fees from Sumitomo Dainippon, Taiho, Takeda, Chugai Pharma, AbbVie, Bayer, Rakuten Medical, Otsuka Pharma, KAKEN Pharma, KYOWA KIRIN, SHIONOGI, PRA Health Science; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, Rakuten Medical, Ono Pharma, Daiichi-Sankyo, AstraZeneca; participation on a Data Safety Monitoring Board or Advisory Board for MSD, Daiichi-Sankyo, Amgen, Novartis, Boehringer Ingelheim, Janssen Pharma, AbbVie, Bayer, Astellas Pharma. CS-P was an employee of Novartis Institutes for BioMedical Research and holds patents on TIM-3 through Harvard/BWH and CoStim/Novartis. CS-P is employed by and has options in Larkspur Biosciences. SS is an employee of Novartis Institutes for BioMedical Research. SC is an NIBR employee and holds NVS stocks. AX has nothing to disclose. SG is an employee of Novartis Institutes for BioMedical Research. AP is an employee of Novartis Institutes for BioMedical Research., (© 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: In contrast to the well-known prognostic values of the cardiorenal linkage, it remains unclear whether impaired cognitive function affects cardiac prognosis in relation to cardiac sympathetic innervation and renal function in patients with heart failure (HF)., Methods and Results: A total of 433 consecutive HF patients with left ventricular ejection fraction (LVEF) <50% underwent the Mini-Mental State Examination (MMSE) and a neuropsychological test for screening of cognition impairment or subclinical dementia. Following metaiodobenzylguanidine (MIBG) scintigraphy, patient outcomes with a primary endpoint of lethal cardiac events (CEs) were evaluated for a mean period of 14.8 months. CEs were documented in 84 HF patients during follow-up. MMSE score, estimated glomerular filtration rate (eGFR) and standardized heart-to-mediastinum ratio of MIBG activity (sHMR) were significantly reduced in patients with CEs compared with patients without CEs. Furthermore, overall multivariate analysis revealed that these parameters were significant independent determinants of CEs. The cutoff values of MMSE score (<26), sHMR (<1.80) and eGFR (<47.0 mL/min/1.73 m 2 ) determined by receiver operating characteristic (ROC) analysis successfully differentiated HF patients at more increased risk for CEs from other HF patients., Conclusions: Impairment of cognitive function is not only independently related to but also synergistically increases cardiac mortality risk in association with cardiac sympathetic function and renal function in patients with HF.

Background: The atherogenic characteristics of heterozygous familial hypercholesterolemia (HeFH) increase the risk of premature atherosclerotic cardiovascular disease including not only coronary artery disease but ischemic stroke. Asymptomatic intracranial artery stenosis/occlusion (IASO) is a major cause of ischemic stroke, but it has not yet been fully characterized in patients with HeFH., Methods and Results: This study analyzed 147 clinically diagnosed subjects with HeFH who underwent magnetic resonance imaging/magnetic resonance angiography imaging for evaluation of IASO (≥50% diameter stenosis). Major adverse cerebrovascular and cardiovascular events (cardiac death, ischemic stroke, and acute coronary syndrome) were compared in patients with HeFH with and without asymptomatic IASO. Asymptomatic IASO was observed in 13.6% of patients with HeFH. The untreated low-density lipoprotein cholesterol level (240±95 versus 244±75 mg/dL; P =0.67) did not differ between the 2 groups. Despite the use of lipid-lowering therapies (statin, P =0.71; high-intensity statin, P =0.81; ezetimibe, P =0.33; proprotein convertase subxilisin/kexin type 9 inhibitor, P =0.39; low-density lipoprotein apheresis, P =0.14), on-treatment low-density lipoprotein cholesterol level in patients with both HeFH and IASO was still suboptimally controlled (97±62 versus 105±50 mg/dL; P =0.17), accompanied by a higher triglyceride level (median, 109 versus 79 mg/dL; P =0.001). During the 12.4-year observational period (interquartile range, 6.2-24.6 years), asymptomatic IASO exhibited a 4.04-fold greater likelihood of experiencing a major adverse cardiovascular event (95% CI, 1.71-9.55; P =0.001) in patients with HeFH. This increased risk of a major adverse cardiovascular event was consistently observed in a multivariate Cox proportional hazards model adjusting clinical characteristics (hazard ratio, 4.32 [95% CI, 1.71-10.9]; P =0.002)., Conclusions: A total of 13.6% of Japanese subjects with HeFH presented with asymptomatic IASO. Despite lipid-lowering therapies, patients with both HeFH and IASO more likely had elevated risk of cerebrovascular and cardiovascular events. Our findings highlight asymptomatic IASO as a phenotypic feature of HeFH-related atherosclerosis, which ultimately affects future outcomes.

Background: Fibrosis is a common final pathway leading to end-stage renal failure. As the renal medulla and cortex contain different nephron segments, we analyzed the factors associated with the progression of renal medullary and cortical fibrosis., Methods: A total of 120 patients who underwent renal biopsy at Kawashima Hospital between May 2019 and October 2022 were enrolled in this retrospective study. Renal medullary and cortical fibrosis and stiffness were evaluated using Masson's trichrome staining and shear wave elastography, respectively. Maximum urine osmolality in the Fishberg concentration test was also examined., Results: Medullary fibrosis was positively correlated with cortical fibrosis (p < 0.0001) and log-converted urinary β2-microglobulin (MG) (log urinary β2-MG) (p = 0.022) and negatively correlated with estimated glomerular filtration rate (eGFR) (p = 0.0002). Cortical fibrosis also correlated with log urinary β2-MG, eGFR, and maximum urine osmolality. Multivariate analysis revealed that cortical fibrosis levels (odds ratio [OR]: 1.063) and medullary stiffness (OR: 1.089) were significantly associated with medullar fibrosis (≧45%). The severe fibrosis group with both medullary fibrosis (≧45%) and cortical fibrosis (≧25%) had lower eGFR and maximum urine osmolality values and higher urinary β2-MG levels than the other groups., Conclusions: Patients with disorders involving both renal medullary and cortical fibrosis had decreased maximum urine osmolality but had no abnormalities in the urinary concentrating capacities with either condition. Renal medullary and cortical fibrosis were positively correlated with urinary β2-MG, but not with urinary N-acetyl-beta-D-glucosaminidase., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Purpose: Robotic-assisted thoracoscopic surgery (RATS) is a relatively new approach to lung cancer surgery. To promote the development of RATS procedures, we investigated the factors related to short-term postoperative outcomes., Methods: We analyzed the records of patients who underwent RATS lobectomy for primary lung cancer at our institution between June, 2018 and January, 2023. The primary outcome was operative time, and the estimated value of surgery-related factors was calculated by linear regression analysis. The secondary outcome was surgical morbidity and the risk was assessed by logistic regression analysis., Results: The study cohort comprised 238 patients. Left upper lobectomy had the longest mean operative time, followed by right upper lobectomy. Postoperative complications occurred in 13.0% of the patients. Multivariate analysis revealed that upper lobectomy, the number of staples used for interlobular fissures, and the number of cases experienced by the surgeon were significantly associated with a longer operative time. The only significant risk factor for postoperative complications was heavy smoking., Conclusion: Patients with well-lobulated middle or lower lobe lung cancer who are not heavy smokers are recommended for the introductory period of RATS lobectomy. Improving the procedures for upper lobectomy and dividing incomplete interlobular fissures will promote the further development of RATS., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Immune checkpoint inhibitors are the leading approaches in tumor immunotherapy. The aim of the study was to establish recommended phase 2 doses (RP2Ds) of intravenous cetrelimab, a checkpoint inhibitor, alone and with oral erdafitinib in Japanese patients with advanced solid tumors. This open-label, non-randomized, dose-escalation phase 1/1b study enrolled adults with advanced solid tumors who were ineligible for standard therapy. Study was conducted in two parts: phase 1a assessed cetrelimab at three dosing levels (80 mg every 2 weeks [Q2W], 240 mg Q2W, and 480 mg Q4W); phase 1b assessed cetrelimab+erdafitinib at two dosing levels (240 mg Q2W + 6 mg once daily [QD] and 240 mg Q2W + 8 mg QD). Primary endpoint was frequency and severity of dose-limiting toxicities (DLTs) of cetrelimab ± erdafitinib. In total 22 patients (phase 1a, n = 9; phase 1b, n = 13) were enrolled. Median duration of follow-up was 8.64 months in phase 1a and 2.33 months in phase 1b. In phase 1a, DLTs weren't reported while in phase 1b, 1 patient who received 240 mg cetrelimab + 6 mg erdafitinib reported Stevens-Johnson syndrome (grade 3, immune-related). Overall, 88.9% patients in phase 1a (grade ≥ 3: 44.4%) and 100.0% in phase 1b (grade ≥ 3: 53.8%) experienced ≥ 1 treatment-related adverse events (TEAEs); 33.3% in phase 1a and 38.5% in phase 1b reported serious TEAEs, of which 11.1% patients in phase 1a and 15.4% in phase 1b had TEAEs which led to treatment discontinuation. Cetrelimab alone and in combination with erdafitinib showed manageable safety in Japanese patients with advanced solid tumors. RP2Ds were determined as 480 mg cetrelimab Q4W for monotherapy, and cetrelimab 240 mg Q2W + erdafitinib 8 mg QD for combination therapy., (© 2024. The Author(s).)

Fabry disease is an X-linked hereditary disorder caused by deficient α-galactosidase A (GLA) activity. Patients with Fabry disease are often treated with enzyme replacement therapy (ERT). However, ERT often induces the formation of neutralizing antidrug antibodies (ADAs), which may impair the therapeutic efficacy. Here, we report the case of a 32-year-old man with Fabry disease and resultant neutralizing ADAs who was treated by switching from agalsidase-α to agalsidase-β. We monitored biomarkers, such as plasma globotriaosylsphingosine (lyso-Gb3), urinary globotriaosylceramide (Gb3), urinary mulberry bodies, renal and cardiac parameters, and disease severity during the treatment period. Although plasma lyso-Gb3 and urinary Gb3 levels quickly decreased within two months after the initiation of ERT with agalsidase-α, they gradually increased thereafter. The urinary mulberry bodies continued to appear. Both the ADA titer and serum mediated GLA inhibition rates started to increase after two months. Moreover, 3.5 years after ERT, the vacuolated podocyte area in the renal biopsy decreased slightly from 23.1 to 18.9%. However, plasma lyso-Gb3 levels increased, and urinary Gb3, mulberry body levels, and ADA titers remained high. Therefore, we switched to agalsidase-β which reduced, but did not normalize, plasma lyso-Gb3 levels and stabilized renal and cardiac parameters. Disease severity was attenuated. However, urinary Gb3 and mulberry body levels did not decrease noticeably in the presence of high ADA titers. The kidneys take up a small amount of the administered recombinant enzyme, and the clearance of Gb3 that has accumulated in the kidney may be limited despite the switching from agalsidase-α to agalsidase-β., (© 2023. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Introduction: The distal tibial nail (DTN) is a novel retrograde intramedullary nail used for distal tibial fracture stabilization. We investigated the clinical results of DTN use for distal tibial fractures and compared them with those reported in the literature on locking plates and antegrade intramedullary nails., Materials and Methods: This multicenter, prospective, observational cohort study examined distal tibial fractures with AO/OTA classification 43 types: A1, A2, A3 or C1. The primary outcomes included bone union rate, soft tissue problems, and surgical complications. Secondary outcomes were EuroQol-5 Dimension-5 Level (EQ-5D-5L), Self-Administered Foot Evaluation Questionnaire (SAFE-Q), and American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot clinical scores 1 year postoperatively. Incidence of varus or valgus/anterior-posterior flexion deformity with a difference of ≥5° and postoperative reduction loss rate were evaluated., Results: Five men and five women were enrolled (mean age, 69 years [range, 30-77 years]), including one open-fracture-type Gustilo type IIIB case. Bone union was observed in all patients at 6 months postoperatively. Delayed union, leg edema, and guide pin breakage were observed in three, one, and one cases, respectively. No soft tissue or surgical complications were observed. During the final follow-up, the EQ-5D-5L, SAFE-Q, and AOFAS hindfoot scores were 0.876 (0.665-1.0), 83-92, and AOFAS 92.6 (76-100), respectively. Varus and retroflexion deformities were observed in one case each., Discussion: DTN has been reported to have biomechanically equivalent or stronger fixation strength than locking plates or antegrade intramedullary nails. In addition, while DTN was thought to be less invasive for soft tissue and can avoid injury to the knee, it was thought that care should be taken to avoid medial malleolus fractures and posterior tibialis tendon injuries. Comparisons with literature treatment results for locking plates and antegrade intramedullary nails showed comparable to advantageous results., Conclusions: DTN treatment results for distal tibial fractures were as good as those for locking plates and antegrade intramedullary nails. DTN is useful for stabilization and does not compromise the surrounding soft tissues., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: 123 I-meta-iodobenzylguanidine (mIBG) has been applied to patients with chronic heart failure (CHF). However, the relationship between 123 I-mIBG activity and lethal arrhythmic events (ArE) is not well defined. This study aimed to determine this relationship in Japanese and European cohorts., Results: We calculated heart-to-mediastinum (H/M) count ratios and washout rates (WRs) of 827 patients using planar 123 I-mIBG imaging. We defined ArEs as sudden cardiac death, arrhythmic death, and potentially lethal events such as sustained ventricular tachycardia, cardiac arrest with resuscitation, and appropriate implantable cardioverter defibrillator (ICD) discharge, either from a single ICD or as part of a cardiac resynchronization therapy device (CRTD). We analyzed the incidence of ArE with respect to H/M ratios, WRs and New York Heart Association (NYHA) functional classes among Japanese (J; n = 581) and European (E; n = 246) cohorts. We also simulated ArE rates versus H/M ratios under specific conditions using a machine-learning model incorporating 13 clinical variables. Consecutive patients with CHF were selected in group J, whereas group E comprised candidates for cardiac electronic devices. Groups J and E mostly comprised patients with NYHA functional classes I/II (95%) and II/III (91%), respectively, and 21% and 72% were respectively implanted with ICD/CRTD devices. The ArE rate increased with lower H/M ratios in group J, but the relationship was bell-shaped, with a high ArE rate within the intermediate H/M range, in group E. This bell-shaped curve was also evident in patients with NYHA classes II/III in the combined J and E groups, particularly in those with a high (> 15%) mIBG WR and with ischemic, but not in those with non-ischemic etiologies. Machine learning-based prediction of ArE risk aligned with these findings, indicating a bell-shaped curve in NYHA class II/III but not in class I., Conclusions: The relationship between cardiac 123 I-mIBG activity and lethal arrhythmic events is influenced by the background of patients. The bell-shaped relationship in NYHA classes II/III, high WR, and ischemic etiology likely aids in identifying patients at high risk for ArEs., (© 2024. The Author(s).)

Activated microglia contribute to many neuroinflammatory diseases in the central nervous system. In this study, we attempted to identify an anti-inflammatory compound that could suppress microglial activation. We performed high-throughput screening with a chemical library developed at our institute. We performed a luciferase assay of nuclear factor-kappa B (NF-κB) reporter stable HT22 cells and identified a compound that was confirmed to inhibit the anti-inflammatory response in BV2 microglial cells. The selected dihydropyridine derivative can suppress the expression response of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF), as well as NF-κB phosphorylation and nuclear translocation, and reduce the intracellular calcium level. Thus, our identified compound has a potential role in suppressing microglial activation and may contribute to the development of a new therapeutic molecule against neuroinflammatory diseases.

Objectives: This study was conducted to verify the effectiveness of Anterior Support Screw (AS2) for unstable femoral trochanteric fractures., Design: A multicenter, prospective, randomized controlled trial SETTING: This study was conducted across 15 academic medical centers in Japan PATIENTS/PARTICIPANTS: We enrolled 240 cases of femoral trochanteric fractures with posterior crushing and intramedullary displacement of proximal bone fragments across 15 institutions in Japan., Intervention: All patients were subjected to a reduction in which the anterior cortex was brought into contact. The patients were randomly assigned to the anterior support screw group (AS2 group) and the non-screw group (control group)., Main Outcome Measurements: Two computed-tomography (CT) scans were taken immediately after surgery and early postoperative period (day 14-21) to investigate the reduction loss rate of the anterior cortex and sliding distances in the early postoperative period., Results: The reduction loss rate was 4.5 % in the AS2 group and 16.8 % in the control group, indicating a significantly lower reduction loss rate in the AS2 group (p = 0.003). The average sliding distance was 1.8 mm in the AS2 group and 2.8 mm in the control group, indicating a significantly shorter sliding distance in the AS2 group (p < 0.0001)., Conclusion: Adding a screw in front of the intramedullary nail significantly reduces reduction loss, and maintains anterior bony contact. This study also showed that these screws suppress the sliding distance during the postoperative period., Level of Evidence: Therapeutic Level I., Competing Interests: Declaration of competing interest In this study, Zimmer Biomet and its affiliates were involved in preparing research implementation plans, research management, and statistical analysis. Each research institution receives research funds from Zimmer Biomet in return for the data provided., (Copyright © 2024. Published by Elsevier Ltd.)

Maintaining the mucus layer is crucial for the innate immune system. Urolithin A (Uro A) is a gut microbiota-derived metabolite; however, its effect on mucin production as a physical barrier remains unclear. This study aimed to elucidate the protective effects of Uro A on mucin production in the colon. In vivo experiments employing wild-type mice, NF-E2-related factor 2 (Nrf2)-deficient mice, and wild-type mice treated with an aryl hydrocarbon receptor (AhR) antagonist were conducted to investigate the physiological role of Uro A. Additionally, in vitro assays using mucin-producing cells (LS174T) were conducted to assess mucus production following Uro A treatment. We found that Uro A thickened murine colonic mucus via enhanced mucin 2 expression facilitated by Nrf2 and AhR signaling without altering tight junctions. Uro A reduced mucosal permeability in fluorescein isothiocyanate-dextran experiments and alleviated dextran sulfate sodium-induced colitis. Uro A treatment increased short-chain fatty acid-producing bacteria and propionic acid concentration. LS174T cell studies confirmed that Uro A promotes mucus production through the AhR and Nrf2 pathways. In conclusion, the enhanced intestinal mucus secretion induced by Uro A is mediated through the actions of Nrf-2 and AhR, which help maintain intestinal barrier function., (© 2024. The Author(s).)

Cancer is a common health problem worldwide. Early cancer education for adolescents and young adults (AYAs) is important for the prevention or early detection of cancer. In this questionnaire-based cross-sectional study, we examined the cancer awareness among parents of AYAs. Japanese adults with junior or senior high school children were included in this study. The cancer awareness measure (CAM) was used to assess cancer awareness, and the survey was conducted in December 2021. Warning signs, barriers to seeking help, and risk factors were surveyed using an online anonymous questionnaire. In addition, personal information, the presence of other cancer survivors, attendance at cancer seminars, conversations with children about cancer, interest in cancer education for children, and previous cancer screening were surveyed. A t-test or Spearman correlation coefficient was used to compare the total CAM scores for the individual factors. The relationship between cancer-screening behavior and individual factors was analyzed using the χ2 test. In addition, multiple regression analysis or logistic regression analysis was used to identify the factors influencing cancer awareness or cancer-screening behavior. Responses were obtained from the 612 participants. The mean CAM score was 3.7 for cancer warning signs, 4.3 for barriers to seeking help, and 6.5 for risk factors. Cancer warning signs were associated with gender and the presence of a spouse, family member, or friend who had experienced cancer. Barriers to seeking help were associated with age, gender, and education, while risk factors were associated with gender, education, and conversations about cancer with children. Moreover, these scores were associated with each cancer screening behavior. Cancer awareness among Japanese adults with AYAs was influenced by gender, academic background, occupation, the presence of cancer survivors around them, and whether they had conversations about cancer with their children, as well as their cancer screening behavior., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: First-line pembrolizumab plus chemotherapy (pembrolizumab-chemotherapy) demonstrated improved efficacy and a manageable safety profile versus placebo plus chemotherapy (placebo-chemotherapy) in the subgroup analysis of Japanese patients with advanced/metastatic esophageal cancer in KEYNOTE-590 at a median follow-up of 24.4 months. Longer-term data from the Japanese subgroup analysis of KEYNOTE-590 are reported., Methods: Patients were randomly assigned 1:1 to pembrolizumab 200 mg or placebo every 3 weeks for ≤ 35 cycles plus chemotherapy (cisplatin 80 mg/m 2 and 5-fluorouracil 800 mg/m 2 /day). Endpoints included overall survival (OS) and progression-free survival (PFS; investigator-assessed per RECIST v1.1; dual primary) and safety (secondary). Early tumor shrinkage (ETS) and depth of response (DpR) were assessed post hoc., Results: Overall, 141 patients were enrolled in Japan. As of July 9, 2021, median follow-up was 36.6 months (range, 29.8-45.7). Pembrolizumab-chemotherapy showed a trend toward favorable OS (hazard ratio [HR], 0.70; 95% confidence interval [CI] 0.47-1.03) and PFS (0.57; 0.39-0.83) versus placebo-chemotherapy. In the pembrolizumab-chemotherapy group, patients with ETS ≥ 20% (55/74; 74.3%) versus < 20% (19/74; 25.7%) had favorable OS (HR, 0.23; 95% CI 0.12-0.42) and PFS (0.24; 0.13-0.43). Patients with DpR ≥ 60% (31/74; 41.9%) versus < 60% (43/74; 58.1%) had favorable OS (HR, 0.37; 95% CI 0.20-0.68) and PFS (0.24; 0.13-0.43). Grade 3-5 treatment-related adverse events occurred in 55/74 patients (74.3%) with pembrolizumab-chemotherapy and 41/67 patients (61.2%) with placebo-chemotherapy., Conclusions: With longer-term follow-up of Japanese patients with advanced/metastatic esophageal cancer, efficacy continued to favor pembrolizumab-chemotherapy compared with placebo-chemotherapy, with no new safety signals observed., Clinical Trial Registration: ClinicalTrials.gov, NCT03189719., (© 2024. The Author(s).)

Aim: We studied the effects of overhydration (OH), Kt/Vurea and β2-microglobulin (β2-MG) on coronary artery calcification and mortality in patients undergoing haemodialysis (HD)., Methods: The Agatston coronary artery calcium score (CACS), postdialysis body composition using bioimpedance analysis, single-pool Kt/Vurea and predialysis β2-MG at baseline were assessed and followed up for 3 years in patients undergoing HD. We performed logistic regression analyses for a CACS ≥400 and Cox proportional hazard analyses for all-cause and cardiovascular mortality., Results: The study involved 338 patients with a median age of 67 (56-74) years, dialysis duration of 70 (33-141) months and diabetes prevalence of 39.1% (132/338). Patients with a CACS ≥400 (n = 222) had significantly higher age, dialysis duration, male prevalence, diabetes prevalence, C-reactive protein, predialysis β2-MG, OH, extracellular water/total body water and overhydration/extracellular water (OH/ECW) but significantly lower Kt/Vurea than patients with a CACS <400 (n = 116) (p < .05). OH/ECW, Kt/Vurea and predialysis β2-MG were significant predictors of a CACS ≥400 (p < .05) after adjusting for age, dialysis duration, serum phosphate and magnesium. In all patients, cut-off values of OH/ECW, Kt/Vurea and predialysis β2-MG for a CACS ≥400 were 16%, 1.74 and 28 mg/L, respectively. After adjusting for dialysis duration, OH/ECW ≥16%, Kt/Vurea ≥1.74 and β2-MG ≥28 mg/L were significant predictors of 3-year all-cause mortality but not 3-year cardiovascular mortality., Conclusion: Higher OH/ECW, higher predialysis β2-MG and lower Kt/Vurea values are significant risk factors for a CACS ≥400 and 3-year all-cause mortality in patients undergoing maintenance HD., (© 2024 Asian Pacific Society of Nephrology.)

Aim: The effects of iron on vascular calcification in rats and vascular smooth muscle cells were recently reported, but clinical studies on iron and vascular calcification are scant. We studied the associations of absolute iron deficiency, coronary artery calcification and mortality in patients with maintenance haemodialysis (MHD)., Methods: Transferrin saturation (TSAT), ferritin, mean corpuscular haemoglobin (MCH) and Agatston coronary artery calcium score (CACS) were studied at baseline in MHD patients and followed up for 3 years. Cox proportional hazard analyses for mortality and linear regression analyses for CACS were performed., Results: In 306 patients, the median age was 67 (56-81) years, dialysis duration was 76 (38-142) months, and diabetes prevalence was 42.5%. Fifty-two patients had died by 3 years. Patients with absolute iron deficiency (TSAT <20% and ferritin <100 ng/mL) (n = 102) showed significantly higher CACS (p = .0266) and C-reactive protein (p = .0011), but a lower frequency of iron formulation administration compared with patients without absolute iron deficiency at baseline (n = 204). Absolute iron deficiency was a significant predictor for 3-year cardiovascular (CV) mortality (hazard ratio: 2.08; p = .0466), but not for 3-year all-cause mortality. CACS was significant predictor for both 3-year CV and all-cause mortality (p <.05). Absolute iron deficiency and MCH were significant determinants of CACS (p < .05)., Conclusion: MHD patients with absolute iron deficiency showed significantly higher CACS than others, and absolute iron deficiency was a significant risk factor for coronary artery calcification and 3-year CV mortality in MHD patients, but was not a significant predictor for 3-year all-cause mortality., (© 2024 Asian Pacific Society of Nephrology.)

Purpose: NPB-22 (quinolin-8-yl 1-pentyl-1H-indazole-3-carboxylate), Adamantyl-THPINACA (N-(1-adamantantyl)-1-[(tetrahydro-2H-pyran-4-yl)methyl]-1H-indazole-3-carboxamide), and CUMYL-4CN-B7AICA (1-(4-cyanobutyl)-N-(2-phenylpropan-2-yl)-1H- pyrrolo[2,3-b]pyridine-3-carboxamide), synthetic cannabinoids were evaluated in terms of CB 1 (cannabinoid receptor type 1) and CB 2 (cannabinoid receptor type 2) activities, and their biological effects when inhaled similar to cigarettes were examined., Methods: The half maximal effective concentration values of the aforementioned synthetic cannabinoids at the CB 1 and CB 2 were investigated using [ 35 S]guanosine-5'-O-(3-thio)-triphosphate binding assays. In addition, their biological effects were evaluated using the inhalation exposure test with mice. The smoke generated was recovered by organic solvents in the midget impingers, and the thermal degradation compounds of the smoke components were identified and quantified using a liquid chromatography-photo diode array detector., Results: NPB-22 and Adamantyl-THPINACA had equivalent CB 1 activity in in vitro assays. Meanwhile, NPB-22 had a weaker biological effect on some items on the inhalation exposure test than Adamantyl-THPINACA. When analyzing organic solvents in the midget impingers, it was revealed that NPB-22 was degraded to 8-quinolinol and pentyl indazole 3-carboxylic acid by combustion. In addition, these degradation compounds did not have CB 1 activity., Conclusion: It was estimated that the biological effects of NPB-22 on the inhalation exposure test weakened because it underwent thermal degradation by combustion, and the resultant degradation compounds did not have any CB 1 activity in vitro., (© 2024. The Author(s).)

Purpose: To evaluate the safety and efficacy of new staple-line reinforcement (SLR) in pulmonary resection through a prospective study and to compare the results of this study with historical control data in an exploratory study., Methods: The subjects of this study were 48 patients who underwent thoracoscopic lobectomy. The primary endpoint was air leakage from the staple line. The secondary endpoints were the location of air leakage, duration of air leakage, and postoperative pulmonary complications., Results: The incidence of intraoperative air leakage from the staple line was 6.3%. Three patients had prolonged air leakage as a postoperative pulmonary complication. No malfunction was found in patients who underwent SLR with the stapling device. When compared with the historical group, the SLR group had a significantly lower incidence of air leakage from the staple line (6.3% vs. 28.5%, P < 0.001) and significantly shorter indwelling chest drainage time (P = 0.049) and length of hospital stay (P < 0.001)., Conclusions: The use of SLR in pulmonary resection was safe and effective. When compared with conventional products, SLR could control intraoperative air leakage from the staple line and shorten time needed for indwelling chest drainage and the length of hospital stay., (© 2024. The Author(s).)

Competing Interests: The authors declare that they have no conflict of interest.

Introduction: Although the prognosis of Langerhans cell histiocytosis (LCH) is excellent, the high recurrence rate and permanent consequences, such as central diabetes insipidus and LCH-associated neurodegenerative diseases, remain to be resolved. Based on previous reports that patients with high-risk multisystem LCH show elevated levels of inflammatory molecules, we hypothesised that dexamethasone would more effectively suppress LCH-associated inflammation, especially in the central nervous system (CNS). We further hypothesised that intrathecal chemotherapy would effectively reduce CNS complications. We administer zoledronate to patients with multifocal bone LCH based on an efficacy report from a small case series., Methods and Analysis: This phase II study (labelled the LCH-19-MSMFB study) is designed to evaluate the significance of introducing dexamethasone and intrathecal chemotherapy for multisystem disease and zoledronate for multifocal bone disease in previously untreated, newly diagnosed children, adolescents (under 20 years) and adults under 40 years. The primary endpoint is the 3-year event-free survival rate by risk group of under 20 years and the 3-year event-free survival rate of 20 years and over., Ethics and Dissemination: This study was approved by the Central Review Board of the National Hospital Organisation Nagoya Medical Centre (Nagoya, Japan) on 21 January 2022 and was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp/en-latest-detail/jRCTs041210027). Written informed consent will be obtained from all patients and/or their guardians., Trial Registration Number: jRCTs041210027., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: A previous study suggested older drivers with subjective memory concerns (SMC) had increased odds of experiencing car collisions, but whether SMC in different contexts and the number of SMC applicable items change this association is unknown. The aim of this study was to examine the association between SMC and car collisions among older drivers in Japan., Methods: This cross-sectional study was conducted using data from a Japanese community-based cohort study. Participants were community-dwelling older adults aged ≥60 years. SMC was assessed using five questions: 1) "Do you feel you have more problems with memory than most?" 2) "Do you have any difficulty with your memory?" 3) "Do you forget where you have left things more than you used to?" 4) "Do you forget the names of close friends or relatives?" and 5) "Do other people find you forgetful?" Participants were asked about their experiences with car collisions during the previous two years., Results: A total of 13,137 older drivers (72.1 ± 5.5 years old, and 43.6 % female) were analyzed. Cochran-Armitage trend test showed that as the number of SMC applicable items increased, the percentage of the experiences of car collisions significantly increased (6.8 %-15.8 %, P < 0.001). Logistic regression models showed each SMC question was associated with an increased odds ratio (OR) of car collisions (OR 1.26 to 1.71, all P < 0.001) after adjusting for confounding factors. As the number of SMC applicable items increased, the OR of car collisions significantly increased (OR 1.19 to 2.28, all P < 0.05, P for trend <0.001)., Conclusions: This cross-sectional study among community-dwelling older drivers in Japan suggested each SMC question and the number of applicable items were associated with car collisions. SMC may be a sign of increased risk of traffic incidents for older drivers., Competing Interests: None., (© 2024 The Authors.)

The design and synthesis of N-desmethyl and N-methyl destruxin E analogs have been demonstrated. The X-ray single crystal structure of destruxin E (1a) revealed a stable three-dimensional (3D) structure, including a s-cis amide bond at the MeVal-MeAla moiety and two intramolecular hydrogen bonds between NH(β-Ala) and OC(Ile) and between NH(Ile) and OC(β-Ala). N-Desmethyl analogs 2a (MeAla → Ala) and 2b (MeVal → Val) were synthesized through macrolactonization similar to our previously reported synthesis of 1a. Conversely, for the synthesis of N-methyl analogs 2c (Ile → MeIle) and 2d (β-Ala → Meβ-Ala), macrolactonization did not proceed; therefore, cyclization precursors 10c and 10d were designed to maintain the intramolecular hydrogen bonds described above during their cyclization. The macrolactamization proceeded despite the presence of a less reactive N-methylamino group at the N-terminus in both cases. Analog 2a, which exhibits multiple conformers in solutions, was inactive at 50 μM, whereas analog 2b, which exhibits a conformation similar to that of 1a in solutions, exhibited morphological changes against osteoclast-like multinuclear cells at 1.6 μM. The activity of the MeIle analog 2c, which cannot take the intramolecular hydrogen bond (Ile)NH•••OC(β-Ala) in 1a, was markedly diminished compared with that of 1a, and that of the Meβ-Ala analog 2d, which cannot take the intramolecular hydrogen bond (β-Ala)NH•••OC(Ile) in 1a, was further reduced to one-fourth of that of 2c. The overall results indicate that both the s-cis amide bond at the MeVal-MeAla moiety and two intramolecular hydrogen bonds (β-Ala)NH•••OC(Ile) and (Ile)NH•••OC(β-Ala) are important for constraining the conformation of the macrocyclic peptide backbone in destruxin E, thereby exhibiting its potent biological activity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Takayuki Doi reports financial support was provided by Mitsubishi Tanabe Pharma Corporation. Masahito Yoshida reports financial support was provided by Uehara Memorial Foundation. Masahito Yoshida reports financial support was provided by Takeda Science Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

We encountered a 64-year-old woman who experienced fulminant myocarditis and underwent treatment with veno-arterial extracorporeal membrane oxygenation and Impella CP support. Subsequently, she underwent a device upgrade to Impella 5.5 and received continuous hemodiafiltration for 3 months. During mechanical circulatory support, she developed refractory anemia and thrombocytopenia, leading to a diagnosis of myelodysplastic syndrome. Following the removal of the devices, she no longer required blood transfusions. She received HeartMate 3 left ventricular assist device implantation as a destination therapy indication despite the presence of myelodysplastic syndrome. She was successfully managed by aspirin-free antithrombotic therapy without any hemocompatibility-related adverse events for 4 months after index discharge on foot. We present a patient with a unique and rare presentation, wherein HeartMate 3 was implanted and successfully managed without aspirin to prevent bleeding complications associated with myelodysplastic syndrome., (© 2024. The Japanese Society for Artificial Organs.)

Caspase-4 (CASP4) is a member of the inflammatory caspase subfamily and promotes inflammation. Here, we report that CASP4 in lung adenocarcinoma cells contributes to both tumor progression via angiogenesis and tumor hyperkinesis and tumor cell killing in response to high interferon (IFN)-γ levels. We observe that elevated CASP4 expression in the primary tumor is associated with cancer progression in patients with lung adenocarcinoma. Further, CASP4 knockout attenuates tumor angiogenesis and metastasis in subcutaneous tumor mouse models. CASP4 enhances the expression of genes associated with angiogenesis and cell migration in lung adenocarcinoma cell lines through nuclear factor kappa-light chain-enhancer of activated B cell signaling without stimulation by lipopolysaccharide or tumor necrosis factor. CASP4 is induced by endoplasmic reticulum stress or IFN-γ via signal transducer and activator of transcription 1. Most notably, lung adenocarcinoma cells with high CASP4 expression are more prone to IFN-γ-induced pyroptosis than those with low CASP4 expression. Our findings indicate that the CASP4 level in primary lung adenocarcinoma can predict metastasis and responsiveness to high-dose IFN-γ therapy due to cancer cell pyroptosis., (© 2024. The Author(s).)

Background and Aims: The PROMINENT trial, a cardiovascular outcome trial of the triglyceride- and remnant cholesterol-lowering agent pemafibrate, has shown neutral results despite reduction in plasma triglycerides and remnant cholesterol. We tested the hypothesis that absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B explain the results of the PROMINENT trial., Methods: Among 108,431 individuals from the Copenhagen General Population Study (CGPS), those who met the key inclusion criteria of the PROMINENT trial were analyzed to mimic the trial design. Endpoint atherosclerotic cardiovascular disease (ASCVD) was cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization as defined in PROMINENT., Results: In the PROMINENT trial, treatment with pemafibrate resulted in -7 mg/dL (-0.18 mmol/L; -18 %) change in remnant cholesterol, +10 mg/dL (+0.26 mmol/L; +12 %) LDL cholesterol, and +5 mg/dL (+0.05 g/L; +5 %) apolipoprotein B. In the CGPS mimicking PROMINENT, the estimated hazard ratios for ASCVD were 0.97 (95 % confidence interval: 0.94-0.99) for a -7 mg/dL (-0.18 mmol/L) change in remnant cholesterol, 1.04 (1.01-1.07) for a +10 mg/dL (+0.26 mmol/L) change in LDL cholesterol, and 1.02 (1.01-1.03) for a +5 mg/dL (+0.05 g/L) change in apolipoprotein B. When combining absolute changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B, the estimated hazard ratio for ASCVD was 1.05 (0.96-1.14) in the CGPS mimicking PROMINENT compared to 1.03 (0.91-1.15) in the PROMINENT trial., Conclusions: Absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B can explain results of the PROMINENT trial. The 3 mg/dL (0.08 mmol/L) higher total atherogenic cholesterol together with 5 mg/dL (0.05 g/L) higher apolipoprotein B seem to explain the trend toward more ASCVD in the pemafibrate arm., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: BGN reports consultancies or talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Amarin, Kowa, Denka, Novartis, Novo Nordisk, Esperion, Silence Therapeutics, Abbott, Mankind, Lilly, and Arrowhead. TD reports a consultancy by Novo Nordisk. AL reports a talk sponsored by Amarin and a consultancy by Novartis., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Mucopolysaccharide polysulfate (MPS) is widely used as an active ingredient in topical preparations for the treatment of asteatosis and blood flow disorders. Although topical MPS products can increase cutaneous blood flow (CBF), the underlying mechanism remains unclear., Objective: In this study, we aimed to elucidate how MPS increases CBF. We investigated the association of nitric oxide (NO), a powerful mediator associated with increased local blood volume, with the blood flow-accelerating action of MPS in mice. In addition, we verified the effects of MPS on NO production in different skin cell types, such as keratinocytes (KCs), endothelial cells (ECs), and dermal fibroblasts (DFs)., Methods: We used raster-scanning optoacoustic imaging mesoscopy to observe in vivo changes in the skin blood volume. NO production was determined in each cell using an NO indicator. An enzyme-linked immunoassay was used to measure the phosphorylated nitric oxide synthase (NOS) levels in ECs, DFs, and KCs in the presence or absence of MPS., Results: Topical application of MPS increased the skin blood volume in mice, and this increase was abolished through the addition of NOS inhibitors. MPS promoted the dose-dependent production of NO in various cells, which caused alterations in the phosphorylation state of NOS., Conclusion: Our findings demonstrate that MPS promotes an increase in skin blood volume and NO production in various skin cell types. These results suggest that MPS can potentially accelerate CBF through the NO biosynthesis pathway in different skin cell types., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: TAS-117 is a highly potent and selective, oral, allosteric pan-AKT inhibitor under development for advanced/metastatic solid tumors. The safety, clinical pharmacology, pharmacogenomics and efficacy were investigated., Methods: This phase I, open-label, non-randomized, dose-escalating, first-in-human study enrolled patients with advanced/metastatic solid tumors and comprised three phases (dose escalation phase [DEP], regimen modification phase [RMP], and safety assessment phase [SAP]). The SAP dose and regimen were determined in the DEP and RMP. Once-daily and intermittent dosing (4 days on/3 days off, 21-day cycles) were investigated. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 of the DEP and RMP and incidences of adverse events (AEs) and adverse drug reactions (ADRs) in the SAP. Secondary endpoints included pharmacokinetics, pharmacodynamics, pharmacogenomics, and antitumor activity., Results: Of 66 enrolled patients, 65 received TAS-117 (DEP, n = 12; RMP, n = 10; SAP, n = 43). No DLTs were reported with 24-mg/day intermittent dosing, which was selected as a recommended dose in SAP. In the SAP, 98.5% of patients experienced both AEs and ADRs (grade ≥ 3, 67.7% and 60.0%, respectively). In the dose range tested (8 to 32 mg/day), TAS-117 pharmacokinetics were dose proportional, and pharmacodynamic analysis showed a reduction of phosphorylated PRAS40, a direct substrate of AKT. Four patients in the SAP had confirmed partial response., Conclusion: Oral doses of TAS-117 once daily up to 16 mg/day and intermittent dosing of 24 mg/day were well tolerated. TAS-117 pharmacokinetics were dose proportional at the doses evaluated. Antitumor activity may occur through AKT inhibition., Trial Registration: jRCT2080222728 (January 29, 2015)., (© 2024. The Author(s).)

An association between Hymenoptera (bee and wasp) stings and nephrotic syndrome has been rarely reported. We report a case of nephrotic syndrome after multiple Hymenoptera stings, and membranous nephropathy was later diagnosed by a kidney biopsy. The patient was a 79-year-old woman who was stung by Hymenoptera at seven sites on her body. A weight gain of 3.7 kg was observed in the patient at 1 week after being stung, and she had considerable edema in both lower extremities. A urine protein concentration of 14.8 g/g creatinine and a serum albumin concentration of 1.7 g/dL led to the diagnosis of nephrotic syndrome. A percutaneous kidney biopsy 8 days after the Hymenoptera stings showed stage I membranous nephropathy. She was in complete remission 1 week after the administration of oral prednisolone 40 mg/day, which was started 14 days after Hymenoptera stings, and had no relapse of nephrotic syndrome. To the best of our knowledge, this is the first report of biopsy-proven membranous nephropathy caused by Hymenoptera stings., (© 2023. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Introduction: We examined the efficacy of a multidomain intervention in preventing cognitive decline among Japanese older adults with mild cognitive impairment (MCI)., Methods: Participants aged 65-85 years with MCI were randomized into intervention (management of vascular risk factors, exercise, nutritional counseling, and cognitive training) and control groups. The primary outcome was changes in the cognitive composite score over a period of 18 months., Results: Of 531 participants, 406 completed the trial. The between-group difference in composite score changes was 0.047 (95% CI: -0.029 to 0.124). Secondary analyses indicated positive impacts of interventions on several secondary health outcomes. The interventions appeared to be particularly effective for individuals with high attendance during exercise sessions and those with the apolipoprotein E ε4 allele and elevated plasma glial fibrillary acidic protein levels., Discussion: The multidomain intervention showed no efficacy in preventing cognitive decline. Further research on more efficient strategies and suitable target populations is required., Highlights: This trial evaluated the efficacy of multidomain intervention in individuals with MCI. The trial did not show a significant difference in preplanned cognitive outcomes. Interventions had positive effects on a wide range of secondary health outcomes. Those with adequate adherence or high risk of dementia benefited from interventions., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Pembrolizumab plus epacadostat (indoleamine 2,3-dioxygenase-1 inhibitor) was well tolerated in Japanese patients with advanced solid tumors in part A of the nonrandomized, open-label, phase 1 KEYNOTE-434 study (NCT02862457). We report results from part B, which evaluated epacadostat plus pembrolizumab and chemotherapy in Japanese patients with advanced non-small-cell lung cancer (NSCLC)., Methods: Eligible patients aged ≥ 20 years had histologically or cytologically confirmed stage IIIB or IV NSCLC with no prior systemic therapy, and ECOG performance status of 0 or 1. Patients received epacadostat 100 mg orally twice-daily, pembrolizumab 200 mg intravenously every-3-weeks for ≤ 35 cycles, and 4 cycles of chemotherapy (cohort 1: cisplatin plus pemetrexed, non-squamous; cohort 2: carboplatin plus pemetrexed, non-squamous; cohort 3: carboplatin plus paclitaxel, squamous or non-squamous). Primary endpoint was incidence of dose-limiting toxicities (DLTs). Following unfavorable results from other studies, a protocol amendment removed epacadostat from the treatment combination., Results: Of 19 patients, 7 were enrolled in cohort 1, and 6 each in cohorts 2 and 3. Median follow-up was 13.7 (range, 4.2-27.8) months. Five of 17 (29%) DLT-evaluable patients experienced ≥ 1 DLT (cohort 1, n = 1; cohorts 2 and 3, n = 2 each); most commonly maculopapular rash (grade 3, n = 3) and increased alanine aminotransferase (grade 2, n = 1; grade 3, n = 2). All patients experienced treatment-related adverse events (AEs); 58% experienced grade 3 or 4 treatment-related AEs. Objective response rate was 47%., Conclusion: The combination of epacadostat plus pembrolizumab and chemotherapy was found to be tolerable in Japanese patients with advanced NSCLC., Trial Registration: ClinicalTrials.gov , NCT02862457., (© 2023. Merck & Co., Inc., Rahway, NJ, USA and its affiliates.)

Study Design: A prospective study., Objective: To measure 3-dimensional cervical range of motion (ROM) by noninvasive optical tracking-based motion-capture technology in patients undergoing laminoplasty, and to elucidate the postoperative effects of laminoplasty on cervical mobility., Summary of Background Data: Cervical laminoplasty is a motion-sparing decompression surgery for degenerative cervical myelopathy. Unlike cervical laminectomy and fusion, the true postoperative impact of laminoplasty on neck motion has not been well studied., Methods: Participants comprised 25 patients undergoing double-door cervical laminoplasty for degenerative cervical myelopathy in a single center. Maximum flexion/extension, left/right rotation, and left/right side bending were recorded using the motion-capture device preoperatively and 3 months postoperatively. ROMs in 3 orthogonal axes were calculated. Preoperative differences in C2-7 Cobb angles on lateral flexion/extension x-rays were also measured as the radiologic ROM to assess reliability. Preoperative and 1-year postoperative Japanese Orthopaedic Association score, Neck Disability Index [NDI], and Euro-QOL were recorded, and correlations with ROMs were assessed., Results: Preoperative mean (±SD) ROMs for flexion/extension, rotation, and side bending were 90±17, 107±16, and 53±17 degrees, respectively. Although radiologic sagittal ROM measurement showed a smaller range than motion capture, averaging 36±13 degrees, a moderate to strong correlation between radiologic and motion capture values was observed (R=0.57, P=0.003). Preoperative NDI showed a negative correlation with coronal ROM (rho=-0.547, P=0.02). Postoperative ROM showed a significant reduction in rotation (95±16 degrees, P=0.002) but not in flexion/extension or side bending., Conclusions: Three-dimensional motion-capture analysis allowed reliable measurement of cervical ROM. Rotational ROM was significantly reduced after laminoplasty, showing that cervical kinematics are still significantly altered., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In the KEYNOTE-590 study, first-line pembrolizumab plus chemotherapy provided statistically significant improvement in overall survival, progression-free survival, and objective response rate compared with chemotherapy, with a manageable safety profile in patients with advanced esophageal cancer. Prespecified health-related quality-of-life (HRQoL) outcomes are reported., Materials and Methods: Change from baseline to week 18 in the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/QoL (GHS/QoL) and QLQ-Esophageal cancer module (OES18) dysphagia, pain, and reflux scales were evaluated., Results: The HRQoL analysis included 730 patients who received treatment and completed ≥1 HRQoL assessment. Least squares mean (LSM) change from baseline to week 18 was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 reflux scales. The QLQ-OES18 dysphagia (LSM difference, -5.54; 95% CI, -10.93 to -0.16) and pain (LSM difference, -2.94; 95% CI, -5.86 to -0.02) scales favored pembrolizumab plus chemotherapy over placebo plus chemotherapy. Median time to confirmed deterioration (TTD) was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 dysphagia and reflux scales. Compared with chemotherapy, pembrolizumab plus chemotherapy prolonged median TTD, as seen on the QLQ-OES18 pain scale (HR, 0.69; 95% CI, 0.51 to 0.95)., Conclusion: The use of pembrolizumab plus chemotherapy maintained HRQoL at week 18 relative to baseline and was comparable with placebo plus chemotherapy. These HRQoL results together with published reports of efficacy, support the use of pembrolizumab plus chemotherapy as first-line therapy for advanced/metastatic esophageal cancer., Clinicaltrials.gov Id: NCT03189719., (© The Author(s) 2024. Published by Oxford University Press.)

E7820 and Indisulam (E7070) are sulfonamide molecular glues that modulate RNA splicing by degrading the splicing factor RBM39 via ternary complex formation with the E3 ligase adaptor DCAF15. To identify biomarkers of the antitumor efficacy of E7820, we treated patient-derived xenograft (PDX) mouse models established from 42 patients with solid tumors. The overall response rate was 38.1% (16 PDXs), and tumor regression was observed across various tumor types. Exome sequencing of the PDX genome revealed that loss-of-function mutations in genes of the homologous recombination repair (HRR) system, such as ATM, were significantly enriched in tumors that responded to E7820 (p = 4.5 × 10 3 ). Interestingly, E7820-mediated double-strand breaks in DNA were increased in tumors with BRCA2 dysfunction, and knockdown of BRCA1/2 transcripts or knockout of ATM, ATR, or BAP1 sensitized cancer cells to E7820. Transcriptomic analyses revealed that E7820 treatment resulted in the intron retention of mRNAs and decreased transcription, especially for HRR genes. This induced HRR malfunction probably leads to the synthetic lethality of tumor cells with homologous recombination deficiency (HRD). Furthermore, E7820, in combination with olaparib, exerted a synergistic effect, and E7820 was even effective in an olaparib-resistant cell line. In conclusion, HRD is a promising predictive biomarker of E7820 efficacy and has a high potential to improve the prognosis of patients with HRD-positive cancers., (© 2024. The Author(s).)

Purpose: Nurses' clinical reasoning skills regarding impaired swallowing can help prevent patient complications and maintain quality of life. Clinical reasoning skills need content-validated defining characteristics (DCs). We aimed to validate the content of these DCs for nursing diagnosis "impaired swallowing.", Methods: Content validation of the DCs was performed by 275 dysphagia nursing experts in Japan, using 3 rounds of the Delphi technique and Fehring's Diagnostic Content Validation (DCV) model. Three rounds of questionnaires on 84 DCs were completed via printed mail., Findings: The valid response rates for each round were as follows: round 1, 90.2%; round 2, 77.8%; and round 3, 71.3%. Of the 84 DCs, 77 that met the consensus criteria were categorized as major (n = 18), minor (n = 45), and excluded (n = 14). There were four minor DCs other than the oral, pharyngeal, and esophageal phases. DCs listed from outside NANDA-I included 12 major, 16 minor, and 3 excluded characteristics. Of the NANDA-I DCs, 5 were no consensus and 11 were excluded. The total DCV score for the 63 major and minor DCs was 0.8., Conclusions: Our results recommend the addition of 28 DCs and the exclusion of 11 for the NANDA-I nursing diagnosis "impaired swallowing" (00103). Major DCs were prominent indicators of impaired swallowing and signs of aspiration or pharyngeal residuals. Minor DCs included not only the three phases but also other signs necessary for a comprehensive understanding of impaired swallowing., Implications for Nursing Practice: This validation study strengthens the clinical usefulness of the DCs for impaired swallowing, which can improve nurses' clinical reasoning skills. Major and minor DCs can increase the awareness of impaired swallowing and enable accurate intervention, thereby preventing patient complications and maintaining quality of life., (© 2024 NANDA International, Inc.)

Accumulating evidence suggests that endothelial cells can be useful therapeutic targets. One of the potential targets is an endothelial cell-specific protein, Roundabout4 (ROBO4). ROBO4 has been shown to ameliorate multiple diseases in mice, including infectious diseases and sepsis. However, its mechanisms are not fully understood. In this study, using RNA-seq analysis, we found that ROBO4 downregulates prostaglandin-endoperoxide synthase 2 (PTGS2), which encodes cyclooxygenase-2. Mechanistic analysis reveals that ROBO4 interacts with IQ motif-containing GTPase-activating protein 1 (IQGAP1) and TNF receptor-associated factor 7 (TRAF7), a ubiquitin E3 ligase. In this complex, ROBO4 enhances IQGAP1 ubiquitination through TRAF7, inhibits prolonged RAC1 activation, and decreases PTGS2 expression in inflammatory endothelial cells. In addition, Robo4-deficiency in mice exacerbates PTGS2-associated inflammatory diseases, including arthritis, edema, and pain. Thus, we reveal the molecular mechanism by which ROBO4 suppresses the inflammatory response and vascular hyperpermeability, highlighting its potential as a promising therapeutic target for inflammatory diseases., (© 2024. The Author(s).)

Background: The early detection and prevention of many cancers is possible. Therefore, public awareness about cancer risk factors and warning signs must be increased to ensure early diagnosis. Although Japan has implemented mandatory cancer education in junior high and high schools, few studies have evaluated teachers' cancer awareness. This study aimed to determine Japanese junior high and high school teachers' awareness of cancer and related factors., Methods: This cross-sectional study obtained data through an online questionnaire survey using questions from the Cancer Awareness Measure (CAM) developed by Cancer Research UK. Thirty items were selected from three CAM modules: cancer risk factors, cancer warning signs, and barriers to seeking help. Descriptive statistics were used for socio-demografic data and CAM module questions. The χ 2 test was performed on the relationship between cancer awareness and socio-demographic data. Multiple logistic regression analysis was used to identify factors influencing cancer awareness., Results: Respondents included 316 junior high school and 463 high school teachers (541 men; 238 women; average age = 48.2 years; average teaching experience = 23.5 years). An average of 5.41 out of 11 cancer risk factors were recognized. More than 70% of teachers recognized smoking, exposure to another person's cigarette smoke, and having a close relative with cancer as risk factors. On average, 4.52 out of 9 cancer warning signs were recognized. More than 50% of teachers recognized the warning signs of unexplained lump or swelling, unexplained weight loss, and unexplained bleeding. Barriers to seeking help had a low average score of 4.51 out of 20. However, the most commonly recognized "barriers to seeking help" were "too busy to make time," "difficult to make an appointment," "worried about what the doctor might find," and "too scared." Moreover, the common factors that affected awareness of cancer risk factors and cancer warning signs were gender and cancer experience of relatives. Factors that affected awareness of "barriers to seeking help" were "participation in cancer-related workshops," age, gender, and cancer experience of relatives., Conclusions: Cancer awareness education should consider interventions that can improve knowledge of the symptoms and signs related to cancer without increasing the awareness of barriers to seeking help., (© 2024. The Author(s).)

Objective: This study investigates the relationship of living environment factors with satisfaction, work engagement, perceived productivity, and stress among teleworkers., Background: Given the increase in telecommuting since the onset of the pandemic, the study aims to identify how to create an optimum environment for telecommuting workers., Methods: By examining the relationships among these factors via multiple regression analysis, a comprehensive investigation of the telecommuting working environment is conducted, encompassing physical aspects and facilities as well as lifestyle rhythms and relationships with housemates. In doing so, the author identifies measures to create a more favorable living environment. The work environment of remote workers is examined from various perspectives using the framework of the SHEL model: Software (work content, lifestyle, etc .), Hardware (furniture, equipment, etc .), Environment (indoor environment), and Liveware (relationships with family members who reside with the worker)., Results: The results suggest that positive factors, such as satisfaction and work engagement, are strongly influenced by the degree of job autonomy and the availability of a workspace dedicated to personal use. Negative aspects, such as stress, are significantly impacted by environmental noise, interruptions due to household tasks, and the use of ergonomic furniture., Competing Interests: The author declares that they have no competing interests., (©2024 Doi.)

Treatment options for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) are improving. Current guidelines recommend first-line pembrolizumab plus chemotherapy for patients with unresectable or metastatic ESCC, which has led to improvements in survival outcomes. Antiangiogenic therapy combined with immune checkpoint inhibitors can act synergistically to convert the immunosuppressive tumor microenvironment to an immune supportive microenvironment, thus enhancing antitumor immune responses. In preclinical models, the antiangiogenic agent lenvatinib combined with an anti-PD-1 agent showed synergistic antitumor activity. We describe the design and rationale for the randomized, open-label, phase III LEAP-014 study of lenvatinib in combination with pembrolizumab plus chemotherapy in patients with advanced or metastatic ESCC. Overall survival and progression-free survival are the dual primary end points. Clinical Trial Registration: NCT04949256 (ClinicalTrials.gov).

BACKGROUND: Characteristics of taxane-induced peripheral neuropathy (PN) could be different between paclitaxel and nab-paclitaxel. The purpose of this prospective observational multicenter cohort study was to compare tri-weekly nab-paclitaxel to weekly standard paclitaxel regarding the severity, onset and recovery of sensory and motor PN in patients with breast cancer., Methods: Patients with histologically confirmed breast cancer who were scheduled to receive standard weekly paclitaxel (80 mg/m 2 ) or tri-weekly nab-paclitaxel (260 mg/m 2 ) at institutions in our multicenter group were eligible for this study. Sensory and motor PN were evaluated every 3 weeks until PN improved for up to one year using patient-reported outcome., Results: Between February 2011 and April 2013, 115 patients were enrolled, including 57 and 58 in the paclitaxel and nab-paclitaxel groups, respectively. The incidence of moderate or severe sensory PN was not significantly different between the two groups (p = 0.40). The incidence of moderate or higher motor PN was more frequent in the nab-paclitaxel group than in the paclitaxel group (p = 0.048). The median period for demonstrating PN were shorter in the nab-paclitaxel group than in the paclitaxel group (sensory, p = 0.003; motor, p = 0.001). The recovery of motor PN was slower in the nab-paclitaxel group than in the paclitaxel group (p = 0.035), while the recovery period of sensory PN was not statistically different., Conclusion: Nab-paclitaxel induced sensory PN sooner than paclitaxel, and no difference was observed in the severity and recovery duration between the two agents. Motor PN was more severe, started sooner, and improved over a longer period in the nab-paclitaxel-treated patients than in the paclitaxel-treated patients., (© 2024. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Driver oncogenes are investigated upfront at diagnosis using multi-CDx systems with next-generation sequencing techniques or multiplex reverse-transcriptase polymerase chain reaction assays. Additionally, from 2019, comprehensive genomic profiling (CGP) assays have been available in Japan for patients with advanced solid tumors who had completed or were expected to complete standard chemotherapy. These assays are expected to comprehensively detect the driver oncogenes, especially for patients with non-small cell lung cancer (NSCLC). However, there are no reports of nationwide research on the detection of driver oncogenes in patients with advanced NSCLC who undergo CGP assays, especially in those with undetected driver oncogenes at diagnosis. In this study, we investigated the proportion of driver oncogenes detected in patients with advanced NSCLC with undetectable driver oncogenes at initial diagnosis and in all patients with advanced NSCLC who underwent CGP assays. We retrospectively analyzed data from 986 patients with advanced NSCLC who underwent CGP assays between August 2019 and March 2022, using the Center for Cancer Genomics and Advanced Therapeutics database. The proportion of driver oncogenes newly detected in patients with NSCLC who tested negative for driver oncogenes at diagnosis and in all patients with NSCLC were investigated. Driver oncogenes were detected in 451 patients (45.7%). EGFR was the most common (16.5%), followed by KRAS (14.5%). Among the 330 patients with undetected EGFR, ALK, ROS1, and BRAF V600E mutations at diagnosis, 81 patients (24.5%) had newly identified driver oncogenes. CGP assays could be useful to identify driver oncogenes in patients with advanced NSCLC, including those initially undetected, facilitating personalized treatment., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The purpose of preoperative biliary drainage (PBD) is to reduce complications during the perioperative period. The extrahepatic bile duct comprises distal and hilar bile ducts and assessing the need for PBD must be considered separately for each duct, as surgical procedures and morbidities vary. The representative disease-causing distal bile duct obstruction is pancreatic cancer. A randomized controlled trial has revealed that PBD carries the risk of recurrent cholangitis and pancreatitis before surgery, thus eliminating the need for PBD when early surgery is feasible. However, neoadjuvant therapy has seen a rise in recent years, resulting in longer preoperative waiting periods and an increased demand for PBD. In such cases, metal stents are preferable to plastic stents due to their lower stent occlusion rates. When endoscopic transpapillary biliary drainage (EBD) is not viable, endoscopic ultrasound-guided biliary drainage may be a suitable substitute. In the hilar bile duct, the representative disease-causing obstruction is hilar cholangiocarcinoma. PBD's necessity has long been a subject of contention. In spite of earlier criticisms of routine PBD, recent views have emerged recommending PBD, particularly when major hepatectomy is required, to prevent postoperative liver failure. Given the risk of tumor seeding associated with percutaneous transhepatic biliary drainage, EBD is preferable. Nevertheless, as its shortcomings involve recurrent cholangitis until surgery due to stent or tube obstruction, it is necessary to seek out novel approaches to circumvent complications. In this review we summarize the current evidence for PBD in patients with distal and hilar biliary obstruction., (© 2024 Japan Gastroenterological Endoscopy Society.)

Study Design: A prospective, single-center, observational study., Objective: To explore the association between serum levels of bone turnover markers and ossification of the posterior longitudinal ligament (OPLL) in the thoracic spine., Summary of Background Data: The relationship between bone turnover markers, such as N-terminal propeptide of type I procollagen (PINP) or tartrate-resistant acid phosphate 5b (TRACP-5b), and OPLL has previously been examined. However, the correlation between these markers and thoracic OPLL, which is more severe than cervical-only OPLL, remains unclear., Methods: This prospective study included 212 patients from a single institution with compressive spinal myelopathy and divided them into those without OPLL (Non-OPLL group, 73 patients) and those with OPLL (OPLL group, 139 patients). The OPLL group was further subdivided into cervical OPLL (C-OPLL, 92 patients) and thoracic OPLL (T-OPLL, 47 patients) groups. Patients' characteristics and biomarkers related to bone metabolism, such as calcium, inorganic phosphate (Pi), 25-hydroxyvitamin D, 1α,25 dihydroxyvitamin D, PINP, and TRACP-5b, were compared between the Non-OPLL and OPLL groups, as well as the C-OPLL and T-OPLL groups. Bone metabolism biomarkers were also compared after adjusting for age, sex, body mass index, and the presence of renal impairment using propensity score-matched analysis., Results: The OPLL group had significantly lower serum levels of Pi and higher levels of PINP versus the Non-OPLL group as determined by propensity score-matched analysis. The comparison results between the C-OPLL and T-OPLL groups using a propensity score-matched analysis showed that T-OPLL patients had significantly higher concentrations of bone turnover markers, such as PINP and TRACP-5b, compared with C-OPLL patients., Conclusions: Increased systemic bone turnover may be associated with the presence of OPLL in the thoracic spine, and bone turnover markers such as PINP and TRACP-5b can help screen for thoracic OPLL., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Published studies on mRNA coronavirus disease 2019 (COVID-19) vaccine effects focus on younger individuals, comprising the majority of the workforce. Studies in elderly adults are sparse., Methods: In total, 107 subjects were recruited (median age 78; interquartile range [IQR], 58.5-90.5; range, 35-105 years). Factors associated with antibody titer after the third mRNA COVID-19 vaccination were compared between 49 elderly (age ≥80; median, 94; IQR, 86-97; range, 80-105 years) and 58 younger (age ≤79; median, 61; IQR, 46-71; range, 35-79 years) adults., Results: Among body mass index (BMI) categories, the group of underweight elderly adults had a lower antibody titer compared to those with normal weight (P < .01 after 1, 3, and 5 months). Elderly adults were less likely to maintain effective antibody titer (≥4160 AU/mL) compared to younger adults: 76% versus 98%, P < .001 after 1 month, and 45% versus 78%, P < .001 after 3 months. Elderly adults who maintained effective antibody titer for 5 months had a higher BMI (22.9 kg/m2 vs 20.1 kg/m2, P = .02), and were less likely to have underweight BMI (0% vs 31%, P = .02) compared to the subjects who failed to maintain effective antibody titer., Conclusions: These results highlight the impact of nutritional status and the deleterious effect of underweight BMI on antibody titer and its maintenance among elderly adults following booster mRNA COVID-19 vaccination., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The management of hypertriglyceridemia in patients with chronic kidney disease (CKD) is important. Pemafibrate, a novel selective peroxisome proliferator-activated receptor-alpha modulator with less toxic effects on liver and kidney function than those of other fibrates, has recently been approved for the treatment of patients with an estimated glomerular filtration rate (eGFR) lower than 30 mL/min/1.73 m 2 . However, the efficacy and safety of pemafibrate in patients with severe renal impairment have not yet been established., Methods: This single-center, retrospective observational study included 12 outpatients with CKD and hypertriglyceridemia, who were newly started on low-dose pemafibrate (0.1 mg/day) treatment between December 2021 and May 2023 and whose eGFRs were less than 30 mL/min/1.73 m 2 at baseline. Blood samples were collected before and at 12 weeks after pemafibrate treatment., Results: After 12 weeks of treatment, the serum triglyceride level was significantly decreased, whereas the high-density lipoprotein cholesterol level was significantly increased. The serum alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, and uric acid levels were also significantly decreased, without worsening of the eGFR and serum creatinine levels. In the subgroup analysis, there were no significant differences in the changes in clinical parameters regardless of statin use and CKD stage at baseline., Conclusions: Low-dose pemafibrate administration in patients with severe renal impairment resulted in significant improvements in triglyceride, high-density lipoprotein cholesterol, and serum uric acid levels, and liver function, without adverse events., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Shima et al.)

Neuroendocrine tumors (NETs) of the ampulla of Vater are rare. Therefore, there is a lack of comprehensive information regarding their pathogenesis. We herein present the case of a patient with a 5-mm ampullary NET who demonstrated the presence of lymphatic invasion after undergoing endoscopic papillectomy. A 44-year-old woman was referred to our hospital for treatment of a grade 1 NET in the ampulla of Vater. Endoscopic ultrasonography revealed a hypoechoic mass within the submucosal layer without obvious infiltration into the common bile duct or the main pancreatic duct. We performed underwater endoscopic papillectomy (UEP) to remove the tumor with a negative margin. Pathological evaluation of the resected specimen showed a grade 1 NET with a negative margin. However, pancreaticoduodenectomy was subsequently performed because of the risk of lymph node metastasis, which was expected due to the significant number of NET cells infiltrating the endothelium of the lymphatic vessels. No lymph node metastasis or recurrence was observed during the 26-month follow-up period. UEP is a useful method to achieve complete resection for diagnostic and therapeutic purposes. UEP may be a novel option for endoscopic treatment of ampullary NET., (© 2024. Japanese Society of Gastroenterology.)

Synthetic cannabinoids, a type of new psychoactive substances, are likely to be rapidly metabolized; thus, the detection of their metabolites, rather than the parent compound, is a common method used to prove drug consumption. Although the analysis of metabolites is generally performed by mass spectrometry, it is limited to structural estimation because of few commercially available standards. In particular, distinguishing between positional isomers is difficult. Synthetic cannabinoids with a cumyl moiety can be hydroxylated at the cumyl moiety during metabolism, but it remains unclear whether the hydroxylation occurs at the ortho, meta, or para position. This study determined the structures of a metabolite formed by mono-hydroxylation at the cumyl moiety of the synthetic cannabinoid CUMYL-THPINACA, used as a model compound. Chemical synthesis was performed to create possible metabolites with one hydroxyl group at the ortho, meta, or para positions of the cumyl moiety. Using the synthesized metabolites and liquid chromatography-quadrupole time-of-flight mass spectrometry, the metabolite detected in the microsomal reaction of CUMYL-THPINACA was identified as a compound mono-hydroxylated at the para position based on retention time and product ion spectra. Moreover, the rapid metabolism of CUMYL-THPINACA was demonstrated with an in vitro half-life of 4.9 min and the identified metabolite could be detected for a relatively long time in vitro. The synthesized metabolite may be utilized as a good reference standard for proof of CUMYL-THPINACA consumption. These findings have potential applications in the synthesis of metabolites of other synthetic cannabinoids bearing a cumyl moiety., (© 2023 John Wiley & Sons, Ltd.)