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Soichiro Hozawa,1 Keita Ono,2 Naoyuki Makita,3 Hitomi Uchimura,3 Yoshifumi Arita,3 Takehiro Hirai,2 Naoki Tashiro3 1Hiroshima Allergy and Respiratory Clinic, Hiroshima, Japan; 2AstraZeneca K.K., Tokyo, Japan; 3AstraZeneca K.K., Osaka, JapanCorrespondence: Soichiro Hozawa, Hiroshima Allergy and Respiratory Clinic, 6F, 1-9-28 Hikari-machi, Higashi-ku, Hiroshima, 732-0052, Japan, Tel +81-82-568-1167, Fax +81-82-568-1239, Email hozawa@vesta.ocn.ne.jpPurpose: Japanese guidelines recommend that patients with uncontrolled asthma be referred by non-specialists to specialists (allergists and/or pulmonologists). This study investigated the reality of clinical practice in asthma patients referred to specialists in Japan.Patients and Methods: This was a retrospective, observational cohort study of asthma patients in a health insurance claim database (Cross Fact) referred from facilities with non-specialists to those with specialists from January 2016 to December 2018. The referred asthma patients were defined as patients with ≥ 4 inhaled corticosteroid (ICS)-containing prescriptions during a 1-year baseline period, with an asthma diagnosis, and who had visited a facility with specialists. Asthma exacerbation, maintenance treatment, laboratory tests, and medical procedures before and after referral were analyzed.Results: Data for 2135 patients were extracted, of which 420 with referral codes were analyzed. The proportion of patients with asthma exacerbations was 50.2% (95% confidence interval [CI]: 45.4– 55.1%) before referral and 37.4% (95% CI: 32.7– 42.2%) after, a significant decrease (P< 0.001; McNemar test). The proportions of patients prescribed ICS alone, long-acting beta-agonists (LABA), and ICS/LABA were lower after referral than before, but the proportions of patients prescribed long-acting muscarinic antagonists (LAMA), ICS/LABA/LAMA, and biologics increased after referral. More asthma-related laboratory tests were performed after referral, and spirometry incidence increased from 16.4% before referral to 51.4% after referral.Conclusion: This study shows a decrease in asthma exacerbations, change in asthma treatments, and increase in laboratory tests after referral to a specialist, suggesting that referrals to specialists lead to better management of asthma.Keywords: asthma, database, referral, specialist, symptom exacerbation

A joint spatio–temporal distribution model of mackerel (ages 3–10) was developed to investigate the age-based responses of mackerel to three environmental drivers: sea surface temperature (SST), mixed layer depth, and chlorophyll-a concentration during the summer months 2010–20 in the Nordic Seas. The study showed that SST was the most important variable amongst the ones tested and had the strongest impact on the distribution of the younger age classes (3–5), which had a narrower range of favourable SST and a stronger aversion to cold temperatures than older individuals. Consequently, the impact of SST differed regionally; in the polar front regions, SST explained up to 61% of the variability in the observed density of young individuals, where Arctic water masses likely acted as a barrier to these young individuals. That said, part of it could be confounded with the limited migration capability of young mackerels, which could not reach the furthest frontal regions. In warmer southern waters, the same environmental variables had less explanatory power for mackerel of all ages. Individuals in the south were likely not constrained by temperature and perhaps more influenced by other variables, such as food availability or ocean current (throughout their migration path), for which appropriate data are lacking. Moreover, the model showed that older mackerel were distributed more to the north and west, and their migration pattern changed when the 2013 year-class no longer migrated to the west compared to previous year-classes. Additionally, all-year classes started migrating more eastward from summer 2018. [ABSTRACT FROM AUTHOR]

The Northeast Atlantic mackerel is an income breeder with indeterminate fecundity, spawning in multiple batches at optimal temperatures around 11°C in the upper water column during February–July along the continental shelf from 36–62°N. Based on macroscopic staging of gonads (N ∼62000) collected in 2004–2021, we detected an on-going extension of spawning activities into the Norwegian Sea feeding area (62–75°N), reaching stable levels around 2012 onwards. This poleward expansion increased as more fish entered the area, whilst the maximum proportions of spawners concurrently dropped from about 75 to 15% from May to July. Detailed histological examinations in 2018 confirmed the macroscopic results but clarified that 38% of the spawning-capable females in July terminated their spawning by atresia. We suggest that increased access to suitable spawning areas (≥10°C), following ocean warming from 2002 onwards, functions as a proximate cause behind the noticed expansion, whereas the ultimate trigger was the historic drop in body growth and condition about 10 years later. Driven by these energetic constraints, mackerel likely spawn in the direction of high prey concentrations to rebuild body resources and secure the future rather than current reproduction success. The ambient temperature that far north is considered suboptimal for egg and larval survival. [ABSTRACT FROM AUTHOR]

Background: The optimal duration of anticoagulation therapy for patients with cancer and acute low-risk pulmonary embolism (PE) is clinically relevant, but evidence is lacking. Prolonged anticoagulation therapy could have a potential benefit for prevention of thrombotic events; however, it could also increase the risk of bleeding., Methods: In a multicenter, open-label, adjudicator-blinded, randomized clinical trial at 32 institutions in Japan, we randomly assigned patients with cancer and acute low-risk PE of the simplified version of the Pulmonary Embolism Severity Index score of 1, in a 1:1 ratio, to receive either an 18-month or a 6-month rivaroxaban treatment. The primary end point was recurrent venous thromboembolism (VTE) at 18 months. The major secondary end point was major bleeding at 18 months according to the criteria of the International Society on Thrombosis and Hemostasis. The primary hypothesis was that an 18-month treatment was superior to a 6-month treatment in terms of the primary end point., Results: From February 2021 to March 2023, 179 patients were randomized, and after the exclusion of one patient who withdrew consent, 178 were included in the intention-to-treat population: 89 patients in the 18-month rivaroxaban group and 89 in the 6-month rivaroxaban group. The mean age was 65.7 years; 47% of the patients were men, and 12% had symptoms of PE at baseline. The primary end point of recurrent VTE occurred in 5 of the 89 patients (5.6%) in the 18-month rivaroxaban group and in 17 of the 89 (19.1%) in the 6-month rivaroxaban group (odds ratio, 0.25 [95% CI, 0.09-0.72]; P =0.01). Among 22 recurrent VTE, 5 patients presented with a symptomatic recurrent VTE; recurrent PE occurred in 11 patients, including 2 with main and 4 with lobar PEs; and recurrent deep vein thrombosis was seen in 11 patients, including 3 with proximal deep vein thromboses. The major secondary end point of major bleeding occurred in 7 of the 89 patients (7.8 %) in the 18-month rivaroxaban group and in 5 of the 89 patients (5.6%) in the 6-month rivaroxaban group (odds ratio, 1.43 [95% CI, 0.44-4.70]; P =0.55)., Conclusions: In patients with cancer and acute low-risk PE of the simplified version of the Pulmonary Embolism Severity Index score of 1, the 18-month rivaroxaban treatment was superior to the 6-month rivaroxaban treatment with respect to recurrent VTE events.

Purpose: To compare image quality and diagnostic performance among SS-EPI diffusion weighted imaging (DWI), multi-shot (MS) EPI DWI, and reduced field-of-view (rFOV) DWI for muscle-invasive bladder cancer (MIBC)., Materials and Methods: This retrospective study included 73 patients with bladder cancer who underwent multiparametric MRI in our referral center between August 2020 and February 2023. Qualitative image assessment was performed in 73; and quantitative assessment was performed in 66 patients with maximum lesion diameter > 10 mm. The diagnostic performance of the imaging finding of muscle invasion was evaluated in 47 patients with pathological confirmation of MIBC. T2-weighted imaging, SS-EPI DWI, MS-EPI DWI, rFOV DWI, and dynamic contrast-enhanced imaging were acquired with 3 T-MRI. Qualitative image assessment was performed by three readers who rated anatomical distortion, clarity of bladder wall, and lesion conspicuity using a four-point scale. Quantitative assessment included calculation of SNR and CNR, and grading of the presence of muscle layer invasion according to the VI-RADS diagnostic criteria. Wilcoxon matched pairs signed rank test was used to compare qualitative and quantitative image quality. McNemar test and receiver-operating characteristic analysis were used to compare diagnostic performance., Results: Anatomical distortion was less in MS-EPI DWI, rFOV DWI, and SS-EPI DWI, in that order with significant difference. Clarity of bladder wall was greater for MS-EPI DWI, SS-EPI DWI, and rFOV DWI, in that order. There were significant differences between any two combinations of the three DWI types, except between SS-EPI DWI and MS-EPI in Reader 1. Lesion conspicuity, diagnostic performance, SNR and CNR were not significantly different among the three DWI types., Conclusions: Among the three DWI sequences evaluated, MS-EPI DWI showed the least anatomical distortion and superior bladder wall delineation but no improvement in diagnostic performance for MIBC. MS-EPI DWI may be considered for additional imaging if SS-EPI DWI is of poor quality., Competing Interests: Declarations Conflict of interest None. Ethical approval This retrospective cross-sectional study was approved by the Ethics Review Board of our institute. The study was performed per the ethical standards laid down in the 1964 Declaration of Helsinki. Informed consent The requirement to obtain informed consent for the study was waived due to its observational nature., (© 2024. The Author(s).)

As a fundamental right, all women should have equal access to menstrual hygiene management (MHM). However, certain sociocultural contexts foster an atmosphere of secrecy surrounding menstruation, which discourages open discussion. The present study seeks to explore the relationship between attitudes on menstrual secrecy and MHM practices among young women in rural areas of the Lao People's Democratic Republic (Lao PDR). In March 2023, a cross-sectional survey using semi-structured self-administered questionnaires was conducted on 80 women (age range, 15-24 years) randomly selected from eight villages in the central part of Lao PDR. Logistic regression analysis was performed to examine the associations between sociodemographic and economic characteristics, MHM practices, social support, and attitudes toward secrecy regarding menstruation. Among the 70 respondents, 68 (97.1%) reported being satisfied with current MHM practices; however, 27 (38.6%) agreed that menstruation should not be discussed with others. Some women lacked access to private spaces for changing pads or washing. The results of the logistic regression analysis indicated that women with higher monthly disposable income were less likely to endorse menstruation secrecy (odds ratio: 0.15, 95% confidence interval: 0.02-0.85). No significant associations were found between MHM practices and attitudes on secrecy. Although no direct association was found between MHM practices and attitudes on menstruation secrecy, some participants remain in unfavorable MHM environments., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ono 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.)

The genetic architecture of white matter lesions (WMLs) in Asian populations has not been well-characterized. Here, we performed a genome-wide association study (GWAS) to identify loci associated with the WML volume. Brain MRI and DNA samples were collected from 9479 participants in the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD). The GWAS confirmed three known WML-associated loci (SH3PXD2A, GFAP, and TRIM47). The lead variant of GFAP was a common missense variant (p.D295N) in East Asians. Meta-GWAS using the publicly available summary statistics of UK Biobank identified one previously unreported locus 6q23.2 (SLC2A12). Integration with expression quantitative trait locus data implied the newly identified locus affects SLC2A12 expression. The effect sizes of 20 lead variants at the WML-associated loci were moderately correlated between JPSC-AD and UK Biobank. These results indicate that the alteration in GFAP protein caused by the common missense variant in East Asians influences the WML volume., Competing Interests: Competing interests Toshiharu Ninomiya reports receiving grants from Suntory Holdings Limited. The other authors have nothing to disclose., (© 2024. The Author(s).)

Otolith organs in the inner ear and neuromasts in the fish lateral-line harbor two populations of hair cells oriented to detect stimuli in opposing directions. The underlying mechanism is highly conserved: the transcription factor EMX2 is regionally expressed in just one hair cell population and acts through the receptor GPR156 to reverse cell orientation relative to the other population. In mouse and zebrafish, loss of Emx2 results in sensory organs that harbor only one hair cell orientation and are not innervated properly. In zebrafish, Emx2 also confers hair cells with reduced mechanosensory properties. Here, we leverage mouse and zebrafish models lacking GPR156 to determine how detecting stimuli of opposing directions serves vestibular function, and whether GPR156 has other roles besides orienting hair cells. We find that otolith organs in Gpr156 mouse mutants have normal zonal organization and normal type I-II hair cell distribution and mechano-electrical transduction properties. In contrast, gpr156 zebrafish mutants lack the smaller mechanically evoked signals that characterize Emx2-positive hair cells. Loss of GPR156 does not affect orientation-selectivity of afferents in mouse utricle or zebrafish neuromasts. Consistent with normal otolith organ anatomy and afferent selectivity, Gpr156 mutant mice do not show overt vestibular dysfunction. Instead, performance on two tests that engage otolith organs is significantly altered - swimming and off-vertical-axis rotation. We conclude that GPR156 relays hair cell orientation and transduction information downstream of EMX2, but not selectivity for direction-specific afferents. These results clarify how molecular mechanisms that confer bi-directionality to sensory organs contribute to function, from single hair cell physiology to animal behavior., Competing Interests: KO, AJ, NH, AJ, HC, MD, RE, KC, KK, BT No competing interests declared

Background: Sleep apnea (SA), subjective sleep duration (SSD), and objective sleep duration (OSD) were reported as risk factors for atrial fibrillation (AF). However, the association between AF and the combination of SA and OSD has not been clarified. Nor has a mismatch between SSD and OSD been investigated., Methods and Results: We assessed SA with polysomnography, OSD with actigraphy, and SSD in patients who underwent radiofrequency catheter ablation for persistent AF. We investigated associations among SA, OSD, OSD×3% oxygen desaturation index (3%ODI), and AF recurrence, considering SSD-OSD (i.e., the difference between SSD and OSD) and OSD. Seventy of 94 (74.4%) participants had moderate-to-severe SA (apnea-hypopnea index [AHI] ≥15). Participants were classified into OSD tertiles. Participants in Tertile 3 (mean OSD: 7.3 h) had decreased SSD-OSD (0.0 h) with increased Stage N1 sleep. Over 27.6 months, 10 AF recurrences occurred in 51 participants without treatment for SA. AHI ≥20 and OSD Tertile 3 were associated with AF recurrence (hazard ratios 5.7 [95% confidence interval 1.1-24.7] and 10.3 [95% confidence interval 1.2-88.4], respectively). Participants with AF recurrence had a higher OSD×3%ODI., Conclusions: SA and long OSD were predictors of recurrent AF through long exposure to intermittent hypoxia during sleep. SSD-OSD was low in patients with long OSD, possibly because of decreased sleep quality.

Background: Central venous catheter (CVC) is often used in the perioperative management of esophageal cancer. The position of the CVC tip has been reported to shift with body positioning and, although infrequent, may traverse into the azygos vein arch. Herein, we describe a case where a migrated CVC tip in the azygous vein arch was identified during esophageal cancer surgery, preventing CVC dissection concurrent with azygous vein arch resection., Case Presentation: A 65-year-old man was diagnosed with advanced esophageal cancer and was referred to our department for surgery after undergoing neoadjuvant chemotherapy. He underwent robot-assisted subtotal esophagectomy, followed by gastric conduit reconstruction via the posterior sternal route. Thoracic manipulation was performed with the patient in the prone position. During the surgery, a foreign body was found in the azygos vein arch, indicating that a central venous catheter had inadvertently entered the azygos vein arch. The catheter was retracted by 5 cm, and after confirming that no catheter remained in the azygos arch, the azygos vein arch was separated using an autosuture device., Conclusions: Central venous catheter migration can occur in a various vessels. During prone esophageal cancer surgery, elevating the right upper extremity may alter the catheter tip's position from its the preoperative position. CVC amputation should be observed because the azygos vein arch is often amputated to facilitate upper mediastinal dissection during esophageal cancer surgery., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication The patient provided permission for the publication of this case report. Patient anonymity was maintained. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Selenium-dependent glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, preventing unrestrained (phospho)lipid peroxidation by reducing phospholipid hydroperoxides (PLOOH). However, the contribution of other phospholipid peroxidases in ferroptosis protection remains unclear. We show that cells lacking GPX4 still exhibit substantial PLOOH-reducing capacity, suggesting a contribution of alternative PLOOH peroxidases. By scrutinizing potential candidates, we found that although overexpression of peroxiredoxin 6 (PRDX6), a thiol-specific antioxidant enzyme with reported PLOOH-reducing activity, failed to prevent ferroptosis, its genetic loss sensitizes cancer cells to ferroptosis. Mechanistically, we uncover that PRDX6, beyond its known peroxidase activity, acts as a selenium-acceptor protein, facilitating intracellular selenium utilization and efficient selenium incorporation into selenoproteins, including GPX4. Its physiological significance was demonstrated by reduced GPX4 expression in Prdx6-deficient mouse brains and increased sensitivity to ferroptosis in PRDX6-deficient tumor xenografts in mice. Our study highlights PRDX6 as a critical player in directing cellular selenium utilization and dictating ferroptosis sensitivity., Competing Interests: Declaration of interests M.C. is a co-founder and shareholder of ROSCUE Therapeutics GmbH. M.C., B.P., and T.N. hold patents for some of the compounds described herein. M.C. is a member of the journal advisory board., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Extracorporeal membrane oxygenation (ECMO) might be required as a treatment option in patients with critical pulmonary embolism (PE). However, the clinical features and outcomes of the use of ECMO for critical acute PE are still limited. The present study aimed to clarify the clinical characteristics, management strategies and outcomes of patients with acute PE requiring ECMO in the current era using data from a large-scale observational database., Methods: We analyzed the data of the COMMAND VTE Registry-2: a physician-initiated, multicenter, retrospective cohort study enrolling consecutive patients with acute symptomatic venous thromboembolism (VTE). Among 2035 patients with acute symptomatic PE, there were 76 patients (3.7%) requiring ECMO., Results: Overall, the mean age was 58.4 years, and 34 patients (44.7%) were men. Cardiac arrest or circulatory collapse at diagnosis was reported in 67 patients (88.2%). The 30-day incidence of all-cause death was 30.3%, which were all PE-related deaths. The 30-day incidence of major bleeding was 54.0%, and the vast majority of bleedings were procedure site-related bleeding events and surgery-related bleeding (22.4%). The 30-day incidence of all-cause death was 6.3% in 16 patients with surgical intervention, 43.8% in 16 patients with catheter intervention, 25.0% in 16 patients with thrombolytic therapy, and 39.3% in 28 patients with anticoagulation only., Conclusions: The current large real-world VTE registry in Japan revealed clinical features and outcomes of critical acute PE requiring ECMO in the current era, which suggested several unmet needs for future clinical trials., (© 2024. The Author(s).)

Background: The impact of high-risk coronary artery plaques identified using optical coherence tomography on late luminal narrowing and clinical events remains poorly understood., Methods and Results: This multicenter prospective study included 176 patients who underwent percutaneous coronary intervention and serial optical coherence tomography at baseline and 1-year follow-up to investigate nontarget regions with angiographically intermediate stenosis. At 1 year after percutaneous coronary intervention, the coronary artery lumen area decreased significantly from 6.06 (95% CI, 5.60-6.53) mm 2 to 5.88 (95% CI, 5.41-6.35) mm 2 (difference, -0.18; 95% CI, -0.22 to -0.14 mm 2 ; P <0.001), particularly in thin-cap fibroatheromas, thick-cap fibroatheromas, mixed plaques, and fibrous plaques. The prevalence of fibroatheroma decreased from 38% to 36% ( P <0.001), whereas calcified plaque increased from 31% to 34% ( P <0.001), accompanied by a significant increase in calcium thickness and angle. Diabetes and current smoking habits were independently associated with increasing calcium prevalence. Patients with thin-cap fibroatheroma had a significantly higher 3-year risk of ischemia-driven nontarget vessel revascularization (hazard ratio, 2.42 [95% CI, 1.03-5.71]; P =0.04), primarily due to revascularization in the imaged region. No significant association was observed between coronary artery calcium prevalence and clinical outcomes within 3 years., Conclusions: The coronary artery lumen area significantly decreased over a 1-year interval, particularly in thin-cap fibroatheromas, thick-cap fibroatheromas, mixed plaques, and fibrous plaques. Although thin-cap fibroatheroma prevalence was associated with higher risk of ischemia-driven nontarget vessel revascularization, no significant association was noted between coronary artery calcium prevalence and clinical outcomes within 3 years. The interaction between calcium progression and long-term clinical events necessitates further investigation., Registration: URL: https://www.umin.ac.jp/ctr/; Unique Identifier: UMIN000031937.

Visuospatial perception is often impaired in people with Alzheimer's disease (AD). Because visuospatial information is thought to be processed in the visual dorsal stream, it is believed that brain activities in the dorsal stream will be altered in AD patients. In this study, we investigated whether regional brain activity related to visuospatial perception were associated with AD progression markers. An optic-flow task, which activates the dorsal stream associated with visuospatial perception, was performed, and the brain activities evoked by the task were evaluated using magnetoencephalography (MEG). First, we evaluated the responses to optic-flow stimuli in 21 cognitively unimpaired participants and determined the regions of interest (ROIs) where optic-flow activities were activated. Task-related activations were observed in 14 cortical regions including the dorsal stream: the right and left medial ventral occipital cortex (MVOcC), lateral occipital cortex (LOcC), precuneus (Pcun), inferior parietal lobule (IPL), superior parietal lobule (SPL), posterior superior temporal sulcus (pSTS), and fusiform gyri (FuG). Next, we performed correlation analyses between task-related activity in each ROI and two AD progression markers, global amyloid burden and parahippocampal gyrus (PHG) volume, for 25 participants who underwent amyloid positron emission tomography (PET) scans. We found that the global amyloid burden was negatively correlated with task-related activity in the left MVOcC and right SPL [r = -0.488 (p = 0.013) and r = -0.421 (p = 0.038), respectively]. Furthermore, significant positive correlations were observed between PHG volume and task-related activity in both the left and right SPL [r = 0.500 (p = 0.011) and r = 0.549 (p = 0.005), respectively]. Since the SPL is known to be responsible for visuospatial perception, these results suggest that MEG neuronal activity of patients performing the optic-flow activity can detect changes in brain activity associated with visuospatial impairment related to AD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ST, KK, HM, YM and TA are employees of Ricoh Company, Ltd. The authors declare that no other competing interests exist. The other authors have no competing financial conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to investigate the effects of nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., loxoprofen) on pharyngitis-induced dysphagia in rats., Design: A pharyngitis rat model was generated by topical application of acetic acid to the laryngopharyngeal region. Changes in water swallowing were evaluated by endoscopic observation over time. A histological analysis of the laryngopharyngeal mucosa was performed. The effects of loxoprofen, antibacterial drugs, and transient receptor potential (TRP) channel inhibitors were investigated in model rats., Results: After acetic acid treatment, water-evoked swallowing was impaired on day 1 (prolonging the swallowing latency and interval and decreasing the number of swallows), and recovered until day 6. Administration of loxoprofen significantly alleviated impaired water swallowing. Histologically, loxoprofen significantly improved inflammation of the pharynx, including submucosal edema, but did not affect the loss of taste bud-like structures in the arytenoid. In contrast, the administration of antibacterial drugs or TRP channel inhibitors did not affect the impairment of water swallowing in the model group., Conclusion: These results demonstrate the efficacy of systemic administration of loxoprofen in improving swallowing impairment in a pharyngitis model rat. This study is the first to provide scientific evidence for the use of NSAIDs in the management of pharyngitis., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chihiro Nakatomi reports financial support was provided by Daiichi Sankyo Healthcare Co Ltd. Sayaka Kubo reports a relationship with Daiichi Sankyo Healthcare Co Ltd that includes: employment. Tomoki Shimada reports a relationship with Daiichi Sankyo Healthcare Co Ltd that includes: employment. Keiko Tsuji reports a relationship with Daiichi Sankyo Healthcare Co Ltd that includes: employment. Sayaka Kubo, Tomoki Shimada, Keiko Tsuji has patent pending to Japan Patent Office. 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 Elsevier Ltd. All rights reserved.)

We report a case of adult T-cell leukemia/lymphoma (ATLL) with angioimmunoblastic T-cell lymphoma (AITL/nTFHL-AI)-like feature. An 88-year-old Japanese woman with seropositive for the Human T-lymphotropic virus type 1 (HTLV-1) was incidentally diagnosed with generalized lymphadenopathy. Biopsy of the cervical lymph node demonstrated the proliferation of small- or medium-sized and large atypical lymphocytes associated with eosinophils, high endothelial venules, and clear cells. Immunohistochemical analysis revealed atypical lymphocytes were CD3- and CD4-positive. Atypical T cells bore the T-follicular helper phenotype (PD1, ICOS, and BCL6) and were positive for CD25 and chemokine receptor 4. Epstein-Barr virus encoded RNA-positive cells were scattered in the background via in situ hybridization. The histological findings were similar to those of AITL/nTFHL-AI; however, the immunohistochemical results did not exclude the possibility of ATLL. Southern blot analysis detected integration of HTLV-1 proviral DNA. The RHOA Gly 17 Val (G17V) mutation was detected by the peptide nucleic acid-locked nucleic acid clamp method. Finally, the patient was diagnosed with ATLL with AITL-like feature and exhibited a similar morphology, immunophenotype, and mutational signature to AITL/nTFHL-AI. ATLL mimics other types of T-cell lymphomas. Thus, in HTLV-1 endemic areas, routine screening for HTLV-1 serology is necessary to avoid misdiagnosis of other lymphoid malignancies., (© 2024 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Background: Neutron beams utilized for performing BNCT are composed of a mixture of neutrons and gamma rays. Although much of the dose delivered to the cancer cells comes from the high LET particles produced by the boron neutron capture reaction, the dose delivered to the healthy tissues from unwanted gamma rays cannot be ignored. With the increase in the number of accelerators for BNCT, a detector system that is capable of measuring gamma ray dose in a mixed neutron/gamma irradiation field is crucial. Currently, BeO TLDs encased in quartz glass are used to measure gamma ray dose in a BNCT irradiation field. However, this type of TLD is no longer commercially available. A replacement dosimetry system is required to perform the recommended ongoing quality assurance of gamma ray measurement for a clinical BNCT system., Purpose: The purpose of this study is to evaluate the characteristics of a BeO OSLD detector system under a mixed neutron and gamma ray irradiation field and to assess the suitability of the system for routine quality assurance measurements of an accelerator-based BNCT facility., Methods: The myOSLD system by RadPro International GmbH was evaluated using the accelerator-based neutron source designed for clinical BNCT (NeuCure BNCT system). The readout constancy, linearity, dose rate effect, and fading effect of the OSLD were evaluated. Free-in-air and water phantom measurements were performed and compared with the TLD results and Monte Carlo simulation results. The PHITS Monte Carlo code was used for this study., Results: The readout constancy was found to be stable over a month-long period and similar to the TLD results. The OSLD readout signal was found to be linear, with a high coefficient of determination (R 2  ≥ 0.999) up to a proton charge of 3.6 C. There was no significant signal fading or dose rate dependency. The central axis depth dose and off-axis dose profile measurements agreed with both the TLD and Monte Carlo simulation results, within one standard deviation., Conclusion: The myOSLD system was characterized using an accelerator system designed for clinical BNCT. The experimental measurements confirmed the OSLD achieved similar, if not superior to, the currently utilized dosimetry system for routine QA of an accelerator-based BNCT system. The OSLD system would be a suitable replacement for the current TLD system for performing routine QA of gamma ray dose measurement in a BNCT irradiation field., (© 2024 The Author(s). Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Le Fort I (LF1) osteotomy, a common orthognathic procedure for the maxilla aimed at achieving maxillary mobility by separating the pterygomaxillary suture, poses a risk of bad fracture that may lead to complications and inadequate mobility. Our study analyzed two- and three-dimensional computed tomography images to identify the anatomical factors associated with bad fractures due to an LF1 osteotomy. Point 'a' is where the lateral pterygomaxillary suture on the axial image aligns with the zygomatic alveolar line near the line used for an LF1 osteotomy, with the base line connecting the bilateral 'a' points.Two risk factors were identified on the pterygoid side: (i) when the distance from point 'a' to the intersection of the base line and the medial pterygoid plate was <6.0 mm; and (ii) when the distance from the piriform aperture margin to the base line was <44.78 mm. Six risk factors were identified on the maxillary side, including the distance between the most anterior and most lateral points of the internal surface of the maxillary sinus being <31.9 mm. Our analyses revealed that fractures that occur during pterygomaxillary suture separation in an LF1 osteotomy are influenced by anatomical factors of the maxilla and pterygoid process, which form the pterygomaxillary suture., 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 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Objective: We investigated preoperative patient factors associated with prognosis in 263 bladder cancer (BC) patients undergoing radical cystectomy (RC). We also developed new risk stratification models for prognosis., Methods: This retrospective study included patients treated at Tottori University Hospital and affiliated hospitals between January 2010 and December 2019. The relationship between preoperative patient factors and overall recurrence-free and cancer-specific survival (CSS) was analyzed. The modified Glasgow prognosis score (mGPS) was calculated using serum albumin and C-reactive protein (CRP) levels. Statistical analyses included the log-rank test and Cox proportional hazards regression., Results: Eastern Cooperative Oncology Group performance status (ECOG-PS), mGPS, and clinical tumor stage independently predicted CSS in multivariate analysis. A new risk stratification model included ECOG-PS ≥2, clinical tumor stage ≥3, serum albumin <3.5 g/dL, and serum CRP >0.5 mg/dL. Risk groups were defined as 0 factors (low risk), 1-2 factors (intermediate risk), and 3-4 factors (high risk). High-risk patients showed significantly poorer 3-year cancer-free survival: 86.9% (low risk), 76.7% (intermediate risk), and 50.0% (high risk)., Conclusions: ECOG-PS, clinical tumor stage, and mGPS are predictive of poor cancer-free survival post-RC for BC. Our model offers the potential for prognostic prediction in these patients., (© 2024 The Japanese Urological Association.)

Objective: To clarify the infection control measures required in the event of a new infectious disease outbreak, we conducted a questionnaire survey on the infection control measures implemented against coronavirus disease 2019 (COVID-19)., Methods: An invitation to participate in this survey was sent to the heads of 2689 facilities affiliated with the members of the Japanese Society for Infection Prevention and Control in February 2023, requesting responses to the online survey using Google Forms by March 2023., Results: Six hundred and forty-five facilities, including 20 clinics and 625 hospitals, participated in the survey. This survey revealed that various infection control measures were implemented, including universal masking in the non-COVID-19 ward (96.5 %), screening tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on scheduled admission (89.0 %), SARS-CoV-2 tests (98.7 %), and isolation in private rooms (76.5 %) for inpatients with fever. However, nosocomial infections and clusters of COVID-19 occurred in 94.4 % and 90.9 % of cases during the investigation period, respectively. One of the reasons for these results is that healthcare personnel (HCP) and patients were common index cases of nosocomial infections, and the most common cause of clusters was the work of symptomatic HCPs. These results suggest that HCPs should understand that they can be index cases or spreaders. On the other hand, the most common support from external facilities was healthcare centers, followed by physicians or nurses from other hospitals., Conclusion: In response to the emergence of infections, it is important to consider implementing infection control measures for HCPs and patients., Competing Interests: Declaration of Competing interest None., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Objective: The aim of this study was to assess the prevalence of peritumoral enhancement (PTE) in patients with muscle-invasive bladder cancer (MIBC) and non-MIBC (NMIBC) and to propose a modified diagnostic criterion for Vesical Imaging Reporting and Data System (VI-RADS) that incorporates PTE., Materials and Methods: This retrospective study included 95 patients with bladder cancer (age, 72 ± 11; 77 men; 36 MIBCs and 59 Non-MIBCs) who underwent multiparametric MRI in our referral center between 2011 and 2023. The images were interpreted by four radiologists. The readers classified the possibility of muscle layer invasion into categories 1-5, based on the VI-RADS categorical diagnostic criterion. PTE was defined as a linear contrast enhancement observed at the edge of tumor invasion which is convex outward from the normal bladder wall and contrasts more than the normal muscle layer and tumor. A modified VI-RADS that upgrades the final VI-RADS category to 4 if PTE is present when the original VI-RADS category is 3 or less was proposed. The frequency of PTE in the MIBC and NMIBC groups was compared using the Fisher's exact test. Sensitivity and specificity for the diagnosis of MIBC were compared with the original VI-RADS using McNemar test. Pathologic diagnosis was used as the reference standard., Results: PTE was present in 70-81% (25/36-29/36) of MIBC and absent in 92-98% (54/59-58/59) of non-MIBC. For all readers, the PTE was significantly more frequent (p < 0.001) in the MIBC group than the NMIBC group. The sensitivities of modified VI-RADS (75.0-86.1%) were significantly higher than those of original VI-RADS (41.7-55.6%) (p = 0.002-0.008). The specificity of modified VI-RADS (91.5-98.3%) were not statistically different from original VI-RADS (98.3-100%)., Conclusions: In conclusion, PTE is a highly specific finding for MIBC. modified VI-RADS incorporating PTE increases sensitivity for MIBC., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Amyloidosis is a disease in which amyloid protein is deposited in organs and tissues, resulting in functional impairment. Amyloidosis occurs in 12%-30% of patients with multiple myeloma, but in rare cases, amyloidosis may precede the diagnosis of multiple myeloma. Our patient was a 76-year-old Japanese male on dialysis. Multiple nodules accompanied by ulcers were observed on his tongue. He had no subjective symptoms or clinical findings associated with multiple myeloma. The histopathological findings suggested amyloidosis. We suspected both systemic and localized amyloidosis and performed a comprehensive systemic examination. Since the patient had been on dialysis for only a short period of time (~3 months), dialysis-related amyloidosis was ruled out. After blood and urine tests, a diagnosis of multiple myeloma was made. Chemotherapy treatment was started, but the patient's multiple myeloma could not be suppressed and the tongue amyloidosis worsened, leading to his death 2 years and 2 months after the initial diagnosis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Hideka Kanemoto et al.)

Amidine-substituted allosteric receptors 2 a and 2 b for benzenediols were synthesized. Receptor 2 a with five-membered amidines exhibited greater allostericity than the amide-substituted receptor 1, while 2 b with six-membered amidines exhibited less allostericity. NMR titration experiments revealed that a significant enthalpic factor was involved in the allostericity of these receptors. X-ray and DFT optimized structures of 2 a and 2 b revealed that 2 a adopted a coplanar conformation with π-conjugation between the amidines and the phenylene ring of the hydrindacene framework, resulting in high allostericity due to inactivation of the initial binding., (© 2024 The Author(s). ChemPlusChem published by Wiley-VCH GmbH.)

Aims: Safety of aspirin-free strategy immediately after percutaneous coronary intervention (PCI) for cardiovascular events in patients with diabetes was unknown., Methods and Results: We conducted the prespecified subgroup analysis on diabetes in the STOPDAPT-3 trial, which randomly compared prasugrel (3.75 mg/day) monotherapy (2984 patients) to dual antiplatelet therapy (DAPT) with prasugrel and aspirin (2982 patients) in patients with acute coronary syndrome or high bleeding risk. The co-primary endpoints were major bleeding events (Bleeding Academic Research Consortium 3 or 5) and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or stroke) at 1 month. Of 5966 study patients, there were 2715 patients (45.5%) with diabetes. Patients with diabetes more often had chronic coronary syndrome, heart failure or cardiogenic shock, and comorbidities than those without. Patients with diabetes compared to those without had higher incidences of major bleeding and cardiovascular events. Regardless of diabetes, the effect of no-aspirin relative to DAPT was not different for the co-primary bleeding (diabetes: 5.05% versus 5.47%; HR, 0.92; 95%CI, 0.66-1.28 and non-diabetes: 3.99% versus 4.07%; HR, 0.98; 95%CI, 0.69-1.38; P for interaction = 0.81) and cardiovascular (diabetes: 5.54% versus 5.15%; HR, 1.08; 95%CI, 0.78-1.49 and non-diabetes: 2.95% versus 2.47%; HR, 1.20; 95%CI, 0.79-1.82; P for interaction = 0.70) endpoints. The incidences of subacute definite or probable stent thrombosis and any coronary revascularization were higher in the no-aspirin group than in the DAPT group regardless of diabetes., Conclusions: The effects of an aspirin-free prasugrel monotherapy (3.75 mg/day) relative to DAPT for major bleeding and cardiovascular events were not different regardless of diabetes. Clinical trial registration: ShorT and OPtimal duration of Dual AntiPlatelet Therapy after everolimus-eluting cobalt-chromium stent-3 [STOPDAPT-3]; NCT04609111., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: White blood cell (WBC) counts were reported to be a risk factor for acute adverse events in patients with venous thromboembolism (VTE). However, there are limited data on VTE patients without active cancer., Methods and Results: The COMMAND VTE Registry-2 was a multicenter study enrolling 5,197 consecutive patients with acute symptomatic VTE. We divided 3,668 patients without active cancer into 4 groups based on WBC count quartiles (Q1-Q4) at diagnosis: Q1, ≤5,899 cells/μL; Q2, 5,900-7,599 cells/μL, Q3, 7,600-9,829 cells/μL; and Q4, ≥9,830 cells/μL. Patients in Q4 more often presented with pulmonary embolism (PE) than patients in Q1, Q2, and Q3 (68% vs. 37%, 53%, and 61%, respectively; P<0.001). The proportion of massive PEs among all PEs was higher in Q4 than in Q1, Q2, and Q3 (21% vs. 3.4%, 5.8%, and 11%, respectively; P<0.001). Compared with Q1, Q2, and Q3, patients in Q4 had a higher cumulative 5-year incidence of all-cause death (17.0%, 15.2%, 16.1%, and 22.8%, respectively; P<0.001) and major bleeding (10.9%, 11.0%, 10.3%, and 14.4%, respectively; P=0.002). The higher mortality risk of Q4 relative to Q2 was consistent regardless of the presentations of VTEs., Conclusions: An elevated WBC count on VTE diagnosis was associated with a higher risk of mortality and major bleeding regardless of VTE presentation, suggesting the potential usefulness of WBC counts for further risk stratification.

The cochlea contains two extracellular fluids, perilymph and endolymph. Endolymph exhibits high potential of approximately +80 to +110 mV (depending on species), which sensitizes sensory hair cells. Other properties of this unique fluid remain elusive, owing to its minuscule volume in rodent cochlea. We therefore developed a technique to collect high-purity endolymph from mouse cochleae. Comprehensive proteomic analysis of sampled endolymph using liquid chromatography with mass spectrometry identified 301 proteins, dominated by molecules engaged in immunity and proteostasis. Approximately 30% of these proteins were undetectable in our perilymph. A combination of mass spectrometry and different approaches revealed that, compared to perilymph, endolymph was enriched with α 2 -macroglobulin, osteopontin, apolipoprotein D, apolipoprotein E, and apolipoprotein J/clusterin. In other cells or tissues, α 2 -macroglobulin, apolipoprotein E, and apolipoprotein J contribute to the clearance of degraded proteins from extracellular fluid. Altogether, with the proteins described here, endolymph may play a protective role in stabilizing cochlear homeostasis., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Background/Objectives : Anti-vascular endothelial growth factor (VEGF) therapy is the first-line treatment for neovascular age-related macular degeneration (nvAMD). While proactive and adequate treatment generally leads to better visual outcomes, various factors, including the disease type, ocular findings, lifestyle, and systemic status, affect the visual prognosis in clinical settings. This study aimed to identify the factors that affect the visual prognosis in patients with nvAMD treated with anti-VEGF therapy. Methods : We conducted a multicenter retrospective cohort study at eight tertiary referral centers in Japan, where we reviewed the medical records of patients newly diagnosed with nvAMD between January 2014 and December 2019. These patients had started treatment with either ranibizumab (0.5 mg) or aflibercept (2.0 mg) and were followed for at least 1 year. We evaluated the impact of the disease type, systemic factors, and initial fundus findings on the best-corrected visual acuity (BCVA) at 1 year. Results : This study included 182 patients (129 men, 53 women), with a mean age of 75.0 ± 8.6 years. The disease types were categorized as typical AMD (53%), polypoidal choroidal vasculopathy (PCV) (43%), and retinal angiomatous proliferation (RAP) (4%). Univariate analysis identified age, the baseline logarithm of the minimum angle of resolution BCVA, intraretinal fluid (IRF), pigment epithelial detachment (PED), and subretinal hyperreflective material (SHRM). Multivariate analysis identified the following significant risk factors associated with vision worsening: age, smoking history, diabetes, and the presence of IRF and PED. Conclusions : The presence of IRF, PED, and SHRM at the start of treatment and a history of smoking and diabetes may be associated with a poor visual prognosis in patients with nvAMD.

Background: Increased fall risk caused by vestibular system impairment is a significant problem associated with aging. A vestibule is composed of linear acceleration-sensing otoliths and rotation-sensing semicircular canals. Otoliths, composed of utricle and saccule, detect linear accelerations. Otolithic organs partially play a role in falls due to aging. Aging possibly changes the morphology and functions of otoliths. However, the specific associations between aging and otolith changes remain unknown. Therefore, this study aimed to clarify these associations in mice., Methods: Young C56BL/6 N (8 week old) and old (108-117 weeks old) mice were used in a micro-computed tomography (μCT) experiment for morphological analysis and a linear acceleration experiment for functional analysis. Young C56BL/6 N (8 week old) and middle-aged (50 week old) mice were used in electron microscopy experiments for morphological analysis., Results: μCT revealed no significant differences in the otolith volume ( p  = 0.11) but significant differences in the otolith density ( p  = 0.001) between young and old mice. μCT and electron microscopy revealed significant differences in the structure of striola at the center of the otolith (μCT; p  = 0.029, electron microscopy; p  = 0.017). Significant differences were also observed in the amplitude of the eye movement during the vestibulo-ocular reflex induced by linear acceleration (maximum amplitude of stimulation = 1.3G [ p  = 0.014]; maximum amplitude of stimulation = 0.7G [ p  = 0.015]), indicating that the otolith function was worse in old mice than in young mice., Discussion: This study demonstrated the decline in otolith function with age caused by age-related morphological changes. Specifically, when otolith density decreased, inertial force acting on the hair cells decreased, and when the structure of striola collapsed, the function of cross-striolar inhibition decreased, thereby causing a decline in the overall otolith function., Competing Interests: The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ueda, Imai, Ito, Okayasu, Harada, Kamakura, Ono, Katsuno, Tanaka, Tatsumi, Hibino, Wanaka and Kitahara.)

Background: Knee osteoarthritis (KOA) is a globally prevalent condition leading to joint pain and disabilities. Surgical interventions such as opening-wedge high tibial osteotomy (OWHTO) and opening-wedge distal tuberosity osteotomy (OWDTO) aim to alleviate symptoms and delay disease progression. Quadriceps strength, crucial for knee function, may decline postoperatively, affecting patient outcomes. However, little is known about quadriceps strength variation after OWHTO and OWDTO. This study investigated changes in quadriceps strength before and after OWHTO and OWDTO., Methods: This retrospective study included patients who underwent OWHTO or OWDTO between 2016 and 2022. Quadriceps strength and demographic and surgical data were collected preoperatively and at 6 and 12 months postoperatively. Statistical analyses were performed to compare changes in quadriceps strength over time., Results: Of 120 knees, 52 (OWHTO, 27; OWDTO, 25) were included in this study. Quadriceps strength increased over 12 months post-OWHTO, significantly improving at 12 months compared to the preoperative and 6-month values. In OWDTO, the strength improved but not significantly., Conclusions: Quadriceps strength improved following OWHTO and OWDTO, with OWHTO showing significant enhancements. Future studies should investigate the relationship between quadriceps strength and functional outcomes and guide rehabilitation strategies for improved postoperative recovery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: The aim of this article is to update evidence on the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) and provide information to the taskforce for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis (RA)., Methods: We searched various databases for randomised controlled trials on RA published until June 2022, with no language restriction. For each of the 15 clinical questions, two independent reviewers screened the articles, evaluated the core outcomes, and performed meta-analyses., Results: Subcutaneous injection of methotrexate (MTX) showed similar efficacy to oral MTX in MTX-naïve RA patients. Ozoralizumab combined with MTX improved drug efficacy compared to the placebo in RA patients with inadequate response (IR) to conventional synthetic DMARD (csDMARD). Rituximab with and without concomitant csDMARDs showed similar efficacy to other biological DMARDs (bDMARDs) in bDMARD-IR RA patients. Combined Janus kinase inhibitors and MTX achieved similar clinical responses and equal safety during a 4-year period compared to tumour necrosis factor inhibitors in MTX-IR RA patients. Biosimilars showed efficacy equivalent to that of the original bDMARDs in csDMARD-IR and bDMARD-IR RA patients., Conclusions: This systematic review provides latest evidence for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for RA management., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

A 79-year-old male patient with type 2 diabetic nephropathy and hypertension was admitted to our hospital because of acute kidney injury with significantly elevated serum creatinine (8.12 mg/dL) and urinary β2-microglobulin (β2MG, 31,748 μg/L) levels. α-glucosidase inhibitor (α-GI) miglitol, started two weeks prior to presentation, was discontinued because drug-induced acute interstitial nephritis (AIN) was suspected. Renal biopsy revealed AIN and diabetic nephropathy. The drug-induced lymphocyte stimulation test for miglitol was also positive. After the discontinuation of miglitol, the urinary β2MG levels decreased to the normal range. This case raises the possibility that α-GI miglitol can worsen the renal function in patients with underlying renal dysfunction.

Phase 3 clinical trials have validated the clinical efficacy of some anti-amyloid β (Aβ) antibody therapies, such as lecanemab and donanemab. To date, several clinical trials of anti-Aβ drugs have been conducted. However, most of these methods have been unsuccessful. Various Aβ aggregates are present during Aβ aggregation. The difference in the clinical efficacy of anti-Aβ antibody therapy may be attributed to variations in the Aβ aggregates targeted. Lecanemab primarily targets protofibrils, and donanemab targets plaques. Solanezumab and bapinezumab target Aβ aggregates of monomers alone or from monomers to low molecular weight oligomers. Anti-Aβ antibody therapies with clinical cognitive efficacy are thus characterized by targeting large-molecular-weight Aβ aggregates, such as protofibrils and plaques. In addition, a positive association was observed between the reduction in amyloid deposition and the inhibition of cognitive decline.

Understanding the molecular mechanisms of epicardial epithelial-to-mesenchymal transition (EMT), particularly in directing cell fate toward epicardial derivatives, is crucial for regenerative medicine using human induced pluripotent stem cell (iPSC)-derived epicardium. Although transforming growth factor β (TGF-β) plays a pivotal role in epicardial biology, orchestrating EMT during embryonic development via downstream signaling through SMAD proteins, the function of SMAD proteins in the epicardium in maintaining vascular homeostasis or mediating the differentiation of various epicardial-derived cells (EPDCs) is not yet well understood. Our study reveals that TGF-β-independent SMAD3 expression autonomously predicts epicardial cell specification and lineage maintenance, acting as a key mediator in promoting the angiogenic-oriented specification of the epicardium into cardiac pericyte progenitors. This finding uncovers a novel role for SMAD3 in the human epicardium, particularly in generating cardiac pericyte progenitors that enhance cardiac microvasculature angiogenesis. This insight opens new avenues for leveraging epicardial biology in developing more effective cardiac regeneration strategies., Competing Interests: Declaration of interests Y.Y. is a scientific advisor of Orizuru Therapeutics and receives grants from Takeda Pharmaceutical Company and Altos Labs, Inc. outside the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

In the pathophysiology of Alzheimer's disease (AD), the amyloid hypothesis, which posits that amyloid β-protein (Aβ) abnormally aggregates and damages neurons with tau, has been proposed. It was originally thought that the accumulation of insoluble amyloid fibrils in the brain leads to AD-inducing neurotoxicity; however, in recent years, the positioning of early and intermediate aggregates has also been emphasized. In particular, following the positive results of phase 3 clinical trials of lecanemab and its approval in Japan and the United States, the pathology of protofibrils, which are the target molecules of lecanemab, has attracted attention. Using high-speed atomic force microscopy, we have previously reported that lecanemab, which has a high affinity for protofibrils, binds to and surrounds them. Donanemab, a recombinant monoclonal antibody that primarily targets fibrils composed of N3pG Aβ, has also attracted attention because of its efficacy in phase 3 clinical trials in patients with early stage AD.

Background: The role of activities of daily living (ADL) as a predictor of adverse outcomes in patients with pneumonia is unclear. This study aimed to assess the association between ADL, including physical and cognitive function, and death or readmission in older inpatients with pneumonia., Methods: This retrospective, single-center, observational study included consecutive older inpatients with pneumonia between October 2018 and December 2019. ADL was assessed using the Functional Independence Measure (FIM). Functional decline during hospitalization was defined as a decrease of at least 1 point in FIM at discharge from admission. The primary outcome was the time to composite 180-day mortality and readmission from any cause after discharge., Results: In total, 363 patients (median [interquartile range] age: 80 [73-86] years, male: 68 %) were divided according to the median FIM scores (≥100, n = 183 and < 100, n = 180). Among the patients, 25 experienced functional decline during hospitalization, 69 were readmitted, and 17 died. In the Kaplan-Meier analysis, both the lower FIM group and the functional decline group had significantly lower event-free rates than the higher FIM groups and the non-functional decline groups (log-rank test, p < 0.001), respectively. After multivariate analysis, both the lower FIM (adjusted HR, 2.11; 95 % CI, 1.24-3.58; p = 0.006) and functional decline (adjusted HR, 3.18; 95 % CI, 1.44-7.05; p = 0.005) were significantly associated with the primary outcome., Conclusions: In older patients hospitalized with pneumonia, ADL limitations at discharge and a decline in ADL were associated with poor outcomes., 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. Published by Elsevier Ltd.)

A 75-year-old man with a history of small intestinal angioectasia underwent transcatheter edge-to-edge repair for severe functional mitral regurgitation, resulting in recovery of large von Willebrand Factor multimers. This case highlights the potential of transcatheter edge-to-edge repair to manage both heart failure and acquired von Willebrand disease associated with functional mitral regurgitation., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 Published by Elsevier on behalf of the American College of Cardiology Foundation.)