Search

Context: Diabetic retinopathy (DR) is a common microvascular complication of diabetes, and identifying the risk factors for severe DR is important., Objective: We aimed to investigate the relationship between severe DR and the extracellular water to total body water ratio (ET ratio)., Design: Retrospective cross-sectional study., Setting: Department of Endocrinology, Metabolism, and Diabetes at Kyushu University Hospital., Patients: A total of 205 adults with type 2 diabetes (T2D) were included. The patients were divided into two groups: non-proliferative DR (non-PDR; n = 161, 126 with no DR and 35 with simple DR) and proliferative DR (PDR; n = 44, 18 with pre-proliferative DR and 26 with PDR)., Main Outcome Measure: The ET ratio was measured using bioelectrical impedance analysis., Results: The ET ratio was significantly higher in the PDR group than in the non-PDR group (0.390 vs. 0.398; P < .0001). Multivariate logistic regression analysis showed that the ET ratio was significantly associated with PDR, independent of known risk factors for DR progression. In the subgroup analysis by age, multivariate logistic regression analysis revealed a significant association between the ET ratio and PDR, independent of known risk factors for DR progression in patients younger than 60 years. However, in patients 60 years and older, only the urinary albumin to creatinine ratio (UACR) showed a significant association with PDR in a model using the UACR and the ET ratio., Conclusion: In patients with T2D younger than 60 years, the ET ratio may be a useful indicator for identifying severe DR., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. 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. See the journal About page for additional terms.)

Background and Objective: Mucus plugs and underlying airway tree structure can affect airflow limitation and prognosis in patients with chronic obstructive pulmonary disease (COPD), but their relative roles are unclear. This study used two COPD cohorts to examine whether mucus plugs on computed tomography (CT) were associated with airflow limitation and clinical outcomes independent of other airway structural changes and emphysema., Methods: Based on visual CT assessment, patients with mucus plugs in 0, 1-2 and ≥3 lung segments were assigned to no-, low- and high-mucus groups. Loss of health-related independence and mortality were prospectively recorded for 3 and 10 years in the Kyoto-Himeji and Hokkaido cohorts, respectively. The percentages of the wall area of the central airways (WA%), total airway count (TAC) and emphysema were quantified on CT., Results: Of 199 and 96 patients in the Kyoto-Himeji and Hokkaido cohorts, 34% and 30%, respectively, had high mucus scores. In both cohorts, TAC was lower in the high-mucus group than in the no-mucus group, whereas their emphysema severity did not differ. High mucus score and low TAC were independently associated with airflow limitation after adjustment for WA% and emphysema. In multivariable models adjusted for WA% and emphysema, TAC, rather than mucus score, was associated with a greater rate of loss of independence, whereas high mucus score, rather than TAC, was associated with increased mortality., Conclusion: Mucus plugs and lower airway branch count on CT had distinct roles in airflow limitation, health-related independence and mortality in patients with COPD., (© 2024 The Author(s). Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Hemorrhagic shock and resuscitation (HSR) enhances the risk of acute lung injury (ALI). This study investigated the protective effect of carbamazepine (CBZ) on HSR-induced ALI in rats. Male Sprague-Dawley rats were allocated into five distinct groups through randomization: control (SHAM), saline + HSR (HSR), CBZ + HSR (CBZ/HSR), dimethyl sulfoxide (DMSO) + HSR (DMSO/HSR), and CBZ + chloroquine (CQ) + HSR (CBZ/CQ/HSR). Subsequently, HSR models were established. To detect tissue damage, we measured lung histological changes, lung injury scores, and wet/dry weight ratios. We measured neutrophil counts as well as assessed the expression of inflammatory factors using RT-PCR to determine the inflammatory response. We detected autophagy-related proteins LC3II/LC3I, P62, Beclin-1, and Atg12-Atg5 using western blotting. Pretreatment with CBZ improved histopathological changes in the lungs and reduced lung injury scores. The CBZ pretreatment group exhibited significantly reduced lung wet/dry weight ratio, neutrophil aggregation and number, and inflammation factor (TNF-α and iNOS) expression. CBZ changed the expression levels of autophagy-related proteins (LC3II/LC3I, beclin-1, Atg12-Atg5, and P62), suggesting autophagy activation. However, after injecting CQ, an autophagy inhibitor, the beneficial effects of CBZ were reversed. Taken together, CBZ pretreatment improved HSR-induced ALI by suppressing inflammation, at least in part, through activating autophagy. Thus, our study offers a novel perspective for treating HSR-induced ALI., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Li 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.)

Purpose: To compare the outcomes of endovascular aortic aneurysm repair using a chimney technique (ch-EVAR) with those of the standard EVAR (st-EVAR) for ruptured abdominal aortic aneurysms (RAAA)., Materials and Methods: We implemented ch-EVAR for juxtarenal RAAA based on obvious anatomical indications after converting the strategy for RAAA from open repair to EVAR. A retrospective, cohort-based study was conducted on patients with RAAA who were treated using EVAR in our hospital between July 2011 and March 2022. EVAR cases were extracted, and outcomes were compared between ch-EVAR and st-EVAR. Patient clinical status, anatomical variables, treatment, and follow-up data were evaluated., Results: A total of 56 (82%) and 12 (18%) patients were treated by st-EVAR and ch-EVAR, respectively. Thirty-day mortality rates were comparable between the 2 groups [8.9% in st-EVAR vs 8.3% in ch-EVAR ( p = 0.95)]. Short-term outcomes showed that no type Ia endoleak occurred in either group. Midterm outcomes, including sac enlargement [7.5% in st-EVAR vs 0% in ch-EVAR (p= 0.37)], shrinkage [77.5% in st-EVAR vs 80.0% in ch-EVAR (p= 0.86)], and overall survival and freedom from aneurysm-related reintervention at 3 years [64.7% and 96.4% in the EVAR group vs 91.7% and 100% in the ch-EVAR group, respectively (p= 0.30 and 0.52)], were not significantly different between the 2 groups., Conclusion: Ch-EVAR for RAAA showed remarkably excellent outcomes, comparable to those of st-EVAR. Ch-EVAR is considered technically feasible in experienced centers. The indications for EVAR for RAAA may be further expanded using the chimney technique, resulting in overall improved outcomes for RAAA., Clinical Impact: This is a retrospective, single-center analysis of 68 patients with ruptured abdominal aortic aneurysms (RAAAs) treated by endovascular repair (EVAR) to investigate the efficacy of the chimney technique for juxtarenal RAAA. Thirty-day mortality rate was 8.3% for the chimney EVAR group, which was equivalent to that in the standard EVAR group. Mid-term outcomes including sac enlargement/shrinkage, overall survival, and freedom from aneurysm-related reintervention were comparable between the two groups. This report suggests the possibility of broadening the selection criteria of the current endovascular strategy using the chimney technique., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Frailty is significantly correlated with a higher incidence of medical complications during hospitalization after esophagectomy. As frailty is thought to be a reversible condition, improving the reserve capacity through preoperative physical therapy is expected to reduce the risk of postoperative pulmonary complications (PPCs). Herein, we report our experience with preoperative physical therapy in a patient with esophageal cancer who was considered to have inadequate fitness for surgery owing to poor physical performance., Case Presentation: A 72-year-old man (height: 169.5 cm, weight: 54.7 kg, body mass index: 18.9 kg/m 2 ) with esophagogastric junction tumors (cStage IIIA) was hospitalized and scheduled to undergo surgery based on preoperative screening. He was categorized as frail according to the revised Japanese version of the Cardiovascular Health Study criteria and the Mini Nutritional Assessment Short-Form indicated severe malnutrition. We focused on physical therapy to improve exercise tolerance and prevent PPCs and devised a short-term intensive physical therapy program comprising minimal exercises that the patient could perform efficiently. The program consisted of only inspiratory muscle training and aerobic exercises. His maximal inspiratory pressure (MIP) and 6-min walking distance improved by 30 cm H 2 O and 145 m, respectively, on the day before surgery compared with those on day 8. The percentage predicted value of the MIP improved from 56.6% at the start of physical therapy to 102.9% on the day before surgery. On day 43, the patient underwent subtotal esophagectomy and was able to ambulate on postoperative day 5 without respiratory complications., Conclusion: We conducted a short-term, intensive, and minimal preoperative physical therapy program for a patient with esophageal cancer who had physical frailty. Preoperative physical therapy to increase the reserve capacity may result in a favorable postoperative course even in patients with physical frailty., (© 2024 The Author(s). Physiotherapy Research International published by John Wiley & Sons Ltd.)

To investigate the yet-unknown roles of prostaglandins (PGs) in the uterus, we analyzed the expression of various PG receptors in the uterus. We found that three types of Gs-coupled PG receptors, DP, EP2, and EP4, were expressed in luminal epithelial cells from the peri-implantation period to late pregnancy. DP expression was also induced in stromal cells within the mesometrial region, whereas EP4 was expressed in stromal cells within the anti-mesometrial region during the peri-implantation period. The timing of DP induction after embryo attachment correlated well with that of cyclooxygenase-2 (COX-2); however, COX-2-expressing stromal cells were located in the vicinity of the embryo, whereas DP-expressing stromal cells surrounded these cells on the mesometrial side. Specific [ 3 H]PGD 2 -binding activity was detected in the decidua of uteri, with PGD 2 synthesis comparable to that of PGE 2 detected in the uteri during the peri-implantation period. Administration of the COX-2-specific inhibitor celecoxib caused adverse effects on decidualization, as demonstrated by the attenuated weight of the implantation sites, which was recovered by the simultaneous administration of a DP agonist. Such a rescuing effect of the DP agonist was mimicked by an EP4 agonist, but not an EP2 agonist. While the importance of DP signaling was shown pharmacologically, DP/EP2 double deficiency did not affect implantation and decidualization, suggesting the contribution of EP4 to these processes. Indeed, administration of an EP4 antagonist substantially affected decidualization in DP/EP2-deficient mice. These results suggest that COX-2-derived PGD 2 and PGE 2 contribute to decidualization via a coordinated pathway of DP and EP4 receptors., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest regarding the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Despite clinical implications, the pathogenesis of mucus plugging in asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap (ACO) remains unclear. We hypothesized that distinct airway microbiomes might affect mucus plugging differently among ACO, asthma, and COPD and among different extents of airway eosinophilic inflammation., Methods: The sputum microbiome, sputum cell differential count, and mucus plug score on computed tomography were cross-sectionally evaluated in patients with chronic airflow limitation., Results: Patients with ACO, asthma, or COPD were enrolled (n = 56, 10, and 25). Higher mucus plug scores were associated with a greater relative abundance of the phylum Proteobacteria (rho = 0.29) only in patients with ACO and a greater relative abundance of the phylum Actinobacteria (rho = 0.46) only in patients with COPD. In multivariable models including only patients with ACO, the presence of mucus plugs was associated with a greater relative abundance of the phylum Proteobacteria and the genus Haemophilus, independent of smoking status, airflow limitation, and emphysema severity. Moreover, the mucus score was associated with a greater relative abundance of the genus Streptococcus (rho = 0.46) in patients with a high sputum eosinophil count (n = 22) and with that of the genus Haemophilus (rho = 0.46) in those with a moderate sputum eosinophil count (n = 26)., Conclusions: The associations between mucus plugging and the microbiome in ACO differed from those in COPD and asthma. Greater relative abundances of the phylum Proteobacteria and genus Haemophilus may be involved in mucus plugging in patients with ACO and moderate airway eosinophilic inflammation., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

A 78-year-old woman with a history of intractable otitis media presented with a fever, hearing impairment, thigh pain, and a skin rash. She had renal dysfunction, positive myeloperoxidase-antineutrophil cytoplasmic autoantibody, otitis media, and multiple nodules in both lungs. She was diagnosed with granulomatosis with polyangiitis, crescentic glomerulonephritis, and interstitial nephritis, which was confirmed in a kidney biopsy specimen. Induction therapy with rituximab and avacopan without glucocorticoids promptly resolved her fever and thigh pain and improved her auditory acuity and nodule in the right lung. The patient experienced no adverse effects with rituximab or avacopan.

Objective: Type II endoleak (T2EL) is the most common type of endoleak after endovascular aneurysm repair (EVAR) and a common indication for reintervention due to late sac enlargement. Although pre-emptive embolization of the inferior mesenteric artery (IMA) has been proposed to prevent this, no studies have prospectively demonstrated its efficacy. This study aimed to prove the validity of IMA embolization during EVAR in selective cases by analyzing the mid-term outcomes of a randomized clinical trial (RCT)., Methods: This single-center, parallel-group, non-blinded RCT included participants at high risk of T2EL, characterized by a patent IMA in conjunction with one or more following risk factors: a patent IMA ≥3 mm in diameter, lumbar arteries ≥2 mm in diameter, or an aortoiliac-type aneurysm. The participants were randomly assigned to two groups in a 1:1 ratio: one undergoing EVAR with IMA embolization and the other without. The primary endpoint was T2EL occurrence. The secondary endpoints included aneurysm sac changes and reintervention. In addition to RCT participants, outcomes of patients with low risk of T2EL were also analyzed., Results: The embolization and non-embolization groups each contained 53 patients. Five-year follow-up after the last patient enrollment revealed that T2ELs occurred in 28.3% and 54.7% of patients in the IMA embolization and non-embolization groups, respectively (P = .006). Both freedom from T2EL-related sac enlargement ≥5 mm and cumulative incidence of sac shrinkage ≥5 mm were significantly higher in the IMA embolization group than in the non-embolization group (95.5% vs 73.6% at 5 years; P = .021; 54.2% vs 33.6% at 5 years; P = .039, respectively). The freedom from T2EL-related sac enlargement ≥10 mm, an alternative indicator for T2EL-related reintervention, showed similar results (100% vs 90.4% at 5 years; P = .019). Outcomes in the low-risk group were preferable than those in the non-embolization group and comparable to those in the IMA embolization group., Conclusions: A lower threshold for pre-emptive IMA embolization when implementing EVAR would be more appropriate if limited to patients at high risk of T2ELs., Competing Interests: Disclosures None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Lower skeletal muscle density may reflect muscle adiposity and metabolic dysregulation that potentially impair disease control and lung function independent of high body mass index (BMI) in patients with asthma., Objective: To investigate whether lower density of pectoralis muscles (PM) and erector spinae muscles (ESM) on chest computed tomography (CT) was associated with airway structural changes in patients with asthma., Methods: Consecutive patients with asthma and healthy control subjects undergoing chest CT were retrospectively analysed. The ESM and PM density, areas of subcutaneous adipose tissue (SAT) near the PM and epicardial adipose tissue (EAT), wall area percent of the airways (WA%), and airway fractal dimension (AFD) were quantified on CT., Results: The study included 179 patients with asthma (52% women) and 88 control subjects (47% women). All the control subjects were ≤ 60 years old. PM and ESM density in female patients with asthma who were ≤ 60 years old were significantly lower than those in control subjects after adjustment for BMI. In female patients with asthma at all ages, lower PM and ESM density (but not SAT or EAT area) was associated with greater WA% and lower AFD after adjusting for age, height, BMI, smoking status, blood eosinophil count, and oral corticosteroid use. The only association between ESM density and AFD was found in male patients with asthma., Conclusion: Lower skeletal muscle density may be associated with airway wall thickening and less complexity of the airway luminal tree in female patients with asthma., Competing Interests: Declaration of competing interest N.T. and T.H. received research grants from Daiichi Sankyo and FUJIFILM Co., Ltd., outside of the submitted work. S.S. received grants from Nippon Boehringer Ingelheim, Philips-Respironics, Fukuda Denshi, Fukuda Lifetec Keiji, and ResMed outside of the submitted work. None of these companies played a role in the design or analysis of the study or in the writing of the manuscript. The other authors have no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Porous materials synthesized through bottom-up approaches, such as metal-organic frameworks and covalent organic frameworks, have attracted attention owing to their design flexibility for functional materials. However, achieving the chemical and thermal stability of these materials for various applications is challenging considering the reversible coordination bonds and irreversible covalent bonds in their frameworks. Thus, ordered carbonaceous frameworks (OCFs) emerge as a promising class of bottom-up materials with good periodicity, thermal and chemical stability, and electrical conductivity. However, a few OCFs have been reported owing to the limited range of precursor molecules. Herein, we designed a hexaazatrinaphthylene-based molecule with enediyne groups as a precursor molecule for synthesizing an OCF. The solid-state Bergman cyclization of enediyne groups at a low temperature formed a microporous polymer and an OCF, exhibiting redox activity and demonstrating their potential for electrochemical applications. The microporous polymer was used as an active material in sodium-ion batteries, while the OCF was used as an electrochemical capacitor. These findings illustrate the utility of the Bergman cyclization reaction for synthesizing microporous polymers and OCFs with a customizable functionality for broad applications.

Follicular helper T (Tfh) cells promote B cell differentiation and antibody production in the B cell follicles of secondary lymphoid organs. Tfh cells express their signature transcription factor BCL6, interleukin (IL)-21, and surface molecules including inducible T cell costimulator, programmed cell death-1 (PD-1), and the chemokine receptor CXCR5. Migration of Tfh cells to B cell follicles largely depends on the CXCR5 expression induced by interactions with antigen-presenting dendritic cells in the T cell area. How Tfh cells acquire sufficient levels of CXCR5 expression, however, has remained unclear. Using our in vitro culture system to generate CXCR5low Tfh-like cells from naïve CD4+ T cells with IL-6 in the absence of other cell types, we found that the active form of vitamin D, calcitriol, markedly enhanced CXCR5 expression after the release from persistent T cell receptor (TCR) stimulation. CH-223191, an aryl hydrocarbon receptor antagonist, further enhanced CXCR5 expression. IL-12 but not IL-4, in place of IL-6, also supported calcitriol to enhance CXCR5 expression even before the release from TCR stimulation, whereas the cell viability sharply decreased after the release. The Tfh-like cells generated with IL-6 and calcitriol exhibited chemotaxis towards CXCL13, expressed IL-21, and helped B cells to produce IgG antibodies in vitro more efficiently than Tfh-like cells generated without added calcitriol. Calcitriol injections into antigen-primed mice increased the proportion of CXCR5+PD-1+CD4+ cells in their lymphoid organs, and enhanced T cell entry into B-cell follicles. These results suggest that calcitriol promotes CXCR5 expression in developing Tfh cells and regulates their functional differentiation., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Society for Immunology.)

We propose two types of novel morphological metrics for quantifying the geometry of tubular structures on computed tomography (CT) images. We apply our metrics to identify irregularities in the airway of patients with chronic obstructive pulmonary disease (COPD) and demonstrate that they provide complementary information to the conventional metrics used to assess COPD, such as the tissue density distribution in lung parenchyma and the wall area ratio of the segmented airway. The three-dimensional shape of the airway and its abstraction as a rooted tree with the root at the trachea carina are automatically extracted from a lung CT volume, and the two metrics are computed based on a mathematical tool called persistent homology; treeH0 quantifies the distribution of branch lengths to assess the complexity of the tree-like structure and radialH0 quantifies the irregularities in the luminal radius along the airway. We show our metrics are associated with clinical outcomes.

Context: Adrenal incidentalomas, including nonfunctioning adrenal incidentalomas (NFAI), are associated with a high prevalence of diabetes mellitus (DM). While NFAI is diagnosed by exclusion when no hormone excess exists, subtle cortisol secretion may exist and contribute to DM development. However, it alone cannot explain the increased risk, and whether other steroid metabolites are involved remains unclear., Purpose: To investigate steroid metabolites associated with DM in patients with NFAI using plasma steroid profiles., Methods: Using liquid chromatography-tandem mass spectrometry, 22 plasma steroid metabolites were measured in 68 patients with NFAI (31 men and 37 women). Data were adjusted for age before normalization., Results: Discriminant analysis showed that plasma steroid profiles discriminated between patients with and without DM in men (n = 10 and = 21, respectively) but not women: 11β-hydroxytestosterone, an adrenal-derived 11-oxygenated androgen, contributed most to this discrimination and was higher in patients with DM than in those without DM (false discovery rate = .002). 11β-hydroxytestosterone was correlated positively with fasting plasma glucose (r = .507) and hemoglobin A1c (HbA1c) (r = .553) but negatively with homeostatic model assessment of β-cell function (HOMA2-B) (r = -.410). These correlations remained significant after adjusting for confounders, including serum cortisol after the 1-mg dexamethasone suppression test. Bayesian kernel machine regression analysis verified the association of 11β-hydroxytestosterone with HbA1c and HOMA2-B in men., Main Conclusion: Plasma steroid profiles differed between those with and without DM in men with NFAI. 11β-hydroxytestosterone was associated with hyperglycemia and indicators related to pancreatic β-cell dysfunction, independently of cortisol., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Preoperative adjuvant therapy for esophageal cancer increases sarcopenia and decreases exercise tolerance, which are risk factors for postoperative pneumonia. Preoperative rehabilitation for patients undergoing esophagectomy effectively reduces the incidence of postoperative pneumonia. Therefore, the risk factors should be optimized by preoperative rehabilitation. Our patient had several risk factors for postoperative pneumonia, including low exercise tolerance, presarcopenia, and low respiratory muscle strength. However, because of the patient's advanced age, multiple comorbidities, and poor nutritional status, we struggled to determine the appropriate exercise intensity. Furthermore, there was a concern that chemotherapy-related adverse events could prevent adequate exercise from being performed. However, with individualized measures such as adjustable exercise intensity settings based on treatment status and nutritional management through multidisciplinary collaboration, it was possible to prevent sarcopenia and maintain exercise tolerance during preoperative adjuvant therapy. Individualized support in preoperative rehabilitation was suggested to contribute to the prevention of sarcopenia and maintenance of exercise tolerance during preoperative adjuvant therapy., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Sakamoto et al.)

The architecture of the actin cortex determines the generation and transmission of stresses, during key events from cell division to migration. However, its impact on myosin-induced cell shape changes remains unclear. Here, we reconstitute a minimal model of the actomyosin cortex with branched or linear F-actin architecture within giant unilamellar vesicles (GUVs, liposomes). Upon light activation of myosin, neither the branched nor linear F-actin architecture alone induces significant liposome shape changes. The branched F-actin network forms an integrated, membrane-bound "no-slip boundary" -like cortex that attenuates actomyosin contractility. By contrast, the linear F-actin network forms an unintegrated "slip boundary" -like cortex, where actin asters form without inducing membrane deformations. Notably, liposomes undergo significant deformations at an optimized balance of branched and linear F-actin networks. Our findings highlight the pivotal roles of branched F-actin in force transmission and linear F-actin in force generation to yield membrane shape changes., (© 2024. The Author(s).)

Background: Associations of fractional exhaled nitric oxide (FeNO) with airway wall remodeling and mucus plugs remain to be explored in smokers and nonsmokers with asthma. Ultra-high-resolution computed tomography (U-HRCT), which allows accurate structural quantification of airways >1 mm in diameter, was used in this study to examine whether higher FeNO was associated with thicker walls of the 3rd to 6th generation airways and mucus plugging in patients with asthma., Methods: The retrospective analyses included consecutive former smokers and nonsmokers with asthma who underwent U-HRCT in a hospital. The ratio of wall area to summed lumen and wall area was calculated as the wall area percent (WA%). Mucus plugging was visually scored., Results: Ninety-seven patients with asthma (including 59 former smokers) were classified into low (<20 ppb), middle (20-35 ppb), and high (>35 ppb) FeNO groups (n = 24, 26, and 47). In analysis including all patients and subanalysis including nonsmokers or former smokers, WA% in the 6th generation airways was consistently higher in the high FeNO group than in the low FeNO group, whereas WA% in the 3rd to 5th generation airways was not. In multivariable models, WA% in the 6th generation airways and the rate of mucus plugging were higher in the high FeNO group than in the low FeNO group after adjusting for age, sex, body mass index, smoking status, lung volume, and allergic rhinitis presence., Conclusions: Higher FeNO may reflect the inflammation and remodeling of relatively peripheral airways in asthma in both former smokers and nonsmokers., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background: Substance use disorder (SUD) is a major health issue in Indonesia, where several barriers to treatment exist, including inaccessibility to treatment services, stigma, and criminalization of drug issues. Peer involvement and the use of telemedicine to deliver psychotherapy are promising approaches to overcome these barriers., Objective: This study aims (1) to describe the development of a new group psychotherapy coprovided by a health care worker and a peer and (2) to evaluate the acceptability, practicality, and preliminary outcomes of the program delivered via videoconferencing in Indonesia., Methods: Building upon an established relapse prevention therapy in Japan, we developed a 3-month weekly group therapy module in the Indonesian language. Adjustments were made via focus group discussions with local stakeholders in terms of substance types, understandability, inclusive language, and cultural relevance. A pilot study was conducted to test the new module provided by a peer and a psychiatrist via videoconferencing, termed tele-Indonesia Drug Addiction Relapse Prevention Program (tele-Indo-DARPP), with a pre- and postcontrolled design. We analyzed data from semistructured feedback interviews and outcome measurements, including the number of days using substances and quality of life, and compared the intervention (tele-Indo-DARPP added to treatment as usual [TAU]) and control (TAU only) arms., Results: In total, 8 people diagnosed with SUD participated in the pilot study with a mean age of 37 (SD 12.8) years. All were men, and 7 (88%) used sedatives as the primary substance. Collectively, they attended 44 of the 48 tele-Indo-DARPP sessions. A total of 3 out of 4 (75%) preferred telemedicine rather than in-person therapy. Positive acceptability and practicality were shown from qualitative feedback, in which the participants who joined the tele-Indo-DARPP reported that they liked the convenience of joining from home and that they were able to open up about personal matters, received helpful advice from peers, and received support from other participants. Providers reported that they feel the module was provider-friendly, and the session was convenient to join without diminishing rapport-building. Meanwhile, troubles with the internet connection and difficulty in comprehending some terminology in the workbook were reported. The intervention arm showed better improvements in psychological health and anxiety symptoms., Conclusions: Group psychotherapy via videoconferencing coprovided by health care workers and peers was acceptable and practical for participants with SUD and service providers in this study. A large-scale study is warranted to examine the effectiveness of the newly developed module in Indonesia., (©Kristiana Siste, Youdiil Ophinni, Enjeline Hanafi, Chika Yamada, Reza Novalino, Albert P Limawan, Evania Beatrice, Vania Rafelia, Peter Alison, Toshihiko Matsumoto, Ryota Sakamoto. Originally published in JMIR Formative Research (https://formative.jmir.org), 18.06.2024.)

Microporous molecular crystals are promising materials because of their designable porosity as well as their resistance to chemical and other stimuli. Here, we developed microporous molecular cocrystals by taking advantage of the specific interactions between porphyrins and fullerene molecules. Single-crystal X-ray diffraction analysis revealed that one nickel(II) porphyrin interacts with two fullerene molecules to form a two-dimensional honeycomb network with an eclipsed stacking mode, providing one-dimensional void channels. After the pores were activated by heat treatment or mechanical grinding, the prepared cocrystal can incorporate gas and solvent molecules reversibly while maintaining its single-crystallinity. Also, it retained its single-crystallinity in the presence of water, acid-base, or high pressure. These findings in this study expand the availability of molecular crystals based on intermolecular interactions as porous materials, which are expected to work under conditions that have not been applicable to other molecule-based porous materials., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Co-published by University of Science and Technology of China and American Chemical Society.)

Objective: The human adrenal cortex comprises three functionally and structurally distinct layers that produce layer-specific steroid hormones. With aging, the human adrenal cortex undergoes functional and structural alteration or "adrenal aging", leading to the unbalanced production of steroid hormones. Given the marked species differences in adrenal biology, the underlying mechanisms of human adrenal aging have not been sufficiently studied. This study was designed to elucidate the mechanisms linking the functional and structural alterations of the human adrenal cortex., Methods: We conducted single-cell RNA sequencing and spatial transcriptomics analysis of the aged human adrenal cortex., Results: The data of this study suggest that the layer-specific alterations of multiple signaling pathways underlie the abnormal layered structure and layer-specific changes in steroidogenic cells. We also highlighted that macrophages mediate age-related adrenocortical cell inflammation and senescence., Conclusions: This study is the first detailed analysis of the aged human adrenal cortex at single-cell resolution and helps to elucidate the mechanism of human adrenal aging, thereby leading to a better understanding of the pathophysiology of age-related disorders associated with adrenal aging., 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 Author(s). Published by Elsevier GmbH.. All rights reserved.)

Ephrin type-A receptor 2 (EPHA2) is a receptor tyrosine kinase that is overexpressed in a variety of cancers, including breast cancer. EPHA2 expression may be causally related to tumorigenesis; therefore, it is important to understand how EPHA2 expression is regulated. We previously reported that EPHA2 antisense RNA (EPHA2-AS), a natural antisense transcript, is an important modulator of EPHA2 mRNA levels and hence production of EPHA2 protein. EPHA2-AS encodes two splice variants, EPHA2-AS1 and EPHA2-AS2. The two variants are constitutively expressed in a concordant manner with EPHA2 mRNA in human breast adenocarcinoma cell lines and in patient samples, with the highest levels detected in the basal-like/triple-negative molecular subtype of breast cancer cells. In this study, we investigated the mechanism of EPHA2-AS1/2 in triple-negative breast cancer using MDA-MB-231 cells. We performed RNA-seq transcriptome analyses of MDA-MB-231 cells treated with AHCC ® , which suppressed expression of EPHA2-AS1/2 and EPHA2 mRNA, and EPHA2-AS1/2-silenced MDA-MB-231 cells. Bioinformatics analyses identified 545 overlapping differentially expressed genes that were significantly up- or down-regulated by these treatments. Subsequent functional enrichment analyses of the overlapping genes in combination with in vitro assays indicated that EPHA2-AS1/2 may promote the proliferation and migration of MDA-MB-231 cells through the EPHA2 -dependent Ras signaling pathways mediated by MAPK8/JNK1, MAPK9/JNK2-NFATC2/NFAT1 (proliferation and migration) and JUND (migration). These results thus suggest that EPHA2-AS1/2 may represent a potential molecular target for triple-negative breast cancer treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Odaka, Sakamoto, Kumagai, Okuma, Nishizawa and Kimura.)

Background: The safety and feasibility of using 1-month dual antiplatelet therapy (DAPT) followed by P2Y 12 inhibitor monotherapy for patients after percutaneous coronary intervention (PCI) with thin-strut biodegradable polymer drug-eluting stents (BP-DES) in daily clinical practice remain uncertain., Methods and results: The REIWA region-wide registry is a prospective study conducted in 1 PCI center and 9 local hospitals in northern Japan. A total of 1,202 patients who successfully underwent final PCI using BP-DES (Synergy: n=400; Ultimaster: n=401; Orsiro: n=401), were enrolled in the registry, and received 1-month DAPT followed by P2Y 12 inhibitor (prasugrel 3.75 mg/day or clopidogrel 75 mg/day) monotherapy. The primary endpoint was a composite of cardiovascular and bleeding events at 12 months, including cardiovascular death, myocardial infarction (MI), definite stent thrombosis (ST), ischemic or hemorrhagic stroke, and Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding. Based on the results of a previous study, we set the performance goal at 5.0%. Over the 1-year follow-up, the primary endpoint occurred in 3.08% of patients, which was lower than the predefined performance goal (P non-inferiority <0.0001). Notably, definite ST occurred in only 1 patient (0.08%) within 1 year (at 258 days). No differences were observed in the primary endpoint between stent types., Conclusions: The REIWA region-wide registry suggests that 1-month DAPT followed by P2Y 12 inhibitor monotherapy is safe and feasible for Japanese patients with BP-DES.

We investigated the impact of the Coronavirus disease 2019 (COVID-19) pandemic on the management of endocrine and metabolic disorders in Japan. We conducted a cross-sectional nationwide questionnaire survey targeting board-certified endocrinologists under the auspices of the Japan Endocrine Society. The questionnaire consisted of multiple-choice questions and open-ended responses. Out of approximately 2,700 specialists, 528 (19.5%) opted to participate, suggesting a high level of interest in COVID-19 management among endocrinologists. The study found that almost half of participants had encountered cases of endocrine and metabolic disorders following COVID-19 infection or vaccination. Conditions related to thyroid diseases, glucose metabolism disorders/diabetes, and hypothalamic-pituitary disorders were particularly prevalent. Diabetes and obesity were identified as having high rates of severe cases or fatalities due to COVID-19. The study also highlighted challenges in routine diagnosis and treatment, emphasizing the potential benefits of combining remote consultations with in-person visits to optimize the frequency of examinations and check-ups during infectious disease outbreak which disrupts access to healthcare providers. The insights obtained from this survey are expected to contribute to ensuring appropriate healthcare provision for patients with endocrine and metabolic disorders by using flexible consultation formats, particularly even in the conditions where medical access may be limited due to future outbreaks of emerging or re-emerging infectious diseases.

Purpose: This study was conducted to evaluate whether thin-slice 2D fat-saturated proton density-weighted images of the shoulder joint in three imaging planes combined with parallel imaging, partial Fourier technique, and denoising approach with deep learning-based reconstruction (dDLR) are more useful than 3D fat-saturated proton density multi-planar voxel images., Methods: Eighteen patients who underwent MRI of the shoulder joint at 3T were enrolled. The denoising effect of dDLR in 2D was evaluated using coefficient of variation (CV). Qualitative evaluation of anatomical structures, noise, and artifacts in 2D after dDLR and 3D was performed by two radiologists using a five-point Likert scale. All were analyzed statistically. Gwet's agreement coefficients were also calculated., Results: The CV of 2D after dDLR was significantly lower than that before dDLR (P < 0.05). Both radiologists rated 2D higher than 3D for all anatomical structures and noise (P < 0.05), except for artifacts. Both Gwet's agreement coefficients of anatomical structures, noise, and artifacts in 2D and 3D produced nearly perfect agreement between the two radiologists. The evaluation of 2D tended to be more reproducible than 3D., Conclusion: 2D with parallel imaging, partial Fourier technique, and dDLR was proved to be superior to 3D for depicting shoulder joint structures with lower noise.

Background: The human adrenal cortex consists of three functionally and structurally distinct layers; zona glomerulosa, zona fasciculata (zF), and zona reticularis (zR), and produces adrenal steroid hormones in a layer-specific manner; aldosterone, cortisol, and adrenal androgens, respectively. Cortisol-producing adenomas (CPAs) occur mostly as a result of somatic mutations associated with the protein kinase A pathway. However, how CPAs develop after adrenocortical cells acquire genetic mutations, remains poorly understood., Methods: We conducted integrated approaches combining the detailed histopathologic studies with genetic, RNA-sequencing, and spatially resolved transcriptome (SRT) analyses for the adrenal cortices adjacent to human adrenocortical tumours., Findings: Histopathological analysis revealed an adrenocortical nodular structure that exhibits the two-layered zF- and zR-like structure. The nodular structures harbour GNAS somatic mutations, known as a driver mutation of CPAs, and confer cell proliferative and autonomous steroidogenic capacities, which we termed steroids-producing nodules (SPNs). RNA-sequencing coupled with SRT analysis suggests that the expansion of the zF-like structure contributes to the formation of CPAs, whereas the zR-like structure is characterised by a macrophage-mediated immune response., Interpretation: We postulate that CPAs arise from a precursor lesion, SPNs, where two distinct cell populations might contribute differently to adrenocortical tumorigenesis. Our data also provide clues to the molecular mechanisms underlying the layered structures of human adrenocortical tissues., Funding: KAKENHI, The Uehara Memorial Foundation, Daiwa Securities Health Foundation, Kaibara Morikazu Medical Science Promotion Foundation, Secom Science and Technology Foundation, ONO Medical Research Foundation, and Japan Foundation for Applied Enzymology., Competing Interests: Declaration of interests The authors have declared that no conflict of interest exists., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Mechanical work serves as the foundation for dynamic cellular processes, ranging from cell division to migration. A fundamental driver of cellular mechanical work is the actin cytoskeleton, composed of filamentous actin (F-actin) and myosin motors, where force generation relies on adenosine triphosphate (ATP) hydrolysis. F-actin architectures, whether bundled by crosslinkers or branched via nucleators, have emerged as pivotal regulators of myosin II force generation. However, it remains unclear how distinct F-actin architectures impact the conversion of chemical energy to mechanical work. Here, we employ in vitro reconstitution of distinct F-actin architectures with purified components to investigate their influence on myosin ATP hydrolysis (consumption). We find that F-actin bundles composed of mixed polarity F-actin hinder network contraction compared to non-crosslinked network and dramatically decelerate ATP consumption rates. Conversely, linear-nucleated networks allow network contraction despite reducing ATP consumption rates. Surprisingly, branched-nucleated networks facilitate high ATP consumption without significant network contraction, suggesting that the branched network dissipates energy without performing work. This study establishes a link between F-actin architecture and myosin energy consumption, elucidating the energetic principles underlying F-actin structure formation and the performance of mechanical work., (© 2024. The Author(s).)

Background: Interstitial lung abnormalities (ILAs) on CT may affect the clinical outcomes in patients with chronic obstructive pulmonary disease (COPD), but their quantification remains unestablished. This study examined whether artificial intelligence (AI)-based segmentation could be applied to identify ILAs using two COPD cohorts., Methods: ILAs were diagnosed visually based on the Fleischner Society definition. Using an AI-based method, ground-glass opacities, reticulations, and honeycombing were segmented, and their volumes were summed to obtain the percentage ratio of interstitial lung disease-associated volume to total lung volume (ILDvol%). The optimal ILDvol% threshold for ILA detection was determined in cross-sectional data of the discovery and validation cohorts. The 5-year longitudinal changes in ILDvol% were calculated in discovery cohort patients who underwent baseline and follow-up CT scans., Results: ILAs were found in 32 (14%) and 15 (10%) patients with COPD in the discovery (n = 234) and validation (n = 153) cohorts, respectively. ILDvol% was higher in patients with ILAs than in those without ILA in both cohorts. The optimal ILDvol% threshold in the discovery cohort was 1.203%, and good sensitivity and specificity (93.3% and 76.3%) were confirmed in the validation cohort. 124 patients took follow-up CT scan during 5 ± 1 years. 8 out of 124 patients (7%) developed ILAs. In a multivariable model, an increase in ILDvol% was associated with ILA development after adjusting for age, sex, BMI, and smoking exposure., Conclusion: AI-based CT quantification of ILDvol% may be a reproducible method for identifying and monitoring ILAs in patients with COPD., (© 2024. The Author(s).)

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.)

Sensing and processing of DNA double-strand breaks (DSBs) are vital to genome stability. DSBs are primarily detected by the ATM checkpoint pathway, where the Mre11-Rad50-Nbs1 (MRN) complex serves as the DSB sensor. Subsequent DSB end resection activates the ATR checkpoint pathway, where replication protein A, MRN, and the Rad9-Hus1-Rad1 (9-1-1) clamp serve as the DNA structure sensors. ATR activation depends also on Topbp1, which is loaded onto DNA through multiple mechanisms. While different DNA structures elicit specific ATR-activation subpathways, the regulation and mechanisms of the ATR-activation subpathways are not fully understood. Using DNA substrates that mimic extensively resected DSBs, we show here that MRN and 9-1-1 redundantly stimulate Dna2-dependent long-range end resection and ATR activation in Xenopus egg extracts. MRN serves as the loading platform for ATM, which, in turn, stimulates Dna2- and Topbp1-loading. Nevertheless, MRN promotes Dna2-mediated end processing largely independently of ATM. 9-1-1 is dispensable for bulk Dna2 loading, and Topbp1 loading is interdependent with 9-1-1. ATR facilitates Mre11 phosphorylation and ATM dissociation. These data uncover that long-range end resection activates two redundant pathways that facilitate ATR checkpoint signaling and DNA processing in a vertebrate system., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

This research focuses on enhancing H 2 adsorption by using the [Mo(PCy 3 ) 2 (CO) 3 ] complex supported on porous materials such as silica gel and mesoporous carbon. The study reports a significant increase in hydrogen adsorption capacity, reaching up to 9.3 times that of the bulk complex. This improvement suggests that using mesoporous materials as supports for the [Mo(PCy 3 ) 2 (CO) 3 ] complex enhances the accessibility of H 2 gas to its open-metal sites., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Introduction: This study is a post hoc analysis of a single-arm trial to determine whether daily viewing of comedy videos for four weeks improves health-related quality of life (HRQOL) and oxidative stress in cancer survivors (UMIN-CTR 000044880). There are no reports of personality traits affecting HRQOL improvement. The purpose of this post hoc analysis was to identify associations with personality traits that may improve HRQOL., Methodology: This analysis compared the baseline scores on the Ten-Item Personality Inventory-Japanese version (TIPI-J) for personality traits in Functional Assessment of Cancer Therapy-G (FACT-G) groups with improved or worsened scores. This grouping was based on the results of previous studies. In addition, the EuroQOL 5 dimension 3 level (EQ-5D-3L), Hospital Anxiety and Depression Scale (HADS) score, biological antioxidant potential (BAP), reactive oxygen metabolite-derived compounds, oxidative stress index, and potential antioxidant potential were assessed for each group. Items related to oxidative stress were tested using t-tests, while other items were tested using Friedman's analysis of variance., Results: Forty-three participants completed the analysis (FACT-G improved [up group], n  = 25; FACT-G decreased [down group], n  = 18). No significant differences in the TIPI-J items existed between the two groups. Significant items for oxidative stress in the FACT-G up group were BAP ( P  = 0.04, Cohen's d  = 0.32) and potential antioxidant capacity ( P  = 0.02, Cohen's d  = 0.41). In the FACT-G down group, the significant item was potential antioxidant capacity ( P = 0.03, Cohen's​​​​​​​ d = 0.46). The FACT-G up group had significant changes over time in the scores of the EuroQOL Visual Analog Scale (EQ-VAS;  χ 2 = 21.151 [df = 4]; P < 0.01), HADS-anxiety (χ 2 = 24.579 [df = 4]; P < 0.01), and HADS-depression (χ 2 = 29.068 [df = 4]; P < 0.01)., Conclusions: Our results suggested that cancer survivors' personality traits did not influence the effects of viewing comedy. It has been suggested that the group with increased FACT-G may have had an improvement in the EQ-VAS, HADS, and potential antioxidant capacity independent of FACT-G., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Sakamoto et al.)

Inborn errors of bile acid metabolism (IEBAM) cause cholestasis during the neonatal period, and 8 types of IEBAM have been reported to date. IEBAM accounts for approximately 2% of cases of cholestasis of unknown cause. As only 10 patients have been identified in Japan, IEBAM presents diagnostic challenges due to the similarity of clinical symptoms with biliary atresia, thus necessitating precise differentiation to avoid unnecessary invasive procedures. Laboratory tests in IEBAM are characterized by normal γ -glutamyltransferase (GGT) and serum total bile acid (STBA) levels despite the presence of cholestasis; therefore, measuring STBA and GGT is essential to distinguishing biliary atresia from IEBAM. With suspected IEBAM, liquid chromatography-mass spectrometry (LC/MS) analysis of urinary bile acids is needed to optimize diagnostic and therapeutic efficacy and avoid open cholangiography and initiate treatment for primary bile acids such as cholic acid or chenodeoxycholic acid. This prospective report aims to increase awareness of IEBAM by highlighting the characteristics of general blood test and bile acid profiles from LC/MS analyses of blood, urine, and stool samples., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Nittono, Suzuki, Suzuki, Sugimoto, Mori, Sakamoto, Takaki, Hayashi, Takei and Kimura.)

A 78-year-old male was admitted to the hospital with acute renal failure and generalized erythema after starting dapagliflozin 10 mg/day for chronic kidney disease (CKD). A skin biopsy revealed superficial perivascular dermatitis with eosinophils. A renal biopsy revealed lymphocytic and eosinophilic infiltration of the interstitium, and focal tubulitis. The patient was diagnosed with a dapagliflozin-induced drug reaction with eosinophilia and systemic symptoms (DRESS), followed by acute interstitial nephritis (AIN), and prednisolone therapy was therefore initiated. The patient's renal function improved, and erythema disappeared. To our knowledge, this is the first report of DRESS caused by dapagliflozin, and the patient was successfully treated with prednisolone.

All tumour cells in a patient have shared and non-shared genetic alterations, and the diversity of mutations is described as intratumoural heterogeneity (ITH). Multiregion sequencing is a genome sequencing analytical technique used for multiple, spatially-separated biopsy tissues that may further our understanding of ITH and tumour evolution. Although genetic mutations in extramammary Paget's disease (EMPD) have recently been detected by next-generation sequencing analysis, there have been no reports of ITH based on multiregion sequencing in EMPD. Thus, we clarified the landscape of ITH and tumour evolution in EMPD. We performed whole-exome sequencing on 35 tissues (30 tumour tissues and five normal skin samples as a paired control), collected from five patients with EMPD. The rate of private mutations was significantly higher than that of ubiquitous and shared mutations. Ubiquitous mutations were not present in driver genes, and most driver genes exhibited private and shared mutations. The most frequent base substitution was C>T in almost all lesions, and most mutational signatures corresponded to signature 1, 2, 3, and 8. The types of proposed aetiology in most lesions were based on age and AID/APOBEC family and BRCA1/BRCA2 mutations. Evolutionary trees were characterized by short trunks and long branches due to the extremely high ratio of private mutations. In contrast, pathogenic factors, such as base substitutions, mutational signatures, and proposed aetiology, were shared. Tumour evolution in EMPD appears to be characterized by a high level of genetic ITH with shared background factors.

Background: We aimed to determine the course of arm swelling caused by the use of taxanes and to identify valid predictors of persistent swelling. Methods and Results: A total of 15 patients with unilateral arm swelling that developed during the course, or within 3 months after termination, of postoperative taxane-based chemotherapy were included in the present study. The patients attended follow-up appointments every 3-6 months for 24 months after their initial visit. Their arm circumference was measured at each follow-up appointment, while ultrasonography of the skin and subcutaneous tissues was performed at the 0-, 6-, 12-, and 24-month follow-ups. Of the 15 patients, 12 (80%) saw their taxane-induced arm swelling resolved within a median of 12 months (range, 3-29 months) after their final taxane administration. Of the 12 patients whose swelling resolved, 9 did not use compression sleeves; however, their course of resolution did not differ from the other 3 patients who regularly used compression sleeves. In the three patients with persistent swelling, the excess subcutaneous thickness in the medial upper arm (median, 283%) was significantly greater than that in the patients whose swelling resolved (120%; p  < 0.05) during their initial visits. Conclusions: Of the 15 patients included in the present study, 80% saw their taxane-induced arm swelling resolve within a median of 12 months after their final taxane administration, independent of the use of compression therapy. Persistent swelling may be predicted during the initial visit based on subcutaneous thickening of the medial upper arm.

Introduction: Air-trapping affects clinical outcomes in patients with chronic obstructive pulmonary disease (COPD) and may be detected by reactance at 5 Hz (X5) on respiratory oscillometry because X5 sensitively reflects the elasticity of the chest wall, airway and lung. However, the longitudinal association between X5 and air-trapping remains to be explored. This study aimed to test whether longitudinal changes in X5 could be associated with air-trapping progression, exacerbations, and mortality in patients with COPD., Methods: In this prospective COPD observational study, the follow-up period consisted of the first 4 years to obtain longitudinal changes in X5 and residual volume (RV) and number of exacerbations and the remaining years (year 4 to 10) to test mortality. Patients were divided into large, middle, and small X5 decline groups based on the tertiles of longitudinal change in X5, and mortality after 4 years was compared between the groups., Results: Patients with COPD (n = 114) were enrolled. The large X5 decline group (n = 38) showed a greater longitudinal change in RV and more exacerbations compared with the small X5 decline group (n = 39) in multivariable models adjusted for age, sex, body mass index, and smoking history. Long-term mortality after the 4-year follow-up was higher in the large X5 decline group than in the small X5 decline group (hazard ratio [95 % confidence interval] = 8.37[1.01, 69.0]) in the multivariable Cox proportional hazard model., Conclusion: Longitudinal changes in respiratory reactance could be associated with progressive air-trapping, exacerbation frequency, and increased mortality in patients with COPD., Competing Interests: Declaration of Competing Interest N. Tanabe, S. Sato and T. Hirai were supported by a grant from FUJIFILM Co., Ltd. FUJIFILM did not have a role in the design or analysis of the study or in the writing of the manuscript. The other authors have no conflict of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: This study aimed to clarify the efficacy of Airbo·Wave EV1 in nighttime compression therapy as part of complex decongestive therapy (CDT) for leg lymphedema. Patients and Methods: We retrospectively reviewed 33 patients with leg lymphedema who used Airbo·Wave EV1 between April 2021 and September 2022. In these patients, the changes in leg volume and skin hardness were assessed using a scale ranging from 1 (softest) to 7 (hardest), and dermal thickness before and after the use of Airbo·Wave EV1 was evaluated. Results: Twenty-two patients used Airbo·Wave EV1 for nighttime compression in CDT. Their skin hardness in the lower calf decreased mildly (mean scale: before, 3.9; after, 3.6 [ p <0.05]), but the leg volume and skin thickness were unchanged. Eleven patients who were nonadherent could restart compression therapy by using Airbo·Wave EV1. Their skin hardness in the medial lower calf (before, 5.1; after, 4.3 [ p <0.05]), leg volume (before, 8412 mL; after, 8191 mL [ p <0.01]), and skin thickness in the medial and lateral lower leg were reduced. Conclusion: Airbo·Wave EV1 could improve skin hardness in the calf area. Moreover, it is a safe procedure for the nonadherent while reducing leg volume reasonably., (@ 2024 The Editorial Committee of Annals of Vascular Diseases.)

Introduction: The association between postoperative patient-reported outcomes (PROs) and patient satisfaction remains poorly defined in patients undergoing surgery for thoracic myelopathy. This study aimed to investigate PROs and patient satisfaction following surgical intervention for thoracic myelopathy., Methods: A prospective cohort of 133 patients who underwent surgery for thoracic myelopathy at 13 hospitals between April 2017 and August 2021 was enrolled. Patient demographics and perioperative complications were recorded. PROs were assessed using questionnaires administered preoperatively and 1 year postoperatively, including the EuroQol-5 dimension, physical and mental component summaries of the 12-item Short-Form Health Survey, Oswestry Disability Index, and numerical rating scales for low back, lower extremity, and plantar pain. Patients were categorized into two groups: satisfied (very satisfied, satisfied, and slightly satisfied) and dissatisfied (neither satisfied nor dissatisfied, slightly dissatisfied, dissatisfied, and very dissatisfied)., Results: The mean age of the patients was 66.5 years, comprising 87 men and 46 women. The most common diagnoses were ossification of the ligamentum flavum (48.8%) and thoracic spondylotic myelopathy (26.3%). Seventy-four (55.6%) and 59 (44.3%) patients underwent decompression surgery and underwent decompression with fusion, respectively. Eight patients required reoperation due to postoperative surgical site infection, hematoma, and insufficient decompression in four, three, and one patient. Ninety (67.7%) patients completed both the preoperative and postoperative PRO questionnaires, all of which demonstrated significant improvement. Among them, 58 (64.4%) and 32 (35.6%) reported satisfaction and dissatisfaction with their treatment, respectively. The satisfied group showed superior improvement in PROs than the dissatisfied group, although there were no significant differences in complication rates between the two groups., Conclusions: The 64.4% satisfaction rate observed in patients undergoing surgery for thoracic myelopathy was lower than that reported in previous studies on cervical or lumbar spine surgery. The dissatisfied group exhibited significantly poorer quality of life (QOL) and higher pain scores than the satisfied group., Competing Interests: Conflicts of Interest: The authors declare that there are no relevant conflicts of interest., (Copyright © 2024 The Japanese Society for Spine Surgery and Related Research.)

Background: Low respiratory function in young adulthood is one of the important factors in the trajectory leading to the future development of COPD, but its morphological characteristics are not well characterised., Methods: We retrospectively enrolled 172 subjects aged 40-49 years with ≥10 pack-years smoking history who underwent lung cancer screening by computed tomography (CT) and spirometry at two Japanese hospitals. Emphysema was visually assessed according to the Fleischner Society guidelines and classified into two types: centrilobular emphysema (CLE) and paraseptal emphysema (PSE). Airway dysanapsis was assessed with the airway/lung ratio (ALR), which was calculated by the geometric mean of the lumen diameters of the 14 branching segments divided by the cube root of total lung volume on a CT scan., Results: Among the subjects, CLE and PSE were observed in 20.9% and 30.8%, respectively. The mean ALR was 0.04 and did not differ between those with and without each type of emphysema. Multivariable regression analysis models adjusted for age, sex, body mass index and smoking status indicated that CLE and a low ALR were independently associated with lower forced expiratory volume in 1 s (FEV 1 )/forced vital capacity (estimate -1.64 (95% CI -2.68- -0.60) and 6.73 (95% CI 4.24-9.24), respectively) and FEV 1 % pred (estimate -2.81 (95% CI -5.10- -0.52) and 10.9 (95% CI 5.36-16.4), respectively)., Conclusions: CLE and airway dysanapsis on CT were independently associated with low respiratory function in younger smokers., Competing Interests: Conflict of interest: T. Oguma reports lecture fees from Kyowa Kirin, AstraZeneca, Kyorin Pharmaceutical, GlaxoSmithKline, Sanofi and Boehringer Ingelheim. S. Sato reports grants or contracts from Nippon Boehringer Ingelheim, FujiFilm, Philips Japan, Fukuda Denshi, Fukuda Lifetec Keiji and ResMed. The other authors report no relevant conflicts of interest., (Copyright ©The authors 2024.)

Exercise-induced increases in shear rate (SR) acutely improve peripheral endothelial function, but the presence of this mechanism in cerebral arteries remains unclear. Thus, we evaluated shear-mediated dilation of the internal carotid artery (ICA), which is an index of cerebrovascular endothelial function, before and after exercise. Shear-mediated dilation was measured with 30 s of hypercapnia in 16 young adults before and 10 min after 30 min of sitting rest (CON) or three cycling exercises on four separate days. The target exercise intensity was 80% of oxygen uptake at the ventilatory threshold. To manipulate the ICA SR during exercise, participants breathed spontaneously (Ex SB , SR increase) or hyperventilated without (Ex HV , no increase in SR) or with ([Formula: see text], restoration of SR increase) addition of CO 2 to inspiratory air. Shear-mediated dilation was calculated as a percent increase in diameter from baseline. Doppler ultrasound measures ICA velocity and diameter. The CON trial revealed that 30 min of sitting did not alter shear-mediated dilation (4.34 ± 1.37% to 3.44 ± 1.23%, P = 0.052). ICA dilation after exercise compared with preexercise levels increased in the Ex SB trial (3.32 ± 1.37% to 4.74 ± 1.84%, P < 0.01), remained unchanged in the Ex HV trial (4.07 ± 1.55% to 3.21 ± 1.48%, P = 0.07), but was elevated in the [Formula: see text] trial (3.35 ± 1.15% to 4.33 ± 2.12%, P = 0.04). Our results indicate that exercise-induced increases in cerebral shear may play a crucial role in improving cerebrovascular endothelial function after acute exercise in young adults. NEW & NOTEWORTHY We found that 30-min cycling (target intensity was 80% of the ventilatory threshold) with increasing shear of the internal carotid artery (ICA) enhanced transient hypercapnia-induced shear-mediated dilation of the ICA, reflecting improved cerebrovascular endothelial function. This enhancement of ICA dilation was diminished by suppressing the exercise-induced increase in ICA shear via hyperventilation. Our results indicate that increases in cerebral shear may be a key stimulus for improving cerebrovascular endothelial function after exercise in young adults.

Aim: This study examined the associations between geriatric factors and decreased opportunities for conversation among older adults amid a period of self-restraint during the COVID-19 pandemic., Methods: A cross-sectional questionnaire-based survey was carried out in October 2020. The participants were 204 residents aged ≥65 years staying at a private care home in Kyoto city, Japan. Logistic regression analysis was carried out with the reduction of conversation opportunities as the dependent variable, and geriatric factors as independent variables after adjusting for age and sex. We compared the decreased frequency of opportunities between residents in the assisted living wing and in the nursing care wing of the private care home., Results: The percentages of respondents who reported a decrease in the opportunities for conversation among themselves were 43.9% for residents in the assisted living wing and 19.7% for those in the nursing care wing. After adjusting for age and sex, the opportunities for conversation was significantly associated with the basic activities of daily living (OR 1.07, 95% CI 1.01-1.12), instrumental self-maintenance (OR 1.25, 95% CI 1.08-1.46), intellectual activity (OR 1.35, 95% CI 1.09-1.66), depression (OR 1.13, 95% CI 1.04-1.23), depressive mood (OR 3.83, 95% CI 1.98-7.42), decreased motivation (OR 3.11, 95% CI 1.58-6.12), appetite loss (OR 4.32, 95% CI 1.54-12.07), swallowing function (OR 1.05, 95% CI 1.00-1.10), chewing difficulty (OR 2.50, 95% CI 1.31-4.75) and eating alone (OR 2.5, 95% CI 1.35-4.62)., Conclusion: Decreased opportunities for conversation was more perceived among older adults with higher daily functioning, suggesting that it is associated with depressed mood, oral function and solitary eating. Geriatr Gerontol Int 2024; 24: 385-391., (© 2024 Japan Geriatrics Society.)

25-Hydroxyvitamin D 3 -23,26-lactone (1) and 1α,25-dihydroxyvitamin D 3 -23,26-lactone (2) have long been considered as among the end metabolites of vitamin D 3 . Recently, however, we found that these lactones exhibit biological activity related to the β-oxidation of fatty acids. We hypothesized that a metabolic pathway might exist to inactivate their physiological activity. Here, by means of metabolic experiments with a variety of cytochrome P450 (CYP) enzymes, we show that CYP3A4 metabolizes the lactones. The metabolites were presumed to be hydroxylated at C4 based on the previous reports showing that metabolism of 25-hydroxyvitamin D 3 by CYP3A4 along with the current LC-MS analysis. To confirm this, we chemically synthesized 4α,25(OH) 2 D 3 -23,26-lactone (3), 4β,25(OH) 2 D 3 -23,26-lactone (4), 1α,4α,25(OH) 3 D 3 -23,26-lactone (5), and 1α,4β,25(OH) 3 D 3 -23,26-lactone (6). HPLC analysis using these authentic compounds as standards revealed that 1 was metabolized to 3 and 4, while 2 was metabolized exclusively to 6 by CYP3A4. Docking studies suggest that the hydroxyl group at C1 in 2 forms hydrogen bonds with Ser119 and Arg212 of CYP3A4, contributing to the fixation of C4β on heme iron in the CYP, thereby resulting in stereoselective hydroxylation at C4.

Purpose: Postprandial hyperglycemia is assumed to have a negative impact on flow-mediated dilation (FMD), an index of endothelial function, and blood flow of the peripheral conduit arteries. This study aimed to determine whether the enhancement of postprandial hyperglycemia by skipping breakfast accelerates endothelial dysfunction and reduces the blood flow in the brachial artery in young men., Methods: Using a randomized cross-over design, ten healthy men completed two trials: with and without breakfast (Eating and Fasting trials, respectively). Venous blood sampling and brachial FMD tests were conducted before, 30, 60, 90, and 120 min after a 75-g oral glucose tolerance test (OGTT)., Results: Skipping breakfast boosted post-OGTT glucose levels than having breakfast (P = 0.01). The magnitude of the decrease in FMD via OGTT did not vary between trials (main effect of trial P = 0.55). Although brachial blood flow tended to decrease after OGTT in both trials (interaction and main effect of time P = 0.61 and P = 0.054, respectively), the decrease in blood flow following OGTT was greater in the Fasting trial than in the Eating trial (main effect of trial, mean difference =  - 15.8 mL/min [95%CI =  - 25.6 to - 6.0 mL/min], P < 0.01)., Conclusion: Skipping breakfast did not enhance the magnitude of the decrease in FMD following glucose loading, but did accelerate hyperglycemia-induced reduction in brachial blood flow. Current findings suggest that even missing one breakfast has negative impacts on the blood flow regulation of the peripheral conduit arteries in young men who habitually eat breakfast., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Effective use of lung volume data measured on computed tomography (CT) requires reference values for specific populations. This study examined whether an equation previously generated for multiple ethnic groups in the United States, including Asians predominantly composed of Chinese people, in the Multi-Ethnic Study of Atherosclerosis (MESA) could be used for Japanese people and, if necessary, to optimize this equation. Moreover, the equation was used to characterize patients with chronic obstructive pulmonary disease (COPD) and lung hyperexpansion., Methods: This study included a lung cancer screening CT cohort of asymptomatic never smokers aged ≥40 years from two institutions (n = 364 and 419) to validate and optimize the MESA equation and a COPD cohort (n = 199) to test its applicability., Results: In all asymptomatic never smokers, the variance explained by the predicted values (R 2 ) based on the original MESA equation was 0.60. The original equation was optimized to minimize the root mean squared error (RMSE) by adjusting the scaling factor but not the age, sex, height, or body mass index terms of the equation. The RMSE changed from 714 ml in the original equation to 637 ml in the optimized equation. In the COPD cohort, lung hyperexpansion, defined based on the 95th percentile of the ratio of measured lung volume to predicted lung volume in never smokers (122 %), was observed in 60 (30 %) patients and was associated with centrilobular emphysema and air trapping on inspiratory/expiratory CT., Conclusions: The MESA equation was optimized for Japanese middle-aged and elderly adults., Competing Interests: Declaration of competing interest N.T. and T.H. received research grants from Daiichi Sankyo and FUJIFILM Co., Ltd., outside of the submitted work. S.S. received grants from Nippon Boehringer Ingelheim, Philips-Respironics, Fukuda Denshi, Fukuda Lifetec Keiji, and ResMed outside of the submitted work. None of these companies played a role in the design or analysis of the study or the writing of the manuscript. The other authors have no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Lung transplantation (LT) recipients are at risk of bone mineral density (BMD) loss. Pre- and post-LT BMD loss has been reported in some cross-sectional studies; however, there are limited studies regarding the serial BMD change in LT recipients. The aim of this study was to investigate the serial BMD changes and the clinical characteristics associated with BMD decline., Methods: This was a single-center, retrospective observational study. BMD was serially measured in thoracic vertebral bodies (Th4, 7, 10) using computed tomography (CT) before and 3 and 12 months after LT. The frequency of osteoporosis and factors associated with pre-LT osteoporosis and post-LT BMD loss were evaluated. The frequency of post-LT compression fracture and its associated factors were also analyzed., Results: This study included 128 adult LT recipients. LT recipients had decreased BMD (151.8 ± 42.2 mg/mL) before LT compared with age-, sex-, and smoking index-matched controls (176.2 ± 35.7 mg/mL). The diagnosis of COPD was associated with pre-LT osteoporosis. LT recipients experience further BMD decline after transplantation, and the percentage of recipients classified as exhibiting osteoporosis increased from 20% at baseline to 43% at 12 months. Recipients who had been taking no or small doses of glucocorticoids before LT had rapid BMD loss after LT. Early bisphosphonate use (within 3 months) after LT attenuated BMD loss and decreased new-onset compression fracture., Conclusion: LT recipients are at high risk for BMD loss and compression fracture after LT. Early bisphosphonate use may decrease BMD loss and compression fracture., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Summary: IgG4-related disease is a multiorgan disorder in which nodules and hypertrophic lesions are observed simultaneously, or separately, in areas including the pancreas, liver, lungs, salivary glands, thyroid glands, and pituitary glands. IgG4-related hypophysis is one of several IgG4-related diseases and is characterized by pituitary gland and pituitary stalk thickening, various degrees of hypopituitarism, and increased serum IgG4 levels. Steroid therapy is effective for patients with IgG4-related hypophysis, but the reported effectiveness of steroid therapy for restoring pituitary function differs between studies. Following an episode of autoimmune pancreatitis 10 years prior, enlargement of the pituitary gland and stalk along with panhypopituitarism and polyuria developed in a 73-year-old male. A high serum IgG4 level and biopsy of the submandibular gland showing infiltration of IgG4-positive plasma cells led to a clinical diagnosis of IgG4-related hypophysitis. Prednisolone treatment reduced the swelling of the pituitary gland and stalk and improved anterior pituitary function. Although arginine vasopressin secretion remained insufficient, polyuria was relieved and kept in remission even after prednisolone treatment was completed. This is the first reported case in which prednisolone was able to maintain both normal anterior pituitary function and remission of polyuria caused by IgG4-related hypophysitis. IgG4-related hypophysitis has previously been associated with a relapse of symptoms during treatment. However, the patient reported in this case study remained in remission for over 3 months after completion of steroid treatment and should be monitored closely for changes in pituitary function., Learning Points: Steroid therapy is the first-line therapy for pituitary dysfunction and pituitary stalk swelling in IgG4-related hypophysitis. In this case, although posterior pituitary function remained insufficient, polyuria was relieved and kept in remission for over 3 months even after prednisolone treatment was completed. IgG4-related hypophysitis has been associated with the relapse of symptoms during steroid tapering, and changes in pituitary function and symptoms should be monitored closely. When we encounter cases of adrenal insufficiency and polyuria during observation of autoimmune pancreatitis or other IgG4-related disease, we should consider the possibility of IgG4-related hypophysitis in mind.

The Cre-loxP strategy for tissue-specific gene inactivation has become a widely employed tool in several research studies. Conversely, inadequate breeding and genotyping without considering the potential for non-specific Cre-recombinase expression may lead to misinterpretations of results. Nestin-Cre transgenic mice, widely used for the selective deletion of genes in neurons, have been observed to have an incidence of Cre-line germline recombination. In this study, we attempted to generate neuron-specific Glucagon-like peptide 1 receptor (Glp1r) knock-out mice by crossing mice harboring the Nestin-Cre transgene with mice harboring the Glp1r gene modified with loxP insertion, in order to elucidate the role of Glp1r signaling in the nervous system. Surprisingly, during this breeding process, we discovered that the null allele emerged in the offspring irrespective of the presence or absence of the Nestin-Cre transgene, with a high probability of occurrence (93.6%). To elucidate the cause of this null allele, we conducted breeding experiments between mice carrying the heterozygous Glp1r null allele but lacking the Nestin-Cre transgene. We confirmed that the null allele was inherited by the offspring independently of the Nestin-Cre transgene. Furthermore, we assessed the gene expression, protein expression, and phenotype of mice carrying the homozygous Glp1r null allele generated from the aforementioned breeding, thereby confirming that the null allele indeed caused a global knock-out of Glp1r. These findings suggest that the null allele in the NestinCre-Glp1r floxed breeding arose due to germline recombination. Moreover, we demonstrated the possibility that germline recombination may occur not only during the spermatogenesis at testis but also during epididymal sperm maturation. The striking frequency of germline recombination in the Nestin-Cre driver underscores the necessity for caution when implementing precise breeding strategies and employing suitable genotyping methods., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kajitani 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.)