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Dystrophinopathy is caused by alterations in the dystrophin gene. The severe phenotype, Duchenne muscular dystrophy (DMD), is caused by a lack of dystrophin in skeletal muscles, resulting in necrosis and regenerating fibers, inflammatory cells, and muscle fibrosis. Progressive muscle weakness is a characteristic finding of this condition. Here, we encountered a rare case of a 10-year-old patient with asymptomatic dystrophinopathy with no dystrophin expression and investigated the reason for the absence of muscle weakness to obtain therapeutic insights for DMD. Using RNA-seq analysis, gene expression in skeletal muscles was compared among patients with asymptomatic dystrophinopathy, three patients with typical DMD, and two patients without dystrophinopathy who were leading normal daily lives. Cathepsin K (CTSK), myosin heavy chain 3 (MYH3), and nodal modulator 3-like genes exhibited a >8-fold change, whereas crystallin mu gene (CRYM) showed a <1/8-fold change in patients with typical DMD compared with their expression in the patient with asymptomatic dystrophinopathy. Additionally, CTSK and MYH3 expression exhibited a >16-fold change (P < 0.01), whereas CRYM expression showed a <1/16-fold change (P < 0.01) in patients with typical DMD compared with their expression in those without dystrophinopathy. CTSK plays an essential role in skeletal muscle loss, fibrosis, and inflammation in response to muscles injected with cardiotoxin, one of the most common reagents that induce muscle injury. Increased CTSK expression is associated with muscle injury or necrosis in patients with DMD. The lack of muscle weakness in the patient with asymptomatic dystrophinopathy might be attributed to the low CTSK expression in the muscles. To the best of our knowledge, this is the first report to demonstrate that CTSK expression was significantly higher in the skeletal muscles of patients with DMD with a typical phenotype than in those without dystrophinopathy., (© 2024 Japanese Society of Neuropathology.)

Objective: This study aimed to determine the effectiveness of sublingual immunotherapy (SLIT) in preventing the exacerbation of asthma., Methods: This retrospective study investigated the changes in the rate of continuous steroid inhalation introduced over three years due to SLIT in 328 patients aged 5-15 years who were diagnosed with allergic rhinitis between January 1, 2018, and December 31, 2019. These patients were not initially prescribed with continuous steroid inhalation. SLIT and symptomatic treatment groups were compared over 3 years using chi-square and Fisher's exact tests, controlling for age with multiple regression analysis. The SLIT subgroups and factors contributing to asthma exacerbation were examined as secondary endpoints., Results: The study comprised 151 patients in the SLIT group and 177 patients in the symptomatic treatment group, with higher average age and IgE levels in the SLIT group. High continuation rates for SLIT were observed over 3 years. Asthma exacerbation within 3 years was notably lower in the SLIT group, particularly in the cedar-only and combined SLIT groups. Multiple regression analysis confirmed the duration of SLIT as a significant factor in preventing asthma exacerbation. Additionally, Fisher's exact test supported these findings., Conclusion: This study demonstrated the effectiveness of SLIT in reducing the exacerbation of asthma in children with allergic rhinitis. SLIT was associated with lower rates of asthma exacerbation over a three-year period compared to symptomatic treatment., Competing Interests: Conflict of interest Organizations or businesses that have provided monetary compensation for lectures, manuscripts, and pamphlets to members of the guideline preparation committee are as follows (the period of interest is between January 2022 and December 2023). K. Kaswashima received honoraria (lecture fee) from Meiji Seika Pharma Co., Ltd. (Tokyo, Japan), Sanofi K. K. (Tokyo, Japan), and Mitsubishi Tanabe Pharma Co. (Osaka, Japan)., (Copyright © 2024. Published by Elsevier B.V.)

While the rapid decrease in estrogen is well known as the main cause of postmenopausal osteoporosis in women, the precise pathogenesis of senile osteoporosis in the elderly regardless of gender is largely unknown. The age-related epigenetic regulation of receptor activator NF-κB (RANK) gene expression was investigated with the use of a high-passaged mouse osteoclast progenitor cell line, RAW264.7, as an in vitro model of aging. In the RAW264.7 cells after repeated passages, receptor RANK expression was downregulated, resulting in decreased soluble RANK ligand (sRANKL)-induced osteoclastogenesis, expression of tartrate-resistant acid phosphatase-5b (TRAcP) and cathepsin K (CTSK). Methylation-specific PCR and bisulfite mapping revealed hypermethylation of CpG-loci located in the RANK gene promoter in multiple-passaged cells. ICON probe-mediated in situ assessment of methylated-cytosine at the CpG loci revealed an increase in the percentage of methylated RAW264.7 cells in the RANK gene in a passage-dependent manner. Conversely, upon treatment with demethylating agent 5-aza-2-deoxycytidine (5-aza-dC), high-passaged RAW264.7 cells displayed restored expression of the RANK gene, osteoclastogenesis, TRAcP and CTSK. Ex vivo cultures of splenic macrophages from young (10.5 W) and aged (12 M) mice also showed that CpG methylation was predominant in the aged animals, resulting in reduced RANK expression and osteoclastogenesis. Reduced RANK expression by age-related accumulation of DNA methylation, albeit in a limited population of osteoclast precursor cells, might be, at least in part, indicative of low-turnover bone characteristic of senile osteoporosis., Competing Interests: VThe authors have no conflicts of interest., (2024 The Japan Society of Histochemistry and Cytochemistry.)

Background: ST-segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock (STEMI-CS) is associated with high mortality rates. Patients admitted during off-hours, specifically on weekends and at night, show higher mortality rates, which is called the "off-hours effect". The off-hours effect in patients with STEMI-CS treated with mechanical circulatory support, especially Impella, has not been fully evaluated., Aims: We aimed to investigate whether off-hours admissions were associated with higher mortality rates in this population., Methods: We used large-scale Japanese registry data for consecutive patients treated with Impella between February 2020 and December 2021 and compared on- and off-hours admissions. On- and off-hours were defined as the time between 8:00 and 19:59 on weekdays and the remaining time, respectively. The Cox proportional hazards model was used to calculate the adjusted hazard ratios (aHRs) for 30-day mortality., Results: Of the 1,207 STEMI patients, 566 (46.9%) patients (mean age: 69 years; 107 females) with STEMI-CS treated with Impella were included. Of these, 300 (53.0%) were admitted during on-hours. During the follow-up period (median 22 days [interquartile range 13-38 days]), 112 (42.1%) and 91 (30.3%) deaths were observed among patients admitted during off- and on-hours, respectively. Off-hours admissions were independently associated with a higher risk of 30-day mortality than on-hours admissions (aHR 1.60, 95% confidence interval: 1.07-2.39; p=0.02)., Conclusions: Our findings indicated the persistence of the "off-hours effect" in STEMI-CS patients treated with Impella. Healthcare professionals should continue to address the disparities in cardiovascular care by improving the timely provision of evidence-based treatments and enhancing off-hours medical services.

Plant hormone-related transcription factors (TFs) are key regulators of plant development, responses to environmental stress such as climate changes, pathogens, and pests. These TFs often function as families that exhibit genetic redundancy in higher plants, and are affected by complex crosstalk mechanisms between different plant hormones. These properties make it difficult to analyze and control them in many cases. In this study, we introduced a chemical inhibitor to manipulate plant hormone-related TFs, focusing on the jasmonate (JA) and ethylene (ET) signaling pathways, with the key TFs MYC2/3/4 and EIN3/EIL1. This study revealed that JAZ10 CMID , the binding domain of the repressor involved in the desensitization of both TFs, is an intrinsically disordered region in the absence of binding partners. Chemical inhibitors have been designed based on this interaction to selectively inhibit MYC TFs while leaving EIN3/EIL1 unaffected. This peptide inhibitor effectively disrupts MYC-mediated responses while activating EIN3-mediated responses and successfully uncouples the crosstalk between JA and ET signaling in Arabidopsis thaliana . Furthermore, the designed peptide inhibitor was also shown to selectively inhibit the activity of MpMYC, an ortholog of AtMYC in Marchantia polymorpha , demonstrating its applicability across different plant species. This underscores the potential of using peptide inhibitors for specific TFs to elucidate hormone crosstalk mechanisms in non-model plants without genetic manipulation. Such a design concept for chemical fixation of the disordered structure is expected to limit the original multiple binding partners and provide useful chemical tools in chemical biology research., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

Background and Purpose: The aim of the study is to examine the present status of reirradiation with high-dose-rate (HDR) brachytherapy for recurrent gynecologic cancer in Japan and to determine the role of this therapy in clinical practice., Materials and Methods: A retrospective multicenter chart review was performed for reirradiation for gynecologic cancer using HDR brachytherapy. Each center provided information on patient characteristics, treatment outcomes, and complications., Results: The study included 165 patients treated at 9 facilities from 2000 to 2018. The analysis of outcomes included 142 patients treated with curative intent. The median follow-up time for survivors was 30 months (range 1-130 months). The 3-year overall survival (OS), progression-free survival (PFS), and local control (LC) rates were 53 % (95 %CI: 42-63 %), 44 % (35-53 %), and 61 % (50-70 %) for cervical cancer; 100 % (NA), 64 % (30-85 %), and 70 % (32-89 %) for endometrial cancer; and 54 % (13-83 %), 38 % (6-72 %), and 43 % (6-78 %) for vulvar and vaginal cancer, respectively. In multivariate analysis, interval to reirradiation (<1 year) was a significant risk factor for OS, PFS and LC; Gross Tumor Volume (≥25 cm 3 ) was a significant risk factor for OS. Toxicities were analyzed in all enrolled patients (n = 165). Grade ≥ 3 late toxicities occurred in 49 patients (30 %). A higher cumulative EQD2 (α/β = 3) was significantly associated with severe complications., Conclusion: Reirradiation with HDR brachytherapy for recurrent gynecologic cancer is effective, especially in cases with a long interval before reirradiation., 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.)

Introduction: Catatonia, a psychomotor disorder characterized by diverse clinical signs, including stupor and mutism, remains elusive in its causes and a challenge to diagnose. Moreover, it is often underrecognized due to its resemblance to disorders of consciousness. However, when diagnosing catatonia, an antipsychotic medication may exacerbate the condition. The first-line treatment typically includes benzodiazepines and/or electroconvulsive therapy (ECT)., Case Report: A 60-year-old woman with systemic lupus erythematosus (SLE) and epilepsy presented with catatonic stupor. Despite stable treatment, she experienced an acute deterioration in consciousness, requiring hospitalization. Her condition improved markedly following a benzodiazepine challenge, as documented on EEG. This improvement was short-lived, but a second benzodiazepine challenge restored her from E1V1M1 (stupor) to E4V5M6 within minutes, as documented by a video recording. The patient was treated with lorazepam 1.5 mg/day orally and did not experience further relapses., Discussion: The diagnosis of catatonia had been based on her scores on the Bush-Francis Catatonia Rating Scale (BFCRS; Screening, 6/14; Severity, 19), despite meeting only two DSM-5 criteria for catatonia (stupor and mutism). The diagnosis was supported by EEG and video documentation, excluding other potential differential diagnoses such as nonconvulsive status epilepticus and encephalopathy. Additional quantitative EEG analyses indicated that benzodiazepine administration increased brainwide alpha and beta band power significantly, suggesting that the benzodiazepine normalized attention, consciousness, and long-range synchronization. This report additionally emphasizes the significance of video recordings in managing catatonia, and it helps in accurately tracking symptoms, documenting comprehensively, and improving patient understanding, which is crucial for treatment adherence., (© 2024 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Purpose: To develop deep learning models using thoracoscopic images to identify visceral pleural invasion (VPI) in patients with clinical stage I lung adenocarcinoma, and to verify if these models can be applied clinically., Methods: Two deep learning models, one based on a convolutional neural network (CNN) and the other based on a vision transformer (ViT), were applied and trained via 463 images (VPI negative: 269 images, VPI positive: 194 images) captured from surgical videos of 81 patients. Model performances were validated via an independent test dataset containing 46 images (VPI negative: 28 images, VPI positive: 18 images) from 46 test patients., Results: The areas under the receiver operating characteristic curves of the CNN-based and ViT-based models were 0.77 and 0.84 (p = 0.304), respectively. The accuracy, sensitivity, specificity, and positive and negative predictive values were 73.91, 83.33, 67.86, 62.50, and 86.36% for the CNN-based model and 78.26, 77.78, 78.57, 70.00, and 84.62% for the ViT-based model, respectively. These models' diagnostic abilities were comparable to those of board-certified thoracic surgeons and tended to be superior to those of non-board-certified thoracic surgeons., Conclusion: The deep learning model systems can be utilized in clinical applications via data expansion., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: Although takotsubo syndrome (TTS) is characterized by transient systolic dysfunction of the left ventricle (LV), the time course and mechanism of LV function recovery remain elusive. The aim of this study is to evaluate cardiac functional recovery in TTS via serial cardiac magnetic resonance feature tracking (CMR-FT). Methods: In this Japanese multicenter registry, patients with newly diagnosed TTS were prospectively enrolled. In patients who underwent serial cardiovascular magnetic resonance (CMR) imaging at 1 month and 1 year after the onset, CMR-FT was performed to determine the global circumferential strain (GCS), global radial strain (GRS) and global longitudinal strain (GLS). We compared LV ejection fraction, GCS, GRS and GLS at 1 month and 1 year after the onset of TTS. Results: Eighteen patients underwent CMR imaging in one month and one year after the onset in the present study. LV ejection fraction had already normalized at 1 month after the onset, with no significant difference between 1 month and 1 year (55.8 ± 9.2% vs. 58.9 ± 7.3%, p = 0.09). CMR-FT demonstrated significant improvement in GCS from 1 month to 1 year (-16.7 ± 3.4% vs. -18.5 ± 3.2%, p < 0.01), while there was no significant difference in GRS and GLS between 1 month and year (GRS: 59.6 ± 24.2% vs. 59.4 ± 17.3%, p = 0.95, GLS: -12.8 ± 5.9% vs. -13.8 ± 4.9%, p = 0.42). Conclusions: Serial CMR-FT analysis revealed delayed improvement of GCS compared to GRS and GLS despite of rapid recovery of LV ejection fraction. CMR-FT can detect subtle impairment of LV systolic function during the recovery process in patients with TTS.

Background: Vessel-level physiological data derived from pressure wire measurements are one of the important determinant factors in the optimal revascularisation strategy for patients with multivessel disease (MVD). However, these may result in complications and a prolonged procedure time., Aims: The feasibility of using the quantitative flow ratio (QFR), an angiography-derived fractional flow reserve (FFR), in Heart Team discussions to determine the optimal revascularisation strategy for patients with MVD was investigated., Methods: Two Heart Teams were randomly assigned either QFR- or FFR-based data of the included patients. They then discussed the optimal revascularisation mode (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) for each patient and made treatment recommendations. The primary endpoint of the trial was the level of agreement between the treatment recommendations of both teams as assessed using Cohen's kappa., Results: The trial included 248 patients with MVD from 10 study sites. Cohen's kappa in the recommended revascularisation modes between the QFR and FFR approaches was 0.73 [95% confidence interval {CI} : 0.62-0.83]. As for the revascularisation planning, agreements in the target vessels for PCI and CABG were substantial for both revascularisation modes (Cohen's kappa=0.72 [95% CI: 0.66-0.78] and 0.72 [95% CI: 0.66-0.78], respectively). The team assigned to the QFR approach provided consistent recommended revascularisation modes even after being made aware of the FFR data (Cohen's kappa=0.95 [95% CI:0.90-1.00])., Conclusions: QFR provided feasible physiological data in Heart Team discussions to determine the optimal revascularisation strategy for MVD. The QFR and FFR approaches agreed substantially in terms of treatment recommendations.

Porous structures are frequently used in surgical implants to strengthen the interlocking power produced by bone ingrowth. Therefore, we aimed to elucidate the mechanism underlying bone ingrowth into a porous structure accompanied by vascularization. A nonbioactive polyetheretherketone implant with a 3D-printed porous structure was prepared and implanted in a bone hole created in the tibias of rabbits. We observed bone ingrowth in the same individual specimens immediately and at 2, 4, 8, and 12 weeks post-implantation using in-vivo computed tomography (CT). Furthermore, a detailed evaluation with blood vessels of each specimen at 2, 4, and 12 weeks was performed with ex-vivo CT and histological specimen. Additional histological evaluation was performed using thin sections of an implant made with thermoplastic polyurethane having the same structure. As a result, the bone invasion began after four weeks, when the construction of fibrous tissue and the spread of new blood vessels within the voids matured. As the bone matured in the load-bearing area, new blood vessels outside the bone matrix regressed. This longitudinal evaluation study suggests that preceding fibrogenesis and vascularization may be key in developing bone ingrowth. STATEMENT OF SIGNIFICANCE: A porous structure is an essential structure for dental and orthopedic implants because it provides strong fixation through bone invasion. Although it was known that vascularization was involved in this, the details were not known. This in vivo study revealed that in order for bone ingrowth to begin, a preparatory period of approximately 4 weeks was required to establish blood flow inside and outside the implant. Furthermore, it was confirmed that by spreading the fibrous structure in advance, it has an advantageous effect on the migration of cells involved in the formation of bones and blood vessels. We pointed out that it is necessary to consider fibrogenesis and vascularization when creating future implants., 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 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: There are no indices to monitor desensitization by low-dose egg oral immunotherapy (eOIT)., Objective: We aimed to examine the relationship between desensitization by low-dose eOIT and the changes in allergen-specific immunoglobulin E (IgE) and IgG4 levels., Methods: We carried out low-dose eOIT in 31 patients with severe egg allergy in our previous two studies. After 4 months of treatment, the patients with no observed allergic symptoms in response to the open hard-boiled egg white challenge tests were classified as the negative group, and the remaining patients, the positive group. The fold-difference levels were calculated using 10 Log (Titer after eOIT/Titer before eOIT)., Results: The 28 patients who completed eOIT with sufficient serum collected before and after eOIT were analyzed. The median fold-difference levels of ovomucoid-specific IgE in the negative and positive groups were 0.819 and 0.953, respectively (P = 0.082). The median fold-difference levels of ovalbumin-specific IgG4 in the negative and positive groups were 2.01 and 1.29, respectively (P = 0.057). In the receiver-operating characteristic curves, the area under the curves of fold-difference ovomucoid-specific IgE and ovalbumin-specific IgG4 were 0.701 and 0.719, respectively. The challenge positive predictive values of fold-difference ovomucoid-specific IgE and ovalbumin-specific IgG4 were 83.8% (cut-off point: 0.934) and 77.8% (cut-off point: 1.87), respectively. Moreover, the challenge positive predictive value in patients with both 0.934 < ovomucoid-specific IgE and ovalbumin-specific IgG4 <1.87 was 100%., Conclusions: The fold-difference levels of allergen-specific IgE and IgG4 in serum are considered useful for monitoring desensitization by low-dose OIT.

The treatment of critical-sized bone defects has long been a major problem for surgeons. In this study, an intramedullary nail shaped three-dimensional (3D)-printed porous titanium implant that is capable of releasing strontium ions was developed through a simple and cost-effective surface modification technique. The feasibility of this implant as a stand-alone solution was evaluated using a rabbit's segmental diaphyseal as a defect model. The strontium-loaded implant exhibited a favorable environment for cell adhesion, and mechanical properties that were commensurate with those of a rabbit's cortical bone. Radiographic, biomechanical, and histological analyses revealed a significantly higher amount of bone ingrowth and superior bone-bonding strength in the strontium-loaded implant when compared to an untreated porous titanium implant. Furthermore, one-year histological observations revealed that the strontium-loaded implant preserved the native-like diaphyseal bone structure without failure. These findings suggest that strontium-releasing 3D-printed titanium implants have the clinical potential to induce the early and efficient repair of critical-sized, load-bearing bone defects., (© 2024 Wiley Periodicals LLC.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first infects the host nasal mucosa, where the viral spike protein binds to angiotensin-converting enzyme 2 (ACE2) on the mucosal cells. This study aimed at searching host cell surface molecules that could contribute to the infection in two views; abundance on host cells and affinity to the spike protein. Since the nasal mucosa is lined by respiratory and olfactory epithelia, and both express an immunoglobulin superfamily member cell adhesion molecule 1 (CADM1), whether CADM1 would participate in the spike protein binding was examined. Immunohistochemistry on the mouse nasal cavity detected CADM1 strongly in the olfactory epithelium at cell-cell contacts and on the apical surface but just faintly in the respiratory epithelium. In contrast, ACE2 was detected in the respiratory, not olfactory, epithelium. When mice were administered intranasally with SARS-CoV-2 S1 spike protein and an anti-CADM1 ectodomain antibody separately, both were detected exclusively on the olfactory, not respiratory, epithelium. Then, the antibody and S1 spike protein were administered intranasally to mice in this order with an interval of 1 h. After 3 h, S1 spike protein was detected as a protein aggregate floating in the nasal cavity. Next, S1 spike protein labeled with fluorescein was added to the monolayer cultures of epithelial cells exogenously expressing ACE2 or CADM1. Quantitative detection of fluorescein bound to the cells revealed that S1 spike protein bound to CADM1 with affinity half as high as to ACE2. Consistently, docking simulation analyses revealed that S1 spike protein could bind to CADM1 three-quarters as strongly as to ACE2 and that the interface of ACE2 was similar in both binding modes. Collectively, intranasal S1 spike protein appeared to prefer to accumulate on the olfactory epithelium, and CADM1 was suggested to contribute to this preference of S1 spike protein based on the molecular abundance and affinity., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

The plant hormone (3 R , 7 S )-jasmonoyl-L-isoleucine ((3 R , 7 S )-JA-Ile) is perceived by the COI1-JAZ co-receptor in Arabidopsis thaliana , leading to the activation of gene expression for plant defense responses, growth, development, and other processes. Therefore, understanding the interaction between the COI1-JAZ co-receptor and its ligands is essential for the development of COI1-JAZ agonists and antagonists as potent chemical tools for regulating (3 R , 7 S )-JA-Ile signaling. This study demonstrated that COI1-JAZ has two independent modes of ligand perception using a differential scanning fluorimetry (DSF) assay. (3 R , 7 S )-JA-Ile is perceived through a one-step model in which (3 R , 7 S )-JA-Ile causes protein-protein interaction between COI1 and JAZ. In contrast, coronatine (COR), a mimic of (3 R , 7 S )-JA-Ile, is perceived through a two-step model in which COR is first perceived by COI1 and then recruits JAZ to form the COI1-COR-JAZ complex. Our results demonstrate two distinct modes of action of molecular glues causing protein-protein interactions., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Background: Hypoalbuminemia is common in critically ill patients and is associated with poor outcomes. However, the relationship between serum albumin levels and clinical outcomes in patients with takotsubo syndrome remains unclear. We examined the impact of hypoalbuminemia on in-hospital mortality in patients with takotsubo syndrome., Methods: Using the multicenter registry of the Tokyo Cardiovascular Care Unit Network between January 2017 and December 2020, we identified 631 eligible patients with takotsubo syndrome (median age, 78 years; male proportion, 22 %) and documented serum albumin levels at admission, which were used to allocate patients to hypoalbuminemia (serum albumin <3.5 g/dL) or normal albumin (serum albumin ≥3.5 g/dL) groups. Patient characteristics and in-hospital mortality were compared between the groups., Results: Hypoalbuminemia was detected in 200 (32 %) patients at admission. The hypoalbuminemia group was older and had a higher proportion of men and preceding physical triggers than the normal albumin group. In-hospital all-cause mortality was greater in the hypoalbuminemia group than in the normal albumin group (9.5 % vs. 1.9 %, p < 0.001). Both cardiac (3.0 % vs. 0.5 %, p = 0.015) and non-cardiac (6.5 % vs. 1.4 %, p = 0.002) mortality was greater in the hypoalbuminemia group. In multivariable logistic regression analysis, hypoalbuminemia was independently associated with increased in-hospital mortality, even after adjusting for confounders, including age, sex, and triggering events (odds ratio, 3.23; 95 % confidence interval, 1.31-7.95; p = 0.011)., Conclusions: In patients with takotsubo syndrome, hypoalbuminemia is a common comorbidity and is associated with a substantial risk of in-hospital death. Close monitoring and comprehensive critical care are required in these patients., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest. This study was approved by the Institutional Review Board of the Tokyo CCU Network Scientific Committee., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19) pandemic impacted various parts of society, including Japanese children with allergies., Objective: This study investigated risk factors for pediatric allergic diseases associated with the state of emergency owing to the COVID-19 pandemic in Japan, including during school closures., Methods: Parents of pediatric patients (0-15 years) with allergies were enrolled and queried regarding the impact of school closure on pediatric allergies compared to that before the COVID-19 pandemic., Results: A valid response was obtained from 2302 parents; 1740 of them had children with food allergies. Approximately 4% (62/1740) of the parents reported accidental food allergen ingestion was increased compared to that before the COVID-19 pandemic. Accidental ingestion during school closures was associated with increased contact with meals containing allergens meant for siblings or other members of the family at home. The exacerbation rate during the pandemic was highest for atopic dermatitis at 13% (127/976), followed by allergic rhinitis at 8% (58/697), and bronchial asthma at 4% (27/757). The main risk factors for worsening atopic dermatitis, allergic rhinitis, and bronchial asthma were contact dermatitis of the mask area (34/120 total comments); home allergens, such as mites, dogs, and cats (15/51 total comments); and seasonal changes (6/25 total comments), respectively., Conclusion: The main factors affecting allergic diseases were likely related to increased time at home, preventive measures against COVID-19, and refraining from doctor visits. Children with allergies were affected by changes in social conditions; however, some factors, such as preventing accidental ingestion and the management of allergens at home, were similar to those before the COVID-19 pandemic. Patients who had received instructions on allergen avoidance at home before the pandemic were able to manage their disease better even when their social conditions changed., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2023. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.)

Background: Takotsubo syndrome (TTS) is an acute cardiovascular disease with clinical manifestations similar to those of acute myocardial infarction (AMI), and TTS sometimes occurs just after catastrophes. Large-scale studies of TTS in Japan are scarce, so we examined data over 9 years from Tokyo metropolitan acute cardiovascular care hospital network registry., Methods: A total of 1626 patients were diagnosed with TTS between 2010 and 2018 at Tokyo Cardiovascular Care Unit Network facilities, and data from all these patients were analyzed. We investigated annual and monthly captured incidence of TTS, temporal trend of the captured incidence proportion of TTS versus AMI, the occurrence of TTS on the day of the great earthquake, and we elucidated the prognostic factors for in-hospital death., Results: The annual incidence proportion of TTS versus AMI increased from 2.3 % to 4.5 % (p < 0.001) over 9 years. The mean TTS patient age was 74.4 years: the peak incidence of TTS was at 80 to 84 years of age for both male and female; females accounted for 78.5 % of patients. The monthly variation of the incidence of TTS was found (p = 0.009). In 2011, a total of 137 cases of TTS occurred, with as many as 6 occurring on March 11, the day of the Great East Japan Earthquake. There was a definable trigger for TTS in 64 % (physical: 36 %; emotional: 27 %; others: 2 %). All-cause in-hospital mortality was 5.3 % and was higher in males than in females (10.3 % vs 3.9 %; p < 0.001). Non-cardiac causes accounted for 62 % of in-hospital mortality. Factors at presentation that were associated with in-hospital all-cause mortality were male sex, low body mass index, and a high C-reactive protein level., Conclusions: This study elucidated the clinical features, in-hospital outcomes, and their attributed factors in patients with TTS in real-world clinical practice in Japan., Competing Interests: Declaration of competing interest All authors declare that there is no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Early-onset atopic dermatitis is a strong risk factor for food allergy, suggesting that early effective treatment may prevent transcutaneous sensitization., Objectives: This study tested whether enhanced treatment of atopic dermatitis to clinically affected and unaffected skin is more effective in preventing hen's egg allergy than reactive treatment to clinically affected skin only., Methods: This was a multicenter, parallel-group, open-label, assessor-blind, randomized controlled trial (PACI [Prevention of Allergy via Cutaneous Intervention] study). This study enrolled infants 7-13 weeks old with atopic dermatitis and randomly assigned infants in a 1:1 ratio to enhanced early skin treatment or conventional reactive treatment using topical corticosteroids (TCSs). The primary outcome was the proportion of immediate hen's egg allergy confirmed by oral food challenge at 28 weeks of age., Results: This study enrolled 650 infants and analyzed 640 infants (enhanced [n = 318] or conventional [n = 322] treatment). Enhanced treatment significantly reduced hen's egg allergy compared with the conventional treatment (31.4% vs 41.9%, P = .0028; risk difference: -10.5%, upper bound of a 1-sided CI: -3.0%), while it lowered body weight (mean difference: -422 g, 95% CI: -553 to -292 g) and height (mean difference: -0.8 cm, 95% CI: -1.22 to -0.33 cm) at 28 weeks of age., Conclusions: This study highlighted the potential of well-controlled atopic dermatitis management as a component of a hen's egg allergy prevention strategy. The enhanced treatment protocol of this trial should be modified before it can be considered as an approach to prevent hen's egg allergy in daily practice to avoid the adverse effects of TCSs. After remission induction by TCSs, maintenance therapy with lower potency TCSs or other topical therapies might be considered as alternative proactive treatments to overcome the safety concerns of TCSs., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1 cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production., (© 2023. The Author(s).)

Background: Although introduction of minimally invasive techniques via anterolateral approaches considerably decreased prolonged limp after total hip arthroplasty (THA), potential damage to the abductor muscles is still a concern. This study aimed to evaluate the residual damage after primary THA with two types of anterolateral approach by assessing fatty infiltration and atrophy of the gluteus medius (GMed) and gluteus minimus (GMin) muscles., Methods: We retrospectively analyzed 100 primary THAs using computed tomography; surgeries were performed by detaching the anterior part of the abductor muscles with a bone fragment (anterolateral approach with trochanteric flip osteotomy) or without it (anterolateral approach without trochanteric flip osteotomy). The change in radiodensities (RDs), cross-sectional areas (CSAs), and clinical scores preoperatively and at 1 year after operation were evaluated., Results: The RD and CSA of GMed increased 1 year postoperatively in 86 and 81% of patients, respectively, while RD and CSA of GMin decreased in 71 and 94%, respectively. The improvement of RD of GMed was more frequently seen in the posterior rather than the anterior part, while the GMin decreased in both parts. The RD decrease of GMin was significantly lower in the anterolateral approach with trochanteric flip osteotomy group than the anterolateral approach without trochanteric flip osteotomy group (P = .0250). However, there was no difference in the clinical scores between the two groups. The change in the RD of GMed was the only factor that correlated with clinical scores., Conclusion: The two anterolateral approaches both improved the RD of GMed, recovery of which was significantly associated with postoperative clinical scores. Although the two approaches showed different recovery patterns in GMin until 1 year after THA, both showed similar improvements in clinical scores., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Low-dose oral immunotherapy (OIT) is a safe treatment for hen's egg allergy; however, comparison of its therapeutic effects with those of high-dose OIT has not been reported., Objective: To compare the efficacy of low- and high-dose boiled egg-white (EW) OIT for hen's egg allergy., Methods: Patients with hen's egg allergy were randomly assigned to two groups: OIT using hard-boiled EW with a maximum maintenance dose of 2 and 20 g in the low-dose (L-D) and high-dose (H-D) groups, respectively. The intake dose was ingested twice a week, increased by approximately 20% per week until reaching the target maintenance dose (2 or 20 g hard-boiled EW), and maintained thereafter according to the schedule. The threshold was confirmed via oral food challenge (OFC) after 6 months, and the difference in the proportion of subjects passing the exit OFC between groups was evaluated., Results: Fifty-two patients (L-D, n = 23; H-D, n = 29) were enrolled. Thirty-three patients (L-D, n = 17; H-D, n = 16) completed the 6-month OIT and underwent an exit OFC. In total, three (L-D, 3/17; H-D, 3/16) patients in each group tested negative for an exit OFC with a 20-g reactive dose (p = 1.000). EW-specific IgE levels in both groups decreased significantly after OIT (L-D, p < 0.001; H-D, p = 0.002)., Conclusions: A threshold-elevating effect was observed in the L-D group, not inferior to that in the H-D group. Low-dose OIT may be appropriate to treat hen's egg allergy for the first 6 months.

Jasmonic acid (JA) regulates plant growth, development and stress responses. Coronatine insensitive 1 (COI1) and jasmonate zinc-finger inflorescence meristem-domain (JAZ) proteins form a receptor complex for jasmonoyl-l-isoleucine, a biologically active form of JA. Three COIs (OsCOI1a, OsCOI1b and OsCOI2) are encoded in the rice genome. In the present study, we generated mutants for each rice COI gene using genome editing to reveal the physiological functions of the three rice COIs. The oscoi2 mutants, but not the oscoi1a and oscoi1b mutants, exhibited severely low fertility, indicating the crucial role of OsCOI2 in rice fertility. Transcriptomic analysis revealed that the transcriptional changes after methyl jasmonate (MeJA) treatment were moderate in the leaves of oscoi2 mutants compared to those in the wild type or oscoi1a and oscoi1b mutants. MeJA-induced chlorophyll degradation and accumulation of antimicrobial secondary metabolites were suppressed in oscoi2 mutants. These results indicate that OsCOI2 plays a central role in JA response in rice leaves. In contrast, the assessment of growth inhibition upon exogenous application of JA to seedlings of each mutant revealed that rice COIs are redundantly involved in shoot growth, whereas OsCOI2 plays a primary role in root growth. In addition, a co-immunoprecipitation assay showed that OsJAZ2 and OsJAZ5 containing divergent Jas motifs physically interacted only with OsCOI2, whereas OsJAZ4 with a canonical Jas motif interacts with all three rice COIs. The present study demonstrated the functional diversity of rice COIs, thereby providing clues to the mechanisms regulating the various physiological functions of JA., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)