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Abstract Background Theoretically, artificial intelligence can provide an accurate automatic solution to measure right ventricular (RV) ejection fraction (RVEF) from cardiovascular magnetic resonance (CMR) images, despite the complex RV geometry. However, in our recent study, commercially available deep learning (DL) algorithms for RVEF quantification performed poorly in some patients. The current study was designed to test the hypothesis that quantification of RV function could be improved in these patients by using more diverse CMR datasets in addition to domain-specific quantitative performance evaluation metrics during the cross-validation phase of DL algorithm development. Methods We identified 100 patients from our prior study who had the largest differences between manually measured and automated RVEF values. Automated RVEF measurements were performed using the original version of the algorithm (DL1), an updated version (DL2) developed from a dataset that included a wider range of RV pathology and validated using multiple domain-specific quantitative performance evaluation metrics, and conventional methodology performed by a core laboratory (CORE). Each of the DL-RVEF approaches was compared against CORE-RVEF reference values using linear regression and Bland–Altman analyses. Additionally, RVEF values were classified into 3 categories: ≤ 35%, 35–50%, and ≥ 50%. Agreement between RVEF classifications made by the DL approaches and the CORE measurements was tested. Results CORE-RVEF and DL-RVEFs were obtained in all patients (feasibility of 100%). DL2-RVEF correlated with CORE-RVEF better than DL1-RVEF (r = 0.87 vs. r = 0.42), with narrower limits of agreement. As a result, DL2 algorithm also showed increasing accuracy from 0.53 to 0.80 for categorizing RV function. Conclusions The use of a new DL algorithm cross-validated on a dataset with a wide range of RV pathology using multiple domain-specific metrics resulted in a considerable improvement in the accuracy of automated RVEF measurements. This improvement was demonstrated in patients whose images were the most challenging and resulted in the largest RVEF errors. These findings underscore the critical importance of this strategy in the development of DL approaches for automated CMR measurements.

Multilayer packaging, commonly referred to as composite materials, is widely utilized in food storage, distribution, and consumption. The employment of plastic packaging, which consists of multiple layers of polymers, ink, paper, and metal, has elicited concerns regarding its detrimental impact on the environment. This article presents an in-depth study of the delamination process of multilayer plastic waste (MLPW) recycling, which is deemed as an effective solution for MLPW recycling. This study aimed to examine the effects of temperature, concentration, width, and ultrasound on the separation of layers in multilayer packaging. The results demonstrated that ultrasound is the most influential factor with nitric acid concentration ranking as the second most significant factor. The findings also disclosed considerable disparities among the time frames, and the impacts of various factors, such as temperature and concentration, lay the groundwork for further investigation into this process. The study underscores the importance of temperature and nitric acid concentration, which can inform the design of future experiments and the development of more efficient methods for layer separation.

Packaging materials can arise from a wide range of sources and are commonly used for food, medicine, household appliances, and items to enclose or protect products during distribution, storage, sale, delivery, and use. The choice of material (paper, plastic, glass, wood, metal, multi-layer or other packaging) to be used depends on the type and properties of product, the purpose of packaging, and the price. The aim of the investigation is to analyse the morphological composition of packaging waste collected separately in Kaunas (Lithuanian) private households and to evaluate its recycling possibilities. The mixture of paper, plastic, and metal packaging waste was analyzed in the winter and spring (one time per month) in the waste management company JSC "Kauno švara".

Latent TGFβ binding proteins (LTBPs) regulate the extracellular availability of latent TGFβ. LTBP4 was identified as a genetic modifier of muscular dystrophy in mice and humans. An in-frame insertion polymorphism in the murine Ltbp4 gene associates with partial protection against muscular dystrophy. In humans, nonsynonymous single nucleotide polymorphisms in LTBP4 associate with prolonged ambulation in Duchenne muscular dystrophy. To better understand LTBP4 and its role in modifying muscular dystrophy, we created transgenic mice overexpressing the protective murine allele of LTBP4 specifically in mature myofibers using the human skeletal actin promoter. Overexpression of LTBP4 protein was associated with increased muscle mass and proportionally increased strength compared to age-matched controls. In order to assess the effects of LTBP4 in muscular dystrophy, LTBP4 overexpressing mice were bred to mdx mice, a model of Duchenne muscular dystrophy. In this model, increased LTBP4 led to greater muscle mass with proportionally increased strength, and decreased fibrosis. The increase in muscle mass and reduction in fibrosis were similar to what occurs when myostatin, a related TGFβ family member and negative regulator of muscle mass, was deleted in mdx mice. Supporting this, we found that myostatin forms a complex with LTBP4 and that overexpression of LTBP4 led to a decrease in myostatin levels. LTBP4 also interacted with TGFβ and GDF11, a protein highly related to myostatin. These data identify LTBP4 as a multi-TGFβ family ligand binding protein with the capacity to modify muscle disease through overexpression.

Latent TGFβ binding proteins are extracellular matrix proteins that bind latent TGFβ to form the large latent complex. Nonsynonymous polymorphisms in LTBP4, a member of the latent TGFβ binding protein gene family, have been linked to several human diseases, underscoring the importance of TGFβ regulation for a range of phenotypes. Because of strong linkage disequilibrium across the LTBP4 gene, humans have two main LTBP4 alleles that differ at four amino acid positions, referred to as IAAM and VTTT for the encoded residues. VTTT is considered the "risk" allele and associates with increased intracellular TGFβ signaling and more deleterious phenotypes in muscular dystrophy and other diseases. We now evaluated LTBP4 nsSNPs in dilated cardiomyopathy, a distinct disorder associated with TGFβ signaling. We stratified based on self-identified ethnicity and found that the LTBP4 VTTT allele is associated with increased risk of dilated cardiomyopathy in European Americans extending the diseases that associate with LTBP4 genotype. However, the association of LTBP4 SNPs with dilated cardiomyopathy was not observed in African Americans. To elucidate the mechanism by which LTBP4 genotype exerts this differential effect, TGFβ's association with LTBP4 protein was examined. LTBP4 protein with the IAAM residues bound more latent TGFβ compared to the LTBP4 VTTT protein. Together these data provide support that LTBP4 genotype exerts its effect through differential avidity for TGFβ accounting for the differences in TGFβ signaling attributed to these two alleles.

This review explores the transformative impact of omics technologies on allergy and asthma research in recent years, focusing on advancements in high-throughput technologies related to genomics and transcriptomics. In particular, the rapid spread of single-cell RNA sequencing has markedly advanced our understanding of the molecular pathology of allergic diseases. Furthermore, high-throughput genome sequencing has accelerated the discovery of monogenic disorders that were previously overlooked as ordinary intractable allergic diseases. We also introduce microbiomics, proteomics, lipidomics, and metabolomics, which are quickly growing areas of research interest, although many of their current findings remain inconclusive as solid evidence. By integrating these omics data, we will gain deeper insights into disease mechanisms, leading to the development of precision medicine approaches that promise to enhance treatment outcomes., Competing Interests: Disclosure statement Supported in part by the Japanese Agency for Medical Research and Development (AMED) (grant JP24ek0410106 [to H.M.]) and a Health, Labor and Welfare Sciences Research Grant (grant 24FE2002 [to H.M.]). Disclosure of potential conflict of interest: H. Saito reports having received a consultation fee from Teikoku Seiyaku, Co, Ltd. H. Morita reports consulting and/or advisory board agreements with Sanofi, LEO Pharma, and Otsuka Pharmaceutical Co, Ltd. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Increased propulsion force (PF) in the paretic limb is associated with improved walking speed in patients with stroke. However, late braking force (LBF), an additional braking force occurring between PF onset and toe-off, is present in a subset of stroke patients. Few studies have investigated the changes in LBF and walking speed in these patients. This study aimed to elucidate the patterns of change in PF and LBF during fast gait in hemiplegics and identify potential compensatory strategies based on the LBF patterns. Data from 100 patients with stroke walking at both comfortable (mean, 0.79 ± 024 m/s) and fast speeds (mean, 1.06 ± 0.35 m/s) were analyzed retrospectively stroke using a 3D motion analyzer. PF was higher during fast-speed walking than that during comfortable-speed walking in all patients, while LBF showed both decreasing and increasing trends during fast-speed walking. In the LBF increasing pattern, a reduction in in-phase coordination of the shank and foot during the pre-swing phase was observed, along with an increase in pelvic hike during fast-speed walking compared to those in the decreasing LBF pattern. Our findings demonstrate that alterations in LBF patterns are associated with gait deviations in patients with stroke at fast speeds., (© 2024. The Author(s).)

Background: Hay fever (HF) presents with various symptoms, including allergic conjunctivitis and rhinitis, and requires cross-organ treatment. This study assessed the impact of the coronavirus disease 2019 (COVID-19) pandemic on HF treatment trends., Methods: This retrospective cohort study utilized data from the JMDC database collected between January 2018 and May 2021. Patients with HF were identified based on the relevant International Classification of Diseases 10th Revision diagnosis codes and the prescription of HF-related medications. The treatment approaches were compared during the cedar and cypress pollen allergy season (January to May in Japan) before and during the COVID-19 pandemic (2018 and 2019, and 2020 and 2021, respectively)., Results: This study included 2,598,178 patients with HF. The numbers of prescribed HF-related claims in 2018, 2019, 2020, and 2021 were 3,332,854, 3,534,198, 2,774,380, and 2,786,681 times, respectively. Oral second-generation antihistamine prescriptions decreased by >10% from 2019 to 2020, with a <10% change in the subsequent year. Anti-allergic eye drop prescriptions also decreased by >10% from 2019 to 2020 but increased by >10% from 2020 to 2021. Compared with 2018, 2019, and 2020, the number of claims in the rhinitis symptoms dominant group was significantly decreased in 2021 (p < 0.001, all). In contrast, the number of claims in the eye symptoms dominant group and the rhinitis and eye symptoms dominant group increased in 2021 compared with that in 2018, 2019, and 2020 (p < 0.001, all)., Conclusion: Changes in HF treatment and related outcomes could be attributed to lifestyle modifications resulting from the COVID-19 pandemic. Measures, such as limiting outdoor activities and adopting mask-wearing practices may have influenced HF symptoms, preventive behaviors, and the overall approach to treating HF., (© 2024 The Author(s). Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Objective: There is heterogeneity in the pathophysiology of chronic rhinosinusitis (CRS). Obtaining a detailed understanding of patient profiles in specific regions can provide valuable information not only for clinical practice but also future research plans. The aim of this study was to investigate the characteristics of patients who underwent endoscopic sinus surgery (ESS) for CRS., Methods: This retrospective, single-center study examined the features of 453 patients with CRS who underwent ESS in the Tokyo area of Japan. The study evaluated various factors in patients with CRS including sex and age, the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) score, the recurrence rate of CRS, comorbidities of asthma and/or allergic diseases, and IgE sensitization to 12 inhaled allergens., Results: Age-related declines in the sensitization rate to inhaled allergens were observed, and the most notable age-related decrease in specific IgE antibodies was observed for house dust mites (HDM) (p = 8.3 × 10 -7 ). Sensitization to HDM, cat dander, and various types of fungi, including Aspergillus, was frequently observed in the CRS with asthma group, with rates of 54%, 17%, and 17%, respectively. We found that 23% of the patients had recurrence. In the recurrence group, the positive rates of specific IgE antibodies for birch and cat dander were significantly higher than in the no recurrence group. Bronchial asthma was identified as an important factor for recurrence. Among male patients, the recurrence group was younger than the no-recurrence group (p = 0.0032). Severe eosinophilic CRS (ECRS) showed early recurrence after surgery, with over the half of the patients experiencing at least one recurrence within 2 years post-surgery. Among patients with ECRS, the recurrence rate for females was 1.92 times higher than for males., Conclusion: Our study revealed the influences of age and sex on various clinical phenotypes of CRS patients undergoing ESS. There was a high sensitization rate to cat dander in both the recurrence and asthma groups. Further research on diverse disease etiologies is necessary to improve therapeutic strategies for patients with CRS., Competing Interests: Declaration of Competing Interest This work was supported in part by a Research Grant from the Jikei University School of Medicine. Tsuguhisa Nakayama reports lecture fees from Sanofi. Mayumi Tamari reports lecture fees from Sanofi, Astra Zeneca UCB Japan, and KYORIN Pharmaceutical Co., Ltd. Mamoru Yoshikawa reports lecture fees from Sanofi and contracted research expenses from Kissei Pharmaceutical. These sources had no role in the design, conduct, preparation, or writing of this manuscript and the rest of the study authors have no conflicts of interest to disclose. The authors have no actual or potential conflict of interest to declare., (Copyright © 2023. Published by Elsevier B.V.)

Background: Disturbance of mucociliary clearance is an important factor in the pathogenesis of asthma. We hypothesized that common variants in genes responsible for ciliary function may contribute to the development of asthma with certain phenotypes., Methods: Three independent adult Japanese populations (including a total of 1,158 patients with asthma and 2,203 non-asthmatic healthy participants) were studied. First, based on the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/), we selected 12 common single-nucleotide polymorphisms (SNPs) with molecular consequences (missense, nonsense, and 3'-untranslated region mutation) in 5 primary ciliary dyskinesia (PCD)-related genes and calculated a PCD-genetic risk score (GRS) as a cumulative effect of these PCD-related genes. Second, we performed a two-step cluster analysis using 3 variables, including PCD-GRS, forced expiratory volume in 1 second (%predicted FEV1), and age of asthma onset., Results: Compared to adult asthma clusters with an average PCD-GRS, clusters with high and low PCD-GRS had similar overall characteristics: adult-onset, female predominance, preserved lung function, and fewer features of type 2 immunity as determined by IgE reactivity and blood eosinophil counts. The allele frequency of rs1530496, a SNP representing an expression quantitative trait locus (eQTL) of DNAH5 in the lung, showed the largest statistically significant difference between the PCD-GRS-High and PCD-GRS-Low asthma clusters (p = 1.4 x 10-15)., Conclusion: Genes associated with PCD, particularly the common SNPs associated with abnormal expression of DNAH5, may have a certain influence on the development of adult-onset asthma, perhaps through impaired mucociliary clearance., Competing Interests: NH has received lecture fees and/or research funding from AstraZeneca, Boehringer Ingelheim, KYORIN Pharmaceutical, GlaxoSmithKline, Novartis, and Sanofi. The rest of the authors have no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Shigemasa 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.)

Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1 GoF ) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1 GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPβ was dependent on JAK1 in the vagus nerve, and CGRPβ suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future., Competing Interests: Declaration of interests B.S.K. is founder of KliRNA Biotech; he has served as a consultant for 23andMe, ABRAX Japan, AbbVie, Almirall, Amgen, Arcutis Biotherapeutics, Arena Pharmaceuticals, argenx, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cara Therapeutics, Clexio Biosciences, Eli Lilly and Company, Escient Pharmaceuticals, Evommune, Galderma, Genentech, GlaxoSmithKline, Granular Therapeutics, Incyte Corporation, Innovaderm Research, Janssen, Kiniksa, LEO Pharma, Maruho, Novartis, Pfizer, Recens Medical, Regeneron Pharmaceuticals, Sanofi, Septerna, Triveni Bio, Vial, and WebMD; he has stock in ABRAX Japan, KliRNA Biotech, Locus Biosciences, and Recens Medical; he holds a patent for the use of JAK1 inhibitors for chronic pruritus; and he has a patent pending for the use of JAK inhibitors for interstitial cystitis. D.A. has contributed to scientific advisory boards at Pfizer, Takeda, FARE, and the KRF. D.B. is the founder of Lab11 Therapeutics.., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In the enhancement of allergy care involving multidisciplinary and multiple medical departments, there is a perceived need for education that targets not only specialists but also non-specialists. However, research on the need for and methods of such education remains inadequate., Objective: To design a remote allergy care education program for all medical practitioners and to validate its necessity and utility., Methods: The Empowering Next Generation Allergist/immunologist toward Global Excellence Task Force (ENGAGE-TF), supported by the Japanese Society of Allergology, initiated a virtual educational program called 'Outreach Lectures' in collaboration with Keio University and Fukui University. This initiative was widely promoted through social media and various institutions, and a survey was conducted through its mailing list., Results: 1139 responses were obtained. More than half were physicians from non-allergy specialties, representing a diverse range of healthcare professions. Over 70% expressed being 'very satisfied,' and over 60% found the difficulty level 'appropriate.' Free-form feedback revealed differences in learning focus based on profession and learning approach based on years of experience., Conclusion: The high participation rate (90%) of non-specialist physicians underscores the demand for addressing allergic conditions in primary care. The effectiveness of virtual / recurrent education, particularly for healthcare professionals with over 11 years of experience, was implied. Further follow-up investigation focusing on quantitative and objective assessment of educational effectiveness is indispensable.

Background: Biologics are increasingly being used in patients with severe uncontrolled asthma. However, the trends in their use for treating severe asthma in Japan remain unclear., Methods: The number of patients with asthma prescribed omalizumab or mepolizumab between April 2017 and March 2018 was estimated according to sex, age, and geographical region using data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan., Results: Overall, 5,014, 3,449 and 7,977 patients were prescribed omalizumab, mepolizumab, or either combination, respectively. The total number of patients prescribed biologics displayed a bimodal distribution with peaks in their early teens and seventies. Biologics were most commonly used by male and female patients in their seventies. Prescription was 1.24 times higher in males than in females up to the teenage years, whereas it was 1.95 times higher in females than in males from their twenties onwards. Omalizumab was prescribed 1.45 times more frequently than mepolizumab, especially in pediatric patients, and was prescribed 1.96 times more often to female patients than to male patients. Regional differences were observed in the proportion of patients prescribed biologics. Correlation analysis suggested a weak relationship (r = 0.3226, p = 0.0270) between the proportion of patients prescribed biologics and board-certified allergists according to the geographic region., Conclusions: In Japan, biologics are prescribed more often to older patients with severe asthma compared to those in other countries. Thus, eliminating the regional disparities in asthma treatment by specialists is necessary to provide appropriate medical care to patients with severe asthma., Competing Interests: Declaration of competing interest YN received consulting fees and an honorarium for speakers bureaus from Novo Nordisk, Daiichi Sankyo, and Sanofi. TM received consulting fees from the Health Insurance Claims Review & Reimbursement services. HM received a research grant from GlaxoSmithKline Japan that was unrelated to the submitted work. TIno received a research grant from Johnson & Johnson Vision Care, SEED Co., Ltd., Novartis Pharma K·K., and Kowa Company, Ltd that was unrelated to the submitted work, consulting fees from Santen Pharmaceutical Co., Ltd. and InnoJin, Inc., and stock or stock options from InnoJin, Inc. MF received an honorarium for speakers bureaus from Sanofi K·K., Kyorin Pharmaceutical Co., Ltd., and Novartis Pharma Co., Ltd. The other authors have no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: In 2022, the "New Capitalism Grand Design and Implementation Plan" was adopted in Japan, emphasizing the promotion and environmental development of startups. Given this context, an investigation into the startup and investment landscape in the allergy sector, both domestically and internationally, becomes imperative., Methods: We analyzed 156 allergy-related startups from Japan, the US, and Europe from 2010 to 2021. Data on corporate information and investment trends were extracted from databases and VC websites., Results: The total investment reached approximately 7.2 billion USD, with a ratio of 20:6:1 for the US, Europe, and Japan, respectively. The US showed a decline post its peak from 2016-2018, while Europe and Japan experienced growth. Notably, the US primarily invested in biopharmaceuticals for atopic dermatitis and food allergies, Europe in asthma-related apps, and Japan in healthcare apps and cross-border startups., Discussion and Conclusion: While Japan's investment environment in the allergy sector remains in its nascent stages and has room for development, the US and Europe are evidently ahead. Considering the rise of startups and funding limitations in Japan, external funding from regions like the US becomes a potential avenue. These findings are anticipated to contribute to the strategic activation of startups in allergy research and development.

Background: Therapies specifically targeting nonhistaminergic pruritus are largely lacking. Difelikefalin (DFK) has been found to reduce itch in various chronic pruritic conditions, including atopic dermatitis (AD)., Objective: We sought to investigate the ability of DFK to impact scratching behavior, inflammatory mediators, and neuronal signaling in a murine model of AD., Methods: The ears of C57BL/6 mice were topically treated with MC903 for 12 consecutive days to induce AD-like inflammation and itch. Before MC903 treatment, mice were treated with either DFK (0.5 mg/kg, intraperitoneal injection twice daily) or vehicle (saline). Skin ear thickness, histological analysis, flow cytometry, RNA-sequencing, and differential gene expression analyses of mouse ear skin were used to examine the effect of DFK on skin inflammation. Scratching behavior was quantified to measure itch behavior in mice that were topically treated with MC903 for 6 consecutive days; then, mice received a single injection of either DFK (1.0 mg/kg, intraperitoneal injection) or saline. Calcium imaging and single-cell RNA-sequencing were used in mouse dorsal root ganglia neurons to determine the size of the neurons activated with DFK treatment. Statistical significance was determined by Mann-Whitney test, unless otherwise noted., Results: DFK rapidly suppressed itch without altering AD-like skin inflammation in MC903 (calcipotriol)-treated mice. In vitro Ca 2+ influx trace of dorsal root ganglia suggested that a major target for DFK is the larger-diameter mechanoreceptors (eg, Aꞵ-fibers), rather than small-diameter pruriceptive C-fibers., Conclusions: These studies support a potential neuromodulatory role of DFK for reducing itch associated with AD in mice., Competing Interests: Disclosure statement This study was sponsored by Cara Therapeutics. Employees of Cara Therapeutics were involved in the study design, the collection, analysis, and interpretation of data, the review of the manuscript, and the decision to submit for publication. Disclosure of potential conflict of interest: K. Nograles was employed with Cara Therapeutics, Inc, at the time of study conduct. J. Goncalves is employed with Cara Therapeutics, Inc. E. Guttman-Yassky received research funds (grants paid to institution) from AbbVie, Almirall, Amgen, AnaptysBio, Asana Biosciences, AstraZeneca, Boehringer Ingelheim, Cara Therapeutics, Celgene, Eli Lilly, Galderma, Glenmark/Ichnos Sciences, Innovaderm, Janssen, KAO, Kiniksa, Kyowa Kirin, LEO Pharma, Novan, Novartis, Pfizer, Ralexar, Regeneron Pharmaceuticals, and UCB and worked as a consultant with AbbVie, Almirall, Amgen, Arena, Asana Biosciences, Aslan Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Celgene, Connect Pharma, Eli Lilly, EMD Serono, Evidera, Galderma, Ichnos Sciences, Incyte, Janssen Biotech, Kyowa Kirin, LEO Pharma, Pandion Therapeutics, Pfizer, RAPT Therapeutics, Regeneron Pharmaceuticals, Inc, Sanofi, SATO Pharmaceutical, Siolta Therapeutics, Target Pharma Solutions, UCB, and Ventyx Biosciences. M. Lebwohl received research funds from AbbVie, Amgen, Arcutis, Avotres, Boehringer Ingelheim, Dermavant Sciences, Eli Lilly, Incyte, Janssen Research & Development, LLC, Ortho Dermatologics, Regeneron, and UCB and worked as a consultant with Aditum Bio, Almirall, AltruBio, Inc, AnaptysBio, Arcutis, Inc, Aristea Therapeutics, Arrive Technologies, Avotres Therapeutics, BiomX, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Dr. Reddy’s Laboratories, Evelo Biosciences, Evommune, Inc, Facilitation of International Dermatology Education, Forte Biosciences, Foundation for Research and Education in Dermatology, Helsinn Therapeutics, Hexima Ltd, LEO Pharma, Meiji Seika Pharma, Mindera, Pfizer, Seanergy, and Verrica. B.S. Kim is founder of Klirna Biotech; he has served as a consultant for 23andMe, ABRAX Japan, AbbVie, Almirall, Amagma Therapeutics, Amgen, Arcutis Biotherapeutics, Arena Pharmaceuticals, argenx, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Clexio Biosciences, Eli Lilly and Company, Escient Pharmaceuticals, Evommune, Galderma, Genentech, GlaxoSmithKline, Granular Therapeutics, Incyte Corporation, Innovaderm Research, Janssen, Kiniksa, LEO Pharma, Maruho, Novartis, Pfizer, Recens Medical, Regeneron Pharmaceuticals, Sanofi, Septerna, Vial, WebMD; he has stock in ABRAX Japan, KliRNA Biotech, Locus Biosciences, and Recens Medical; he holds a patent for the use of JAK1 inhibitors for chronic pruritus; he has a patent pending for the use of JAK inhibitors for interstitial cystitis. He has research grants from AbbVie, Cara Therapeutics, LEO Pharma, and Veradermics. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale: Corticospinal tract (CST) and corticoreticular pathway (CRP) injury patterns (i.e., the continuity of the nerve fibers) are associated with gait disturbance in post-stroke patients. In this case series study, we examined the case of 3 patients with different CST and CRP injury patterns and analyzed the characteristics of gait disturbance in each patient., Patient Concerns: Patient 1 (P1) was a 73-year-old woman who presented with paralysis of the right upper and lower extremities due to a left lacunar infarction. Patient 2 (P2) was a 41-year-old man who presented with paralysis of the right upper and lower extremities due to a left putamen hemorrhage. Patient 3 (P3) was a 57-year-old man who presented with paralysis of the left upper and lower extremities due to a right putamen hemorrhage., Diagnosis: In P1, the CRP in the affected hemisphere was intact, but the CST was discontinuous. In P2, the CST in the affected hemisphere was intact, but the CRP was discontinuous. P3 was discontinuous in both CST and CRP in the affected hemisphere., Outcomes: Over time, all 3 patients improved to the level of gait independence, but they exhibited different gait patterns. Among them, P3 showed a markedly abnormal gait pattern that included spatiotemporal gait asymmetry, lateral shift of the trunk, and hip hiking., Lessons: This case series study demonstrated that even if both the CST and CRP were injured, gait recovered to some extent (i.e., independent level-ground gait), but the abnormal gait pattern might remain remarkable., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Epidemiological studies demonstrated that cleaning work and frequent use of cleaning products are risk factors for asthma. Laundry detergents have been reported to have epithelial barrier-opening effects. However, whether laundry detergents directly induce airway inflammation and its mechanisms in vivo remain to be elucidated., Methods: Two commercial laundry detergents and two commonly used surfactants for cleaning and cosmetics (sodium lauryl sulfate and sodium dodecyl benzene sulfonate) were intranasally administered to mice. Lungs were analyzed using flow cytometry, histology, ELISA, and quantitative PCR. Human bronchial epithelial cells were stimulated with laundry detergents and analyzed using quantitative PCR and western blotting. Involvement of oxidative stress was assessed using an antioxidant. Dust samples from homes were analyzed to determine their detergent content by measuring their critical micelle concentration (CMC)., Results: The administered laundry detergents and surfactants-induced eosinophilic airway inflammation accompanied by increased IL-33 expression and activation of group 2 innate lymphoid cells (ILC2s). Detergent-induced eosinophilic airway inflammation was significantly attenuated in Rag2 -/- Il2rg -/- , Il33 -/- mice, and also in wild-type mice treated with NAC. Detergent-induced IL-33 expression in airways was attenuated by NAC treatment, both in vivo and in vitro. CMCs were found in all of the tested dust extracts, and they differed significantly among the homes., Conclusion: The laundry detergents and surfactants-induced eosinophilic airway inflammation in vivo through epithelial cell and ILC2 activation. They induced IL-33 expression in airway epithelial cells through oxidative stress. Furthermore, detergent residues were present in house dust and are presumably inhaled into the airway in daily life., (© 2023 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Late braking force (LBF) is often observed in the late stance phase of the paretic lower limb of stroke patients. Nevertheless, the effects and association of LBF remain unclear. We examined the kinetic and kinematic parameters associated with LBF and its effect on walking. Herein, 157 stroke patients were enrolled. Participants walked at a comfortable speed selected by them, and their movements were measured using a 3D motion analysis system. The effect of LBF was analyzed as a linear relationship with spatiotemporal parameters. Multiple linear regression analyses were performed with LBF as the dependent variable and kinetic and kinematic parameters as independent variables. LBF was observed in 110 patients. LBF was associated with decreased knee joint flexion angles during the pre-swing and swing phases. In the multivariate analysis, trailing limb angle, cooperativity between the paretic shank and foot, and cooperativity between the paretic and non-paretic thighs were related to LBF (p < 0.01; adjusted R 2  = 0.64). LBF in the late stance phase of the paretic lower limb reduced gait performance in the pre-swing and swing phases. LBF was associated with trailing limb angle in the late stance, coordination between the paretic shank and foot in the pre-swing phase, and coordination between both thighs., (© 2023. The Author(s).)

Objectives: : It is unclear whether the increased center of mass lateral shift during gait induced by leg length difference induces lateral instability. The purpose of this study was to investigate the effect of leg length discrepancy (LLD) on dynamic gait stability and the compensatory kinematic and dynamic strategies for this effect by using the extrapolated center of mass and margin of stability., Methods: : Nineteen healthy male participants walked without insoles (no LLD condition; 0 cm) and with added insoles (LLD condition; 3 cm). Kinematic and kinetic data were analyzed using a three-dimensional motion analyzer and force plates; the values were compared between the two conditions. Correlation analysis was performed on the parameters and the margin of stability and significant changes were identified., Results: Compared with the no-LLD condition, in the LLD condition, lateral stability was maintained on both the short leg side and the long leg side. Nonetheless, changes in joint angles and muscle activity on the frontal plane were observed on the short leg side, although the correlations were not significant. On the long leg side, a moderate negative correlation was found between the lateral flexion angle of the trunk and the margin of stability ( r =-0.56, P=0.011)., Conclusions: The short leg side may compensate for lateral stability by complex changes in joint angles and muscle activity, and the long leg side may compensate for lateral stability by actively adjusting the trunk lateral flexion angle., Competing Interests: CONFLICTS OF INTEREST: The authors declare that they have no conflicts of interest., (2023 The Japanese Association of Rehabilitation Medicine.)

Fujii R, Tamari M, Nonaka Y, Tamiya F, Hosokawa H, Tanaka S. Influence of gait exercise using a walking-assist robot for swing-leg motion in hemiplegic stroke patients: A preliminary study focusing on the immediate effect. Jpn J Compr Rehabil Sci 2022; 13: 49-55., Objective: We analyzed the effect of gait training using a walking-assist robot that assists a subject's knee joint movement and leg swing to achieve toe clearance of the paralyzed-side lower limb during treadmill walking., Methods: The subjects were 10 hemiplegic stroke patients in a rehabilitation ward. The intervention consisted of gait training using the Welwalk WW-1000 (Welwalk) robot for 40 min. Immediately before and after this intervention, a gait analysis of the patients' treadmill walking was performed by a three-dimensional motion capture system. Statistical analyses compared the foot-to-floor distance and the shortening of hip-toe length (SHTL) of the paralyzed side before and after the intervention, and examined the relationship between the change of lower-limb joint kinematics and toe clearance before and after the intervention., Results: The post-intervention SHTL was significantly lower compared to before the intervention, and there was a significant negative correlation between the change in the SHTL and the knee flexion angle from before to after the intervention., Conclusion: Gait exercise using the Welwalk could contribute to the acquisition of more normal leg-swing strategies., Competing Interests: Conflict of interest: The authors declare that there is no conflict of interest., (©Kaifukuki Rehabilitation Ward Association 2022.)

Background: Adrenaline is the first-line medication for managing anaphylaxis. A better understanding of prescription trends for adrenaline auto-injectors (AAIs) is important to improving patient care as well as information on health education interventions and medical guidelines. However, it has been difficult to gather comprehensive data in a sustainable manner. Thus, we aimed to investigate trends in AAI prescriptions in Japan., Methods: We searched the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), a unique and comprehensive database of health insurance claims, and investigated prescriptions for AAIs for all ages (April 2017 to March 2018). We assessed the annual number of prescriptions per person as well as prescription rates per 100,000 population per year by age, sex, and geographic region., Results: A total of 88,039 subjects (56,109 males, 31,930 female) and 116,758 devices (1.33 AAIs per patient per year) were prescribed AAIs at least once a year for all ages. The prescription rate for AAIs was 69.5 per 100,000 population-years. Patients aged 0-9 years were prescribed AAIs at the rate of 278.9 per 100,000 population-years. Patients aged 0-19 years were 6.4 times more likely to be prescribed AAIs than those over 20 years of age. Males were more frequently prescribed AAIs than females in all age groups, except for those aged 20-24 years. We also evaluated differences in prescription rates by geographic region., Conclusions: This comprehensive evaluation revealed trends in AAI prescriptions, thus helping develop preventive strategies with respect to anaphylaxis in Japan., (Copyright © 2022 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Chronic pruritus, or itch, is common and debilitating, but the neuroimmune mechanisms that drive chronic itch are only starting to be elucidated. Recent studies demonstrate that the IL-33 receptor (IL-33R) is expressed by sensory neurons. However, whether sensory neuron-restricted activity of IL-33 is necessary for chronic itch remains poorly understood., Objectives: We sought to determine if IL-33 signaling in sensory neurons is critical for the development of chronic itch in 2 divergent pruritic disease models., Methods: Plasma levels of IL-33 were assessed in patients with atopic dermatitis (AD) and chronic pruritus of unknown origin (CPUO). Mice were generated to conditionally delete IL-33R from sensory neurons. The contribution of neuronal IL-33R signaling to chronic itch development was tested in mouse models that recapitulate key pathologic features of AD and CPUO, respectively., Results: IL-33 was elevated in both AD and CPUO as well as their respective mouse models. While neuron-restricted IL-33R signaling was dispensable for itch in AD-like disease, it was required for the development of dry skin itch in a mouse model that mirrors key aspects of CPUO pathology., Conclusions: These data highlight how IL-33 may be a predominant mediator of itch in certain contexts, depending on the tissue microenvironment. Further, this study provides insight into future therapeutic strategies targeting the IL-33 pathway for chronic itch., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Platelets are thought to be involved in the pathophysiology of asthma, presumably through direct adhesion to inflammatory cells, including group 2 innate lymphoid cells (ILC2s). Here, we tried to elucidate the effects of platelet adhesion to ILC2s in vitro and in vivo, as well as the mechanisms involved., Methods: Alternaria-induced ILC2-dependent airway inflammation models using wild-type and c-mpl -/- mice were evaluated. Both purified CD41 + and CD41 - ILC2s were cultured with IL-2 and IL-33 to determine in vitro Type 2 (T2) cytokine production and cell proliferation. RNA-seq data of flow-cytometry-sorted CD41 + and CD41 - ILC2s were used to isolate ILC2-specific genes. Flow cytometry was performed to determine the expression of CD41 and adhesion-related molecules on ILC2s in both mouse and human tissues., Results: T2 inflammation and T2 cytokine production from ILC2s were significantly reduced in the c-mpl -/- mice compared to wild-type mice. Platelet-adherent ILC2s underwent significant proliferation and showed enhanced T2 cytokine production when exposed to IL-2 and IL-33. The functions of ILC2-specific genes were related to cell development and function. Upstream regulator analysis identified 15 molecules, that are thought to be involved in ILC2 activation. CD41 expression levels were higher in ILC2s from human PBMCs and mouse lung than in those from secondary lymphoid tissues, but they did not correlate with the P-selectin glycoprotein ligand-1 or CD24 expression level., Conclusion: Platelets spontaneously adhere to ILC2s, probably in the peripheral blood and airways, thereby potentiating ILC2s to enhance their responses to IL-33., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Yamada T, Ohta M, Tamari M. Effect of spasticity of the ankle plantar flexors on the walking speed of hemiplegic stroke patients after maximum walking speed exercises. Jpn J Compr Rehabil Sci 2021; 12: 64-69., Objective: This study examined the effect of ankle plantar flexor spasticity on the walking speed of hemiplegic stroke patients immediately following maximum walking speed exercises., Methods: A total of 23 hemiplegic stroke patients were divided into two groups based on the presence ( n = 13) or absence ( n = 10) of ankle plantar flexor spasticity on the paralyzed side. Gait speed, propulsive force during pre-swing, paretic side ankle plantar flexion movement during pre-swing, paretic side ankle dorsiflexion angle during the stance phase, angular velocity of paretic side dorsiflexion during the stance phase, paretic side trailing limb angle in the terminal stance, paretic side plantar flexion angle in the terminal stance, and the timing of maximum dorsiflexion of the ankle joint on the paretic side were measured before and after the maximum walking speed exercises, using a three-dimensional motion analyzer., Results: In the spasticity group, no significant improvement was observed in any of the categories. In contrast, in the non-spasticity group, significant improvement was observed in all categories, except for the paretic side ankle dorsiflexion angle., Conclusion: This study showed that maximum walking speed exercises immediately improved walking speed in hemiplegic stroke patients without ankle plantar flexor spasticity., (©Kaifukuki Rehabilitation Ward Association 2021.)

Discovery of innate lymphoid cells (ILCs), which are non-T and non-B lymphocytes that have no antigen-specific receptors, changed the classical concept of the mechanism of allergy, which had been explained mainly as antigen-specific acquired immunity based on IgE and Th2 cells. The discovery led to dramatic improvement in our understanding of the mechanism of non-IgE-mediated allergic inflammation. Numerous studies conducted in the past decade have elucidated the characteristics of each ILC subset in various organs and tissues and their ontogeny. We now know that each ILC subset exhibits heterogeneity. Moreover, the functions and activating/suppressing factors of each ILC subset were found to differ among both organs and types of tissue. Therefore, in this review, we summarize our current knowledge of ILCs by focusing on the organ/tissue-specific features of each subset to understand their roles in various organs. We also discuss ILCs' involvement in human inflammatory diseases in various organs and potential therapeutic/preventive strategies that target ILCs., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

ETS variant transcription factor 4 (ETV4) is a recently identified transcription factor that regulates gene expression-based biomarkers of asthma and IL6 production in an airway epithelial cell line. Given that ETV4 has not yet been implicated in asthma genetics, we performed genetic association studies of adult asthma in the ETV4 region using two independent Japanese cohorts (a total of 1532 controls and 783 cases). SNPs located between ETV4 and mesenchyme homeobox 1 (MEOX1) were significantly associated with adult asthma, including rs4792901 and rs2880540 (P = 5.63E-5 and 2.77E-5, respectively). The CC haplotype of these two SNPs was also significantly associated with adult asthma (P = 8.43E-7). Even when both SNPs were included in a logistic regression model, the association of either rs4792901 or rs2880540 remained significant (P = 0.013 or 0.007, respectively), suggesting that the two SNPs may have independent effects on the development of asthma. Both SNPs were expression quantitative trait loci, and the asthma risk alleles at both SNPs were correlated with increased levels of ETV4 mRNA expression. In addition, the asthma risk allele at rs4792901 was associated with increased serum IL6 levels (P = 0.041) in 651 healthy adults. Our findings imply that ETV4 is involved in the pathogenesis of asthma, possibly through the heightened production of IL6., (© 2021. The Author(s).)