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The effect of fish oil and corn oil supplementation on plasma lipids and lipoproteins and on low density lipoprotein (LDL) oxidation was examined in 20 treated hypertensive subjects. The randomized double-blind crossover study consisted of two 6-week interventions with 4 g/day of a highly purified fish oil or corn oil. Fish oil significantly (-24%, P < 0.01) reduced plasma triglyceride, and increased LDL-cholesterol (+6%, P < 0.01 compared to corn oil). LDL particles were larger (P < 0.01) after fish oil compared to baseline and LDL size was inversely correlated with plasma triglyceride (P < 0.001) both before and after fish oil supplementation, and positively correlated with high density lipoprotein cholesterol (P < 0.01). Fish oil reduced lag time before onset of copper-induced LDL oxidation (-25%, P < 0.001) and significantly increased production of thiobarbituric acid-reactive substances (TBARS) during oxidation, compared with corn oil. Corn oil had no significant effect on lag time and oxidation rate. Fish oil increased macrophage uptake of copper-oxidized LDL and of macrophage-modified LDL. Corn oil was without effect. Additionally, macrophages that were supplemented with fish oil fatty acids in vitro displayed a significantly (P < 0.001) higher capacity to oxidize LDL than either control cells or cells supplemented with corn oil fatty acids. We conclude that from the standpoint of atherosclerosis, fish oil fatty acids adversely raise the susceptibility of LDL to copper-induced and macrophage-mediated oxidation but that the increase in plasma LDL cholesterol concentration reflects an increase in size that may be favorable.

Background: There is a large population of young athletes who participate in gymnastics, and the prevention of injury in junior athletes is considered important. However, few studies have prospectively investigated the relationship between physical factors and the occurrence of injury., Purpose: To investigate the physical characteristics that are factors in the injury occurrence in elementary and junior high school gymnasts., Study Design: Prospective observational study., Methods: A total of 36 healthy young gymnasts (at national competition level) were enrolled in the study. Once a week for 23 weeks, injuries were prospectively investigated using self-report questionnaires under the supervision of a research staff. Joint range of motion (hip, ankle, shoulder, and wrist), tightness (Thomas test, Ely test, straight leg raise [SLR], triceps surae, combined abduction test [CAT], horizontal flexion test [HFT]), and muscle elasticity (multifidus) were assessed to compare differences in physical function between injured and non-injured participants., Results: Injuries occurred most commonly in the wrist (42.1%), lower back (30.2%), and foot (9.5%) among males, whereas heel (22.2%), knee (16.0%), and lower back (12.8%) were the most common injury sites among females. Wrist injuries in male athletes showed decreased shoulder joint range of motion, and lower back injuries showed decreased hip and shoulder joint range of motion. Lower back injuries in female athletes showed decreased hip extension mobility. Heel and knee joint injuries in females also showed increased range of motion and decreased tightness., Conclusions: The results of this study indicate that the factors related to flexibility differ according to injury location. Further studies are required to clarify the physical factors that influence injury occurrence by examining the effects of the gymnasts' muscle strength, age, individual factors, and left-right differences., Level of Evidence: 3., Competing Interests: The authors report no conflicts of interest, (© The Author(s).)

Background: Asthma is characterized by phenotypes of different clinical, demographic, and pathological characteristics. Identifying the profile of exhaled volatile organic compounds (VOCs) in asthma phenotypes may facilitate establishing biomarkers and understanding asthma background pathogenesis. This study aimed to identify exhaled VOCs that characterize severe asthma phenotypes among patients with asthma., Methods: This was a multicenter cross-sectional study of patients with severe asthma in Japan. Clinical data were obtained from medical records, and questionnaires were collected. Exhaled breath was sampled and subjected to thermal desorption gas chromatography-mass spectrometry (GC/MS)., Results: Using the decision tree established in the previous nationwide asthma cohort study, 245 patients with asthma were divided into five phenotypes and subjected to exhaled VOC analysis with 50 healthy controls (HCs). GC/MS detected 243 VOCs in exhaled breath samples, and 142 frequently detected VOCs (50% of all samples) were used for statistical analyses. Cluster analysis assigning the groups with similar VOC profile patterns showed the highest similarities between phenotypes 3 and 4 (early-onset asthma phenotypes), followed by the similarities between phenotypes 1 and 2 (late-onset asthma phenotypes). Comparisons between phenotypes 1-5 and HC revealed 19 VOCs, in which only methanesulfonic anhydride showed p < 0.05 adjusted by false discovery rate (FDR). Comparison of these phenotypes yielded several VOCs showing different trends (p < 0.05); however, no VOCs showed p < 0.05 adjusted by FDR., Conclusions: Exhaled VOC profiles may be useful for distinguishing asthma and asthma phenotypes; however, these findings need to be validated, and their pathological roles should be clarified., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Objective: Immunoglobulin A (IgA) is suggested to have pathogenic effects in respiratory inflammatory diseases, including asthma. We aimed to analyze the relationship between serum IgA, and clinical indicators and biomarkers of asthma. Methods: This study was a post hoc analysis of the NHOM Asthma Study. In this study, serum IgA was measured using serum samples stored. We determined an association between the serum IgA level and clinical variables and biomarkers using multivariate linear regression and analyzed the differences in clinical indices between IgA high- and IgA low-asthma. Results: In this study, 572 patients with asthma were included in the final analysis. Lower percentage forced expiratory volume in the first second (%FEV 1 ), higher serum eotaxin levels, lower serum ST2 levels, and higher serum MIP-1β levels, were independently and significantly associated with higher serum IgA levels among asthma patients by multivariate linear regression analysis (%FEV 1 , 95% confidence interval [CI], -8.18- -0.613, p  < 0.05; eotaxin, 95% CI, 8.95-46.69, p  < 0.001; ST2, 95% CI, -73.71- -7.37, p  < 0.05; and MIP-1β, 95% CI, 1.47-18.71, p  < 0.05). Furthermore, IgA high-asthma (serum IgA ≥ 238 mg/dL, n  = 270) and IgA low-asthma (serum IgA < 238 mg/dL, n  = 302) were compared separately. %FEV 1 was significantly lower, the percentage of atopy was higher, and serum MIP-1β level was higher in IgA high-asthma. Conclusions: This study suggests that serum IgA may be involved in the worsening of asthma outcomes, as assessed by %FEV 1 and enhanced inflammation via elevated serum MIP-1β.

Asthma is a chronic inflammatory airway disease, in which inflammatory cytokines play a pivotal role. The zinc finger binding protein 36 (ZFP36) family includes ZFP36, ZFP36L1, and ZFP36L2 and is among the RNA-binding proteins (RBPs) reported to cause inflammation. The present study aimed to clarify the roles of the ZFP36 family in asthma, particularly highlighting the relationship between the ZFP36 family and Th2 cells, which are key players in type 2 inflammation in asthma. Real-time PCR analysis revealed the preferential expression of ZFP36 family mRNAs in human white blood cells. Gene expression analysis using public datasets from the GEO database (https://www.ncbi.nlm.nih.gov/gds) showed significantly suppressed expression of ZFP36 family mRNAs in patients with asthma compared to that in healthy controls. Using multiple cytokine assays, Th2 cell transfection with ZFP36 family siRNAs enhanced the expression of inflammatory cytokines IL-8, IFN-γ, CCL3/MIP-1α, CCL4/MIP-1β, and TNF-α and cell surface molecules CCR4 (CD194) and PSGL-1 (CD162). Treatment with IL-2, 4, and 15 significantly suppressed, and corticosteroid significantly enhanced the expressions of ZFP36 family mRNAs by Th2 cells. In conclusion, the ZFP36 family expressed by Th2 cells was suppressed in patients with asthma, leading to the enhanced expression of cytokines and cell surface molecules. Suppressed ZFP36 expression in asthma may be involved in the enhancement of airway inflammation, and the ZFP36 family may be a therapeutic target for inflammatory diseases, including asthma., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The 2014 European Respiratory Society/American Thoracic Society guidelines defined severe asthma based on treatment intensity and estimated the proportion of severe asthma among all asthma cases to be 5-10%. However, data supporting the estimate and comprehensive and sequential data on asthma cases are scarce. We aimed to estimate the national prevalence and proportion of severe asthma during the last decade., Methods: Using a Japanese national administrative database, which covers ≥99% of the population, we evaluated the prevalence and proportion of severe asthma in 2013, 2015, 2017 and 2019. Additionally, we elucidated the demographic characteristics, treatments and outcomes of patients with asthma., Results: The national prevalence of mild-moderate and severe asthma in 2019 was 800 and 36 per 100 000 persons, respectively. While the prevalence of mild-moderate asthma remained almost constant in the study years, the prevalence of severe asthma decreased, resulting in a reduction in the proportion of severe asthma from 5.6% to 4.3%. Although treatment modalities have evolved, such as the increased use of combination inhalers and asthma biologics, approximately 15% of mild-moderate and 45% of severe asthma cases were still considered "uncontrolled". The number of deaths from asthma decreased in patients with both mild-moderate and severe asthma., Conclusions: This study revealed that the prevalence of severe asthma in Japan decreased during the study period and fell below 5% in the most recent data. Despite treatment evolution, a substantial proportion of patients with both mild-moderate and severe asthma still have poor asthma control., Competing Interests: Conflicts of interest: M. Suzukawa reports grants or contracts paid to their institution from Shionogi, Sanofi KK, MSD, Kyorin, Kyowa Kirin, Daiichi Sankyo, GlaxoSmithKline and AstraZeneca, outside the submitted work; payment for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Novartis Pharma KK, GlaxoSmithKline, Sanofi KK and AstraZeneca, outside the submitted work. H. Yasunaga reports support for the present manuscript from the Ministry of Health Labour and Welfare, Japan. The remaining authors have nothing to disclose., (Copyright ©The authors 2024.)

Background: Similar to metformin, dipeptidyl peptidase-4 inhibitors (DPP-4 Is), glucagon-like peptidase 1 receptor agonists (GLP-1 RAs), and sodium glucose co-transporter-2 inhibitors (SGLT-2 Is) may improve control of asthma owing to their multiple potential mechanisms, including differential improvements in glycemic control, direct anti-inflammatory effects, and systemic changes in metabolism., Objective: To investigate whether these novel antihyperglycemic drugs were associated with fewer asthma exacerbations compared with metformin in patients with asthma comorbid with type 2 diabetes., Methods: Using a Japanese national administrative database, we constructed 3 active comparators-new user cohorts of 137,173 patients with a history of asthma starting the novel antihyperglycemic drugs and metformin between 2014 and 2022. Patient characteristics were balanced using overlap propensity score weighting. The primary outcome was the first exacerbation requiring systemic corticosteroids, and the secondary outcomes included the number of exacerbations requiring systemic corticosteroids., Results: DPP-4 Is and GLP-1 RAs were associated with a higher incidence of exacerbations requiring systemic corticosteroids compared with metformin (DPP-4 Is: 18.2 vs 17.4 per 100 person-years, hazard ratio: 1.09, 95% confidence interval [CI]: 1.05-1.14; GLP-1 RAs: 24.9 vs 19.0 per 100 person-years, hazard ratio: 1.14, 95% CI: 1.01-1.28). In contrast, the incidence of exacerbations requiring systemic corticosteroids was similar between the SGLT-2 Is and metformin groups (17.3 vs 18.1 per 100 person-years, hazard ratio: 1.00, 95% CI: 0.97-1.03). While DPP-4 Is and GLP-1 RAs were associated with more exacerbations requiring systemic corticosteroids, SGLT-2 Is were associated with slightly fewer exacerbations requiring systemic corticosteroids (53.7 vs 56.6 per 100 person-years, rate ratio: 0.95, 95% CI: 0.91-0.99)., Conclusions: While DPP-4 Is and GLP-1 RAs were associated with poorer control of asthma compared with metformin, SGLT-2 Is offered asthma control comparable to that of metformin., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

This study aimed to assess the subjective and objective image quality of low-dose computed tomography (CT) images processed using a self-supervised denoising algorithm with deep learning. We trained the self-supervised denoising model using low-dose CT images of 40 patients and applied this model to CT images of another 30 patients. Image quality, in terms of noise and edge sharpness, was rated on a 5-point scale by two radiologists. The coefficient of variation, contrast-to-noise ratio (CNR), and signal-to-noise ratio (SNR) were calculated. The values for the self-supervised denoising model were compared with those for the original low-dose CT images and CT images processed using other conventional denoising algorithms (non-local means, block-matching and 3D filtering, and total variation minimization-based algorithms). The mean (standard deviation) scores of local and overall noise levels for the self-supervised denoising algorithm were 3.90 (0.40) and 3.93 (0.51), respectively, outperforming the original image and other algorithms. Similarly, the mean scores of local and overall edge sharpness for the self-supervised denoising algorithm were 3.90 (0.40) and 3.75 (0.47), respectively, surpassing the scores of the original image and other algorithms. The CNR and SNR for the self-supervised denoising algorithm were higher than those for the original images but slightly lower than those for the other algorithms. Our findings indicate the potential clinical applicability of the self-supervised denoising algorithm for low-dose CT images in clinical settings., (© 2024. The Author(s), under exclusive licence to Japanese Society of Radiological Technology and Japan Society of Medical Physics.)

Objective Dupilumab, a monoclonal antibody specific for the human interleukin (IL)-4 receptor α, is used to treat severe asthma, especially in patients with elevated blood eosinophil counts and fractional exhaled nitric oxide (FeNO). The therapeutic response to dupilumab is highly variable. In this study, we explored new serum biomarkers to accurately predict the effect of dupilumab and examine the effect of dupilumab based on changes in the clinical parameters and cytokine levels. Methods Seventeen patients with severe asthma treated with dupilumab were enrolled. Responders, defined as those with a >0.5-point decrease in the Asthma Control Questionnaire (ACQ) score after 6 months of treatment, were included. Results There were 10 responders and 7 non-responders. Serum type 2 cytokines were equivalent between responders and non-responders; the baseline serum IL-18 level was significantly lower in responders than in non-responders (responders, 194.9±51.0 pg/mL; non-responders, 323.4±122.7 pg/mL, p=0.013). The cut-off value of IL-18 at 230.5 pg/mL could be used to distinguish non-responders from responders (sensitivity 71.4, specificity 80.0, p=0.032). Conclusion A low baseline serum IL-18 level may be a useful predictor of an unfavorable response to dupilumab in terms of the ACQ-6.

Background: Selecting optimal biologics based on type 2 biomarkers has been of interest in severe asthma treatment. However, few direct biomarker stratification-based comparisons have been made., Objective: To compare the effectiveness of anti-IL-5 (mepolizumab, benralizumab), omalizumab, and dupilumab in reducing the number of hospitalizations from asthma and exacerbations across all and eosinophil-stratified subgroups., Methods: A retrospective cohort study using the National Hospital Organization database (2016-2020) was performed. Asthmatic patients using biologics were selected, and the baseline backgrounds of the groups were balanced using inverse probability treatment weighting for propensity scores. Weighted rate ratios (RRs) were obtained using a Poisson regression model., Results: Among the 320 patients with asthma using biologics, 205 (64.1%), 75 (23.4%), and 40 (12.5%) were categorized into the anti-IL-5, omalizumab, and dupilumab groups, respectively. After weighting, there were 47.1, 30.0, and 62.6 hospitalizations per 100 person-years [omalizumab vs. anti-IL-5: weighted RR, 0.61 (0.34-1.08); dupilumab vs. anti-IL-5: 1.48 (0.81-2.72)], and 117.0, 134.6, and 287.3 exacerbations per 100 person-years [omalizumab vs. anti-IL-5: 1.13 (0.83-1.54); dupilumab vs. anti-IL-5: 2.69 (1.91-3.78)] in these respective groups. In patients with eosinophil of ≥ 300/μL, the dupilumab group had more exacerbations compared with the anti-IL-5 group [weighted RR, 2.85 (1.82-4.46)]. In patients with eosinophil of < 300/μL, the omalizumab group had fewer hospitalizations compared with the anti-IL-5 group [weighted RR, 0.32 (0.13-0.51)]., Conclusion: Anti-IL-5 biologics may be more effective than dupilumab in patients with high blood eosinophil counts, while less effective than omalizumab in patients with low eosinophil counts.

Background: Asthma and chronic obstructive pulmonary disease (COPD) overlap (ACO) is characterized by concurrent features of asthma and COPD. Since disease pathogenesis, severities, and treatments differ between asthma and ACO, it is important to differentiate them., Objective: To clarify and compare the characteristics of ACO and asthma and identify the serum biomarkers for differentiating them, especially in older patients., Methods: This study used the data of 639 participants from the nationwide cohort study, the NHOM-Asthma study, an asthma registry in Japan, with complete information on smoking history, respiratory function, and serum biomarkers. ACO was defined as the self-reported comorbidity of COPD or emphysema, or with obstructive pulmonary function and smoking history (pack-years≥10). The clinical characteristics of patients with ACO and asthma without COPD were compared. The serum biomarkers for differentiation were examined using receiver operating characteristic curves and multivariable analysis. The associations between the biomarkers and age were also analyzed., Results: Of the 639 asthma patients, 125 (19.6%) were diagnosed with ACO; these patients were older and male-dominant and had a higher prevalence of comorbidities such as hypertension, diabetes, and stroke. Among the serum biomarkers that were significantly different between ACO and asthma without COPD, the YKL-40/CHI3L1, MMP3, and IL-1RA levels showed a high area under the curve for discriminating ACO. Only the MMP3 and IL-1RA levels were significantly higher among ACO patients, regardless of age and sex; the YKL-40/CHI3L1 levels were not different due to the effect of age., Conclusion: MMP3 and IL-1RA may be useful serum biomarkers for distinguishing ACO from asthma., Competing Interests: Maho Suzukawa received Grants from AstraZeneca, GlaxoSmithKline, Kyorin, Kyowa Kirin, Daiichi Sankyo, Sanofi, and Shionogi and honoraria for lectures from AstraZeneca, Novartis Pharma, GlaxoSmithKline, and Sanofi. Nobuharu Ohshima received honoraria for lectures from AstraZeneca, Novartis Pharma, GlaxoSmithKline, and Sanofi. Yuma Fukutomi received honoraria for lectures from Thermo Fisher Diagnostics, Torii Pharmaceutical, Novartis Pharma, Kyorin, Sanofi, and Taiho Pharmaceutical. Masami Taniguchi received Grants from GlaxoSmithKline and honoraria for lectures from Novartis Pharma, GlaxoSmithKline, and Sanofi. Masahiro Akishita received Grants from Astellas Pharma, Bayer HealthCare, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Kracie Pharma, Mitsubishi-Tanabe Pharma, MSD, and Ono Pharmaceutical and honoraria for lectures from Daiichi Sankyo, MSD, Toa Eiyo, and Towa Pharmaceutical., (© 2023 The Authors.)

Background: Allergic bronchopulmonary aspergillosis (ABPA) develops in the presence or absence of asthma, either atopic or nonatopic. We have tried to explore the essential components in the pathogenesis of the disease, which are either consistent and variable according to the presence and type of asthma., Methods: Non-cystic fibrosis ABPA cases satisfying Asano's criteria were extracted from a prospective registry of ABPA and related diseases in Japan between 2013 and 2023. According to the type of preceding asthma, ABPA was classified into three groups: ABPA sans asthma (no preceding asthma), ABPA with atopic asthma, and ABPA with nonatopic asthma. Exploratory and confirmatory factor analyses were performed to identify the components that determined the clinical characteristics of ABPA., Results: Among 106 cases of ABPA, 25 patients (24%) had ABPA sans asthma, whereas 57 (54%) and 24 (23%) had ABPA with atopic and nonatopic asthma, respectively. Factor analysis identified three components: allergic, eosinophilic, and fungal. Patients with atopic asthma showed the highest scores for the allergic component (p < .001), defined by total and allergen-specific IgE titers and lung opacities, and the lowest scores for the fungal component defined by the presence of specific precipitin/IgG or positive culture for A. fumigatus. Eosinophilic components, including peripheral blood eosinophil counts and presence of mucus plugs/high attenuation mucus in the bronchi, were consistent among the three groups., Conclusion: The eosinophilic component of ABPA is considered as the cardinal feature of ABPA regardless of the presence of preceding asthma or atopic predisposition., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Immunoglobulin A (IgA) is important in local immunity and is also abundant in the blood. This study aimed to evaluate the effects of serum IgA on cultured lung microvascular endothelial cells (HMVEC-Ls), which are involved in the pathogenesis of inflammatory lung diseases. Serum IgA induced adhesion molecules and inflammatory cytokine production from HMVEC-Ls, and enhanced adhesion of peripheral blood mononuclear cells to HMVEC-Ls. In contrast, migration, proliferation, and tube formation of HMVEC-Ls were significantly suppressed by serum IgA. Experiments with siRNAs and western blotting revealed that two known IgA receptors, β1,4-galactosyltransferase 1 (b4GALT1) and asialoglycoprotein receptor 1 (ASGR1), and mitogen-activated protein kinase and nuclear factor-kappa B pathways were partly involved in serum IgA-induced cytokine production by HMVEC-Ls. Collectively, serum IgA enhanced cytokine production and adhesiveness of HMVEC-L, with b4GALT1 and ASGR1 partially being involved, and suppressed angiogenesis. Thus, serum IgA may be targeted to treat inflammatory lung diseases., 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 © 2023 Elsevier Inc. All rights reserved.)

Background: There are two major pathological phenotypes of asthma, type 2 (T2)-high and T2-low asthma, which are important in determining treatment strategies. However, the characteristics and phenotypes of T2-high asthma have not yet been fully identified., Objective: This study aimed to identify the clinical characteristics and phenotypes of patients with T2-high asthma., Methods: This study used data from a nationwide asthma cohort study in Japan, NHOM Asthma Study. T2-high asthma was defined as a blood eosinophils count ≥ 300 /μL and/or fractional exhaled nitric oxide level ≥ 25 ppb, and the clinical characteristics and biomarkers were compared between T2-high and T2-low asthma. Furthermore, T2-high asthma was phenotyped via hierarchical cluster analysis using Ward's method., Results: Patients with T2-high asthma were older, less likely to be female, had longer asthma duration, had lower pulmonary function, and had more comorbidities, including sinusitis and SAS. Patients with T2-high asthma showed higher serum thymus and activation-regulated chemokine and urinary leukotriene E4 levels and lower serum ST2 levels than those with T2-low asthma. There were four phenotypes among patients with T2-high asthma: Cluster 1 (youngest, early-onset, and atopic), Cluster 2 (long duration, eosinophilic, and low lung function), Cluster 3 (elderly, female-dominant, and late-onset), and Cluster 4 (elderly, late-onset, and asthma-COPD overlap-dominant)., Conclusions: Patients with T2-high asthma have distinct characteristics and four distinct phenotypes, in which eosinophil-dominant Cluster 2 is the most severe phenotype. The present findings may be useful in precision medicine for asthma treatment in the future.

Background: Asthma is a heterogeneous disease with multiple phenotypes that are useful in precision medicine. As the population ages, the elderly asthma (EA, aged ≥ 65 years) population is growing, and EA is now a major health problem worldwide., Objective: To characterize EA and identify its phenotypes., Methods: In adult patients with asthma (aged ≥ 18 years) who had been diagnosed with having asthma at least 1 year before study enrollment, 1925 were included in the NHOM-Asthma (registered in UMIN-CTR; UMIN000027776), and the data were used for this study, JFGE-Asthma (registered in UMIN-CTR; UMIN000036912). Data from EA and non-EA (NEA) groups were compared, and Ward's minimum-variance hierarchical clustering method and principal component analysis were performed., Results: EA was characterized by older asthma onset, longer asthma duration and smoking history, more comorbidities, lower pulmonary function, less atopic, lower adherence, and more hospital admissions because of asthma. In contrast, the number of eosinophils, total immunoglobulin E level, oral corticosteroid use, and asthma control questionnaire scores were equivalent between EA and NEA. There were 3 distinct phenotypes in EA, which are as follows: EA1: youngest, late onset, short duration, mild; EA2: early onset, long duration, atopic, low lung function, moderate; and EA3: oldest, eosinophilic, overweight, low lung function, most severe. The classification factors of the EA phenotypes included the age of onset and asthma control questionnaire-6. Similarities were observed between EA and NEA phenotypes after principal component analysis., Conclusion: The EA in Japan may be unique because of the population's high longevity. Characterization of EA phenotypes from the present cohort indicated the need for distinct precision medicine for EA., Trial Registration: JFGE-Asthma registered in UMIN-CTR (https://www.umin.ac.jp/ctr/); UMIN000036912., (Copyright © 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objectives: To clarify whether treatment with systemic corticosteroids at a certain dose was associated with better outcomes in patients with epiglottitis requiring airway management (tracheotomy or airway intubation)., Methods: This was a retrospective cohort study on patients hospitalized for epiglottitis requiring airway management from a nationwide inpatient database (between July 2010 and March 2019). Patients treated with systemic corticosteroids equivalent to methylprednisolone ≥40 mg/d within 2 days of admission and patients who were not treated with corticosteroids within 2 days of admission were compared after inverse probability of treatment weighting using covariate balancing propensity score. The primary outcome was all-cause 30-day in-hospital mortality, and secondary outcomes included all-cause 7-day in-hospital mortality, length of hospital stay, and total medical cost., Results: There were 1986 and 1771 patients in the corticosteroid and control groups, respectively. A total of 72 of 3757 (1.9%) patients died within 30 days of admission, including 17 of 1986 (0.9%) patients in the corticosteroid group and 55 of 1771 (3.1%) in the control group (weighted odds ratio, 0.28 [95% confidence interval, 0.11-0.70]; weighted risk difference, -2.2% [-3.2% to -1.3%]). Treatment with corticosteroids was associated with lower total medical costs (weighted median, $6,187 vs. $6,587; weighted difference, $-1,123 [-2,238 to -8]) but not all-cause 7-day in-hospital mortality (weighted odds ratio, 0.63 [0.22-1.82]; weighted risk difference, -0.3% [-0.9 to 0.2]) and length of hospital stay (weighted median, 13 vs. 13 days; weighted difference, -0.2 days [-2.1 to 1.8])., Conclusions: Systemic corticosteroids may be beneficial to patients with epiglottitis requiring airway management., Level of Evidence: 3 Laryngoscope, 133:344-349, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Asthma is a heterogeneous disease, and phenotyping can facilitate understanding of disease pathogenesis and direct appropriate asthma treatment. This nationwide cohort study aimed to phenotype asthma patients in Japan and identify potential biomarkers to classify the phenotypes., Methods: Adult asthma patients (n = 1925) from 27 national hospitals in Japan were enrolled and divided into Global Initiative for Asthma (GINA) steps 4 or 5 (GINA 4, 5) and GINA Steps 1, 2, or 3 (GINA 1-3) for therapy. Clinical data and questionnaires were collected. Biomarker levels among GINA 4, 5 patients were measured. Ward's minimum variance hierarchical clustering method and tree analysis were performed for phenotyping. Analysis of variance, the Kruskal-Wallis, and chi-square tests were used to compare cluster differences., Results: The following five clusters were identified: 1) late-onset, old, less-atopic; 2) late-onset, old, eosinophilic, low FEV 1 ; 3) early-onset, long-duration, atopic, poorly controlled; 4) early-onset, young, female-dominant, atopic; and 5) female-dominant, T1/T2-mixed, most severe. Age of onset, disease duration, blood eosinophils and neutrophils, asthma control questionnaire Sum 6, number of controllers, FEV 1 , body mass index (BMI), and hypertension were the phenotype-classifying variables determined by tree analysis that assigned 79.5% to the appropriate cluster. Among the cytokines measured, IL-1RA, YKL40/CHI3L1, IP-10/CXCL10, RANTES/CCL5, and TIMP-1 were useful biomarkers for classifying GINA 4, 5 phenotypes., Conclusions: Five distinct phenotypes were identified for moderate to severe asthma and may be classified using clinical and molecular variables (Registered in UMIN-CTR; UMIN000027776.)., (Copyright © 2022 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Biologics have been a key component of severe asthma treatment, and there are currently biologics available that target IgE, IL-5, IL-4/IL-13, and TSLP. Randomized controlled trials have established clinical evidence, but a significant portion of patients with severe asthma in real-life settings would have been excluded from those trials. Therefore, real-world research is necessary, and there is a growing body of information about the long-term efficacy and safety of biologics. Multiple clinical phenotypes of severe asthma exist, and it is crucial to choose patients based on their phenotypes. Blood eosinophil count is an important biomarker for anti-IL-5 therapies, and FeNO and eosinophil counts serve as prediction markers for dupilumab. Reliable markers for predicting response, however, have not yet been fully established for omalizumab. Identification of clinical or biological prediction factors is crucial for the path toward clinical remission because the current treatment goal includes clinical remission, which is defined as a realistic goal for remission off treatment. Additionally, since there are now multiple biologic options and overlaps in eligibility for biologics in clinical practice, the evidence regarding the effectiveness of switching the biologics is crucial. Investigations into the clinical trajectory following the cessation of biologics are another important issue. Recent research on omalizumab, mepolizumab, benralizumab and dupilumab's real-world effectiveness, the prediction factor for the efficacy, and the impact of switching or discontinuation will be reviewed and discussed in this review., (Copyright © 2022 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background: Obesity leads to an increase in the incidence and severity of asthma. Adipokines, such as leptin, secreted by adipocytes induce systemic inflammation, causing airway inflammation. We previously reported that leptin activates both inflammatory and structural cells, including lung fibroblasts. However, little is known about the differential leptin expression and responsiveness to leptin in asthmatic individuals and healthy controls (HC). In this study, we investigated the expression and origin of leptin in asthmatic airways. We also compared the effect of leptin on asthmatic and HC fibroblasts., Methods: Lung specimens from asthmatic and non-asthmatic patients were analyzed by immunohistochemical staining using anti-leptin and anti-CD163 antibodies. Leptin mRNA and protein levels in human monocytes were detected by real-time PCR and western blotting and ELISA, respectively. We used flow cytometry to analyze asthmatic and HC lung fibroblasts for leptin receptor (Ob-R) expression. Further, we determined cytokine levels using cytometric bead array and ELISA and intracellular phosphorylation of specific signaling molecules using western blotting., Results: Asthma specimens displayed accumulation of leptin-positive inflammatory cells, which were also positive for CD163, a high-affinity scavenger receptor expressed by monocytes and macrophages. Leptin expression was observed at both transcript and protein levels in human blood-derived monocytes. No significant differences were observed between asthmatic and HC lung fibroblasts in Ob-R expression, cytokine production, and intracellular phosphorylation of p38 mitogen-activated protein kinase., Conclusions: Our findings reveal similar responsiveness of control and asthmatic fibroblasts to leptin. However, the accumulation of inflammatory leptin-producing monocytes in the airway may contribute to the pathogenesis of asthma., Competing Interests: Conflict of Interest MS received honoraria from AstraZeneca and research funding from AstraZeneca and GlaxoSmithKline. SKW received research funding from Sanofi. The other authors have no conflict of interest., (Copyright © 2022 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)