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Objective: In Japan, the optimal initiation timing and efficacy of single-inhaler triple therapy (SITT) in asthma management remain unexplored. This study investigated SITT initiation timing following an asthma exacerbation, and examined patient demographics and clinical characteristics., Methods: Observational, retrospective cohort study in patients with asthma aged ≥15 years who initiated SITT following their earliest observed asthma exacerbation (February-November 2021), using data from Japanese health insurance claims databases (JMDC and Medical Data Vision [MDV]). The study period ended May 2022 for JMDC and September 2022 for MDV. Descriptive analyses were performed independently by database. Variables evaluated included timing of SITT initiation post exacerbation (prompt, delayed and late, ≤30, 31-180 and >180 days post index, respectively), patient demographics, clinical characteristics, and pre-index treatment., Results: Of patients in the JMDC and MDV databases, most initiated SITT promptly after an asthma exacerbation, 60.8% ( n  = 951/1565) and 44.4% ( n  = 241/543), respectively. Delayed initiation occurred in 22.6% ( n  = 354/1565) and 26.3% ( n  = 143/543) of patients, and late initiation occurred in 16.6% ( n  = 260/1565) and 29.3% ( n  = 159/543), respectively. Most patients were indexed on a moderate asthma-related exacerbation, 97.1% ( n  = 1519/1565) and 68.7% ( n  = 373/543), respectively., Conclusion: Most patients with asthma initiated SITT promptly following a moderate exacerbation, with delayed and late initiation more common among patients with complex clinical profiles. The findings underscore the necessity for future research to examine the interaction between patient characteristics, clinical outcomes, and the timing of SITT initiation to optimize treatment strategies, as clinical practice may vary by exacerbation severity.

A 44-year-old woman underwent a follow-up examination for Crohn's disease 9 years ago. Chest computed tomography (CT) showed an infiltration shadow with a cavity in the right upper lobe. After a CT-guided lung biopsy, epitheloid granuloma was noted, and an acid-fast bacilli examination was smear-positive, but a culture examination was negative. Because the abnormal chest shadow with cavity gradually increased and right shoulder pain appeared, we performed bronchoscopy again six months later. Mycobacterium heckeshornense was isolated from the bronchoalveolar lavage fluid specimen, so we diagnosed her with pulmonary M. heckeshornense disease. Isoniazid, rifampicin, and ethambutol were administered, and the abnormal chest shadow improved.

Background: Real-world data assessing characteristics of patients with asthma initiating inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β 2 -agonist (ICS/LAMA/LABA) triple therapy in Japan are limited., Methods: Descriptive, observational study of patients with asthma aged ≥15 years newly initiating single- or multiple-inhaler triple therapy (SITT: fluticasone furoate/umeclidinium/vilanterol [FF/UMEC/VI], SITT: indacaterol/glycopyrronium bromide/mometasone furoate [IND/GLY/MF] or MITT) or ICS/LABA using JMDC/Medical Data Vision (MDV) health insurance databases from February 2021-February 2022 (first prescription date: index date). Patients were assigned to three non-mutually exclusive cohorts: A) new FF/UMEC/VI initiators; B) new FF/UMEC/VI, IND/GLY/MF, or MITT initiators; C) new FF/UMEC/VI, IND/GLY/MF, MITT or ICS/LABA initiators as initial maintenance therapy (IMT). Patient characteristics were assessed descriptively for 12-months pre-treatment initiation (baseline period)., Results: Cohort A: among new FF/UMEC/VI initiators, 12.8% and 0.1% (JMDC) and 21.7% and 0.9% (MDV) of patients had ≥1 moderate and severe exacerbation; 52.0% (JMDC) and 79.2% (MDV) had ICS/LABA use. Cohort B: most patients initiated FF/UMEC/VI and IND/GLY/MF over MITT (JMDC: 91.3% vs 8.7%; MDV: 67.8% vs 32.2%), with fewer exacerbations and lower rescue medication use. Cohort C: a greater proportion of FF/UMEC/VI initiators as IMT experienced a moderate exacerbation at index versus ICS/LABA initiators as IMT (JMDC: 17.8% vs 10.7%; MDV: 8.0% vs 5.1%)., Conclusions: Patient characteristics were generally similar between treatment groups; SITT initiators had fewer exacerbations and lower rescue medication use than MITT initiators, represented by the greater proportion of IMT among SITT versus MITT initiators. Physicians may have prescribed triple over dual therapy as IMT in response to an exacerbation., Competing Interests: Declaration of competing interest TO has received lecture fees from GSK K.K., Nippon Boehringer Ingelheim Co. Ltd, AstraZeneca K.K., Novartis Pharma K.K., and Teijin Healthcare Ltd. CM, RI, GR, KJR, SGN, LY, and MY are employees of GSK and may hold stocks/shares in GSK, or were at the time of the study. SGN is a PhD candidate at McMaster University, Hamilton, Ontario, Canada., (Copyright © 2024. Published by Elsevier B.V.)

Background: Asthma and obstructive sleep apnea (OSA) are prevalent chronic respiratory disorders, which often coexist and interact with each other. Obesity is an important risk factor shared by them. The rate of obesity is lower in Japan versus Western countries. Hence, the co-existence of asthma and OSA has not been investigated in Japan., Methods: Ninety-seven outpatients with asthma were recruited. Patients wore a portable monitor for sleep study. Background data, pulmonary function, blood tests, and patient-reported outcomes including gastroesophageal reflux disease, sleepiness, sleep quality, asthma control, cough and respiratory symptoms, and health status, were assessed., Results: Of the patients, 19 (19.6 %), 40 (41.2 %), 24 (24.7 %), and 14 (14.4 %) were classified into non-, mild, moderate, and severe OSA groups. Non-OSA patients were younger than those in other groups (p < 0.05). The BMI of patients with moderate and severe OSA, was higher than that of non-OSA patients (p < 0.05). Pulmonary function, FeNO, serum IgE, and the number of peripheral eosinophils were not significantly different between groups. Nonetheless, compared with the other groups, treatment step was the highest, and the Asthma Control Test, Leicester Cough Questionnaire, COPD Assessment Test, and Asthma Health Questionnaire-33 yielded worst scores in the severe OSA group, and predicted the severe OSA after adjustment by BMI., Conclusions: Moderate and severe OSA are highly prevalent among patients with asthma in Japan. Pulmonary function did not differ between groups. However, patients with asthma and severe OSA were linked to more asthma treatment, worse asthma control, more symptoms and cough, and worse health status., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Alterations in the experience-dependent and autonomous elaboration of neural circuits are assumed to underlie autism spectrum disorder (ASD), though it is unclear what synaptic traits are responsible. Here, utilizing a valproic acid-induced ASD marmoset model, which shares common molecular features with idiopathic ASD, we investigate changes in the structural dynamics of tuft dendrites of upper-layer pyramidal neurons and adjacent axons in the dorsomedial prefrontal cortex through two-photon microscopy. In model marmosets, dendritic spine turnover is upregulated, and spines are generated in clusters and survived more often than in control marmosets. Presynaptic boutons in local axons, but not in commissural long-range axons, demonstrate hyperdynamic turnover in model marmosets, suggesting alterations in projection-specific plasticity. Intriguingly, nasal oxytocin administration attenuates clustered spine emergence in model marmosets. Enhanced clustered spine generation, possibly unique to certain presynaptic partners, may be associated with ASD and be a potential therapeutic target., (© 2024. The Author(s).)

Background: Recently, suspected cyhalofop-butyl-resistant populations of allohexaploid weed Echinochloa crus-galli var. crus-galli were discovered in rice fields in Aichi Prefecture, Japan. Analyzing the target-site ACCase genes of cyhalofop-butyl helps understand the resistance mechanism. However, in E. crus-galli, the presence of multiple ACCase genes and the lack of detailed gene investigations have complicated the analysis of target-site genes. Therefore, in this study, we characterized the herbicide response of E. crus-galli lines and thoroughly characterized the ACCase genes, including the evaluation of gene mutations in the ACCase genes of each line., Result: Four suspected resistant lines collected from Aichi Prefecture showed varying degrees of resistance to cyhalofop-butyl and other FOP-class ACCase inhibitors but were sensitive to herbicides with other modes of action. Through genomic analysis, six ACCase loci were identified in the E. crus-galli genome. We renamed each gene based on its syntenic relationship with other ACCase genes in the Poaceae species. RNA-sequencing analysis revealed that all ACCase genes, except the pseudogenized copy ACCase2A, were transcribed at a similar level in the shoots of E. crus-galli. Mutations known to confer resistance to FOP-class herbicides, that is W1999C, W2027C/S and I2041N, were found in all resistant lines in either ACCase1A, ACCase1B or ACCase2C., Conclusion: In this study, we found that the E. crus-galli lines were resistant exclusively to ACCase-inhibiting herbicides, with a target-site resistance mutation in the ACCase gene. Characterization of ACCase loci in E. crus-galli provides a basis for further research on ACCase herbicide resistance in Echinochloa spp. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)

Background: NY-ESO-1 and XAGE1 cancer/testis antigens elicit humoral and cellular immune responses in NSCLC patients. We aimed to predict clinical benefit with ICI monotherapy, using an automated immunoassay of NY-ESO-1/XAGE1 antibodies (Abs)., Methods: This study enrolled 99 NSCLC patients who received nivolumab after chemotherapy, including 21 patients harboring EGFR, ALK, or KRAS alterations. The cutoff value (10 units/mL) of NY-ESO-1 and XAGE1 Ab was determined based on Ab levels in non-malignant controls, and NY-ESO-1/XAGE1 Abs in NSCLC were measured before nivolumab. Differences in PFS and OS between the Ab-positive and Ab-negative groups were retrospectively analyzed using Cox regression analysis after applying inverse probability of treatment weighting (IPTW)., Results: NY-ESO-1/XAGE1 Abs were positive in 28 NSCLC, who responded more highly to nivolumab than the Ab-negatives (response rate 50.0% vs. 15.5 %, p < 0.0007). The IPTW-adjusted positives and negatives for NY-ESO-1/XAGE1 Abs were 24.5 and 70.2, respectively. The Ab-positives showed longer IPTW-adjusted PFS (HR = 0.59, 95 % CI: 0.39-0.90, p = 0.014) and IPTW-adjusted OS (HR = 0.51, 95 % CI: 0.32-0.81, p = 0.004) than the Ab-negatives. Among NSCLC harboring driver genes, the Ab-positives (n = 10) showed longer PFS (HR = 0.34, 95 % CI: 0.13-0.89, p = 0.029) and OS (HR = 0.27, 95 % CI: 0.098-0.75, p = 0.012) than the Ab-negatives (n = 11)., Conclusion: Our immunoassay of NY-ESO-1/XAGE1 Abs is probably useful for predicting the clinical benefit with nivolumab in NSCLC, including those harboring driver genes. These results suggest that our immunoassay may be useful in ICI monotherapy for NSCLC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kanako Sakaeda, Yasuhiro Irino, and Masatoshi Yanagida received personal fees for salary as full-time employees and stock ownership from Sysmex corporation. Satoshi Muto had grants or contracts from JSPS KAKENHI; received payment or honoraria for lectures or manuscript writing from MSD, AstraZeneca, Eli Lilly Japan, Bristol Myers Squibb, Tahiho Pharmaceutical, Chugai Pharmaceutical and “Gan to Kagakuryoho”. Takeshi Masuda received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Daiichi-Sankyo, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Otsuka Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, Kyowa Kirin, Eli Lilly Japan and Chugai Pharmaceutical. Yumiko Sakai and Yusuke Atarashi received personal fees for salary as full-time employees. Noboru Hattori received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Chugai Pharmaceutical, Ono Pharmaceutical, AstraZeneca, Bristol Myers Squibb and MSD. Mikio Oka and Koji Kurose received JSPS KAKENHI Grant, Collaborative Research Fund from Sysmex Corporation and Endowment from Pole Star. The other authors have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In Japan, exacerbations are underreported compared with other countries, possibly due in part to a failure to recognize them. This study aimed to create a simple chronic obstructive pulmonary disease (COPD) Exacerbation Recognition Tool (CERT-J) specifically for Japanese patients. Patients ≥40 years with confirmed COPD or asthma-COPD overlap were included. Focus groups were held to identify words and phrases used by patients to describe symptoms associated with an exacerbation, resulting in candidate items being identified. Following cognitive debriefing, the items were refined based on item frequency, level of endorsement and effect of demographic factors. Exploratory factor analysis (EFA) was then performed to inform an expert panel's choice of items to form the new tool. A total of 41 patients were included in the focus groups and nine patients performed the cognitive debrief. Following this, the expert panel identified 26 items for testing in a further 100 patients (mean age 72 years, forced expiratory volume in 1 s 54.8% predicted and 1.8 exacerbations in the preceding 12 months). Eleven items were associated with breathlessness or activity limitation and seven of these were the most frequently endorsed. EFA identified four factors, with one (breathlessness) being dominant. The expert panel recommended that the CERT-J should include six items: breathlessness and activity limitation (3 items), cough (1 item) and phlegm (2 items). The final CERT-J should benefit patients with COPD by providing them with an increased understanding and recognition of exacerbations. Clinical Trial Registration: GSK K.K (jRCT1080224526).

Background: Poor health-related quality of life (HRQL) at the registration for lung transplantation is related to waitlist mortality. We investigated the relationship between 1-year change in HRQL and subsequent outcomes in patients waitlisted for lung transplantation., Methods: In a 5-year longitudinal study, we analyzed the factors related to waitlist mortality in 197 lung transplant patients registered on the Japan Organ Transplant Network. HRQL was assessed using St. George's Respiratory Questionnaire (SGRQ), and factors related to changes in SGRQ scores were evaluated after 1 year. We assessed the relationship between the 1-year change in SGRQ score and subsequent mortality or hospitalization., Results: Among 197 patients, 108 remained waitlisted during the first-year assessment. During the median follow-up period of 469 d, 28 patients died, and 54 underwent lung transplantation. Univariate Cox proportional hazards analysis revealed that the changes in all components and total score of the SGRQ after 1 year were associated with waitlist mortality (p < 0.05). Stepwise multivariate analysis revealed that the 1-year changes in SGRQ scores were significantly related to waitlist mortality. Forty-three patients with worsened HRQL after 1 year had higher likelihoods of hospitalization (p = 0.038) and mortality (p = 0.026) after 1 and 4 years of follow-up, respectively, than 61 patients without worsened HRQL., Conclusions: Patients with worsened health status during the first year after registration had higher likelihoods of hospitalization and mortality after 1 and 4 years of follow-up, respectively, than those without worsened HRQL. Strategies to improve health status while waiting are needed to reduce waitlist hospitalization or mortality., Competing Interests: Conflict of Interest The authors have no conflicts of interest., (Copyright © 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Checkpoint inhibitor pneumonitis (CIP), caused by the anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) antibody, can be a fatal adverse event in cancer patients. However, no predictive biomarkers for CIP have been identified. Because high-mobility group box 1 (HMGB1) can aggravate lung injury and potentially increase the immune response, it was investigated as a predictive blood marker., Methods: Blood samples, prospectively stored before anti-PD-1/PD-L1 monotherapy between December 2015 and October 2020, were obtained at two university hospitals from 87 and 43 non-small cell lung cancer (NSCLC) patients (discovery and validation cohorts, respectively). We retrospectively evaluated the association of serum HMGB1 levels with the incidence of CIP developed within 3 months of initiating anti-PD-1/PD-L1 therapy., Results: CIP was observed in 9 (10.3%) and 6 (14.0%) patients in the discovery and validation cohorts, respectively. In each cohort, serum HMGB1 levels were significantly and reproducibly higher in patients with CIP. In the discovery cohort, an HMGB1 cut-off level of 11.24 ng/ml was identified by receiver operating characteristic analysis. CIP incidence in the HMGB1 high subgroup was significantly higher than that in the HMGB1 low subgroup in the discovery (41.2% vs. 2.9%) and validation cohorts (36.4% vs. 6.3%). In an exploratory pooled analysis, three patients died of grade 5 CIP; a 19.29 ng/ml HMGB1 cut-off level detected grade 5 CIP with 100% sensitivity and 96.85% specificity., Conclusion: Our results suggest that HMGB1 may be a potential blood marker to predict the development and severity of CIP in NSCLC patients., (© 2022 Asian Pacific Society of Respirology.)

Objectives: This study aimed to identify and investigate changes in the mortality of patients with chronic obstructive pulmonary disease (COPD) at the same institute from the 1990s to the 2000s. We hypothesised that the improvement in long-term mortality of COPD was achieved due to the development of pharmacological and non-pharmacological treatments., Design: This study was a retrospective analysis of two observational prospective cohort studies. One study enrolled subjects from 1995 to 1997 (the 1990s), and the other enrolled subjects from 2005 to 2009 (the 2000s)., Setting: Two studies from a single centre, which was the same university hospital in Japan., Participants: Patients with stable COPD., Primary and Secondary Outcome Measures: We analysed all-cause mortality data from the pooled database. Subanalyses were conducted by stratifying subjects into two groups according to airflow limitation severity as severe/very severe (per cent predicted value of forced expiratory volume in 1 s (%FEV 1 ) <50%) or mild/moderate (%FEV 1 ≥50%)., Results: In total, 280 male patients with COPD were enrolled. Patients in the 2000s (n=130) were significantly older (71.6 vs 68.7 years) and had milder disease (%FEV 1 ; 57.6% vs 47.1%) than those in the 1990s (n=150). Almost all severe/very severe patients in the 2000s received long-acting bronchodilators (LABDs), and they had a significantly lower risk of mortality than those in the 1990s according to Cox proportional regression analyses (OR=0.34, 95% CI 0.13-0.78), with a 48% reduction in 5-year mortality (from 31.0% to 16.1%). Moreover, any LABD use had a significantly positive impact on prognosis, even after adjustments for age, FEV 1 , smoking status, dyspnoea, body size, oxygen therapy and study period., Conclusions: Trends indicating a better prognosis for patients with COPD in the 2000s were observed. This improvement may be associated with the usage of LABDs., Competing Interests: Competing interests: SS reports grants from Nippon Boehringer Ingelheim, Philips-Respironics, Fukuda Denshi, Fukuda Lifetec Keiji and ResMed outside the submitted work. SM reports grants from ROHTO Pharmaceutical outside the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immune checkpoint inhibitors (ICI) are key drugs in systemic therapy for advanced non-small-cell lung cancer (NSCLC) and have recently been incorporated into neoadjuvant and adjuvant settings for surgical resection. Currently, ICI combinations with cytotoxic agents are frequently used in clinical practice, although several ICI clinical trials have failed to produce long-term clinical benefits. Unfortunately, clinical benefit is moderate and limited considering physical and financial burden. Therefore, selecting appropriate patients and regimens for ICI therapy is important, and biomarkers are necessary for their selection. Tumor PD-L1 expression is universally used as a biomarker; however, PD-L1 assays show low analytical validity and reproducibility due to the visual-scoring system by pathologists. Recent tumor immunology studies explore that neoantigens derived from somatic mutations and the collaboration between T and B cells efficiently elicit antitumor responses. This suggests that high tumor mutational burden and T-cell infiltration are predictive biomarkers. However, B cells producing antibody (Ab) remain poorly understood and analyzed as biomarkers. We found that NY-ESO-1 and XAGE1 of cancer-testis antigen frequently elicit spontaneous humoral and cellular immune responses in NSCLC. Serum Ab against these antigens were detected in approximately 25% of NSCLC patients and predicted ICI monotherapy responses. In addition, the Ab levels were decreased with tumor shrinkage after ICI therapy. Thus, NY-ESO-1 and XAGE1 Ab are potentially biomarkers predicting and monitoring response to ICI therapy. For clinical applications, a fully-automated assay system measuring the Ab was developed. Here, we review current ICI therapy, tumor immunology, and biomarkers in NSCLC, and discuss the applicability of the serum biomarkers NY-ESO-1 and XAGE1 Ab., Competing Interests: Declaration of competing interest The Department of Immuno-Oncology (Dr. Oka) is endowed to Kawasaki Medical School by Pole Star Co., Ltd., which does not influence the work reported in this paper. Sakaeda K, Sakai Y, Atarashi Y, Irino Y, and Sato T are employees of Sysmex Corporation. The other authors declare no financial competing interests related to this study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Rationale: Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a systemic immune-mediated condition that can cause fibroinflammatory lesions in multiple organs. Approximately 35% of IgG4-RD patients have some symptoms in the chest and IgG4-related lung disease (IgG4-RLD) is observed in about 10% of IgG4-RD cases. In addition, it is thought that glucocorticoid therapy is effective for IgG4-RD and IgG4-RLD. It is difficult to diagnose IgG4-RLD complicated with another lung disease., Patient Concerns: An 85-year-old Japanese man was hospitalized due to pulmonary consolidations just below the pleura in chest computed tomography while being treated with antibiotics. Previously, an upper lobectomy of the right lung was performed for an upper lung mucinous adenocarcinoma, and he was diagnosed with chronic obstructive pulmonary disease. Although he took antibiotics before admission, C-reactive protein levels were elevated., Diagnosis: IgG4 levels were also elevated (IgG4; 733 mg/dL), and lung biopsy histology showed an abundance of IgG4-positive plasma cell infiltration; about 40% of the affected area was occupied by such infiltration. Based on such findings, we finally diagnosed him as IgG4-RLD., Interventions: We administered 20 mg/d prednisolone., Outcomes: About 2 weeks after administration of prednisolone by intravenous injection, his multifocal pulmonary consolidations just below the pleura were markedly improved and his pulmonary symptoms disappeared. Four weeks after glucocorticoid therapy, IgG4 levels decreased from 831 mg/dL (peak) to 547 mg/dL., Lessons: We should consider IgG4-RLD, a rare disease, when lesions are detected as pulmonary consolidations near the pleura and are unresponsive to antibiotic therapy. Glucocorticoid therapy, however, is very effective for such IgG4-RLD., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Allergen-specific sublingual immunotherapy (SLIT) is a potentially effective disease-modification treatment for patients with allergic asthma. Because CD44 signaling enhances regulatory T (Treg) cell-induction, administering CD44 ligands such as hyaluronan (HA) with allergen-specific SLIT may enhance the therapeutic effects. We evaluated the role of CD44 in Treg cell-induction in T helper type 2 (Th2)-mediated chronic airway inflammation using CD44-/- mice and the efficacy of HA on SLIT in a Dermatophagoides farinae (Df)-induced murine model of chronic asthma. Th2 responses and Treg cell induction were evaluated in CD44-/- mice. We devised a new SLIT model of Df-induced chronic asthma utilizing HA as an adjuvant. The effects of HA added to the new SLIT model were evaluated by the early asthmatic response (EAR) and airway hyperresponsiveness (AHR), eosinophilic airway inflammation, and serum Df-specific IgE levels. Th2-mediated chronic eosinophilic airway inflammation was worse in CD44-/- mice compared with Df-sensitized wild-type (WT) mice. HA enhanced the effect of Df-induced Treg cells in a CD44-dependent manner. Sublingual Df treatment in combination with HA, but not alone, normalized EAR and AHR, and significantly reduced the serum IgE levels and the bronchoalveolar lavage fluid (BALF) eosinophil number. HA also induced Treg cells in a Df-sensitized spleen cell culture in a CD44-dependent manner. The treatment-enhancing effects of HA in this SLIT model were diminished in CD44-/- mice. CD44 is a key contributor to Treg cell induction and critical for the enhancing effects of HA in a Df-induced murine model of chronic asthma., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A 61-year-old woman was transferred with a complaint of a fever and productive cough. She had tested positive for Mycobacterium avium and Nocardia cyriacigeorgica at least twice, and Streptococcus pneumonia (PISP) was isolated (3+) from her purulent sputum. As radiological findings, a lower lung field-dominant infiltration shadow and nodular shadow with cavity were recognized in the bilateral lung fields. We diagnosed her with pneumococcal pneumonia co-infection with M. avium and N. cyriacigeorgica. She was treated with MEPM for pneumococcal pneumonia, a standard regimen containing clarithromycin for pulmonary M. avium complex (MAC) disease, and sulfamethoxazole/trimethoprim for pulmonary nocardiosis. She improved with appropriate treatment.

The prevalence of sleep-disordered breathing (SDB) is reportedly very high. Among SDBs, the incidence of obstructive sleep apnea (OSA) is higher than previously believed, with patients having moderate-to-severe OSA accounting for approximately 20% of adult males and 10% of postmenopausal women not only in Western countries but also in Eastern countries, including Japan. Since 1998, when health insurance coverage became available, the number of patients using continuous positive airway pressure (CPAP) therapy for sleep apnea has increased sharply, with the number of patients about to exceed 500,000 in Japan. Although the "Guidelines for Diagnosis and Treatment of Sleep Apnea Syndrome (SAS) in Adults" was published in 2005, a new guideline was prepared to indicate the standard medical care based on the latest trends, as supervised by and in cooperation with the Japanese Respiratory Society and the "Survey and Research on Refractory Respiratory Diseases and Pulmonary Hypertension" Group, of Ministry of Health, Labor and Welfare and other related academic societies, including the Japanese Society of Sleep Research, in addition to referring to the previous guidelines. Since sleep apnea is an interdisciplinary field covering many areas, this guideline was prepared including 36 clinical questions (CQs). In the English version, therapies and managements for SAS, which were written from CQ16 to 36, were shown. The Japanese version was published in July 2020 and permitted as well as published as one of the Medical Information Network Distribution Service (Minds) clinical practice guidelines in Japan in July 2021., Competing Interests: Conflict of interestYuichi Inoue is receiving daily allowances (lecture fees, etc.) from Alfresa Pharma Corporation, Eisai Corporation, MSD Corporation, Takeda Pharmaceutical Company Limited, along with research expenses from Astellas Pharma Corporation, Eisai Corporation, Takeda Pharmaceutical Company Limited, and Jassen Pharmaceutical K,K. He is also affiliated with the donated courses provided by Astellas Pharma Corporation, Alfresa Pharma Corporation, Eisai Corporation, MSD Corporation, Otsuka Pharmaceutical Co., Ltd., Koike Medical Co., Ltd., Takeda Pharmaceutical Company Limited, and Philips Japan, Ltd. Naohisa Uchimura is receiving daily allowances (lecture fees, etc.) from Eisai Co., Ltd., MSD Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Mitsubishi Electric Co., Ltd., and Meiji Seika Furuma Co., Ltd.; manuscript fees from Eisai Co., Ltd., MSD Co., Ltd. and Otsuka Pharmaceutical Co., Ltd.; and scholarship (incentives) donations from Eisai Co., Ltd., MSD Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and Pfizer Japan Inc. Takatoshi Kasai is receiving research funding from Asahi Kasei Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Paramount Bed Co., Ltd., and ResMed Co., Ltd., along with scholarship (incentives) donations from Philips Japan Co., Ltd. He is also affiliated with the donated courses provided by Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and ResMed Co., Ltd. Fusae Kawana is an officer of the Japan Sleep Comprehensive Examination Association, and is affiliated with the donated courses provided by Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and ResMed Co., Ltd. Shigeru Sakurai is receiving scholarship (incentives) donations from Philips Japan, Ltd. and Kitara Co., Ltd. Takeshi Tanigawa is receiving research funding from Tokyo Electric Power Company Holdings, Inc. Kazuo Chin is receiving daily allowances (lecture fees, etc.) from Philips Japan, Ltd. and Teijin Home Medical Care, and is affiliated with the donated courses provided by Teijin Pharma Limited, Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and ResMed Co., Ltd. Morio Tonogi is receiving research funding from GC Ortholy Corporation. Takeo Nakayama is receiving daily allowances (lecture fees, etc.) from Nippon Boehringer Ingelheim Co., Ltd., Pfizer Co., Ltd., and Janssen Pharmaceutical K.K., as well as receiving scholarship (incentives) donations from JMDC Co., Ltd. Motoo Yamauchi is receiving research funding from Koike Medical Co., Ltd. Toru Oga is affiliated with the donated courses provided by Teijin Pharma Limited, Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and Fukuda Lifetech Keiji Co., Ltd. Yasuhiro Tomita is affiliated with the donated courses provided by Teijin Pharma Limited, Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and ResMed Co., Ltd. Satoshi Hamada is affiliated with a donated course provided by Teijin Pharma Limited. Kimihiko Murase is affiliated with the donated courses provided by Teijin Pharma Limited, Philips Japan, Ltd., Fukuda Denshi Co., Ltd., Fukuda Lifetech Keiji Co., Ltd., and ResMed Co., Ltd. Makoto Uchiyama is receiving daily allowances (lecture fees, etc.) from Eisai Co., Ltd., MSD Co., Ltd., and Takeda Pharmaceutical Company Limited, along with scholarship (incentives) donations from Eisai Co., Ltd. and Meiji Seika Pharma Co., Ltd. Hiromasa Ogawa is affiliated with a donated course provided by Fukuda Lifetech Co., Ltd. Kazuo Mishima is receiving daily allowances (lecture fees, etc.) from Eisai Co., Ltd., MSD Co., Ltd., and Takeda Pharmaceutical Company Limited; research funds from Taisho Pharmaceutical Co., Ltd. and Nobelpharma Co., Ltd.; and scholarship (incentives) donations from Eisai Co., Ltd. and Takeda Pharmaceutical Company Limited. Tsuneto Akashiba, Motoharu Ohi, Misa Takegami, Ryo Tachikawa, Shintaro Chiba, Satoru Tsuiki, Hiroshi Nakamura, Koji Narii, Asako Yagi, Yoshihiro Yamashiro, Masahiro Yoshida, Hiroyuki Mori, Hiroo Wada, Kazumichi Sato, Seiichi Nakata, and Shinichi Momomura have no COIs to declare., (© The Author(s) 2021.)

Background: Interleukin (IL)-5 is essential for allergen induced eosinophilic airway inflammation, but not activation of T helper type 2 (Th2) cells in the lung. Although an excessive Th2 reaction is observed without IL-5 signaling, the mechanisms have remained unknown., Objective: To evaluate the negative-feedback mechanism in eosinophilic airway inflammation, we examined IL-33 triggered eosinophilic airway inflammation in IL-5Rα-/- mice., Methods: Mice were administered intranasal IL-33 for 3 days. Airway hyperresponsiveness (AHR) was evaluated and bronchoalveolar lavage (BAL) was performed 24 h after the last IL-33 treatment. The number of inflammatory cells and cytokine levels in the BAL fluid (BALF) were analyzed, and histologic examination was performed., Results: Compared with IL-33 treated wild-type (WT) mice, intranasal administration of IL-33 in IL-5Rα-/- mice reduced eosinophilic airway inflammation, AHR, and basement membrane thickening, while we found excessive IL-33 induced IL-5 and IL-13 production in the airway without IL-5 signaling. The numbers of eosinophils with a ringshaped nucleus (resident) and segmented nucleus (inflammatory) were increased in WT mice, but not in IL-5Rα-/- mice following intranasal administration of IL-33, and the numbers of SiglecF-positive eosinophils with (resident) or without (inflammatory) expression of CD62L were also significantly increased by IL-33 treatment in WT mice, but not in IL5Rα-/- mice. The number of ILC2 cells in the BALF was significantly higher in IL-33 treated IL-5Rα-/- mice than in IL-33 treated WT mice., Conclusions: These findings suggest the possibility that IL-5 induced eosinophils contribute to the negative-feedback mechanisms in IL-33 induced ILC2 mediated airway inflammation.

Introduction: The Dyspnoea-12 (D-12) is a brief, easy to complete questionnaire for measuring breathlessness., Objectives: To facilitate further efforts to measure dyspnoea in real clinical settings, the authors aimed to develop and validate a Japanese version of the D-12 and also compare the D-12 with the Baseline Dyspnea Index (BDI) and the Activity component of the St. George's Respiratory Questionnaire (SGRQ)., Methods: The standardized procedure in accordance with international guidelines was used to create the translation. A validation study with a cross-sectional observational design was conducted on 122 subjects with stable chronic obstructive pulmonary disease (COPD)., Results: The internal consistency of the D-12 was high (Cronbach's coefficient α = 0.883) and similar to that of the BDI (α = 0.824) and SGRQ Activity (α = 0.872). The relationships between tools were statistically significant (|R s | = 0.53 to 0.66). Although the scores obtained from all three tools were skewed toward the milder end of the respective scales, this deviation was most prominent in the D-12 with a floor effect of 48.4%., Conclusion: The Japanese version of the D-12 was successfully validated, but we should be careful of any floor effect and marked skew to the mild end of the scale, especially in subjects with mild COPD., (© 2021 John Wiley & Sons Ltd.)

Background/aim: We evaluated the efficacy of "the tumor immune microenvironment (TIME) classification" for predicting clinical response to immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC). In addition, we aimed to evaluate the "modified TIME classification", which adds the vascular endothelial growth factor (VEGF) status to TIME., Materials and Methods: Programmed cell death receptor ligand-1 (PD-L1), CD8 T cell tumor-infiltrating lymphocytes (CD8+TILs) count and VEGF expression analyses were performed using immuno - histochemistry in 44 patients who had undergone ICI monotherapy., Results: Regarding TIME classification, type-I (PD-L1 high and CD8+TILs high) had a significantly higher response than the other types. Using the modified TIME classification, type-IA (PD-L1 high, CD8+TILs high, and VEGF low) had a significantly higher response than the other types., Conclusion: The modified TIME classification, which adds tumor VEGF expression to "the TIME classification", could be useful in predicting clinical response to ICI monotherapy., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: To determine the incidence and factors associated with lens opacity after lens-sparing vitrectomy (LSV) for retinopathy of prematurity (ROP)., Design: Retrospective, comparative case series., Participants: Among the 141 eyes of 94 patients who underwent LSV for ROP between 2006 and 2019, 108 eyes of 71 patients with a minimum follow-up of 12 months after LSV were investigated., Methods: Data were collected from patients' charts, including gender, gestational age at birth, birth weight, stage of ROP, postmenstrual age (PMA) at LSV, surgical procedure, preoperative injection of anti-vascular endothelial growth factor (VEGF) agents, subsequent retinal surgeries, and lensectomy during follow-up., Main Outcome Measures: Lens status at last visit, incidence and timing of lensectomy, and risk factors for lens opacity requiring lensectomy., Results: Stages of ROP at LSV were 4A, 4B, and 5 in 92 eyes, 13 eyes, and 3 eyes, respectively. The median PMA at LSV was 40.6 weeks. Thirty-two eyes received anti-VEGF therapy before LSV. Lens opacity was found in 17 eyes (15.7%), of which 10 eyes (9.3%) underwent lensectomy. The period between LSV and lensectomy ranged from 21 days to 131.9 months (median, 21.1 months). Eleven other eyes (10.2%) underwent lensectomy as part of a reoperation for worsening of ROP. A total of 80 eyes (74.1%) preserved clear lenses at the latest follow-up examination after surgery (median, 6.8 years; range, 1-14 years). The Kaplan-Meier estimate showed that the proportion of patients with phakia at 5 and 10 years was 92.4% and 89.0%, respectively. Multivariate Cox regression analysis revealed that eyes with the use of tamponade at LSV (P = 0.005; odds ratio [OR], 25.68; 95% confidence interval [CI], 4.187-157.5) and young PMA at LSV (P = 0.033; OR, 1.047; 95% CI, 1.012-1.099) were associated significantly with lens opacity requiring lensectomy. However, anti-VEGF therapy was not associated with lens opacity requiring lensectomy., Conclusions: Nearly 10% of eyes required lensectomy because of lens opacity after LSV for ROP. The development of lens opacity requiring lensectomy seems to be associated with the use of tamponade and young PMA at LSV., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)