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Background: The coronavirus disease 2019 pandemic prompted healthcare providers to use different approaches from the current standards of care. We aimed to identify the changes in the number of treatments for primary non-small cell lung cancer (NSCLC) and metastatic lung cancer during the pandemic., Methods: We used nationwide insurance claims data from January 2015 to January 2021, and estimated changes in the number of treatments using an interrupted time series analysis., Results: The number of surgical resections for primary NSCLC significantly decreased in April 2020 (-888; 95% confidence interval [CI]: -1530 to -246) and July 2020 (-1314; 95% CI: -1935 to -694), while the number of stereotactic body radiotherapies (SBRTs) increased in April 2020 (95; 95% CI: 8-182) and July 2020 (111; 95% CI: 24-198). The total number of treatments for primary NSCLC remained unchanged; however, non-significant decreases were observed in 2020. The number of surgical resections for metastatic lung cancer significantly decreased in April 2020 (-201; 95% CI: -337 to -65), but it eventually increased in July 2020 (170; 95% CI: 32-308). Additionally, the number of SBRTs significantly increased in April 2020 (37; 95% CI: 3-71) and October 2020 (57; 95% CI: 23-91). The total number of treatments for metastatic lung cancer was maintained, with an initial decrease in April 2020 followed by a subsequent increase in July and October 2020., Conclusion: In Japan, surgical triage for primary and metastatic lung cancer are likely to have been implemented during the pandemic. Despite these proactive measures, patients with primary NSCLC may have been untreated, likely owing to their undiagnosed disease, potentially leading to a deterioration in prognosis. By contrast, patients diagnosed with cancer prior to the pandemic are presumed to have received standard management throughout the course of the pandemic., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Maintaining good asthma control minimizes the risk of exacerbations and lung function decline and is a primary goal of asthma management. The Japanese Pediatric Asthma Guidelines (JPGL) employs different classification criteria for control status from other guidelines, stressing a higher level of control. Based on JPGL, we previously developed a caregiver-completed questionnaire for assessing and achieving best asthma control in preschoolers. In this study, we aimed to develop a questionnaire for school-age children and adolescents., Methods: A working questionnaire comprising 14 items for patients and 34 items for caregivers was administered to 362 asthma patients aged 6-15 years and their caregivers. Separately, physicians filled out a questionnaire to determine JPGL-defined control. Logistic regression analysis was performed to construct a model to predict control levels using data from a randomly selected set of completed questionnaires from two-thirds of the subjects. Validation was performed using the remaining questionnaires., Results: A set of 7 questions, encompassing self-assessed control status at the time of the visit and in the past month, and nocturnal/early morning asthma symptoms for patients and frequency of asthma symptoms, dyspnea, rescue beta-agonist use, and asthma hospitalization for caregivers, were selected and the 7-item model showed a good statistical fit with AIC of 110.5. The model has been named the Best Asthma Control Test for School Children and Adolescents (Best ACT-S). Best ACT-S scores differed significantly in the hypothetical direction among the groups of different JPGL-defined control levels, step-up/down treatment decisions, and presence/non-presence of exacerbations in the previous year., Conclusions: The Best ACT-S is a valid questionnaire for children/adolescents aiming for best asthma control., (Copyright © 2023 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background: Patients with idiopathic interstitial pneumonia (IIP) have a favourable prognosis when they have interstitial pneumonia with autoimmune features (IPAF). However, precise IPAF-related findings from high-resolution computed tomography (HRCT) and lung histopathological specimens and the treatment response have not been fully determined. Therefore, this study was conducted to evaluate the relationship between findings on HRCT or lung histopathological specimens and the progression of interstitial pneumonia in patients with IPAF., Methods: This multicentre cohort study prospectively enrolled consecutive patients with IIP. At the diagnosis of IIP, we systematically evaluated 74 features suggestive of connective tissue diseases and followed them up. HRCT, lung specimens, serum antibodies, and the clinical course were also evaluated., Results: Among 222 patients with IIP, 26 (11.7%) fulfilled the IPAF criteria. During a median observation period of 36 months, patients with IPAF showed better survival than those without IPAF (p = 0.034). While histopathological findings were not related to IPAF, nonspecific interstitial pneumonia (NSIP) with organizing pneumonia (OP) overlap was the most prevalent HRCT pattern (p < 0.001) and the consolidation opacity was the most common radiological finding in IPAF (p = 0.017). Furthermore, in patients with IPAF, the diagnosis of COP or NSIP with OP overlap was associated with a higher increase in %FVC in 1 year than in those with idiopathic pulmonary fibrosis, NSIP, or unclassifiable IIP (p = 0.002)., Conclusions: This study shows the presence of consolidation opacity on HRCT and the diagnosis of COP or NSIP with OP overlap are associated with IPAF and its favourable treatment response in patients with IPAF., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Noriyuki Enomoto received funding from Boehringer Ingelheim Japan Co., Ltd. All of other authors did not receive funding., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Antifibrotic therapy is widely used for patients with progressive fibrotic interstitial lung disease (ILD), regardless of etiology. There is an urgent need for a simple, inexpensive, and repeatable biomarker to evaluate disease severity and mortality risk., Methods: This retrospective multicohort study assessed the neutrophil-lymphocyte ratios (NLRs) of 416 patients with ILD who received antifibrotic therapy (Hamamatsu cohort, n = 217; Seirei cohort, n = 199). The mortality risk vs. NLR relationship was evaluated at therapy initiation and 1 year. The optimal NLR cutoff of 2.7 was selected according to the mortality risk., Results: Survival was shorter in patients with high NLR than with low NLR (median: 2.63 vs. 4.01 years). The NLR classification results (cutoff: 2.7) were longitudinally preserved in >70 % of the patients, and patients with consistently high NLR had a higher risk of mortality than others (median, 2.97 vs. 4.42 years). In multivariate analysis, high NLR was significantly associated with mortality independent of age, sex, forced vital capacity, lung diffusing capacity for carbon monoxide (D LCO ), or the gender-age-physiology (GAP) index. A combined GAP index-NLR assessment classified mortality risk into four groups. Subset analyses revealed that NLR assessment was more applicable to patients without advanced disease, not taking steroids, and with idiopathic pulmonary fibrosis (IPF) than to patients with advanced disease, taking steroids, and patients with Non-IPF., Conclusion: High NLR was associated with an increased mortality risk in patients with ILDs receiving antifibrotic therapy. Assessment of NLR may help predict disease severity and mortality risk in antifibrotic therapy., Competing Interests: Declaration of competing interest The authors declare that no competing interests exist., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Oral immunotherapy (OIT) can ameliorate cow's milk allergy (CMA); however, the achievement of sustained unresponsiveness (SU) is challenging. Regarding the pathogenesis of CMA, recent studies have shown the importance of gut microbiota (Mb) and fecal water-soluble metabolites (WSMs), which prompted us to determine the change in clinical and gut environmental factors important for acquiring SU after OIT for CMA., Methods: We conducted an ancillary cohort study of a multicenter randomized, parallel-group, delayed-start design study on 32 school-age children with IgE-mediated CMA who underwent OIT for 13 months. We defined SU as the ability to consume cow's milk exceeding the target dose in a double-blind placebo-controlled food challenge after OIT followed by a 2-week-avoidance. We longitudinally collected 175 fecal specimens and clustered the microbiome and metabolome data into 29 Mb- and 12 WSM-modules., Results: During OIT, immunological factors improved in all participants. However, of the 32 participants, 4 withdrew because of adverse events, and only 7 were judged SU. Gut environmental factors shifted during OIT, but only in the beginning, and returned to the baseline at the end. Of these factors, milk- and casein-specific IgE and the Bifidobacterium-dominant module were associated with SU (milk- and casein-specific IgE; OR for 10 kU A /L increments, 0.67 and 0.66; 95%CI, 0.41-0.93 and 0.42-0.90; Bifidobacterium-dominant module; OR for 0.01 increments, 1.40; 95%CI, 1.10-2.03), and these associations were observed until the end of OIT., Conclusions: In this study, we identified the clinical and gut environmental factors associated with SU acquisition in CM-OIT., (Copyright © 2023 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Objectives: Cetuximab-based chemotherapy is a standard 1st-line treatment for recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). However, few studies have reported survival data for a treatment sequence consisting of a PCE regimen (paclitaxel + carboplatin + cetuximab) followed by an immune checkpoint inhibitor., Materials and Methods: We retrospectively assessed 37 patients with R/M SCCHN from the oral cavity, oropharynx, hypopharynx, and larynx who received PCE as 1st-line treatment followed by nivolumab as 2nd-line at the National Cancer Center Hospital East between December 2016 and July 2021. For comparison, we also analyzed 14 patients who did not receive nivolumab after PCE., Results: Of the 37 patients who received nivolumab, overall response rate (ORR) by PCE was 48.6%, and median time to response and median progression-free survival (PFS) were 2.1 months (range: 0.8-4.8) and 4.4 months, respectively. In the nivolumab phase, ORR was 10.8%. 23 patients received 3rd-line therapy. Median PFS2, PFS3, and overall survival (OS) were 6.8, 11.6, and 19.5 months, respectively. Subgroup analysis by PD-L1 expression showed no significant difference in OS. Analysis of the comparison group revealed a trend toward improved OS in those who received nivolumab compared to those who did not (HR 0.47, 95%CI [0.19-1.13], p = 0.084)., Conclusion: PCE followed by nivolumab shows a favorable survival outcome, representing the potential for rapid tumor response with PCE and extension of OS by the addition of nivolumab regardless of combined positive score., 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 Ltd. All rights reserved.)

Background: Although remote monitoring (RM) after pacemaker implantation is common, its cost-effectiveness has not been fully investigated. Therefore, we assessed the cost-effectiveness of RM compared with conventional follow-up (CFU) in Japanese patients with pacemakers., Methods: A Markov model was constructed to analyze costs and quality-adjusted life years after pacemaker implantation. The target population was Japanese patients implanted with a dual-chamber pacemaker for bradycardia. Transition probabilities (e.g. atrial fibrillation, stroke, and device trouble) were obtained from literature and expert sources. Additionally, stroke risk was determined according to anticoagulation and CHADS 2 scores. We used a 10-year horizon with sensitivity analyses for significant variables., Results: Compared to CFU, RM was more effective; however, it was also more expensive. When the range of the Japanese willingness-to-pay threshold was considered to be ¥5,000,000, RM was at least cost-neutral relative to the CFU in all elderly patients with pacemakers for bradycardia. The cost-effectiveness of RM relative to CFU could be higher for patients with high CHADS 2 scores, especially in patients with a CHADS 2 score ≥ 3. Scenario analyses changing the interval between visits to an in-office evaluation in the CFU also demonstrated the same conclusions. In particular, when the interval between office visits was 1 year for the CFU, the RM could be more cost-effective., Conclusions: This study demonstrated that RM can be a cost-effective option for Japanese patients, especially those with high CHADS 2 scores and long-term intervals between office visits., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Knee arthroscopy is a minimally invasive surgical technique that allows surgeons to diagnose and treat various knee conditions using much smaller incisions than open surgery. However, it is difficult to fully visualize the posterior compartment of the knee joint using the usual anterior portal approach because of blind spots. The transseptal portal technique enables surgeons to visualize the surgical field and access instruments in the posterior compartment of the knee during arthroscopic surgery. However, creation of the posterior transseptal portal increases the risk of neurovascular injury. Particular attention should be paid to avoid damaging the saphenous nerve, common peroneal nerve, popliteal artery, and tibial nerve. Here, we describe an ultrasonography-guided surgical method for creating the posterior transseptal portal by confirming the surrounding anatomy., (© 2023 The Authors.)

Background: The coronavirus disease 2019 (COVID-19) pandemic forced us to accept changes in our usual diagnostic procedures and treatments for colorectal cancer. This study aimed to determine the impact of the pandemic on colorectal cancer treatment in Japan., Methods: The number of colorectal surgeries, stoma constructions, stent placements or long tube insertions, and neoadjuvant chemoradiotherapies were determined each month using sampling datasets from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. The observation periods before and during the pandemic were January 2015 to January 2020 and April 2020 to January 2021, respectively. An interrupted time-series analysis was used to estimate the changes in the number of procedures during the pandemic., Results: The number of endoscopic surgeries for colon cancer significantly decreased in April and July 2020 and for rectal cancer in April 2020. Additionally, the number of laparoscopic and open surgeries for colon cancer significantly decreased in July 2020 and October 2020, respectively. The number of stoma constructions and stent placements or long tube insertions did not increase during the observation period. Neoadjuvant chemoradiotherapy for rectal cancer significantly increased in April 2020 but levels returned shortly thereafter. These results suggest that the recommendations to overcome the pandemic proposed by expert committees, including the replacement of laparoscopic surgery with open surgery, stoma construction to avoid anastomotic leak, and replacement of surgery on the ileus with stent placement, were not widely implemented in Japan. However, as an exception, neoadjuvant chemoradiotherapy for rectal cancer was performed as an alternative treatment to delay surgery in small quantities., Conclusion: A declining number of surgeries raises concerns about cancer stage progression; however, we found no evidence to suggest cancer progression from the trajectory of the number of stoma constructions and stent placements. In Japan, even during the pandemic, conventional treatments were performed., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The diagnosis and management of myocardial infarction are increasingly complex, and establishing the presence of intracoronary thrombosis has major implications for both the classification and treatment of myocardial infarction., Objectives: The aim of this study was to investigate whether positron emission tomographic (PET) and computed tomographic (CT) imaging could noninvasively detect in vivo thrombus formation in human coronary arteries using a novel glycoprotein IIb/IIIa receptor antagonist-based radiotracer, 18 F-GP1., Methods: In a single-center observational case-control study, patients with or without acute myocardial infarction underwent coronary 18 F-GP1 PET/CT angiography. Coronary artery 18 F-GP1 uptake was assessed visually and quantified using maximum target-to-background ratios., Results: 18 F-GP1 PET/CT angiography was performed in 49 patients with and 50 patients without acute myocardial infarction (mean age: 61 ± 9 years, 75% men). Coronary 18 F-GP1 uptake was apparent in 39 of the 49 culprit lesions (80%) in patients with acute myocardial infarction. False negative results appeared to relate to time delays to scan performance and low thrombus burden in small-caliber distal arteries. On multivariable regression analysis, culprit vessel status was the only independent variable associated with higher 18 F-GP1 uptake. Extracoronary cardiac 18 F-GP1 findings included a high frequency of infarct-related intramyocardial uptake (35%) as well as left ventricular (8%) or left atrial (2%) thrombus., Conclusions: Coronary 18 F-GP1 PET/CT angiography is the first noninvasive selective technique to identify in vivo coronary thrombosis in patients with acute myocardial infarction. This novel approach can further define the role and location of thrombosis within the heart and has the potential to inform the diagnosis, management, and treatment of patients with acute myocardial infarction. (In-Vivo Thrombus Imaging With 18 F-GP1, a Novel Platelet PET Radiotracer [iThrombus]; NCT03943966)., Competing Interests: Funding Support and Author Disclosures The Edinburgh Clinical Research Facilities and Edinburgh Imaging facility is supported by the National Health Service Research Scotland through the National Health Service Lothian Health Board. This work was supported by several grant funding organizations. Drs Tzolos (FS/CRTF/20/24086), Williams (FS/ICRF/20/26002, FS/11/014, and CH/09/002), Newby (CH/09/002, RG/16/10/32375, and RE/18/5/34216), and Dweck (FS/14/78/31020) are supported by the British Heart Foundation. Dr Newby is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA). Dr van Beek is supported by the Scottish Imaging Network: A Platform of Scientific Excellence. Dr Mills is supported by the British Heart Foundation through the award of Personal Chair and a Programme Grant (CH/F/21/90010 and RG/20/10/34966). Dr Dweck is supported by the Sir Jules Thorn Biomedical Research Award 2015 (15/JTA). Dr Slomka and FusionQuant analysis tools are supported by National Heart, Lung, and Blood Institute grant 5R01HL135557. Dr Dey and Autoplaque analysis tools are supported by National Heart, Lung, and Blood Institute grant 1R01HL148787-01A1. Drs Koglin and Stephens are employees of Life Molecular Imaging, which provided reagents for radiotracer production. Dr Williams is a member of the Speakers Bureau for Canon Medical Systems. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Information on changes in asthma prevalence and the treatment status for asthma is used as basic information for taking medical and administrative measures against asthma. However, this information among adults is relatively limited., Methods: To elucidate changes in the prevalence of asthma and treatment status over time among Japanese adults, health insurance claim data from some health insurance societies covering salaried employees and their dependents were studied longitudinally. Claim data from FY1999 to 2007 were obtained from two health insurance societies, and data from FY 2011 to 2019 were obtained from three different health insurance societies, and changes in standardized asthma prevalence among subjects aged 20-59 years, proportion of asthma patients prescribed ICS, leukotriene receptor antagonist (LTRA), and LABA, and the mean number of acute asthma exacerbations per year were analyzed., Results: The prevalence of asthma increased from 1.6% in 1999 to 3.0% in 2007 and 2.9% in 2011 to 4.6% in 2019. Increased trends in asthma prevalence from 2011 to 2019 were more noticeable in subjects in their 50s than those in their 20s for both sexes. The number of emergency visits related to asthma was 1.5 per year in 1999, which decreased to 0.8 per year in 2019. The proportion of people prescribed all anti-asthma medications (ICS, LTRA, and LABA) increased over time., Conclusions: The prevalence of adult asthma among Japanese salaried employees and their dependents has increased over the last 20 years, suggesting more attention should be paid to the prevention of this disease in adults., (Copyright © 2022 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

High pressure is known to dissociate several oligomeric proteins, and regarded as an important tool to shift the oligomerization equilibrium. Native polyacrylamide gel electrophoresis (native PAGE) at high pressure can characterize the dissociates and clearly discriminate the aggregates. However, a band smearing of migration profiles often hinders more detailed analyses (Miwa et al., High Pressure Res. (2019) 39, 218-224). In this paper, we focused on the band smearing dependent on the migration velocity so as to extract both thermodynamic and kinetic parameters. We systematically perturbed the migration velocity by changing the gel concentration and carried out numerical analysis for a series of the migration profiles based on a simple dissociation reaction scheme with limited thermodynamic and kinetic parameters. Then, complete volumetric properties on oligomerization process can be available. We term the present analysis method as a high-pressure native PAGE velocity method. We also report the application of this method to revisit the pressure dissociation of tetrameric lactate dehydrogenase (LDH) from pig heart., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Safety and efficacy data for dupilumab beyond 1 year are lacking for patients from Japan with moderate-to-severe asthma., Methods: The TRAVERSE open-label extension (OLE) study (NCT02134028) assessed the safety and efficacy of dupilumab 300 mg every 2 weeks up to 96 weeks in 2282 patients who completed a previous dupilumab asthma study. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary endpoints included annualized severe exacerbation rate and change from parent study baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV 1 ), asthma control, quality of life, and blood eosinophil levels. Anti-drug antibodies (ADA) were evaluated. We report results in 160 (7.8% of exposed population) patients recruited from Japanese centers with non-oral corticosteroid (OCS)-dependent asthma rolled over from two parent studies, and in subgroups with a type 2 inflammatory phenotype., Results: TEAEs were consistent with the parent studies and the known safety profile of dupilumab. One patient permanently discontinued treatment due to TEAEs. Exacerbation rates remained low and were sustained to Week 96, as were improvements in pre-bronchodilator FEV 1 . Rapid, sustained improvements were observed in dupilumab-treated patients who previously received placebo in a parent study, while further improvements in exacerbation rates, asthma control, and asthma-related quality of life were observed in those continuing dupilumab. Blood eosinophil levels decreased progressively while on treatment. Treatment-emergent ADA responses were highest in patients who had previously received placebo. Efficacy results were consistent in patients with a type 2 phenotype., Conclusions: Long-term dupilumab treatment was well tolerated and efficacious in patients with non-OCS-dependent, moderate-to-severe asthma recruited from Japan. (Funded by Sanofi and Regeneron Pharmaceuticals, Inc.; ClinicalTrials.gov identifier, NCT02134028)., (Copyright © 2022 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background: Despite the rapid widespread use of a high-flow nasal cannula (HFNC) during the COVID-19 pandemic, its indications and appropriate use as perceived by physicians remain poorly known., Methods: In September 2021, we sent a questionnaire to each respiratory physician from 15 institutions in Shizuoka prefecture, Japan. In this survey, we compared the perceptions of HFNC indications and interventions during implementation to those of non-invasive ventilation (NIV) and invasive mechanical ventilation (IMV). Furthermore, this study examined concerns about SARS-CoV-2 infection spread and psychological distress experienced among respondents., Results: Of the 140 respiratory physicians contacted, 87 (62.1%) completed the survey. The results indicate that 96.5% of the respondents agreed with the indication of HFNC for COVID-19, whereas only 13.7% agreed with NIV. The physicians reported that patients with HFNC had a lower frequency of sustained sedation, physical restraint, and implementation in the ICU than that of patients with NIV and IMV. The HFNC was introduced as a respiratory modality following conventional oxygen therapy (COT) in patients with COVID-19, regardless of full or do-not-intubate codes. Additionally, they reported that patients with COVID-19 switched from COT to HFNC significantly earlier than those without COVID-19. Simultaneously, this survey revealed persistent concerns of SARS-CoV-2 infection spread and psychological distress (47.1% and 53.3%, respectively) among respiratory physicians during HFNC use., Conclusion: Clinically, HFNC is considered useful for COVID-19 patients by most respiratory physicians. However, HFNC remains a concern for COVID-19 spread and psychological distress among several respiratory physicians, indicating the need for urgent action., Competing Interests: Conflict of interest All authors declare no actual or potential conflicts of interest., (Copyright © 2022 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

This is an abridged edition of English version of the Clinical Practice Guidelines for the Management of Atopic Dermatitis 2021. Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. In Japan, from the perspective of evidence-based medicine, the current strategies for the treatment of AD consist of three primary measures: (i) use of topical corticosteroids, tacrolimus ointment, and delgocitinib ointment as the main treatment of the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling, and advice about daily life. In the present revised guidelines, the description about three new drugs, namely, dupilumab, delgocitinib, and baricitinib, has been added. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice., (Copyright © 2022 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

This article covers the salient and updated themes of the Japanese Pediatric Guidelines for the Treatment and Management of Asthma (JPGL) 2020 published by the Japanese Society of Pediatric Allergy and Clinical Immunology. In the 2020 guidelines, five new clinical questions (CQs) have been added to address the 12 CQs regarding the treatment of childhood asthma. "Infant and preschool asthma" is diagnosed when young children (<6 years of age) have three or more episodes of clear expiratory wheezing, which continue for more than 24 h, and symptom improvement can be observed after beta-2 agonist inhalation. In children without clear improvement, diagnostic therapeutic trial for the duration of 1 month with controller treatment can be used. Since long-term management is initiated, the treatment level is adjusted based on the current control status and the management of risk factors, with the provision for holistic care. This underscores the smooth transition of pediatric patients into adult services. There are several differences between the JPGL and the guidelines of other countries. Further evidence is obtained as the utility of the newly proposed management plans should be evaluated in the Japanese population., (Copyright © 2022 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Catheter ablation is widely used as first-line therapy for patients with impaired quality of life; however, whether catheter ablation improves survival and other outcomes in atrial fibrillation (AF) cases remains unclear., Objective: The purpose of this study was to evaluate whether catheter ablation reduces adverse clinical outcomes and improves patients' quality of life using data from a contemporary Japanese multicenter registry of patients with early-stage AF., Methods: The Keio Interhospital Cardiovascular Studies-Atrial Fibrillation registered 3318 patients with AF newly diagnosed at or referred to participating hospitals between 2014 and 2018. Propensity score matching based on 47 demographic variables was performed. We extracted 823 pairs who underwent catheter ablation or medical therapy alone. The primary outcome was the composite of all-cause death, stroke, bleeding events, and heart failure hospitalization during a 2-year follow-up period. Additionally, the Atrial Fibrillation Effect on QualiΤy-of-Life scores at baseline and 1-year follow-up were evaluated., Results: Within the matched cohort, the median time since AF diagnosis was 0.3 years (interquartile range [IQR] 0.1‒2.3 years), age was 67.0 years (IQR 59.0‒73.0 years), and the CHA 2 DS 2 -VASc score was 2.0 (IQR 1.0‒2.0). During a median follow-up period of 730 days (IQR 366‒731 days), patients who underwent catheter ablation had a lower risk of primary outcomes (hazard ratio 0.49; 95% confidence interval 0.30‒0.79; P = .004), with a significantly lower risk of heart failure hospitalization (hazard ratio 0.33; 95% confidence interval 0.14-0.77; P = .010) and improved Atrial Fibrillation Effect on QualiΤy-of-Life scores, than did those who received medical therapy., Conclusion: In patients with propensity score-matched, early-stage, real-world AF, catheter ablation was associated with a lower risk of adverse clinical events and improved quality of life as compared with medical therapy., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: In CheckMate 141, nivolumab significantly improved overall survival (OS) in patients with platinum-refractory recurrent or metastatic squamous cell carcinomas (R/M SCC) of the head and neck. However, reports on nivolumab for patients with non-SCC and/or a primary subsite excluded from CheckMate 141 are limited., Materials and Methods: We conducted a retrospective analysis of R/M head and neck cancer patients who received nivolumab. The study subject excluded patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx., Results: A total of 59 patients were included, consisting of 40 males and 19 females with a median age of 61 years. Half of the patients had non-SCC histology. The main primary site included the sinonasal cavity (n = 18), salivary gland (n = 15), and nasopharynx (n = 13). Three (6.0%) patients achieved a complete response and 5 (10.0%) a partial response, giving an overall response rate (ORR) of 16.6%. Median time-to-treatment failure (TTF) and OS were 3.7 and 16.2 months, respectively. Salivary gland and nasopharyngeal cancer achieved relatively higher ORR (25.0 and 36.4%, respectively). On analysis by primary site, nasopharyngeal cancer showed a significantly better TTF and OS than the other primary sites. On analysis by histological findings, no significant difference in TTF and OS was observed between non-SCC and SCC., Conclusion: Nivolumab for cancers involving the salivary gland/nasopharynx and non-SCC histology showed comparable efficacy to that in CheckMate 141. This result indicates that nivolumab may be effective even for patients not included in CheckMate 141., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Spontaneous osteonecrosis of the knee (SONK) causes acute atraumatic knee pain, and meniscus tears may be associated with the pathogenesis of SONK. The purpose of this study was to investigate the relationship of the type of meniscus tear and medial meniscus extrusion with SONK on the medial femoral condyle in patients who underwent surgical treatment with high tibial osteotomy due to severe knee pain., Methods: We enrolled 98 patients with 102 knees who underwent medial opening wedge high tibial osteotomy (OWHTO) under the diagnosis of medial femoral condyle osteonecrosis at our hospital from December 2003 to January 2020. Based on the Koshino classification, cases of SONK were classified as stage 1-4. The relationships of demographic data, X-rays and MRI images, including femorotibial angle (FTA), meniscus tear type, and medial meniscus extrusion (MME), with the stage and volume of SONK were investigated., Results: Ninety-eight patients (29 males and 69 females), with an average age at surgery of 69.2 ± 9.6 years and Body mass index(BMI) of 61.0 ± 17.6 kg/m 2 . In 102 cases of SONK, 11 knees, 18 knees, 46 knees, and 27 knees were classified as stage 1-4, respectively. The mean SONK volume was 2161.61 µm (range 95.67-7484.68 µm) on preoperative MRI. The preoperative FTA (mean 180.86°, range 172-187°) was not associated with the stage or volume of SONK. Meniscus tears were found in all cases of SONK and consisted of 2 degenerations, 2 horizontal tears, 0 vertical tears, 40 radial tears, 4 complex tears, and 54 medial meniscus posterior root tears (MMPRTs). In addition, 99% (101/102) of knees showed more than 3 mm of meniscus extrusion. Although the meniscus tear type was not associated with SONK stage, there was a high rate of tears that caused disruption of the hoop strain, such as MMPRTs (52.9%) or radial tears (39.2%). MME was significantly related to SONK volume (r = 0.387, p < 0.001)., Conclusion: All patients with SONK had coexisting meniscus tears, most menisci had medial extrusion, and a positive correlation was observed between MME and SONK volume., 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 © 2022 Elsevier B.V. All rights reserved.)

Hepatitis B virus (HBV) DNA is detectable in the nails and hair of patients with chronic HBV infection. However, it remains unclear whether HBV DNA can be detectable in the nails and hair of patients with acute HBV infection. We encountered two cases of children with acute HBV infection. HBV DNA in the nails and hair from the two children was evaluated by real-time PCR. To clarify the characteristics of HBV DNA, full-length HBV genome sequencing and phylogenetic tree analysis were performed. The levels of serum HBV DNA in children of cases 1 and 2 at day 0 were 7.6 Log IU/mL and 7.4 Log IU/mL, respectively. Nail HBV DNA was detected in both children (case 1: 4.6 Log IU/mL at day 0, case 2: 5.5 Log IU/mL at day 14). Moreover, hair HBV DNA was detectable in case 2 (4.0 Log IU/mL at day 14). Serum HBV DNA became undetectable within approximately 3-4 months after the first hospital visit. After the resolution of HBV viremia, nail and hair HBV DNA became undetectable. The sequence analysis of serum, nail and hair HBV DNA showed the same HBV genotype in each case (case1: genotype C, case 2: genotype A). In case 1, 3 nucleotides were different in the full-genome HBV sequence between the serum and nails. In case 2, the full-genome HBV sequences were identical among the serum, nails and hair. In conclusion, HBV DNA was detectable in nails and hair of children with acute HBV infection., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Combination therapy with dexamethasone, remdesivir, and baricitinib has become a promising treatment for moderate or severe COVID-19; however, we have observed transient leukocytopenia in COVID-19 patients who received combination therapy., Methods: Twelve consecutive COVID-19 patients treated with combination therapy were included in this retrospective analysis. Blood cell counts collected at the following three time points were analyzed: before the start of therapy (period 1), within 24 h of starting therapy (period 2), and within 48 h of period 2 (period 3)., Results: The leukocyte count significantly decreased in period 2 compared to period 1 and then significantly increased in period 3 without withdrawal of baricitinib. The neutrophil count transiently decreased in period 2 and recovered in period 3., Conclusions: Clinicians should be aware of transient leukocytopenia in patients with COVID-19 during the early phase of combination therapy., Competing Interests: Conflict of Interest The authors have no conflicts of interest to declare in relation to this work., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Introduction: Human norovirus (HuNoV) is a leading cause of infectious gastroenteritis. Since HuNoV shows resistance to alcohol, chlorine-based sanitizers are applied to decontaminate the virus on environmental surfaces. Chlorous acid water (CA) has been recently approved as a novel chlorine-based disinfectant categorized as a Type 2 OTC medicine in Japan. In this study, we aimed to evaluate the capability of CA to inactivate HuNoV., Methods: HuNoV (genogroups GII.2 and GII.4) was exposed to the test disinfectants including CA and sodium hypochlorite (NaClO), and the residual RNA copy was measured by reverse transcription quantitative PCR (RT-qPCR) after pretreatment with RNase. In addition, the log 10 reduction of HuNoV RNA copy number by CA and NaClO was compared in the presence of bovine serum albumin (BSA), sheep red blood cells (SRBC), polypeptone, meat extract or amino acids to evaluate the stability of these disinfectants under organic-matter-rich conditions., Results: In the absence of organic substances, CA with 200 ppm free available chlorine provided >3.0 log 10 reduction in the HuNoV RNA copy number within 5 min. Even under high organic matter load (0.3% each of BSA and SRBC or 0.5% polypeptone), 200 ppm CA achieved >3.0 log 10 reduction in HuNoV RNA copy number while less than 1.0 log 10 reduction was observed with 1,000 ppm sodium hypochlorite (NaClO) in the presence of 0.5% polypeptone. CA reacted with only cysteine, histidine and glutathione while NaClO reacted with all of the amino acids tested., Conclusions: CA is an effective disinfectant to inactivate HuNoV under organic-matter-rich conditions., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Idiopathic pulmonary fibrosis (IPF) is associated with a poor prognosis with variable clinical course. Early identification of patients at high risk for disease progression and death would lead to early therapeutic intervention and thereby improvement of outcomes. Cold-inducible RNA-binding protein (CIRBP) is produced in response to cellular stresses, which is implicated in multiple biological processes, including cell survival and proliferation., Research Question: Is CIRBP a useful biomarker for predicting the outcomes of patients with IPF?, Study Design and Methods: This study included 95 and 93 patients with IPF from two independent hospitals (derivation and validation cohorts, respectively). The associations of serum CIRBP level on IPF diagnosis with disease progression within 1 year after diagnosis (ie, ≥10% relative decline in percent predicted FVC or death) and all-cause mortality were retrospectively analyzed. Discrimination performances for predicting these outcomes were evaluated using the c-index., Results: Serum and lung tissue CIRBP levels were higher in patients with IPF than in control subjects. In the derivation cohort, the CIRBP high subgroup had significantly higher 1-year disease progression rates and lower cumulative survival rates than the CIRBP low subgroup, and the results were replicated in the validation cohort. In multivariate analyses, high serum CIRBP level was independently associated with higher 1-year disease progression and all-cause mortality rates in both cohorts. Combining the Gender-Age-Physiology (GAP) and serum CIRBP models improved the c-indexes for predicting 1-year disease progression and all-cause mortality compared with that of each model alone. The c-indexes of serum CIRBP were particularly high in patients with GAP stage I., Interpretation: This study successfully validated that serum CIRBP level was an independent predictor of 1-year disease progression and all-cause mortality in IPF. CIRBP is a promising biomarker that can help identify high-risk patients with IPF, especially in the early stage., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a devastating and life-threatening condition during its clinical course. Biomarkers for precisely anticipating the prognosis of AE-IPF remain to be fully established. The objective of this study was to clarify whether S100A8 and S100A9, which are calcium-binding proteins mainly produced by activated neutrophils, are significant prognostic biomarkers in AE-IPF., Methods: Thirty-seven patients with AE-IPF who were diagnosed and treated at our hospital were retrospectively evaluated. The serum levels of S100A8 and S100A9 were measured using enzyme-linked immunosorbent assay, and the relationships between these levels and clinical parameters or prognosis were evaluated., Results: The serum levels of S100A8 (median 386.5 ng/mL) and S100A9 (median 60.2 ng/mL) in patients with AE-IPF were significantly higher than those in age-matched healthy controls and in patients at IPF diagnosis (p < 0.001 for all combinations). The serum levels of S100A8 negatively correlated with percent forced vital capacity (r = -0.356, p = 0.049) and positively correlated with peripheral white blood cell number (r = 0.509, p = 0.002). Immunohistochemical staining of autopsy lung specimens showed that neutrophils, present mainly in the alveolar septum, were positive for S100A8 and S100A9. Patients with AE-IPF with higher levels of S100A8 or S100A9 showed significantly worse 3-month survival than those with lower levels (log-rank test, both p = 0.028). Finally, in multivariate analysis, the serum levels of both S100A8 and S100A9 were significant prognostic factors (hazard ratio 4.032, p = 0.023 and hazard ratio 4.327, p = 0.012)., Conclusion: The serum levels of S100A8 and S100A9 at AE were significant prognostic biomarkers in patients with AE-IPF., Competing Interests: Conflict of Interest All authors do not have any potential conflicts of interest. This research was not funded., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

The prognosis of patients with connective tissue disease (CTD) has improved significantly in recent years, but interstitial lung disease (ILD) associated with connective tissue disease (CTD-ILD) remains a refractory condition, which is a leading cause of mortality. Because it is an important prognostic factor, many observational and interventional studies have been conducted to date. However, CTD is a heterogeneous group of conditions, which makes the clinical course, treatment responses, and prognosis of CTD-ILD extremely diverse. To summarize the current understanding and unsolved questions, the Japanese Respiratory Society and the Japan College of Rheumatology collaborated to publish the world's first guide focusing on CTD-ILD, based on the evidence and expert consensus of pulmonologists and rheumatologists, along with radiologists, pathologists, and dermatologists. The task force members proposed a total of 27 items, including 7 for general topics, 9 for disease-specific topics, 3 for complications, 4 for pharmacologic treatments, and 4 for non-pharmacologic therapies, with teams of 2-4 authors and reviewers for each item to prepare a consensus statement based on a systematic literature review. Subsequently, public opinions were collected from members of both societies, and a critical review was conducted by external reviewers. Finally, the task force finalized the guide upon discussion and consensus generation. This guide is expected to contribute to the standardization of CTD-ILD medical care and is also useful as a tool for promoting future research by clarifying unresolved issues., Competing Interests: Conflict of Interest Dr. Yasuhiro Kondoh received honoraria from Shionogi & Co.,Ltd. and Nippon Boehringer Ingelheim Co., Ltd. Takashi Ogura received honoraria from Shionogi & Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd.; grant support and/ or research funding from Nippon Boehringer Ingelheim Co., Ltd.; and subsidies or donations from Nippon Boehringer Ingelheim Co., Ltd. and the Mental Health Okamoto Memorial Foundation. Dr. Takafumi Suda received honoraria from AstraZeneca K.K. and Nippon Boehringer Ingelheim Co., Ltd.; grant support and/or research funding from AstraZeneca K.K. and Ono Pharmaceutical Co., Ltd.; subsidies or donations from Astellas Pharma Inc., MSD K.K., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., and Pfizer Japan Inc. Dr. Hiromi Tomioka received honoraria from Nippon Boehringer Ingelheim Co., Ltd. Dr. Hirofumi Amano received grant support and/or research funding from Sumitomo Dainippon Pharma Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd.; subsidies or donations from Actelion Pharmaceuticals Japan Ltd., Asahi Kasei Pharma Corporation, Astellas Pharma Inc., AYUMI Pharmaceutical Corporation, Eisai Co., Ltd., MSD K.K., Taisho Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical Co., Ltd., Teijin Pharma Ltd., and Bayer Yakuhin, Ltd. Dr. Masaki Anraku belongs to endowed departments sponsored by Tokio Marine & Nichido Fire Insurance Co., Ltd. Dr. Takao Fujii, received honoraria from Asahi Kasei Pharma Corporation, Astellas Pharma Inc., AbbVie GK, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Japan Inc., Ono Pharmaciutical Cooperation Co.,Ltd., and Nippon Boehringer Ingelheim Co., Ltd., and subsidies or donations from Asahi Kasei Pharma Corporation, AbbVie GK, Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, and Ono Pharmaciutical Cooperation Co., Ltd. Dr. Tomoyuki Fujisawa received grant support and/or research funding from Novartis Pharma K.K. Dr. Takahisa Gono received honoraria from Ono Pharmaceutical Co., Ltd. Dr. Masayoshi Harigai received honoraria from Chugai Pharmaceutical Co., Ltd. and subsidies or donations from Eisai Co., Ltd.; and belongs to endowed departments sponsored by AYUMI Pharmaceutical Corporation, Mitsubishi Tanabe Pharma Corporation, and Nippon Kayaku Co., Ltd. Dr. Yoshikazu Inoue received honoraria from Nippon Boehringer Ingelheim Co., Ltd. Dr. Takeshi Johkoh received honoraria from Nippon Boehringer Ingelheim Co., Ltd. Dr. Hideto Kameda received honoraria from Asahi Kasei Pharma Corporation, AbbVie GK, Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical Co., Ltd., Novartis Pharma K.K., Pfizer Japan Inc., Bristol-Myers Squibb K.K., Janssen Pharmaceutical K.K.; grant support and/or research funding from Astellas Pharma Inc., AbbVie GK, Gilead Sciences Inc., Novartis Pharma K.K., and Bristol-Myers Squibb K.K.; and subsidies or donations from Asahi Kasei Pharma Corporation, Astellas Pharma Inc., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, and Chugai Pharmaceutical Co., Ltd. Dr. Kensuke Kataoka received honoraria from Nippon Boehringer Ingelheim Co., Ltd. Dr. Yasuhiro Katsumata received subsidies or donations from Mitsubishi Tanabe Pharma Corporation and Chugai Pharmaceutical Co., Ltd. Dr. Yasushi Kawaguchi received honoraria from Actelion Pharmaceuticals Japan Ltd. and Bayer Yakuhin, Ltd. Dr. Atsushi Kawakami received honoraria from Astellas Pharma Inc., AbbVie GK, Eisai Co., Ltd., MSD K.K., Ono Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., and Pfizer Japan Inc.; grant support and/or research funding from Ono Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Taisho Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., and Bristol-Myers Squibb K.K.; and subsidies or donations from Asahi Kasei Pharma Corporation, Astellas Pharma Inc., AbbVie GK, Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical Co., Ltd., and Pfizer Japan Inc. Dr. Noboru Kitamura received subsidies or donations from Ono Pharmaceutical Co., Ltd. and Chugai Pharmaceutical Co., Ltd. Dr. Kazuhiro Kurasawa received grant support and/or research funding from Pfizer Japan Inc.; and subsidies or donations from Asahi Kasei Pharma Corporation and Mitsubishi Tanabe Pharma Corporation. Dr. Yutaro Nakamura received subsidies or donations from Nippon Boehringer Ingelheim Co., Ltd. Dr. Ran Nakashima received grant support and/or research funding from Takeda Pharmaceutical Co., Ltd. Dr. Yasuhiko Nishioka, received subsidies or donations from Asahi Kasei Pharma Corporation and Pfizer Japan Inc. Dr. Masaki Okamoto received honoraria from Nippon Boehringer Ingelheim Co., Ltd. Dr. Fumikazu Sakai received honoraria from AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., and Nippon Boehringer Ingelheim Co., Ltd., and manuscript fees from Nippon Boehringer Ingelheim Co., Ltd. Dr. Shinji Sato received subsidies or donations from Asahi Kasei Pharma Corporation, Ono Pharmaceutical Co., Ltd., and Chugai Pharmaceutical Co., Ltd. Dr. Tohru Takeuchi received honoraria from Mitsubishi Tanabe Pharma Corporation and Bristol-Myers Squibb K.K. and subsidies or donations from Asahi Kasei Pharma Corporation, Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, and Teijin Pharma Ltd. Dr. Masataka Kuwana received patent royalties and/or licensing fees from Medical & Biological Laboratories Co., Ltd.; honoraria from Actelion Pharmaceuticals Japan Ltd., Astellas Pharma Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., and Janssen Pharmaceutical K.K.; grant support and/or research funding from Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., and Bayer Yakuhin, Ltd.; and subsidies or donations from Asahi Kasei Pharma Corporation, Astellas Pharma Inc., Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., and Bayer Yakuhin, Ltd. Dr. Drs. Shigeki Makino, Noriyuki Enomoto, Hidenori Ichiyasu, Hideya Kitamura, Tomohiro Koga, Osamu Nishiyama, Susumu Sakamoto, Toshimasa Shimizu, Noboru Takayanagi, Reoto Takei, Tamiko Takemura, Yuko Toyoda, Hidehiro Yamada, Hideaki Yamakawa, Yasuhiko Yamano, and Yoshioki Yamasaki declare no conflicts of interest associated with this article., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Introduction: Disturbance in placental epigenetic regulation contributes to the pathogenesis of preeclampsia (PE). Although aberrant placental DNA methylation status in PE has been thoroughly studied, the role of histone modifications, including histone methylation, in PE remains unclear. Moreover, no study has ever reported the association between PE and placental histone methylation status by focusing on histone methyltransferases. The present study aimed to investigate the possible involvement of placental epigenetic regulation by histone methylation via histone methyltransferases in the pathophysiology of PE., Methods: Placental mRNA expression of histone methyltransferases was examined using quantitative RT-PCR. Protein expression of histone methyltransferases and histone methylation status in placentas and trophoblast cell lines were assessed by immunoblotting and immunohistochemistry., Results: Expression profile of histone methyltransferases in the placentas using quantitative RT-PCR revealed that the mRNA expression levels of histone 3 lysine 4 (H3K4) methyltransferases, SETD1A and SMYD3, were significantly increased in placentas from PE patients. Immunoblotting and immunohistochemistry revealed that not only protein expression levels of SETD1A and SMYD3, but also H3K4 methylation status was increased in the trophoblasts from PE placentas. In vitro studies using HTR-8/SV-neo and BeWo cells showed that hypoxia induced the expression levels of SETD1A and SMYD3, and subsequently enhanced H3K4 methylation. Furthermore, the overexpression of SETD1A and SMYD3 in HTR-8/SV-neo cells enhanced H3K4 methylation in response to hypoxia., Discussion: Our study results suggest that placental epigenetic alteration by enhanced histone H3K4 methylation through upregulated SETD1A and SMYD3 might play a role in the pathophysiological process of PE associated with hypoxia., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A 74-year-old man with diabetic nephropathy undergoing dialysis after total knee arthroplasty presented to our hospital with dyspnea and abnormal behavior such as wearing his pants on his head. The patient was in shock with ventricular tachycardia. Urine and blood cultures showed MAM with sterile pyuria. We administered amikacin and imipenem cilastatin, but repeated cultures were persistently positive. Although we initially chose not to administer azithromycin because of a higher risk of fatal arrhythmia, we had no choice but to administer azithromycin because of treatment failure. Upon close monitoring, we observed no arrhythmia, and the blood cultures became negative. The patient was discharged on day 106 without any symptoms. However, 2 months after discontinuation of antibiotics, he was readmitted and diagnosed with prosthetic joint infection due to MAM. He could not undergo total knee arthroplasty resection because of his low tolerance to surgery. We re-administered same antibiotics, and repeated draining and cleaning of his left knee for several weeks. The inflammation in the knee joint gradually improved, and the patient was discharged while treatment with azithromycin and amikacin was continued. After being discharged, the patient did not experience recurrent disease for at least 6 months. Our case suggests that MAM can cause sterile pyuria and infection in a patient with diabetic nephropathy. The macrolide agent is a key drug for MAM infection, and repeated joint lavage in addition to administering antibiotics may be an alternative treatment for prosthetic joint infection in patients with intolerance to surgery., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The coronavirus disease 2019 (COVID-19) pandemic has had a great influence on medical practice in Japan. In this study, an online questionnaire-based survey was conducted among doctors routinely involved in the treatment of asthma. The questions included in the survey pertained to their thoughts on asthma treatment amidst COVID-19, changes in their clinical approach toward patients with asthma, and the behavioral changes in patients in the pandemic era. The results revealed a significant impact of the pandemic on asthma treatment. Regardless of whether or not they were directly involved in the treatment of patients with COVID-19, the doctors had avoided using nebulizers in outpatient wards/clinics and routine pulmonary function testing. An increase in canceled appointments and inappropriate/non-adherence to treatment among their patients were noticeable. Furthermore, the survey revealed an extensive impact of the pandemic on the doctors engaged in asthma treatment irrespective of the differences in their medical backgrounds., Competing Interests: Conflict of Interest The authors have no conflict of interest., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Follicular helper T (Tfh) cells represent a unique subset of helper CD4 + T cells in lymphoid follicles. Recently, Tfh cells were shown to play an important role in asthma through B cell differentiation. Conventional lung DCs are classified into two major subsets: conventional type 1 (cDC1) and type 2 (cDC2). Although the two subsets are different in driving particular T cell responses, the subset that induces Tfh cells in the asthmatic lung primarily has yet to be fully elucidated., Methods: We evaluated Tfh cells, defined by the expression of CD4 and CXCR5, in HDM-challenged mice. Next, we characterized cDC1 and cDC2 purified from antigen-primed lung and examined their Tfh cell-inducing capacity. Additionally, the ability of lung DC-induced Tfh cells to cause germinal center B (GCB) cells to produce antigen-specific IgE was assessed., Results: In HDM-challenged mice, Bcl-6-expressing Tfh cells were significantly increased in the mediastinal lymph nodes. Lung cDC2, but not lung cDC1, increased after HDM priming, and cDC2 secreted larger amounts of IL-6 with higher ICOS-L expression than cDC1. In the co-cultures with OVA-specific naïve CD4 + T cells, cDC2 from OVA-primed lung induced Bcl-6-expressing Tfh cells more efficiently, together with larger amounts of IL-6 and IL-21, than cDC1. Blockage of IL-6 or ICOS-L significantly reduced Tfh cell induction. Finally, cDC2-induced Tfh cells enabled GCB cells to produce OVA-specific IgE., Conclusions: In asthmatic lung, cDC2 is the primary DC subset responsible for Tfh cell differentiation and plays an important role in humoral immunity in asthma by inducing Tfh cells., (Copyright © 2021 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Purpose: The objective of this study was to elucidate the impact on clinical outcomes resulting from re-irradiation for locally recurrent (LR) brain metastases (BM) using CyberKnife® stereotactic radiosurgery (SRS)., Materials and Methods: Seventy-seven patients with 254 LR BM lesions treated using SRS re-irradiation between January 2014 and December 2018 were analysed in this retrospective study. The local control (LC), overall survival (OS) rates, and adverse events were assessed. The adverse events were classified according to the Common terminology for adverse event (CTCAE) v5.0., Results: The median follow-up duration was 8.9 months. The median age of the patients was 55 years (IQR: 47-62). The 3, 6, and 9-month LC and OS rates were 92.2%, 73.4%, and 73.4% and 79.2%, 61.0%, and 48.1%, respectively. On multivariate analysis the gender (male vs. female; HR, 1.79; 95% CI, 1.06-3.01; P=0.028), type of first brain radiation (WBI vs. SRS) followed by re-irradiation using SRS (HR, 9.32; 95% CI, 2.77-15.27; P<0.001) tumour volume (>12cc vs. ≤12cc; HR, 1.84; 95% CI, 1.10-3.11; P=0.02), and recursive partitioning analysis (RPA) (I vs. II & III; HR, 0.38; 95% CI, 0.19-0.70; P=0.001) were independent predictive factor for OS. Radionecrosis was reported in 3 patients., Conclusion: With acceptable toxicity, SRS re-irradiation for LR BM showed a favourable rate for LC and OS and reported better OS for the female gender, a patient undergoing first brain radiation with SRS, tumour volume ≤12cc, and RPA-I. This result needs to be further evaluated in future clinical studies., (Copyright © 2021 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Objectives: Interstitial lung disease (ILD) is a common pulmonary manifestation of rheumatoid arthritis (RA) associated with clinical heterogeneity and high mortality. This study aimed to determine whether non-invasive biomarkers, especially monocyte count in peripheral blood, would be useful for predicting outcomes in patients with RA-associated ILD (RA-ILD)., Methods: We retrospectively reviewed the medical records of 72 patients with RA-ILD. We assessed clinical characteristics, laboratory findings at the time of diagnosis. We used Cox proportional hazard analyses to determine significant variables associated with outcomes. Cumulative survival rates were calculated using the Kaplan-Meier method., Results: The median age was 68.6 years (58% male). The 5-year survival rate was 78.4%. Cox proportional hazard analyses adjusted by age and sex showed that increased monocyte count and neutrophil count were significantly associated with poor prognosis in patients with RA-ILD. According to optimal cutoff levels, patients with high monocyte counts (≥458/μl) had significantly lower survival rates than those with low monocyte counts (<458/μl). Similarly, patients with high neutrophil counts (≥9394/μl) had significantly lower survival rates than those with low neutrophil counts (<9394/μl). Combinatorial assessments with peripheral monocyte and neutrophil counts revealed that the patients with both high monocyte and neutrophil counts had the lowest survival., Conclusions: Increased monocyte and neutrophil counts might be potential cellular biomarkers to predict poor outcomes in patients with RA-ILD., (Copyright © 2021. Published by Elsevier Ltd.)

Background: It has been reported that a large decline in estimated glomerular filtration rate (eGFR) over time is associated with increased incidence of cardiovascular disease. We investigated whether this association differs according to the baseline eGFR., Methods: A total of 4666 patients (male 71%) with measurements of eGFR at both baseline and 1 year and that had no cardiovascular events at 1-year follow-up were retrieved from the Shinken Database between June 2004 and March 2015. The study population was divided into three groups by baseline eGFR (mL/min/1.73 m 2 ): high (≥60, n = 1650), intermediate (45-59, n = 1947), and low (<45, n = 1069) eGFR groups. Each eGFR group was further divided into two groups by eGFR slope (change at 1 year, <-10 and ≥-10 mL/min/1.73 m 2 ). The patient characteristics and the incidences of cardiovascular events within 3 years (after 1-year follow-up) were compared between the negatively large eGFR slope (<-10) and others (≥-10) in each eGFR group., Results: A total of 187 cardiovascular events occurred during the mean follow-up of 2.8 ± 0.6 years. The adjusted hazard ratios of eGFR slope (<-10 with reference to ≥-10) were 2.37 (95% CI, 1.28-4.40), 3.10 (95% CI, 1.78-5.40), and 2.66 (95% CI, 1.15-6.13) in the high, middle, and low eGFR groups, respectively. Similar results were found in patients with structural heart disease, but not in those without., Conclusions: Decline in eGFR was associated with an increase in cardiovascular events, and this effect was consistent regardless of the baseline eGFR., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Presence of interstitial lung disease (ILD) is thought to be associated with mortality in microscopic polyangiitis (MPA); however, evidence on MPA-ILD remains lacking. Acute exacerbation (AE) refers to rapidly progressive, fatal respiratory deterioration that may develop in patients with various ILDs. No study has investigated the clinical significance of AE in MPA-ILD., Research Question: We aimed to determine the clinical picture and prognostic factors, the incidence of AE, and the risk factors in patients with MPA-ILD., Study Design and Methods: Eighty-four consecutive patients with MPA-ILD and 95 patients with MPA-non-ILD were analyzed. We also compared 80 patients with MPA-ILD and 80 patients with idiopathic interstitial pneumonia without myeloperoxidase-antineutrophil cytoplasmic antibody positivity (ILD alone), who were matched for age, sex, and chest high-resolution CT scan pattern., Results: The MPA-ILD group had a higher frequency of men and smokers and was associated with higher mortality than the MPA-non-ILD group. The matched MPA-ILD group had a higher mortality rate than the matched ILD alone group. There was no significant difference in AE incidence between the matched MPA-ILD and ILD alone groups (1-year AE cumulative incidence rate, 7.5% and 5.2%, respectively; P = .75). In the MPA-ILD group, a lower percent predicted FVC (%FVC) was independently associated with a higher mortality rate (hazard ratio [HR], 0.96 per 1% increase; P < .01) and a higher AE incidence rate (HR, 0.96 per 1% increase; P = .01). On multivariable Cox regression analysis with time-dependent covariates, developing AE during their clinical course was strongly associated with shorter survival (HR, 17.1; P < .001)., Interpretation: MPA-ILD represented a distinct phenotype with poor prognosis. Lower %FVC was an independent prognostic factor. Patients with lower %FVC had a risk of developing AE, which was a strong prognostic determinant. The specific management for MPA-ILD and AE should be established., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The clinical utility of prophylactic granulocyte-colony stimulating factor (G-CSF) in patients receiving platinum agents plus etoposide for neuroendocrine carcinoma (NEC) is unknown., Methods: Chemotherapy-naïve patients with NEC who received platinum agents plus etoposide were retrospectively evaluated. The occurrence of severe neutropenia and febrile neutropenia (FN) and efficacy of chemotherapy were compared between patients who did (G-CSF group) and did not receive prophylactic G-CSF (non-G-CSF group)., Results: Among 58 patients, 51 (87.9%) and 7 (12.1%) had small-cell lung cancer and large-cell NEC, respectively, and 24 (41.4%) and 34 (58.6%) received cisplatin and carboplatin, respectively. The G-CSF and non-G-CSF groups included 32 and 26 patients, respectively. The non-G-CSF group displayed significantly higher rates of grade 3-4 neutropenia {88.5% [95% confidence interval (CI) = 69.8% - 97.6%] vs. 56.2% [95% CI = 37.7% - 73.6%], P = 0.009} and FN [50.9% (95% CI = 30% - 70%) vs. 18.8% (95% CI = 7.2% - 36.4%), P = 0.023] than the G-CSF group. In multivariate analysis, non-G-CSF was an independent risk factor for grade 3-4 neutropenia and FN. The rate of treatment delay was significantly higher in the non-G-CSF group (69.2% vs. 31.2%, P = 0.001). The relative dose intensity was significantly higher in the G-CSF group (86.7% vs. 74.1%, P < 0.001). The overall response rate, progression-free survival, and overall survival were comparable between the two groups., Conclusions: In patients with NEC receiving platinum agents plus etoposide, prophylactic G-CSF significantly reduced the risks of severe neutropenia and FN., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Planktothrix species are distributed worldwide, and these prevalent cyanobacteria occasionally form potentially devastating toxic blooms. Given the ecological and taxonomic importance of Planktothrix agardhii as a bloom species, we set out to determine the complete genome sequence of the type strain Planktothrix agardhii NIES-204. Remarkably, we found that the 5S ribosomal RNA genes are not adjacent to the 16S and 23S ribosomal RNA genes. The genomic structure of P. agardhii NIES-204 is highly similar to that of another P. agardhii strain isolated from a geographically distant site, although they differ distinctly by a large inversion. We identified numerous gene clusters that encode the components of the metabolic pathways that generate secondary metabolites. We found that the aeruginosin biosynthetic gene cluster was more similar to that of another toxic bloom-forming cyanobacterium Microcystis aeruginosa than to that of other strains of Planktothrix, suggesting horizontal gene transfer. Prenyltransferases encoded in the prenylagaramide gene cluster of Planktothrix strains were classified into two phylogenetically distinct types, suggesting a functional difference. In addition to the secondary metabolite gene clusters, we identified genes for inorganic nitrogen and phosphate uptake components and gas vesicles. Our findings contribute to further understanding of the ecologically important genus Planktothrix., (Copyright © 2020. Published by Elsevier B.V.)

Context: Although idiopathic pulmonary fibrosis (IPF) has worse outcomes compared with most malignancies, patients with IPF receive poor access to optimal palliative care., Objectives: This study aimed to characterize the practice of pulmonologists regarding palliative care and end-of-life communication for patients with IPF and identify perceived difficulties and barriers thereto., Methods: Self-administered questionnaires were sent by mail to representative pulmonologists from Shizuoka prefecture, Japan. Physician-reported practice, difficulties, timing of end-of-life communication, and barriers related to palliative care were investigated., Results: Among the 135 participants, 130 (96%) completed the questionnaire. Most of the participants reported that patients with IPF complained of dyspnea and cough. However, less morphine was prescribed for IPF than for lung cancer. The participants experienced greater difficulty in providing palliative care for IPF than for lung cancer. Moreover, actual end-of-life discussions in patients with IPF were conducted later than the physician-perceived ideal timing. Among the barriers identified, few established treatment and difficulty in predicting prognosis (odds ratio [OR] 2.0; P = 0.04), discrepancies in understanding and care goals among patients, family, and medical staff (OR 2.2; P = 0.03), and inadequate communication about goal of care (OR 2.3; P = 0.003) were significantly associated with the physician-perceived difficulties in providing palliative care for patients with IPF., Conclusion: Pulmonologists experienced greater difficulty in providing palliative care to patients with IPF than to those with lung cancer. Clinical studies on the optimal palliative care for patients with IPF are urgently required., (Copyright © 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Nonspecific interstitial pneumonia (NSIP) and organizing pneumonia (OP) are major subtypes of idiopathic interstitial pneumonias (IIPs) and closely related to connective tissue diseases (CTDs). "NSIP with OP overlap" is a controversial finding that has recently appeared in the criteria of interstitial pneumonia with autoimmune features (IPAF). However, details of this controversial entity are not well known., Objective: To determine the frequency of "NSIP with OP overlap" pattern in IIPs and to identify differences from idiopathic NSIP (iNSIP)., Methods: In 524 patients with interstitial pneumonia from 39 institutes who underwent surgical lung biopsy, 444 were diagnosed as IIPs by a multidisciplinary discussion meeting via a cloud-based integrated database. Among these patients, 44 (9.9%) who had iNSIP and 21 (4.7%) with histopathologically-defined "NSIP with OP overlap" pattern (a pathological NSIP and OP pattern, but without a UIP pattern) were retrospectively studied., Results: Patients with "NSIP with OP overlap" pattern showed a significantly greater extent of consolidation (p < 0.001), more subpleural ground glass attenuation (p = 0.036), and more peripheral + bronchovascular distribution (p = 0.009) on high-resolution computed tomography than those with iNSIP. The incidences of newly-developed CTDs during follow-up was similar between the groups and polymyositis/dermatomyositis was the most frequent CTD in both groups. Nearly half of the patients fulfilled IPAF criteria, but no significant difference was found between iNSIP and "NSIP with OP overlap" pattern (47.7% vs. 42.9, p = 0.712). The incidence of acute exacerbation and the survival rates were similar between the groups., Conclusions: The incidence of "NSIP with OP overlap" pattern is 4.7% in IIPs. The frequency of newly-developed CTDs during follow-up, mainly polymyositis/dermatomyositis, the frequency of acute exacerbation, and the survival rate in "NSIP with OP overlap" pattern are similar to those of iNSIP., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: In the LIBERTY ASTHMA QUEST (ClinicalTrials.gov: NCT02414854) study, dupilumab 200 mg and 300 mg every 2 weeks vs matched-volume placebo reduced severe asthma exacerbations and improved lung function (FEV 1 ), asthma control, and quality of life in patients with uncontrolled, moderate-to-severe asthma (N = 1902). Here, we examine the safety and efficacy of dupilumab in the subpopulation of Japanese patients who participated in QUEST (n = 114; 6%)., Methods: Endpoints assessed were annualized severe exacerbation rates and the effect of treatment over the 52-week treatment period on FEV 1 , asthma control, asthma-related quality of life, and markers of type 2 inflammation., Results: In Japanese patients, dupilumab 200 and 300 mg every 2 weeks vs matched placebo reduced severe asthma exacerbation rates by 44% (P = 0.33) and 75% (P = 0.03), respectively, and improved FEV 1 at Week 12 by 0.20 L (P = 0.05) and 0.17 L (P = 0.12). FEV 1 improvements were rapid (by Week 2) and sustained throughout treatment. Significant and/or numerical improvements vs placebo in asthma control and quality of life were also observed throughout treatment. For each endpoint, greater efficacy was observed in patients with elevated baseline levels of type 2 inflammatory biomarkers (blood eosinophils or FeNO). Dupilumab treatment significantly reduced levels of FeNO and total IgE, but not blood eosinophils., Conclusions: In this subanalysis of QUEST, the efficacy and safety of dupilumab in Japanese patients was comparable to that observed in the overall intention-to-treat population, suggesting no variability in efficacy on the basis of Japanese ethnicity. (Funded by Sanofi and Regeneron Pharmaceuticals, Inc.; ClinicalTrials.gov number: NCT02414854)., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Idiopathic pleuroparenchymal fibroelastosis (iPPFE) is a rare interstitial lung disease characterized by unique radiological and pathological findings. However, pathological evaluations are available only in a limited number of patients. Therefore, several clinical diagnostic criteria have been proposed. Nevertheless, the applicability of these criteria has not yet been validated. Moreover, the clinical course of iPPFE and its prognosis have not yet been completely elucidated., Methods: The present study assessed previously proposed clinical diagnostic criteria by comparing the clinical features between pathologically diagnosed iPPFE (p-iPPFE) and clinically diagnosed iPPFE (c-iPPFE). Subsequently, the clinical features of iPPFE were characterized and compared with those of idiopathic pulmonary fibrosis (IPF, n = 323)., Results: Clinical characteristics of c-iPPFE (n = 27) and p-iPPFE (n = 35) were similar. No significant difference was observed in terms of prognosis between c-iPPFE and p-iPPFE. The number of patients with iPPFE (both c-iPPFE and p-iPPFE) who developed lung cancer was significantly lower than that of patients with IPF. However, acute exacerbation (AE) showed similar incidence in patients with iPPFE and IPF. Survival of patients with iPPFE was significantly worse than that of patients with IPF (5-year survival rate: 38.5% vs. 63.5%, p < 0.0001), and the most common cause of death was chronic respiratory failure (73.8%), followed by AE (14.3%). Male gender was the only poor prognostic factor of iPPFE., Conclusion: The present study demonstrated efficiency of clinical diagnosis and also revealed clinically important characteristics of iPPFE that should be considered for management of iPPFE., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Programmed cell death protein 1 immune checkpoint inhibitors (ICIs) have been reported to improve the survival of patients with NSCLC. On the expansion of clinical administration for a variety of cancers, immune-related adverse events have been typically recognized to be associated with ICIs, therefore, necessitating the monitoring and management of these patients. Among immune-related adverse events, immune-related interstitial lung disease (ir-ILD) is a serious complication that interrupts treatment and can occasionally be fatal. However, no prospective studies have investigated the incidence of ir-ILD and associated risk factors for its development in the clinical setting., Methods: This is a prospective cohort study consisting of patients with NSCLC treated with ICIs. Baseline characteristics, including laboratory data, pulmonary function tests, daily symptoms of dyspnea defined by the modified Medical Research Council, and antitumor response were assessed., Results: Among the 138 patients with NSCLC who received anti-programmed cell death protein 1 monotherapy, 20 patients (14.5%) had ir-ILD within median 51.5 days (interquartile range: 29-147). This was approximately three times higher than those in clinical trials. A total of 11 patients (55.0%), including all eight patients with high-grade ir-ILD (≥grade 3), developed ir-ILD within 60 days. Impaired spirometry, decreased forced vital capacity and forced expiratory volume in 1 second, and daily symptoms of dyspnea measured using the modified Medical Research Council scale were identified as risk factors for ir-ILD development. In addition, combination assessment of forced vital capacity and forced expiratory volume in 1 second successfully classified patients at risk for ir-ILD development., Conclusions: The incidence of ir-ILD was substantially higher in the clinical setting. Assessment of spirometry and daily dyspneic symptoms before ICI treatment may be useful in monitoring and managing patients with NSCLC., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

The Japanese Guideline for Childhood Asthma (JGCA) 2020 is a translation of the Japanese Pediatric Guideline for the Treatment and Management of Asthma (JPGL) 2017 into English, which was published by the Japanese Society of Pediatric Allergy and Clinical Immunology. It makes recommendations for best practices in the management of childhood asthma, including management of acute exacerbations and non-pharmacological and pharmacological management. These guidelines will be of interest to non-specialist physicians involved in the care of children with asthma. In JPGL, JPGL2017 is the first evidence-based guidelines updated according to the GRADE system and Minds approach, and it addresses eight clinical questions about the treatment of childhood asthma. In children aged ≤5 years, infant and preschool asthma is diagnosed according to the response to short acting beta2 agonists or the effect of a therapeutic trial during 1 month with controller treatment and worsening after treatment cessation. Long-term management both promotes pharmacological therapy and measures against risk factors that induce exacerbation, better patient education and a partnership with trinity. In addition, long-term management should not be carried out without review but rather be based on a cycle of evaluation, adjustment and treatment. In JPGL2017, the transdermal patch and oral beta2 agonists are positioned as drugs within the concept of "short-term additional treatment" to be used until the symptoms are stabilized when the control state transiently deteriorates., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion, which is frequently encountered in clinical practice. Skin barrier dysfunction leads to enhanced skin irritability to non-specific stimuli and epicutaneous sensitization. In the lesion site, a further inflammation-related reduction in skin barrier function, enhanced irritability and scratching-related stimuli deteriorate eczema, leading to vicious cycle of inflammation. The current strategies to treat AD in Japan from the perspective of evidence-based medicine consist of three primary measures: (i) the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)