Search

The local structure of the filled tetragonal tungsten bronze (TTB) niobate Ba3Nb5−xTixO15 (x = 0, 0.1, 0.7, 1.0), showing a metal-insulator transition with Ti substitution, has been studied by Nb K-edge extended X-ray absorption fine structure (EXAFS) measurements as a function of temperature. The Ti substitution has been found to have a substantial effect on the local structure, that remains largely temperature independent in the studied temperature range of 80–400 K. The Nb-O bonds distribution shows an increased octahedral distortion induced by Ti substitution, while Nb-Ba distances are marginally affected. The Nb-O bonds are stiffer in the Ti substituted samples, which is revealed by the temperature dependent mean square relative displacements (MSRDs). Furthermore, there is an overall increase in the configurational disorder while the system with Nb 4d electrons turns insulating. The results underline a clear relationship between the local structure and the electronic transport properties suggesting that the metal-insulator transition and possible thermoelectric properties of TTB structured niobates can be tuned by disorder.

The clinical course of patients with idiopathic pulmonary fibrosis (IPF) is generally marked by a decline in pulmonary function over time, although recently there is increasing recognition that fatal deterioration from acute exacerbation can occur at any stage. The patient described in the present case study was a 65-yr-old male who presented with exertional dyspnoea and fever of 2 weeks' duration. He had no history of chronic lung disease or physiological or radiological hallmarks of pre-existing disease. He underwent surgical lung biopsy and the histological examination showed a background pattern of usual interstitial pneumonia (UIP) with a pattern of focal acute diffuse alveolar damage (DAD) in the area where normal lung architecture was preserved. It is notable that the pathological diagnosis of this rapidly progressive interstitial pneumonia was DAD on UIP, which is typically seen in acute exacerbations of IPF. Unusual findings on high-resolution computed tomography scan were also noted. We presume that in this case acute exacerbation developed in the very early course of IPF. Given the possibility that similar cases may have arisen among patients diagnosed with acute interstitial pneumonia or acute respiratory distress syndrome, the histopathology of rapidly progressive interstitial pneumonia may need to be revisited.

Background: Multiple first-line treatment options have been developed for advanced non-small cell lung cancer (NSCLC) in each subgroup determined by predictive biomarkers, specifically driver oncogene and programmed cell death ligand-1 (PD-L1) status. However, the methodology for optimal treatment selection in individual patients is not established. This study aimed to develop artificial intelligence (AI)-based personalized survival prediction model according to treatment selection., Methods: The prediction model was built based on random survival forest (RSF) algorithm using patient characteristics, anticancer treatment histories, and radiomics features of the primary tumor. The predictive accuracy was validated with external test data and compared with that of cox proportional hazard (CPH) model., Results: A total of 459 patients (training, n = 299; test, n = 160) with advanced NSCLC were enrolled. The algorithm identified following features as significant factors associated with survival: age, sex, performance status, Brinkman index, comorbidity of chronic obstructive pulmonary disease, histology, stage, driver oncogene status, tumor PD-L1 expression, administered anticancer agent, six markers of blood test (sodium, lactate dehydrogenase, etc.), and three radiomics features associated with tumor texture, volume, and shape. The C-index of RSF model for test data was 0.841, which was higher than that of CPH model (0.775, P < 0.001). Furthermore, the RSF model enabled to identify poor survivor treated with pembrolizumab because of tumor PD-L1 high expression and those treated with driver oncogene targeted therapy according to driver oncogene status., Conclusions: The proposed AI-based algorithm accurately predicted the survival of each patient with advanced NSCLC. The AI-based methodology will contribute to personalized medicine., Trial Registration: The trial design was retrospectively registered study performed in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Nagoya University Graduate School of Medicine (approval: 2020 - 0287)., Competing Interests: Declarations Ethics approval and consent to participate The trial design was retrospectively registered study performed in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Nagoya University Graduate School of Medicine (approval: 2020 − 0287). Because of retrospective design, the requirement to obtain informed consent was waived according to the ethical guidelines for life sciences and medical research involving human subjects of Japan, which was approved by institutional review boards of each participating institutions. Consent for publication Not applicable. Competing interests J Koyama has a patent JP2022-043291 pending. M Morise receives lecture fees from Taiho, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Chugai, Astra Zeneca, Ono, Pfizer, and MSD; is the principal investigator of clinical trials initiated by Chugai, Astra Zeneca, Ono, Pfizer, Merck Serono, Kissei, Taiho, and Novartis; and receives research grants as an investigator to initiate clinical trials for Boehringer Ingelheim and Eli Lilly outside of the submitted work. In addition, M Morise has a patent JP2022-043291 pending; T Furukawa has a patent JP2022-043291 pending; and H Yokota has a patent JP2022-043291 pending. Y Kondoh serves as a consultant to Asahi Kasei, Healios, Shionogi, Boehringer Ingelheim, Janssen, Chugai, and Taiho; received lecture fees from Asahi Kasei, Shionogi, Boehringer Ingelheim, Astra Zeneca, Eisai, Janssen, Bristol Myers Squibb, KYORIN, Mitsubishi Tanabe, Novartis, and Teijin outside of the submitted work. N Hashimoto reports research grants from Boehringer Ingelheim and non-financial support from Astra Zeneca, Glaxo Smith Kline, Novartis, and Boehringer Ingelheim outside of the submitted work. All remaining authors have nothing to disclose., (© 2024. The Author(s).)

Receptor kinase (RK) families process information from small molecules, short peptides, or glycan ligands to regulate core cellular pathways in plants. To date, whether individual plant RKs are capable of processing signals from distinct types of ligands remains largely unexplored. Addressing this requires the discovery of structurally unrelated ligands that engage the same receptor. Here, we focus on FLAGELLIN-SENSING 2 (FLS2), an RK that senses a peptide of bacterial flagellin to activate antibacterial immunity in Arabidopsis. We interrogate >20,000 potential interactions between small molecules and the sensory domain of FLS2 using a large-scale reverse chemical screen. We discover two small molecules that interact with FLS2 in atypical ways. The surrogate ligands weakly activate the receptor to drive a functional antibacterial response channeled via unusual gene expression programs. Thus, chemical probes acting as biased ligands can be exploited to discover unexpected levels of output flexibility in RKs signal transduction., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Rationale: Accurate prognostic awareness (PA) and knowledge of the disease are critical for decision-making regarding treatment options, advance care planning, and end-of-life care. However, they have not been investigated in patients with interstitial lung disease (ILD)., Objectives: To determine the prevalence of patients with ILD who have accurate PA and/or knowledge of acute exacerbation. In addition, to determine whether accurate PA is associated with end-of-life medical interventions and quality of dying and death., Methods: Through a nationwide bereavement survey, we examined the prevalence of accurate PA and knowledge of acute exacerbation (AE) in patients with ILD who died in acute general hospitals between January 2018 and February 2020. Patients' PA and knowledge were assessed from the perspective of the bereaved. We also quantified the quality of dying and death from the perspective of the bereaved using three scales, the Good Death Inventory, the Quality of Dying and Death (QODD) questionnaire, and the single-item QODD overall score, and obtained information on end-of-life interventions from the electronic medical record. We examined the associations of accurate PA with end-of-life interventions and quality of dying and death., Results: A total of 296 patients whose caregivers completed questionnaires were analyzed. One hundred sixty-three patients (55.1%, 95% confidence interval [CI] = 49.2-60.8) who died of ILD had accurate PA and 138 (46.9%, 95% CI = 35.9-47.4) recognized that their disease could have AE. Multivariate regression analysis showed that accurate PA was associated with significantly fewer intensive care unit (ICU) deaths (odds ratio = 0.28, 95% CI = 0.10-0.82, P = 0.02). Patients with accurate PA had better quality of dying and death on all the three scales., Conclusions: Approximately half of the patients who died of ILD did not recognize that their disease could lead to death or AE. The lower number of ICU deaths and better quality of dying and death in patients with accurate PA suggest the potential benefits of obtaining accurate PA in patients with ILD.

Background: Multidisciplinary discussion (MDD), in which physicians, radiologists, and pathologists communicate and diagnose together, has been reported to improve diagnostic accuracy compared to diagnoses made solely by physicians. However, even among experts, diagnostic concordance of MDD is not always good, and some patients may not receive a specific diagnosis due to insufficient findings. A provisional diagnosis based on the ontology with a diagnostic confidence level has recently been proposed. Additionally, we developed an artificial intelligence model to differentiate idiopathic pulmonary fibrosis (IPF) from other chronic interstitial lung diseases (ILD)s, which needs validation in a broader population., Methods: This prospective nationwide ILD registry has recruited patients with newly diagnosed ILD at the referral respiratory hospitals in Japan and provides rapid MDD diagnoses and treatment recommendations through a central online MDD platform with a 3-year follow-up period. A modified diagnostic ontology is used. If no diagnosis reaches more than 50% certainty, the diagnosis is unclassifiable ILD. If multiple diseases are expected, the diagnosis with a high probability takes precedence. If the confidence levels for the top two possible diagnoses are equal, the diagnosis can be unclassifiable. The registry uses tentative diagnostic criteria for nonspecific interstitial pneumonia with organising pneumonia and smoking-related ILD not otherwise specified as possible new entities. Central MDD diagnosticians review the clinical data, test results, radiology images, and pathological specimens on a dedicated website and conduct MDD diagnoses using online meetings with a cloud-based reporting system. This study aims to (1) provide MDD diagnoses with treatment recommendations; (2) determine the overall ILD rates in Japan; (3) clarify the reasons for unclassifiable ILDs; (4) evaluate possible new disease entities; (5) identify progressive phenotypes and create a clinical prediction model; (6) measure the agreement rate between institutional and central diagnoses in ILD referral and non-referral centres; (7) identify key factors for each specific ILD diagnosis; and (8) create a new disease classification system based on treatment strategies, including the use of antifibrotic drugs., Discussion: This study will provide ILD frequencies, including new entities, using central MDD on dedicated online systems, and develop a machine learning model for ILD diagnosis and prognosis prediction., Trial Registration: UMIN-CTR Clinical Trial Registry (UMIN000040678)., (© 2024. The Author(s).)

Background and Objective: Patients with fibrotic interstitial lung disease (FILD) have impaired health status. The simple questionnaire in the COPD assessment test (CAT) has been validated for idiopathic pulmonary fibrosis (IPF) and connective tissue disease-related interstitial lung disease (CTD-ILD), but no or limited data exist for patients with FILD as a whole. The aim of this study was to evaluate the reliability, repeatability and responsiveness of the CAT, and estimate the minimal clinically important difference (MCID) in patients with FILD., Methods: This study was a retrospective chart review of 358 consecutive patients with FILD including 131 with IPF, who underwent clinical assessment over 6-12 month intervals. We assessed the cross-sectional and longitudinal validity of the CAT. MCID was estimated using distribution methods and anchor methods with mean change and regression models., Results: Internal consistency (Cronbach's alpha = 0.898) and repeatability (intraclass correlation coefficient [ICC] = 0.865) for the CAT score was acceptable. A cross-sectional study showed constructive validity. Changes in the CAT over 6-12 months were significantly associated with change in anchors including physiological function, exercise capacity, and dyspnea regardless of IPF diagnosis. The estimated MCIDs of the CAT for the deterioration and improvement directions were at least +5 and at least -3 points, respectively., Conclusions: The CAT is a reliable, responsive and clinically relevant instrument for assessing health status in patients with FILD., Competing Interests: Declaration of competing interest YK reports advisory board fees and personal fees from Asahi Kasei Pharma Corp., Shionogi & Co.Ltd., and Boehringer Ingelheim Co., Ltd., advisory board fees from Janssen Pharmaceutical K.K., Healios K.K., Chugai Pharmaceutical Co., Ltd., and Taiho Pharmaceutical Co., Ltd., and personal fees from AstraZeneca K.K., Eisai inc., KYORIN Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma, and Novartis Pharma K.K., outside the presentation work. YY reports personal fee Boehringer Ingelheim Co., Ltd. and Bristol-Myers Squibb Co., Ltd. outside the present work. KK reports personal fee from Boehringer Ingelheim Co., Ltd. outside the present work. The other authors have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: The diagnosis of fibrotic hypersensitivity pneumonitis (fHP) from other interstitial lung diseases, particularly idiopathic pulmonary fibrosis (IPF), is often difficult. This study aimed to examine computed tomography (CT) findings that were useful for differentiating between fHP and IPF and to develop and validate a radiological diagnostic model., Methods: In this study, 246 patients (fHP, n = 104; IPF, n = 142) from two institutions were included and randomly divided into the test (n = 164) and validation (n = 82) groups (at a 2:1 ratio). Three radiologists evaluated CT findings, such as pulmonary fibrosis, small airway disease, and predominant distribution, and compared them between fHP and IPF using binomial logistic regression and multivariate analysis. A prognostic model was developed from the test group and validated with the validation group., Results: Ground-glass opacity (GGO) with traction bronchiectasis (TB), honeycombing, hypoattenuation area, three-density pattern, diffuse craniocaudal distribution, peribronchovascular opacities in the upper lung, and random distribution were more common in fHP than in IPF. In multivariate analysis, GGO with TB, peribronchovascular opacities in the upper lung, and random distribution were significant features. The area under the curve of the fHP diagnostic model with the three aforementioned CT features was 0.733 (95% confidence interval [CI], 0.655-0.811, p < 0.001) in the test group and 0.630 (95% CI, 0.504-0.755, p < 0.047) in the validation group., Conclusion: GGO with TB, peribronchovascular opacities in the upper lung, and random distribution were important CT features for differentiating fHP from IPF., Competing Interests: Declaration of competing interest KK received lectures fees from Boehringer Ingelheim. YK received lectures fees from Boehringer Ingelheim. YM received grants from Boehringer Ingelheim, and lectures fees from Boehringer Ingelheim and AstraZeneca. TJ received lectures fees from Bohlinger Ingelheim, AstraZeneca, and Kyorin Inc. The other authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: The INCREASE trial, conducted in the United States, showed that inhaled treprostinil improved exercise capacity in pulmonary hypertension associated with interstitial lung disease (PH-ILD). However, hemodynamic and pharmacokinetic measurements were not performed in the trial. The objective of this trial was to evaluate the efficacy on hemodynamics and exercise capacity, safety, and pharmacokinetics (PK) of inhaled treprostinil in Japanese patients with PH-ILD., Methods: This trial was a multicenter, non-randomized, open-label, single-arm trial of patients with PH-ILD. Inhaled treprostinil was administered at 3 breaths (18 μg)/session four times daily, and the dose was gradually increased to a maximum of 12 breaths (72 μg)/session. The primary endpoints were the change of pulmonary vascular resistance index (PVRI) and peak 6-min walking distance (6MWD) from baseline to week 16. Endpoints also included other efficacy parameters, safety, and PK., Results: Twenty patients received inhaled treprostinil. At week 16, PVRI decreased from baseline by -40.1% (95% CI, -53.1 to -27.2) and peak 6MWD increased by 13.0 m (95% CI, -15.0 to 49.0). The most frequently reported adverse events related with treprostinil were cough, malaise and blood pressure decreased. PK was similar to those in pulmonary arterial hypertension (PAH) patients., Conclusions: Treatment with inhaled treprostinil using the same dosing regimen as in the INCREASE trial resulted in improvements in hemodynamics and exercise capacity with a favorable tolerability and safety profile in Japanese patients with PH-ILD., Competing Interests: Declaration of competing interest Seiichiro Sakao received honoraria from Nippon Shinyaku. Co., Ltd.; Yasuhiro Kondoh received honoraria from Nippon Boehringer Ingelheim.; Hideyuki Kinoshita received honoraria from Nippon Shinyaku Co., Ltd.; Osamu; Nishiyama received honoraria from Janssen Pharmaceutical K.K, Nippon Boehringer Ingelheim, and Nippon Shinyaku Co., Ltd.; Takeshi Ogo received honoraria from Bayer Pharma Japan, Janssen Pharmaceutical K.K, and Nippon Shinyaku Co., Ltd.; Nobuhiro Tanabe received honoraria from Bayer Pharma Japan, Janssen Pharmaceutical K.K, and Nippon Shinyaku Co., Ltd.; Shun Minatsuki received research funding from Fukuda Denshi Co. Ltd. and Sumitomo Mitsui Trust Bank.; Kazuhiko Nakayama has no conflict of interest.; Yu Taniguchi received research grant from Janssen Pharmaceutical K.K.; Kenta Takahashi and Masahiro Takatsu are employees of Mochida Pharmaceutical. They have received remuneration and travel fees within the framework of their employment.; Takashi Ogura received honoraria from Nippon Boehringer Ingelheim., (Copyright © 2024 [The Author]. Published by Elsevier B.V. All rights reserved.)

Background: Coagulopathy is a major cause of morbidity and mortality in COVID-19 patients. Hypercoagulability in COVID-19 results in deep vein thrombosis, thromboembolic complications, and diffuse intravascular coagulation. Microbiome dysbiosis influences the clinical course of COVID-19. However, the role of dysbiosis in COVID-19-associated coagulopathy is not fully understood., Objectives: The present study tested the hypothesis that the microbiota-derived proapoptotic corisin is involved in the coagulation system activation during SARS-CoV-2 infection., Methods: This cross-sectional study included 47 consecutive patients who consulted for symptoms of COVID-19. A mouse acute lung injury model was used to recapitulate the clinical findings. A549 alveolar epithelial, THP-1, and human umbilical vein endothelial cells were used to evaluate procoagulant and anticoagulant activity of corisin., Results: COVID-19 patients showed significantly high circulating levels of corisin, thrombin-antithrombin complex, D-dimer, tumor necrosis factor-α, and monocyte-chemoattractant protein-1 with reduced levels of free protein S compared with healthy subjects. The levels of thrombin-antithrombin complex, D-dimer, and corisin were significantly correlated. A monoclonal anticorisin-neutralizing antibody significantly inhibited the inflammatory response and coagulation system activation in a SARS-CoV-2 spike protein-associated acute lung injury mouse model, and the levels of corisin and thrombin-antithrombin complex were significantly correlated. In an in vitro experiment, corisin increased the tissue factor activity and decreased the anticoagulant activity of thrombomodulin in epithelial, endothelial, and monocytic cells., Conclusion: The microbiota-derived corisin is significantly increased and correlated with activation of the coagulation system during SARS-CoV-2 infection, and corisin may directly increase the procoagulant activity in epithelial, endothelial, and monocytic cells., Competing Interests: Declaration of competing interests E.C.G., C.N.D.'A.-G., and I.C. hold patents on corisin and the anticorisin monoclonal antibody reported in this study. The other authors declare no competing interests related to this manuscript., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: No comprehensive analysis of the pulmonary sequelae of coronavirus disease 2019 (COVID-19) in Japan based on respiratory function tests and chest computed tomography (CT) has been reported. We evaluated post-COVID-19 conditions, especially focusing on pulmonary sequelae assessed by pulmonary function tests and chest CT., Methods: For this prospective cohort study, we enrolled 1069 patients who presented pneumonia at the time of admission in 55 hospitals from February 2020 to September 2021. Disease severity was classified as moderateⅠ, moderate II, and severe, defined primarily according to the degree of respiratory failure. The data on post-COVID-19 conditions over 12 months, pulmonary function, and chest CT findings at 3 months were evaluated in this study. Additionally, the impact of COVID-19 severity on pulmonary sequelae, such as impaired diffusion capacity, restrictive pattern, and CT abnormalities, was also evaluated., Results: The most frequently reported post-COVID-19 conditions at 3 months after COVID-19 were muscle weakness, dyspnea, and fatigue (48.4%, 29.0%, and 24.7%, respectively). The frequency of symptoms gradually decreased over subsequent months. In pulmonary function tests at 3 months, the incidence of impaired diffusion capacity and restrictive pattern increased depending on disease severity. There also were differences in the presence of chest CT abnormalities at the 3 months, which was markedly correlated with the severity., Conclusion: We reported a comprehensive analysis of post-COVID-19 condition, pulmonary function, and chest CT abnormalities in Japanese patients with COVID-19. The findings of this study will serve as valuable reference data for future post-COVID-19 condition research in Japan., Competing Interests: Declaration of Competing interest The authors have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Interstitial lung diseases (ILDs) are a heterogeneous group of disorders, a subset of which develop progressive pulmonary fibrosis (PPF). There is little information on the epidemiology and treatment of PPFs in Japan. This retrospective cohort study estimated the incidence probability of progression to PPFs in patients with fibrosing ILDs other than idiopathic pulmonary fibrosis in a real-world Japanese setting. Management procedures and treatment patterns were also quantified., Methods: Data were extracted from the Medical Data Vision database from 01-Jan-2012 to 28-May-2020, comprising a 6.91-year patient identification period, 1-year pre-index period, and post-index period. The primary outcome was the cumulative incidence probability of progression to PPF up to 24 months. Subgroup analyses were performed by the presence/absence of connective tissue disease-ILD and by pre-specified ILD clinical diagnosis., Results: Of the 34,960 eligible patients (mean age: 71.1 years, males: 52.5%), 14,580 (41.7%) progressed to PPF. The 24-month incidence probability of progression to PPF was 39.5%. A relatively comparable percentage of patients progressed across all ILD subtypes. Oral corticosteroids and tacrolimus were the most common therapies during the pre- and post-index periods. Treatment rates were very low in the post-index period., Conclusions: This is the first claims database study to estimate the incidence probability of progression to PPF in Japan. Progression appeared common in patients with chronic fibrosing ILDs, with comparable percentages of patients across all subtypes developing PPF at 2 years. Future studies should assess the impact of regular monitoring and early intervention on treating fibrotic ILDs and preventing progression., Competing Interests: Declaration of competing interest Yasuhiro Kondoh reports consulting fees from Boehringer Ingelheim, Chugai Pharmaceutical Co., Ltd., Healios K.K., Janssen Pharmaceutical K.K., Shionogi and Co., Ltd., and Taiho Pharmaceutical Co.; payments or honoraria from Boehringer Ingelheim, Bristol-Myers Squibb, Eisai Inc., Janssen Pharmaceutical K.K., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma, Novartis Pharma K.K., Shionogi and Co., Ltd., and Teijin Pharma. Tomohiro Ito, Kumiko Saito, Haikun Bao, and Wataru Sakamoto are employees of Boehringer Ingelheim., (Copyright © 2024 The Author. Published by Elsevier B.V. All rights reserved.)

Background: Acute exacerbation (AE) is a potentially lethal event in patients with usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF). However, to date, no pathological predictors of AE have been identified. This retrospective study aimed to elucidate the pathological features that could predict AE in patients with UIP., Methods: We reviewed the pathological findings of 91 patients with UIP/IPF and correlated these findings with AE events. Thirteen histological variables related to acute lung injury were evaluated by three independent observers and classified as positive or negative. The patients' clinical data during follow-up were collected and reviewed for AE. A recursive partition using the Gini index for the prediction of AE was performed, with each pathological finding as a candidate for branching., Results: Twenty patients (22%) developed AE during the median follow-up duration of 40 months. Thirty-eight patients died (15 due to AE and 23 for other reasons). The median time interval from surgical lung biopsy to AE onset was 497 (interquartile range: 901-1657) days. Histologically, squamous metaplasia was positively associated with AE (odds ratio: 4.7, P = 0.015) and worse event-free survival in patients with UIP (P = 0.04). Leaf scoring based on the Gini index for recursive partition, including five positive findings (squamous metaplasia, neutrophilic infiltration, septal widening, Kuhn's hyaline, and fibrin), showed a sensitivity of 90% with a specificity of 74.7% (area under curve: 0.89)., Conclusions: We found that squamous metaplasia is an important histopathological finding that predicts AE events and tends to unfavorable outcome in patients with UIP/IPF., Competing Interests: Declaration of competing interest Yasuhiro Kondoh received lecture fees from YK: Boehringer Ingelheim Co., Ltd; Takeshi Johkoh received lecture fees from Nihon Bohringer Ingelheim Japan, Kyorin, and AstraZeneca; Kensuke Kataoka received manuscript fees from Nippon Boehringer Ingelheim; Yasuhiko Yamano received manuscript fees from Nippon Boehringer Ingelheim and Bristol-Myers Squibb. The other authors have no conflict of interest to disclose., (Copyright © 2024 The Author. Published by Elsevier B.V. All rights reserved.)

Aims: Progressive pulmonary fibrosis (PPF) is a newly recognised clinical phenotype of interstitial lung diseases in the 2022 interstitial pulmonary fibrosis (IPF) guidelines. This category is based entirely on clinical and radiological factors, and the background histopathology is unknown. Our objective was to investigate the histopathological characteristics of PPF and to examine the correlation between usual interstitial pneumonia (UIP) and prognosis in this new disease type. We hypothesised that the presence of UIP-like fibrosis predicts patients' survival in PPF cases., Methods and Results: We selected 201 cases fulfilling the clinical criteria of PPF from case archives. Cases diagnosed as IPF by a multidisciplinary team were excluded. Whole slide images were evaluated by three pathologists who were blinded to clinical and radiological data. We measured areas of UIP-like fibrosis and calculated what percentage of the total lesion area they occupied. The presence of focal UIP-like fibrosis amounting to 10% or more of the lesion area was seen in 148 (73.6%), 168 (83.6%) and 165 (82.1%) cases for each pathologist, respectively. Agreement of the recognition of UIP-like fibrosis in PPF cases was above κ = 0.6 between all pairs. Survival analysis showed that the presence of focal UIP-like fibrosis correlated with worsened survival under all parameters tested (P < 0.001)., Conclusions: The presence of UIP-like fibrosis is a core pathological feature of clinical PPF, and its presence within diseased areas is associated with poorer prognosis. This study highlights the importance of considering the presence of focal UIP-like fibrosis in the evaluation and management of PPF., (© 2024 John Wiley & Sons Ltd.)

Background: Clinical guidance on the identification and management of connective tissue disease-associated interstitial lung disease (CTD-ILD) is needed for optimal clinical practice. We aimed to develop clinical algorithms for identifying and managing three common CTD-ILDs: those associated with systemic sclerosis (SSc-ILD), rheumatoid arthritis (RA-ILD), and polymyositis/dermatomyositis (PM/DM-ILD)., Research Design and Methods: Meetings were held October-November 2023 to create consensus-based algorithms for identifying and managing SSc-ILD, RA-ILD, and PM/DM-ILD in clinical practice, based on expert consensus statements for identification and management of CTD-ILD previously derived from a Delphi process., Results: We developed clinical algorithms for SSc-ILD, RA-ILD, and PM/DM-ILD that highlight both commonalities and differences in the identification and management of these CTD-ILDs. Importantly, ILD should be suspected in patients with SSc, RA, or PM/DM who have respiratory symptoms. Chest high-resolution computed tomography has utility for screening, diagnosis and assessment of severity. Furthermore, regular follow-up and multidisciplinary management are important. Disease-specific considerations include unique risk factors such as anti-topoisomerase I antibodies in SSc-ILD, high-titer cyclic citrullinated peptide antibodies in RA, anti-aminoacyl tRNA synthetase antibodies in PM/DM, and anti-melanoma differentiation-associated gene 5 antibody in DM., Conclusions: These algorithms may help physicians to identify and manage patients with SSc-ILD, RA-ILD, or PM/DM-ILD.

Background: Extracellular mitochondrial DNA (mtDNA) is released from damaged cells and increases in the serum and bronchoalveolar lavage fluid (BALF) of idiopathic pulmonary fibrosis (IPF) patients. While increased levels of serum mtDNA have been reported to be linked to disease progression and the future development of acute exacerbation (AE) of IPF (AE-IPF), the clinical significance of mtDNA in BALF (BALF-mtDNA) remains unclear. We investigated the relationships between BALF-mtDNA levels and other clinical variables and prognosis in IPF., Methods: Extracellular mtDNA levels in BALF samples collected from IPF patients were determined using droplet-digital PCR. Levels of extracellular nucleolar DNA in BALF (BALF-nucDNA) were also determined as a marker for simple cell collapse. Patient characteristics and survival information were retrospectively reviewed., Results: mtDNA levels in serum and BALF did not correlate with each other. In 27 patients with paired BALF samples obtained in a stable state and at the time of AE diagnosis, BALF-mtDNA levels were significantly increased at the time of AE. Elevated BALF-mtDNA levels were associated with inflammation or disordered pulmonary function in a stable state (n = 90), while being associated with age and BALF-neutrophils at the time of AE (n = 38). BALF-mtDNA ≥ 4234.3 copies/µL in a stable state (median survival time (MST): 42.4 vs. 79.6 months, p < 0.001) and ≥ 11,194.3 copies/µL at the time of AE (MST: 2.6 vs. 20.0 months, p = 0.03) were associated with shorter survival after BALF collection, even after adjusting for other known prognostic factors. On the other hand, BALF-nucDNA showed different trends in correlation with other clinical variables and did not show any significant association with survival time., Conclusions: Elevated BALF-mtDNA was associated with a poor prognosis in both IPF and AE-IPF. Of note, at the time of AE, it sharply distinguished survivors from non-survivors. Given the trends shown by analyses for BALF-nucDNA, the elevation of BALF-mtDNA might not simply reflect the impact of cell collapse. Further studies are required to explore the underlying mechanisms and clinical applications of BALF-mtDNA in IPF., (© 2024. The Author(s).)

Objective: Interferon-λ3 (IFNλ3) is a cytokine with antiviral functions on barrier surfaces, and it is associated with disease activity in autoimmune diseases. This study assessed the clinical significance of serum IFNλ3 levels in polymyositis/dermatomyositis (PM/DM)-associated interstitial lung disease (ILD)., Methods: We measured serum IFNλ3 levels in 221 patients with PM/DM-ILD (155 in the derivation cohort, 66 in the validation cohort) and 38 controls. We evaluated factors associated with mortality risk among 79 patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM-ILD., Results: Serum IFNλ3 levels at diagnosis were significantly higher in patients with PM/DM-ILD than in healthy controls. Remarkably, serum IFNλ3 levels were specifically increased in patients with anti-MDA5 antibody-positive DM-ILD in both the derivation and validation cohorts. In anti-MDA5 antibody-positive DM-ILD, patients with high IFNλ3 levels (>120 pg/mL) had significantly lower survival rates than those with low IFNλ3 levels (≤120 pg/mL). A multivariate analysis revealed that high IFNλ3 levels, as well as old age and low Pao 2 , were significantly associated with poor prognoses in patients with anti-MDA5 antibody-positive DM-ILD. In a classification analysis of patients with anti-MDA5 antibody-positive DM-ILD based on age, IFNλ3 level, and Pao 2 , patients with old age (>53 years), high IFNλ3 levels (>120 pg/mL), and low Pao 2 (<75 mm Hg) had the worst survival. In lung pathologic analyses, IFNλ3-positive staining was observed in macrophages, airway epithelial cells, the pleural region, and intrapulmonary veins in patients with anti-MDA5 antibody-positive DM-ILD., Conclusion: Serum IFNλ3 is a promising biomarker for identifying patients at high risk of poor outcomes in anti-MDA5 antibody-positive DM-ILD., (© 2023 American College of Rheumatology.)

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with a poor prognosis and an unknown cause that generally progresses to pulmonary fibrosis and leads to irreversible tissue alteration. The "Guidelines for the treatment of idiopathic pulmonary fibrosis 2017," specializing in the treatment of IPF for the first time in Japan and presenting evidence-based standard treatment methods suited to the state of affairs in Japan, was published in 2017, in line with the 2014 version of "Formulation procedure for Minds Clinical Practice Guidelines." Because new evidence had accumulated, we formulated the "Guidelines for the treatment of Idiopathic Pulmonary Fibrosis 2023 (revised 2nd edition)." While keeping the revision consistent with the ATS/ERS/JRS/ALAT IPF treatment guidelines, new clinical questions (CQs) on pulmonary hypertension were added to the chronic stage, in addition to acute exacerbation and comorbid lung cancer, which greatly affect the prognosis but are not described in the ATS/ERS/JRS/ALAT IPF guidelines. Regarding the advanced stages, we additionally created expert consensus-based advice for palliative care and lung transplantation. The number of CQs increased from 17 in the first edition to 24. It is important that these guidelines be used not only by respiratory specialists but also by general practitioners, patients, and their families; therefore, we plan to revise them appropriately in line with ever-advancing medical progress., Competing Interests: Declaration of competing interest Masashi Bando received lecture fees from AstraZeneca K.K., Shionogi & Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd. Sakae Homma received lecture fees from Nippon Boehringer Ingelheim Co., Ltd. and belongs to Endowed departments by Shionogi & Co., Ltd., Chugai Pharmaceutical Co., Ltd., Teijin Pharma Ltd. and Nippon Boehringer Ingelheim Co., Ltd. Hiroshi Date received lecture fees from Covidien Japan Inc. and Johnson & Johnson K.K. and donations from Adachi Co., Ltd., Hogy Medical Co., Ltd. and Taiho Pharmaceutical Co., Ltd. Kazuma Kishi received lecture fees from AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd. and research funding from MSD K. K., Taiho Pharmaceutical Co., Ltd. and Chugai Pharmaceutical Co., Ltd. and donations from Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K. and Nippon Boehringer Ingelheim Co., Ltd. Atsushi Miyamoto received lecture fees from Nippon Boehringer Ingelheim Co., Ltd. Takeo Nakayama received lecture fees from Eli Lilly Japan K.K., Pfizer Japan, Inc. and Janssen Pharmaceutical K.K. and research finding from I&H Co., Ltd., Cocokarafine Group Co., Ltd. And Konica Minolta, Inc. and donations from Cancerscan Inc. and Yuyama Manufacturing Co., Ltd. Arata Azuma received lecture fees from Taiho Pharmaceutical Co., Ltd., Toray Industries, Inc. and Nippon Boehringer Ingelheim Co., Ltd. Yasuhiro Kondoh received lecture fees from Nippon Boehringer Ingelheim Co., Ltd., Bristol-Myers Squibb K.K. and Janssen Pharmaceutical K.K. Takeshi Johkoh received lecture fees from Nippon Boehringer Ingelheim Co., Ltd. Yasuhiko Nishioka received lecture fees from MSD K. K., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd. and research funding from Taiho Pharmaceutical Co., Ltd., TMS Co., Ltd., Chugai Pharmaceutical Co., Ltd. and Bonac Corporation and donations from Asahi Kasei Pharma Corporation, Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd. and Eli Lilly Japan K.K. Junya Fukuoka received research funding from National Institute of Advanced Industrial Science and Technology and Future Corporation. Yasunari Miyazaki received donations from Chugai Pharmaceutical Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd. and lecture fees from AstraZeneca K.K. and Nippon Boehringer Ingelheim Co., Ltd. Ichiro Yoshino received lecture fees from MSD K. K., AstraZeneca K.K., Intuitive Surgical G.K., Ono Pharmaceutical Co., Ltd., Covidien Japan Inc., Johnson & Johnson K.K., Daiichi Sankyo Company, Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co. and Eli Lilly Japan K.K. and donations from Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Eli Lilly Japan K.K. and Pfizer Japan, Inc. Takafumi Suda received lecture fees from AstraZeneca K.K. and Nippon Boehringer Ingelheim Co., Ltd. and research funding from Chugai Pharmaceutical Co., Nippon Boehringer Ingelheim Co. and Bristol-Myers Squibb K.K. and donations from Shionogi & Co., Ltd. and Chugai Pharmaceutical Co. Yoshihito Goto, Susumu Sakamoto and Hiroyoshi Yamauchi have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Pulmonary hypertension (PH) is defined by elevated mean pulmonary arterial pressure (MPAP), and elevated pulmonary vascular resistance (PVR) reflects pulmonary vascular abnormalities. The clinical significance of non-severe PH in patients with various interstitial lung diseases (ILDs) has not been fully elucidated. We aimed to investigate the clinical significance of MPAP and PVR for mortality in patients with newly diagnosed ILD., Methods: We retrospectively analysed consecutive patients with ILD at initial evaluations that included right heart catheterisation from 2007 to 2018. These patients were classified by MPAP and PVR using the 2022 the European Society of Cardiology (ESC)/the European Respiratory Society (ERS) guidelines for PH. The clinical significance of MPAP and PVR for mortality was analysed., Results: Among 854 patients, 167 (19.6%) had MPAP>20 mm Hg. The proportion of patients with PVR>2 Wood units (WU) among those with MPAP≤20 mm Hg, 202 WU was associated with a higher mortality rate (HR 1.61, 95% CI 1.28 to 2.02, p<0.0001) even in a group with MPAP≤20 mm Hg., Conclusions: Mild elevation of PVR was associated with a higher mortality rate in patients with newly diagnosed ILD, even in those with MPAP≤20 mm Hg., Competing Interests: Competing interests: YK reports consulting fees from Asahi Kasei Pharma Corporation, Boehringer Ingelheim, Chugai Pharmaceutical, Healios K.K., Janssen Pharmaceutical KK, Shionogi and Taiho Pharmaceutical and lecture fees from Asahi Kasei Pharma Corporation, Bristol Myers Squibb, Boehringer Ingelheim, Eisai, Janssen Pharmaceutical KK, KYORIN Pharmaceutical, Mitsubishi Tanabe Pharma, NIPPON SHINYAKU, Novartis Pharma KK, Shionogi and Teijin Pharma outside the submitted work. TK reports lecture fees from GlaxoSmithKline KK outside the submitted work. KK reports lecture fees from Nippon Boehringer Ingelheim outside the submitted work. The other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Recent guidelines discourage the use of pulmonary arterial hypertension (PAH)-targeted therapies in patients with pulmonary hypertension (PH) associated with respiratory diseases. Therefore, stratifications of the effectiveness of PAH-targeted therapies are important for this group., Objectives: The authors aimed to identify phenotypes that might benefit from initial PAH-targeted therapies in patients with PH associated with interstitial pneumonia and combined pulmonary fibrosis and emphysema., Methods: We categorized 270 patients with precapillary PH (192 interstitial pneumonia, 78 combined pulmonary fibrosis and emphysema) into severe and mild PH using a pulmonary vascular resistance of 5 WU. We investigated the prognostic factors and compared the prognoses of initial (within 2 months after diagnosis) and noninitial treatment groups, as well as responders (improvements in World Health Organization functional class, pulmonary vascular resistance, and 6-minute walk distance) and nonresponders., Results: Among 239 treatment-naive patients, 46.0% had severe PH, 51.8% had mild ventilatory impairment (VI), and 40.6% received initial treatment. In the severe PH with mild VI subgroup, the initial treatment group had a favorable prognosis compared with the noninitial treatment group. The response rate in this group was significantly higher than the others (48.2% vs 21.8%, ratio 2.21 [95% CI: 1.17-4.16]). In multivariate analysis, initial treatment was a better prognostic factor for severe PH but not for mild PH. Within the severe PH subgroup, responders had a favorable prognosis., Conclusions: This study demonstrated an increased number of responders to initial PAH-targeted therapy, with a favorable prognosis in severe PH cases with mild VI. A survival benefit was not observed in mild PH cases. (Multi-institutional Prospective Registry in Pulmonary Hypertension associated with Respiratory Disease; UMIN000011541)., Competing Interests: This study was supported by grants from Grant-in-Aid for Scientific Research (20FC1027, 23FC1031) from the Ministry of Health, Labour and Welfare of Japan, the Medical Research Fund of the Japan Medical Association (No. 16ek0109127h0002 and No. JP18lk1601003h0001), and the Nonprofit Organization Japan PH registry. Dr Tanabe has received remuneration from Nippon Shinyaku, Janssen Pharmaceutical K.K., and Bayer Yakuhin, and belongs to a department endowed by Nippon Shinyaku. Dr Kumamaru has received consultation fees from Mitsubishi-Tanabe Pharma Corp, and EPS Corp; speaker fee from Chugai Pharmaceutical Co, Ltd; and a research grant from Pfizer Japan Inc. Drs Kumamaru, Kinukawa, and Miyata are affiliated with the Department of Health Quality Assessment at the University of Tokyo, a social collaboration department supported by the National Clinical Database, Johnson & Johnson K.K., Nipro Corp, and Intuitive Surgical Sàrl. Dr Nishiyama has received remuneration from Nippon Shinyaku, Janssen Pharmaceutical K.K., and Boehringer Ingelheim. Dr Tsujino has received remuneration from Nippon Shinyaku and Janssen Pharmaceutical K.K., and belongs to a department endowed by Nippon Shinyaku, Mochida Pharmaceutical Co Ltd, Boehringer Ingelheim, Takeyama Co, Ltd, Kaneka Medics Co, and Medical System Network Co Ltd. Dr Inoue has received remuneration from Boehringer Ingelheim. Dr Hirata has received a research grant from Janssen Pharmaceutical K.K. Dr Kuwana has received remuneration from Nippon Shinyaku. Dr Handa has received a research grant from Fujifilm Corp and belongs to a department endowed by Teijin Pharma Ltd. Dr Taniguchi has received a research grant from Janssen Pharmaceutical K.K. Dr Matsubara has received remuneration from Nippon Shinyaku, Janssen Pharmaceutical K.K., Bayer Yakuhin, Mochida Pharmaceutical. Co Ltd, and Kaneka Medics Co; and research grants from Nippon Shinyaku, Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co Ltd, and Insmed Incorporated. Dr Tatsumi has received remuneration from Janssen Pharmaceutical K.K. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background and Objective: The relative effectiveness of initial non-invasive respiratory strategies for acute respiratory failure using continuous positive airway pressure (CPAP) or high-flow nasal cannula (HFNC) is unclear., Methods: We conducted a multicenter, open-label, parallel-group randomized controlled trial to compare the efficacy of CPAP and HFNC on reducing the risk of meeting the prespecified criteria for intubation and improving clinical outcomes of acute hypoxemic respiratory failure. The primary endpoint was the time taken to meet the prespecified criteria for intubation within 28 days., Results: Eighty-five patients were randomly assigned to the CPAP or HFNC group. Eleven (28.9%) in the CPAP group and twenty (42.6%) in the HFNC group met the criteria for intubation within 28 days. Compared with HFNC, CPAP reduced the risk of meeting the intubation criteria (hazard ratio [HR], 0.327; 95% CI, 0.148-0.724; p = 0.006). There were no significant between-group differences in the intubation rates, in-hospital and 28-day mortality rates, ventilator-free days, duration of the need for respiratory support, or duration of hospitalization for respiratory illness. Pulmonary oxygenation was significantly better in the CPAP group, with significantly lower pH and higher partial pressure of carbon dioxide, but there were no differences in the respiratory rate between groups. CPAP and HFNC were associated with few possibly causal adverse events., Conclusion: CPAP is more effective than HFNC at reducing the risk of meeting the intubation criteria in patients with acute hypoxemic respiratory failure., (© 2023 Asian Pacific Society of Respirology.)

Background: Little is known about the annual change in Krebs von Lungen-6 (KL-6) and its correlation with forced vital capacity (FVC) in limited cutaneous systemic sclerosis-associated interstitial lung disease (lcSSc-ILD). We aimed to clarify the correlation during the clinical course., Methods: We retrospectively reviewed data from consecutive patients with lcSSc-ILD. We measured FVC and KL-6 annually and calculated their annual changes using the difference in absolute values. Decline in FVC was defined as annual decline in FVC ≥5 %., Results: Thirty-eight patients with SSc-ILD were included. The median age was 62 years and 58 % were female. The median FVC was 87.3 % and the median KL-6 was 1629 U/ml. The median observation period was 55.2 months and the annual changes in FVC and KL-6 were evaluated 151 times simultaneously. The annual change in KL-6 had a significant negative correlation with that in FVC in the first year from the initial evaluation (from the baseline to one-year follow-up) (r = -0.819, p < 0.01), but not after the first year. In the multivariable analysis adjusted by age, sex, and FVC at each year, the annual change of KL-6 (per 100 U/ml) was significantly associated with decline in FVC in the first year (odds ratio: 3.03, 95 % confidence interval: 1.21-7.59, p = 0.02), but not after the first year., Conclusions: Only in the first year from the initial evaluation, there was negative correlation between the annual change in FVC and that in KL-6 and the annual elevation in KL-6 was associated with decline in FVC in patients with lcSSc-ILD., Competing Interests: Conflict of interest Yasuhiro Kondoh received Honoraria from Boehringer Ingelheim, Co., Ltd. and SEKISUI MEDICAL Co., Ltd. Reoto Takei, Yasuhiko Yamano, Kensuke Kataoka, Jun Fukihara, Hajime Sasano, Toshiki Yokoyama, Toshiaki Matsuda and Tomoki Kimura have no conflict of interest., (© 2023 Published by Elsevier B.V. on behalf of The Japanese Respiratory Society.)

This study investigated the utility of periostin, a matricellular protein, as a prognostic biomarker in patients with idiopathic pulmonary fibrosis (IPF) who received nintedanib. Monomeric and total periostin levels were measured by enzyme-linked immunosorbent assay in 87 eligible patients who participated in a multicenter prospective study. Forty-three antifibrotic drug-naive patients with IPF described in previous studies were set as historical controls. Monomeric and total periostin levels were not significantly associated with the change in forced vital capacity (FVC) or diffusing capacity of the lungs for carbon monoxide (D LCO ) during any follow-up period. Higher monomeric and total periostin levels were independent risk factors for overall survival in the Cox proportional hazard model. In the analysis of nintedanib effectiveness, higher binarized monomeric periostin levels were associated with more favorable suppressive effects on decreased vital capacity (VC) and D LCO in the treatment group compared with historical controls. Higher binarized levels of total periostin were associated with more favorable suppressive effects on decreased D LCO but not VC. In conclusion, higher periostin levels were independently associated with survival and better therapeutic effectiveness in patients with IPF treated with nintedanib. Periostin assessments may contribute to determining therapeutic strategies for patients with IPF., (© 2023. The Author(s).)

This literature review aimed to evaluate the effectiveness of rituximab (RTX) in patients with systemic sclerosis (SSc). PubMed was searched for articles, published through 31 March 2022, on any controlled studies using RTX in the treatment of SSc. Of 85 identified articles, 9 were selected by title/abstract screening and full text examination. All nine articles reported outcomes of forced vital capacity (%FVC), and seven reported those of modified Rodnan skin scores (mRSS). The results showed that among the seven controlled studies evaluating skin lesions in patients with SSc, four showed a significant improvement of mRSS by RTX when compared with a control group, whereas three showed no significant effect. Among the nine controlled studies evaluating lung lesions, five showed a significant improvement of %FVC compared with a control group, whereas four showed no significant effect. In conclusion, RTX may be effective in the treatment of skin and lung lesions in patients with SSc. The profiles of SSc patients for whom RTX was indicated were unclear, although patients with diffuse cutaneous SSc and those positive for anti-topoisomerase I antibody were considered potential targets. Additional studies are needed to assess the long-term effectiveness of RTX in the treatment of patients with SSc., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although it has been a fatal disease for many patients, the development of treatment strategies and vaccines have progressed over the past 3 years, and our society has become able to accept COVID-19 as a manageable common disease. However, as COVID-19 sometimes causes pneumonia, post-COVID pulmonary fibrosis (PCPF), and worsening of preexisting interstitial lung diseases (ILDs), it is still a concern for pulmonary physicians. In this review, we have selected several topics regarding the relationships between ILDs and COVID-19. The pathogenesis of COVID-19-induced ILD is currently assumed based mainly on the evidence of other ILDs and has not been well elucidated specifically in the context of COVID-19. We have summarized what has been clarified to date and constructed a coherent story about the establishment and progress of the disease. We have also reviewed clinical information regarding ILDs newly induced or worsened by COVID-19 or anti-SARS-CoV-2 vaccines. Inflammatory and profibrotic responses induced by COVID-19 or vaccines have been thought to be a risk for de novo induction or worsening of ILDs, and this has been supported by the evidence obtained through clinical experience over the past 3 years. Although COVID-19 has become a mild disease in most cases, it is still worth looking back on the above-reviewed information to broaden our perspectives regarding the relationship between viral infection and ILD. As a representative etiology for severe viral pneumonia, further studies in this area are expected., (Copyright © 2023. Published by Elsevier B.V.)

The E3 ubiquitin ligase RFFL is an apoptotic inhibitor highly expressed in cancers and its knockdown suppresses cancer cell growth and sensitizes to chemotherapy. RFFL also participates in peripheral protein quality control which removes the functional cell surface ΔF508-CFTR channel and reduces the efficacy of pharmaceutical therapy for cystic fibrosis (CF). Although RFFL inhibitors have therapeutic potential for both cancer and CF, they remain undiscovered. Here, a chemical array screening has identified α-tocopherol succinate (αTOS) as an RFFL ligand. NMR analysis revealed that αTOS directly binds to RFFL's substrate-binding region without affecting the E3 enzymatic activity. Consequently, αTOS inhibits the RFFL-substrate interaction, ΔF508-CFTR ubiquitination and elimination from the plasma membrane of epithelial cells, resulting in the increased functional CFTR channel. Among the α-tocopherol (αTOL) analogs we tested, only αTOS inhibited the RFFL-substrate interaction and increased the cell surface ΔF508-CFTR, depending on RFFL expression. Similarly, the unique proapoptotic effect of αTOS was dependent on RFFL expression. Thus, unlike other αTOL analogs, αTOS acts as an RFFL protein-protein interaction inhibitor which may explain its unique biological properties among αTOL analogs. Moreover, αTOS may act as a CFTR stabilizer, a novel class of drugs that extend cell surface ΔF508-CFTR lifetime., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Acute respiratory distress syndrome (ARDS) is a life-threatening inflammatory lung injury with high mortality; no approved medication exists. Efficacy and safety of bone marrow-derived, allogeneic, multipotent adult progenitor cells (invimestrocel) plus standard treatment in patients with ARDS caused by pneumonia was evaluated., Methods: A randomized, open-label, standard therapy-controlled, phase 2 study (January 2019-September 2021) conducted in 29 centers in Japan. Patients with ARDS caused by pneumonia, with extensive early fibroproliferation on high-resolution computed tomography and low risk of systemic organ failure identified by an Acute Physiology and Chronic Health Evaluation (APACHE II) score were included. Patients were randomized 2:1 to receive a single intravenous infusion of 9.0 × 10 8 cells of invimestrocel (administered at a rate of up to 10 mL/min over 30-60 min by free flow) plus standard treatment (N = 20) or standard treatment (N = 10) consistent with the clinical practice guidelines of the Japanese Respiratory Society for the management of ARDS. Primary endpoint was ventilator-free days (VFDs) through day 28 after study treatment. Analysis of covariance was performed with treatment group, age, partial pressure arterial oxygen/fraction of inspired oxygen ratio, and APACHE II score as covariates., Results: Median (interquartile range) number of VFDs was numerically higher in the invimestrocel group versus standard group (20.0 [0.0-24.0] vs 11.0 [0.0-14.0]) but was not statistically significantly different (least square [LS] means [95% confidence interval (CI)]: invimestrocel group, 11.6 [6.9-16.3]; standard group, 6.2 [- 0.4 to 12.8]; LS mean difference [95% CI], 5.4 [- 1.9 to 12.8]; p = 0.1397). Ventilator weaning rate at day 28 was 65% (13/20) versus 30% (3/10), and mortality rate was 21% (4/19) versus 29% (2/7) at day 28 and 26% (5/19 patients) versus 43% (3/7 patients) at day 180, for the invimestrocel and standard groups, respectively. No allergic or serious adverse reactions were associated with invimestrocel., Conclusions: In Japanese patients with ARDS caused by pneumonia, invimestrocel plus standard treatment resulted in no significant difference in the number of VFDs but may result in improved survival compared with standard treatment. Invimestrocel was well tolerated., Trial Registration: ClinicalTrials.gov, Identifier: NCT03807804; January 8, 2019; https://clinicaltrials.gov/ct2/show/NCT03807804 ., (© 2023. BioMed Central Ltd., part of Springer Nature.)

While high-level evidence is lacking, numerous retrospective studies have depicted the value of supplemental oxygen in idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases, and its use should be encouraged where necessary. The clinical course and survival of patients with IPF who have been introduced to oxygen therapy is still not fully understood. The objective of this study was to clarify overall survival, factors associated with prognosis, and causes of death in IPF patients after the start of oxygen therapy. This is a prospective cohort multicenter study, enrolling patients with IPF who started oxygen therapy at 19 hospitals with expertise in interstitial lung disease. Baseline clinical data at the start of oxygen therapy and 3-year follow-up data including death and cause of death were assessed. Factors associated with prognosis were analyzed using univariable and multivariable analyses. One hundred forty-seven eligible patients, of whom 86 (59%) were prescribed ambulatory oxygen therapy and 61 (41%) were prescribed long-term oxygen therapy, were recruited. Of them, 111 died (76%) during a median follow-up of 479 days. The median survival from the start of oxygen therapy was 537 ± 74 days. In the univariable analysis, low body mass index (BMI), low forced vital capacity (FVC), low diffusion capacity (D LCO ), resting hypoxemia, short 6 min-walk distance, and high COPD assessment test (CAT) score were significantly associated with poor prognosis. Multivariable analysis revealed low BMI, low FVC, low D LCO , low minimum SpO 2 on 6MWT, and high CAT score were independent factors for poor prognosis. The overall survival of IPF patients after starting oxygen therapy is about 1.5 years. In addition to pulmonary function tests, 6MWT and patient reported outcomes can be used to predict prognosis more accurately.Clinical Trial Registration: UMIN000009322., (© 2023. Springer Nature Limited.)

Background: Idiopathic pulmonary fibrosis (IPF) is characterised by worsening dyspnoea and exercise intolerance., Research Question: Does a long-term pulmonary rehabilitation improve exercise tolerance in patients with IPF treated with standard antifibrotic drugs, which are expected to reduce disease progression?, Methods: This open-label randomised controlled trial was performed at 19 institutions. Stable patients receiving nintedanib were randomised into pulmonary rehabilitation and control groups (1:1). The pulmonary rehabilitation group underwent initial rehabilitation which included twice-weekly sessions of monitored exercise training for 12 weeks, followed by an at-home rehabilitation programme for 40 weeks. The control group received usual care only, without pulmonary rehabilitation. Both groups continued to receive nintedanib. The primary and main secondary outcomes were change in 6 min walking distance (6MWD) and change in endurance time (using cycle ergometry) at week 52., Results: Eighty-eight patients were randomised into pulmonary rehabilitation (n=45) and control (n=43) groups. Changes in 6MWD were -33 m (95% CI -65 to -1) and -53 m (95% CI -86 to -21) in the pulmonary rehabilitation and control groups, respectively, with no statistically significant difference (mean difference, 21 m (95% CI -25 to 66), p=0.38). Changes in endurance time were significantly better in the pulmonary rehabilitation (64 s, 95% CI -42.3 to 171)) than in the control (-123 s (95% CI -232 to -13)) group (mean difference, 187 s (95% CI 34 to 153), p=0.019)., Interpretation: Although pulmonary rehabilitation in patients taking nintedanib did not improve 6MWD in the long term, it led to prolonged improvement in endurance time., Trial Registration Number: UMIN000026376., Competing Interests: Competing interests: The following authors received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events outside the submitted work: KK and ON (Nippon Boehringer Ingerheim); TaO (Nippon Boehringer Ingerheim; Shionogi; Eisai; Astellas Pharma; Bristol-Myers Squibb; Taiho Pharmaceutical); TT and HT (Nippon Boehringer Ingerheim; KYORIN Pharmaceutical; AstraZeneca K.K.; Teijin Pharma Limited), KT (Nippon Boehringer Ingerheim; Teijin Pharma); HIs, KI and HaS (Nippon Boehringer Ingerheim); YK (Nippon Boehringer Ingerheim; Asahi Kasei Pharma Corp.; Shionogi; Janssen Pharmaceutical K.K.; Healios K.K.; Taiho Pharmaceutical; AstraZeneca K.K.; Eisai; KYORIN Pharmaceutical; Mitsubishi Tanabe Pharma; Novartis Pharma K.K.)., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objective: Interstitial lung disease (ILD) is progressive with high symptom burdens and poor prognosis. Patients with ILD need optimal palliative care to maintain their quality of life, however, few nationwide surveys have addressed palliative care for ILD., Methods: A nationwide, self-administered questionnaire was conducted. Questionnaires were sent by mail to pulmonary specialists certified by the Japanese Respiratory Society (n = 3423). The current practices of PC for ILD, end-of-life communication, referral to a PC team, barriers to PC for ILD, and comparison of PC between ILD and lung cancer (LC)., Results: 1332 (38.9%) participants completed the questionnaire, and the data of 1023 participants who had cared for ILD patients in the last year were analysed. Most participants reported that ILD patients often or always complained of dyspnoea and cough, but only 25% had referred them to a PC team. The timing of end-of-life communication tended to be later than the physician-perceived ideal timing. The participants experienced significantly greater difficulty in symptomatic relief and decision-making in PC for ILD compared to LC. Prescription of opioids for dyspnoea was less frequent for ILD than for LC. ILD-specific barriers in PC included an 'inability to predict prognosis', 'lack of established treatments for dyspnoea', 'shortage of psychological and social support', and 'difficulty for patients/families to accept the disease's poor prognosis'., Conclusion: Pulmonary specialists experienced more difficulty in providing PC for ILD compared to LC and reported considerable ILD-specific barriers in PC. Multifaceted clinical studies are needed to develop optimal PC for ILD., (© 2023 Asian Pacific Society of Respirology.)

Purpose: We determined the clinical relevance of early C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) change in blood as surrogate markers of pro-tumor inflammation (PTI) for predicting clinical outcome of programmed cell death (PD)-1/programmed cell death ligand (PD-L) 1 inhibitor treatment in non-small-cell lung carcinoma (NSCLC)., Methods: We retrospectively reviewed NSCLC patients treated with anti-PD-1 or PD-L1 inhibitors. Early CRP change was defined as the ratio of 6 weeks CRP to baseline CRP, and early NLR change was defined as that of the 6 weeks NLR to baseline NLR. PTI index was determined by combinatorial evaluation of early CRP change and early NLR change, PTI index low: both of these were low, intermediate: either of these was low, high; both of these were high., Results: The study included 217 patients. Early CRP change and early NLR change were both associated with PFS and OS. The combinatorial evaluation using these two markers enabled the clear stratification of PFS and OS. The median PFS in patient with PTI index low was 13.9 months, while the median PFS in those with PTI index high was 2.5 months (p < 0.01, log-rank test). The median OS in patients with PTI index low was not reached; the median OS in those with PTI index high was only 15.4 months (p < 0.01, log-rank test)., Conclusions: The combinatorial early CRP change and early NLR change as PTI biomarkers have clinical potential in identifying NSCLC patients who can achieve a durable response and long-term survival using PD-1/PD-L1 inhibitors., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Health-related quality of life (HRQoL) captures different aspects of the fibrotic interstitial lung disease (FILD) evaluation from the patient's perspective. However, little is known about how HRQoL changes in patients with non-idiopathic pulmonary fibrosis (IPF) FILD, especially in those with progressive pulmonary fibrosis (PPF). The aim of this study is to clarify whether HRQoL deteriorates in patients with non-IPF FILD and to evaluate the differences in the changes in HRQoL between those with and without PPF., Methods: We collected data from consecutive patients with non-IPF FILD and compared annual changes in HRQoL over 2 years between patients with PPF and those without. The St George's respiratory questionnaire (SGRQ) and COPD assessment test (CAT) were used to assess HRQoL. Changes in the SGRQ and CAT scores for 24 months from baseline were evaluated with a mixed-effect model for repeated measures., Results: A total of 396 patients with non-IPF FILD were reviewed. The median age was 65 years and 202 were male (51.0%). The median SGRQ and CAT scores were 29.6 and 11, respectively. Eighty-six (21.7%) showed PPF. Both SGRQ and CAT scores were significantly deteriorated in patients with PPF compared to those without PPF ( p  < 0.01 for both). Clinically important deterioration in the SGRQ and CAT scores were observed in 40.0 and 35.7% of patients with PPF and 11.7 and 16.7% of those without, respectively. PPF was significantly associated with clinically important deterioration in the SGRQ score (odds ratio 5.04; 95%CI, 2.61-9.76, p  < 0.01) and CAT score (odds ratio 2.78; 95%CI, 1.27-6.06, p  = 0.02)., Conclusion: The SGRQ and CAT scores were significantly deteriorated in patients with non-IPF FILD and PPF. Considering an evaluation of HRQoL would be needed when assessing PPF., Competing Interests: YK reports consultant and lecture fees from Boehringer Ingelheim Co., Ltd. and lecture fees from Sekisui Medical Co., Ltd. TF reports grants from Nippon Boehringer Ingelheim Co., Ltd., outside the submitted work. TJ reports lecture fees from Boehringer Ingelheim Co., Ltd., Astra Zeneca Co. Ltd., and Kyorin Co. Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Takei, Matsuda, Fukihara, Sasano, Yamano, Yokoyama, Kataoka, Kimura, Suzuki, Furukawa, Fukuoka, Johkoh and Kondoh.)

It was reported that the 2020 guideline for hypersensitivity pneumonitis (HP) might result in the overdiagnosis of fibrotic HP (fHP). fHP and other types of interstitial pneumonias have several overlapping characteristics, and a high diagnostic concordance rate of fHP is rarely obtained. Therefore, we investigated the impact of the 2020 HP guideline on the pathological diagnosis of cases previously diagnosed as interstitial pneumonia. We identified 289 fibrotic interstitial pneumonia cases from 2014 to 2019 and classified them into four categories according to the 2020 HP guideline: typical, probable, and indeterminate for fHP and alternative diagnosis. The original pathological diagnosis of 217 cases were compared to their classification as either typical, probable, or indeterminate for fHP according to the 2020 guideline. The clinical data, including serum data and pulmonary function tests, were compared among the groups. Diagnoses changed from non-fHP to fHP for 54 (25%) of the 217 cases, of which, 8 were typical fHP and 46 were probable fHP. The ratio of typical and probable fHP cases to the total number of VATS cases was significantly lower when using transbronchial lung cryobiopsy (p < 0.001). The clinical data of these cases bore a more remarkable resemblance to those diagnosed as indeterminate for fHP than to those diagnosed as typical or probable. The pathological criteria in the new HP guidelines increase the diagnosis of fHP. However, it is unclear whether this increase leads to overdiagnosis, and requires further investigation. Transbronchial lung cryobiopsy may not be helpful when using the new criteria to impart findings for fHP diagnosis., (© 2023. The Author(s).)

Background: Therapeutic strategies in patients with interstitial pneumonia with autoimmune features (IPAF) and histological usual interstitial pneumonia (UIP) pattern (IPAF-UIP) have not been thoroughly evaluated. We compared the therapeutic efficacy of anti-fibrotic therapy with that of immunosuppressive treatment for patients with IPAF-UIP., Methods: In this retrospective case series, we identified consecutive IPAF-UIP patients treated with anti-fibrotic therapy or immunosuppressive therapy. Clinical characteristics, one-year treatment response, acute exacerbation, and survival were studied. We performed a stratified analysis by the pathological presence or absence of inflammatory cell infiltration., Results: Twenty-seven patients with anti-fibrotic therapy and 29 with immunosuppressive treatment were included. There was a significant difference in one-year forced vital capacity (FVC) change between patients with anti-fibrotic treatment (4 in 27 improved, 12 stable, and 11 worsened) and those with immunosuppressive treatment (16 in 29 improved, eight stable, and five worsened) (p = 0.006). There was also a significant difference in one-year St George's Respiratory Questionnaire (SGRQ) change between patients with anti-fibrotic therapy (2 in 27 improved, ten stable, and 15 worsened) and those with immunosuppressive treatment (14 in 29 improved, 12 stable, and worsened) (p < 0.001). There was no significant difference in survival between the groups (p = 0.32). However, in the subgroup with histological inflammatory cell infiltration, survival was significantly better with immunosuppressive therapy (p = 0.02)., Conclusion: In IPAF-UIP, immunosuppressive therapy seemed to be superior to anti-fibrotic treatment in terms of therapeutic response, and provided better outcomes in the histological inflammatory subgroup. Further prospective studies are needed to clarify the therapeutic strategy in IPAF-UIP., Competing Interests: Conflict of Interest Dr. Kondoh and Dr. Kataoka have received fees fromBoehringer Ingelheim Co., Ltd. that were unrelated to the present work. The authors have no other conflicts of interest to declare., (Copyright © 2023. Published by Elsevier B.V.)

TEAD is a transcription factor responsible for the output of the tumor suppressor Hippo pathway. The transcriptional activity of TEAD requires molecular interaction with its transcriptional coactivator, YAP. Aberrant activation of TEAD is deeply involved in tumorigenesis and is associated with poor prognosis, suggesting that inhibitors targeting the YAP-TEAD system are promising as antitumor agents. In this study, we identified NPD689, an analog of the natural product alkaloid emetine, as an inhibitor of the YAP-TEAD interaction. NPD689 suppressed the transcriptional activity of TEAD and reduced the viability of human malignant pleural mesothelioma and non-small cell lung cancer cells but not the viability of normal human mesothelial cells. Our results suggest that NPD689 is not only a new useful chemical tool for elucidating the biological role of the YAP-TEAD system but also has potential as a starting compound for developing a cancer therapeutic agent that targets the YAP-TEAD interaction., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Introduction: Nintedanib is recommended for the treatment of idiopathic pulmonary fibrosis (IPF); however, treatment discontinuation due to adverse events (AEs) is common. A large-scale post-marketing surveillance study is investigating the real-world tolerability/safety of nintedanib in Japanese patients with IPF in routine clinical practice. Here, we report a 12-month interim analysis of this study., Methods: The study included Japanese patients with IPF who started nintedanib between 31 August 2015 and 25 December 2018. The primary outcome was the frequency of adverse drug reactions (ADRs), defined as AEs for which a causal relationship with nintedanib could not be excluded. The secondary outcome was change from baseline in forced vital capacity (FVC). Outcomes were analysed in patients who stopped ('discontinued' subgroup) and continued ('continued' subgroup) nintedanib after 12 months. A multivariate analysis was performed to determine potential risk factors for treatment discontinuation., Results: Of 5578 patients in the safety analysis set, 2795 (50.1%) discontinued nintedanib within 12 months of treatment initiation. Overall, 3767 patients (67.5%) had ADRs, with 1356 (24.3%) discontinuing nintedanib because of an ADR. Among patients in the 'discontinued' subgroup (n = 2795), 1442 (51.6%) discontinued because of an ADR. The most common ADRs causing discontinuation within 3 and 12 months were hepatic function abnormal (n = 137/730; 18.8%) and diarrhoea (n = 190/1442; 13.2%), respectively. At 12 months, the decrease in FVC from baseline was smaller in the 'continued' versus the 'discontinued' subgroup (adjusted mean ± standard error change - 104.4 ± 10.9 ml vs. - 311.2 ± 29.2 ml). Stage III/IV IPF and FVC < 70% predicted at baseline were risk factors for early treatment discontinuation., Conclusion: About 50% of Japanese patients with IPF discontinued nintedanib within the first year of treatment, with worse lung function being associated with an increased risk of early treatment discontinuation., Trial Registration: ClinicalTrials.gov: NCT02607722; European Union electronic register of Post-Authorisation Studies: EUPAS10891., (© 2023. The Author(s).)

Molnupiravir (MOV) and nirmatrelvir/ritonavir (NMV/r) are efficacious oral antiviral agents for patients with the 2019 coronavirus (COVID-19). However, little is known about their effectiveness in older adults and those at high risk of disease progression. This retrospective single-center observational study assessed and compared the outcomes of COVID-19 treated with MOV and NMV/r in a real-world community setting. We included patients with confirmed COVID-19 combined with one or more risk factors for disease progression from June to October 2022. Of 283 patients, 79.9% received MOV and 20.1% NMV/r. The mean patient age was 71.7 years, 56.5% were men, and 71.7% had received ≥3 doses of vaccine. COVID-19-related hospitalization (2.8% and 3.5%, respectively; p = 0.978) or death (0.4% and 3.5%, respectively; p = 0.104) did not differ significantly between the MOV and NMV/r groups. The incidence of adverse events was 2.7% and 5.3%, and the incidence of treatment discontinuation was 2.7% and 5.3% in the MOV and NMV/r groups, respectively. The real-world effectiveness of MOV and NMV/r was similar among older adults and those at high risk of disease progression. The incidence of hospitalization or death was low.