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Abstract Impact Bronchopulmonary dysplasia has multiple definitions that are currently based on phenotypic characteristics. Using an unsupervised machine learning approach, we created BPD subclasses (e.g., endotypes) by clustering whole microarray data. T helper 17 cell differentiation was the most significant pathway differentiating the BPD endotypes. Introduction Bronchopulmonary dysplasia (BPD) is the most common complication of extreme prematurity. Discovery of BPD endotypes in an unbiased format, derived from the peripheral blood transcriptome, may uncover patterns underpinning this complex lung disease. Methods An unsupervised agglomerative hierarchical clustering approach applied to genome-wide expression of profiling from 62 children at day of life five was used to identify BPD endotypes. To identify which genes were differentially expressed across the BPD endotypes, we formulated a linear model based on least-squares minimization with empirical Bayes statistics. Results Four BPD endotypes (A, B,C,D) were identified using 7,319 differentially expressed genes. Across BPD endotypes, 5,850 genes had a p value

Abstract The present document is the result of a consensus reached by a panel of experts from European and non-European countries on Occupational Rhinitis (OR), a disease of emerging relevance which has received little attention in comparison to occupational asthma. The document covers the main items of OR including epidemiology, diagnosis, management, socio-economic impact, preventive strategies and medicolegal issues. An operational definition and classification of OR tailored on that of occupational asthma, as well as a diagnostic algorithm based on steps allowing for different levels of diagnostic evidence are proposed. The needs for future research are pointed out. Key messages are issued for each item.

The present document is the result of a consensus reached by a panel of experts from European and non-European countries on Occupational Rhinitis (OR), a disease of emerging relevance which has received little attention in comparison to occupational asthma. The document covers the main items of OR including epidemiology, diagnosis, management, socio-economic impact, preventive strategies and medicolegal issues. An operational definition and classification of OR tailored on that of occupational asthma, as well as a diagnostic algorithm based on steps allowing for different levels of diagnostic evidence are proposed. The needs for future research are pointed out. Key messages are issued for each item.

Background: The use of machine learning(ML) methods would improve the diagnosis of small airway dysfunction(SAD) in subjects with chronic respiratory symptoms and preserved pulmonary function(PPF). This paper evaluated the performance of several ML algorithms associated with the impulse oscillometry(IOS) analysis to aid in the diagnostic of respiratory changes in SAD. We also find out the best configuration for this task. Methods: IOS and spirometry were measured in 280 subjects, including a healthy control group (n = 78), a group with normal spirometry (n = 158) and a group with abnormal spirometry (n = 44). Various supervised machine learning (ML) algorithms and feature selection strategies were examined, such as Support Vector Machines (SVM), Random Forests (RF), Adaptive Boosting (ADABOOST), Navie Bayesian (BAYES), and K-Nearest Neighbors (KNN). Results: The first experiment of this study demonstrated that the best oscillometric parameter (BOP) was R5, with an AUC value of 0.642, when comparing a healthy control group(CG) with patients in the group without lung volume-defined SAD(PPFN). The AUC value of BOP in the control group was 0.769 compared with patients with spirometry defined SAD(PPFA) in the PPF population. In the second experiment, the ML technique was used. In CGvsPPFN, RF and ADABOOST had the best diagnostic results (AUC = 0.914, 0.915), with significantly higher accuracy compared to BOP (p < 0.01). In CGvsPPFA, RF and ADABOOST had the best diagnostic results (AUC = 0.951, 0.971) and significantly higher diagnostic accuracy (p < 0.01). In the third, fourth and fifth experiments, different feature selection techniques allowed us to find the best IOS parameters (R5, (R5-R20)/R5 and Fres). The results demonstrate that the performance of ADABOOST remained essentially unaltered following the application of the feature selector, whereas the diagnostic accuracy of the remaining four classifiers (RF, SVM, BAYES, and KNN) is marginally enhanced. Conclusions: IOS combined with ML algorithms provide a new method for diagnosing SAD in subjects with chronic respiratory symptoms and PPF. The present study's findings provide evidence that this combination may help in the early diagnosis of respiratory changes in these patients. [ABSTRACT FROM AUTHOR]

Neu1 is a sialidase enzyme that plays a crucial role in the regulation of glycosylation in a variety of cellular processes, including cellular signaling and inflammation. In recent years, numerous evidence has suggested that human NEU1 is also involved in the pathogenesis of various respiratory diseases, including lung infection, chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis. This review paper aims to provide an overview of the current research on human NEU1 and respiratory diseases. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung disease and a major health burden worldwide. Extracellular vesicles (EVs) are nanosized vesicles which possess a lipid bilayer structure that are secreted by various cells. They contain a variety of bioactive substances, which can regulate various physiological and pathological processes and are closely related to the development of diseases. Recently, EVs have emerged as a novel tool for intercellular crosstalk, which plays an essential role in COPD development. This paper reviews the role of EVs in the development of COPD and their potential clinical value, in order to provide a reference for further research on COPD. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited treatment options. Circular RNAs (circRNAs) have emerged as a novel class of non-coding RNAs with diverse functions in cellular processes. This review paper aims to explore the potential involvement of circRNAs in the pathogenesis of IPF and their diagnostic and therapeutic implications. We begin by providing an overview of the epidemiology and risk factors associated with IPF, followed by a discussion of the pathophysiology underlying this complex disease. Subsequently, we delve into the history, types, biogenesis, and functions of circRNAs and then emphasize their regulatory roles in the pathogenesis of IPF. Furthermore, we examine the current methodologies for detecting circRNAs and explore their diagnostic applications in IPF. Finally, we discuss the potential utility of circRNAs in the treatment of IPF. In conclusion, circRNAs hold great promise as novel biomarkers and therapeutic targets in the management of IPF. [ABSTRACT FROM AUTHOR]

Background: Current techniques used to obtain lung samples have significant limitations and do not provide reproducible biomarkers of inflammation. We have developed a novel technique that allows multiple sampling methods from the same area (or multiple areas) of the lung under direct bronchoscopic vision. It allows collection of mucosal lining fluid and bronchial brushing from the same site; biopsy samples may also be taken. The novel technique takes the same time as standard procedures and can be conducted safely., Methods: Eight healthy smokers aged 40-65 years were included in this study. An absorptive filter paper was applied to the bronchial mucosa under direct vision using standard bronchoscopic techniques. Further samples were obtained from the same site using bronchial brushings. Bronchoalveolar lavage (BAL) was obtained using standard techniques. Chemokine (C-C Motif) Ligand 20 (CCL20), CCL4, CCL5, Chemokine (C-X-C Motif) Ligand 1 (CXCL1), CXCL8, CXCL9, CXCL10, CXCL11, Interleukin 1 beta (IL-1β), IL-6, Vascular endothelial growth factor (VEGF), Matrix metalloproteinase 8 (MMP-8) and MMP-9 were measured in exudate and BAL. mRNA was collected from the bronchial brushings for gene expression analysis., Results: A greater than 10 fold concentration of all the biomarkers was detected in lung exudate in comparison to BAL. High yield of good quality RNA with RNA integrity numbers (RIN) between 7.6 and 9.3 were extracted from the bronchial brushings. The subset of genes measured were reproducible across the samples and corresponded to the inflammatory markers measured in exudate and BAL., Conclusions: The bronchoabsorption technique as described offers the ability to sample lung fluid direct from the site of interest without the dilution effects caused by BAL. Using this method we were able to successfully measure the concentrations of biomarkers present in the lungs as well as collect high yield mRNA samples for gene expression analysis from the same site. This technique demonstrates superior sensitivity to standard BAL for the measurement of biomarkers of inflammation. It could replace BAL as the method of choice for these measurements. This method provides a systems biology approach to studying the inflammatory markers of respiratory disease progression., Trial Registration: NHS Health Research Authority (13/LO/0256).

Background: Multiple prolonged symptoms are observed in patients who recover from acute coronavirus disease 2019 (COVID-19), defined as long COVID. Cough and sputum are presented by patients with long COVID during the acute and post-acute phases. This study aimed to identify specific risk factors for cough and sputum in patients with long COVID. Methods: Hospitalized patients with COVID-19 aged 18 years were enrolled in a multicenter cohort study at 26 medical institutions. Clinical data during hospitalization and patient-reported outcomes after discharge were collected from medical records, paper-based questionnaires, and smartphone apps. Results: At the 3-, 6-, and 12-month follow-ups, there were no differences in the incidence rates of wet and dry coughs. In contrast, the proportion of patients presenting sputum without coughing increased over time compared to those with sputum and coughing. Univariate analyses of cough and sputum at all follow-up visits identified intermittent mandatory ventilation (IMV), smoking, and older age as risk factors for prolonged symptoms. At the 12-month follow-up, persistent cough and sputum were associated with the characteristics of severe COVID-19 based on imaging findings, renal and liver dysfunction, pulmonary thromboembolism, and higher serum levels of LDH, KL-6, and HbA1C. The Kaplan–Meier curves showed that the severity of acute COVID-19 infection was correlated with prolonged cough and sputum production. Multivariable logistic regression analysis showed that IMV ventilator management were independent risk factors for prolonged cough and sputum at 12 months. Conclusions: In a Japanese population with long COVID, prolonged cough and sputum production were closely associated with severe COVID-19. These findings emphasize that a preventive approach including appropriate vaccination and contact precaution and further development of therapeutic drugs for COVID-19 are highly recommended for patients with risk factors for severe infection to avoid persistent respiratory symptoms. [ABSTRACT FROM AUTHOR]

This correction notice addresses an error in the original article titled "Silencing of CD147 inhibits cell proliferation, migration, invasion, lipid metabolism dysregulation and promotes apoptosis in lung adenocarcinoma via blocking the Rap1 signaling pathway." The authors identified that Figures 1 and 2 were inadvertently swapped. The correction provides the correct figures and captions, and assures readers that the corrections do not alter the interpretations or validity of the research. The error does not significantly impact the overall findings and conclusions of the paper. [Extracted from the article]

Reference 1 Wu J, Zhang H, Shi Y, Wang J, Han Y, Zhang Q, Wang N, Liu S, Zhang Y, Zi H, Wang F, Liu A, Song Y, Jia C, Feng Y, Liu Q, Wan L, Ji M, Long Z, Huang J, Liu L, Sun Y, Tang S, Dong X, Zhou X, Jiang W, Shen L, Jiang H. Reference values of impulse oscillometry (IOS) for healthy Chinese children aged 4-17 years. Correction: Reference values of impulse oscillometry (IOS) for healthy Chinese children aged 4-17 years Jinhong Wu, Hao Zhang, Yongsheng Shi, Jinrong Wang, Yuling Han, Qiaoling Zhang, Ning Wang, Sha Liu, Yuehua Zhang, Huifen Zi, Fei Wang, Aihong Liu, Yuxin Song, ChunMei Jia, Yong Feng, Quanhua Liu, liya Wan, Minghong Ji, Zhen Long, Jianfeng Huang, Li Liu, Yun Sun, Suping Tang, Xiaoyan Dong, Xiaojian Zhou, Wenhui Jiang, Li Shen and Haohua Jiang contributed equally to the paper B Correction: Respiratory Research (2022) 23:182 b https://doi.org/10.1186/s12931-022-02080-z Following publication of the original article [[1]], the authors identified that the article note about equal contribution was missing. [Extracted from the article]

The article is a response to a comment on the classification of interstitial lung diseases (ILDs). The authors acknowledge that the number of unique ILDs is not over 200, as frequently reported in several papers. The classification of ILDs has evolved over the years, incorporating clinical, radiological, and pathological patterns. There is ongoing debate on whether to lump or split ILD patients based on disease behavior, with the potential for identifying new targeted therapies. The authors believe that a dynamic disease classification, considering etiologies, phenotypes, endotypes, and disease behavior, will guide treatment approaches in the future. [Extracted from the article]

Background: Patients with neutrophil-mediated asthma have poor response to glucocorticoids. The roles and mechanisms of group 3 innate lymphoid cells (ILC3s) in inducing neutrophilic airway inflammation and glucocorticoid resistance in asthma have not been fully clarified. Methods: ILC3s in peripheral blood were measured by flow cytometry in patients with eosinophilic asthma (EA) and non-eosinophilic asthma (NEA). ILC3s were sorted and cultured in vitro for RNA sequencing. Cytokines production and signaling pathways in ILC3s after IL-1β stimulation and dexamethasone treatment were determined by real-time PCR, flow cytometry, ELISA and western blot. Results: The percentage and numbers of ILC3s in peripheral blood was higher in patients with NEA compared with EA, and negatively correlated with blood eosinophils. IL-1β stimulation significantly enhanced CXCL8 and CXCL1 production in ILC3s via activation of p65 NF-κB and p38/JNK MAPK signaling pathways. The expression of neutrophil chemoattractants from ILC3s was insensitive to dexamethasone treatment. Dexamethasone significantly increased phosphorylation of glucocorticoid receptor (GR) at Ser226 but only with a weak induction at Ser211 residues in ILC3s. Compared to human bronchial epithelial cell line (16HBE cells), the ratio of p-GR S226 to p-GR S211 (p-GR S226/S211) was significantly higher in ILC3s at baseline and after dexamethasone treatment. In addition, IL-1β could induce Ser226 phosphorylation and had a crosstalk effect to dexamethasone via NF-κB pathway. Conclusions: ILC3s were elevated in patients with NEA, and associated with neutrophil inflammation by release of neutrophil chemoattractants and were glucocorticoid (GC) resistant. This paper provides a novel cellular and molecular mechanisms of neutrophil inflammation and GC-resistance in asthma. Trial registration The study has been prospectively registered in the World Health Organization International Clinical Trials Registry Platform (ChiCTR1900027125) [ABSTRACT FROM AUTHOR]

Electronic cigarettes (or e-cigarettes) can be used as smoking cessation aid. Some studies tend to show that they are less hazardous than tobacco cigarettes, even if it does not mean they are completely safe. The huge variation in study designs assessing in vitro toxicity of e-cigarettes aerosol makes it difficult to make comparisons and draw robust and irrefutable conclusions. In this paper, we review this heterogeneity (in terms of e-cigarette products, biological models, and exposure conditions) with a special focus on the wide disparity in the doses used as well as in the way they are expressed. Finally, we discuss the major issue of dosimetry and show how dosimetry tools enable to align data between different exposure systems or data from different laboratories and therefore allow comparisons to help further exploring the risk potential of e-cigarettes. [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypertension (PH) is a progressive and fatal cardiopulmonary disease characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance and artery pressure. Vascular remodeling is associated with the excessive cell proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). In this paper, the effects of heat shock protein-110 (HSP110) on PH were investigated. Methods: The C57BL/6 mice and human PASMCs (HPASMCs) were respectively exposed to hypoxia to establish and simulate PH model in vivo and cell experiment in vitro. To HSP110 knockdown, the hypoxia mice and HPASMCs were infected with adeno-associated virus or adenovirus carring the shRNAs (short hairpin RNAs) for HSP110 (shHSP110). For HSP110 and yes-associated protein (YAP) overexpression, HPASMCs were infected with adenovirus vector carring the cDNA of HSP110 or YAP. The effects of HSP110 on PH development in mice and cell proliferation, migration and autophagy of PASMCs under hypoxia were assessed. Moreover, the regulatory mechanisms among HSP110, YAP and TEA domain transcription factor 4 (TEAD4) were investigated. Results: We demonstrated that expression of HSP110 was significantly increased in the pulmonary arteries of mice and HPASMCs under hypoxia. Moreover, knockdown of HSP110 alleviated hypoxia-induced right ventricle systolic pressure, vascular wall thickening, right ventricular hypertrophy, autophagy and proliferation of PASMCs in mice. In addition, knockdown of HSP110 inhibited the increases of proliferation, migration and autophagy of HPASMCs that induced by hypoxia in vitro. Mechanistically, HSP110 knockdown inhibited YAP and transcriptional co-activator with PDZ-binding motif (TAZ) activity and TEAD4 nuclear expression under hypoxia. However, overexpression of HSP110 exhibited the opposite results in HPASMCs. Additionally, overexpression of YAP partially restored the effects of shHSP110 on HPASMCs. The interaction of HSP110 and YAP was verified. Moreover, TEAD4 could promote the transcriptional activity of HSP110 by binding to the HSP110 promoter under hypoxia. Conclusions: Our findings suggest that HSP110 might contribute to the development of PH by regulating the proliferation, migration and autophagy of PASMCs through YAP/TAZ-TEAD4 pathway, which may help to understand deeper the pathogenic mechanism in PH development. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) and interstital lung disease (ILD) are incurable conditions characterised by airflow limitation, persisting respiratory symptoms, and progressive respiratory failure. People living with COPD or ILD often suffer from chronic and severe breathlessness, with limited treatment options and low engagement rates with current therapies. Group singing represents a potential community-based therapy to improve quality of life for patients with COPD or ILD and breathlessness.Methods: This protocol papers describes SINFONIA, a parallel, double-arm, randomised, blinded-analysis, mixed-methods phase II/III trial of guided, online group singing that will be conducted over 24 months. Adults with confirmed COPD or ILD, on stable treatment for at least four weeks at time of recruitment, with a modified Medical Research Council (mMRC) dyspnoea score of two or greater, who are capable and willing to give consent, and not currently participating in pulmonary rehabilitation will be eligible to participate. Carers may optionally enrol in the trial. Data will be collected on quality of life, anxiety and depression, breathlessness, mastery of breathing, exercise tolerance, loneliness, healthcare utilisation, and carer quality of life (optional). Participants will be randomised 1:1 to intervention or control arms with intervention arm attending one 90 min, guided, online, group singing session per week for 12 weeks and control arm continuing routine care. Phase II of the trial aims to determine the feasibility and acceptability of guided, online group singing and will collect preliminary data on effectiveness. Phase III aims to determine whether guided, online group singing has an effect on quality of life with the primary outcome being a between arm difference in quality of life (36-item Short Form Survey) measured at 12 weeks.Discussion: SINFONIA is the first study is the first of its kind in Australia and to our knowledge, the first to deliver the singing intervention program entirely online. Determining the feasibility, acceptability, and effectiveness of guided, online group singing is an important step towards improving low-cost, low-risk, community-based therapeutic options for patients living with COPD or ILD and breathlessness.Trial Registration: Phase II- ACTRN12621001274864 , registered 20th September 2021; Phase III- ACTRN12621001280897 , registered 22nd September 2021. [ABSTRACT FROM AUTHOR]

Background: Chronic Obstructive Pulmonary Disease (COPD) is a common inflammatory disease of the airways characterized by irreversible airflow limitation, ranking the third highest cause of death worldwide. Extracellular vesicles (EVs) are important intercellular communication mediators released by cells into their extracellular environment with the capacity to transfer biological signals. EVs involved in COPD hold great potential to understand disease pathogenesis and identify important biomarkers. This systematic review aims to examine all available research on EVs in the pathogenesis and diagnosis of COPD to identify existing knowledge and support further research within the field.Methods: Publications were searched using PubMed and EMBASE with the search terms (Exosomes or extracellular vesicles or microvesicles or microparticles or ectosomes) AND (chronic obstructive pulmonary disease or COPD or emphysema or bronchitis).Results: Initial search yielded 512 papers of which 142 were manually selected for review and 43 were eligible for analyses. The studies were divided into groups according to the role of EVs in pathogenesis, EV origin and cargo, their role in COPD exacerbations and their diagnostic utility. EVs were found to be involved in the mechanism of pathogenesis of COPD, derived from various cell types, as well as containing modified levels of miRNAs. EVs also varied according to the pathophysiological status of disease, therefore presenting a possible method for COPD diagnosis and progress monitoring.Conclusion: The current findings show the limited but good quality research looking at the role of EVs in COPD, demonstrating the need for more studies to better define and provide further insight into the functional characteristics of EV in COPD pathogenesis. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via the original article. [ABSTRACT FROM AUTHOR]

Background: The novel coronavirus SARS-CoV-2 has caused a global COVID-19 pandemic, leading to worldwide changes in public health measures. In addition to changes in the public sector (lockdowns, contact restrictions), hospitals modified care to minimize risk of infection and to mobilize resources for COVID-19 patients. Our study aimed to assess the impact of these measures on access to care and behaviour of patients with thoracic malignancies.Methods: Thoracic oncology patients were surveyed in October 2020 using paper-based questionnaires to assess access to ambulatory care services and tumor-directed therapy during the COVID-19 pandemic. Additionally, behaviour regarding social distancing and wearing of face masks were assessed, as well as COVID-19 exposure, testing and vaccination. Results are presented as absolute and relative frequencies for categorical variables and means with standard deviation for numerical variables. We used t-test, and ANOVA to compare differences in metric variables and Chi2-test to compare proportions between groups.Results: 93 of 245 (38%) patients surveyed completed the questionnaire. Respiration therapy and physical therapy were unavailable for 57% to 70% of patients during March/April. Appointments for tumor-directed therapy, tumor imaging, and follow-up care were postponed or cancelled for 18.9%, 13.6%, and 14.8% of patients, respectively. Patients reported their general health as mostly unaffected. The majority of patients surveyed did not report reducing their contacts with family. The majority reduced contact with friends. Most patients wore community masks, although a significant proportion reported respiratory difficulties during prolonged mask-wearing. 74 patients (80%) reported willingness to be vaccinated against SARS-CoV-2.Conclusions: This survey provides insights into the patient experience during the second wave of the COVID-19 pandemic in Munich, Germany. Most patients reported no negative changes to cancer treatments or general health; however, allied health services were greatly impacted. Patients reported gaps in social distancing, but were prepared to wear community masks. The willingness to get vaccinated against SARS-CoV-2 was high. This information is not only of high relevance to policy makers, but also to health care providers. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic has affected the world extraordinarily. This disease has a potential to cause a significantly severe course of disease leading to respiratory complications, multiple organ failure and possibly death. In the fight against this pandemic-causing disease, medical professionals around the world are searching for pharmacological agents that could treat and prevent disease progression and mortality. To speed the search of promising treatment options, already existing pharmacological agents are repurposed for the potential treatment of COVID-19 and tested in clinical trials. The aim of this literature review is to investigate the efficacy and safety of repurposed pharmacological agents for the treatment of COVID-19 at different pathophysiologic stages of the disease. For this literature review, online-databases PubMed and Google Scholar were utilised. Keywords "COVID-19", "SARS-CoV-2", "pathogenesis", "drug targets", "pharmacological treatment", "cytokine storm", "coagulopathy" and individual drug names were used. Scientific articles, including reviews, clinical trials, and observational cohorts, were collected and analysed. Furthermore, these articles were examined for references to find more clinical trials testing for the potential treatment of COVID-19. In total, 97 references were used to conduct this research paper.Results: The most beneficial pharmacological agent for the treatment of COVID-19 are corticosteroids, especially dexamethasone, for the treatment of mechanically ventilated COVID-19 patients. Other promising agents are remdesivir for the treatment of patients with COVID-19 pneumonia requiring minimal supplemental oxygen therapy, and IL-6 receptor antagonist monoclonal antibodies in severe COVID-19. Lopinavir/ritonavir, as well as chloroquine or hydroxychloroquine with or without azithromycin demonstrate the least efficacy in the treatment of COVID-19. The clinical benefits of the treatment of a COVID-19-specific coagulopathy with increased dosing of anticoagulation need further research and confirmation of randomised controlled trials.Conclusion: The search for pharmacological treatment of COVID-19 has elicited great controversy. Whereas drugs like chloroquine, hydroxychloroquine, and lopinavir/ritonavir have not shown proven benefit, the agents remdesivir and dexamethasone are recommended for clinical use for the treatment of COVID-19. Further randomised trials for other pharmacological treatment strategies are awaited. [ABSTRACT FROM AUTHOR]

Background: The mannitol test is an indirect bronchial challenge test widely used in diagnosing asthma. Response to the mannitol test correlates with the level of eosinophilic and mast cell airway inflammation, and a positive mannitol test is highly predictive of a response to anti-inflammatory treatment with inhaled corticosteroids. The response to mannitol is a physiological biomarker that may, therefore, be used to assess the response to other anti-inflammatory treatments and may be of particular interest in early phase studies that require surrogate markers to predict a clinical response. The main objectives of this review were to assess the practical aspects of using mannitol as an endpoint in clinical trials and provide the clinical researcher and respiratory physician with recommendations when designing early clinical trials.Methods: The aim of this review was to summarise previous uses of the mannitol test as an outcome measure in clinical intervention studies. The PubMed database was searched using a combination of MeSH and keywords. Eligible studies included intervention or repeatability studies using the standard mannitol test, at multiple timepoints, reporting the use of PD15 as a measure, and published in English.Results: Of the 193 papers identified, 12 studies met the inclusion criteria and data from these are discussed in detail. Data on the mode of action, correlation with airway inflammation, its diagnostic properties, and repeatability have been summarised, and suggestions for the reporting of test results provided. Worked examples of power calculations for dimensioning study populations are presented for different types of study designs. Finally, interpretation and reporting of the change in the response to the mannitol test are discussed.Conclusions: The mechanistic and practical features of the mannitol test make it a useful marker of disease, not only in clinical diagnoses, but also as an outcome measure in intervention trials. Measuring airway hyperresponsiveness to mannitol provides a novel and reproducible test for assessing efficacy in intervention trials, and importantly, utilises a test that links directly to underlying drivers of disease. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via the original article. [ABSTRACT FROM AUTHOR]

Epidemiological studies have found strong associations between air pollution and respiratory effects including development and/or exacerbation of asthma and chronic obstructive pulmonary disease (COPD) as well as increased occurrence of respiratory infections and lung cancer. It has become increasingly clear that also polycyclic aromatic hydrocarbons (PAHs) may affect processes linked to non-malignant diseases in the airways. The aim of the present paper was to review epidemiological studies on associations between gas phase and particle-bound PAHs in ambient air and non-malignant respiratory diseases or closely related physiological processes, to assess whether PAH-exposure may explain some of the effects associated with air pollution. Based on experimental in vivo and in vitro studies, we also explore possible mechanisms for how different PAHs may contribute to such events. Epidemiological studies show strongest evidence for an association between PAHs and asthma development and respiratory function in children. This is supported by studies on prenatal and postnatal exposure. Exposure to PAHs in adults seems to be linked to respiratory functions, exacerbation of asthma and increased morbidity/mortality of obstructive lung diseases. However, available studies are few and weak. Notably, the PAHs measured in plasma/urine also represent other exposure routes than inhalation. Furthermore, the role of PAHs measured in air is difficult to disentangle from that of other air pollution components originating from combustion processes. Experimental studies show that PAHs may trigger various processes linked to non-malignant respiratory diseases. Physiological- and pathological responses include redox imbalance, oxidative stress, inflammation both from the innate and adaptive immune systems, smooth muscle constriction, epithelial- and endothelial dysfunction and dysregulated lung development. Such biological responses may at the molecular level be initiated by PAH-binding to the aryl hydrocarbon receptor (AhR), but possibly also through interactions with beta-adrenergic receptors. In addition, reactive PAH metabolites or reactive oxygen species (ROS) may interfere directly with ion transporters and enzymes involved in signal transduction. Overall, the reviewed literature shows that respiratory effects of PAH-exposure in ambient air may extend beyond lung cancer. The relative importance of the specific PAHs ability to induce disease may differ between the biological endpoint in question. [ABSTRACT FROM AUTHOR]

Background: Chronic rhinosinusitis (CRS) is defined as a condition of inflammation in the paranasal sinus mucosa persisting for more than 12 weeks. We previously reported that the prevalence of CRS was about 8 % in China. Here, we aim to investigate the occupational and environmental risk factors associated with CRS.Methods: Data were collected from seven Chinese cities: Urumqi, Changchun, Beijing, Wuhan, Chengdu, Huaian and Guangzhou. CRS was diagnosed according to the European Position Paper on Rhinosinusitis and Nasal Polyps (EP(3)OS) document. Participants were asked to complete a standardized questionnaire, which was developed by the Global Allergy and Asthma European Network (GA(2)LEN) project and covered sociodemographic characteristics, CRS-related symptoms and occupational and environmental exposures. We evaluated the association between CRS and various occupational and environmental factors using odds ratios (ORs) and 95 % confidence intervals (95 % CIs).Results: The total study population consisted of 10,633 subjects, 850 (7.99 %) of whom were defined as having CRS according to the EP(3)OS criteria. We found that there were significant associations between occupational and environmental factors and CRS. Specifically, having a clearance-related job, occupational exposure to dust, occupational exposure to poisonous gas, a pet at home or carpet at home or at the workplace were risk factors for CRS. Additionally, the method used to keep warm in winter, the duration of time spent using air conditioning in summer and the frequency of exposure to mouldy or damp environments were significantly different in subjects with and without CRS.Conclusions: Our data showed that some occupational and environmental exposures are strongly associated with CRS, which aids in understanding the epidemiology of CRS. [ABSTRACT FROM AUTHOR]

Background: Numerous studies indicate an association between vitamin D status and inflammatory biomarkers in patients with asthma, but findings are inconsistent. This review aims to summarize the relationship between serum vitamin D status, assessed by 25-hydroxyvitamin D (25(OH)D) level, and inflammatory biomarkers in children and adults with asthma. Methods: A literature search of interventional and observational studies on 25(OH)D up to November 2022 was conducted across six electronic databases. Outcomes of interest included a range of inflammatory biomarkers classified in four categories: T helper 2 (Th2) pro-inflammatory, non-Th2 pro-inflammatory, anti-inflammatory, and non-specific biomarkers. Study characteristics were extracted and risk of bias was evaluated using the American Academy of Nutrition and Dietetics tool. Meta-analysis was conducted on studies with a low risk of bias, while narrative reporting was used to present the direction of associations (positive, no association, or negative) for each biomarker, overall and within the low-risk studies. Results: We included 71 studies (3 interventional, 68 observational) involving asthma patients. These studies investigated the association between serum 25(OH)D and Th2 pro-inflammatory biomarkers (N = 58), non-Th2 pro-inflammatory biomarkers (N = 18), anti-inflammatory biomarkers (N = 16), and non-specific biomarkers (N = 10). Thirteen (18.3%) studies, 50 (70.4%), and 8 (11.3%) were at high, moderate, and low risk of bias, respectively. In all studies, irrespective of risk of bias, the most frequently reported finding was no significant association, followed by a negative association between 25(OH)D and pro-inflammatory biomarkers and a positive association with anti-inflammatory biomarkers. In low-risk studies, one biomarker could be meta-analysed. The pooled estimate for 25(OH)D and serum IgE showed a negative association (β (95% CI)= − 0.33 (–0.65 to − 0.01); I2 = 88%; N = 4 studies). A negative association between 25(OH)D and blood eosinophils was also observed in the largest of three studies, as well as with cathelicidin (LL-37) in the only study reporting it. For other biomarkers, most low-risk studies revealed no significant association with 25(OH)D. Conclusion: Serum 25(OH)D is negatively associated with serum IgE and possibly with blood eosinophils and LL-37, supporting an in vivo immunomodulatory effect of 25(OH)D. Future research should employ rigorous methodologies and standardized reporting for meta-analysis aggregation to further elucidate these associations. [ABSTRACT FROM AUTHOR]

X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy. Most (80%) children with XLMTM have profound muscle weakness and hypotonia at birth resulting in severe respiratory insufficiency, the inability to sit up, stand or walk, and early mortality. At birth, 85–90% of children with XLMTM require mechanical ventilation, with more than half requiring invasive ventilator support. Historically, ventilator-dependent children with neuromuscular-derived respiratory failure of this degree and nature, static or progressive, are not expected to achieve complete independence from mechanical ventilator support. In the ASPIRO clinical trial (NCT03199469), participants receiving a single intravenous dose of an investigational gene therapy (resamirigene bilparvovec) started showing significant improvements in daily hours of ventilation support compared with controls by 24 weeks post-dosing, and 16 of 24 dosed participants achieved ventilator independence between 14 and 97 weeks after dosing. At the time, there was no precedent or published guidance for weaning chronically ventilated children with congenital neuromuscular diseases off mechanical ventilation. When the first ASPIRO participants started showing dramatically improved respiratory function, the investigators initiated efforts to safely wean them off ventilator support, in parallel with primary protocol respiratory outcome measures. A group of experts in respiratory care and physiology and management of children with XLMTM developed an algorithm to safely wean children in the ASPIRO trial off mechanical ventilation as their respiratory muscle strength increased. The algorithm developed for this trial provides recommendations for assessing weaning readiness, a stepwise approach to weaning, and monitoring of children during and after the weaning process. [ABSTRACT FROM AUTHOR]

The WHO recently published a Tobacco Knowledge Summary (TKS) synthesizing current evidence on tobacco and COPD, aiming to raise awareness among a broad audience of health care professionals. Furthermore, it can be used as an advocacy tool in the fight for tobacco control and prevention of tobacco-related disease. This article builds on the evidence presented in the TKS, with a greater level of detail intended for a lung-specialist audience. Pulmonologists have a vital role to play in advocating for the health of their patients and the wider population by sharing five key messages: (1) Smoking is the leading cause of COPD in high-income countries, contributing to approximately 70% of cases. Quitting tobacco is an essential step toward better lung health. (2) People with COPD face a significantly higher risk of developing lung cancer. Smoking cessation is a powerful measure to reduce cancer risk. (3) Cardiovascular disease, lung cancer and type-2 diabetes are common comorbidities in people with COPD. Quitting smoking not only improves COPD management, but also reduces the risk of developing these coexisting conditions. (4) Tobacco smoke also significantly impacts children's lung growth and development, increasing the risk of respiratory infections, asthma and up to ten other conditions, and COPD later in life. Governments should implement effective tobacco control measures to protect vulnerable populations. (5) The tobacco industry's aggressive strategies in the marketing of nicotine delivery systems and all tobacco products specifically target children, adolescents, and young adults. Protecting our youth from these harmful tactics is a top priority. [ABSTRACT FROM AUTHOR]

Background: Complicated pleural infection comprises of complex effusions and empyema. When tube thoracostomy is ineffective, treatment options include surgical drainage, deloculation and decortication or intrapleural fibrinolysis. We performed a systematic review and meta-analysis to examine which technique is superior in treating complicated pleural infections. Methods: PubMed, MEDLINE and EMBASE databases were searched for studies published between January 2000 to July 2023 comparing surgery and intrapleural fibrinolysis for treatment of complicated pleural infection. The primary outcome was treatment success. Secondary outcomes included hospital length of stay, chest drain duration and in-hospital mortality. Results: Surgical management of complicated pleural infections was more likely to be successful than intrapleural fibrinolysis (RR 1.18; 95% CI 1.02, 1.38). Surgical intervention group benefited from statistically significant shorter hospital length of stay (MD: 3.85; 95% CI 1.09, 6.62) and chest drain duration (MD: 3.42; 95% CI 1.36, 5.48). There was no observed difference between in-hospital mortality (RR: 1.00; 95% CI 0.99, 1.02). Conclusion: Surgical management of complicated pleural infections results in increased likelihood of treatment success, shorter chest drain duration and hospital length of stay in the adult population compared with intrapleural fibrinolysis. In-hospital mortality did not differ. Large cohort and randomized research need to be conducted to confirm these findings. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) stands as a significant global health challenge, with its intricate pathophysiological manifestations often demanding advanced diagnostic strategies. The recent applications of artificial intelligence (AI) within the realm of medical imaging, especially in computed tomography, present a promising avenue for transformative changes in COPD diagnosis and management. This review delves deep into the capabilities and advancements of AI, particularly focusing on machine learning and deep learning, and their applications in COPD identification, staging, and imaging phenotypes. Emphasis is laid on the AI-powered insights into emphysema, airway dynamics, and vascular structures. The challenges linked with data intricacies and the integration of AI in the clinical landscape are discussed. Lastly, the review casts a forward-looking perspective, highlighting emerging innovations in AI for COPD imaging and the potential of interdisciplinary collaborations, hinting at a future where AI doesn't just support but pioneers breakthroughs in COPD care. Through this review, we aim to provide a comprehensive understanding of the current state and future potential of AI in shaping the landscape of COPD diagnosis and management. [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypertension (PH) is a long-term disease that impacts approximately 1% of the world's population. Currently, levosimendan (Lev) is proposed for PH treatment. However, the mechanism of Lev in the treatment of PH is unknown. Methods: We used hypoxia-induced pulmonary artery smooth muscle cells (PASMCs) to establish a PH cell model. A number of cell biology methods were performed to assay alterations in cell proliferation, migration and apoptosis after Lev treatment. qRT-PCR and WB were performed to test the levels of circUSP34 and miR-1298, and BMP/Smad protein respectively. In addition, the regulatory relationship between circUSP34 or BMPR2 with miR-1298 was verified through the use of double luciferase as well as RIP assay. In addition, we explored the regulatory effect of Lev on the circUSP34/miR-1298/BMP/Smad axis using a rat PH model. Results: Our results demonstrate that Lev inhibited PASMCs cell proliferation, migration and promoted apoptosis exposed to hypoxia. In hypoxia-treated PASMCs, circUSP34 expression got downregulated while miR-1298 upregulated, whereas the addition with Lev resulted in upregulation of circUSP34 expression and downregulation of miR-1298 expression, indicating that circUSP34 can target and regulate miR-1298. In addition, miR-1298 targets and regulates the expression of BMPR2. In a rat PH model induced by hypoxia combined with SU5416, Lev upregulated circUSP34 targeting miR-1298-mediated BMP/Smad axis to alleviate the PH phenotype. Conclusion: We have shown that Lev can be used as a therapeutic drug for PH patients, which works through the circUSP34/miR-1298/BMP/Smad axis to alleviate PH symptoms. [ABSTRACT FROM AUTHOR]

Background: Currently, there is conflicting information and guidance on the effective management of Alpha 1 Antitrypsin Deficiency (AATD). Establishing a consensus of assessment and disease management specific to AATD is important for achieving a standardized treatment pathway and for improving patient outcomes. Here, we aim to utilize the Delphi method to establish a European consensus for the assessment and management of patients with severe AATD. Methods: Two rounds of a Delphi survey were completed online by members of the European Alpha-1 Research Collaboration (EARCO). Respondents were asked to indicate their agreement with proposed statements for patients with no respiratory symptoms, stable respiratory disease, and worsening respiratory disease using a Likert scale of 1–7. Levels of agreement between respondents were calculated using a weighted average. Results: Round 1 of the Delphi survey was sent to 103 members of EARCO and 38/103 (36.9%) pulmonologists from across 15 countries completed all 109 questions. Round 2 was sent to all who completed Round 1 and 36/38 (94.7%) completed all 79 questions. Responses regarding spirometry, body plethysmography, high-resolution computed tomography, and the initiation of augmentation therapy showed little variability among physicians, but there was discordance among other aspects, such as the use of low-dose computed tomography in both a research setting and routine clinical care. Conclusions: These results provide expert opinions for the assessment and monitoring of patients with severe AATD, which could be used to provide updated recommendations and standardized treatment pathways for patients across Europe. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease(COPD) is a gradually worsening and fatal heterogeneous lung disease characterized by airflow limitation and increasingly decline in lung function. Currently, it is one of the leading causes of death worldwide. The consistent feature of COPD is airway inflammation. Several inflammatory factors are known to be involved in COPD pathogenesis; however, anti-inflammatory therapy is not the first-line treatment for COPD. Although bronchodilators, corticosteroids and roflumilast could improve airflow and control symptoms, they could not reverse the disease. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway plays an important novel role in the immune system and has been confirmed to be a key mediator of inflammation during infection, cellular stress, and tissue damage. Recent studies have emphasized that abnormal activation of cGAS-STING contributes to COPD, providing a direction for new treatments that we urgently need to develop. Here, we focused on the cGAS-STING pathway, providing insight into its molecular mechanism and summarizing the current knowledge on the role of the cGAS-STING pathway in COPD. Moreover, we explored antagonists of cGAS and STING to identify potential therapeutic strategies for COPD that target the cGAS-STING pathway. [ABSTRACT FROM AUTHOR]

Background: In recent years, the incorporation of LAMAs into asthma therapy has been expected to enhance symptom control. However, a significant number of patients with asthma continue to experience poorly managed symptoms. There have been limited investigations on LAMA-induced airway alterations in asthma treatment employing IOS. In this study, we administered a LAMA to patients with poorly controlled asthma, evaluated clinical responses and respiratory function, and investigated airway changes facilitated by LAMA treatments using the IOS. Methods: Of a total of 1282 consecutive patients with asthma, 118 exhibited uncontrolled symptoms. Among them, 42 switched their treatment to high-dose fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) (ICS/LABA/LAMA). The patients were then assessed using AHQ-33 or LCQ and ACT. Spirometry parameters (such as FEV1 or MMEF) and IOS parameters (such as R20 or AX) were measured and compared before and after exacerbations and the addition of LAMA. Results: Of the 42 patients, 17 who switched to FF/UMEC/VI caused by dyspnea exhibited decreased pulmonary function between period 1 and baseline, followed by an increase in pulmonary function between baseline and period 2. Significant differences were observed in IOS parameters such as R20, R5-R20, Fres, or AX between period 1 and baseline as well as between baseline and period 2. Among the patients who switched to inhaler due to cough, 25 were classified as responders (n = 17) and nonresponders (n = 8) based on treatment outcomes. Among nonresponders, there were no significant differences in spirometry parameters such as FEV1 or PEF and IOS parameters such as R20 or AX between period 1 and baseline. However, among responders, significant differences were observed in all IOS parameters, though not in most spirometry parameters, between period 1 and baseline. Furthermore, significant differences were noted between baseline and period 2 in terms of FEV1, %MMEF, %PEF, and all IOS parameters. Conclusion: ICS/LABA/LAMA demonstrates superiority over ICS/LABA in improving symptoms and lung function, which is primarily attributed to the addition of LAMA. Additionally, IOS revealed the effectiveness of LAMA across all airway segments, particularly in the periphery. Hence, LAMA can be effective against various asthma phenotypes characterized by airway inflammation, even in real-world cases. [ABSTRACT FROM AUTHOR]

Background: Japanese guidelines recommend triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) and no concurrent asthma diagnosis who experience frequent exacerbations and have blood eosinophil (EOS) count ≥ 300 cells/mm3, and in patients with COPD and asthma with continuing/worsening symptoms despite receiving dual ICS/LABA therapy. These post-hoc analyses of the KRONOS study in patients with COPD and without an asthma diagnosis, examine the effects of fixed-dose triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) versus dual therapies on lung function and exacerbations based on blood EOS count – focusing on blood EOS count 100 to < 300 cells/mm3 – as a function of exacerbation history and COPD severity. Methods: In KRONOS, patients were randomized to receive treatments that included BGF 320/14.4/10 µg, glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10 µg, or budesonide/formoterol fumarate dihydrate (BFF) 320/10 µg via metered dose inhaler (two inhalations twice-daily for 24 weeks). These post-hoc analyses assessed changes from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over 12–24 weeks and moderate or severe COPD exacerbations rates over 24 weeks. The KRONOS study was not prospectively powered for these subgroup analyses. Results: Among patients with blood EOS count 100 to < 300 cells/mm3, least squares mean treatment differences for lung function improvement favored BGF over BFF in patients without an exacerbation history in the past year and in patients with moderate and severe COPD, with observed differences ranging from 62 ml to 73 ml across populations. In this same blood EOS population, moderate or severe exacerbation rates were reduced for BGF relative to GFF by 56% in patients without an exacerbation history in the past year, by 47% in patients with moderate COPD, and by 50% in patients with severe COPD. Conclusions: These post-hoc analyses of patients with moderate-to-very severe COPD from the KRONOS study seem to indicate clinicians may want to consider a step-up to triple therapy in patients with persistent/worsening symptoms with blood EOS count > 100 cells/mm3, even if disease severity is moderate and there is no recent history of exacerbations. Trial registration: ClinicalTrials.gov registry number NCT02497001 (registration date, 13 July 2015). [ABSTRACT FROM AUTHOR]

Small airway fibrosis is the main contributor to physiological airway dysfunction in COPD. One potential mechanism contributing to small airway fibrosis is epithelial mesenchymal transition (EMT). When associated with angiogenesis (so called EMT-Type-3) it may well also be the link with the development of cancer, which is closely associated with COPD and predominantly in large airways. In a recent study published in Respiratory Research, Qin Wang and colleagues investigated the role of urokinase plasminogen activator receptor (uPAR) in EMT in small airway epithelium of COPD patients. However, there are some issues with the paper which we wish to comment on. [ABSTRACT FROM AUTHOR]