BACKGROUND:We report a pilot clinical trial investigating the feasibility of liquid biopsy genotyping (LBG) at the time of radiological suspicion of advanced NSCLC, incorporating a micro-cost model (MCM). (PLAsma Genomic Testing in Advanced NSCLC; The PLAN trial, ClinicalTrials.gov Identifier: NCT05542485). METHODS:Patients with a radiologic suspicion of stage III-IV lung cancer were recruited from four cancer centres in Ireland between August 2023 and July 2024. LBG was performed using the Archer LiquidplexTM NGS assay. The MCM considered staff time, consumables and capital costs and savings from avoidance of repeat tissue biopsy genotyping (TBG) or inappropriate systemic therapy such as immunotherapy for EGFR + NSCLC. RESULTS:A total of 138 patients were enrolled in the study with 38 excluded from the primary analysis (Squamous=16; SCLC = 22). Of patients that were eligible, LBG was completed in 100 % (100/100). TBG was completed in 68 % (68/100; insufficient tissue 20 %; 20/100; declining ECOG PS 12 %; 12/100). Repeat tissue biopsies were avoided in 12 % (12/100) of patients due to available LBG reports. The median calendar days from LBG to receipt of genomic report was 21 days shorter for LBG (z = -6.8, p < 0.01) versus TBG, as a median (range: 1-104 days). For evaluable paired cases with both TBG and LBG available (n = 68), concordance was 90 % (61/68). LBG resulted in detection of 5 actionable variants. LBG (€1135) was less than half the cost of TBG (€2404). LBG also resulted in overall cost savings of €20,288 (reduced TBG; use of immunotherapy). CONCLUSIONS:LBG reduces the time to genomic diagnosis in patients with newly diagnosed NSCLC compared to tissue genotyping, identifies actionable variants not reported in tissue, and results in overall cost savings.

Lung cancer is the leading cause of cancer-related mortality worldwide, with nonsmall cell lung cancer (NSCLC) accounting for the majority of cases. Despite advancements in therapeutics, outcomes remain poor due to late-stage diagnoses and the molecular complexity of the disease. Liquid biopsy, a minimally invasive diagnostic approach, has emerged as a potentially transformative tool in lung cancer. The detection of tumour-derived biomarkers, such as circulating-tumour DNA, circulating tumour cells and exosomes, can be analysed for molecular profiling, early detection and monitoring of disease progression. There have been significant advancements of liquid biopsy technologies, such as next-generation sequencing and droplet digital PCR, that identify actionable mutations, detect resistance mechanisms and improve therapeutic outcomes. While there are still challenges like detecting early-stage disease and the risk of false positives, the combination of multi-omics data and artificial intelligence has the potential for more personalised and precise cancer treatments. Liquid biopsy represents a paradigm shift in the early detection and personalised treatment of lung cancer, offering significant potential to improve patient outcomes.

Introduction Low-dose chest CT (LDCT) has demonstrated the ability to detect early-stage lung cancer (LC) and improve disease-specific mortality in high-risk individuals. Use of LC risk scores such as the Prostate, Lung, Colorectal, Ovarian Model Score (PLCOM2012) improves the sensitivity, specificity and positive predictive value for LC screening. Screening programmes have identified that primary care participation, patient engagement and improved accessibility may enhance the success of LC screening. Currently, there is no LC screening programme in Ireland. This first pilot study of LC screening will investigate (1) the feasibility, including uptake, of LC screening in a community setting, based on primary care-based participant invitation with mobile CT scanning and (2) novel blood/breath biomarkers in high-risk individuals who participate in the LC screening trial, to identify biologic parameters that may supplement existing risk scores, to maximise LC early detection.Methods and analysis In a pilot feasibility clinical trial, approximately 30 000 adults aged between 55 and 74 from participating general practitioner (GP) practices will be invited to a ‘lung health check (LHC)’ prescreening, involving a telephone assessment of eligibility and risk status, based on the PLCOM2012/Liverpool Score V.2. High-risk individuals will be invited to the LHC, which will take place in a mobile unit strategically located in the community and include a respiratory disease assessment, baseline spirometry, smoking cessation advice, an LDCT and in a selected cohort, blood/breath/sputum biospecimen collection. Two rounds of screening will take place at an interval of 12 months.Ethics, dissemination and registration details In this pilot feasibility trial, the uptake of LC screening using a community-based strategy among high-risk participants will be investigated. The study has been approved by Beaumont Hospital Research Ethics Committee and is registered with clinicaltrials.gov (NCT07099027). Novel features of our design include directly calling participants and our translational arm of the study, which will focus on blood/breath/sputum biomarkers associated with LC.

INTRODUCTION:Altered complement component 3 (C3) activation in patients with alpha-1 antitrypsin (AAT) deficiency (AATD) has been reported. To understand the potential impact on course of inflammation, the aim of this study was to investigate whether C3d, a cleavage-product of C3, triggers interleukin (IL)-1β secretion via activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. The objective was to explore the effect of AAT augmentation therapy in patients with AATD on the C3d/complement receptor 3 (CR3) signalling axis of monocytes and on circulating pro-inflammatory markers. METHODS:Inflammatory mediators were detected in blood from patients with AATD (n=28) and patients with AATD receiving augmentation therapy (n=19). Inflammasome activation and IL-1β secretion were measured in monocytes of patients with AATD, and following C3d stimulation in the presence or absence of CR3 or NLRP3 inhibitors. RESULTS:C3d acting via CR3 induces NLRP3 and pro-IL-1β production, and through induction of endoplasmic reticulum (ER) stress and calcium flux, triggers caspase-1 activation and IL-1β secretion. Treatment of individuals with AATD with AAT therapy results in decreased plasma levels of C3d (3.0±1.2 µg/mL vs 1.3±0.5 µg/mL respectively, p<0.0001) and IL-1β (115.4±30 pg/mL vs 73.3±20 pg/mL, respectively, p<0.0001), with a 2.0-fold decrease in monocyte NLRP3 protein expression (p=0.0303), despite continued ER stress activation. DISCUSSION:These results provide strong insight into the mechanism of complement-driven inflammation associated with AATD. Although the described variance in C3d and NLRP3 activation decreased post AAT augmentation therapy, results demonstrate persistent C3d and monocyte ER stress, with implications for new therapeutics and clinical practice.

IntroductionMuscle loss is an important extrapulmonary manifestation of COPD. Dual energy X-ray absorptiometry (DXA) is the method of choice for body composition measurement but is not widely used for muscle mass evaluation. The pectoralis muscle area (PMA) is quantifiable by CT and predicts cross-sectional COPD-related morbidity. There are no studies that compare PMA with DXA measures or that evaluate longitudinal relationships between PMA and lung disease progression.MethodsParticipants from our longitudinal tobacco-exposed cohort had baseline and 6-year chest CT (n=259) and DXA (n=164) data. Emphysema was quantified by CT density histogram parenchymal scoring using the 15th percentile technique. Fat-free mass index (FFMI) and appendicular skeletal mass index (ASMI) were calculated from DXA measurements. Linear regression model relationships were reported using standardised coefficient (β) with 95% CI.ResultsPMA was more strongly associated with DXA measures than with body mass index (BMI) in both cross-sectional (FFMI: β=0.76 (95% CI 0.65 to 0.86), p<0.001; ASMI: β=0.76 (95% CI 0.66 to 0.86), p<0.001; BMI: β=0.36 (95% CI 0.25 to 0.47), p<0.001) and longitudinal (ΔFFMI: β=0.43 (95% CI 0.28 to 0.57), p<0.001; ΔASMI: β=0.42 (95% CI 0.27 to 0.57), p<0.001; ΔBMI: β=0.34 (95% CI 0.22 to 0.46), p<0.001) models. Six-year change in PMA was associated with 6-year change in emphysema (β=0.39 (95% CI 0.23 to 0.56), p<0.001) but not with 6-year change in airflow obstruction.ConclusionsPMA is an accessible measure of muscle mass and may serve as a useful clinical surrogate for assessing skeletal muscle loss in smokers. Decreased PMA correlated with emphysema progression but not lung function decline, suggesting a difference in the pathophysiology driving emphysema, airflow obstruction and comorbidity risk.

Background: Tracheostomy insertion in patients with coronavirus disease 2019 (COVID-19) presents unique challenges. Patients frequently have high ventilatory requirements, and as an aerosol generating procedure, tracheostomy insertion creates the potential for staff transmission. Problems with tracheostomies contribute to morbidity and mortality, and tracheostomy changes may increase risks of staff transmission. We sought to quantify the incidence of clinically necessitated tracheostomy changes, establish the indications for change and investigate the incidence of staff transmission. Methods: We conducted a single institution, retrospective, observational cohort study of all intensive care unit (ICU) patients with COVID-19 who had a tracheostomy between March 2020 and April 2021. The institution is a large tertiary referral centre in Ireland. Results: Forty-three patients had a tracheostomy during the study period. All were a Shiley™ Flexible Adult Taperguard or Shiley™ XLT Tracheostomy. 14 patients (33%) required a tracheostomy change, with the majority (57%) involving a change from a standard size to an extended length tracheostomy. Persistent leak was the most common indication for change (71.6%). Other indications included patient-ventilator dyssynchrony, persistent cough and accidental decannulation. No staff transmission of COVID-19 occurred during this study. Conclusions: The incidence of tracheostomy change was 33%, highlighting the importance of selecting the right tracheostomy for each patient. We discuss how key characteristics of tracheostomies such as type, size, length and inner diameter may impact flow, resistance and work of breathing, leading to unplanned tracheostomy change. No staff transmission occurred arising from tracheostomy insertion, adding to increasing evidence that tracheostomy insertion in COVID-19 appears safe with adherence to guidelines describing the correct use of personal protective equipment.

Introduction: Small diagnostic tissue samples can be inadequate in testing an expanding list of validated oncogenic driver alterations and fail to reflect intratumour heterogeneity (ITGH) in lung cancer. Liquid biopsies are non-invasive and may better reflect ITGH. Most liquid biopsies are performed in the context of circulating tumour DNA (ctDNA) in plasma but Exhaled Breath Condensate (EBC) shows promise as a lung-specific liquid biopsy. Methods: In this prospective, proof-of-concept study we carried out targeted Next Generation Sequencing (NGS) on diagnostic tissue samples from 125 patients with lung cancer and compared results to plasma and EBC for 5 oncogenic driver mutations (EGFR, KRAS, PIK3CA, ERBB2, BRAF) using an ultrasensitive PCR technique (UltraSEEK T Lung Panel on the MassARRAY (R) System, Agena Bioscience, San Diego, CA, USA). Results: There was a significantly higher failure rate due to unamplifiable DNA in tissue NGS (57/125, 45.6%) compared to plasma (27/125, 21.6%, p <= 0.001 and EBC (26/125,20.8%, p = 0.001. Consequently, both plasma and EBC identified higher number of mutations compared to tissue NGS. Specifically, there were significantly higher numbers of mutations detected in EGFR, KRAS and PIK3CA in plasma (p = 9.82 x 10(-3), p = 3.14 x 10(-5), p = 1.95 x 10(-3)) and EBC (p = 2.18 x 10(-3), p = 2.28 x 10(-4),p = 0.016) compared to tissue NGS. There was considerable divergence in mutation profiles between plasma and EBC with 34/76 (44%) mutations detected in plasma and 37/74 (41.89%) in EBC unique to their respective liquid biopsy. Conclusions: The results suggest that EBC is effective in identifying clinically relevant alterations in patients with lung cancer using UltraSEEK T and has a potential role as an adjunct to plasma testing.

Alpha-1 antitrypsin (AAT) is the canonical serine protease inhibitor of neutrophil-derived proteases and can modulate innate immune mechanisms through its anti-inflammatory activities mediated by a broad spectrum of protein, cytokine, and cell surface interactions. AAT contains a reactive methionine residue that is critical for its protease-specific binding capacity, whereby AAT entraps the protease on cleavage of its reactive centre loop, neutralises its activity by key changes in its tertiary structure, and permits removal of the AAT-protease complex from the circulation. Recently, however, the immunomodulatory role of AAT has come increasingly to the fore with several prominent studies focused on lipid or protein-protein interactions that are predominantly mediated through electrostatic, glycan, or hydrophobic potential binding sites. The aim of this review was to investigate the spectrum of AAT molecular interactions, with newer studies supporting a potential therapeutic paradigm for AAT augmentation therapy in disorders in which a chronic immune response is strongly linked.

Background: The current COVID-19 pandemic has placed enormous strain on healthcare systems worldwide. Understanding of COVID-19 is rapidly evolving. Pneumonia associated with COVID-19 may lead to respiratory failure requiring mechanical ventilation. The rise in patients requiring mechanical ventilation may lead to an increase in tracheostomies being performed in patients with COVID-19. Performing tracheostomy in patients with active SARS-CoV-2 infection poses a number of challenges. Methods: These guidelines were written following multidisciplinary agreement between Otolaryngology, Head and Neck Surgery, Respiratory Medicine and the Department of Anaesthetics and Critical Care Medicine in the Royal College of Surgeons in Ireland. A literature review was performed and a guideline for elective tracheostomy insertion in patients with COVID-19 proposed. Conclusion: The decision to perform tracheostomy in patients with COVID-19 should be undertaken by senior members of the multidisciplinary team. Steps should be taken to minimise risks to healthcare workers. (C) 2020 Published by Elsevier Ltd on behalf of Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland.

Background Chronic respiratory diseases are responsible for significant patient morbidity, mortality, and healthcare use. Community virtual ward (CVW) models of care have been successfully implemented to manage patients with complex medical conditions. Aims To explore the feasibility and clinical outcomes of a CVW model of care in patients with chronic respiratory disease. Methods Patients known to specialist respiratory services with Chronic Obstructive Pulmonary Disease (COPD) and/or asthma were admitted to the CVW for disease optimisation and exacerbation management. Individualised management plans were delivered in the patients’ home by hospital-based respiratory and community nursing teams, incorporating remote technology to monitor vital signs. Symptoms and health status at admission and discharge were compared. Results Twenty patients were admitted. One-quarter of patients had asthma, 50% COPD, and 25% combined asthma/COPD. Patients had severe disease, mean (SD) FEV 1 50(20) % predicted, and an average 6.4(5.7) exacerbations of disease in the previous 12 months. Patients received personalised disease and self-management education. All acute exacerbations ( n = 11) were successfully treated in the community. The average length of CVW admission was 10(4) days. By discharge, 60% of COPD and 66% of asthma patients recorded improvements in symptoms score exceeding the minimal clinically important difference. Fifty percent had clinically meaningful improvements in health status. Conclusion A CVW model facilitates the delivery of combined specialist and generalist care to patients with chronic respiratory disease in the community and improves symptoms and health status. The principles of the model are transferable to other conditions to improve overall health and reduce emergency hospital care.

INTRODUCTION:There are few existing severity scoring systems in the literature, and no formally widely accepted chest X-ray template for reporting COVID-19 infection. We aimed to modify the chest X-ray COVID-19 severity scoring system from the Brixia scoring system with placement of more emphasis on consolidation and to assess if the scoring tool could help predict intubation.METHODS:A severity chest X-ray scoring system was modified from the Brixia scoring system. PCR positive COVID-19 positive patient's chest X-rays admitted to our hospital over 3 months were reviewed and correlated with; non-invasive ventilation, intubation and death. An analysis was performed using a receiver operating curve to predict intubation from all admission chest X-rays.RESULTS:The median score of all 325 admission chest X-rays was 3 (Interquartile range (IQR) 0-6.5). The median score of admission chest X-rays of those who did not require ICU admission and survived was 1.5 (IQR 0-5); and 9 (IQR 4.75-12) was median admission score of those requiring intubation. The median scores of the pre-intubation ICU chest X-rays was 11.5 (IQR 9-14.125), this increased from a median admission chest X-ray score for this group of 9 (P-value < 0.01). A cut-off score of 6 had a sensitivity of 77% and specificity of 73% in predicting the need for intubation.CONCLUSION:Higher chest X-ray severity scores are associated with intubation, need for non-invasive ventilation and death. This tool may also be helpful in predicting intubation.