BACKGROUND: Comparative evidence on the diagnostic yield of endobronchial ultrasound (EBUS)-guided sampling techniques for mediastinal lesions remains limited. We conducted a network meta-analysis (NMA) to evaluate EBUS-...BACKGROUND: Comparative evidence on the diagnostic yield of endobronchial ultrasound (EBUS)-guided sampling techniques for mediastinal lesions remains limited. We conducted a network meta-analysis (NMA) to evaluate EBUS-guided transbronchial needle aspiration (EBUS-TBNA), intranodal forceps biopsy (EBUS-IFB), transbronchial needle core biopsy (EBUS-TBNB) and transbronchial mediastinal cryobiopsy (EBUS-TMC). METHODS: Random-effects NMA was performed within Bayesian and frequentist frameworks. Frequentist estimates were reported as risk ratios (RRs) with 95% CIs and, where applicable, 95% predictive intervals (PrIs). Bayesian ranking was assessed using surface under the cumulative ranking curve (SUCRA) values. RESULTS: 35 studies involving 3751 patients were included. EBUS-TMC (RR 1.27, 95% CI 1.16 to 1.39; 95% PrI 0.89-1.81) and EBUS-IFB (RR 1.21, 95% CI 1.07 to 1.38; 95% PrI 0.84-1.75) may provide higher diagnostic yield than EBUS-TBNA, whereas EBUS-TBNB did not show a clear advantage (RR 1.10, 95% CI 0.98 to 1.23). However, all 95% PrIs crossed unity, suggesting uncertainty about reproducibility in future settings. SUCRA rankings favoured EBUS-TMC followed by EBUS-IFB, EBUS-TBNB and EBUS-TBNA but should not be interpreted as certainty of superiority. Subgroup analyses suggested greater benefits of EBUS-TMC and EBUS-IFB in benign diseases, sarcoidosis and lymphoma but similar performance in lung cancer. Most adverse events were mild to moderate, although EBUS-TMC had a higher reported adverse-event rate. CONCLUSION: EBUS-TMC and EBUS-IFB may improve diagnostic yield over EBUS-TBNA in selected diseases and experienced centres. Given the very low certainty of evidence, wide PrIs and exploratory SUCRA rankings, these findings should be viewed as hypothesis-generating rather than definitive evidence. PROSPERO REGISTRATION NUMBER: CRD420251236286.
OBJECTIVE: Vitamins A and D regulate numerous genes through intersecting metabolic pathways, influencing lung development and asthma. This article aimed to examine the impact of vitamins A and D on lung function, epigene...OBJECTIVE: Vitamins A and D regulate numerous genes through intersecting metabolic pathways, influencing lung development and asthma. This article aimed to examine the impact of vitamins A and D on lung function, epigenetic ageing and regulatory epigenetics in children and adults with asthma. METHODS: Two asthma cohorts, GACRS (Genetic Epidemiology of Asthma in Costa Rica Study; 1165 children) and ODOLLFA (Omic Determinants of Longitudinal Lung Function in Asthma; 1041 adults) were included. Serum miRNA profiles, blood DNA methylation and plasma/serum vitamin A and D levels were measured. Associations between vitamin levels and lung function (forced expiratory volume in 1 s (FEV), forced vital capacity (FVC), FEV/FVC), miRNA expression and DNA methylation were evaluated. In adults, mediation analysis assessed whether methylation status and miRNAs mediated the relationship between vitamins and lung function or epigenetic ageing. RESULTS: In children, higher vitamin A was associated with higher FEV (β=2.5, p=4.9 × 10) and FVC (β=7.6, p=7.7 × 10) but lower FEV/FVC (β=-3.9, p=2.0 × 10); vitamin D showed no association. In adults, both vitamins were positively associated with FEV (vitamin A: β=4.7, p=9.3 × 10, vitamin D: β=0.16, p=8.6 × 10) and FVC (vitamin A: β=3.4, p=3.0 × 10, vitamin D: β=0.18, p=4.6 × 10); only vitamin A was associated with FEV/FVC (vitamin A: β=2.5, p=3.9 × 10). Vitamin D sufficiency corresponded to lower epigenetic ageing in adults. Higher vitamin levels were associated with IRF5 regulatory cytosine hypomethylation at cytosine-guanine dinucleotides (CpG), corresponding to better lung function and lower ageing. Distinct vitamin-associated miRNAs were identified, with shared targets enriched in immune and cell-cycle pathways. Mediation analyses indicated statistical partial effects through methylation and miRNAs. CONCLUSIONS: Vitamin A, but not vitamin D, in children was associated with better lung function and lower epigenetic ageing in asthma, with effects mediated by DNA methylation and miRNA regulation.
pulmonary disease (MAC-PD) frequently recurs after treatment but predictors of recurrence remain unclear. We retrospectively analysed patients with successfully treated MAC-PD from two tertiary centres. Chest CT findings...pulmonary disease (MAC-PD) frequently recurs after treatment but predictors of recurrence remain unclear. We retrospectively analysed patients with successfully treated MAC-PD from two tertiary centres. Chest CT findings-including bronchiectasis, cellular bronchiolitis, cavity, nodule and consolidation scores-were assessed before and after treatment. Multivariable competing risk regression analyses were performed to identify factors associated with recurrence. Among 538 patients, 216 (40.1%) experienced recurrence. A higher post-treatment cellular bronchiolitis score was independently associated with recurrence (adjusted subdistribution HR 1.64, 95% CI 1.46 to 1.84; p<0.001). A score ≥3 was associated with increased recurrence risk in both nodular bronchiectatic and fibrocavitary phenotypes. Residual cellular bronchiolitis on post-treatment CT demonstrated the strongest predictive performance and may serve as a radiological marker of recurrence risk.
Monocytes are central to innate and adaptive immunity, regulating tissue homeostasis and inflammation. However, data on their steady-state biodistribution in healthy humans are limited. We developed a non-invasive method...Monocytes are central to innate and adaptive immunity, regulating tissue homeostasis and inflammation. However, data on their steady-state biodistribution in healthy humans are limited. We developed a non-invasive method to track radiolabelled autologous monocytes. Monocytes showed distinct intravascular transit kinetics vs neutrophils, with 45 min recovery of 47% for neutrophils vs 7% for monocytes (p=0.008), indicating predominant distribution in marginated pools. In patients with psoriatic and rheumatoid arthritis but no documented lung disease, we observed preferential early retention of monocytes in the lungs (transit half-life 25.2 min vs 14.2 min; p=0.008) compared with healthy volunteers, with reduced intravascular recovery in patients with rheumatoid arthritis (4.3% vs 12%; p=0.0043). These findings provide the first direct evidence of human monocyte pulmonary transit kinetics, systemic biodistribution and fate in health and inflammatory disease, advancing understanding of in vivo monocyte biology.
BACKGROUND: Lung cancer (LC) is the most common cause of cancer death in the UK and worldwide, but screening with low-dose CT (LDCT) reduces LC deaths. The UK National Screening Committee has recommended nationwide roll-...BACKGROUND: Lung cancer (LC) is the most common cause of cancer death in the UK and worldwide, but screening with low-dose CT (LDCT) reduces LC deaths. The UK National Screening Committee has recommended nationwide roll-out of LDCT screening, but the optimal risk thresholds for eligibility remain uncertain. METHODS: We conducted a cost-effectiveness analysis in the Yorkshire Lung Screening Trial (YLST) population comparing three eligibility criteria: US Preventive Services Task Force (USPSTF), Prostate Lung Colorectal and Ovarian study (PLCO) ≥1.51% and Liverpool Lung Project model (LLP) ≥5%. A Markov model estimated a no-screening counterfactual. Scenario analyses assessed how increasing PLCO (1.51%-7%) and LLP (5%-9%) thresholds affected LC detection, costs and quality-adjusted life years (QALYs). Payouts per detected LC were calculated using mortality and utility estimates from the literature and cost data from the trial. RESULTS: Incremental cost-effectiveness ratios (ICERs) versus no screening were £3949 (USPSTF), £3797 (LLP≥5%) and £4013 (PLCO≥1.51%). PLCO yielded the largest numbers screened and LCs detected, most QALYs gained and highest incremental net monetary benefit. Raising LLP and PLCO thresholds reduced both ICERs and QALYs gained. CONCLUSION: All three screening eligibility criteria are cost-effective according to the UK's willingness to pay threshold of £20 000/QALY. Within the range of thresholds observed in YLST, PLCO thresholds between ≥1.51% and ≥4% offered the most efficient cost-benefit trade-offs. Evidence suggests that lowering thresholds further would detect more LC cases while remaining cost-effective. These findings support the criteria implemented in YLST, but do not by themselves identify the optimal screening threshold for the wider UK population. TRIAL REGISTRATION NUMBER: ISRCTN42704678.
Hu Y, Zhang H, Xu Y
… +27 more, Yang H, Yu Q, Cai N, Xu J, Zhang Y, Liu D, Kang K, Mo S, Li S, Zhang J, Tang P, Tan Y, Zeng J, Zhong T, Yang Q, Wang W, Gu D, Zhu C, Ning Y, Zhang K, Dai Y, Shi C, Lin D, Ji L, Cai Y, Gou D, Chen X
BACKGROUND: The prompt and precise diagnosis of active pulmonary tuberculosis (TB) is crucial for controlling this disease and yet it remains a global challenge. The objective of this study was to identify a set of micro...BACKGROUND: The prompt and precise diagnosis of active pulmonary tuberculosis (TB) is crucial for controlling this disease and yet it remains a global challenge. The objective of this study was to identify a set of microRNAs (miRNAs) whose expression in plasma could be used as a triage test for diagnosing TB. METHODS: A total of 879 plasma samples were collected in seven clinical centres from healthy individuals and patients displaying TB-like symptoms and/or radiological features consistent with TB. The samples were classified as TB, pneumonia, lung cancer and HC subgroups based on subsequent diagnostic assessments.We performed quantitative profiling of 264 plasma miRNAs in a training cohort (n=410) and an independent external test cohort (n=469). After dimensionality reduction and feature selection analysis, we identified nine discriminative miRNAs and used them to train an ensemble model in a training cohort using the scikit-learn library, which was subsequently evaluated in the external test cohort. RESULTS: The ensemble model showed notable accuracy in discriminating TB from non-TB patients, yielding areas under the curve (AUC) of 0.84 (95% CI 0.80 to 0.88) for the training cohort and 0.86 (95% CI 0.82 to 0.90) for the external test cohort. When tested against subgroups of laboratory confirmed and clinically diagnosed but unconfirmed TB, the AUC values were 0.89 (95% CI 0.85 to 0.93) and 0.83 (95% CI 0.79 to 0.88), respectively. In smear-negative confirmed TB patients, the AUC exceeded 0.83, with a sensitivity and specificity of 0.75. CONCLUSIONS: Our miRNA ensemble model, based on detecting a nine-miRNA expression biosignature in plasma, demonstrated promising ability to diagnose TB and distinguish it from other common lung diseases but further studies are needed to assess its clinical applicability. TRIAL REGISTRATION NUMBER: ChiCTR2000039734.
INTRODUCTION: Efficient preventive management of acute exacerbation of chronic obstructive pulmonary disease (COPD) is predicated on accurate risk stratification. We compared the performance of exacerbation history (curr...INTRODUCTION: Efficient preventive management of acute exacerbation of chronic obstructive pulmonary disease (COPD) is predicated on accurate risk stratification. We compared the performance of exacerbation history (current standard of care) versus a revised version of a multivariable risk scoring tool (Acute COPD Exacerbation Prediction Tool (ACCEPT)) using primary-care UK data. METHODS: We used validated case definitions to identify diagnosed patients with COPD ≥40 years old from the UK Clinical Practice Research Datalink Aurum (2004-2020). For each patient, a single annual COPD visit was randomly selected as the index date. The outcome was the occurrence of ≥1 moderate/severe exacerbation(s) within a year of the index date. We conducted time-to-event analyses of the latest version of ACCEPT (ACCEPT 2.0) and developed a recalibrated version (ACCEPT 3.0-UK). Model performance was evaluated using discrimination (time-dependent area under the receiver operating characteristic curve (AUC)), calibration and net benefit. RESULTS: The final cohort included 158 384 patients (55.0% male; mean age 71.5 years). ACCEPT 2.0 achieved an AUC of 0.77 for predicting moderate/severe exacerbations, outperforming both any and frequent exacerbator categories (AUC: 0.69 and 0.67, respectively). However, it overpredicted exacerbation events (observed-to-expected (O/E) ratio: 0.81 (95% CI 0.80 to 0.81)). Recalibration resolved this overprediction, yielding O/E ratio of 1.00 (95% CI 0.99 to 1.00), while maintaining discrimination (AUC: 0.77). ACCEPT 3.0-UK was net beneficial and superior to exacerbation history across a wide range of risk thresholds. CONCLUSION: ACCEPT 3.0-UK has substantially higher performance than exacerbation history, quantifies predicted risks for shared decision-making and is likely to confer clinical utility for risk stratification in primary care.
Airway-occluding mucus plugs (MPs)-as identified on CT scans-are frequent in patients with chronic obstructive pulmonary disease (COPD). Prior studies have shown that body mass index (BMI) tends to be lower among individ...Airway-occluding mucus plugs (MPs)-as identified on CT scans-are frequent in patients with chronic obstructive pulmonary disease (COPD). Prior studies have shown that body mass index (BMI) tends to be lower among individuals with MPs. To further investigate this relationship, we assessed whether BMI is associated with MPs in two large, multicentre cohorts of tobacco-exposed participants with and without COPD. In multivariable models, lower BMI was associated with an increased prevalence of MPs in COPD and non-COPD groups. Future studies are warranted to elucidate the mechanisms underlying this association.
INTRODUCTION: People diagnosed with tuberculosis (TB) after death (postmortem) experience the ultimate diagnostic delay. We aimed to identify social and health factors associated with postmortem TB diagnosis in England....INTRODUCTION: People diagnosed with tuberculosis (TB) after death (postmortem) experience the ultimate diagnostic delay. We aimed to identify social and health factors associated with postmortem TB diagnosis in England. METHODS: We conducted a national retrospective cohort study using routinely collected surveillance data from the UK Health Security Agency's National TB Surveillance System (NTBS) between 1 January 2010 and 31 December 2022. Of 72 058 people notified with TB, 19 without a recorded diagnostic outcome were excluded, leaving 72 039 for analysis. The primary outcome was postmortem versus antemortem TB diagnosis. Associations were assessed using univariate and multivariable logistic regression. RESULTS: Of 72 039 participants, 574 were diagnosed postmortem, averaging 0.84 cases per week. With the exception of age 0-4 years (adjusted odds ratio, aOR, 5.36 (95%CI 1.62-17.67), the likelihood of postmortem diagnosis increased markedly with age, from aOR 2.96 (95% CI 1.14 to 7.64) at age 35-39 years to 85.67 (95% CI 32.34 to 226.97) at age ≥90 years. Male sex (aOR 1.62; 95% CI 1.31 to 2.00), UK birth (aOR 1.53; 95% CI 1.10 to 2.14), alcohol misuse (aOR 3.08; 95% CI 1.30 to 7.30) and drug misuse (aOR 2.48; 95% CI 1.21 to 5.12) were associated with increased odds of postmortem diagnosis. Compared with London, all other National Health Service regions had increased odds of postmortem diagnosis. BCG vaccination (aOR 0.49; 95% CI 0.29 to 0.84) and pulmonary TB (aOR 0.60; 95% CI 0.48 to 0.75) were associated with lower odds. DISCUSSION: Postmortem TB diagnosis in England is frequent and associated with being in early childhood (0-4 years), older age, male sex, UK birth, substance misuse and notification outside London. Recognising postmortem TB diagnosis as a 'never event' and developing targeted interventions to reduce diagnostic delays are essential to achieve England's TB elimination goals.
Dietary nitrate (NO₃) supplementation has been shown to improve vascular function and exercise capacity in chronic obstructive pulmonary disease and in pulmonary hypertension. In a double-blind, placebo-controlled crosso...Dietary nitrate (NO₃) supplementation has been shown to improve vascular function and exercise capacity in chronic obstructive pulmonary disease and in pulmonary hypertension. In a double-blind, placebo-controlled crossover study in 20 patients with idiopathic pulmonary fibrosis who desaturated on exercise, endurance shuttle walk test improved by a median (IQR) difference of 31 s (-9.5 to 100.0; (p=0.043)), following a single dose of 140 mL NO₃ rich beetroot juice, as did brachial artery flow mediated dilatation; +4.25% (95% CI -0.71% to 8.45%; p=0.036), compared with following placebo NO₃ depleted placebo juice. Longer-term studies are needed to see if these acute effects translate into sustained benefit.ISRCTN14888729 Registration date 14 July 2015, https://doi.org/10.1186/ISRCTN14888729.
Mølbaek-Engbjerg T, Ali M, Horner D
… +10 more, Brustad N, Sultan T, Jensen SK, Thorsen J, Vahman N, Brix S, Schoos AM, Stokholm J, Bønnelykke K, Chawes BLK
BACKGROUND: Asthma is an inflammatory airway disease originating in early life, but it is understudied whether childhood trajectories of haematological and immunoglobulin (Ig) measures associate with risk of developing a...BACKGROUND: Asthma is an inflammatory airway disease originating in early life, but it is understudied whether childhood trajectories of haematological and immunoglobulin (Ig) measures associate with risk of developing asthma. METHODS: We modelled trajectories of blood neutrophils, lymphocytes, eosinophils, platelets and Ig (IgE, IgA, IgM and IgG) measured at ages 4, 5, 6, 7, 12 and 18 years in the Copenhagen Prospective Studies on Asthma in Childhood 2000 birth cohort (n=411) and investigated association with asthma diagnosis, airway obstruction using spirometry (forced expiratory volume in 1 s (FEV)) and plethysmography (specific airway resistance (sRaw)), type 2 airway inflammation (fractional exhaled nitric oxide (FeNO)) and airway hyper-responsiveness (AHR) at age 18. We employed linear regression, linear mixed model (LMM) with variable slopes and intercepts and latent class trajectory (LCT) analysis adjusting for relevant confounders. RESULTS: In the LMM analyses, increasing blood neutrophils through childhood (slope, adjusted OR (aOR)=1.30 per 10 cells/L, 95% CI 1.01 to 1.68, p=0.040), higher eosinophils (intercept, aOR=1.51 per 10 cells/L, 95% CI 1.17 to 1.98, p=0.002), higher total IgE and increasing total IgE (intercept, aOR=1.28 per IgE g/L, 95% CI 1.00 to 1.63, p=0.049; slope, aOR=1.37, 95% CI 1.07 to 1.77, p=0.015) were significantly associated with asthma at age 18. Further, higher eosinophils (intercept, beta estimate=3.84 ppb per 10 cells/L, 95% CI 1.53 to 6.15, p=0.001), higher total IgE and increasing total IgE (intercept, beta estimate=3.91 ppb per g/L, 95% CI 1.64 to 6.18, p=0.001; slope, beta estimate=4.84, 95% CI 2.55 to 7.14, p=4.4×10⁵) were associated with higher FeNO, whereas higher platelet count (intercept, beta estimate=-0.07 L per 10 cells/L, 95% CI -0.12 to -0.03, p=0.002) was associated with lower FEV at age 18, and increasing total IgE was associated with increased AHR, that is, lower methacholine dose causing a 20% drop in FEV (slope, beta estimate=-0.75 per g/L, 95% CI -1.24 to -0.27, p=0.002). The LCT models confirmed that specific childhood trajectories of eosinophils and total IgE were associated with higher FeNO levels and increased AHR, and that a specific platelet count trajectory was associated with lower FEV. There were no consistent associations with trajectories of lymphocytes, IgG, IgA or IgM and no associations with sRaw. CONCLUSION: Trajectories of haematological and Ig measures throughout childhood, particularly platelet counts, eosinophils and total IgE, were associated with airway inflammation, reduced lung function and increased AHR at age 18.