Air Pollution Exposure and Interstitial Lung Features in SPIROMICS Participants with COPD.

RATIONALE: It is unknown whether air pollution is associated with radiographic features of interstitial lung disease in individuals with chronic obstructive pulmonary disease (COPD). OBJECTIVES: To determine whether air pollution increases prevalence of interstitial lung abnormalities (ILA) or percent high-attenuation area (HAA) on computed tomography (CT) in individuals with a heavy smoking history and COPD. METHODS: We performed a cross-sectional study of SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), focused on current or former smokers with COPD. 10-year exposure to particulate matter < 2.5 µm (PM2.5), nitrogen oxides (NOx), nitrogen dioxide (NO2), and ozone (O3) prior to enrollment CTs (completed between 2010-2015) were estimated with validated spatiotemporal models at residential addresses. We applied adjusted multivariable modified Poisson regression and linear regression to investigate associations between pollution exposure and relative risk of ILA or increased percent HAA (between -600 and -250 Hounsfield units) respectively. We assessed for effect modification by MUC5B-promoter polymorphism (GT/TT vs GG at rs3705950), smoking status, sex, and percent emphysema. RESULTS: Among 1272 participants with COPD assessed for HAA, 424 were current smokers, 249 were carriers of the variant MUC5B allele (GT/TT). 519 participants were assessed for ILA. We found no association between pollution exposure and ILA or HAA. Associations between pollutant exposures and risk of ILA were modified by the presence of MUC5B polymorphism (p-value interaction term for NOx = 0.04 and PM2.5 = 0.05) and smoking status (p-value interaction term for NOx = 0.05, NO2 = 0.01, and O3 = 0.05). With higher exposure to NOx and PM2.5, MUC5B variant carriers had increased risk of ILA (Relative Risk [RR] per 26ppb NOx 2.41; 95% Confidence Interval [CI] 0.97 to 6.0) and RR per 4 µg·m-3 PM2.5 1.43; 95% CI 0.93 to 2.2). With higher exposure to NO2, former smokers had increased risk of ILA (RR per 10ppb 1.64; 95% CI 1.0 to 2.7). CONCLUSIONS: Exposure to ambient air pollution was not associated with interstitial features on CT in this population of heavy smokers with COPD. MUC5B modified the association between pollution and ILA, suggesting that gene-environment interactions may influence prevalence of interstitial lung features in COPD.

Exploratory Study on COPD Phenotypes and their Progression: Integrating SPECT and qCT Imaging Analysis.

Background: The objective of this study is to understand chronic obstructive pulmonary disease (COPD) phenotypes and their progressions by quantifying heterogeneities of lung ventilation from the single photon emission computed tomography (SPECT) images and establishing associations with the quantitative computed tomography (qCT) imaging-based clusters and variables. Methods: Eight COPD patients completed a longitudinal study of three visits with intervals of about a year. CT scans of these subjects at residual volume, functional residual capacity, and total lung capacity were taken for all visits. The functional and structural qCT-based variables were derived, and the subjects were classified into the qCT-based clusters. In addition, the SPECT variables were derived to quantify the heterogeneity of lung ventilation. The correlations between the key qCT-based variables and SPECT-based variables were examined. Results: The SPECT-based coefficient of variation (CV Total ), a measure of ventilation heterogeneity, showed strong correlations (|r| ≥ 0.7) with the qCT-based functional small airway disease percentage (fSAD% Total ) and emphysematous tissue percentage (Emph% Total ) in the total lung on cross-sectional data. As for the two-year changes, the SPECT-based maximum tracer concentration (TC max ), a measure of hot spots, exhibited strong negative correlations with fSAD% Total , Emph% Total , average airway diameter in the left upper lobe, and airflow distribution in the middle and lower lobes. Conclusion: Small airway disease is highly associated with the heterogeneity of ventilation in COPD lungs. TC max is a more sensitive functional biomarker for COPD progression than CV Total . Besides fSAD% Total and Emph% Total , segmental airways narrowing and imbalanced ventilation between upper and lower lobes may contribute to the development of hot spots over time.

Vessel and Airway Characteristics in One-Year CT-defined Rapid Emphysema Progression: SPIROMICS.

Rationale: Rates of emphysema progression vary in chronic obstructive pulmonary disease (COPD), and the relationship with vascular and airway pathophysiology remain unclear. Objective: We sought to determine if indices of peripheral (segmental and beyond) pulmonary arterial (PA) dilation measured via computed tomography (CT) are associated with a 1-year index of emphysema (EI: %voxels<-950HU) progression. Methods: 599 GOLD 0-3 former and never-smokers were evaluated from the SubPopulations and InterMediate Outcome Measures in COPD Study (SPIROMICS) cohort: rapid-emphysema-progressors (RP, n=188; 1-year ΔEI>1%), non-progressors (NP, n=301; 1-year ΔEI±0.5%) and never-smokers (NS: N=110). Segmental PA cross-sectional areas were standardized to associated airway luminal areas (Segmental : Pulmonary Artery-to-Airway Ratio: PAARseg). Full inspiratory CT scan-derived total (arteries + veins) pulmonary vascular volume (TPVV) was compared to vessel volume with radius smaller than 0.75mm (SVV.75/TPVV). Airway-to-lung ratios (an index of dysanapsis and COPD risk) were compared to TPVV-lung-volume-ratios. Results: Compared with NP, RP exhibited significantly larger PAARseg (0.73±0.29 vs. 0.67±0.23; p=0.001), lower TPVV-to-lung-volume ratio (3.21%±0.42% vs. 3.48%±0.38%; p=5.0 x 10-12), lower airway-to-lung-volume ratio (0.031±0.003 vs. 0.034±0.004; p=6.1 x 10-13) and larger SVV.75/TPVV (37.91%±4.26% vs. 35.53±4.89; p=1.9 x 10-7). In adjusted analyses, a 1-SD increment in PAARseg was associated with a 98.4% higher rate of severe exacerbations (95%CI: 29 to 206%; p = 0.002) and 79.3% higher in odds of being in the rapid emphysema progression group (95%CI: 24% to 157%; p = 0.001). At year-2 followup, the CT-defined RP group demonstrated a significant decline in post-bronchodilator-FEV1% predicted. Conclusion: Rapid one-year progression of emphysema was associated with indices indicative of higher peripheral pulmonary vascular resistance and a possible role played by pulmonary vascular-airway dysanapsis.

Return of participant-level clinical trial results to participants: pilot of a simplified centralised approach.

OBJECTIVES: Public access databases such as clinicaltrials.gov achieve dissemination of clinical trial design and aggregated study results. However, return of participant-level data is rarely done. A key barrier includes the proprietary ownership of data by the sponsor. Additionally, investigators may not have access to centralised data, and per International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice, must maintain the confidentiality of participants. This study piloted an approach to return both individual and aggregate clinical trial data to parents of children participating in a series of open-label clinical trials. SETTING AND DESIGN: A small biotech company obtained central ethics approval (centralised institutional review board [IRB], non-exempt). The study was advertised via parent advocacy groups. Parents of trial participants were offered the option to contact an employee (coordinator) within the company, requesting return of their child's study results. Ethics approval covered participation in six countries. The study focused on the sequential clinical trials of vamorolone VBP15-002 (NCT02760264) and VBP15-003 (NCT02760277) (post-results). INTERVENTIONS: Contact initiated by the parent enabled the coordinator to obtain informed consent (and separate General Data Protection Regulations consent), with phone translation when needed. Using date of birth and study site location provided by the parent, the data manager reported the participant number to the coordinator. The coordinator retrieved and compiled data, along with an aggregate summary, which was mailed via a password protected and encrypted memory device to the parent. Prereturn and postreturn surveys were sent to consented parents (n=19; 40% of 48 total trial participants) and investigators. RESULTS: Prereturn surveys indicated a request for as much data as offered, in all formats offered. Postreturn survey showed high satisfaction with the process and data returned. Survey of the physician site investigators (n=10; 100% participation of investigators) voiced general satisfaction with the process, with some reservations. CONCLUSIONS: This pilot study demonstrates an innovative, cost-effective, centralised and labour conservative approach to return of participant-level and aggregate data to participants in studies.

Improved pulmonary function and exercise tolerance despite persistent pulmonary fibrosis over 1 year after severe COVID-19 infection.

We conducted a prospective single-centre cohort study of 104 multi-ethnic severe COVID-19 survivors from the first wave of the pandemic 15 months after hospitalisation. Of those who were assessed at 4 and 15 months, improvement of ground glass opacities correlated with worsened fibrotic reticulations. Despite a high prevalence of fibrotic patterns (64%), pulmonary function, grip strength, 6 min walk distance and frailty normalised. Overall, dyspnoea, cough and exhaustion did not improve and were not correlated with pulmonary function or radiographic fibrosis at 15 months, suggesting non-respiratory aetiologies. Monitoring persistent, and often subclinical, fibrotic interstitial abnormalities will be needed to determine their potential for future progression.

The Effect of Chronic Altitude Exposure on COPD Outcomes in the SPIROMICS Cohort.

RATIONALE: Individuals with COPD have airflow obstruction and maldistribution of ventilation. For those living at high altitude, any gas exchange abnormality is compounded by reduced partial pressures of inspired oxygen. OBJECTIVES: Does residence at higher-altitude exposure affect COPD outcomes, including lung function, imaging characteristics, symptoms, health status, functional exercise capacity, exacerbations, or mortality? METHODS: From the SPIROMICS cohort, we identified individuals with COPD living below 1,000 ft (305 m) elevation (n= 1,367) versus above 4,000 ft (1,219 m) elevation (n= 288). Multivariable regression models were used to evaluate associations of exposure to high altitude with COPD-related outcomes. MEASUREMENTS AND MAIN RESULTS: Living at higher altitude was associated with reduced functional exercise capacity as defined by 6MWD (-32.3 m, (-55.7 to -28.6)). There were no differences in patient-reported outcomes as defined by symptoms (CAT, mMRC), or health status (SGRQ). Higher altitude was not associated with a different rate of FEV1 decline. Higher altitude was associated with lower odds of severe exacerbations (IRR 0.65, (0.46 to 0.90)). There were no differences in small airway disease, air trapping, or emphysema. In longitudinal analyses, higher altitude was associated with increased mortality (HR 1.25, (1.0 to 1.55)); however, this association was no longer significant when accounting for air pollution. CONCLUSIONS: Chronic altitude exposure is associated with reduced functional exercise capacity in individuals with COPD, but this did not translate into differences in symptoms or health status. Additionally, chronic high-altitude exposure did not affect progression of disease as defined by longitudinal changes in spirometry.

The IAAM LTBP4 Haplotype is Protective Against Dystrophin-Deficient Cardiomyopathy.

Background: Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes. Methods and Results: We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (-0.80%) and SF (-0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (-11.01 mL/m2, p = 0.03) while for dp116 were correlated with decreased EF (-4.14%, p = <0.001). The rs10880 genotype in the LTBP4 gene, previously shown to prolong ambulation, was also associated with increased EF and decreased EDV (+3.29%, p = 0.002, and -10.62 mL/m2, p = 0.008) with a recessive model. Conclusions: We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4 genotype of DCM in DMD.

Investigating distributions of inhaled aerosols in the lungs of post-COVID-19 clusters through a unified imaging and modeling approach.

BACKGROUND: Recent studies, based on clinical data, have identified sex and age as significant factors associated with an increased risk of long COVID. These two factors align with the two post-COVID-19 clusters identified by a deep learning algorithm in computed tomography (CT) lung scans: Cluster 1 (C1), comprising predominantly females with small airway diseases, and Cluster 2 (C2), characterized by older individuals with fibrotic-like patterns. This study aims to assess the distributions of inhaled aerosols in these clusters. METHODS: 140 COVID survivors examined around 112 days post-diagnosis, along with 105 uninfected, non-smoking healthy controls, were studied. Their demographic data and CT scans at full inspiration and expiration were analyzed using a combined imaging and modeling approach. A subject-specific CT-based computational model analysis was utilized to predict airway resistance and particle deposition among C1 and C2 subjects. The cluster-specific structure and function relationships were explored. RESULTS: In C1 subjects, distinctive features included airway narrowing, a reduced homothety ratio of daughter over parent branch diameter, and increased airway resistance. Airway resistance was concentrated in the distal region, with a higher fraction of particle deposition in the proximal airways. On the other hand, C2 subjects exhibited airway dilation, an increased homothety ratio, reduced airway resistance, and a shift of resistance concentration towards the proximal region, allowing for deeper particle penetration into the lungs. CONCLUSIONS: This study revealed unique mechanistic phenotypes of airway resistance and particle deposition in the two post-COVID-19 clusters. The implications of these findings for inhaled drug delivery effectiveness and susceptibility to air pollutants were explored.

Airway tree caliber heterogeneity and airflow obstruction among older adults.

INTRODUCTION: Smaller mean airway tree caliber is associated with airflow obstruction and chronic obstructive pulmonary disease (COPD). We investigated whether airway tree caliber heterogeneity was associated with airflow obstruction and COPD. METHODS: Two community-based cohorts (MESA Lung, CanCOLD) and a longitudinal case-control study of COPD (SPIROMICS) performed spirometry and computed tomography measurements of airway lumen diameters at standard anatomic locations and total lung volume. Percent-predicted airway lumen diameters were calculated using sex-specific reference equations accounting for age, height and lung volume. The association of airway tree caliber heterogeneity, quantified as the standard deviation (SD) of percent-predicted airway lumen diameters, with baseline forced expired volume in 1-second (FEV1), FEV1/forced vital capacity (FEV1/FVC) and COPD, as well as longitudinal spirometry, were assessed using regression models adjusted for age, sex, height, race-ethnicity, and mean airway tree caliber. RESULTS: Among 2,505 MESA Lung participants (mean±SD age: 69±9 years; 53% female, mean airway tree caliber: 99±10% predicted, airway tree caliber heterogeneity: 14±5%; median follow-up: 6.1 years), participants in the highest quartile of airway tree caliber heterogeneity exhibited lower FEV1 (adjusted mean difference: -125 ml, 95%CI:-171,-79), lower FEV1/FVC (adjusted mean difference: -0.01, 95%CI:-0.02,-0.01), and higher odds of COPD (adjusted OR 1.42, 95%CI:1.01-2.02) when compared with the lowest quartile, whereas longitudinal changes in FEV1 and FEV1/FVC did not differ significantly. Observations in CanCOLD and SPIROMICS were consistent. CONCLUSION: Among older adults, airway tree caliber heterogeneity was associated with airflow obstruction and COPD at baseline but was not associated with longitudinal changes in spirometry.

Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone). METHODS: A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2. RESULTS: A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78, p = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups. DISCUSSION: Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03439670. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.

Peripheral Blood Mononuclear Cell Gene Expression Associated with Pulmonary Microvascular Perfusion: The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease Study.

Rationale Chronic obstructive pulmonary disease (COPD) and emphysema are associated with endothelial damage and altered pulmonary microvascular perfusion. Molecular mechanisms underlying these changes are poorly understood in patients due, in part, to the inaccessibility of the pulmonary vasculature. Peripheral blood mononuclear cells (PBMC) interact with the pulmonary endothelium. Objective To test the association between gene expression in PBMCs and pulmonary microvascular perfusion in COPD. Methods The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited two independent samples of COPD cases and controls with 10 or more pack-years. In both samples, pulmonary microvascular blood flow, pulmonary microvascular blood volume (PMBV), and mean transit time were assessed on contrast-enhanced MRI, and PBMC gene expression was assessed by microarray. Additional replication was performed in a third sample with PMBV measures on contrast-enhanced, dual-energy CT. Differential expression analyses were adjusted for age, gender, race-ethnicity, educational attainment, height, weight, smoking status, and pack-years. Results The 79 participants in the discovery sample had mean age of 69±6 years, 44% were female, 25% were non-white, 34% were current smokers and 66% had COPD. There were large PBMC gene expression signatures associated with pulmonary microvascular perfusion traits, with several replicated in the replication sets with MRI (n=47) or dual-energy CT scan (n=157) measures. Many of the identified genes are involved in inflammatory processes, including NF-κB and chemokine signaling pathways. Conclusions PBMC gene expression in NF-κB, inflammatory and chemokine signaling pathways was associated pulmonary microvascular perfusion in COPD, potentially offering new targetable candidates for novel therapies.

Partners in vaccination: A community-based intervention to promote COVID-19 vaccination among low-income homebound and disabled adults.

BACKGROUND: Care managers (CM) for low-income disabled clients may address COVID-19 vaccine hesitancy with specific training. OBJECTIVE: To assess the Partners in Vaccination (PIV) that trained CMs of a homecare program for disabled adults to promote COVID-19 vaccination. METHODS: We randomized 78 CMs to PIV intervention (N = 38) or control (N = 40). PIV featured motivational interviewing (MI) skills and educational materials for unvaccinated clients. The primary outcome was first COVID-19 vaccination between December 1, 2021 and June 30, 2022 for clients of intervention CMs versus control CMs. Mixed method analysis included key informant interviews conducted from 5/24/22 to 7/25/22 with CMs, administrators, and clients about the PIV intervention. RESULTS: Among 1939 clients of 78 study CMs, 528 (26.8 %) were unvaccinated by December 1, 2021 (274 clients of intervention CMs; 254 clients of control CMs). These clients' mean age was 62.3 years old (SD = 22.4) and 54 % were Black or Hispanic/Latino. First vaccination rate did not differ for intervention and control groups (6.2 % vs. 5.9 %, p = .89) by 6/30/2022. Barriers to addressing COVID-19 vaccination from interviews with 7 CMs and administrators were competing responsibilities and potentially antagonizing clients. Seven interviewed clients (five vaccinated and two unvaccinated) cited concerns about vaccination they heard from their family/friends and belief that risks of COVID-19 infection may be less than vaccination. Yet, some clients were receptive to physician recommendations. CONCLUSION: Training CMs to promote COVID-19 vaccination for disabled clients did not increase first vaccination rates. CMs preferred their usual role of coordinating care and, even after the training, expressed discomfort with this potentially polarizing topic.

LungViT: Ensembling Cascade of Texture Sensitive Hierarchical Vision Transformers for Cross-Volume Chest CT Image-to-Image Translation.

Chest computed tomography (CT) at inspiration is often complemented by an expiratory CT to identify peripheral airways disease. Additionally, co-registered inspiratory-expiratory volumes can be used to derive various markers of lung function. Expiratory CT scans, however, may not be acquired due to dose or scan time considerations or may be inadequate due to motion or insufficient exhale; leading to a missed opportunity to evaluate underlying small airways disease. Here, we propose LungViT - a generative adversarial learning approach using hierarchical vision transformers for translating inspiratory CT intensities to corresponding expiratory CT intensities. LungViT addresses several limitations of the traditional generative models including slicewise discontinuities, limited size of generated volumes, and their inability to model texture transfer at volumetric level. We propose a shifted-window hierarchical vision transformer architecture with squeeze-and-excitation decoder blocks for modeling dependencies between features. We also propose a multiview texture similarity distance metric for texture and style transfer in 3D. To incorporate global information into the training process and refine the output of our model, we use ensemble cascading. LungViT is able to generate large 3D volumes of size 320 × 320 × 320. We train and validate our model using a diverse cohort of 1500 subjects with varying disease severity. To assess model generalizability beyond the development set biases, we evaluate our model on an out-of-distribution external validation set of 200 subjects. Clinical validation on internal and external testing sets shows that synthetic volumes could be reliably adopted for deriving clinical endpoints of chronic obstructive pulmonary disease.

Airway Tree Caliber and Susceptibility to Pollution-associated Emphysema: MESA Air and Lung Studies.

RATIONALE: Airway tree morphology varies in the general population and may modify the distribution and uptake of inhaled pollutants. OBJECTIVES: We hypothesized that smaller airway caliber would be associated with emphysema progression and would increase susceptibility to air pollutant-associated emphysema progression. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) is a general population cohort of adults 45-84 years old from six U.S. communities. Airway tree caliber was quantified as the mean of airway lumen diameters measured from baseline cardiac computed tomography (CT) (2000-02). Percent emphysema, defined as percentage of lung pixels below -950 Hounsfield units, was assessed up to 5 times per participant via cardiac CT scan (2000-07) and equivalent regions on lung CT scan (2010-18). Long-term outdoor air pollutant concentrations (PM2.5, NOx, O3) were estimated at residential address with validated spatio-temporal models. Linear mixed models estimated the association between airway tree caliber and emphysema progression; modification of pollutant-associated emphysema progression was assessed using multiplicative interaction terms. MAIN RESULTS: Among 6,793 participants (mean±SD age: 62±10 years), baseline airway tree caliber was 3.95±1.1 mm and median (interquartile range) of percent emphysema was 2.88 (1.21-5.68). In adjusted analyses, 10-year emphysema progression rate was 0.75 percentage points (95%CI 0.54-0.96%) higher in the smallest compared to largest airway tree caliber quartile. Airway tree caliber also modified air pollutant-associated emphysema progression. CONCLUSIONS: Smaller airway tree caliber was associated with accelerated emphysema progression and modified air pollutant-associated emphysema progression. A better understanding of mechanisms of airway-alveolar homeostasis and air pollutant deposition are needed.

Diagnostic outcome of pro bono neurogenetic diagnostic service in Sri Lanka: A wealth creation.

The inherited disease community in Sri Lanka has been widely neglected. This article aimed to present accumulated knowledge in establishing a pro bono cost-effective national, island-wide, free-of-charge molecular diagnostic service, suggesting a model for other developing countries. The project provided 637 molecular diagnostic tests and reports free of charge to a nation with limited resources. We pioneered the implementation of mobile clinics and home visits, where the research team acted as barefoot doctors with the concept of the doctor and the researcher at the patient's doorstep. Establishing pro bono, cost-effective molecular diagnostics is feasible in developing countries with limited resources and state funding through the effort of dedicated postgraduate students. This service could provide an accurate molecular diagnosis of Duchenne muscular dystrophy, Huntington's disease, Spinocerebellar ataxia, and Spinal muscular atrophy, a diagnostic yield of 54% (343/637), of which 43% (147/343) of the patients identified as amenable for available gene therapies. Initiated human resource development by double doctoral degree opportunities with international collaborations. Established a neurobiobank and a national registry in Sri Lanka, a rich and unique repository, wealth creation for translational collaborative research and sharing of information in neurological diseases, as well as a lodestar for aspiring initiatives from other developing countries.

Loss of Airway Phylogenetic Diversity Is Associated with Clinical and Pathobiological Markers of Disease Development in COPD.

RATIONALE: The airway microbiome has the potential to shape COPD pathogenesis, but its relationship to outcomes in milder disease is unestablished. OBJECTIVES: Identify sputum microbiome characteristics associated with markers of COPD in participants of the SubPopulations and InteRmediate Outcome Measures of COPD Study (SPIROMICS). METHODS: Sputum DNA from 877 participants were analyzed using 16S rRNA gene sequencing. Relationships between baseline airway microbiota composition and clinical, radiographic and muco-inflammatory markers, including longitudinal lung function trajectory, were examined. MEASUREMENTS AND MAIN RESULTS: Participant data represented predominantly milder disease (GOLD 0-2: N=732/877). Phylogenetic diversity (range of different species within a sample) correlated positively with baseline lung function, declined with higher GOLD stage, and correlated negatively with symptom burden, radiographic markers of airway disease, and total mucin concentrations (p<0.001). In co-variate adjusted regression models, organisms robustly associated with better lung function included members of Alloprevotella, Oribacterium, and Veillonella. Conversely, lower lung function, greater symptoms and radiographic measures of small airway disease associated with enrichment in members of Streptococcus, Actinobacillus, Actinomyces, and other genera. Baseline sputum microbiota features also associated with lung function trajectory during SPIROMICS follow up (stable/improved, decliner, or rapid decliner). The 'stable/improved' group (slope of FEV1 regression ≥ 66th percentile) had higher bacterial diversity at baseline, associated with enrichment in Prevotella, Leptotrichia, and Neisseria. In contrast, the 'rapid decliner' group (FEV1 slope ≤ 33rd percentile) had significantly lower baseline diversity, associated with enrichment in Streptococcus. CONCLUSIONS: In SPIROMICS baseline airway microbiota features demonstrate divergent associations with better or worse COPD-related outcomes.

Title-molecular diagnostics of dystrophinopathies in Sri Lanka towards phenotype predictions: an insight from a South Asian resource limited setting.

BACKGROUND: The phenotype of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients is determined by the type of DMD gene variation, its location, effect on reading frame, and its size. The primary objective of this investigation was to determine the frequency and distribution of DMD gene variants (deletions/duplications) in Sri Lanka through the utilization of a combined approach involving multiplex polymerase chain reaction (mPCR) followed by Multiplex Ligation Dependent Probe Amplification (MLPA) and compare to the international literature. The current consensus is that MLPA is a labor efficient yet expensive technique for identifying deletions and duplications in the DMD gene. METHODOLOGY: Genetic analysis was performed in a cohort of 236 clinically suspected pediatric and adult myopathy patients in Sri Lanka, using mPCR and MLPA. A comparative analysis was conducted between our findings and literature data. RESULTS: In the entire patient cohort (n = 236), mPCR solely was able to identify deletions in the DMD gene in 131/236 patients (DMD-120, BMD-11). In the same cohort, MLPA confirmed deletions in 149/236 patients [DMD-138, BMD -11]. These findings suggest that mPCR has a detection rate of 95% (131/138) among all patients who received a diagnosis. The distal and proximal deletion hotspots for DMD were exons 45-55 and 6-15. Exon 45-60 identified as a novel in-frame variation hotspot. Exon 45-59 was a hotspot for BMD deletions. Comparisons with the international literature show significant variations observed in deletion and duplication frequencies in DMD gene across different populations. CONCLUSION: DMD gene deletions and duplications are concentrated in exons 45-55 and 2-20 respectively, which match global variation hotspots. Disparities in deletion and duplication frequencies were observed when comparing our data to other Asian and Western populations. Identified a 95% deletion detection rate for mPCR, making it a viable initial molecular diagnostic approach for low-resource countries where MLPA could be used to evaluate negative mPCR cases and cases with ambiguous mutation borders. Our findings may have important implications in the early identification of DMD with limited resources in Sri Lanka and to develop tailored molecular diagnostic algorithms that are regional and population specific and easily implemented in resource limited settings.

Structural Predictors of Lung Function Decline in Young Smokers with Normal Spirometry.

RATIONALE: Chronic obstructive pulmonary disease (COPD) due to tobacco smoking commonly presents when extensive lung damage has occurred. OBJECTIVES: We hypothesised that structural change would be detected early in the natural history of COPD and would relate to loss of lung function with time. METHODS: We recruited 431 current smokers (median age 39 years, 16 pack-years smoked) and recorded symptoms by the COPD Assessment Test (CAT), spirometry and quantitative thoracic CT (QCT) scans at study entry. These scans results were compared to 67 never smoking controls. 368 participants were followed every six months with measurement of post-bronchodilator spirometry for a median of 32 months. The rate of FEV1 decline, adjusted for current smoking status, age and sex was related to the initial QCT appearances and symptoms, measured with the CAT. MEASUREMENTS AND MAIN RESULTS: There were no material differences in demography or subjective CT appearances between the young smokers and controls, but 55.7% of the former had a CAT score above 10 and 24.2% reported chronic bronchitis. QCT assessments of Disease Probability-defined functional small airways disease, ground glass opacification, bronchovascular prominence and small blood vessel to total pulmonary vessel volume ratio were increased compared to controls and were all associated with a faster FEV1 decline as was a higher CAT score. CONCLUSIONS: Radiologic abnormalities on CT are already established in young smokers with normal lung function and is associated with FEV1 loss independently of the impact of symptoms. Structural abnormalities are present early in the natural history of COPD and are markers of disease progression. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).