Air pollution, weather and positive airway pressure treatment adherence in adults with sleep apnea: a retrospective community-based repeated-measures longitudinal study.

We assessed the relation between air pollution, weather, and adherence to positive airway pressure (PAP) therapy in a retrospective community-based repeated-measures study of adults with obstructive sleep apnea who purchased PAP devices from a registered provider between 2013 and 2017 (Ottawa, Ontario, Canada) and had at least one day of data. Daily PAP-derived data, air pollution, and weather databases were linked using postal code. The exposures were mean nocturnal (8:00 p.m. to 8:00 a.m.) (i) residential concentrations of nitrogen dioxide (NO2 ), fine particulate matter <=2.5 µm (PM2.5 ), ozone (O3 ), and Air Quality Health Index (AQHI), and (ii) temperature, relative humidity, and barometric pressure. Covariates in the main model were demographics, season, exposure year, and PAP therapy mode. We analysed 8148 adults (median age of 54 years and 61% men) and 2,071,588 days of data. Based on daily data, the median (interquartile range) daily PAP usage was 416 (323-487) min. Using mixed-effect regression analyses to incorporate daily data and clustering by individuals, we found a statistically significant decrease in adherence for increased levels of NO2 , PM2.5 , and AQHI. The largest effect was for NO2 : a decrease in daily PAP use while comparing the highest versus lowest quartiles (Qs) was 3.4 (95% confidence interval [CI] 2.8-3.9) min. Decreased PAP adherence was also associated with increased temperature (Q4 versus Q1: 2.6 [95% CI: 1.5-3.7] min) and decreased barometric pressure (Q1 versus Q4: 2.0 [95% CI 1.5-2.5] min). We observed modest but statistically significant acute effects of air pollution and weather on daily PAP adherence.

Concentration-dependent alterations in the human plasma proteome following controlled exposure to diesel exhaust.

Traffic-related air pollution (TRAP) exposure is associated with systemic health effects, which can be studied using blood-based markers. Although we have previously shown that high TRAP concentrations alter the plasma proteome, the concentration-response relationship between blood proteins and TRAP is unexplored in controlled human exposure studies. We aimed to identify concentration-dependent plasma markers of diesel exhaust (DE), a model of TRAP. Fifteen healthy non-smokers were enrolled into a double-blinded, crossover study where they were exposed to filtered air (FA) and DE at 20, 50 and 150 µg/m3 PM2.5 for 4h, separated by ≥ 4-week washouts. We collected blood at 24h post-exposure and used label-free mass spectrometry to quantify proteins in plasma. Proteins exhibiting a concentration-response, as determined by linear mixed effects models (LMEMs), were assessed for pathway enrichment using WebGestalt. Top candidates, identified by sparse partial least squares discriminant analysis and LMEMs, were confirmed using enzyme-linked immunoassays. Thereafter, we assessed correlations between proteins that showed a DE concentration-response and acute inflammatory endpoints, forced expiratory volume in 1 s (FEV1) and methacholine provocation concentration causing a 20% drop in FEV1 (PC20). DE exposure was associated with concentration-dependent alterations in 45 proteins, which were enriched in complement pathways. Of the 9 proteins selected for confirmatory immunoassays, based on complementary bioinformatic approaches to narrow targets and availability of high-quality assays, complement factor I (CFI) exhibited a significant concentration-dependent decrease (-0.02 µg/mL per µg/m3 of PM2.5, p = 0.04). Comparing to FA at discrete concentrations, CFI trended downward at 50 (-2.14 ± 1.18, p = 0.08) and significantly decreased at 150 µg/m3 PM2.5 (-2.93 ± 1.18, p = 0.02). CFI levels were correlated with FEV1, PC20 and nasal interleukin (IL)-6 and IL-1ß. This study details concentration-dependent alterations in the plasma proteome following DE exposure at concentrations relevant to occupational and community settings. CFI shows a robust concentration-response and association with established measures of airway function and inflammation.

Design, delivery, and evaluation of a knowledge translation intervention for multi-stakeholders.

BACKGROUND: Knowledge translation (KT) is a key competency for trainees (graduate students and post-doctoral fellows), the new generation of researchers who must learn how to synthesize, disseminate, exchange, and ethically apply knowledge to improve patient and health system services, products, and outcomes. KT training is a key enabler to support KT competency development. Yet, there is a dearth of research on the design, delivery, and evaluation of KT training for trainees. METHODS: The study applied a QUAN(qual) mixed methods approach with an embedded experimental model design. A heart and lung patient was also recruited to participate as a partner and researcher in the study. A multi-faceted KT intervention for trainees was designed, delivered, and evaluated. Data were collected using surveys and focus groups. Quantitative data were analyzed using descriptive and inferential statistics in R Studio and MS Excel. Qualitative data were analyzed in NVivo using thematic analysis. RESULTS: Participation in each KT intervention varied, with 8-42 participants attending KT webinars, 61 attendees in the Three Minute Thesis (3MT) Competition Heat, and 31 participants in the Patient & Public Forum. In total, 27 trainees and 4 faculty participated in at least one of the KT webinars. Trainee participants reported satisfaction, as well as statistically significant increases in 10/13 KT competencies after receiving one or more components of the KT intervention. Additionally, participating faculty, patients, and the public were satisfied with the intervention components they participated in. Several challenges and facilitators were also identified to improve the KT intervention. CONCLUSIONS: The KT intervention is a promising initiative that can be adopted and adapted across various post-secondary settings to support trainees' competency development in KT. This evaluation demonstrates that trainees will respond to opportunities for KT training and that capacity for KT competencies can be advanced through a multi-faceted intervention that involves trainees, faculty, patients, and health system collaborators in its design and delivery. This evaluation study contributes the design and results of a novel KT intervention for multi-stakeholders. TRIAL REGISTRATION: N/A.

Controlled Diesel Exhaust Exposure Induces a Concentration-dependent Increase in Airway Inflammation: A Clinical Trial.

Rationale: Air pollution exposure is harmful to human airways, and its impacts are best studied using concentration-response relationships. However, most concentration-response research on airway health has investigated chronic exposures, with less being known about acute effects, which can be robustly studied using controlled human exposures. Objectives: To investigate the concentration relationship between airway health measures and diesel exhaust (DE). Methods: We conducted a double-blind crossover study with 17 healthy nonsmokers exposed to filtered air and DE standardized to 20, 50, and 150 µg/m3 of particulate matter ⩽2.5 µm in aerodynamic diameter for 4 hours. Before, during, and up to 24 hours from the exposure start, we measured lung function, airway responsiveness, and airway inflammation using spirometry, methacholine challenge, and fractional exhaled nitric oxide (FeNO), respectively. In addition, we measured nasal airway inflammation using differential cell counts and cytokines in nasal lavage and epithelial lining fluid at 24 hours. We assessed DE concentration responses and associations between outcomes using linear mixed effects models and repeated measures correlations, respectively, thereafter adjusting for multiple comparisons. Results: DE exposure increased percentage ΔFeNO at 4 hours (ß = 0.16 ± 0.06). Compared with filtered air, percentage ΔFeNO trended toward an increase at concentrations of 20 µg/m3 (ß = 18.66 ± 8.76) and 50 µg/m3 (ß = 19.33 ± 8.92) and increased significantly at 150 µg/m3 (ß = 34.43 ± 8.92). In addition, DE exposure induced a trend toward increased nasal IL-6 at 24 hours (percentage difference, 0.88; 95% confidence interval, 0.08, 1.70). There were no effects of DE exposure on FeNO at 24 hours, lung function, airway responsiveness, or nasal cell counts. Conclusions: DE induces a concentration-dependent increase in FeNO, indicating that it may be a sensitive marker of an acute inflammatory response in the airways. We report responses at concentrations below those in previous controlled DE exposure studies, and we document particulate matter ⩽2.5 µm in aerodynamic diameter concentration-response estimates at exposure levels routinely experienced in the community and occupational settings. Clinical trial registered with www.clinicaltrials.gov (NCT03234790).

Exposure to diesel exhaust alters the functional metagenomic composition of the airway microbiome in former smokers.

The lung microbiome plays a crucial role in airway homeostasis, yet we know little about the effects of exposures such as air pollution therein. We conducted a controlled human exposure study to assess the impact of diesel exhaust (DE) on the human airway microbiome. Twenty-four participants (former smokers with mild to moderate COPD (N = 9), healthy former smokers (N = 7), and control healthy never smokers (N = 8)) were exposed to DE (300 µg/m3 PM2.5) and filtered air (FA) for 2 h in a randomized order, separated by a 4-week washout. Endobronchial brushing samples were collected 24 h post-exposure and sequenced for the 16S microbiome, which was analyzed using QIIME2 and PICRUSt2 to examine diversity and metabolic functions, respectively. DE exposure altered airway microbiome metabolic functions in spite of statistically stable microbiome diversity. Affected functions included increases in: superpathway of purine deoxyribonucleosides degradation (pathway differential abundance 743.9, CI 95% 201.2 to 1286.6), thiazole biosynthesis I (668.5, CI 95% 139.9 to 1197.06), and L-lysine biosynthesis II (666.5, CI 95% 73.3 to 1257.7). There was an exposure-by-age effect, such that menaquinone biosynthesis superpathways were the most enriched function in the microbiome of participants aged >60, irrespective of smoking or health status. Moreover, exposure-by-phenotype analysis showed metabolic alterations in former smokers after DE exposure. These observations suggest that DE exposure induced substantial changes in the metabolic functions of the airway microbiome despite the absence of diversity changes.

Concentration-dependent increase in symptoms due to diesel exhaust in a controlled human exposure study.

BACKGROUND: Traffic-related air pollution (TRAP) exposure causes adverse effects on wellbeing and quality of life, which can be studied non-invasively using self-reported symptoms. However, little is known about the effects of different TRAP concentrations on symptoms following controlled exposures, where acute responses can be studied with limited confounding. We investigated the concentration-response relationship between diesel exhaust (DE) exposure, as a model TRAP, and self-reported symptoms. METHODS: We recruited 17 healthy non-smokers into a double-blind crossover study where they were exposed to filtered air (FA) and DE standardized to 20, 50, 150 µg/m3 PM2.5 for 4 h, with a ≥ 4-week washout between exposures. Immediately before, and at 4 h and 24 h from the beginning of the exposure, we administered visual analog scale (VAS) questionnaires and grouped responses into chest, constitutional, eye, neurological, and nasal categories. Additionally, we assessed how the symptom response was related to exposure perception and airway function. RESULTS: An increase in DE concentration raised total (ß ± standard error = 0.05 ± 0.03, P = 0.04), constitutional (0.01 ± 0.01, P = 0.03) and eye (0.02 ± 0.01, P = 0.05) symptoms at 4 h, modified by perception of temperature, noise, and anxiety. These symptoms were also correlated with airway inflammation. Compared to FA, symptoms were significantly increased at 150 µg/m3 for the total (8.45 ± 3.92, P = 0.04) and eye (3.18 ± 1.55, P = 0.05) categories, with trends towards higher values in the constitutional (1.49 ± 0.86, P = 0.09) and nasal (1.71 ± 0.96, P = 0.08) categories. CONCLUSION: DE exposure induced a concentration-dependent increase in symptoms, primarily in the eyes and body, that was modified by environmental perception. These observations emphasize the inflammatory and sensory effects of TRAP, with a potential threshold below 150 µg/m3 PM2.5. We demonstrate VAS questionnaires as a useful tool for health monitoring and provide insight into the TRAP concentration-response at exposure levels relevant to public health policy.

Air Pollution and the Effectiveness of Positive Airway Pressure Therapy in Individuals With Sleep Apnea: A Retrospective Community-Based Repeated-Measures Longitudinal Study.

BACKGROUND: Ambient air pollution may affect the severity of untreated OSA, but it is unknown whether air pollution adversely impacts the effectiveness of positive airway pressure (PAP) therapy. RESEARCH QUESTION: Do short-term changes in outdoor air pollution adversely impact adults with OSA using PAP therapy? STUDY DESIGN AND METHODS: We conducted a retrospective community-based repeated-measures longitudinal study of adults with OSA who purchased a PAP device from a registered equipment provider between 2013 and 2017 (Ontario, Canada) and had data on the daily device-derived residual apnea-hypopnea index (AHIFlow). We linked daily PAP-derived data to air pollution databases using postal codes. The primary exposures were mean nocturnal (8 pm to 8 am) residential concentrations of ozone, fine particulate matter, nitrogen dioxide, carbon monoxide, sulfur dioxide, and the Air Quality Health Index (AQHI). Potential confounders considered were demographics, season and year of exposure, initial OSA severity, other PAP parameters, and climate-related variables. RESULTS: Eight thousand one hundred forty-eight adults were analyzed with a median of 89 days (interquartile range [IQR], 29-302 days) of observation during which PAP was used for ≥ 4 h. The median daily AHIFlow was 1.2/h (IQR, 0.5-2.5/h). In mixed multivariate regression analyses, an increase in air pollution was associated with a statistically significant increase in AHIFlow for most statistical models. The largest effect was for the AQHI: an increase in AHIFlow while comparing highest vs lowest quartiles was 0.07/h (95% CI, 0.05-0.10/h). INTERPRETATION: We demonstrated a modest but statistically significant increase in residual respiratory events during PAP therapy associated with an increase in air pollution concentrations.

Acute air pollution exposure increases TET enzymes in human PBMCs.

BACKGROUND: Exposure to traffic-related air pollution is associated with increased morbidity and mortality. Negative health impact of diesel exhaust (DE) exposure may in part be mediated via epigenetic modulation. Ten-eleven translocation (TET) enzymes catalyze the active DNA demethylation process and play important roles in epigenetic regulation. OBJECTIVES: We sought to assess the expression of TET enzymes in human PBMCs and the differentiation of immune subsets in response to acute DE exposure at a range of concentrations. METHODS: Thirteen healthy participants were recruited for this randomized, double-blind, controlled human exposure study to DE. In this 4-arm crossover study, each participant was exposed for 4 hours to 3 different concentrations of DE (DE diluted to have particulate matter with a diameter of ≤2.5 micron concentration nominally set at 20, 50, and 150 µg/m3) and filtered air. Blood was collected at baseline and 4 and 24 hours after the exposure start time. The composition of PBMCs and their TET enzymes' expression were evaluated with flow cytometry. Cytokines in plasma were measured by electrochemiluminescence multiplex assays. RESULTS: DE exposure decreased the proportion of B cells, TH17 cells, and activated T cells in PBMCs. TET enzymes were upregulated in PBMCs, especially in TH1, TH2, and TH17 cells, at 4 hours following DE exposure. The expression of TET enzymes correlated with proinflammatory cytokine secretion in plasma. CONCLUSIONS: We demonstrated that acute DE exposure impacted peripheral blood leukocyte proportions and TET enzymes' expression in lymphocyte subsets at DE concentration of 50 µg/m3 and above. Our finding suggests that even a modest exposure to air pollution can impact the circulating immune cells via epigenetic modulation.

Defining the effects of traffic-related air pollution on the human plasma proteome using an aptamer proteomic array: A dose-dependent increase in atherosclerosis-related proteins.

BACKGROUND: Traffic-related air pollution (TRAP) is a critical risk factor and major contributor to respiratory and cardiovascular disease (CVD). The effects of TRAP beyond the lungs can be related to changes in circulatory proteins. However, such TRAP-mediated changes have not been defined in an unbiased manner using a controlled human model. OBJECTIVE: To detail global protein changes (the proteome) in plasma following exposure to inhaled diesel exhaust (DE), a paradigm of TRAP, using controlled human exposures. METHODS: In one protocol, ex-smokers and never-smokers were exposed to filtered air (FA) and DE (300 µg PM2.5/m3), on order-randomized days, for 2 h. In a second protocol, independent never-smoking participants were exposed to lower concentrations of DE (20, 50 or 150 µg PM2.5/m3) and FA, for 4 h, on order-randomized days. Each exposure was separated by 4 weeks of washout. Plasma samples obtained 24 h post-exposure from ex-smokers (n = 6) were first probed using Slow off-rate modified aptamer proteomic array. Plasma from never-smokers (n = 11) was used for independent assessment of proteins selected from the proteomics study by immunoblotting. RESULTS: Proteomics analyses revealed that DE significantly altered 342 proteins in plasma of ex-smokers (n = 6). The top 20 proteins therein were primarily associated with inflammation and CVD. Plasma from never-smokers (n = 11) was used for independent assessment of 6 proteins, amongst the top 10 proteins increased by DE in the proteomics study, for immunoblotting. The abundance of all six proteins (fractalkine, apolipoproteins (APOB and APOM), IL18R1, MIP-3 and MMP-12) was significantly increased by DE in plasma of these never-smokers. DE-mediated increase was shown to be concentration-dependent for fractalkine, APOB and MMP-12, all biomarkers of atherosclerosis, which correlated with plasma levels of IL-6, a subclinical marker of CVD, in independent participants. CONCLUSION: This investigation details changes in the human plasma proteome due to TRAP. We identify specific atherosclerosis-related proteins that increase concentration-dependently across a range of TRAP levels applicable worldwide.

Impact of Exposure to Diesel Exhaust on Inflammation Markers and Proteases in Former Smokers with Chronic Obstructive Pulmonary Disease: A Randomized, Double-blinded, Crossover Study.

Rationale: There is growing evidence that chronic obstructive pulmonary disease (COPD) can be caused and exacerbated by air pollution exposure. Objectives: To document the impact of short-term air pollution exposure on inflammation markers, proteases, and antiproteases in the lower airways of older adults with and without COPD. Methods: Thirty participants (10 ex-smokers with mild to moderate COPD and 20 healthy participants [9 ex-smokers and 11 never-smokers]), with an average age of 60 years, completed this double-blinded, controlled, human crossover exposure study. Each participant was exposed to filtered air (control) and diesel exhaust (DE), in washout-separated 2-hour periods, in a randomly assigned order. Bronchoscopy was performed 24 hours after exposure to collect lavage. Cell counts were performed on blood and airway samples. ELISAs were performed to measure acute inflammatory proteins, matrix proteinases, and antiproteases in the airway and blood samples. Measurements and Main Results: In former smokers with COPD, but not in the other participants, exposure to DE increased serum amyloid A (effect estimate, 1.67; 95% confidence interval [CI], 1.21-2.30; P = 0.04) and matrix metalloproteinase 10 (effect estimate, 2.61; 95% CI, 1.38-4.91; P = 0.04) in BAL. Circulating lymphocytes were increased after DE exposure (0.14 [95% CI, 0.05-0.24] cells × 109/L; P = 0.03), irrespective of COPD status. Conclusions: A controlled human crossover study of DE exposure reveals that former smokers with COPD may be susceptible to an inflammatory response compared with ex-smokers without COPD or never-smoking healthy control participants. Clinical trial registered with www.clinicaltrials.gov (NCT02236039).

Concentration-dependent health effects of air pollution in controlled human exposures.

BACKGROUND: Air pollution is a leading contributor to premature mortality worldwide and is often represented by particulate matter (PM), a key contributor to its harmful health effects. Concentration-response relationships are useful for quantifying the effects of air pollution in relevant populations and in considering potential effect thresholds. Controlled human exposures can provide data on acute effects and concentration-response relationships that complement epidemiological studies. OBJECTIVES: We examined PM concentration-responses after controlled human air pollution exposures to examine exposure-response markers, assess effect modifiers, and identify potential effect thresholds. METHODS: We reviewed primary research from published controlled human exposure studies where responses were reported at multiple target PM concentrations or summarized per unit change in PM to identify concentration-dependent effects. RESULTS: Of the 191 publications identified through PubMed and supplementary searches, 31 were eligible. Eligible studies collectively represented four pollutant models: concentrated ambient particles, engineered carbon nanoparticles, diesel exhaust, and woodsmoke. We identified concentration-dependent effects on oxidative stress markers, inflammation, and cardiovascular function that overlapped across different pollutants. Metabolic syndrome and glutathione s-transferase mu 1 genotype were identified as potential effect modifiers. DISCUSSION: Improved understanding of concentration-response relationships is integral to biomonitoring and mitigation of health effects through impact assessment and policy. Although we identified potential concentration-response markers, thresholds, and modifiers, our conclusions on these relationships were limited by a dearth of eligible publications, considerable variability in methodology, and inconsistent reporting standards between studies. More research is required to validate these observations. We recommend that future studies harmonize estimate reporting to facilitate the identification of robust response markers across research and applied settings.