Biomarkers of Immersion in Virtual Reality Based on Features Extracted from the EEG Signals: A Machine Learning Approach.

Virtual reality (VR) enables the development of virtual training frameworks suitable for various domains, especially when real-world conditions may be hazardous or impossible to replicate because of unique additional resources (e.g., equipment, infrastructure, people, locations). Although VR technology has significantly advanced in recent years, methods for evaluating immersion (i.e., the extent to which the user is engaged with the sensory information from the virtual environment or is invested in the intended task) continue to rely on self-reported questionnaires, which are often administered after using the virtual scenario. Having an objective method to measure immersion is particularly important when using VR for training, education, and applications that promote the development, fine-tuning, or maintenance of skills. The level of immersion may impact performance and the translation of knowledge and skills to the real-world. This is particularly important in tasks where motor skills are combined with complex decision making, such as surgical procedures. Efforts to better measure immersion have included the use of physiological measurements including heart rate and skin response, but so far they do not offer robust metrics that provide the sensitivity to discriminate different states (idle, easy, and hard), which is critical when using VR for training to determine how successful the training is in engaging the user's senses and challenging their cognitive capabilities. In this study, electroencephalography (EEG) data were collected from 14 participants who completed VR jigsaw puzzles with two different levels of task difficulty. Machine learning was able to accurately classify the EEG data collected during three different states, obtaining accuracy rates of 86% and 97% for differentiating easy versus hard difficulty states and baseline vs. VR states. Building on these results may enable the identification of robust biomarkers of immersion in VR, enabling real-time recognition of the level of immersion that can be used to design more effective and translative VR-based training. This method has the potential to adjust aspects of VR related to task difficulty to ensure that participants are immersed in VR.

Accuracy of Pulse Oximetry for Long-Term Oxygen Therapy Assessment in Chronic Obstructive Pulmonary Disease.

Rationale: Landmark studies of long-term oxygen therapy (LTOT) in patients with chronic obstructive pulmonary disease (COPD) used arterial oxygen pressure (PaO2) to define severe hypoxemia; however, oxygen saturation as measured by pulse oximetry (SpO2) is commonly used instead. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend evaluation with arterial blood gas (ABG) analysis if SpO2 is ⩽92%. This recommendation has not been evaluated in stable outpatients with COPD undergoing testing for LTOT. Objectives: To evaluate the performance of SpO2 compared with ABG analysis of PaO2 and arterial oxygen saturation (SaO2) to detect severe resting hypoxemia in patients with COPD. Methods: Retrospective analysis of paired SpO2 and ABG values from stable outpatients with COPD who underwent LTOT assessment in a single center. We calculated false negatives (FNs) as an SpO2 >88% or >89% in the presence of pulmonary hypertension with a PaO2 ⩽55 mm Hg or ⩽59 mm Hg in the presence of pulmonary hypertension. Test performance was assessed using receiver operating characteristic (ROC) analysis, intraclass correlation coefficient (ICC), test bias, precision, and accuracy root-mean-square (Arms). An adjusted multivariate analysis was used to evaluate factors affecting SpO2 bias. Results: Of 518 patients, the prevalence of severe resting hypoxemia was 74 (14.3%), with 52 missed by SpO2 (FN, 10%), including 13 (2.5%) with an SpO2 > 92% (occult hypoxemia). FNs and occult hypoxemia in Black patients were 9% and 1.5%, respectively, and were 13% and 5%, respectively, among active smokers. The correlation between SpO2 and SaO2 was acceptable (ICC = 0.78; 95% confidence interval, 0.74-0.81); and the bias of SpO2 was 0.45%, with a precision of 2.6 (-4.65 to +5.55%) and Arms of 2.59. These measurements were similar in Black patients, but in active smokers, correlation was lower and bias showed greater overestimation of SpO2. ROC analysis suggests that the optimal SpO2 cutoff to warrant LTOT evaluation by ABG analysis is ⩽94%. Conclusions: SpO2 as the only measure of oxygenation carries a high FN rate in detecting severe resting hypoxemia in patients with COPD undergoing evaluation for LTOT. Reflex measurement of PaO2 by ABG analysis should be used as recommended by GOLD, ideally at a cutoff higher than an SpO2 ⩽92%, especially in active smokers.

Lower respiratory tract microbiome composition and community interactions in smokers.

The lung microbiome impacts on lung function, making any smoking-induced changes in the lung microbiome potentially significant. The complex co-occurrence and co-avoidance patterns between the bacterial taxa in the lower respiratory tract (LRT) microbiome were explored for a cohort of active (AS), former (FS) and never (NS) smokers. Bronchoalveolar lavages (BALs) were collected from 55 volunteer subjects (9 NS, 24 FS and 22 AS). The LRT microbiome composition was assessed using 16S rRNA amplicon sequencing. Identification of differentially abundant taxa and co-occurrence patterns, discriminant analysis and biomarker inferences were performed. The data show that smoking results in a loss in the diversity of the LRT microbiome, change in the co-occurrence patterns and a weakening of the tight community structure present in healthy microbiomes. The increased abundance of the genus Ralstonia in the lung microbiomes of both former and active smokers is significant. Partial least square discriminant and DESeq2 analyses suggested a compositional difference between the cohorts in the LRT microbiome. The groups were sufficiently distinct from each other to suggest that cessation of smoking may not be sufficient for the lung microbiota to return to a similar composition to that of NS. The linear discriminant analysis effect size (LEfSe) analyses identified several bacterial taxa as potential biomarkers of smoking status. Network-based clustering analysis highlighted different co-occurring and co-avoiding microbial taxa in the three groups. The analysis found a cluster of bacterial taxa that co-occur in smokers and non-smokers alike. The clusters exhibited tighter and more significant associations in NS compared to FS and AS. Higher degree of rivalry between clusters was observed in the AS. The groups were sufficiently distinct from each other to suggest that cessation of smoking may not be sufficient for the lung microbiota to return to a similar composition to that of NS.

Identification of male COPD patients with exertional hypoxemia who may benefit from long-term oxygen therapy.

Several studies have documented increased exercise capacity with supplemental oxygen therapy in patients with COPD and exertional hypoxemia, but a large trial failed to demonstrate a survival benefit in this population. Due to the heterogeneity observed in therapeutic responses, we sought to retrospectively evaluate survival in male COPD patients with exertional hypoxemia who had a clinically meaningful improvement in exercise capacity while using supplemental oxygen compared to their 6-minute walk test distance (6MWD) while walking on room air. We defined them as responders or non-responders based on a change in 6MWD of greater or less than 54m. We compared their clinical and physiologic characteristics, and their survival over time. From 817 COPD subjects who underwent an assessment for home oxygen during the study period, 140 met inclusion criteria, with 70 (50%) qualifying as responders. There were no significant differences in demographics, lung function, or baseline oxygenation between the groups. The only difference noted was in the baseline 6MWD on room air, with responders to oxygen therapy having significantly lower values (137 ± 74m, 27 ± 15% predicted) compared to non-responders (244 ± 108, 49 ± 23% predicted). Despite their poorer functional capacity, mortality was significantly lower in responders after adjusting for age, comorbidities, and FEV1 (HR 0.51; CI 0.31-0.83; p = 0.007) compared to non-responders after a median follow-up time of 3 years. We conclude that assessing the immediate effects of oxygen on exercise capacity may be an important way to identify individuals with exertional hypoxemia who may benefit in the long-term from ambulatory oxygen. Prospective long-term studies in this subset of patients with exercise induced hypoxemia are warranted.

Impact of a Computerized Clinical Decision Support System to Improve Chronic Obstructive Pulmonary Disease Diagnosis and Testing for Alpha-1 Antitrypsin Deficiency.

Rationale: Chronic obstructive pulmonary disease (COPD) and alpha-1 antitrypsin deficiency (AATD) are underrecognized diseases. This is in part due to the underdiagnosis and lack of confirmation of COPD but also from poor adherence to AATD screening recommendations. Objectives: A clinical decision support system (CDSS) to guide primary care providers improves spirometry testing and confirmation of COPD diagnosis in subjects at risk and improves AATD screening in patients with confirmed COPD. Methods: A CDSS was created to be applied to all Veterans attending single-center Veterans Affairs primary care clinics. The CDSS had an algorithmic dialogue with components executed in phases during different clinic visits: screening for COPD risk using the COPD population screening (COPD-PS) questionnaire, spirometry recommendation, and ordering tool for subjects with a prior diagnosis of COPD or subjects considered high risk by the COPD-PS, dialogue to confirm or discard the diagnosis of COPD, and recommendations for AATD screening in subjects with confirmed COPD. The latter was performed by ordering alpha-1 antitrypsin (AAT) serum levels. Each step of the CDSS algorithm approach was recorded and available to be retrieved at a later date for analysis. Results: Over 6 years, a total of 6,235 Veterans >40 years of age completed the CDSS. According to the COPD-PS questionnaire, 962 (18.5%) subjects were identified as high risk for COPD. An additional 579 subjects with a prior diagnosis of COPD also entered the subsequent steps of the CDSS algorithm. Of the high-risk cohort, the CDSS led to an increase in spirometry testing from 24% to 83% and led to a new diagnosis of COPD in 342 (43%). In the prior COPD diagnosis group, spirometry testing increased from 58% to 84%, leading to COPD reconfirmation in only 326 (67%). A total of 489 (68%) subjects with confirmed COPD completed AAT testing prompted by the CDSS, with 23 subjects identified with AATD and one with severe AATD. Conclusions: In the Veterans Affairs system, the use of a clinical decision support system algorithm that incorporates screening for COPD and AATD improves COPD over- and underdiagnosis and screening rates of AATD in a primary care setting.

Persistent nucleation and size dependent attachment kinetics produce monodisperse PbS nanocrystals.

Modern syntheses of colloidal nanocrystals yield extraordinarily narrow size distributions that are believed to result from a rapid "burst of nucleation" (La Mer, JACS, 1950, 72(11), 4847-4854) followed by diffusion limited growth and size distribution focusing (Reiss, J. Chem. Phys., 1951, 19, 482). Using a combination of in situ X-ray scattering, optical absorption, and 13C nuclear magnetic resonance (NMR) spectroscopy, we monitor the kinetics of PbS solute generation, nucleation, and crystal growth from three thiourea precursors whose conversion reactivity spans a 2-fold range. In all three cases, nucleation is found to be slow and continues during >50% of the precipitation. A population balance model based on a size dependent growth law (1/r) fits the data with a single growth rate constant (k G) across all three precursors. However, the magnitude of the k G and the lack of solvent viscosity dependence indicates that the rate limiting step is not diffusion from solution to the nanoparticle surface. Several surface reaction limited mechanisms and a ligand penetration model that fits data our experiments using a single fit parameter are proposed to explain the results.

Growth kinetics determine the polydispersity and size of PbS and PbSe nanocrystals.

A library of thio- and selenourea derivatives is used to adjust the kinetics of PbE (E = S, Se) nanocrystal formation across a 1000-fold range (k r = 10-1 to 10-4 s-1), at several temperatures (80-120 °C), under a standard set of conditions (Pb : E = 1.2 : 1, [Pb(oleate)2] = 10.8 mM, [chalcogenourea] = 9.0 mM). An induction delay (t ind) is observed prior to the onset of nanocrystal absorption during which PbE solute is observed using in situ X-ray total scattering. Density functional theory models fit to the X-ray pair distribution function (PDF) support a Pb2(µ2-S)2(Pb(O2CR)2)2 structure. Absorption spectra of aliquots reveal a continuous increase in the number of nanocrystals over more than half of the total reaction time at low temperatures. A strong correlation between the width of the nucleation phase and reaction temperature is observed that does not correlate with the polydispersity. These findings are antithetical to the critical concentration dependence of nucleation that underpins the La Mer hypothesis and demonstrates that the duration of the nucleation period has a minor influence on the size distribution. The results can be explained by growth kinetics that are size dependent, more rapid at high temperature, and self limiting at low temperatures.

Persistence of airway inflammation in smokers who switch to electronic cigarettes.

As opposed to smoking cessation with nicotine-replacement therapy and/or varenicline, nicotine-containing e-cigarette use does not improve some airway inflammatory markers. https://bit.ly/3FyqIt9.

Distinct Exosomal miRNA Profiles from BALF and Lung Tissue of COPD and IPF Patients.

Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are chronic, progressive lung ailments that are characterized by distinct pathologies. Early detection biomarkers and disease mechanisms for these debilitating diseases are lacking. Extracellular vesicles (EVs), including exosomes, are small, lipid-bound vesicles attributed to carry proteins, lipids, and RNA molecules to facilitate cell-to-cell communication under normal and diseased conditions. Exosomal miRNAs have been studied in relation to many diseases. However, there is little to no knowledge regarding the miRNA population of bronchoalveolar lavage fluid (BALF) or the lung-tissue-derived exosomes in COPD and IPF. Here, we determined and compared the miRNA profiles of BALF- and lung-tissue-derived exosomes of healthy non-smokers, smokers, and patients with COPD or IPF in independent cohorts. Results: Exosome characterization using NanoSight particle tracking and TEM demonstrated that the BALF-derived exosomes were ~89.85 nm in size with a yield of ~2.95 × 1010 particles/mL in concentration. Lung-derived exosomes were larger in size (~146.04 nm) with a higher yield of ~2.38 × 1011 particles/mL. NGS results identified three differentially expressed miRNAs in the BALF, while there was one in the lung-derived exosomes from COPD patients as compared to healthy non-smokers. Of these, miR-122-5p was three- or five-fold downregulated among the lung-tissue-derived exosomes of COPD patients as compared to healthy non-smokers and smokers, respectively. Interestingly, there were a large number (55) of differentially expressed miRNAs in the lung-tissue-derived exosomes of IPF patients compared to non-smoking controls. Conclusions: Overall, we identified lung-specific miRNAs associated with chronic lung diseases that can serve as potential biomarkers or therapeutic targets.

Decrease in Exacerbations During the Coronavirus Disease 2019 Pandemic in a Cohort of Veterans with COPD.

BACKGROUND: Studies have shown a decline in hospitalizations due to acute exacerbations of COPD (AECOPD) during the coronavirus disease 2019 (COVID-19) pandemic. However, the impact of the pandemic in AECOPD of all severities in longitudinal cohorts of patients is lacking. METHODS: We conducted analysis of 123 individuals with COPD who have been followed since 2017. AECOPDs of mild (treatment at home), moderate (emergency department or urgent visit evaluation), and severe (hospitalization) type were assessed by chart review and patient interview. Compliance with preventive measures to avoid COVID-19 infection was assessed in 2020. Differences between the rate of AECOPD by year was analyzed as well as differences in preventive measures by COPD disease severity. RESULTS: During the COVID-19 pandemic in 2020, there was a significant reduction in AECOPDs in our cohort with 26 participants (21%) having an exacerbation compared to 46 (37%) in 2019, 52 (42%) in 2018, and 44 (36%) in 2017. Mean exacerbation rates decreased 54% overall and 74% in frequent exacerbators compared with the prior 3-year average. The decrease was noted in AECOPDs of all severities. Overall, there was a high rate of reported compliance with social distancing and face mask use that was significantly higher in the group with more severe COPD based on symptoms and forced expiratory volume in 1 second. CONCLUSIONS: Individuals with COPD, including frequent exacerbators, showed a marked decrease in AECOPD during the COVID-19 pandemic and high adherence to recommended preventive measures. Evaluation of the impact of preventive strategies on AECOPD in a non-pandemic setting may be of value and requires further study.

Management of lung disease in alpha-1 antitrypsin deficiency: what we do and what we do not know.

Management of lung disease in patients with alpha-1 antitrypsin deficiency (AATD) includes both non-pharmacological and pharmacological approaches. Lifestyle changes with avoidance of environmental pollutants, including tobacco smoke, improving exercise levels and nutritional status, all encompassed under a disease management program, are crucial pillars of AATD management. Non-pharmacological therapies follow conventional treatment guidelines for chronic obstructive pulmonary disease. Specific pharmacological treatment consists of administering exogenous alpha-1 antitrypsin (AAT) protein intravenously (augmentation therapy). This intervention raises AAT levels in serum and lung epithelial lining fluid, increases anti-elastase capacity, and decreases several inflammatory mediators in the lung. Radiologically, augmentation therapy reduces lung density loss over time, thus delaying disease progression. The effect of augmentation therapy on other lung-related outcomes, such as exacerbation frequency/length, quality of life, lung function decline, and mortality, are less clear and questions regarding dose optimization or route of administration are still debatable. This review discusses the rationale and available evidence for these interventions in AATD.

Association of Systemic Endothelial-Derived and Platelet-Derived Microparticles With Clinical Outcomes in Chronic Obstructive Pulmonary Disease.

PURPOSE: Endothelial and platelet microparticles (eMPs and pMPs), markers of cellular activation, dysfunction, or apoptosis, have been associated with multiple cardiovascular conditions. Chronic obstructive pulmonary disease (COPD) is associated with cardiovascular comorbidities and platelet/endothelial dysfunction. We analyzed whether eMPs and pMPs are associated with COPD status and/or severity. PATIENTS AND METHODS: A total of 58 COPD patients and 19 controls were enrolled and followed for an average of 1.17 years. Characterization of COPD included lung function, Body mass index-airflow Obstruction-Dyspnea-Exercise (BODE) scores, health-related quality of life, exacerbations, comorbidities, and mortality. Plasma collection to measure eMPs and pMPs via flow cytometry was performed at enrollment as well as during acute exacerbation in 17 participants. We measured pMPs (CD31+, CD41+31+, CD 62P+), eMPs (ULEX lectin+, CD51+, CD54+, CD62E+), the apoptotic CD62E+/CD31+ ratio, and Annexin V MP. RESULTS: As a group, COPD participants had no difference in all MP levels studied compared with controls. No significant correlations with diffusion capacity for carbon monoxide, quality of life, and exacerbation status were found in all MPs studied. However, the eMP ULEX and the pMP CD 62P+ were higher among COPD Global initiative for chronic Obstructive Lung Disease (GOLD) stage 3 patients compared to controls. The CD62E+/CD31+ ratio was lower in controls and GOLD stage 1 COPD participants compared with GOLD stage 2/3 COPD participants, suggesting increased apoptosis. eMP ULEX lectin+ decreased during acute exacerbations and pMP41+31+ significantly increased as BODE score increased. CONCLUSIONS: After adjusting for comorbidities, most eMPs and pMPs studied do not correlate significantly with COPD status or severity.

The Impact of Yoga on Inspiratory Muscle Performance in Veterans with COPD: A Pilot Study.

Chronic obstructive pulmonary disease (COPD) causes respiratory muscle weakness that leads to disabling dyspnea and poor functional performance. Therapies are often geared to improve inspiratory muscle performance. Yoga has been shown to improve exercise capacity, quality of life, and some pulmonary function measures in COPD, but little research has examined the effects of yoga training on inspiratory muscle performance. The purpose of this study was to investigate the effects of yoga training on inspiratory muscle performance in military veterans using the Test of Incremental Respiratory Endurance (TIRE). A prospective pilot study examined a 6-week yoga training program consisting of asana (poses) and pranayama (controlled breathing). Subjects had baseline inspiratory muscle weakness. The TIRE measured inspiratory muscle performance via the PrO2 device, providing maximal inspiratory pressure, sustained maximal inspiratory pressure, and inspiratory duration. Secondary measures included 6-minute walk distance, St. George Respiratory Questionnaire, Hospital Anxiety and Depression Scale, and spirometry. Mean age and BMI of subjects were 67 ± 3.6 years and 20.7 ± 3.3, respectively. The majority of subjects had severe (28.7%) or very severe (57.1%) COPD. Statistically significant improve m e n t s were seen in maximal inspiratory pressure (39.0 ± 14.1 cmH2O to 56.4 ± 20.6 cmH2O) and sustained maximal inspiratory pressure (244.1 ± 100.6 PTU to 308.1 ± 121.2 PTU). No statistically significant improvements we re observed in 6-minute walk distance, St. George Respiratory Questionnaire, Hospital Anxiety and Depression Scale, or spirometry. Yoga training has the potential in improve inspiratory muscle performance in veterans with severe to very severe COPD who present with inspiratory muscle weakness. This is of importance because improving inspira-tory muscle performance has been shown to improve COPD outcomes.

A 28-day clinical trial of aerosolized hyaluronan in alpha-1 antiprotease deficiency COPD using desmosine as a surrogate marker for drug efficacy.

INTRODUCTION: A previous 2-week clinical trial of aerosolized hyaluronan (HA) in COPD showed a rapid reduction in lung elastic fiber breakdown, as measured by sputum levels of the unique elastin crosslinks, desmosine and isodesmosine (DID). To further assess the therapeutic efficacy of HA and the utility of DID as surrogate markers for the development of pulmonary emphysema, we have conducted a 28-day randomized, double-blind, placebo-controlled, phase 2 trial of HA involving 27 subjects with alpha-1 antiprotease deficiency COPD. METHODS: The study drug consisted of a 3 ml inhalation solution containing 0.03% HA with an average molecular weight of 150 kDa that was self-administered twice daily. DID levels were measured in urine, sputum, and plasma using tandem mass spectrometry. RESULTS: Free urine DID in the HA group showed a significant negative correlation with time between days 14 and 35 (r = -1.0, p = 0.023) and was statistically significantly decreased from baseline at day 35 (15.4 vs 14.2 ng/mg creatinine, p = 0.035). A marked decrease in sputum DID was also seen in the HA group between days 1 and 28 (0.96 vs 0.18 ng/mg protein), but the difference was not significant, possibly due to the small number of adequate specimens. Plasma DID remained unchanged following HA treatment and no significant reductions in urine, sputum, or plasma DID were seen in the placebo group. CONCLUSIONS: The results support additional clinical trials to further evaluate the therapeutic effect of HA and the use of DID as a real-time marker of drug efficacy.

Performance of Spherical Quantum Well Down Converters in Solid State Lighting.

We report the color conversion performance of amber and red emitting quantum dots (QDs) on InGaN solid-state lighting (SSL) light emitting diode (LED) packages. Spherical quantum well (SQW) architectures (CdS/CdSe1-xSx/CdS) were prepared using a library of thio- and selenourea synthesis reagents and high throughput synthesis robotics. CdS/CdSe1-xSx QDs with narrow luminescence bands were coated with thick CdS shells (thickness = 1.6-7.5 nm) to achieve photoluminescence quantum yields (PLQY) up to 88% at amber and red emission wavelengths (λmax = 600-642 nm, FWHM < 45 nm). The photoluminescence from SQWs encapsulated in silicone and deposited on LED packages was monitored under accelerated aging conditions (oven temperature = 85 °C, relative humidity = 5-85%, blue optical power density = 3-45 W/cm2) by monitoring the red photon output over several hundred hours of continuous operation. The growth of a ZnS shell on the SQW surface increases the stability under long-term operation but also reduces the PLQY, especially of SQWs with thick CdS shells. The results illustrate that the outer ZnS shell layer is key to optimizing the PLQY and the long-term stability of QDs during operation on SSL packages.

State-Level Disparity in Lung Cancer Survival in the United States.

Rationale: The cancer mortality-to-incidence ratio (MIR) can serve as a population-based indicator for cancer care outcomes. In the US, evaluation of lung cancer survival by individual states has not been evaluated. Objective: To assess the association between lung cancer survival by using MIRs and state-level health disparities in the United States. Methods: We calculated 5-year lung cancer MIR averages from 2011 to 2015 using the United States Cancer Statistics (USCS) data. America's Health Rankings (AHR) is a platform using weighted measures in five different categories to calculate annual state health rankings. Five-year averages from 2011 to 2015 of the health uninsured rate and 4-year averages from 2011 to 2014 of health spending per capita were obtained from the U.S. Census Bureau and Centers for Medicare & Medicaid Services. Linear regression analyses were performed to determine the associations between cancer survival value (CSV) = (1 - MIR) × 100% and state health variables. Results: During the study period, the 5-year averages of age-adjusted incidence, mortality rates, and CSVs were 60.3 ± 2.1 per 100,000 population, 43.4 ± 2.1 per 100,000, and 27.9 ± 3.9%, respectively. Among the 50 states, Connecticut had the highest CSV (38.6 ± 1.7%) whereas Nevada had the lowest CSV (18.7 ± 6.5%). Hawaii had the highest health ranking and Mississippi had the lowest ranking in 2016. States with better health rankings, lower health uninsured rates, and higher health spending were significantly associated with higher CSVs (R 2 = 0.418, P < 0.001; R 2 = 0.352, P < 0.001; R 2 = 0.142, P = 0.007, respectively). Conclusions: There are significant differences in lung cancer survival within the United States. Lung cancer survival by using CSV was strongly associated with state health disparities, and it can be an applicable measure to evaluate the state-level health disparities in the United States.

Cigarette smoke induction of S100A9 contributes to chronic obstructive pulmonary disease.

S100 calcium-binding protein A9 (S100A9) is elevated in plasma and bronchoalveolar lavage fluid (BALF) of patients with chronic obstructive pulmonary disease (COPD), and aging enhances S100A9 expression in several tissues. Currently, the direct impact of S100A9-mediated signaling on lung function and within the aging lung is unknown. Here, we observed that elevated S100A9 levels in human BALF correlated with age. Elevated lung levels of S100A9 were higher in older mice compared with in young animals and coincided with pulmonary function changes. Both acute and chronic exposure to cigarette smoke enhanced S100A9 levels in age-matched mice. To examine the direct role of S100A9 on the development of COPD, S100a9-/- mice or mice administered paquinimod were exposed to chronic cigarette smoke. S100A9 depletion and inhibition attenuated the loss of lung function, pressure-volume loops, airway inflammation, lung compliance, and forced expiratory volume in 0.05 s/forced vital capacity, compared with age-matched wild-type or vehicle-administered animals. Loss of S100a9 signaling reduced cigarette smoke-induced airspace enlargement, alveolar remodeling, lung destruction, ERK and c-RAF phosphorylation, matrix metalloproteinase-3 (MMP-3), matrix metalloproteinase-9 (MMP-9), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and keratinocyte-derived chemokine (KC) release into the airways. Paquinimod administered to nonsmoked, aged animals reduced age-associated loss of lung function. Since fibroblasts play a major role in the production and maintenance of extracellular matrix in emphysema, primary lung fibroblasts were treated with the ERK inhibitor LY3214996 or the c-RAF inhibitor GW5074, resulting in less S100A9-induced MMP-3, MMP-9, MCP-1, IL-6, and IL-8. Silencing Toll-like receptor 4 (TLR4), receptor for advanced glycation endproducts (RAGE), or extracellular matrix metalloproteinase inducer (EMMPRIN) prevented S100A9-induced phosphorylation of ERK and c-RAF. Our data suggest that S100A9 signaling contributes to the progression of smoke-induced and age-related COPD.

Association between African Dust Transport and Acute Exacerbations of COPD in Miami.

BACKGROUND: Air pollution is increasingly recognized as a risk factor for acute exacerbation of chronic obstructive pulmonary disease (COPD). Changing climate and weather patterns can modify the levels and types of air pollutants. For example, dust outbreaks increase particulate air pollution. OBJECTIVE: This paper examines the effect of Saharan dust storms on the concentration of coarse particulate matter in Miami, and its association with the risk of acute exacerbation of COPD (AECOPD). METHODS: In this prospective cohort study, 296 COPD patients (with 313 events) were followed between 2013 and 2016. We used Light Detection and Ranging (LIDAR) and satellite-based Aerosol Optical Depth (AOD) to identify dust events and quantify particulate matter (PM) exposure, respectively. Exacerbation events were modeled with respect to location- and time-lagged dust and PM exposures, using multivariate logistic regressions. MEASUREMENTS AND MAIN RESULTS: Dust duration and intensity increased yearly during the study period. During dust events, AOD increased by 51% and particulate matter ≤2.5 µm in aerodynamic diameter (PM2.5) increased by 25%. Adjusting for confounders, ambient temperature and local PM2.5 exposure, one-day lagged dust exposure was associated with 4.9 times higher odds of two or more (2+ hereto after) AECOPD events (odds ratio = 4.9; 95% CI = 1.8-13.4; p < 0.001). Ambient temperature exposure also showed a significant association with 2+ and 3+ AECOPD events. The risk of AECOPD lasted up to 15 days after dust exposure, declining from 10× higher on day 0 to 20% higher on day 15. CONCLUSIONS: Saharan dust outbreaks observed in Miami elevate the concentration of PM and increase the risk of AECOPD in COPD patients with recurring exacerbations.