Early Evidence of Chronic Obstructive Pulmonary Disease Obscured by Race-Specific Prediction Equations.

Rationale: The identification of early chronic obstructive pulmonary disease (COPD) is essential to appropriately counsel patients regarding smoking cessation, provide symptomatic treatment, and eventually develop disease-modifying treatments. Disease severity in COPD is defined using race-specific spirometry equations. These may disadvantage non-White individuals in diagnosis and care. Objectives: Determine the impact of race-specific equations on African American (AA) versus non-Hispanic White individuals. Methods: Cross-sectional analyses of the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort were conducted, comparing non-Hispanic White (n = 6,766) and AA (n = 3,366) participants for COPD manifestations. Measurements and Main Results: Spirometric classifications using race-specific, multiethnic, and "race-reversed" prediction equations (NHANES [National Health and Nutrition Examination Survey] and Global Lung Function Initiative "Other" and "Global") were compared, as were respiratory symptoms, 6-minute-walk distance, computed tomography imaging, respiratory exacerbations, and St. George's Respiratory Questionnaire. Application of different prediction equations to the cohort resulted in different classifications by stage, with NHANES and Global Lung Function Initiative race-specific equations being minimally different, but race-reversed equations moving AA participants to more severe stages and especially between the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 and preserved ratio impaired spirometry groups. Classification using the established NHANES race-specific equations demonstrated that for each of GOLD stages 1-4, AA participants were younger, had fewer pack-years and more current smoking, but had more exacerbations, shorter 6-minute-walk distance, greater dyspnea, and worse BODE (body mass index, airway obstruction, dyspnea, and exercise capacity) scores and St. George's Respiratory Questionnaire scores. Differences were greatest in GOLD stages 1 and 2. Race-reversed equations reclassified 774 AA participants (43%) from GOLD stage 0 to preserved ratio impaired spirometry. Conclusions: Race-specific equations underestimated disease severity among AA participants. These effects were particularly evident in early disease and may result in late detection of COPD.

Pirfenidone in fibrotic hypersensitivity pneumonitis: a double-blind, randomised clinical trial of efficacy and safety.

BACKGROUND: Fibrotic hypersensitivity pneumonitis (FHP) is an irreversible lung disease with high morbidity and mortality. We sought to evaluate the safety and effect of pirfenidone on disease progression in such patients. METHODS: We conducted a single-centre, randomised, double-blinded, placebo-controlled trial in adults with FHP and disease progression. Patients were assigned in a 2:1 ratio to receive either oral pirfenidone (2403 mg/day) or placebo for 52 weeks. The primary end point was the mean absolute change in the per cent predicted forced vital capacity (FVC%). Secondary end points included progression-free survival (PFS, time to a relative decline ≥10% in FVC and/or diffusing capacity of the lung for carbon monoxide (DLCO), acute respiratory exacerbation, a decrease of ≥50 m in the 6 min walk distance, increase or introduction of immunosuppressive drugs or death), change in FVC slope and mean DLCO%, hospitalisations, radiological progression of lung fibrosis and safety. RESULTS: After randomising 40 patients, enrolment was interrupted by the COVID-19 pandemic. There was no significant between-group difference in FVC% at week 52 (mean difference -0.76%, 95% CI -6.34 to 4.82). Pirfenidone resulted in a lower rate of decline in the adjusted FVC% at week 26 and improved PFS (HR 0.26, 95% CI 0.12 to 0.60). Results for other secondary end points showed no significant difference between groups. No deaths occurred in the pirfenidone group and one death (respiratory) occurred in the placebo group. There were no treatment-emergent serious adverse events. CONCLUSIONS: The trial was underpowered to detect a difference in the primary end point. Pirfenidone was found to be safe and improved PFS in patients with FHP. TRIAL REGISTRATION MUMBER: NCT02958917.

Use of the Spirometric "Fixed-Ratio" Underdiagnoses COPD in African-Americans in a Longitudinal Cohort Study.

BACKGROUND: COPD diagnosis is tightly linked to the fixed-ratio spirometry criteria of FEV1/FVC < 0.7. African-Americans are less often diagnosed with COPD. OBJECTIVE: Compare COPD diagnosis by fixed-ratio with findings and outcomes by race. DESIGN: Genetic Epidemiology of COPD (COPDGene) (2007-present), cross-sectional comparing non-Hispanic white (NHW) and African-American (AA) participants for COPD diagnosis, manifestations, and outcomes. SETTING: Multicenter, longitudinal US cohort study. PARTICIPANTS: Current or former smokers with ≥ 10-pack-year smoking history enrolled at 21 clinical centers including over-sampling of participants with known COPD and AA. Exclusions were pre-existing non-COPD lung disease, except for a history of asthma. MEASUREMENTS: Subject diagnosis by conventional criteria. Mortality, imaging, respiratory symptoms, function, and socioeconomic characteristics, including area deprivation index (ADI). Matched analysis (age, sex, and smoking status) of AA vs. NHW within participants without diagnosed COPD (GOLD 0; FEV1 ≥ 80% predicted and FEV1/FVC ≥ 0.7). RESULTS: Using the fixed ratio, 70% of AA (n = 3366) were classified as non-COPD, versus 49% of NHW (n = 6766). AA smokers were younger (55 vs. 62 years), more often current smoking (80% vs. 39%), with fewer pack-years but similar 12-year mortality. Density distribution plots for FEV1 and FVC raw spirometry values showed disproportionate reductions in FVC relative to FEV1 in AA that systematically led to higher ratios. The matched analysis demonstrated GOLD 0 AA had greater symptoms, worse DLCO, spirometry, BODE scores (1.03 vs 0.54, p < 0.0001), and greater deprivation than NHW. LIMITATIONS: Lack of an alternative diagnostic metric for comparison. CONCLUSIONS: The fixed-ratio spirometric criteria for COPD underdiagnosed potential COPD in AA participants when compared to broader diagnostic criteria. Disproportionate reductions in FVC relative to FEV1 leading to higher FEV1/FVC were identified in these participants and associated with deprivation. Broader diagnostic criteria for COPD are needed to identify the disease across all populations.

The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human Vγ9Vδ2 T cells.

In humans, Vγ9Vδ2 T cells detect tumor cells and microbial infections, including Mycobacterium tuberculosis, through recognition of small pyrophosphate containing organic molecules known as phosphoantigens (pAgs). Key to pAg-mediated activation of Vγ9Vδ2 T cells is the butyrophilin 3A1 (BTN3A1) protein that contains an intracellular B30.2 domain critical to pAg reactivity. Here, we have demonstrated through structural, biophysical, and functional approaches that the intracellular B30.2 domain of BTN3A1 directly binds pAg through a positively charged surface pocket. Charge reversal of pocket residues abrogates binding and Vγ9Vδ2 T cell activation. We have also identified a gain-of-function mutation within this pocket that, when introduced into the B30.2 domain of the nonstimulatory BTN3A3 isoform, transfers pAg binding ability and Vγ9Vδ2 T cell activation. These studies demonstrate that internal sensing of changes in pAg metabolite concentrations by BTN3A1 molecules is a critical step in Vγ9Vδ2 T cell detection of infection and tumorigenesis.

Open-source environmental data as an alternative to snail surveys to assess schistosomiasis risk in areas approaching elimination.

BACKGROUND: Although the presence of intermediate snails is a necessary condition for local schistosomiasis transmission to occur, using them as surveillance targets in areas approaching elimination is challenging because the patchy and dynamic quality of snail host habitats makes collecting and testing snails labor-intensive. Meanwhile, geospatial analyses that rely on remotely sensed data are becoming popular tools for identifying environmental conditions that contribute to pathogen emergence and persistence. METHODS: In this study, we assessed whether open-source environmental data can be used to predict the presence of human Schistosoma japonicum infections among households with a similar or improved degree of accuracy compared to prediction models developed using data from comprehensive snail surveys. To do this, we used infection data collected from rural communities in Southwestern China in 2016 to develop and compare the predictive performance of two Random Forest machine learning models: one built using snail survey data, and one using open-source environmental data. RESULTS: The environmental data models outperformed the snail data models in predicting household S. japonicum infection with an estimated accuracy and Cohen's kappa value of 0.89 and 0.49, respectively, in the environmental model, compared to an accuracy and kappa of 0.86 and 0.37 for the snail model. The Normalized Difference in Water Index (an indicator of surface water presence) within half to one kilometer of the home and the distance from the home to the nearest road were among the top performing predictors in our final model. Homes were more likely to have infected residents if they were further from roads, or nearer to waterways. CONCLUSION: Our results suggest that in low-transmission environments, leveraging open-source environmental data can yield more accurate identification of pockets of human infection than using snail surveys. Furthermore, the variable importance measures from our models point to aspects of the local environment that may indicate increased risk of schistosomiasis. For example, households were more likely to have infected residents if they were further from roads or were surrounded by more surface water, highlighting areas to target in future surveillance and control efforts.

Soil Properties and Moisture Synergistically Influence Nontuberculous Mycobacterial Prevalence in Natural Environments of Hawai'i.

Nontuberculous mycobacteria (NTM) are opportunistic pathogens that cause chronic pulmonary disease (PD). NTM infections are thought to be acquired from the environment; however, the basal environmental factors that drive and sustain NTM prevalence are not well understood. The highest prevalence of NTM PD cases in the United States is reported from Hawai'i, which is unique in its climate and soil composition, providing an opportunity to investigate the environmental drivers of NTM prevalence. We used microbiological sampling and spatial logistic regression complemented with fine-scale soil mineralogy to model the probability of NTM presence across the natural landscape of Hawai'i. Over 7 years, we collected and microbiologically cultured 771 samples from 422 geographic sites in natural areas across the Hawaiian Islands for the presence of NTM. NTM were detected in 210 of these samples (27%), with Mycobacterium abscessus being the most frequently isolated species. The probability of NTM presence was highest in expansive soils (those that swell with water) with a high water balance (>1-m difference between rainfall and evapotranspiration) and rich in Fe-oxides/hydroxides. We observed a positive association between NTM presence and iron in wet soils, supporting past studies, but no such association in dry soils. High soil-water balance may facilitate underground movement of NTM into the aquifer system, potentially compounded by expansive capabilities allowing crack formation under drought conditions, representing further possible avenues for aquifer infiltration. These results suggest both precipitation and soil properties are mechanisms by which surface NTM may reach the human water supply. IMPORTANCE Nontuberculous mycobacteria (NTM) are ubiquitous in the environment, being found commonly in soils and natural bodies of freshwater. However, little is known about the environmental niches of NTM and how they relate to NTM prevalence in homes and other human-dominated areas. To characterize NTM environmental associations, we collected and cultured 771 samples from 422 geographic sites in natural areas across Hawai'i, the U.S. state with the highest prevalence of NTM pulmonary disease. We show that the environmental niches of NTM are most associated with highly expansive, moist soils containing high levels of iron oxides/hydroxides. Understanding the factors associated with NTM presence in the natural environment will be crucial for identifying potential mechanisms and risk factors associated with NTM infiltration into water supplies, which are ultimately piped into homes where most exposure risk is thought to occur.

HLA-DPB1 E69 genotype and exposure in beryllium sensitisation and disease.

OBJECTIVES: Human leukocyte antigen-DP beta 1 (HLA-DPB1) with a glutamic acid at the 69th position of the ß chain (E69) genotype and inhalational beryllium exposure individually contribute to risk of chronic beryllium disease (CBD) and beryllium sensitisation (BeS) in exposed individuals. This retrospective nested case-control study assessed the contribution of genetics and exposure in the development of BeS and CBD. METHODS: Workers with BeS (n=444), CBD (n=449) and beryllium-exposed controls (n=890) were enrolled from studies conducted at nuclear weapons and primary beryllium manufacturing facilities. Lifetime-average beryllium exposure estimates were based on workers' job questionnaires and historical and industrial hygienist exposure estimates, blinded to genotype and case status. Genotyping was performed using sequence-specific primer-PCR. Logistic regression models were developed allowing for over-dispersion, adjusting for workforce, race, sex and ethnicity. RESULTS: Having no E69 alleles was associated with lower odds of both CBD and BeS; every additional E69 allele increased odds for CBD and BeS. Increasing exposure was associated with lower odds of BeS. CBD was not associated with exposure as compared to controls, yet the per cent of individuals with CBD versus BeS increased with increasing exposure. No evidence of a gene-by-exposure interaction was found for CBD or BeS. CONCLUSIONS: Risk of CBD increases with E69 allele frequency and increasing exposure, although no gene by environment interaction was found. A decreased risk of BeS with increasing exposure and lack of exposure response in CBD cases may be due to the limitations of reconstructed exposure estimates. Although reducing exposure may not prevent BeS, it may reduce CBD and the associated health effects, especially in those carrying E69 alleles.

Exposures to low-levels of fine particulate matter are associated with acute changes in heart rate variability, cardiac repolarization, and circulating blood lipids in coronary artery disease patients.

Exposure to air pollution is a major risk factor for cardiovascular disease, disease risk factors, and mortality. Specifically, particulate matter (PM), and to some extent ozone, are contributors to these effects. In addition, exposures to these pollutants may be especially dangerous for susceptible populations. In this repeated-visit panel study, cardiovascular markers were collected from thirteen male participants with stable coronary artery disease. For 0-4 days prior to the health measurement collections, daily concentrations of fine PM (PM2.5) and ozone were obtained from local central monitoring stations located near the participant's homes. Then, single (PM2.5) and two-pollutant (PM2.5 and ozone) models were used to assess whether there were short-term changes in cardiovascular health markers. Per interquartile range increase in PM2.5, there were decrements in several heart rate variability metrics, including the standard deviation of the normal-to-normal intervals (lag 3, -5.8%, 95% confidence interval (CI) = -11.5, 0.3) and root-mean squared of successive differences (five day moving average, -8.1%, 95% CI = -15.0, -0.7). In addition, increases in PM2.5 were also associated with changes in P complexity (lag 1, 4.4%, 95% CI = 0.5, 8.5), QRS complexity (lag 1, 4.9%, 95% CI = 1.4, 8.5), total cholesterol (five day moving average, -2.1%, 95% CI = -4.1, -0.1), and high-density lipoprotein cholesterol (lag 2, -1.6%, 95% CI = -3.1, -0.1). Comparisons to our previously published work on ozone were conducted. We found that ozone affected inflammation and endothelial function, whereas PM2.5 influenced heart rate variability, repolarization, and lipids. All the health changes from these two studies were found at concentrations below the United States Environmental Protection Agency's National Ambient Air Quality Standards. Our results imply clear differences in the cardiovascular outcomes observed with exposure to the two ubiquitous air pollutants PM2.5 and ozone; this observation suggests different mechanisms of toxicity for these exposures.

Age-associated B Cells Appear in Patients with Granulomatous Lung Diseases.

Rationale: A subpopulation of B cells (age-associated B cells [ABCs]) is increased in mice and humans with infections or autoimmune diseases. Because depletion of these cells might be valuable in patients with certain lung diseases, the goal was to find out if ABC-like cells were at elevated levels in such patients.Objectives: To measure ABC-like cell percentages in patients with lung granulomatous diseases.Methods: Peripheral blood and BAL cells from patients with sarcoidosis, beryllium sensitivity, or hypersensitivity pneumonitis and healthy subjects were analyzed for the percentage of B cells that were ABC-like, defined by expression of CD11c, low levels of CD21, FcRL 1-5 (Fc receptor-like protein 1-5) expression, and, in some cases, T-bet.Measurements and Main Results: ABC-like cells in blood were at low percentages in healthy subjects and higher percentages in patients with sarcoidosis as well as at high percentages among BAL cells of patients with sarcoidosis, beryllium disease, and hypersensitivity pneumonitis. Treatment of patients with sarcoidosis led to reduced percentages of ABC-like cells in blood.Conclusions: Increased levels of ABC-like cells in patients with sarcoidosis may be useful in diagnosis. The increase in percentage of ABC-like cells in patients with lung granulomatous diseases and decrease in treated patients suggests that depletion of these cells may be valuable.

Assessment of Soil Features on the Growth of Environmental Nontuberculous Mycobacterial Isolates from Hawai'i.

Environmental nontuberculous mycobacteria (NTM), with the potential to cause opportunistic lung infections, can reside in soil. This might be particularly relevant in Hawai'i, a geographic hot spot for NTM infections and whose soil composition differs from many other areas of the world. Soil components are likely to contribute to NTM prevalence in certain niches as food sources or attachment scaffolds, but the particular types of soils, clays, and minerals that impact NTM growth are not well-defined. Hawai'i soil and chemically weathered rock (saprolite) samples were examined to characterize the microbiome and quantify 11 mineralogical features as well as soil pH. Machine learning methods were applied to identify important soil features influencing the presence of NTM. Next, these features were directly tested in vitro by incubating synthetic clays and minerals in the presence of Mycobacteroides abscessus and Mycobacterium chimaera isolates recovered from the Hawai'i environment, and changes in bacterial growth were determined. Of the components examined, synthetic gibbsite, a mineral form of aluminum hydroxide, inhibited the growth of both M. abscessus and M. chimaera, while other minerals tested showed differential effects on each species. For example, M. abscessus (but not M. chimaera) growth was significantly higher in the presence of hematite, an iron oxide mineral. In contrast, M. chimaera (but not M. abscessus) counts were significantly reduced in the presence of birnessite, a manganese-containing mineral. These studies shed new light on the mineralogic features that promote or inhibit the presence of Hawai'i NTM in Hawai'i soil.IMPORTANCE Globally and in the United States, the prevalence of NTM pulmonary disease-a potentially life-threatening but underdiagnosed chronic illness-is prominently rising. While NTM are ubiquitous in the environment, including in soil, the specific soil components that promote or inhibit NTM growth have not been elucidated. We hypothesized that NTM culture-positive soil contains minerals that promote NTM growth in vitro Because Hawai'i is a hot spot for NTM and a unique geographic archipelago, we examined the composition of Hawai'i soil and identified individual clay, iron, and manganese minerals associated with NTM. Next, individual components were evaluated for their ability to directly modulate NTM growth in culture. In general, gibbsite and some manganese oxides were shown to decrease NTM, whereas iron-containing minerals were associated with higher NTM counts. These data provide new information to guide future analyses of soil-associated factors impacting persistence of these soil bacteria.

The impact of weather and climate on pollen concentrations in Denver, Colorado, 2010-2018.

BACKGROUND: Increasing evidence indicates that climate change is affecting the timing of pollen season and concentrations of allergenic pollens. To date, pollen trends and their associations with meteorological variables have not been studied in most of the United States. OBJECTIVE: The purpose of this study was to investigate the effects of weather and climate on pollen concentrations and pollen season timing in Denver, Colorado. METHODS: We retrospectively analyzed tree, grass, and weed pollen counts and meteorological variables from 2010-2018 using linear and Poisson regression models. RESULTS: Pollen season timing did not demonstrate uniform trends from 2010 to 2018. Certain species demonstrated earlier season start dates (linden, oak) or end dates (birch, maple), and others had later end dates (oak, grass). Only a few species demonstrated changes in season duration (linden, oak, maple, birch) and peak date (maple, birch). Pollen concentrations either remained stable or increased over the years. Temperature and carbon dioxide levels increased over the study period, with the exception of decreased temperature in August. Wind speed remained stable or decreased over the study period. CONCLUSION: This study illustrates the complex interactions between pollens and meteorology. Meteorological variables associated with climate change do appear to affect allergenic pollens, though the relationship is variable both amongst pollens and from year to year.

Relationships between indicators of cardiovascular disease and intensity of oil and natural gas activity in Northeastern Colorado.

BACKGROUND: Oil and natural gas (O&G) extraction emits pollutants that are associated with cardiovascular disease, the leading cause of mortality in the United States. OBJECTIVE: We evaluated associations between intensity of O&G activity and cardiovascular disease indicators. METHODS: Between October 2015 and May 2016, we conducted a cross-sectional study of 97 adults living in Northeastern Colorado. For each participant, we collected 1-3 measurements of augmentation index, systolic and diastolic blood pressure (SBP and DBP), and plasma concentrations of interleukin (IL)- 1ß, IL-6, IL-8 and tumor necrosis factor alpha (TNF-α). We modelled the intensity of O&G activity by weighting O&G well counts within 16 km of a participant's home by intensity and distance. We used linear models accounting for repeated measures within person to evaluate associations. RESULTS: Adjusted mean augmentation index differed by 6.0% (95% CI: 0.6, 11.4%) and 5.1% (95%CI: -0.1, 10.4%) between high and medium, respectively, and low exposure tertiles. The greatest mean IL-1ß, and α-TNF plasma concentrations were observed for participants in the highest exposure tertile. IL-6 and IL-8 results were consistent with a null result. For participants not taking prescription medications, the adjusted mean SBP differed by 6 and 1 mm Hg (95% CIs: 0.1, 13 mm Hg and -6, 8 mm Hg) between the high and medium, respectively, and low exposure tertiles. DBP results were similar. For participants taking prescription medications, SBP and DBP results were consistent with a null result. CONCLUSIONS: Despite limitations, our results support associations between O&G activity and augmentation index, SBP, DBP, IL-1ß, and TNF-α. Our study was not able to elucidate possible mechanisms or environmental stressors, such as air pollution and noise.

Class II major histocompatibility complex mutant mice to study the germ-line bias of T-cell antigen receptors.

The interaction of αß T-cell antigen receptors (TCRs) with peptides bound to MHC molecules lies at the center of adaptive immunity. Whether TCRs have evolved to react with MHC or, instead, processes in the thymus involving coreceptors and other molecules select MHC-specific TCRs de novo from a random repertoire is a longstanding immunological question. Here, using nuclease-targeted mutagenesis, we address this question in vivo by generating three independent lines of knockin mice with single-amino acid mutations of conserved class II MHC amino acids that often are involved in interactions with the germ-line-encoded portions of TCRs. Although the TCR repertoire generated in these mutants is similar in size and diversity to that in WT mice, the evolutionary bias of TCRs for MHC is suggested by a shift and preferential use of some TCR subfamilies over others in mice expressing the mutant class II MHCs. Furthermore, T cells educated on these mutant MHC molecules are alloreactive to each other and to WT cells, and vice versa, suggesting strong functional differences among these repertoires. Taken together, these results highlight both the flexibility of thymic selection and the evolutionary bias of TCRs for MHC.

The association between ambient temperature and childhood asthma: a systematic review.

The objectives of this study are to review available information on the association between ambient temperature and childhood asthma, and to elucidate the possible underlying mechanisms of this relationship. A systematic review was conducted based on the papers retrieved from four databases, including PubMed, ProQuest, ScienceDirect, and Scopus. Papers examining the association of absolute temperature or temperature variation with childhood asthma published from 1 January 2000 to 31 December 2016 were included. Thirteen papers have quantified the effect of absolute temperature on childhood asthma, and six papers have examined the effect of intra- or inter-day temperature variation on childhood asthma. All studies were conducted in urban areas. Aeroallergen sensitizations were only considered in the analyses of one study. Discrepancy existed in the significance of the relationship between absolute temperature and childhood asthma, and also in the shape of this relationship (i.e. linear or non-linear) and whether temperature effects were lagged. Increasing evidence is suggesting non-linear relationship between absolute temperature and childhood asthma. Future research should investigate the burden of childhood asthma specifically attributable to extreme temperatures and temperature variation using advanced statistical approach, particularly in rural areas, after properly considering aeroallergens and air pollution. Projecting future burden of childhood asthma under climate change scenarios is also warranted.

Influence of exposure differences on city-to-city heterogeneity in PM2.5-mortality associations in US cities.

BACKGROUND: Multi-city population-based epidemiological studies have observed heterogeneity between city-specific fine particulate matter (PM2.5)-mortality effect estimates. These studies typically use ambient monitoring data as a surrogate for exposure leading to potential exposure misclassification. The level of exposure misclassification can differ by city affecting the observed health effect estimate. METHODS: The objective of this analysis is to evaluate whether previously developed residential infiltration-based city clusters can explain city-to-city heterogeneity in PM2.5 mortality risk estimates. In a prior paper 94 cities were clustered based on residential infiltration factors (e.g. home age/size, prevalence of air conditioning (AC)), resulting in 5 clusters. For this analysis, the association between PM2.5 and all-cause mortality was first determined in 77 cities across the United States for 2001-2005. Next, a second stage analysis was conducted evaluating the influence of cluster assignment on heterogeneity in the risk estimates. RESULTS: Associations between a 2-day (lag 0-1 days) moving average of PM2.5 concentrations and non-accidental mortality were determined for each city. Estimated effects ranged from -3.2 to 5.1% with a pooled estimate of 0.33% (95% CI: 0.13, 0.53) increase in mortality per 10 µg/m3 increase in PM2.5. The second stage analysis determined that cluster assignment was marginally significant in explaining the city-to-city heterogeneity. The health effects estimates in cities with older, smaller homes with less AC (Cluster 1) and cities with newer, smaller homes with a large prevalence of AC (Cluster 3) were significantly lower than the cluster consisting of cities with older, larger homes with a small percentage of AC. CONCLUSIONS: This is the first study that attempted to examine whether multiple exposure factors could explain the heterogeneity in PM2.5-mortality associations. The results of this study were found to explain a small portion (6%) of this heterogeneity.

Extreme precipitation and emergency room visits for influenza in Massachusetts: a case-crossover analysis.

BACKGROUND: Influenza peaks during the wintertime in temperate regions and during the annual rainy season in tropical regions - however reasons for the observed differences in disease ecology are poorly understood. We hypothesize that episodes of extreme precipitation also result in increased influenza in the Northeastern United States, but this association is not readily apparent, as no defined 'rainy season' occurs. Our objective was to evaluate the association between extreme precipitation (≥ 99th percentile) events and risk of emergency room (ER) visit for influenza in Massachusetts during 2002-2008. METHODS: A case-crossover analysis of extreme precipitation events and influenza ER visits was conducted using hospital administrative data including patient town of residence, date of visit, age, sex, and associated diagnostic codes. Daily precipitation estimates were generated for each town based upon data from the National Oceanic and Atmospheric Administration. Odds ratio (OR) and 95% confidence intervals (CI) for associations between extreme precipitation and ER visits for influenza were estimated using conditional logistic regression. RESULTS: Extreme precipitation events were associated with an OR = 1.23 (95%CI: 1.16, 1.30) for ER visits for influenza at lag days 0-6. There was significant effect modification by race, with the strongest association observed among Blacks (OR = 1.48 (1.30, 1.68)). CONCLUSIONS: We observed a positive association between extreme precipitation events and ER visits for influenza, particularly among Blacks. Our results suggest that influenza is associated with extreme precipitation in a temperate area; this association could be a result of disease ecology, behavioral changes such as indoor crowding, or both. Extreme precipitation events are expected to increase in the Northeastern United States as climate change progresses. Additional research exploring the basis of this association can inform potential interventions for extreme weather events and influenza transmission.

Ozone exposure is associated with acute changes in inflammation, fibrinolysis, and endothelial cell function in coronary artery disease patients.

BACKGROUND: Air pollution is a major risk factor for cardiovascular disease, of which ozone is a major contributor. Several studies have found associations between ozone and cardiovascular morbidity, but the results have been inconclusive. We investigated associations between ozone and changes across biological pathways associated with cardiovascular disease. METHODS: Using a panel study design, 13 participants with coronary artery disease were assessed for markers of systemic inflammation, heart rate variability and repolarization, lipids, blood pressure, and endothelial function. Daily measurements of ozone and particulate matter (PM2.5) were obtained from central monitoring stations. Single (ozone) and two-pollutant (ozone and PM2.5) models were used to assess percent changes in measurements per interquartile ranges of pollutants. RESULTS: Per interquartile increase in ozone, changes in tissue plasminogen factor (6.6%, 95% confidence intervals (CI) = 0.4, 13.2), plasminogen activator inhibitor-1 (40.5%, 95% CI = 8.7, 81.6), neutrophils (8.7% 95% CI = 1.5, 16.4), monocytes (10.2%, 95% CI = 1.0, 20.1), interleukin-6 (15.9%, 95% CI = 3.6, 29.6), large-artery elasticity index (-19.5%, 95% CI = -34.0, -1.7), and the baseline diameter of the brachial artery (-2.5%, 95% CI = -5.0, 0.1) were observed. These associations were robust in the two-pollutant model. CONCLUSIONS: We observed alterations across several pathways associated with cardiovascular disease in 13 coronary artery disease patients following ozone exposures, independent of PM2.5. The results support the biological plausibility of ozone-induced cardiovascular effects. The effects were found at concentrations below the EPA National Ambient Air Quality Standards for both ozone and PM2.5.

CpG Type A Induction of an Early Protective Environment in Experimental Multiple Sclerosis.

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory, demyelinating disease of the CNS that mimics human multiple sclerosis (MS), and it is thought to be driven by Th1 and Th17 myelin-reactive cells. Although adaptive immunity is clearly pivotal in the pathogenesis of EAE, with an essential role of CD4+ T cells, little is known of early, innate responses in this experimental setting. CpG-rich oligodeoxynucleotides (ODNs), typically found in microbial genomes, are potent activators of TLR9 in plasmacytoid dendritic cells (pDCs). In this study, we compared the effects of two types of CpG, namely, type A and type B, on EAE. We found that treatment with CpG type A ODN (CpG-A), known to induce high amounts of IFN-α in pDCs, significantly reduced disease severity in EAE, relative to controls (12.63 ± 1.86 versus 23.49 ± 1.46, resp.; p = 0.001). Treatment also delayed onset of neurological deficits and reduced spinal cord demyelination, while increasing the percentage of splenic regulatory (Foxp3+ CD4+) T cells. CpG-A likewise reduced the levels of IL-17 and IFN-γ in the CNS. Mechanistic insight into those events showed that CpG-A promoted a regulatory phenotype in pDCs. Moreover, adoptive transfer of pDCs isolated from CpG-A-treated mice inhibited CNS inflammation and induced disease remission in acute-phase EAE. Our data thus identify a link between TLR9 activation by specific ligands and the induction of tolerance via innate immunity mechanisms.

Molecular mechanism for differential recognition of membrane phosphatidylserine by the immune regulatory receptor Tim4.

Recognition of phosphatidylserine (PS) lipids exposed on the extracellular leaflet of plasma membranes is implicated in both apoptotic cell removal and immune regulation. The PS receptor T cell immunoglobulin and mucin-domain-containing molecule 4 (Tim4) regulates T-cell immunity via phagocytosis of both apoptotic (high PS exposure) and nonapoptotic (intermediate PS exposure) activated T cells. The latter population must be removed at lower efficiency to sensitively control immune tolerance and memory cell population size, but the molecular basis for how Tim4 achieves this sensitivity is unknown. Using a combination of interfacial X-ray scattering, molecular dynamics simulations, and membrane binding assays, we demonstrate how Tim4 recognizes PS in the context of a lipid bilayer. Our data reveal that in addition to the known Ca(2+)-coordinated, single-PS binding pocket, Tim4 has four weaker sites of potential ionic interactions with PS lipids. This organization makes Tim4 sensitive to PS surface concentration in a manner capable of supporting differential recognition on the basis of PS exposure level. The structurally homologous, but functionally distinct, Tim1 and Tim3 are significantly less sensitive to PS surface density, likely reflecting the differences in immunological function between the Tim proteins. These results establish the potential for lipid membrane parameters, such as PS surface density, to play a critical role in facilitating selective recognition of PS-exposing cells. Furthermore, our multidisciplinary approach overcomes the difficulties associated with characterizing dynamic protein/membrane systems to reveal the molecular mechanisms underlying Tim4's recognition properties, and thereby provides an approach capable of providing atomic-level detail to uncover the nuances of protein/membrane interactions.