Iny Jhun

Effect modification of ozone-related mortality risks by temperature in 97 US cities

Many time-series studies have characterized the relationship between short-term ozone exposure and adverse health outcomes, controlling for temperature as a confounder. Temperature may also modify ozone effects, though this has been largely under-investigated. In this study, we explored whether temperature modifies the effect of short-term ozone exposure on mortality. We used the database developed for the National Morbidity and Mortality Air Pollution Study to estimate ozone mortality risks in 97 US cities in May through September, 1987-2000. We treated temperature as a confounder as well as an effect modifier by estimating risks at low, moderate, and high temperature categories. When temperature was treated as a confounder, a 10-ppb increase in daily 24-h ozone was associated with a 0.47% (95% CI: 0.19%-0.76%) increase in mortality. When we assessed effect modification by temperature, the interaction between ozone and temperature was not statistically significant. However, there was a U-shaped pattern in mortality risk, which was greater at the low (<25th percentile) and high (>75th percentile) temperature levels than moderate temperature levels. At the high temperature category, a 10% increase in AC prevalence mitigated mortality risk associated with 10-ppb of ozone exposure by -0.18% (95% CI: -0.35%, -0.02%). Furthermore, ozone mortality risk in the high temperature category increased as we restricted our analyses to hotter days. On days where temperatures exceeded the 75th, 90th, and 95th percentile temperatures, a 10-ppb increase in ozone was associated with a 0.65% (95% CI: 0.20%-1.09%), 0.83% (95% CI: 0.17%-1.48%), and 1.35% (95% CI: 0.44%-2.27%) increase in mortality, respectively. These results suggested that high temperatures may exacerbate physiological responses to short-term ozone exposure.

Aag DNA Glycosylase Promotes Alkylation-Induced Tissue Damage Mediated by Parp1

Alkylating agents comprise a major class of front-line cancer chemotherapeutic compounds, and while these agents effectively kill tumor cells, they also damage healthy tissues. Although base excision repair (BER) is essential in repairing DNA alkylation damage, under certain conditions, initiation of BER can be detrimental. Here we illustrate that the alkyladenine DNA glycosylase (AAG) mediates alkylation-induced tissue damage and whole-animal lethality following exposure to alkylating agents. Aag-dependent tissue damage, as observed in cerebellar granule cells, splenocytes, thymocytes, bone marrow cells, pancreatic β-cells, and retinal photoreceptor cells, was detected in wild-type mice, exacerbated in Aag transgenic mice, and completely suppressed in Aag −/− mice. Additional genetic experiments dissected the effects of modulating both BER and Parp1 on alkylation sensitivity in mice and determined that Aag acts upstream of Parp1 in alkylation-induced tissue damage; in fact, cytotoxicity in WT and Aag transgenic mice was abrogated in the absence of Parp1. These results provide in vivo evidence that Aag-initiated BER may play a critical role in determining the side-effects of alkylating agent chemotherapies and that Parp1 plays a crucial role in Aag-mediated tissue damage.

Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney

Significance Ischemia reperfusion (I/R)-induced tissue injury and inflammation encompasses a wide range of human disease, including stroke, hepatic and renal failure, and myocardial infarction. Generation of highly reactive oxygen and nitrogen species during I/R results in DNA damage that is subject to numerous DNA repair processes. Base excision repair (BER) initiated by various DNA glycosylases is critical for the repair of reactive oxygen and nitrogen species (RONS)-induced DNA damage. Our data describe a new paradigm wherein the Aag BER DNA glycosylase enzyme promotes, rather than prevents, tissue injury and inflammation in liver, brain, and kidney following I/R. This finding reveals a detrimental facet of DNA repair during inflammation and presents a novel target for controlling I/R-induced injury. Inflammation is accompanied by the release of highly reactive oxygen and nitrogen species (RONS) that damage DNA, among other cellular molecules. Base excision repair (BER) is initiated by DNA glycosylases and is crucial in repairing RONS-induced DNA damage; the alkyladenine DNA glycosylase (Aag/Mpg) excises several DNA base lesions induced by the inflammation-associated RONS release that accompanies ischemia reperfusion (I/R). Using mouse I/R models we demonstrate that Aag−/− mice are significantly protected against, rather than sensitized to, I/R injury, and that such protection is observed across three different organs. Following I/R in liver, kidney, and brain, Aag−/− mice display decreased hepatocyte death, cerebral infarction, and renal injury relative to wild-type. We infer that in wild-type mice, Aag excises damaged DNA bases to generate potentially toxic abasic sites that in turn generate highly toxic DNA strand breaks that trigger poly(ADP-ribose) polymerase (Parp) hyperactivation, cellular bioenergetics failure, and necrosis; indeed, steady-state levels of abasic sites and nuclear PAR polymers were significantly more elevated in wild-type vs. Aag−/− liver after I/R. This increase in PAR polymers was accompanied by depletion of intracellular NAD and ATP levels plus the translocation and extracellular release of the high-mobility group box 1 (Hmgb1) nuclear protein, activating the sterile inflammatory response. We thus demonstrate the detrimental effects of Aag-initiated BER during I/R and sterile inflammation, and present a novel target for controlling I/R-induced injury.

School Environmental Intervention to Reduce Particulate Pollutant Exposures for Children with Asthma

BACKGROUND Home-based interventions to improve indoor air quality have demonstrated benefits for asthma morbidity, yet little is known about the effect of environmental interventions in the school setting. OBJECTIVE We piloted the feasibility and effectiveness of a classroom-based air cleaner intervention to reduce particulate pollutants in classrooms of children with asthma. METHODS In this pilot randomized controlled trial, we assessed the effect of air cleaners on indoor air particulate pollutant concentrations in 18 classrooms (9 control, 9 intervention) in 3 urban elementary schools. We enrolled 25 children with asthma (13 control, 12 intervention) aged 6 to 10 years. Classroom air pollutant measurements and spirometry were completed once before and twice after randomization. Asthma symptoms were surveyed every 3 months. RESULTS Baseline classroom levels of fine particulate matter (particulate matter with diameter of <2.5 μm [PM2.5]) and black carbon (BC) were 6.3 and 0.41 μg/m3, respectively. When comparing the intervention to the control group, classroom PM2.5 levels were reduced by 49% and 42% and BC levels were reduced by 58% and 55% in the first and second follow-up periods, respectively (P < .05 for all comparisons). When comparing the children randomized to intervention and control classrooms, there was a modest improvement in peak flow, but no significant changes in forced expiratory volume in 1 second (FEV1) and asthma symptoms. CONCLUSIONS In this pilot study, a classroom-based air cleaner intervention led to significant reductions in PM2.5 and BC. Future large-scale studies should comprehensively evaluate the effect of school-based environmental interventions on pediatric asthma morbidity.

PM2.5 mass and species trends in Santiago, Chile, 1998 to 2010: The impact of fuel-related interventions and fuel sales

Improving air quality in Santiago has been a high priority for the Chilean government. In this paper, we examine trends of fine particulate matter (PM2.5) mass and species concentrations during the period 1998 to 2010 and explore the impact of fuel-related interventions and fuel sales on concentration changes. Smoothing spline functions were utilized to characterize and account for nonlinear relationships between pollutant concentrations and different parameters. Meteorology-adjusted PM2.5 concentrations were lower by 21.8 µg/m3 in 2010 compared to 1998. In this model, wind speed was the most important determinant of PM2.5 levels. A decrease in 24-hr average wind speed below 1.0 m/s was associated with a significant increase in daily PM2.5 levels, indicating a high sensitivity of PM2.5 concentrations to the accumulation of local emissions. The same regression model framework was applied to examine the trends of lead, bromine, and sulfur concentrations. Removal of lead and bromine from gasoline achieved dramatic decreases in their atmospheric concentrations. Nonetheless, both elements continue to persist, likely in the form of PbBrCl. The reduction of diesel sulfur content from 1,500 to 50 ppm corresponded to a 32% decrease in particulate sulfur levels. Lastly, a surge in PM2.5 was observed in 2005–2008. Further regression analyses suggested this was prompted by a rise in monthly petroleum-based fuel sales. Implications: In this paper, we elucidate meteorology-adjusted trends of PM2.5 mass and species concentrations in Santiago and assess the efficacy of fuel-related interventions, such as the removal of lead from gasoline and reduction of sulfur content in diesel. In addition, we explore the impact of fuel sales on PM2.5 trends. Given that fuel consumption is likely to increase further in this rapidly growing city, understanding its impact on PM2.5 trends can inform future air quality control efforts in Santiago. Supplemental Materials: Supplemental materials are available for this paper. Go to the publishers online edition of the Journal of the Air & Waste Management Association.

The impact of weather changes on air quality and health in the United States in 1994–2012

Air quality is heavily influenced by weather conditions. In this study, we assessed the impact of long-term weather changes on air quality and health in the US during 1994–2012. We quantified past weather-related increases, or ‘weather penalty’, in ozone (O3) and fine particulate matter (PM2.5), and thereafter estimated the associated excess deaths. Using statistical regression methods, we derived the weather penalty as the additional increases in air pollution relative to trends assuming constant weather conditions (i.e., weather-adjusted trends). During our study period, temperature increased and wind speed decreased in most US regions. Nationally, weather-related 8 h max O3 increases were 0.18 ppb per year (95% CI: 0.06, 0.31) in the warm season (May–October) and 0.07 ppb per year (95% CI: 0.02, 0.13) in the cold season (November–April). The weather penalties on O3 were relatively larger than PM2.5 weather penalties, which were 0.056 µg m−3 per year (95% CI: 0.016, 0.096) in warm months and 0.027 µg m−3 per year (95% CI: 0.010, 0.043) in cold months. Weather penalties on O3 and PM2.5 were associated with 290 (95% CI: 80, 510) and 770 (95% CI: 190, 1350) excess annual deaths, respectively. Over a 19-year period, this amounts to 20 300 excess deaths (5600 from O3, 14 700 from PM2.5) attributable to the weather penalty on air quality

Early exposure to dogs and farm animals reduces risk of childhood asthma

Commentary on: Fall T, Lundholm C, Ortqvist AK, et al. Early Exposure to Dogs and Farm Animals and the Risk of Childhood Asthma. JAMA Pediatr 2015;169:e153219. Asthma is one of the most common chronic diseases of childhood. The risk of developing asthma is associated with environmental exposures, including tobacco smoke, air pollution, dust mites, endotoxin and farm animals.1 A lower prevalence of asthma among children in farm environments supports the hygiene hypothesis on the role of childhood exposure to microbes in developing a more favourable immune system. The effect of exposures to domestic dogs has been less clear. Fall et al undertook a nationwide study to investigate the association between early exposures to dogs as well as farm environment and risk of childhood …

Utility of Clinical Risk Stratification in the Selection of Muscle-Invasive Bladder Cancer Patients for Neoadjuvant Chemotherapy: A Retrospective Cohort Study.

Introduction: Level I evidence supports the use of cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer prior to radical cystectomy (RC). On average, 30–40% of patients achieve a complete pathologic response (i.e., stage pT0) after receiving NAC. Some centers risk-stratify patients, suggesting that there may be a higher-risk population that would derive the most benefit from NAC. Recently, a risk-stratification model developed at M.D. Anderson Cancer Center (MDACC) specified criteria for clinical staging and patient selection for NAC. We applied this model to our own RC patient cohort and evaluated our own experience with clinical risk stratification and the effect of NAC on post treatment risk categories. Methods: We retrospectively reviewed the charts of consecutive patients who underwent RC at two institutions between 2004 and 2014 and noted whether or not they received NAC. We determined the clinical stage by reviewing the exam under anesthesia, transurethral resection biopsy (TURBT) pathology, and preoperative imaging. Patients with cT2-T4a node-negative disease were included. Those with sarcomatoid features or adenocarcinoma were excluded. Patients were classified as high risk if they had tumor-associated hydronephrosis, clinical stage≥T3b-T4a disease, variant histology (i.e., micropapillary or small cell), or lymphovascular invasion (LVI), as specified by the MDACC model. Variables were examined for associations with cancer-specific survival (CSS), overall survival (OS), and risk-category reclassification. Results: We identified 166 patients with a median follow-up time of 22.2 months. In all, 117 patients (70.5%) did not receive NAC, 68 (58.1%) of whom we classified as high risk. Among patients not receiving NAC, CSS and OS were significantly decreased in high-risk patients (log-rank test p = 0.01 for both comparisons). The estimated age-adjusted hazard ratios of high-risk classification for cancer-specific and overall death were 3.2 (95% CI: 1.2 to 8.6) and 2.2 (95% CI: 1.1 to 4.4), respectively. On post-RC final pathology, 23 (46.9%) low-risk patients were up-classified to high risk and 17 (25.0%) high-risk patients were down-classified. Complete pathologic responses (pT0) were achieved in 7 (6.0%) patients and partial responses (pT1, pTa, pTis) were achieved in 28 (23.9%) patients. Of the 49 patients who did receive NAC, 43 (87.8%) received cisplatin-based and six (12.2%) received carboplatin-based regimens. Applying the MDACC model, we categorized 41 (83.7%) patients as high risk prior to NAC treatment. On final pathology, 3 (37.5%) low-risk patients were up-classified and 17 (41.5%) high-risk patients were down-classified. Complete pathologic responses (pT0) were seen in 13 (26.5%) patients and partial responses were seen in 10 (20.4%) patients. Although the utilization of NAC was not statistically significantly associated with CSS or OS (log-rank test p > 0.05 for both comparisons), it was associated with a 1.2 times increased odds (95% CI: 0.4 to 2.1) of post-RC reclassification from high to low risk on age-adjusted logistic regression. Conclusions: We found similar results using the clinical risk-stratification model in our cohort and showed that the high-risk category was associated with lower CSS and OS. NAC was associated with a higher probability of risk reclassification from high to low risk.

Effect modification of ambient particle mortality by radon: a time series analysis in 108 U.S. cities

ABSTRACT Numerous studies have reported a positive association between ambient fine particles and daily mortality, but little is known about the particle properties or environmental factors that may contribute to these effects. This study assessed potential modification of radon on PM2.5 (particulate matter with an aerodynamic diameter <2.5 μm)-associated daily mortality in 108 U.S. cities using a two-stage statistical approach. First, city- and season-specific PM2.5 mortality risks were estimated using over-dispersed Poisson regression models. These PM2.5 effect estimates were then regressed against mean city-level residential radon concentrations to estimate overall PM2.5 effects and potential modification by radon. Radon exposure estimates based on measured short-term basement concentrations and modeled long-term living-area concentrations were both assessed. Exposure to PM2.5 was associated with total, cardiovascular, and respiratory mortality in both the spring and the fall. In addition, higher mean city-level radon concentrations increased PM2.5-associated mortality in the spring and fall. For example, a 10 µg/m3 increase in PM2.5 in the spring at the 10th percentile of city-averaged short-term radon concentrations (21.1 Bq/m3) was associated with a 1.92% increase in total mortality (95% CI: 1.29, 2.55), whereas the same PM2.5 exposure at the 90th radon percentile (234.2 Bq/m3) was associated with a 3.73% increase in total mortality (95% CI: 2.87, 4.59). Results were robust to adjustment for spatial confounders, including average planetary boundary height, population age, percent poverty and tobacco use. While additional research is necessary, this study suggests that radon enhances PM2.5 mortality. This is of significant regulatory importance, as effective regulation should consider the increased risk for particle mortality in cities with higher radon levels. Implications: In this large national study, city-averaged indoor radon concentration was a significant effect modifier of PM2.5-associated total, cardiovascular, and respiratory mortality risk in the spring and fall. These results suggest that radon may enhance PM2.5-associated mortality. In addition, local radon concentrations partially explain the significant variability in PM2.5 effect estimates across U.S. cities, noted in this and previous studies. Although the concept of PM as a vector for radon progeny is feasible, additional research is needed on the noncancer health effects of radon and its potential interaction with PM. Future air quality regulations may need to consider the increased risk for particle mortality in cities with higher radon levels.

Ambient Temperature and Sudden Infant Death Syndrome in the United States

Background: Sudden infant death syndrome (SIDS) is a leading cause of infant mortality in the United States. While thermal stress is implicated in many risk factors for SIDS, the association between ambient temperature and SIDS remains unclear. Methods: We obtained daily individual-level infant mortality data and outdoor temperature data from 1972 to 2006 for 210 US cities. We applied a time-stratified case–crossover analysis to determine the effect of ambient temperature on the risk of SIDS by season. We stratified the analysis by race, infant age, and climate. Results: There were a total of 60,364 SIDS cases during our study period. A 5.6°C (10°F) higher daily temperature on the same day was associated with an increased SIDS risk of 8.6% (95% confidence interval [CI] = 3.6%, 13.8%) in the summer, compared with a 3.1% decrease (95% CI = −5.0%, −1.3%) in the winter. Summer risks were greater among black infants (18.5%; 95% CI = 9.3%, 28.5%) than white infants (3.6%; 95% CI = −2.3%, 9.9%), and among infants 3–11 months old (16.9%; 95% CI = 8.9%, 25.5%) than infants 0–2 months old (2.7%; 95% CI = −3.5%, 9.2%). The temperature–SIDS association was stronger in climate clusters in the Midwest and surrounding northern regions. Conclusions: Temperature increases were associated with an elevated risk of SIDS in the summer, particularly among infants who were black, 3 months old and older, and living in the Midwest and surrounding northern regions.