Tropical Cyclone Exposures and Risks of Emergency Medicare Hospital Admission for Cardiorespiratory Diseases in 175 Urban United States Counties, 1999-2010.

BACKGROUND: Although injuries experienced during hurricanes and other tropical cyclones have been relatively well-characterized through traditional surveillance, less is known about tropical cyclones' impacts on noninjury morbidity, which can be triggered through pathways that include psychosocial stress or interruption in medical treatment. METHODS: We investigated daily emergency Medicare hospitalizations (1999-2010) in 180 US counties, drawing on an existing cohort of high-population counties. We classified counties as exposed to tropical cyclones when storm-associated peak sustained winds were ≥21 m/s at the county center; secondary analyses considered other wind thresholds and hazards. We matched storm-exposed days to unexposed days by county and seasonality. We estimated change in tropical cyclone-associated hospitalizations over a storm period from 2 days before to 7 days after the storm's closest approach, compared to unexposed days, using generalized linear mixed-effect models. RESULTS: For 1999-2010, 175 study counties had at least one tropical cyclone exposure. Cardiovascular hospitalizations decreased on the storm day, then increased following the storm, while respiratory hospitalizations were elevated throughout the storm period. Over the 10-day storm period, cardiovascular hospitalizations increased 3% (95% confidence interval = 2%, 5%) and respiratory hospitalizations increased 16% (95% confidence interval = 13%, 20%) compared to matched unexposed periods. Relative risks varied across tropical cyclone exposures, with strongest association for the most restrictive wind-based exposure metric. CONCLUSIONS: In this study, tropical cyclone exposures were associated with a short-term increase in cardiorespiratory hospitalization risk among the elderly, based on a multi-year/multi-site investigation of US Medicare beneficiaries ≥65 years.

Estimating policy-relevant health effects of ambient heat exposures using spatially contiguous reanalysis data.

BACKGROUND: Regional National Weather Service (NWS) heat advisory criteria in New York State (NYS) were based on frequency of heat events estimated by sparse monitoring data. These may not accurately reflect temperatures at which specific health risks occur in large geographic regions. The objectives of the study were to use spatially resolved temperature data to characterize health risks related to summertime heat exposure and estimate the temperatures at which excessive risk of heat-related adverse health occurs in NYS. We also evaluated the need to adjust current heat advisory threshold and messaging based on threshold temperatures of multiple health outcomes. METHODS: We assessed the effect of multi-day lag exposure for maximum near-surface air temperature (Tmax) and maximum Heat Index derived from the gridded National Land Data Assimilation System (NLDAS) reanalysis dataset on emergency department (ED) visits/ hospitalizations for heat stress, dehydration, acute kidney failure (AKF) and cardiovascular diseases (CVD) using a case-crossover analysis during summers of 2008-2012. We assessed effect modification using interaction terms and stratified analysis. Thresholds were estimated using piecewise spline regression. RESULTS: We observed an increased risk of heat stress (Risk ratio (RR) = 1.366, 95% confidence interval (CI): 1.347, 1.386) and dehydration (RR = 1.024, 95% CI: 1.021, 1.028) for every 1 °C increase in Tmax on the day of exposure. The highest risk for AKF (RR = 1.017, 95% CI: 1.014, 1.021) and CVD (RR = 1.001, 95% CI: 1.000, 1.002) were at lag 1 and 4 respectively. The increased risk of heat-health effects persists up to 6 days. Rural areas of NYS are at as high a risk of heat-health effects as urban areas. Heat-health risks start increasing at temperatures much lower than the current NWS criteria. CONCLUSION: Reanalysis data provide refined exposure-response functions for health research, in areas with sparse monitor observations. Based on this research, rural areas in NYS had similar risk for health effects of heat. Heat advisories in New York City (NYC) had been reviewed and lowered previously. As such, the current NWS heat advisory threshold was lowered for the upstate region of New York and surrounding areas. Enhanced outreach materials were also developed and disseminated to local health departments and the public.

Development and validation of improved PM2.5 models for public health applications using remotely sensed aerosol and meteorological data.

In this study, Moderate Resolution Imaging Spectrometer (MODIS) satellite measurements of aerosol optical depth (AOD) from different retrieval algorithms have been correlated with ground measurements of fine particulate matter less than 2.5 µm (PM2.5). Several MODIS AOD products from different satellites (Aqua vs. Terra), retrieval algorithms (Dark Target vs. Deep Blue), collections (5.1 vs. 6), and spatial resolutions (10 km vs. 3 km) for cities in the Western, Midwestern, and Southeastern USA have been evaluated. We developed and validated PM2.5 prediction models using remotely sensed AOD data. These models were further improved by incorporating meteorological variables (temperature, relative humidity, precipitation, wind gust, and wind direction) from the North American Land Data Assimilation System Phase 2 (NLDAS-2). Adding these meteorological data significantly improved the simulation quality of all the PM2.5 models, especially in the Western USA. Temperature, relative humidity, and wind gust were significant meteorological variables throughout the year in the Western USA. Wind speed was the most significant meteorological variable for the cold season while for the warm season, temperature was the most prominent one in the Midwestern and Southeastern USA. Using this satellite-derived PM2.5 data can improve the spatial coverage, especially in areas where PM2.5 ground monitors are lacking, and studying the connections between PM2.5 and public health concerns including respiratory and cardiovascular diseases in the USA can be further advanced.

Fine particulate matter and incident coronary heart disease in the REGARDS cohort.

Chronic exposure to fine particulate matter (PM2.5) is accepted as a causal risk factor for coronary heart disease (CHD). However, most of the evidence for this hypothesis is based upon cohort studies in whites, comprised of either only males or females who live in urban areas. It is possible that many estimates of the effect of chronic exposure to PM2.5 on risk for CHD do not generalize to more diverse samples. METHODS: Therefore, we estimated the relationship between chronic exposure to PM2.5 and risk for CHD in among participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort who were free from CHD at baseline (n=17,126). REGARDS is a sample of whites and blacks of both genders living across the continental United States. We fit Cox proportional hazards models for time to CHD to estimate the hazard ratio for baseline 1-year mean PM2.5 exposure, adjusting for environmental variables, demographics, and other risk factors for CHD including the Framingham Risk Score. RESULTS: The hazard ratio (95% CI) for a 2.7-µg/m3 increase (interquartile range) 1-year mean concentration of PM2.5 was 0.94 (0.83-1.06) for combined CHD death and nonfatal MI, 1.13 (0.92-1.40) for CHD death, and 0.85 (0.73-0.99) for nonfatal MI. We also did not find evidence that these associations depended upon overall CHD risk factor burden. CONCLUSIONS: Our results do not provide strong evidence for an association between PM2.5 and incident CHD in a heterogeneous cohort, and we conclude that the effects of chronic exposure to fine particulate matter on CHD require further evaluation.

Reconnoitering the linkage between cardiovascular disease mortality and long-term exposures to outdoor environmental factors in the USA using remotely-sensed data.

This ecological study aimed to assess the association between long-term exposures to outdoor environmental factors and mortality rate from cardiovascular disease (CVD) in a diverse and spatially distributed population from 3,094 counties within the U.S. (n > 3,780,000 CVD deaths) using satellite-derived data of PM2.5 concentrations, sunlight, and maximum heat index. Multivariable logistic regression analyses were conducted to determine whether PM2.5, sunlight and maximum heat index were related to the odds of the total CVD death rate based on gender, race, and age taking into consideration the confounding risk factors of diabetes, obesity, leisure- time physical inactivity, smoking and socioeconomic status. The study has shown that elevated levels of PM2.5, sunlight and heat long-term exposures are significantly associated with an increase in the odds ratio of the total CVD mortality. The results suggest a 9.8% (95% CI = 6.3% - 13.4%), 0.9% (95% CI = 0.5% - 1.2%), and 0.7% (95% CI = 0.5% - 11.2%) increase in total CVD mortality associated with 10 µg/m3 increase in PM2.5 concentrations, 1,000 kJ/m2 increases in sunlight, and 1 oF increase in heat index, respectively. The odds ratios for the CVD death rate due to long-term exposures of PM2.5, sunlight, and heat index were significantly greater than 1.0 for all categories except for Asians, Hispanics, and American Indians, indicating that the effect of long-term exposures to particulate matter, sunlight radiation, and maximum heat on CVD mortality is trivial for Asians, Hispanics, and American Indians. Among the categories of age, the group of 65 years and older had the highest odds ratios, suggesting that the age group of 65 years and older are the most vulnerable group to the environmental exposures of PM2.5 (OR = 1.179, 95% CI = 1.124 - 1.237), sunlight (OR = 1.047, 95% CI = 1.041 - 1.053), and maximum heat (OR = 1.014, 95% CI = 1.011 - 1.016). The odds ratios of CVD mortality due to the environmental exposures were higher for Blacks than those for Whites. The odds ratios for all categories were attenuated with the inclusion of diabetes, obesity, leisure-time physical inactivity, smoking, and income covariates, reflecting the effect of other medical conditions, lifestyle, behavioral and socioeconomic factors on the CVD death rate besides the environmental factors.

Fine Particulate Matter (PM2.5) and the Risk of Stroke in the REGARDS Cohort.

BACKGROUND: Ambient particulate matter has been shown to be associated with declining human health, although the association between fine particulate matter (PM2.5) and stroke is uncertain. METHODS: We utilized satellite-derived measures of PM2.5 to examine the association between exposure and stroke in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. We used a time-stratified case-crossover design, with exposure lags of 1 day, 2 days, and 3 days. We examined all strokes, as well as ischemic and hemorrhagic strokes separately. RESULTS: Among 30,239 participants in the REGARDS study, 746 incident events were observed: 72 hemorrhagic, 617 ischemic, and 57 of unknown type. Participants exposed to higher levels of PM2.5 more often resided in urban areas compared to rural, and in the southeastern United States. After adjustment for temperature and relative humidity, no association was observed between PM2.5 exposure and stroke, regardless of the lag (1-day lag OR = .99, 95% CI: .83-1.19; 2-day lag OR = .95, 95% CI: .80-1.14; 3-day lag OR = .95, 95% CI = .79-1.13). Similar results were observed for the stroke subtypes. CONCLUSIONS: In this large cohort of African-Americans and whites, no association was observed between PM2.5 and stroke. The ability to examine this association with a large number of outcomes and by stroke subtype helps fill a gap in the literature examining the association between PM2.5 and stroke.

The association of remotely sensed outdoor fine particulate matter with cancer incidence of respiratory system in the USA.

This study aimed to assess the association between exposure to fine particulate matter (PM2.5) and respiratory system cancer incidence in the US population (n = 295,404,580) using a satellite-derived estimate of PM2.5 concentrations. Linear and logistic regression analyses were performed to determine whether PM2.5 was related to the odds of respiratory system cancer (RSC) incidence based on gender and race. Positive linear regressions were found between PM2.5 concentrations and the age-adjusted RSC incidence rates for all groups (Males, Females, Whites, and Blacks) except for Asians and American Indians. The linear relationships between PM2.5 and RSC incidence rate per 1 µg/m3 PM2.5 increase for Males, Females, Whites, Blacks, and all categories combined had slopes of, respectively, 7.02 (R2 = 0.36), 2.14 (R2 = 0.14), 3.92 (R2 = 0.23), 5.02 (R2 = 0.21), and 4.15 (R2 = 0.28). Similarly, the logistic regression odds ratios per 10 µg/m3 increase of PM2.5 were greater than one for all categories except for Asians and American Indians, indicating that PM2.5 is related to the odds of RSC incidence. The age-adjusted odds ratio for males (OR = 2.16, 95% CI = 1.56-3.01) was higher than that for females (OR = 1.50, 95% CI = 1.09-2.06), and it was higher for Blacks (OR = 2.12, 95% CI = 1.43-3.14) than for Whites (OR = 1.72, 95% CI = 1.23-2.42). The odds ratios for all categories were attenuated with the inclusion of the smoking covariate, reflecting the effect of smoking on RSC incidence besides PM2.5.

Assimilation of SMOS Retrievals in the Land Information System.

The Soil Moisture and Ocean Salinity (SMOS) satellite provides retrievals of soil moisture in the upper 5 cm with a 30-50 km resolution and a mission accuracy requirement of 0.04 cm3 cm-3. These observations can be used to improve land surface model soil moisture states through data assimilation. In this paper, SMOS soil moisture retrievals are assimilated into the Noah land surface model via an Ensemble Kalman Filter within the NASA Land Information System. Bias correction is implemented using Cumulative Distribution Function (CDF) matching, with points aggregated by either land cover or soil type to reduce sampling error in generating the CDFs. An experiment was run for the warm season of 2011 to test SMOS data assimilation and to compare assimilation methods. Verification of soil moisture analyses in the 0-10 cm upper layer and root zone (0-1 m) was conducted using in situ measurements from several observing networks in the central and southeastern United States. This experiment showed that SMOS data assimilation significantly increased the anomaly correlation of Noah soil moisture with station measurements from 0.45 to 0.57 in the 0-10 cm layer. Time series at specific stations demonstrate the ability of SMOS DA to increase the dynamic range of soil moisture in a manner consistent with station measurements. Among the bias correction methods, the correction based on soil type performed best at bias reduction but also reduced correlations. The vegetation-based correction did not produce any significant differences compared to using a simple uniform correction curve.

Short- and long-term sunlight radiation and stroke incidence.

OBJECTIVE: Examine whether long- and short-term sunlight radiation is related to stroke incidence. METHODS: Fifteen-year residential histories merged with satellite, ground monitor, and model reanalysis data were used to determine sunlight radiation (insolation) and temperature exposure for a cohort of 16,606 stroke and coronary artery disease-free black and white participants aged ≥45 years from the 48 contiguous United States. Fifteen-, 10-, 5-, 2-, and 1-year exposures were used to predict stroke incidence during follow-up in Cox proportional hazard models. Potential confounders and mediators were included during model building. RESULTS: Shorter exposure periods exhibited similar, but slightly stronger relationships than longer exposure periods. After adjustment for other covariates, the previous year's monthly average insolation exposure below the median gave a hazard ratio (HR) of 1.61 (95% confidence interval [CI], 1.15-2.26), and the previous year's highest compared to the second highest quartile of monthly average maximum temperature exposure gave an HR of 1.92 (95%, 1.27-2.92). INTERPRETATION: These results indicate a relationship between lower levels of sunlight radiation and higher stroke incidence. The biological pathway of this relationship is not clear. Future research will show whether this finding stands, the pathway for this relationship, and whether it is due to short- or long-term exposures.

Sunlight exposure and cardiovascular risk factors in the REGARDS study: a cross-sectional split-sample analysis.

BACKGROUND: Previous research has suggested that vitamin D and sunlight are related to cardiovascular outcomes, but associations between sunlight and risk factors have not been investigated. We examined whether increased sunlight exposure was related to improved cardiovascular risk factor status. METHODS: Residential histories merged with satellite, ground monitor, and model reanalysis data were used to determine previous-year sunlight radiation exposure for 17,773 black and white participants aged 45+ from the US. Exploratory and confirmatory analyses were performed by randomly dividing the sample into halves. Logistic regression models were used to examine relationships with cardiovascular risk factors. RESULTS: The lowest, compared to the highest quartile of insolation exposure was associated with lower high-density lipoprotein levels in adjusted exploratory (-2.7 mg/dL [95% confidence interval: -4.2, -1.2]) and confirmatory (-1.5 mg/dL [95% confidence interval: -3.0, -0.1]) models. The lowest, compared to the highest quartile of insolation exposure was associated with higher systolic blood pressure levels in unadjusted exploratory and confirmatory, as well as the adjusted exploratory model (2.3 mmHg [95% confidence interval: 0.8, 3.8]), but not the adjusted confirmatory model (1.6 mg/dL [95% confidence interval: -0.5, 3.7]). CONCLUSIONS: The results of this study suggest that lower long-term sunlight exposure has an association with lower high-density lipoprotein levels. However, all associations were weak, thus it is not known if insolation may affect cardiovascular outcomes through these risk factors.

The relationship between long-term sunlight radiation and cognitive decline in the REGARDS cohort study.

Sunlight may be related to cognitive function through vitamin D metabolism or circadian rhythm regulation. The analysis presented here sought to test whether ground and satellite measures of solar radiation are associated with cognitive decline. The study used a 15-year residential history merged with satellite and ground monitor data to determine sunlight (solar radiation) and air temperature exposure for a cohort of 19,896 cognitively intact black and white participants aged 45+ from the 48 contiguous United States. Exposures of 15, 10, 5, 2, and 1-year were used to predict cognitive status at the most recent assessment in logistic regression models; 1-year insolation and maximum temperatures were chosen as exposure measures. Solar radiation interacted with temperature, age, and gender in its relationships with incident cognitive impairment. After adjustment for covariates, the odds ratio (OR) of cognitive decline for solar radiation exposure below the median vs above the median in the 3rd tertile of maximum temperatures was 1.88 (95 % CI: 1.24, 2.85), that in the 2nd tertile was 1.33 (95 % CI: 1.09, 1.62), and that in the 1st tertile was 1.22 (95 % CI: 0.92, 1.60). We also found that participants under 60 years old had an OR = 1.63 (95 % CI: 1.20, 2.22), those 60-80 years old had an OR = 1.18 (95 % CI: 1.02, 1.36), and those over 80 years old had an OR = 1.05 (0.80, 1.37). Lastly, we found that males had an OR = 1.43 (95 % CI: 1.22, 1.69), and females had an OR = 1.02 (0.87, 1.20). We found that lower levels of solar radiation were associated with increased odds of incident cognitive impairment.

Environmental Public Health Applications Using Remotely Sensed Data.

We describe a remote sensing and GIS-based study that has three objectives: (1) characterize fine particulate matter (PM2.5), insolation and land surface temperature using NASA satellite observations, EPA ground-level monitor data and North American Land Data Assimilation System (NLDAS) data products on a national scale; (2) link these data with public health data from the REasons for Geographic And Racial Differences in Stroke (REGARDS) national cohort study to determine whether these environmental risk factors are related to cognitive decline, stroke and other health outcomes; and (3) disseminate the environmental datasets and public health linkage analyses to end users for decision-making through the Centers for Disease Control and Prevention (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) system. This study directly addresses a public health focus of the NASA Applied Sciences Program, utilization of Earth Sciences products, by addressing issues of environmental health to enhance public health decision-making.

CXCL9/10-engineered dendritic cells promote T cell activation and enhance immune checkpoint blockade for lung cancer.

Immune checkpoint blockade (ICB) with PD-1/PD-L1 inhibition has revolutionized the treatment of non-small cell lung cancer (NSCLC). Durable responses, however, are observed only in a subpopulation of patients. Defective antigen presentation and an immunosuppressive tumor microenvironment (TME) can lead to deficient T cell recruitment and ICB resistance. We evaluate intratumoral (IT) vaccination with CXCL9- and CXCL10-engineered dendritic cells (CXCL9/10-DC) as a strategy to overcome resistance. IT CXCL9/10-DC leads to enhanced T cell infiltration and activation in the TME and tumor inhibition in murine NSCLC models. The antitumor efficacy of IT CXCL9/10-DC is dependent on CD4+ and CD8+ T cells, as well as CXCR3-dependent T cell trafficking from the lymph node. IT CXCL9/10-DC, in combination with ICB, overcomes resistance and establishes systemic tumor-specific immunity in murine models. These studies provide a mechanistic understanding of CXCL9/10-DC-mediated host immune activation and support clinical translation of IT CXCL9/10-DC to augment ICB efficacy in NSCLC.

Estimating ground-level PM(2.5) concentrations in the southeastern U.S. using geographically weighted regression.

Most of currently reported models for predicting PM(2.5) concentrations from satellite retrievals of aerosol optical depth are global methods without considering local variations, which might introduce significant biases into prediction results. In this paper, a geographically weighted regression model was developed to examine the relationship among PM(2.5), aerosol optical depth, meteorological parameters, and land use information. Additionally, two meteorological datasets, North American Regional Reanalysis and North American Land Data Assimilation System, were fitted into the model separately to compare their performances. The study area is centered at the Atlanta Metro area, and data were collected from various sources for the year 2003. The results showed that the mean local R(2) of the models using North American Regional Reanalysis was 0.60 and those using North American Land Data Assimilation System reached 0.61. The root mean squared prediction error showed that the prediction accuracy was 82.7% and 83.0% for North American Regional Reanalysis and North American Land Data Assimilation System in model fitting, respectively, and 69.7% and 72.1% in cross validation. The results indicated that geographically weighted regression combined with aerosol optical depth, meteorological parameters, and land use information as the predictor variables could generate a better fit and achieve high accuracy in PM(2.5) exposure estimation, and North American Land Data Assimilation System could be used as an alternative of North American Regional Reanalysis to provide some of the meteorological fields.

CCL21-DC in situ vaccination in murine NSCLC overcomes resistance to immunotherapy and generates systemic tumor-specific immunity.

BACKGROUND: Despite recent advances in immunotherapy, many patients with non-small cell lung cancer (NSCLC) do not respond to immune checkpoint inhibitors (ICI). Resistance to ICI may be driven by suboptimal priming of antitumor T lymphocytes due to poor antigen presentation as well as their exclusion and impairment by the immunosuppressive tumor microenvironment (TME). In a recent phase I trial in patients with NSCLC, in situ vaccination (ISV) with dendritic cells engineered to secrete CCL21 (CCL21-DC), a chemokine that facilitates the recruitment of T cells and DC, promoted T lymphocyte tumor infiltration and PD-L1 upregulation. METHODS: Murine models of NSCLC with distinct driver mutations (KrasG12D/P53+/-/Lkb1-/- (KPL); KrasG12D/P53+/- (KP); and KrasG12D (K)) and varying tumor mutational burden were used to evaluate the efficacy of combination therapy with CCL21-DC ISV plus ICI. Comprehensive analyses of longitudinal preclinical samples by flow cytometry, single cell RNA-sequencing (scRNA-seq) and whole-exome sequencing were performed to assess mechanisms of combination therapy. RESULTS: ISV with CCL21-DC sensitized immune-resistant murine NSCLCs to ICI and led to the establishment of tumor-specific immune memory. Immunophenotyping revealed that CCL21-DC obliterated tumor-promoting neutrophils, promoted sustained infiltration of CD8 cytolytic and CD4 Th1 lymphocytes and enriched progenitor T cells in the TME. Addition of ICI to CCL21-DC further enhanced the expansion and effector function of T cells both locally and systemically. Longitudinal evaluation of tumor mutation profiles revealed that CCL21-DC plus ICI induced immunoediting of tumor subclones, consistent with the broadening of tumor-specific T cell responses. CONCLUSIONS: CCL21-DC ISV synergizes with anti-PD-1 to eradicate murine NSCLC. Our data support the clinical application of CCL21-DC ISV in combination with checkpoint inhibition for patients with NSCLC.

Plasticity of Extrachromosomal and Intrachromosomal BRAF Amplifications in Overcoming Targeted Therapy Dosage Challenges.

Focal amplifications (FA) can mediate targeted therapy resistance in cancer. Understanding the structure and dynamics of FAs is critical for designing treatments that overcome plasticity-mediated resistance. We developed a melanoma model of dual MAPK inhibitor (MAPKi) resistance that bears BRAFV600 amplifications through either extrachromosomal DNA (ecDNA)/double minutes (DM) or intrachromosomal homogenously staining regions (HSR). Cells harboring BRAFV600E FAs displayed mode switching between DMs and HSRs, from both de novo genetic changes and selection of preexisting subpopulations. Plasticity is not exclusive to ecDNAs, as cells harboring HSRs exhibit drug addiction-driven structural loss of BRAF amplicons upon dose reduction. FA mechanisms can couple with kinase domain duplications and alternative splicing to enhance resistance. Drug-responsive amplicon plasticity is observed in the clinic and can involve other MAPK pathway genes, such as RAF1 and NRAS. BRAF FA-mediated dual MAPKi-resistant cells are more sensitive to proferroptotic drugs, extending the spectrum of ferroptosis sensitivity in MAPKi resistance beyond cases of dedifferentiation. SIGNIFICANCE: Understanding the structure and dynamics of oncogene amplifications is critical for overcoming tumor relapse. BRAF amplifications are highly plastic under MAPKi dosage challenges in melanoma, through involvement of de novo genomic alterations, even in the HSR mode. Moreover, BRAF FA-driven, dual MAPKi-resistant cells extend the spectrum of resistance-linked ferroptosis sensitivity. This article is highlighted in the In This Issue feature, p. 873.

The association of remotely-sensed outdoor temperature with blood pressure levels in REGARDS: a cross-sectional study of a large, national cohort of African-American and white participants.

BACKGROUND: Evidence is mounting regarding the clinically significant effect of temperature on blood pressure. METHODS: In this cross-sectional study the authors obtained minimum and maximum temperatures and their respective previous week variances at the geographic locations of the self-reported residences of 26,018 participants from a national cohort of blacks and whites, aged 45+. Linear regression of data from 20,623 participants was used in final multivariable models to determine if these temperature measures were associated with levels of systolic or diastolic blood pressure, and whether these relations were modified by stroke-risk region, race, education, income, sex hypertensive medication status, or age. RESULTS: After adjustment for confounders, same-day maximum temperatures 20 °F lower had significant associations with 1.4 mmHg (95% CI: 1.0, 1.9) higher systolic and 0.5 mmHg (95% CI: 0.3, 0.8) higher diastolic blood pressures. Same-day minimum temperatures 20 °F lower had a significant association with 0.7 mmHg (95% CI: 0.3, 1.0) higher systolic blood pressures but no significant association with diastolic blood pressure differences. Maximum and minimum previous-week temperature variabilities showed significant but weak relationships with blood pressures. Parameter estimates showed effect modification of negligible magnitude. CONCLUSIONS: This study found significant associations between outdoor temperature and blood pressure levels, which remained after adjustment for various confounders including season. This relationship showed negligible effect modification.

Inhibition of Granulocytic Myeloid-Derived Suppressor Cells Overcomes Resistance to Immune Checkpoint Inhibition in LKB1-Deficient Non-Small Cell Lung Cancer.

LKB1 inactivating mutations are commonly observed in patients with KRAS-mutant non-small cell lung cancer (NSCLC). Although treatment of NSCLC with immune checkpoint inhibitors (ICI) has resulted in improved overall survival in a subset of patients, studies have revealed that co-occurring KRAS/LKB1 mutations drive primary resistance to ICIs in NSCLC. Effective therapeutic options that overcome ICI resistance in LKB1-mutant NSCLC are limited. Here, we report that loss of LKB1 results in increased secretion of the C-X-C motif (CXC) chemokines with an NH2-terminal Glu-Leu-Arg (ELR) motif in premalignant and cancerous cells, as well as in genetically engineered murine models (GEMM) of NSCLC. Heightened levels of ELR+ CXC chemokines in LKB1-deficient murine models of NSCLC positively correlated with increased abundance of granulocytic myeloid-derived suppressor cells (G-MDSC) locally within the tumor microenvironment and systemically in peripheral blood and spleen. Depletion of G-MDSCs with antibody or functional inhibition via all-trans-retinoic acid (ATRA) led to enhanced antitumor T-cell responses and sensitized LKB1-deficent murine tumors to PD-1 blockade. Combination therapy with anti-PD-1 and ATRA improved local and systemic T-cell proliferation and generated tumor-specific immunity. Our findings implicate ELR+ CXC chemokine-mediated enrichment of G-MDSCs as a potential mediator of immunosuppression in LKB1-deficient NSCLC and provide a rationale for using ATRA in combination with anti-PD-1 therapy in patients with LKB1-deficient NSCLC refractory to ICIs. SIGNIFICANCE: These findings show that accumulation of myeloid-derived suppressor cells in LKB1-deficient non-small cell lung cancer can be overcome via treatment with all-trans-retinoic acid, sensitizing tumors to immunotherapy.

Downscaling NLDAS-2 daily maximum air temperatures using MODIS land surface temperatures.

We have developed and applied a relatively simple disaggregation scheme that uses spatial patterns of Land Surface Temperature (LST) from MODIS warm-season composites to improve the spatial characterization of daily maximum and minimum air temperatures. This down-scaling model produces qualitatively reasonable 1 km daily maximum and minimum air temperature estimates that reflect urban and coastal features. In a 5-city validation, the model was shown to provide improved daily maximum air temperature estimates in the three coastal cities, compared to 12 km NLDAS-2 (North American Land Data Assimilation System). Down-scaled maximum temperature estimates for the other two (non-coastal) cities were marginally worse than the original NLDAS-2 temperatures. For daily minimum temperatures, the scheme produces spatial fields that qualitatively capture geographic features, but quantitative validation shows the down-scaling model performance to be very similar to the original NLDAS-2 minimum temperatures. Thus, we limit the discussion in this paper to daily maximum temperatures. Overall, errors in the down-scaled maximum air temperatures are comparable to errors in down-scaled LST obtained in previous studies. The advantage of this approach is that it produces estimates of daily maximum air temperatures, which is more relevant than LST in applications such as public health. The resulting 1 km daily maximum air temperatures have great potential utility for applications such as public health, energy demand, and surface energy balance analyses. The method may not perform as well in conditions of strong temperature advection. Application of the model also may be problematic in areas having extreme changes in elevation.

Assessing United States County-Level Exposure for Research on Tropical Cyclones and Human Health.

BACKGROUND: Tropical cyclone epidemiology can be advanced through exposure assessment methods that are comprehensive and consistent across space and time, as these facilitate multiyear, multistorm studies. Further, an understanding of patterns in and between exposure metrics that are based on specific hazards of the storm can help in designing tropical cyclone epidemiological research. OBJECTIVES: a) Provide an open-source data set for tropical cyclone exposure assessment for epidemiological research; and b) investigate patterns and agreement between county-level assessments of tropical cyclone exposure based on different storm hazards. METHODS: We created an open-source data set with data at the county level on exposure to four tropical cyclone hazards: peak sustained wind, rainfall, flooding, and tornadoes. The data cover all eastern U.S. counties for all land-falling or near-land Atlantic basin storms, covering 1996-2011 for all metrics and up to 1988-2018 for specific metrics. We validated measurements against other data sources and investigated patterns and agreement among binary exposure classifications based on these metrics, as well as compared them to use of distance from the storm's track, which has been used as a proxy for exposure in some epidemiological studies. RESULTS: Our open-source data set was typically consistent with data from other sources, and we present and discuss areas of disagreement and other caveats. Over the study period and area, tropical cyclones typically brought different hazards to different counties. Therefore, when comparing exposure assessment between different hazard-specific metrics, agreement was usually low, as it also was when comparing exposure assessment based on a distance-based proxy measurement and any of the hazard-specific metrics. DISCUSSION: Our results provide a multihazard data set that can be leveraged for epidemiological research on tropical cyclones, as well as insights that can inform the design and analysis for tropical cyclone epidemiological research. https://doi.org/10.1289/EHP6976.