Surrogate Exposure Research Articles

Abstract 1672: Overall survival in metastatic melanoma correlates with pembrolizumab exposure and T cell exhaustion markers

Abstract Background: There are few clinically validated predictive biomarkers for benefit to immune checkpoint blockade (ICB) in metastatic melanoma. Real world evidence has shown patients with higher exposure to ICB have improved best overall response (BOR) and longer survival [1]. Increased expression of T cell exhaustion markers and specific chemokine signatures have been associated with poor response to ICB in metastatic melanoma [2]. We sought to determine the relationship between pharmacokinetic (PK) and clinical outcomes of patients with metastatic melanoma treated with pembrolizumab. Translational correlative objectives included identifying expression of circulating T cell exhaustion markers and specific chemokine signatures in patients with progressive disease. Methods: Metastatic melanoma patients received weight based pembrolizumab and had serial peripheral blood draws. BRAF mutation positive patients were pre-treated with targeted therapy, otherwise pembrolizumab was first line. Plasma trough levels were assessed using the Abcam® pembrolizumab ELISA kit. BOR groups: complete response (CR), partial response (PR) and progressive disease (PD), were classified as per irRECIST. The T-cell exhaustion and chemokine markers were determined using Flow Cytometry on the BD Science Fortessa® X20. The cohort was stratified into high versus low pembrolizumab trough concentrations, split by the median. Kaplan-Meier survival analysis for progression free (PFS) and overall survival (OS) was performed based on these groups. Non-parametric correlation analysis was used to test for correlations between clinical characteristics, pembrolizumab trough concentrations and translational markers. Results: Twenty-eight patients were enrolled. Median follow up was 32.5 months. The pembrolizumab plasma trough levels were not significantly different between BOR categorical groups. Trough levels are a valid surrogate for drug exposure[3]. There were no significant correlations between pembrolizumab trough levels and expression of T-cell exhaustion and chemokine markers over time.The high pembrolizumab exposure group experienced significantly longer OS (median not reached versus 48 months, p=0.014), than the low exposure group. A similar positive exposure PFS relationship was found (median not reached versus 48 months, p=0.045). There was significantly higher frequency of co-expression of CXCR6 and TIM3 on CD4+ T cells for PD (mean 21.5% CI 14.9% - 26.06%) compared to CR (mean 12.2% CI 9.40% - 14.99%) (p=0.003) and PR (mean 9.9% CI 7.76% - 12.05%) (p=0.0001). There was also significantly higher frequency of co-expression of CXCR6 and TIM3 on CD8+ T cells for PD (mean 32.59% CI 25.76% - 39.43%) compared to PR (mean 21.9% CI 18.22% - 25.56%) (p=0.032).Conclusions: We describe a positive exposure PFS and exposure OS relationship for pembrolizumab in metastatic melanoma. The data indicate the co-expression of CXCR6 and T-cell exhaustion markers on circulating CD4+ and CD8+ T cells are potential biomarkers of disease progression on single-agent pembrolizumab.AcknowledgementsThis study was funded by a Hunter Medical Research Institute Project Grant (HMRI983).Hunter Cancer Biobank Serial Blood Collection Project Citation Format: Vishal Navani, Moira C. Graves, Giovana Celli Marchett, Hiren Mandaliya, Nikola A. Bowden, Andre Van Der Westhuizen. Overall survival in metastatic melanoma correlates with pembrolizumab exposure and T cell exhaustion markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1672.

Overall survival in metastatic melanoma correlates with pembrolizumab exposure and T cell exhaustion markers.

Trial data support an absence of an exposure–survival relationship for pembrolizumab. As these relationships remain unexamined in a real‐world setting, we determined them in metastatic melanoma prospectively in an observational study. Translational objectives included identifying biomarkers of progressive disease (PD). Checkpoint blockade naïve patients receiving 2 mg/kg Q3W pembrolizumab had pharmacokinetic and clinical outcome data collected. Trough, a valid surrogate for drug exposure, was assessed using ELISA. T‐cell exhaustion and chemokine markers were determined using flow cytometry. Geometric means of exposures and biomarkers were tested against objective response groups using one‐way ANOVA. The cohort was split by the median into high versus low pembrolizumab exposure groups. Kaplan–Meier progression‐free survival (PFS) and overall survival (OS) curves were estimated for high versus low exposure, compared using the log rank test. The high pembrolizumab exposure group (n = 14) experienced substantially longer median OS (not reached vs. 48 months, p = .014), than the low exposure group (n = 14). A similar positive exposure PFS relationship was found (median not reached vs. 48 months, p = .045). The frequency of TIM‐3 expression on CD4+ T cells was significantly higher in PD (mean 27.8%) than complete response (CR) (13.38%, p = .01) and partial response (12.4%, p = .05). There was a near doubling of CXCR6 and TIM‐3 co‐expression on CD4+ T cells in PD (mean 23.3%) versus CR (mean 11.4, p = .003) and partial response (9.8%, p = .0001). We describe positive exposure‐PFS and exposure‐OS relationships for pembrolizumab in metastatic melanoma. TIM‐3, alongside co‐expression of CXCR6 and TIM‐3 on circulating CD4+ T cells are potential bio markers of treatment failure.

Persistent brainwave disruption and cognitive impairment induced by acute sarin surrogate sub-lethal dose exposure

Warfare neurotoxicants such as sarin, soman or VX, are organophosphorus compounds which irreversibly inhibit cholinesterase. High-dose exposure with nerve agents (NA) is known to produce seizure activity and related brain damage, while less is known about the effects of acute sub-lethal dose exposure. The aim of this study was to characterize behavioral, brain activity and neuroinflammatory modifications at different time points after exposure to 4-nitrophenyl isopropyl methylphosphonate (NIMP), a sarin surrogate. In order to decipher the impacts of sub-lethal exposure, we chose 4 different doses of NIMP each corresponding to a fraction of the median lethal dose (LD50). First, we conducted a behavioral analysis of symptoms during the first hour following NIMP challenge and established a specific scoring scale for the intoxication severity. The intensity of intoxication signs was dose-dependent and proportional to the cholinesterase activity inhibition evaluated in mice brain. The lowest dose (0.3 LD50) did not induce significant behavioral, electrocorticographic (ECoG) nor cholinesterase activity changes. Animals exposed to one of the other doses (0.5, 0.7 and 0.9 LD50) exhibited substantial changes in behavior, significant cholinesterase activity inhibition, and a disruption of brainwave distribution that persisted in a dose-dependent manner. To evaluate long lasting changes, we conducted ECoG recording for 30 days on mice exposed to 0.5 or 0.9 LD50 of NIMP. Mice in both groups showed long-lasting impairment of theta rhythms, and a lack of restoration in hippocampal ChE activity after 1-month post-exposure. In addition, an increase in neuroinflammatory markers (IBA-1, TNF-α, NF-κB) and edema were transiently observed in mice hippocampus. Furthermore, a novel object recognition test showed an alteration of short-term memory in both groups, 1-month post-NIMP intoxication. Our findings identified both transient and long-term ECoG alterations and some long term cognitive impairments following exposure to sub-lethal doses of NIMP. These may further impact morphopathological alterations in the brain.

Childhood leukemia near nuclear sites in Belgium: An ecological study at small geographical level

BackgroundA previous investigation of the occurrence of childhood acute leukemia around the Belgian nuclear sites has shown positive associations around one nuclear site (Mol-Dessel). In the following years, the Belgian Cancer Registry has made data available at the smallest administrative unit for which demographic information exists in Belgium, i.e. the statistical sector. This offers the advantage to reduce the potential misclassification due to large geographical scales. MethodsThe current study performed for the period 2006–2016 uses Poisson models to investigate (i) the incidence of childhood acute leukemia within 20 km around the four Belgian nuclear sites, (ii) exposure-response relationships between cancer incidence and surrogate exposures from the nuclear sites (distance, wind direction frequency and exposure by hypothetical radioactive discharges taking into account historical meteorological conditions). All analyses are carried out at statistical sector level. ResultsHigher incidence rate ratios were found for children <15 years (7 cases, RR = 3.01, 95% CI: 1.43;6.35) and children <5 years (< 5 cases, RR = 3.62, 95% CI: 1.35;9.74) living less than 5 km from the site of Mol-Dessel. In addition, there was an indication for positive exposure-response relationships with the different types of surrogate exposures. ConclusionResults confirm an increased incidence of acute childhood leukemia around Mol-Dessel, but the number of cases remains very small. Random variation cannot be excluded and the ecological design does not allow concluding on causality. These findings emphasize the need for more in-depth research into the risk factors of childhood leukemia, for a better understanding of the etiology of this disease.

Risk of bladder cancer in male Japanese workers exposed to ortho-toluidine and other aromatic amines.

Nine bladder cancer (BCa) cases were reported among aromatic amine-exposed male workers at a factory manufacturing organic dye/pigment intermediates in Japan. We aimed to evaluate the characteristics of aromatic amine-exposed workers by cross-sectional observation, and the risk of BCa by assessing the standardized incidence ratio (SIR). In the cross-sectional study, our subjects were: 9 BCa patients, 36 aromatic amine-exposed non-patients, and 79 non-exposed workers from 3 factories. We evaluated the subjects' medical history, urinalysis, qualitative determination of nuclear matrix protein 22, and urinary cytology. For SIR assessment, 98 aromatic amine-exposed workers from 1 factory were included, and the Japanese general male population was used as a referent population. Since no direct aromatic amine-exposure data were available, we calculated surrogate exposure levels using information on job sites, exposure potency, and duration. Coexistent aromatic amines were ortho-toluidine (OT), aniline, para-toluidine, ortho-anisidine, 2,4-xylidine, and ortho-chloroaniline. The prevalence rates of cystitis and bladder lesion-related symptoms in both BCa patients and aromatic amine-exposed non-patient workers were significantly higher than those of non-exposed workers. Overall, the SIR for BCa in OT-exposed workers was 56.8 (95% CI 27.7-104.3) and apparent dose-response relationships were revealed between the SIR and the surrogate exposure level in the 0-10-year lagged analyses. Overall, SIRs in other aromatic amine-exposed workers were also significantly high but no or unclear dose-response relationships were observed. We conclude that OT may be responsible for the increased risk of BCa. Regular monitoring of bladder lesion-related symptoms is essential for the early identification of BCa.

Progression of Interstitial Fibrosis and Tubular Atrophy in Low Immunological Risk Renal Transplants Monitored by Sequential Surveillance Biopsies: The Influence of TAC Exposure and Metabolism.

The combination of tacrolimus (TAC) and mycophenolate is the most widely employed maintenance immunosuppression in renal transplants. Different surrogates of tacrolimus exposure or metabolism such as tacrolimus trough levels (TAC-C0), coefficient of variation of tacrolimus (CV-TAC-C0), time in therapeutic range (TTR), and tacrolimus concentration dose ratio (C/D) have been associated with graft outcomes. We explore in a cohort of low immunological risk renal transplants (n = 85) treated with TAC, mycophenolate mofetil (MMF), and steroids and then monitored by paired surveillance biopsies the association between histological lesions and TAC-C0 at the time of biopsy as well as CV-TAC-C0, TTR, and C/D during follow up. Interstitial inflammation (i-Banff score ≥ 1) in the first surveillance biopsy was associated with TAC-C0 (odds ratio (OR): 0.69, 95% confidence interval (CI): 0.50–0.96; p = 0.027). In the second surveillance biopsy, inflammation was associated with time below the therapeutic range (OR: 1.05 and 95% CI: 1.01–1.10; p = 0.023). Interstitial inflammation in scarred areas (i-IFTA score ≥ 1) was not associated with surrogates of TAC exposure/metabolism. Progression of interstitial fibrosis/tubular atrophy (IF/TA) was observed in 35 cases (41.2%). Multivariate regression logistic analysis showed that mean C/D (OR: 0.48; 95% CI: 0.25–0.92; p = 0.026) and IF/TA in the first biopsy (OR: 0.43, 95% CI: 0.24–0.77, p = 0.005) were associated with IF/TA progression between biopsies. A low C/D ratio is associated with IF/TA progression, suggesting that TAC nephrotoxicity may contribute to fibrosis progression in well immunosuppressed patients. Our data support that TAC exposure is associated with inflammation in healthy kidney areas but not in scarred tissue.

Two-phase analysis and study design for survival models with error-prone exposures.

Increasingly, medical research is dependent on data collected for non-research purposes, such as electronic health records data. Health records data and other large databases can be prone to measurement error in key exposures, and unadjusted analyses of error-prone data can bias study results. Validating a subset of records is a cost-effective way of gaining information on the error structure, which in turn can be used to adjust analyses for this error and improve inference. We extend the mean score method for the two-phase analysis of discrete-time survival models, which uses the unvalidated covariates as auxiliary variables that act as surrogates for the unobserved true exposures. This method relies on a two-phase sampling design and an estimation approach that preserves the consistency of complete case regression parameter estimates in the validated subset, with increased precision leveraged from the auxiliary data. Furthermore, we develop optimal sampling strategies which minimize the variance of the mean score estimator for a target exposure under a fixed cost constraint. We consider the setting where an internal pilot is necessary for the optimal design so that the phase two sample is split into a pilot and an adaptive optimal sample. Through simulations and data example, we evaluate efficiency gains of the mean score estimator using the derived optimal validation design compared to balanced and simple random sampling for the phase two sample. We also empirically explore efficiency gains that the proposed discrete optimal design can provide for the Cox proportional hazards model in the setting of a continuous-time survival outcome.

The aryl hydrocarbon receptor reduces LC3II expression and controls endoplasmic reticulum stress.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor whose physiological function is poorly understood. The AhR is highly expressed in barrier organs such as the skin, intestine, and lung. The lungs are continuously exposed to environmental pollutants such as cigarette smoke (CS) that can induce cell death mechanisms such as apoptosis, autophagy, and endoplasmic reticulum (ER) stress. CS also contains toxicants that are AhR ligands. We have previously shown that the AhR protects against apoptosis, but whether the AhR also protects against autophagy or ER stress is not known. Using cigarette smoke extract (CSE) as our in vitro surrogate of environmental tobacco exposure, we first assessed the conversion of LC3I to LC3II, a classic feature of both autophagic and ER stress-mediated cell death pathways. LC3II was elevated in CSE-exposed lung structural cells [mouse lung fibroblasts (MLFs), MLE12 and A549 cells] when AhR was absent. However, this heightened LC3II expression could not be explained by increased expression of key autophagy genes (Gabarapl1, Becn1, Map1lc3b), upregulation of upstream autophagic machinery (Atg5-12, Atg3), or impaired autophagic flux, suggesting that LC3II may be autophagy independent. This was further supported by the absence of autophagosomes in Ahr-/- lung cells. However, Ahr-/- lung cells had widespread ER dilation, elevated expression of the ER stress markers CHOP and GADD34, and an accumulation of ubiquitinated proteins. These findings collectively illustrate a novel role for the AhR in attenuating ER stress by a mechanism that may be autophagy independent.

Development and Validation of a Crowd-Generated Indicator of Air Pollution Exposures and Health Response using Web Search Log Mining.

Background. Traditional air pollution epidemiologic models use ground-based monitors and/or satellite estimates of ozone and PM2.5 concentrations as surrogates of exposure. It is possible that crowd-sourced or online data may be more effective at reflecting population exposures than these traditional indicators. Here, we constructed models to “nowcast” observed elevated pollution levels, using online search queries to create a Crowd-Generated Air Pollution (CGAP) metric and compared the output to monitoring data. We then used the CGAP metric to examine short-term associations of ED visits for pediatric asthma. Methods. A search term Dictionary Learner-Long-Short Term Memory (DL-LSTM) composite model was developed to combine meteorological data, air pollution measures, and pollution-related search data for Atlanta, and daily CGAP index was generated for ozone and PM2.5 from 2007 to 2008. Daily counts of ED visits for asthma among children aged 5 to 17 were collected as well. Using quasi-Poisson generalized linear models, we assessed short-term associations of measured ambient concentration and modeled CGAP index with ED visits. Results. Both ambient ozone and PM2.5 levels were associated with asthma ED visits. We observed similar patterns for indices from DL-LSTM model trained by meteorological data, air pollution measures, and search data (r = 0.88, p &lt; 0.0001 for ozone; r = 0.71, p &lt; 0.0001). The quasi-Akaike information criterion (AIC) of the modeled CGAP index was similar to or lower than that of ambient levels (3179.399 vs. 3173.754 for ozone; 3177.887 vs. 3198.606 for PM2.5). Conclusion. Our findings provided preliminary validation of the CGAP metric, based on a DL-LSTM algorithm. Results using CGAP were comparable to findings using stationary monitoring data for air pollution. The modeled CGAP index showed promise as a means of potentially providing a sensitive, comprehensive predictor of short-term changes in pediatric asthma ED visits due to urban air pollution exposures.

Modeling of Residential Indoor Concentrations of Ambient PM2.5, Ozone for the Catheterization Genetics (CATHGEN) Study

Air pollution epidemiological studies of ambient fine particulate matter (PM2.5) and ozone (O3) often use outdoor concentrations from central-site monitors as exposure surrogates, which can add bias or uncertainty in health effect estimates. The goal of this study was to improve exposure assessments of ambient PM2.5 and O3 for a 10-year epidemiological study with 2,271 participants with coronary artery disease in central North Carolina called the Catheterization Genetics (CATHGEN) study. We developed an exposure modeling approach to estimate three tiers of individual-level exposure metrics for ambient PM2.5 and O3. We used a hybrid outdoor air quality model (based on satellite- and ground-based air pollution measurements, chemical transport and land-use models) linked to a residential air exchange rate model (based on building characteristics, indoor-outdoor temperatures, wind speed) and mass-balance infiltration model to determine residential air exchange rates (AER, Tier 1), infiltration factors (Finf, Tier 2), and indoor concentrations (Cin, Tier 3). For each of the 2,271 participant homes, we applied the exposure model to determine daily house-specific PM2.5 and O3 exposure metrics (Tiers 1-3) for the 365 days before each participant’s cardiac catheterization date. The daily modeled exposure metrics for all 828,915 participant days showed considerable temporal and house-to-house variability of AER, Finf and Cout (Tiers 1-3). Our study demonstrates the ability to apply an outdoor air quality model linked to a residential infiltration model to determine individual-level ambient PM2.5 and O3 exposure metrics for a large, long-term epidemiological study, in support of improving risk estimation.

Attributing School Air Pollution Levels to Features of the Built Environment in New York City

Background: Exposure to traffic-related air pollution (TRAP) has been linked to asthma prevalence and exacerbations. Children spend a significant portion of their day in school where exposure to pollutants can be high based on geographic features of the built environment. The study objective was to determine the distributions of geographic indicators of traffic and built environment features and the association with school-based TRAP exposure in New York City (NYC).Methods: Spatial data on the proximity and density of roadways and built environment features were examined for a 250-meter buffer around NYC elementary and middle schools (N=1184). Annual average levels of particulate matter &lt;2.5 microns (PM2.5), black carbon (BC), and nitrogen dioxide (NO2) were determined based on land use regression models of street-level pollution measured by the New York City Community Air Survey. Spatial data were categorized using k-means cluster analysis and clusters were associated with air pollution using analysis of variance.Results: Based on significant correlations with air pollutants, three geographic indicators were included for cluster analysis: number of bus stops; truck route density (total km route/km2 land); and percentage of area covered with trees (i.e. tree canopy). Four clusters were identified: 1. Higher truck route density (n=103 schools); 2. Higher number of bus stops (n=378); 3. Higher tree canopy (n=250); and 4. Lower in all 3 indicators (n=453). In general, the levels of PM2.5, BC, and NO2 were highest among schools with higher truck route density, followed by higher number of bus stops, and lowest with higher tree canopy (p=0.001).Conclusions: School-aged children may experience higher levels of air pollution based on their school’s proximity to geographic indicators of diesel vehicle emission. Geographic indicators may serve as surrogates of chronic school exposure to air pollution. Future studies will determine if clusters are associated with school asthma prevalence.

Comparing spatial exposure surrogates with detections and concentrations of unconventional oil and gas-related chemicals in residential drinking water

Approximately 30 epidemiologic studies of unconventional oil and gas development (UOG) to date have identified associations with adverse health outcomes, such as birth outcomes, asthma, and cancer. These studies used spatial surrogates of exposure, which are feasible approaches for assessing aggregate exposures in large-scale studies. However, exposures and pathways captured by these surrogates (e.g., water contamination, air pollution) are poorly understood. We used logistic and linear regression to assess whether commonly-used spatial surrogates were associated with UOG-related chemicals in residential drinking water, an exposure pathway of public health concern. We compared detections and concentrations of 64 organic and inorganic chemicals from 94 private water wells in Bradford County, Pennsylvania with count of UOG wells within a buffer around the home, distance to nearest UOG well, and inverse distance weighted (IDW) and inverse distance-squared weighted well counts at buffer sizes of 2, 5, and 10km. We also compared chemical concentrations to health-based drinking water standards to understand human health risks from exposure. A total of 28 chemicals were detected in ≥20% of water samples, generally at low concentrations, though seven chemicals exceeded health-based drinking water standards at one or more homes. Of the organics, only benzene and toluene were associated with spatial surrogates. The odds of detecting benzene or toluene decreased by 55% and 50%, respectively, with each increasing kilometer between the residence and nearest UOG well (95%CI: 0.24-0.87 and 0.27-0.94); there were no clear relationships between other chemicals and metrics. Concentrations of iron, manganese, and sulfate were consistently inversely associated with IDW metrics, but the other 14 inorganics were poorly associated with metrics. Preliminary results indicate that spatial surrogates are weakly associated with detections and concentrations of UOG-related chemicals. More complex models incorporating groundwater flow and contaminant fate/transport may be needed to accurately capture drinking water exposure for health studies.

In Defense of the Weight-of-Evidence Approach to Literature Review in the Integrated Science Assessment

In Defense of the Weight-of-Evidence Approach to Literature Review in the Integrated Science Assessment

Environmental DNA and RNA as Records of Human Exposome, Including Biotic/Abiotic Exposures and Its Implications in the Assessment of the Role of Environment in Chronic Diseases.

Most of environment-related diseases often result from multiple exposures of abiotic and/or biotic stressors across various life stages. The application of environmental DNA/RNA (eDNA/eRNA) to advance ecological understanding has been very successfully used. However, the eminent extension of eDNA/eRNA-based approaches to estimate human exposure to biotic and/or abiotic environmental stressors to understand the environmental causes of chronic diseases has yet to start. Here, we introduce the potential of eDNA/eRNA for bio-monitoring of human exposome and health effects in the real environmental or occupational settings. This review is the first of its kind to discuss how eDNA/eRNA-based approaches can be applied for assessing the human exposome. eDNA-based exposome assessment is expected to rely on our ability to capture the genome- and epigenome-wide signatures left behind by individuals in the indoor and outdoor physical spaces through shedding, excreting, etc. Records of eDNA/eRNA exposome may reflect the early appearance, persistence, and presence of biotic and/or abiotic-exposure-mediated modifications in these nucleic acid molecules. Functional genome- and epigenome-wide mapping of eDNA offer great promise to help elucidate the human exposome. Assessment of longitudinal exposure to physical, biological, and chemical agents present in the environment through eDNA/eRNA may enable the building of an integrative causal dynamic stochastic model to estimate environmental causes of human health deficits. This model is expected to incorporate key biological pathways and gene networks linking individuals, their geographic locations, and random multi-hits of environmental factors. Development and validation of monitoring of eDNA/eRNA exposome should seriously be considered to introduce into safety and risk assessment and as surrogates of chronic exposure to environmental stressors. Here we highlight that eDNA/eRNA reflecting longitudinal exposure of both biotic and abiotic environmental stressors may serve as records of human exposome and discuss its application as molecular tools for understanding the toxicogenomics basis of environment-related health deficits.

The Affordable Care Act Is Associated With Increased Coverage and Decreased Charges, but Limited Improvement in Access to Vascular Surgery for Medicaid Patients

The Centers for Medicare and Medicaid Services estimate that 10 million people gained Medicaid coverage following implementation of the Patient Protection and Affordable Care Act (ACA); yet, it remains unclear how the expansion of Medicaid coverage has affected vascular surgical practice. We examined patients (18-65 years) in the National Inpatient Sample undergoing vascular procedures and total charges pre-ACA implementation (2006-2013) and post-ACA implementation (2014-October 2015). Western and Southern US census regions were surrogate exposure markers for Medicaid expansion status. International Classification of Diseases, 9th edition, procedure codes identified carotid endarterectomy, carotid artery stenting, abdominal aortic aneurysm repair (AAA) repair, endovascular AAA repair (EVAR), thoracic EVAR (TEVAR), major amputation (AMP), minor amputation (mAMP), and arteriovenous fistula/graft creation. Generalized linear models with modified Poisson distributions were calculated to compare pre- versus post-ACA outcomes, adjusted for gender and race/ethnicity. A difference-in-differences (DiD) analysis was conducted to compare post-ACA changes in vascular surgery access for Western versus Southern regions. A total of 196,684 procedures (South) and 76,031 procedures (West) were included. The proportion of uninsured patients undergoing surgery in the West decreased from 6.8% pre-ACA to 3.4% post-ACA but increased from 7.3% pre-ACA to 10.2% post-ACA in the South (P < .001). A significantly greater proportion of vascular procedures were covered by Medicaid in the West (pre-ACA 19.8% vs post-ACA 37.1%) compared to the South (pre-ACA 12.9% vs post-ACA 24.8%; P < .001; Figure). Total charges were reduced in the West (median pre-ACA $65,601 [interquartile range (IQR), $84,893], post-ACA ($55,718 [IQR, $83,950]) compared to the South (pre-ACA $44,124 [IQR, $55,079], post-ACA $39.199 [IQR, 60,142]; P < .001). In regression analyses, the post-ACA relative risk (RR) of undergoing surgery in the West versus South for Medicaid patients demonstrated a higher proportion undergoing surgery on DiD for carotid endarterectomy (adjusted RR [aRR] 2.37 [standard error, 0.05]; P < .001), mAMP (aRR, 1.17 [standard error, 0.03]; P < .001) and TEVAR (aRR, 1.35 [standard error, 0.17]; P = .008), but the RR decreased on DiD for arteriovenous fistula/graft creation (aRR, 0.49 [standard error, 0.04]; P < .001) and peripheral vascular intervention (aRR, 0.85 [standard error, 0.03]; P < .001). There were no significant differences post-ACA implementation for AAA (P = .36), carotid artery stenting (P = .49), EVAR (P = .18), lower extremity revascularization (P = .23), and AMP (P = .59) (Table). Implementation of the ACA’s Medicaid expansion was associated with significant transformation in payer mix for vascular surgery and reduction in the median charges per patient; however, improving access to limb revascularization and reducing amputations continues to lag for Medicaid patients. Future research is needed to understand the impact of Medicaid expansion on individual patient level outcomes and population health measures.TableGeneralized linear model with modified Poisson regression comparing the likelihood of a Medicaid patient undergoing a given vascular procedure in the Western versus Southern Region (referent) stratified by pre-Affordable Care Act (ACA) implementation vs post-ACA implementation and adjusted for gender and race/ethnicityWestern regionSouthern regionPre versus Post DiDP valueINTERPRETATIONAdjusted RR post-ACASEP valueAdjusted RR post-ACASEP valueAAA0.950.11.640.800.09.01.36No significant differences in AAA occurrence post-ACAAVF/AVG0.490.04<.0010.510.04<.001<.001Significantly larger decrease in AVF/AVG in the West post-ACACEA2.370.05<.0011.440.04<.001<.001Significantly greater increase in CEA in the West post-ACACAS1.350.11.0051.170.09.06.49No significant differences in CAS occurrence post-ACAEVAR3.460.13<.0014.770.09<.001.18No significant difference in the increase of EVAR post-ACALER0.970.05.461.010.03.71.23No significant differences in LER occurrence post-ACAMinor AMP1.170.03<.0010.880.03<.001<.001Significantly greater increase in minor AMP in the West post-ACAMajor AMP1.030.04.430.790.03<.001.58No significant changes in major AMP post-ACAPVI0.850.03<.0011.240.02<.001<.001PVI decreased in the West but increased in the South post-ACATEVAR1.350.17.071.450.14.009.008Significantly greater increase in TEVAR in the West post-ACAAAA, Abdominal aortic aneurysm; AMP, amputation; AVF, arteriovenous fistula; AVG, arteriovenous graft; CAS, carotid artery stenting; CEA, carotid endarterectomy; DiD, difference-in-difference; EVAR, endovascular aortic aneurysm repair; LER, lower extremity revascularization; PVI, peripheral vascular intervention; RR, relative risk; TEVAR, thoracic endovascular aortic repair.ARR of undergoing the procedure in the West compared to the South and least squares means estimates describing difference-in-differences for Medicaid patients pre- and post-ACA expansion are reported. 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Assessment of residential exposures to agricultural pesticides: A scoping review.

The assessment of residential exposure to agricultural pesticides is a major issue for public health, regulatory and management purposes. In recent years, research into this field has developed considerably. The purpose of this scoping review is to provide an overview of scientific literature characterizing residential exposure to agricultural pesticides and to identify potential gaps in this research area. This work was conducted according to the JBI and PRISMA guidelines. Three databases were consulted. At least two experts selected the eligible studies. Our scoping review enabled us to identify 151 articles published between 1988 and 2019 dealing with the assessment of residential exposure to agricultural pesticides. Of these, 98 (64.9%) were epidemiological studies investigating possible links between pesticide exposure and the onset of adverse health effects, principally cancers and reproductive outcomes. They predominantly used Geographic Information Systems and sometimes surveys or interviews to calculate surrogate exposure metrics, the most common being the amounts of pesticides applied or the surface area of crops around the dwelling. Twenty-six (17.2%) were observational measurement studies conducted to quantify levels of pesticide exposure and identify their possible determinants. These studies assessed exposure by measuring pesticides in biological and environmental matrices, mostly in urines and house dust. Finally, we found only eight publications (5.3%) that quantified the risk to human health due to residential exposure for management purposes, in which exposure was mainly determined using probabilistic models. Pesticide exposure appears to be largely correlated with the spatial organization of agriculture activities in a territory. The determinants and routes of exposure remain to be explored to improve the conduct of epidemiological and risk assessment studies and to help prevent future exposures. Improvement could be expected from small-scale studies combining different methods of exposure assessment.

Comparison of Polycyclic Aromatic Hydrocarbons Exposure Across Occupations Using Urinary Metabolite 1-Hydroxypyrene.

Polycyclic aromatic hydrocarbons (PAHs) are well-known carcinogens causing lung and skin cancers in exposed workers. Certain occupations, such as coke production, have been associated with high PAH exposure; however, the number of occupations tested to date remains small. Here, we sought to compare PAH exposure across a wide range of occupations based on levels of 1-hydroxypyrene (1-OHP), the urinary exposure surrogate of PAHs. We collected urine 1-OHP data from the Korean National Environmental Health Survey (KoNEHS), a nationwide biomonitoring survey. We developed a linear regression model, controlling for sex, age, smoking, and survey cycle, and obtained resulting residuals. Then, we computed the fraction of exceeding the third quartile (Q3) level of residuals for each occupation, which is employed as a relative exposure indicator across occupations. A total of 15 125 measurements derived from three cycles of KoNEHS were used for analysis. The overall geometric means (GMs) and geometric standard deviation (GSD) of urine 1-OHP levels were 0.16 µg g-1 creatinine and 3.07, respectively. Among the sub-major occupational groups, 'construction and mining related elementary occupations' showed the highest fraction (0.45) of exceeding the Q3 level of residuals. Among the minor occupational groups, 'deliverers' showed a high fraction (0.42) of exceeding the Q3 level of residuals, which indicates rapidly growing occupations to be addressed. Our results provide ancillary information regarding PAH exposure across occupations, especially for occupations for which PAH exposure has not been well characterized.

Radiation engineering analysis of shielding materials to assess their ability to protect astronauts in deep space from energetic particle radiation

This paper explores the changes in the radiation quantity whole body effective dose equivalent (E) caused by galactic cosmic rays (GCRs) by varying position, geometry, material, and thickness of radiation shielding in order to determine possible launch characteristics of a vehicle design. The On-Line Tool for the Assessment of Radiation in Space (OLTARIS) was used to simulate deep space missions lasting 180 or 400 days with a mission radiation surrogate exposure limit of 150 mSv. Previous work used only spherical shielding; however, the shielding geometries investigated in this paper were right circular cylinders and spheres comprised of aluminum, polyethylene, liquid methane, water, and liquid hydrogen. Materials were evaluated individually, in multi-material pressure vessel mock-ups, and personal protection forms for individual astronauts. With single-material shielding, a single launch of shielding material to low Earth orbit (LEO) was possible for all materials for a 180 day mission, but insufficient for a 400 day mission. Multi-material and personal protection forms, as well, were found to be suitable for a 180 day mission, but not for a 400 day mission. Overall, no feasible designs in these analyses were able to meet the surrogate limit and protect an astronaut for 400 days.

Psychoactive pharmaceuticals in aquatic systems: A comparative assessment of environmental monitoring approaches for water and fish

Environmental monitoring and surveillance studies of pharmaceuticals routinely examine occurrence of substances without current information on human consumption patterns. We selected 10 streams with diverse annual flows and differentially influenced by population densities to examine surface water occurrence and fish accumulation of select psychoactive medicines, for which consumption is increasing in the Czech Republic. We then tested whether passive sampling can provide a useful surrogate for exposure to these substances through grab sampling, body burdens of young of year fish, and tissue specific accumulation of these psychoactive contaminants. We identified a statistically significant (p < 0.05) relationship between ambient grab samples and passive samplers in these streams when psychoactive contaminants were commonly quantitated by targeted liquid chromatography with tandem mass spectrometry, though we did not observe relationships between passive samplers and tissue specific pharmaceutical accumulation. We further observed smaller lotic systems with elevated contamination when municipal effluent discharges from more highly populated cities contributed a greater extent of instream flows. These findings identify the importance of understanding age and species specific differences in fish uptake, internal disposition, metabolism and elimination of psychoactive drugs across surface water quality gradients.

Fine-Scale Modeling of Individual Exposures to Ambient PM2.5, EC, NOx, CO for the Coronary Artery Disease and Environmental Exposure (CADEE) Study.

Air pollution epidemiological studies often use outdoor concentrations from central-site monitors as exposure surrogates, which can induce measurement error. The goal of this study was to improve exposure assessments of ambient fine particulate matter (PM2.5), elemental carbon (EC), nitrogen oxides (NOx), and carbon monoxide (CO) for a repeated measurements study with 15 individuals with coronary artery disease in central North Carolina called the Coronary Artery Disease and Environmental Exposure (CADEE) Study. We developed a fine-scale exposure modeling approach to determine five tiers of individual-level exposure metrics for PM2.5, EC, NOx, CO using outdoor concentrations, on-road vehicle emissions, weather, home building characteristics, time-locations, and time-activities. We linked an urban-scale air quality model, residential air exchange rate model, building infiltration model, global positioning system (GPS)-based microenvironment model, and accelerometer-based inhaled ventilation model to determine residential outdoor concentrations (Cout_home, Tier 1), residential indoor concentrations (Cin_home, Tier 2), personal outdoor concentrations (Cout_personal, Tier 3), exposures (E, Tier 4), and inhaled doses (D, Tier 5). We applied the fine-scale exposure model to determine daily 24-h average PM2.5, EC, NOx, CO exposure metrics (Tiers 1–5) for 720 participant-days across the 25 months of CADEE. Daily modeled metrics showed considerable temporal and home-to-home variability of Cout_home and Cin_home (Tiers 1–2) and person-to-person variability of Cout_personal, E, and D (Tiers 3–5). Our study demonstrates the ability to apply an urban-scale air quality model with an individual-level exposure model to determine multiple tiers of exposure metrics for an epidemiological study, in support of improving health risk assessments.