Door to needle time trends after transition to tenecteplase: A Multicenter Texas stroke registry.

BACKGROUND: Tenecteplase (TNK) is considered a promising option for the treatment of acute ischemic stroke (AIS) with the potential to decrease door-to-needle times (DTN). This study investigates DTN metrics and trends after transition to tenecteplase. METHODS: The Lone Star Stroke (LSS) Research Consortium TNK registry incorporated data from three Texas hospitals that transitioned to TNK. Subject data mapped to Get-With-the-Guidelines stroke variables from October 1, 2019 to March 31, 2023 were limited to patients who received either alteplase (ALT) or TNK within the 90 min DTN times. The dataset was stratified into ALT and TNK cohorts with univariate tables for each measured variable and further analyzed using descriptive statistics. Logistic regression models were constructed for both ALT and TNK to investigate trends in DTN times. RESULTS: In the overall cohort, the TNK cohort (n = 151) and ALT cohort (n = 161) exhibited comparable population demographics, differing only in a higher prevalence of White individuals in the TNK cohort. Both cohorts demonstrated similar clinical parameters, including mean NIHSS, blood glucose levels, and systolic blood pressure at admission. In the univariate analysis, no difference was observed in median DTN time within the 90 min time window compared to the ALT cohort [40 min (30-53) vs 45 min (35-55); P = .057]. In multivariable models, DTN times by thrombolytic did not significantly differ when adjusting for NIHSS, age (P = .133), or race and ethnicity (P = .092). Regression models for the overall cohort indicate no significant DTN temporal trends for TNK (P = .84) after transition; nonetheless, when stratified by hospital, a single subgroup demonstrated a significant DTN upward trend (P = 0.002). CONCLUSION: In the overall cohort, TNK and ALT exhibited comparable temporal trends and at least stable DTN times. This indicates that the shift to TNK did not have an adverse impact on the DTN stroke metrics. This seamless transition is likely attributed to the similarity of inclusion and exclusion criteria, as well as the administration processes for both medications. When stratified by hospital, the three subgroups demonstrated variable DTN time trends which highlight the potential for either fatigue or unpreparedness when switching to TNK. Because our study included a multi-ethnic cohort from multiple large Texas cities, the stable DTN times after transition to TNK is likely applicable to other healthcare systems.

Multicenter exploration of tenecteplase transition factors: A quantitative analysis.

BACKGROUND: Tenecteplase (TNK) is gaining recognition as a novel therapy for acute ischemic stroke (AIS). Despite TNK offering a longer half-life, time and cost saving benefits and comparable treatment and safety profiles to Alteplase (ALT), the adoption of TNK as a treatment for AIS presents challenges for hospital systems. OBJECTIVE: Identify barriers and facilitators of TNK implementation at acute care hospitals in Texas. METHODS: This prospective survey used open-ended questions and Likert statements generated from content experts and informed by qualitative research. Stroke clinicians and nurses working at 40 different hospitals in Texas were surveyed using a virtual platform. RESULTS: The 40 hospitals had a median of 34 (IQR 24.5-49) emergency department beds and 42.5 (IQR 23.5-64.5) inpatient stroke beds with 506.5 (IQR 350-797.5) annual stroke admissions. Fifty percent of the hospitals were Comprehensive Stroke Centers, and 18 (45 %) were solely using ALT for treatment of eligible AIS patients. Primary facilitators to TNK transition were team buy-in and a willingness of stroke physicians, nurses, and pharmacists to adopt TNK. Leading barriers were lack of clinical evidence supporting TNK safety profile inadequate evidence supporting TNK use and a lack of American Heart Association guidelines support for TNK administration in all AIS cases. CONCLUSION: Understanding common barriers and facilitators to TNK adoption can assist acute care hospitals deciding to implement TNK as a treatment for AIS. These findings will be used to design a TNK adoption Toolkit, utilizing implementation science techniques, to address identified obstacles and to leverage facilitators.

A qualitative study of barriers and facilitators to using tenecteplase to treat acute ischemic stroke.

BACKGROUND: Tenecteplase (TNK) is emerging as an alternative to alteplase (ALT) for thrombolytic treatment of acute ischemic stroke (AIS). Compared to ALT, TNK has a longer half-life, shorter administration time, lower cost, and similarly high efficacy in treating large vessel occlusion. Nevertheless, there are barriers to adopting TNK as a treatment for AIS. This study aimed to identify thematic barriers and facilitators to adopting TNK as an alternative to ALT as a thrombolytic for eligible AIS patients. METHODS: Qualitative research methodology using hermeneutic cycling and purposive sampling was used to interview four stroke clinicians in Texas. Interviews were recorded and transcribed verbatim. Enrollment was complete when saturation was reached. All members of the research team participated in content analysis during each cycle and in thematic analysis after saturation. RESULTS: Interviews were conducted between November 2022 and February 2023 with stroke center representatives from centers that either had successfully adopted TNK, or had not yet adopted TNK. Three themes and eight sub-themes were identified. The theme "Evidence" had three sub-themes: Pro-Con Balance, Fundamental Knowledge, and Pharmacotherapeutics. The theme "Process Flow" had four subthemes: Proactive, Reflective self-doubt, Change Process Barriers, and Parameter Barriers. The theme "Consensus" had one sub-theme: Getting Buy-In. CONCLUSION: Clinicians experience remarkably similar barriers and facilitators to adopting TNK. The results lead to a hypothesis that providing evidence to support a practice change, and identifying key change processes, will help clinicians achieve consensus across teams that need to 'buy in' to adopting TNK for AIS treatment.

Polymorphisms in genes of melatonin biosynthesis and signaling support the light-at-night hypothesis for breast cancer.

Light-at-night triggers the decline of pineal gland melatonin biosynthesis and secretion and is an IARC-classified probable breast-cancer risk factor. We applied a large-scale molecular epidemiology approach to shed light on the putative role of melatonin in breast cancer. We investigated associations between breast-cancer risk and polymorphisms at genes of melatonin biosynthesis/signaling using a study population of 44,405 women from the Breast Cancer Association Consortium (22,992 cases, 21,413 population-based controls). Genotype data of 97 candidate single nucleotide polymorphisms (SNPs) at 18 defined gene regions were investigated for breast-cancer risk effects. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CI) by logistic regression for the main-effect analysis as well as stratified analyses by estrogen- and progesterone-receptor (ER, PR) status. SNP-SNP interactions were analyzed via a two-step procedure based on logic regression. The Bayesian false-discovery probability (BFDP) was used for all analyses to account for multiple testing. Noteworthy associations (BFDP < 0.8) included 10 linked SNPs in tryptophan hydroxylase 2 (TPH2) (e.g. rs1386492: OR = 1.07, 95% CI 1.02-1.12), and a SNP in the mitogen-activated protein kinase 8 (MAPK8) (rs10857561: OR = 1.11, 95% CI 1.04-1.18). The SNP-SNP interaction analysis revealed noteworthy interaction terms with TPH2- and MAPK-related SNPs (e.g. rs1386483R ∧ rs1473473D ∧ rs3729931D: OR = 1.20, 95% CI 1.09-1.32). In line with the light-at-night hypothesis that links shift work with elevated breast-cancer risks our results point to SNPs in TPH2 and MAPK-genes that may impact the intricate network of circadian regulation.

The association between the incidence of postmenopausal breast cancer and occupational exposure to selected organic solvents, Montreal, Canada, 2008-2011.

BACKGROUND: Breast cancer is the most diagnosed cancer among women and recognized risk factors explain 25%-47% of cases. Organic solvents are used widely in the workplace and exposure may increase the risk of developing breast cancer, yet there are insufficient data to confirm this hypothesis. We sought to determine whether past occupational exposures to selected organic solvents were associated with the incidence of invasive breast cancer in postmenopausal women in Montréal, Canada. METHODS: From a population-based case-control study (2008-2011), using in-depth interviews we elicited information on risk factors and lifetime occupational histories. Industrial hygienists and chemists translated job descriptions into specific chemical and physical exposures. We assessed 11 individual solvents and four solvent groups. Unconditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for metrics of past exposures to selected solvents. Exposure metrics included any previous exposure, average frequency in hours per week, duration in years, and average cumulative concentration weighted by hours per workweek exposed. RESULTS: We enrolled 695 cases and 608 controls. We found increased ORs for average cumulative concentration of exposure to mononuclear aromatic hydrocarbons (OR: 1.52, 95% CI: 1.04, 2.28), chlorinated alkanes (OR: 2.42, 95% CI: 1.23, 5.68), toluene (OR: 1.59, 95% CI: 1.02, 2.59), and a group of organic solvents with reactive metabolites (OR: 1.53, 95% CI: 1.08, 2.24). Positive associations were found across all exposure metrics and were higher among women with estrogen-positive/progesterone-negative tumors. CONCLUSION: Our findings suggest occupational exposure to certain organic solvents may increase the risk of incident postmenopausal breast cancer.

The association between the incidence of Lyme disease in the USA and indicators of greenness and land cover.

Lyme disease (LD) is the most common vector-borne illness in the USA. Incidence is related to specific environmental conditions such as temperature, metrics of land cover, and vertebrate species diversity. To determine whether greenness, as measured by the Normalized Difference Vegetation Index (NDVI), and other selected indices of land cover were associated with the incidence of LD in the northeastern USA for the years 2000-2018, we conducted an ecological analysis of incidence rates of LD in counties of 15 "high" incidence states and the District of Columbia for 2000-2018. Annual counts of LD by county were obtained from the US Centers for Disease Control and values of NDVI were acquired from the Moderate Resolution Imaging Spectroradiometer instrument aboard Terra and Aqua Satellites. County-specific values of human population density, area of land and water were obtained from the US Census. Using quasi-Poisson regression, multivariable associations were estimated between the incidence of LD, NDVI, land cover variables, human population density, and calendar year. We found that LD incidence increased by 7.1% per year (95% confidence interval: 6.8-8.2%). Land cover variables showed complex non-linear associations with incidence: average county-specific NDVI showed a "u-shaped" association, the standard deviation of NDVI showed a monotonic upward relationship, population density showed a decreasing trend, areas of land and water showed "n-shaped" relationships. We found an interaction between average and standard deviation of NDVI, with the highest average NDVI category; increased standard deviation of NDVI showed the greatest increase in rates. These associations cannot be interpreted as causal but indicate that certain patterns of land cover may have the potential to increase exposure to infected ticks and thereby may contribute indirectly to increased rates of LD. Public health interventions could make use of these results in informing people where risks may be high.

Translocation of bacterial LPS is associated with self-reported cognitive abilities in men living with HIV receiving antiretroviral therapy.

BACKGROUND: Gut damage allows translocation of bacterial lipopolysaccharide (LPS) and fungal ß-D-glucan (BDG) into the blood. This microbial translocation contributes to systemic inflammation and risk of non-AIDS comorbidities in people living with HIV, including those receiving antiretroviral therapy (ART). We assessed whether markers of gut damage and microbial translocation were associated with cognition in ART-treated PLWH. METHODS: Eighty ART-treated men living with HIV from the Positive Brain Health Now Canadian cohort were included. Brief cognitive ability measure (B-CAM) and 20-item patient deficit questionnaire (PDQ) were administered to all participants. Three groups were selected based on their B-CAM levels. We excluded participants who received proton pump inhibitors or antiacids in the past 3 months. Cannabis users were also excluded. Plasma levels of intestinal fatty acid binding protein (I-FABP), regenerating islet-derived protein 3 α (REG3α), and lipopolysaccharides (LPS = were quantified by ELISA, while 1-3-ß-D-glucan BDG) levels were assessed using the Fungitell assay. Univariable, multivariable, and splines analyses were performed. RESULTS: Plasma levels of I-FABP, REG3α, LPS and BDG were not different between groups of low, intermediate and high B-CAM levels. However, LPS and REG3α levels were higher in participants with PDQ higher than the median. Multivariable analyses showed that LPS association with PDQ, but not B-CAM, was independent of age and level of education. I-FABP, REG3α, and BDG levels were not associated with B-CAM nor PDQ levels in multivariable analyses. CONCLUSION: In this well characterized cohort of ART-treated men living with HIV, bacterial but not fungal translocation was associated with presence of cognitive difficulties. These results need replication in larger samples.

Using Operant Reach Chambers to Assess Mouse Skilled Forelimb Use After Stroke.

Skilled forelimb reaching and grasping are important components of rodent motor performance. The isometric pull task can serve as a tool for quantifying forelimb function following stroke or other CNS injury as well as in forelimb rehabilitation. This task has been extensively developed for use in rats. Here, we describe methods of setup and training of an operant reach chamber for mice. Using a reward of peanut oil, mice are adaptively trained to pull a handle positioned slightly outside of an operant chamber, with automated recording of the number of attempts, force generated, success rate, and latency to maximal force.

A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: application to BRCA1 and BRCA2.

A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance.

Ambient exposures to selected volatile organic compounds and the risk of prostate cancer in Montreal.

Little is known about environmental factors that may increase the risk of prostate cancer. We estimated associations between incident prostate cancer and environmental concentrations of five ambient volatile organic compounds (VOCs): benzene; n-decane; ethylbenzene; hexane; and 1,2,4-trimethylbenzene. Methods: This study is based on a population-based case-control study of incident prostate cancer (PROtEuS) in men ≤ 75 years of age living in Montreal, Canada, in 2005 to 2012. We included 1172 cases and 1177 population controls. We had personal information, lifetime residential addresses, occupational exposures, and a variety of area-wide covariables. We inferred concentrations of the five VOCs using Bayesian geostatistical models using data from a dense environmental survey conducted in Montreal in 2005 to 2006. We used different sets of adjustments to estimate odds ratios (OR) and confidence intervals. Results: We found nonlinear associations such that the ORs increased monotonically and then either flattened or fell off with increased exposures. The model that contained other environmental variables and contextual variables led to lower ORs and results were similar when we restricted analyses to controls recently screened or tested for prostate cancer or cases with low- or high-grade tumors. A change from the 5th to 25th percentile in mean environmental benzene levels led to an adjusted OR of 2.00 (95% confidence interval = 1.47, 2.71). Conclusion: We found positive associations between prostate cancer and concentrations of benzene and ethylbenzene, independently of previous testing for prostate cancer or tumor grade, suggesting that exposure to certain ambient VOCs may increase incidence.

Spatial modeling of ambient concentrations of volatile organic compounds in Montreal, Canada.

Volatile organic compounds (VOCs) are components of the complex mixture of air pollutants within cities and can cause various adverse health effects. Therefore, it is necessary to understand their spatial distribution for exposure assessment in epidemiological studies. Objectives: The objective was to model measured concentrations of five VOCs within the city of Montreal, Canada, developing spatial prediction models that can be used in health studies. Methods: We measured concentrations using 3M 3500 Organic Vapor Monitors, over 2-week periods, for three monitoring campaigns between 2005 and 2006 in over 130 locations in the city. Using GC/MSD (Gas Chromatography/Mass Selective Detector), we measured concentrations of benzene, n-decane, ethylbenzene, hexane, and trimethylbenzene. We fitted four different models that combine land-use regression and geostatistical methods to account for the potential spatial structure that remains after accounting for the land-use variables. The fitted models also accounted for possible variations in the concentration of air pollutants across campaigns. Results: The highest concentrations for all VOCs were found in December with hexane being the most abundant followed by ethylbenzene. We obtained predicted surfaces for the VOCs for the three campaigns and mean surfaces across campaigns. We found higher concentrations of some VOCs along highways and in the Eastern part of Montreal, which is a highly industrialized area. Conclusions: Each of the fitted models captured the spatial and across-campaigns variability for each VOC, and we found that different VOCs required different model structures.

LZK-dependent stimulation of astrocyte reactivity promotes corticospinal axon sprouting.

Injury to the adult mammalian central nervous system induces compensatory plasticity of spared axons-referred to as collateral axon sprouting-that can facilitate neural recovery. The contribution of reactive astrocytes to axon sprouting remains elusive. Here, we sought to investigate the role of axon degeneration-reactive astrocytes in the regulation of collateral axon sprouting that occurs in the mouse spinal cord after unilateral photothrombotic stroke of the primary motor cortex. We identified astrocytic leucine zipper-bearing kinase (LZK) as a positive regulator of astrocyte reactivity to corticospinal axon degeneration. Remarkably, genetic stimulation of astrocyte reactivity, via LZK overexpression in adult astrocytes, enhanced corticospinal axon sprouting. LZK promoted the production of astrocyte-derived ciliary neurotrophic factor (CNTF) that likely enhanced axon growth in mice with astrocytic LZK overexpression after injury. Our finding that LZK-dependent stimulation of astrocyte reactivity promotes corticospinal axon sprouting highlights the potential of engineering astrocytes to support injury-induced axon plasticity for neural repair.

A genome-wide gene-based gene-environment interaction study of breast cancer in more than 90,000 women.

Background: Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene-environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this. Methods: We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P<0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test. Results: After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (PGXE=4.44×10-6). Conclusion: In this transcriptome-informed genome-wide gene-environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk. Impact: Our study suggests a limited role of gene-environment interactions in breast cancer risk.

Long-term exposure to fine particulate matter and ozone and the onset of systemic autoimmune rheumatic diseases: an open cohort study in Quebec, Canada.

OBJECTIVES: To estimate associations between fine particulate matter (PM2.5) and ozone and the onset of systemic autoimmune rheumatic diseases (SARDs). METHODS: An open cohort of over 6 million adults was constructed from provincial physician billing and hospitalization records between 2000 and 2013. We defined incident SARD cases (SLE, Sjogren's syndrome, scleroderma, polymyositis, dermatomyositis, polyarteritis nodosa and related conditions, polymyalgia rheumatic, other necrotizing vasculopathies, and undifferentiated connective tissue disease) based on at least two relevant billing diagnostic codes (within 2 years, with at least 1 billing from a rheumatologist), or at least one relevant hospitalization diagnostic code. Estimated PM2.5 and ozone concentrations (derived from remote sensing and/or chemical transport models) were assigned to subjects based on residential postal codes, updated throughout follow-up. Cox proportional hazards models with annual exposure levels were used to calculate hazard ratios (HRs) for SARDs incidence, adjusting for sex, age, urban-versus-rural residence, and socioeconomic status. RESULTS: The adjusted HR for SARDS related to one interquartile range increase in PM2.5 (3.97 µg/m3) was 1.12 (95% confidence interval 1.08-1.15), but there was no clear association with ozone. Indirectly controlling for smoking did not alter the findings. CONCLUSIONS: We found associations between SARDs incidence and PM2.5, but no relationships with ozone. Additional studies are needed to better understand interplays between the many constituents of air pollution and rheumatic diseases.

Outcomes From a Nursing-Driven Acute Stroke Care Protocol for Telehealth Encounters.

INTRODUCTION: Nursing care is widely recognized to be a vital element in stroke care delivery. However, no publications examining clinical education and optimal workflow practices as predictors of acute ischemic stroke care metrics exist. This study aimed to explore the impact of a nurse-led workflow to improve patient care that included telestroke encounters in the emergency department. METHODS: A nonrandomized prospective pre- and postintervention unit-level feasibility study design was used to explore how implementing nurse-driven acute stroke care affects the efficiency and quality of telestroke encounters in the emergency department. Nurses and providers in the emergency department received education/training, and then the Nursing-Driven Acute Ischemic Stroke Care protocol was implemented. RESULTS: There were 180 acute ischemic stroke encounters (40.3%) in the control phase and 267 (59.7%) in the postintervention phase with similar demographic characteristics. Comparing the control with intervention times directly affected by the nurse-driven protocol, there was a significant reduction in median door-to-provider times (5 [interquartile range 12] vs 2 [interquartile range 9] minutes, P < .001) and in median door-to-computed tomography scan times (9 [interquartile range 18] vs 5 [interquartile range 11] minutes, P < .001); however, the metrics potentially affected by extraneous variables outside of the nurse-driven protocol demonstrated longer median door-to-ready times (21 [interquartile range 24] vs 25 [interquartile range 25] minutes, P < .001). Door-to-specialist and door-to-needle times were not significantly different. DISCUSSION: In this sample, implementation of the nurse-driven acute stroke care protocol is associated with improved nurse-sensitive stroke time metrics but did not translate to faster delivery of thrombolytic agents for acute ischemic stroke, emphasizing the importance of well-outlined workflows and standardized stroke code protocols at every point in acute ischemic stroke care.

Ecological studies of COVID-19 and air pollution: How useful are they?

BACKGROUND: Results from ecological studies have suggested that air pollution increases the risk of developing and dying from COVID-19. Drawing causal inferences from the measures of association reported in ecological studies is fraught with challenges given biases arising from an outcome whose ascertainment is incomplete, varies by region, time, and across sociodemographic characteristics, and cannot account for clustering or within-area heterogeneity. Through a series of analyses, we illustrate the dangers of using ecological studies to assess whether ambient air pollution increases the risk of dying from, or transmitting, COVID-19. METHODS: We performed an ecological analysis in the continental United States using county-level ambient concentrations of fine particulate matter (PM2.5) between 2000 and 2016 and cumulative COVID-19 mortality counts through June 2020, December 2020, and April 2021. To show that spurious associations can be obtained in ecological data, we modeled the association between PM2.5 and the prevalence of human immunodeficiency virus (HIV). We fitted negative binomial models, with a logarithmic offset for county-specific population, to these data. Natural cubic splines were used to describe the shape of the exposure-response curves. RESULTS: Our analyses revealed that the shape of the exposure-response curve between PM2.5 and COVID-19 changed substantially over time. Analyses of COVID-19 mortality through June 30, 2021, suggested a positive linear relationship. In contrast, an inverse pattern was observed using county-level concentrations of PM2.5 and the prevalence of HIV. CONCLUSIONS: Our analyses indicated that ecological analyses are prone to showing spurious relationships between ambient air pollution and mortality from COVID-19 as well as the prevalence of HIV. We discuss the many potential biases inherent in any ecological-based analysis of air pollution and COVID-19.

The association between the incidence of post-menopausal breast cancer and residential greenness.

BACKGROUND: There is little data as to whether exposure to residential greenness is associated with the incidence of breast cancer. Lack of physical activity and obesity are two of the accepted risk factors for postmenopausal breast cancer and living near green areas may contribute to an active lifestyle and maintaining a normal body mass index and, consequently, residential greenness may be associated with lower incidence rates. OBJECTIVES: The objective of this study was to determine whether there was an association between past exposure to residential greenness and the incidence of invasive postmenopausal breast cancer among Canadian women living in Montreal, Quebec, in the mid-2000s. METHODS: We conducted a population-based, case-control study of incident postmenopausal breast cancer in Montreal, Canada, and herein we show analyses by level of greenness surrounding participants' homes. Incident cases were identified between 2008 and 2011 from all but one hospital that treated breast cancer in the Montreal area. Population controls were identified from provincial electoral lists of Montreal residents and frequency-matched to cases on age. Residential greenness was estimated using the maximum daily normalized difference vegetation index averaged over the growing season ("maximum NDVI"). Maximum NDVI was assigned at the home address of recruitment for the years 1992-1998 (about 15 years before diagnosis), and we measured subjects' personal information, exposure to NO2 and ultrafine particles, and area-wide variables to control for potential confounding effects. Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer associated with residential greenness were estimated using logistic regression models adjusting for various combinations of potential confounders. We assessed the functional form of maximum NDVI using natural cubic splines. RESULTS: We found that the response functions between incident postmenopausal breast cancer and maximum NDVI were consistent with linearity. The age-adjusted and fully-adjusted ORs, per increase in the interquartile range (IQR=0.13) of maximum NDVI measured with a 250 m buffer around residences, were 0.95 (95%CI: 0.86-1.04) and 1.00 (95%CI: 0.84-1.11), respectively. For maximum NDVI measured using a 1000 m buffer (IQR=0.05), these were 0.98 (95%CI: 0.94-1.02) and 0.99 (95%CI: 0.95-1.03), respectively. CONCLUSIONS: Our findings suggest that exposure to NDVI evaluated where participants were interviewed is not associated with the risk of incident postmenopausal breast cancer.

Household determinants of biocontaminant exposures in Canadian homes.

Exposure to biocontaminants, such as dust mites, animal dander, bacteria, and mold, is associated with a range of health effects. This study identified household characteristics associated with indoor biocontaminant loadings in four Canadian cities. Floor dust was collected in 290 Canadian homes in Edmonton, Halifax, Montreal, and Windsor. The dust samples were analyzed for house dust mite allergens (Der f 1 and Der p 1), cat allergen (Fel d 1), cockroach allergen (Bla g 1), beta-(1,3)-D-glucan, and endotoxin. Household information was obtained through questionnaires and home inspections. We performed univariate and multivariate analyses to identify household determinants of biocontaminant loadings and mold odor presence. We observed large regional variations for all biocontaminants, except for cockroach allergen. The ranges of the contaminants measured in loadings and concentrations were similar to that of previous Canadian studies. Household characteristics including presence of carpeting, low floor cleaning frequency, older home age, presence of pets, and indoor relative humidity above 45% were positively associated with the presence of multiple indoor biocontaminants. High floor cleaning frequency and use of dehumidifiers were negatively associated with the presence of multiple indoor biocontaminants. Mold odor was positively associated with older home age, past water damage, and visible mold growth.

Sex-Specific Effects of Prenatal and Early Life Inorganic and Methylated Arsenic Exposure on Atherosclerotic Plaque Development and Composition in Adult ApoE-/- Mice.

BACKGROUND: Epidemiologic studies indicate that early life arsenic exposures are linked to an increased risk of cardiovascular diseases. Different oxidation and methylation states of arsenic exist in the environment and are formed in vivo via the action of arsenic (+3 oxidation state) methyltransferase (As3MT). Methylated arsenicals are pro-atherogenic postnatally, but pre- and perinatal effects are unclear. This is particularly important because methylated arsenicals are known to cross the placenta. OBJECTIVES: We tested the effects of early life exposure to inorganic and methylated arsenicals on atherosclerotic plaque formation and its composition in apolipoprotein E knock-out (apoE-/-) mice and evaluated whether apoE-/- mice lacking As3MT expression were susceptible to this effect. METHODS: We exposed apoE-/- or apoE-/-/As3MT-/- mice to 200 ppb inorganic or methylated arsenic in the drinking water from conception to weaning and assessed atherosclerotic plaques in the offspring at 18 wk of age. Mixed regression models were used to estimate the mean difference in each outcome relative to controls, adjusting for sex and including a random effects term to account for within-litter clustering. RESULTS: Early life exposure to inorganic arsenic, and more profoundly methylated arsenicals, resulted in significantly larger plaques in the aortic arch and sinus in both sexes. Lipid levels in these plaques were higher without a substantial difference in macrophage numbers. Smooth muscle cell content was not altered, but collagen content was lower. Importantly, there were sex-specific differences in these observations, where males had higher lipids and lower collagen in the plaque, but females did not. In mice lacking As3MT, arsenic did not alter the plaque size, although the size was highly variable. In addition, control apoE-/-/As3MT-/- mice had significantly larger plaque size compared with control apoE-/-. CONCLUSION: This study shows that early life exposure to inorganic and methylated arsenicals is pro-atherogenic with sex-specific differences in plaque composition and a potential role for As3MT in mice. https://doi.org/10.1289/EHP8171.

Delayed diapedesis of CD8 T cells contributes to long-term pathology after ischemic stroke in male mice.

OBJECTIVE: Stroke is a debilitating disorder with significant annual mortality and morbidity rates worldwide. Immune cells are recruited to the injured brain within hours after stroke onset and can exhibit either protective or detrimental effects on recovery. However, immune cells, including CD8 T cells, persist in the injured brain for weeks, suggesting a longer-term role for the adaptive immune system during functional recovery. The aim of this study was to determine if the delayed secondary diapedesis of CD8 T cells into the ischemic brain negatively impacts functional recovery after transient ischemic stroke in male mice. RESULTS: Mice exhibited an increased number of leukocytes in the ipsilesional hemispheres at 14 days (3-fold; p < 0.001) and 30 days (2.2-fold; p = 0.02) after transient middle cerebral artery occlusion (tMCAo) compared to 8 days post-tMCAo, at which time acute neuroinflammation predominantly resolves. Moreover, mice with higher ipsilesional CD8 T cells at 30 days (R2 = 0.52, p < 0.01) exhibited worse functional recovery. To confirm a detrimental role of chronic CD8 T cell diapedesis on recovery, peripheral CD8 T cells were depleted beginning 10 days post-tMCAo. Delayed CD8 T cell depletion improved motor recovery on the rotarod (F(1,28) = 4.264; p = 0.048) compared to isotype control-treated mice. CD8 T cell-depleted mice also exhibited 2-fold (p < 0.001) reduced leukocyte infiltration at 30 days post-tMCAo. Specifically, macrophage, neutrophil, and CD4 T cell numbers were reduced in the ipsilesional hemisphere of the CD8 T cell-depleted mice independent of inflammatory status of the post-stroke CNS (e.g. microglial phenotype and cytokine production). RNAseq identified a unique profile for brain infiltrating CD8 T cells at 30 days post-tMCAo, with 46 genes differentially expressed relative to CD8 T cells at 3 days post-tMCAo. CONCLUSION: Our data reveal a role for CD8 T cells in the chronic phase post-stroke that can be therapeutically targeted. We demonstrate long-term CD8 T cell recruitment into the ipsilesional hemisphere that affects both immune cell numbers present in the injured brain and functional recovery through one month after stroke onset.