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.

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.

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.

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.

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.

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.

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.

B cells migrate into remote brain areas and support neurogenesis and functional recovery after focal stroke in mice.

Lymphocytes infiltrate the stroke core and penumbra and often exacerbate cellular injury. B cells, however, are lymphocytes that do not contribute to acute pathology but can support recovery. B cell adoptive transfer to mice reduced infarct volumes 3 and 7 d after transient middle cerebral artery occlusion (tMCAo), independent of changing immune populations in recipient mice. Testing a direct neurotrophic effect, B cells cocultured with mixed cortical cells protected neurons and maintained dendritic arborization after oxygen-glucose deprivation. Whole-brain volumetric serial two-photon tomography (STPT) and a custom-developed image analysis pipeline visualized and quantified poststroke B cell diapedesis throughout the brain, including remote areas supporting functional recovery. Stroke induced significant bilateral B cell diapedesis into remote brain regions regulating motor and cognitive functions and neurogenesis (e.g., dentate gyrus, hypothalamus, olfactory areas, cerebellum) in the whole-brain datasets. To confirm a mechanistic role for B cells in functional recovery, rituximab was given to human CD20+ (hCD20+) transgenic mice to continuously deplete hCD20+-expressing B cells following tMCAo. These mice experienced delayed motor recovery, impaired spatial memory, and increased anxiety through 8 wk poststroke compared to wild type (WT) littermates also receiving rituximab. B cell depletion reduced stroke-induced hippocampal neurogenesis and cell survival. Thus, B cell diapedesis occurred in areas remote to the infarct that mediated motor and cognitive recovery. Understanding the role of B cells in neuronal health and disease-based plasticity is critical for developing effective immune-based therapies for protection against diseases that involve recruitment of peripheral immune cells into the injured brain.

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.

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.

Short-Chain Fatty Acids Improve Poststroke Recovery via Immunological Mechanisms.

Recovery after stroke is a multicellular process encompassing neurons, resident immune cells, and brain-invading cells. Stroke alters the gut microbiome, which in turn has considerable impact on stroke outcome. However, the mechanisms underlying gut-brain interaction and implications for long-term recovery are largely elusive. Here, we tested the hypothesis that short-chain fatty acids (SCFAs), key bioactive microbial metabolites, are the missing link along the gut-brain axis and might be able to modulate recovery after experimental stroke. SCFA supplementation in the drinking water of male mice significantly improved recovery of affected limb motor function. Using in vivo wide-field calcium imaging, we observed that SCFAs induced altered contralesional cortex connectivity. This was associated with SCFA-dependent changes in spine and synapse densities. RNA sequencing of the forebrain cortex indicated a potential involvement of microglial cells in contributing to the structural and functional remodeling. Further analyses confirmed a substantial impact of SCFAs on microglial activation, which depended on the recruitment of T cells to the infarcted brain. Our findings identified that microbiota-derived SCFAs modulate poststroke recovery via effects on systemic and brain resident immune cells.SIGNIFICANCE STATEMENT Previous studies have shown a bidirectional communication along the gut-brain axis after stroke. Stroke alters the gut microbiota composition, and in turn, microbiota dysbiosis has a substantial impact on stroke outcome by modulating the immune response. However, until now, the mediators derived from the gut microbiome affecting the gut-immune-brain axis and the molecular mechanisms involved in this process were unknown. Here, we demonstrate that short-chain fatty acids, fermentation products of the gut microbiome, are potent and proregenerative modulators of poststroke neuronal plasticity at various structural levels. We identified that this effect was mediated via circulating lymphocytes on microglial activation. These results identify short-chain fatty acids as a missing link along the gut-brain axis and as a potential therapeutic to improve recovery after stroke.

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.

IAT-TiMeS: Intra-Arterial Thrombectomy Transfer Metric Study in Texas.

OBJECTIVE: We aim to report intra-arterial thrombectomy transfer metrics for ischemic stroke patients that were transferred to hub hospitals for possible intra-arterial thrombectomy in multiple geographic regions throughout the state of Texas and to identify potential barriers and delays in the intra-arterial thrombectomy transfer process. METHOD: We prospectively collected data from 8 participating Texas comprehensive stroke/thrombectomy capable centers from 7 major regions in the State of Texas. We collected baseline clinical and imaging data related to the pre-transfer evaluation, transfer metrics, and post-transfer clinical and imaging data. RESULTS: A total of 103 acute ischemic stroke patients suspected/confirmed to have large vessel occlusions between December 2016 to May 2019 that were transferred to hubs as possible intra-arterial thrombectomy candidates were enrolled. A total of 56 (54%) patients were sent from the spoke to the hub via ground ambulance with 47 (46%) patients traveling via air ambulance. The median spoke arrival to hub arrival time was 174 min, median spoke arrival to departure from spoke was 131 min, and median travel time was 39 min. The spoke arrival time to transfer initiation was 68 min. CT-perfusion obtained at the spoke and earlier initiation of transfer were statistically associated with shorter transfer times. CONCLUSION: Transfer of intra-arterial thrombectomy patients in Texas may take over 4 h from spoke arrival to hub arrival. This time may be shortened by earlier transfer initiation and acceptance.

Exposure to ambient air pollution and the incidence of lung cancer and breast cancer in the Ontario Population Health and Environment Cohort.

Lung and female breast cancers are highly prevalent worldwide. Although the association between exposure to ambient fine particulate matter (PM2.5 ) and lung cancer has been recognized, there is less evidence for associations with other common air pollutants such as nitrogen dioxide (NO2 ) and ozone (O3 ). Even less is known about potential associations between these pollutants and breast cancer. We conducted a population-based cohort study to investigate the associations of chronic exposure to PM2.5 , NO2 , O3 and redox-weighted average of NO2 and O3 (Ox ) with incident lung and breast cancer, using the Ontario Population Health and Environment Cohort (ONPHEC), which includes all long-term residents aged 35-85 years who lived in Ontario, Canada, 2001-2015. Incident lung and breast cancers were ascertained using the Ontario Cancer Registry. Annual estimates of exposures were assigned to the residential postal codes of subjects for each year during follow-up. We used Cox proportional-hazards models adjusting for personal- and neighborhood-level covariates. Our cohorts for lung and breast cancer analyses included ~4.9 million individuals and ~2.5 million women, respectively. During follow-up, 100,146 incident cases of lung cancer and 91,146 incident cases of breast cancer were diagnosed. The fully adjusted analyses showed positive associations of lung cancer incidence with PM2.5 (hazard ratio [HR] = 1.02 [95% CI: 1.01-1.05] per 5.3 µg/m3 ) and NO2 (HR = 1.05 [95% CI: 1.03-1.07] per 14 ppb). No associations with lung cancer were observed for O3 or Ox . Relationships between PM2.5 and NO2 with lung cancer exhibited a sublinear shape. We did not find compelling evidence linking air pollution to breast cancer.

Long-term exposure to air pollution and the incidence of multiple sclerosis: A population-based cohort study.

BACKGROUND: Evidence of the adverse neurological effects of exposure to ambient air pollution is emerging, but little is known about its effect on the development of multiple sclerosis (MS), the most common autoimmune disease of the central nervous system. OBJECTIVES: To investigate the associations between MS incidence and long-term exposures to fine particles (PM2.5), nitrogen dioxide (NO2), and ozone (O3) METHODS: We conducted a population-based cohort study to investigate the associations between long-term exposures to PM2.5, NO2, and O3 and the incidence of MS. Our study population included all Canadian-born residents aged 20-40 years who lived in the province of Ontario, Canada from 2001 to 2013. Incident MS was ascertained from a validated registry. We assigned estimates of annual concentrations of these pollutants to the residential postal codes of subjects for each year during the 13 years of follow-up. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for each pollutant separately using random-effects Cox proportional hazards models. We conducted various sensitivity analyses, such as lagging exposure up to 5 years and adjusting for access to neurological care, annual average temperature, and population density. RESULTS: Between 2001 and 2013, we identified 6203 incident cases of MS. The adjusted HR of incident MS was 0.96 (95% CI: 0.86-1.07) for PM2.5, 0.91(95% CI: 0.81-1.02) for NO2, and 1.09 (95% CI: 0.98-1.23) for O3. These results were robust to various sensitivity analyses conducted. CONCLUSIONS: In this large population-based cohort, we did not observe significant associations between MS incidence and long-term exposures to PM2.5, NO2, and O3 in adults in Ontario, 2001-2013.

Gene-environment interactions involving functional variants: Results from the Breast Cancer Association Consortium.

Investigating the most likely causal variants identified by fine-mapping analyses may improve the power to detect gene-environment interactions. We assessed the interplay between 70 single nucleotide polymorphisms identified by genetic fine-scale mapping of susceptibility loci and 11 epidemiological breast cancer risk factors in relation to breast cancer. Analyses were conducted on up to 58,573 subjects (26,968 cases and 31,605 controls) from the Breast Cancer Association Consortium, in one of the largest studies of its kind. Analyses were carried out separately for estrogen receptor (ER) positive (ER+) and ER negative (ER-) disease. The Bayesian False Discovery Probability (BFDP) was computed to assess the noteworthiness of the results. Four potential gene-environment interactions were identified as noteworthy (BFDP < 0.80) when assuming a true prior interaction probability of 0.01. The strongest interaction result in relation to overall breast cancer risk was found between CFLAR-rs7558475 and current smoking (ORint = 0.77, 95% CI: 0.67-0.88, pint = 1.8 × 10-4 ). The interaction with the strongest statistical evidence was found between 5q14-rs7707921 and alcohol consumption (ORint =1.36, 95% CI: 1.16-1.59, pint = 1.9 × 10-5 ) in relation to ER- disease risk. The remaining two gene-environment interactions were also identified in relation to ER- breast cancer risk and were found between 3p21-rs6796502 and age at menarche (ORint = 1.26, 95% CI: 1.12-1.43, pint =1.8 × 10-4 ) and between 8q23-rs13267382 and age at first full-term pregnancy (ORint = 0.89, 95% CI: 0.83-0.95, pint = 5.2 × 10-4 ). While these results do not suggest any strong gene-environment interactions, our results may still be useful to inform experimental studies. These may in turn, shed light on the potential interactions observed.

Spatial variations in ambient ultrafine particle concentrations and the risk of incident prostate cancer: A case-control study.

BACKGROUND: Diesel exhaust contains large numbers of ultrafine particles (UFPs, <0.1µm) and is a recognized human carcinogen. However, epidemiological studies have yet to evaluate the relationship between UFPs and cancer incidence. METHODS: We conducted a case-control study of UFPs and incident prostate cancer in Montreal, Canada. Cases were identified from all main Francophone hospitals in the Montreal area between 2005 and 2009. Population controls were identified from provincial electoral lists of French Montreal residents and frequency-matched to cases using 5-year age groups. UFP exposures were estimated using a land use regression model. Exposures were assigned to residential locations at the time of diagnosis/recruitment as well as approximately 10-years earlier to consider potential latency between exposure and disease onset. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated per interquartile range (IQR) increase in UFPs (approximately 4000 particles/cm3) using logistic regression models adjusting for individual-level and ecological covariates. RESULTS: Ambient UFP concentrations were associated with an increased risk of prostate cancer (OR=1.10, 95% CI: 1.01, 1.19) in fully adjusted models when exposures were assigned to residences 10-years prior to diagnosis. This risk estimate increased slightly (OR=1.17, 95% CI; 1.01, 1.35) when modeled as a non-linear natural spline function. A smaller increased risk (OR=1.04, 95% CI: 0.97, 1.11) was observed when exposures were assigned to residences at the time of diagnosis. CONCLUSIONS: Exposure to ambient UFPs may increase the risk of prostate cancer. Future studies are needed to replicate this finding as this is the first study to evaluate this relationship.

The association between the incidence of postmenopausal breast cancer and concentrations at street-level of nitrogen dioxide and ultrafine particles.

BACKGROUND: There is scant information as to whether traffic-related air pollution is associated with the incidence of breast cancer. Nitrogen dioxide (NO2) and ultrafine particles (UFPs, <0.1µm), are two pollutants that capture intra-urban variations in traffic-related air pollution and may also be associated with incidence. METHODS: We conducted a population-based, case-control study of street-level concentrations of NO2 and UFPs and incident postmenopausal breast cancer in Montreal, Canada. 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 using 5-year age groups. Concentrations of NO2 and UFPs were estimated using two separate land-use regression models. Exposures were assigned to residential locations at the time of recruitment, and we identified residential histories of women who had lived in these residences for 10 years or more. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models adjusting for individual-level and ecological covariates. We assessed the functional form of NO2 and UFP exposures using natural cubic splines. RESULTS: We found that the functional form of the response functions between incident postmenopausal breast cancer and concentrations of NO2 and UFPs were consistent with linearity. For NO2, we found increasing risks of breast cancer for all subjects combined and stronger associations when analyses were restricted to those women who had lived at their current address for 10 years or more. Specifically, the OR, adjusted for personal covariates, per increase in the interquartile range (IQR=3.75 ppb) of NO2 was 1.08 (95%CI: 0.92-1.27). For women living in their homes for 10 years or more, the adjusted OR was 1.17 (95%CI: 0.93-1.46; IQR=3.84 ppb); for those not living at that home 10 years before the study, it was 0.93 (95%CI: 0.64, 1.36; IQR=3.65 ppb). For UFPs, the ORs were lower than for NO2, with little evidence of association in any of the models or sub-analyses and little variability in the ORs (about 1.02 for an IQR of ~3500cm-3). On the other hand, we found higher ORs amongst cases with positive oestrogen and progesterone receptor status; namely for NO2, the OR was 1.13 (95%CI: 0.94-1.35) and for UFPs it was 1.05 (95%CI: 0.96-1.14). CONCLUSIONS: Our findings suggest that exposure to ambient NO2 and UFPs may increase the risk of incident postmenopausal breast cancer especially amongst cases with positive oestrogen and progesterone receptor status.

Comparison of spatiotemporal prediction models of daily exposure of individuals to ambient nitrogen dioxide and ozone in Montreal, Canada.

BACKGROUND: In previous studies investigating the short-term health effects of ambient air pollution the exposure metric that is often used is the daily average across monitors, thus assuming that all individuals have the same daily exposure. Studies that incorporate space-time exposures of individuals are essential to further our understanding of the short-term health effects of ambient air pollution. OBJECTIVES: As part of a longitudinal cohort study of the acute effects of air pollution that incorporated subject-specific information and medical histories of subjects throughout the follow-up, the purpose of this study was to develop and compare different prediction models using data from fixed-site monitors and other monitoring campaigns to estimate daily, spatially-resolved concentrations of ozone (O3) and nitrogen dioxide (NO2) of participants' residences in Montreal, 1991-2002. METHODS: We used the following methods to predict spatially-resolved daily concentrations of O3 and NO2 for each geographic region in Montreal (defined by three-character postal code areas): (1) assigning concentrations from the nearest monitor; (2) spatial interpolation using inverse-distance weighting; (3) back-extrapolation from a land-use regression model from a dense monitoring survey, and; (4) a combination of a land-use and Bayesian maximum entropy model. We used a variety of indices of agreement to compare estimates of exposure assigned from the different methods, notably scatterplots of pairwise predictions, distribution of differences and computation of the absolute agreement intraclass correlation (ICC). For each pairwise prediction, we also produced maps of the ICCs by these regions indicating the spatial variability in the degree of agreement. RESULTS: We found some substantial differences in agreement across pairs of methods in daily mean predicted concentrations of O3 and NO2. On a given day and postal code area the difference in the concentration assigned could be as high as 131ppb for O3 and 108ppb for NO2. For both pollutants, better agreement was found between predictions from the nearest monitor and the inverse-distance weighting interpolation methods, with ICCs of 0.89 (95% confidence interval (CI): 0.89, 0.89) for O3 and 0.81 (95%CI: 0.80, 0.81) for NO2, respectively. For this pair of methods the maximum difference on a given day and postal code area was 36ppb for O3 and 74ppb for NO2. The back-extrapolation method showed a higher degree of disagreement with the nearest monitor approach, inverse-distance weighting interpolation, and the Bayesian maximum entropy model, which were strongly constrained by the sparse monitoring network. The maps showed that the patterns of agreement differed across the postal code areas and the variability depended on the pair of methods compared and the pollutants. For O3, but not NO2, postal areas showing greater disagreement were mostly located near the city centre and along highways, especially in maps involving the back-extrapolation method. CONCLUSIONS: In view of the substantial differences in daily concentrations of O3 and NO2 predicted by the different methods, we suggest that analyses of the health effects from air pollution should make use of multiple exposure assessment methods. Although we cannot make any recommendations as to which is the most valid method, models that make use of higher spatially resolved data, such as from dense exposure surveys or from high spatial resolution satellite data, likely provide the most valid estimates.

A structured review of panel studies used to investigate associations between ambient air pollution and heart rate variability.

INTRODUCTION: Dysfunction of the autonomic nervous system is one of the postulated pathways linking short-term exposure to air pollution to adverse cardiovascular outcomes. A hypothesis is that exposure to air pollution decreases heart rate variability, a recognized independent predictor of poorer cardiovascular prognosis. METHODS: We conducted a structured review of panel studies published between 1946 and July 2015 of the association between ambient air pollution and parameters of heart rate variability reflecting autonomic nervous function. We focused on exposure to mass concentrations of fine particles (PM2.5), nitrogen dioxide (NO2), and ozone (O3), and four commonly used indices of heart rate variability (HRV): standard deviation of all normal-to-normal intervals (SDNN); root mean square of successive differences in adjacent normal-to-normal intervals (RMSSD); high frequency power (HF); and low frequency power (LF). We searched bibliographic databases and references of identified articles and abstracted characteristics of their design and conduct, and synthesized the quantitative findings in graphic form according to health condition of the study population and the functional form of the HRV indices used in the regression analyses. RESULTS: A total of 33 panel studies were included: 31, 12, and 13 studies were used to investigate ambient exposure to PM2.5, NO2 and O3, respectively. We found substantial variation across studies in terms of design characteristics and statistical methodologies, and we identified some studies that may have had methodological and statistical issues. Because many panel studies were not comparable to each other, meta-analyses were not generally possible, although we were able to pool the results obtained amongst older adults who had cardiovascular disease for the 24-h average concentrations of PM2.5 prior to the heart rate variability measurements. In studies of PM2.5 among older adults with cardiovascular disease, logarithmic transformations of the HRV indices were used in ten studies. Negative associations across all HRV indices were found in 60-86% of these studies for periods of exposures ranging from 5-min to 5-days. The pooled percent changes for an increase of 10µg/m(3) in the 24-h prior to the measurements of HRV were: -2.11% for SDNN (95% confidence interval (95%CI): -4.00, -0.23%), -3.29% for RMSSD (95%CI: -6.32, -0.25%), -4.76% for LF (95%CI: -12.10, 2.58%), and -1.74% for HF (95%CI: -7.79, 4.31%). No transformations were used in seven studies of PM2.5 among older adults with cardiovascular disease, and we found for absolute differences pooled changes in the HRV indices, for an increase of 10µg/m(3), of -0.31ms for SDNN (95%CI: -1.02, 0.41ms) and -1.22ms for RMSSD (95%CI: -2.37; -0.07ms). For gaseous pollutants, negative associations over periods of exposure ranging from 5-min or to 5-days prior to the heart rate variability measurements were reported in 71-83% of studies of NO2 and 57-100% of studies of O3, depending of the indices of heart rate variability. However, many of these studies had statistical or methodological issues, and in the few studies without these issues the confidence intervals were relatively wide and mostly included the null. CONCLUSIONS AND DISCUSSION: We were not persuaded by the results that there was an association between PM2.5 and any of the four indices of heart rate variability. For NO2 and O3 the number of high-quality studies was insufficient to draw any definite conclusions. Further panel studies with improved design and methodologies are needed to help establish or refute an association between ambient exposure to air pollution and heart rate variability.