Early rhombic lip Protogenin+ve stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma.

We identify a population of Protogenin-positive (PRTG+ve) MYChigh NESTINlow stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RLVZ). Oncogenic transformation of early Prtg+ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG+ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RLVZ, a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTGhigh compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RLVZ PRTG+ve stem cells inhabiting a specific perivascular niche. Targeting the PRTGhigh compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB.

Failure of human rhombic lip differentiation underlies medulloblastoma formation.

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

Stereotactic radiosurgery versus whole brain radiotherapy in patients with intracranial metastatic disease and small-cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Patients with small-cell lung cancer (SCLC) are at high risk for intracranial metastatic disease (IMD). Although stereotactic radiosurgery (SRS) has supplanted whole brain radiotherapy (WBRT) as first-line treatment for IMD in most solid cancers, WBRT remains first-line treatment for IMD in patients with SCLC. We aimed to evaluate the efficacy of SRS in comparison with WBRT and assess treatment outcomes following SRS. METHODS: In this systematic review and meta-analysis, we searched MEDLINE, Embase, CENTRAL, and grey literature sources for controlled trials and cohort studies published in English reporting on SRS for IMD treatment in patients with SCLC from inception to March 23, 2022. Studies were excluded that did not report on SRS for IMD secondary to SCLC. Summary data were extracted. The primary outcome was overall survival, presented as pooled hazard ratios (HR) through random-effects meta-analysis for studies comparing SRS with WBRT with or without SRS boost, and as medians for single-arm SRS studies. This study is registered with the Open Science Framework, DOI 10.17605/OSF.IO/8M4HC, and PROSPERO, CRD42021258197. FINDINGS: Of 3823 identified records, 31 were eligible for inclusion; seven were included in the meta-analysis. Overall survival following SRS was longer than following WBRT with or without SRS boost (HR 0·85; 95% CI 0·75-0·97; n=7 studies; n=18 130 patients), or WBRT alone (0·77; 0·72-0·83; n=7 studies; n=16 961 patients), but not WBRT plus SRS boost (1·17, 0·78-1·75; n=4 studies; n=1167 patients). Using single-arm studies, pooled median overall survival from SRS was 8·99 months (95% CI 7·86-10·16; n=14 studies; n=1682 patients). Between-study heterogeneity was considerable when pooled among all comparative studies (I2=71·9%). INTERPRETATION: These results suggest survival outcomes are equitable following treatment with SRS compared with WBRT in patients with SCLC and IMD. Future prospective studies should focus on tumour burden and differences in local and distant intracranial progression between WBRT-treated and SRS-treated patients with SCLC. FUNDING: None.

Erythroblastic oncogene B-2 status and intracranial metastatic disease in patients with gastrointestinal cancer: a systematic review.

PURPOSE: The incidence of intracranial metastatic disease (IMD) in patients with gastrointestinal (GI) cancers is rising. Expression of the erythroblastic oncogene B-2 (ERBB2) is associated with an in increased risk of IMD in patients with breast cancer. The implications of ERBB2 expression for IMD risk in patients with GI cancers is less clear. The objective of this systematic review was to determine the incidence of IMD and OS in patients with ERBB2+ gastrointestinal cancers. METHODS: A literature search of MEDLINE, EMBASE, CENTRAL, and grey literature sources was conducted from date of database inception to July 2021. Included studies reported outcomes on patients with IMD secondary to ERBB2 GI cancers. RESULTS: Fourteen cohort studies met inclusion criteria, of which thirteen were retrospective. Eleven studies reported on gastric, esophageal, or gastroesophageal junction cancers. Three studies directly compared incidence of IMD based on ERBB2 status and among these, ERBB2+ patients had a higher incidence of IMD. One study indicated that ERBB2+ patients had significantly longer OS from the times of primary cancer (P = .015) and IMD diagnosis (P = .01), compared with patients with ERBB2- disease. CONCLUSIONS: In this systematic review, patients with ERBB2+ GI cancer were more likely to develop IMD. Future study is required on the prognostic and predictive value of ERBB2 status in patients with GI cancers.

Evaluating the Sensitivity of PM2.5-Mortality Associations to the Spatial and Temporal Scale of Exposure Assessment.

BACKGROUND: The temporal and spatial scales of exposure assessment may influence observed associations between fine particulate air pollution (PM2.5) and mortality, but few studies have systematically examined this question. METHODS: We followed 2.4 million adults in the 2001 Canadian Census Health and Environment Cohort for nonaccidental and cause-specific mortality between 2001 and 2011. We assigned PM2.5 exposures to residential locations using satellite-based estimates and compared three different temporal moving averages (1, 3, and 8 years) and three spatial scales (1, 5, and 10 km) of exposure assignment. In addition, we examined different spatial scales based on age, employment status, and urban/rural location, and adjustment for O3, NO2, or their combined oxidant capacity (Ox). RESULTS: In general, longer moving averages resulted in stronger associations between PM2.5 and mortality. For nonaccidental mortality, we observed a hazard ratio of 1.11 (95% CI = 1.08, 1.13) for the 1-year moving average compared with 1.23 (95% CI = 1.20, 1.27) for the 8-year moving average. Respiratory and lung cancer mortality were most sensitive to the spatial scale of exposure assessment with stronger associations observed at smaller spatial scales. Adjustment for oxidant gases attenuated associations between PM2.5 and cardiovascular mortality and strengthened associations with lung cancer. Despite these variations, PM2.5 was associated with increased mortality in nearly all of the models examined. CONCLUSIONS: These findings support a relationship between outdoor PM2.5 and mortality at low concentrations and highlight the importance of longer-exposure windows, more spatially resolved exposure metrics, and adjustment for oxidant gases in characterizing this relationship.

Disease assimilation: The mortality impacts of fine particulate matter on immigrants to Canada.

BACKGROUND: Immigrants make up 20% of the Canadian population; however, little is known about the mortality impacts of fine particulate matter (PM2.5) air pollution on immigrants compared with non-immigrants, or about how impacts may change with duration in Canada. DATA AND METHODS: This study used the 2001 Canadian Census Health and Environment Cohort, a longitudinal cohort of 3.5 million individuals, of which 764,000 were classified as immigrants (foreign-born). Postal codes from annual income tax files were used to account for mobility among respondents and to assign annual PM2.5 concentrations from 1998 to 2016. Exposures were estimated as a three-year moving average prior to the follow-up year. Cox survival models were used to determine hazard ratios (HRs) for cause-specific mortality, comparing the Canadian and foreign-born populations, with further stratification by year of immigration grouped into 10-year cohorts. RESULTS: Differences in urban-rural settlement patterns resulted in greater exposure to PM2.5 for immigrants compared with non-immigrants (mean = 9.3 vs. 7.5 µg/m3), with higher exposures among more recent immigrants. In fully adjusted models, immigrants had higher HRs per 10 µg/m3 increase in PM2.5 concentration compared with Canadian-born individuals for cardiovascular mortality (HR [95% confidence interval] = 1.22 [1.12 to 1.34] vs. 1.12 [1.07 to 1.18]) and cerebrovascular mortality (HR = 1.25 [1.03 to 1.52] vs. 1.03 [0.93 to 1.15]), respectively. However, tests for differences between the two groups were not significant when Cochran's Q test was used. No significant associations were found for respiratory outcomes, except for lung cancer in non-immigrants (HR = 1.10 [1.02 to 1.18]). When stratified by year of immigration, differences in HRs across varied by cause of death. DISCUSSION: In Canada, PM2.5 is an equal-opportunity risk factor, with immigrants experiencing similar if not higher mortality risks compared with non-immigrants for cardiovascular-related causes of death. Some notable differences also existed with cerebrovascular and lung cancer deaths. Continued reductions in air pollution, particularly in urban areas, will improve the health of the Canadian population as a whole.

Evaluation of a method to indirectly adjust for unmeasured covariates in the association between fine particulate matter and mortality.

BACKGROUND: Indirect adjustment via partitioned regression is a promising technique to control for unmeasured confounding in large epidemiological studies. The method uses a representative ancillary dataset to estimate the association between variables missing in a primary dataset with the complete set of variables of the ancillary dataset to produce an adjusted risk estimate for the variable in question. The objective of this paper is threefold: 1) evaluate the method for non-linear survival models, 2) formalize an empirical process to evaluate the suitability of the required ancillary matching dataset, and 3) test modifications to the method to incorporate time-varying exposure data, and proportional weighting of datasets. METHODS: We used the association between fine particle air pollution (PM2.5) with mortality in the 2001 Canadian Census Health and Environment Cohort (CanCHEC, N = 2.4 million, 10-years follow-up) as our primary dataset, and the 2001 cycle of the Canadian Community Health Survey (CCHS, N = 80,630) as the ancillary matching dataset that contained confounding risk factor information not available in CanCHEC (e.g., smoking). The main evaluation process used a gold-standard approach wherein two variables (education and income) available in both datasets were excluded, indirectly adjusted for, and compared to true models with education and income included to assess the amount of bias correction. An internal validation for objective 1 used only CanCHEC data, whereas an external validation for objective 2 replaced CanCHEC with the CCHS. The two proposed modifications were applied as part of the validation tests, as well as in a final indirect adjustment of four missing risk factor variables (smoking, alcohol use, diet, and exercise) in which adjustment direction and magnitude was compared to models using an equivalent longitudinal cohort with direct adjustment for the same variables. RESULTS: At baseline (2001) both cohorts had very similar PM2.5 distributions across population characteristics, although levels for CCHS participants were consistently 1.8-2.0 µg/m3 lower. Applying sample-weighting largely corrected for this discrepancy. The internal validation tests showed minimal downward bias in PM2.5 mortality hazard ratios of 0.4-0.6% using a static exposure, and 1.7-3% when a time-varying exposure was used. The external validation of the CCHS as the ancillary dataset showed slight upward bias of -0.7 to -1.1% and downward bias of 1.3-2.3% using the static and time-varying approaches respectively. CONCLUSIONS: The CCHS was found to be fairly well representative of CanCHEC and its use in Canada for indirect adjustment is warranted. Indirect adjustment methods can be used with survival models to correct hazard ratio point estimates and standard errors in models missing key covariates when a representative matching dataset is available. The results of this formal evaluation should encourage other cohorts to assess the suitability of ancillary datasets for the application of the indirect adjustment methodology to address potential residual confounding.

Low concentrations of fine particle air pollution and mortality in the Canadian Community Health Survey cohort.

BACKGROUND: Approximately 2.9 million deaths are attributed to ambient fine particle air pollution around the world each year (PM2.5). In general, cohort studies of mortality and outdoor PM2.5 concentrations have limited information on individuals exposed to low levels of PM2.5 as well as covariates such as smoking behaviours, alcohol consumption, and diet which may confound relationships with mortality. This study provides an updated and extended analysis of the Canadian Community Health Survey-Mortality cohort: a population-based cohort with detailed PM2.5 exposure data and information on a number of important individual-level behavioural risk factors. We also used this rich dataset to provide insight into the shape of the concentration-response curve for mortality at low levels of PM2.5. METHODS: Respondents to the Canadian Community Health Survey from 2000 to 2012 were linked by postal code history from 1981 to 2016 to high resolution PM2.5 exposure estimates, and mortality incidence to 2016. Cox proportional hazard models were used to estimate the relationship between non-accidental mortality and ambient PM2.5 concentrations (measured as a three-year average with a one-year lag) adjusted for socio-economic, behavioural, and time-varying contextual covariates. RESULTS: In total, 50,700 deaths from non-accidental causes occurred in the cohort over the follow-up period. Annual average ambient PM2.5 concentrations were low (i.e. 5.9 µg/m3, s.d. 2.0) and each 10 µg/m3 increase in exposure was associated with an increase in non-accidental mortality (HR = 1.11; 95% CI 1.04-1.18). Adjustment for behavioural covariates did not materially change this relationship. We estimated a supra-linear concentration-response curve extending to concentrations below 2 µg/m3 using a shape constrained health impact function. Mortality risks associated with exposure to PM2.5 were increased for males, those under age 65, and non-immigrants. Hazard ratios for PM2.5 and mortality were attenuated when gaseous pollutants were included in models. CONCLUSIONS: Outdoor PM2.5 concentrations were associated with non-accidental mortality and adjusting for individual-level behavioural covariates did not materially change this relationship. The concentration-response curve was supra-linear with increased mortality risks extending to low outdoor PM2.5 concentrations.

Diabetes Status and Susceptibility to the Effects of PM2.5 Exposure on Cardiovascular Mortality in a National Canadian Cohort.

BACKGROUND: Diabetes is infrequently coded as the primary cause of death but may contribute to cardiovascular disease (CVD) mortality in response to fine particulate matter (PM2.5) exposure. We analyzed all contributing causes of death to examine susceptibility of diabetics to CVD mortality from long-term exposure. METHODS: We linked a subset of the 2001 Canadian Census Health and Environment Cohort (CanCHEC) with 10 years of follow-up to all causes of death listed on death certificates. We used survival models to examine the association between CVD deaths (n = 123,500) and exposure to PM2.5 among deaths that co-occurred with diabetes (n = 20,600) on the death certificate. More detailed information on behavioral covariates and diabetes status at baseline available in the Canadian Community Health Survey (CCHS)-mortality cohort (n = 12,400 CVD deaths, with 2,800 diabetes deaths) complemented the CanCHEC analysis. RESULTS: Among CanCHEC subjects, comention of diabetes on the death certificate increased the magnitude of association between CVD mortality and PM2.5 (HR = 1.51 [1.39-1.65] per 10 µg/m) versus all CVD deaths (HR = 1.25 [1.21-1.29]) or CVD deaths without diabetes (HR = 1.20 [1.16-1.25]). Among CCHS subjects, diabetics who used insulin or medication (included as proxies for severity) had higher HR estimates for CVD deaths from PM2.5 (HR = 1.51 [1.08-2.12]) relative to the CVD death estimate for all respondents (HR = 1.31 [1.16-1.47]). CONCLUSIONS: Mention of diabetes on the death certificate resulted in higher magnitude associations between PM2.5 and CVD mortality, specifically among those who manage their diabetes with insulin or medication. Analyses restricted to the primary cause of death likely underestimate the role of diabetes in air pollution-related mortality. See video abstract at, http://links.lww.com/EDE/B408.

KCNQ1 p.L353L affects splicing and modifies the phenotype in a founder population with long QT syndrome type 1.

BACKGROUND: Variable expressivity and incomplete penetrance between individuals with identical long QT syndrome (LQTS) causative mutations largely remain unexplained. Founder populations provide a unique opportunity to explore modifying genetic effects. We examined the role of a novel synonymous KCNQ1 p.L353L variant on the splicing of exon 8 and on heart rate corrected QT interval (QTc) in a population known to have a pathogenic LQTS type 1 (LQTS1) causative mutation, p.V205M, in KCNQ1-encoded Kv7.1. METHODS: 419 adults were genotyped for p.V205M, p.L353L and a previously described QTc modifier (KCNH2-p.K897T). Adjusted linear regression determined the effect of each variant on QTc, alone and in combination. In addition, peripheral blood RNA was extracted from three controls and three p.L353L-positive individuals. The mutant transcript levels were assessed via qPCR and normalised to overall KCNQ1 transcript levels to assess the effect on splicing. RESULTS: For women and men, respectively, p.L353L alone conferred a 10.0 (p=0.064) ms and 14.0 (p=0.014) ms increase in QTc and in men only a significant interaction effect in combination with the p.V205M (34.6 ms, p=0.003) resulting in a QTc of ∼500 ms. The mechanism of p.L353L's effect was attributed to approximately threefold increase in exon 8 exclusion resulting in ∼25% mutant transcripts of the total KCNQ1 transcript levels. CONCLUSIONS: Our results provide the first evidence that synonymous variants outside the canonical splice sites in KCNQ1 can alter splicing and clinically impact phenotype. Through this mechanism, we identified that p.L353L can precipitate QT prolongation by itself and produce a clinically relevant interactive effect in conjunction with other LQTS variants.

Associations between fine particulate matter and mortality in the 2001 Canadian Census Health and Environment Cohort.

BACKGROUND: Large cohort studies have been used to characterise the association between long-term exposure to fine particulate matter (PM2.5) air pollution with non-accidental, and cause-specific mortality. However, there has been no consensus as to the shape of the association between concentration and response. METHODS: To examine the shape of this association, we developed a new cohort based on respondents to the 2001 Canadian census long-form. We applied new annual PM2.5 concentration estimates based on remote sensing and ground measurements for Canada at a 1km spatial scale from 1998 to 2011. We followed 2.4 million respondents who were non-immigrants aged 25-90 years and did not reside in an institution over a 10 year period for mortality. Exposures were assigned as a 3-year mean prior to the follow-up year. Income tax files were used to account for residential mobility among respondents using postal codes, with probabilistic imputation used for missing postal codes in the tax data. We used Cox survival models to determine hazard ratios (HRs) for cause-specific mortality. We also estimated Shape Constrained Health Impact Functions (a concentration-response function) for selected causes of death. RESULTS: In models stratified by age, sex, airshed, and population centre size, and adjusted for individual and neighbourhood socioeconomic variables, HR estimates for non-accidental mortality were HR = 1.18 (95% CI: 1.15-1.21) per 10µg/m3 increase in concentration. We observed higher HRs for cardiovascular disease (HR=1.25; 95% CI: 1.19-1.31), cardio-metabolic disease (HR = 1.27; 95% CI: 1.21-1.33), ischemic heart disease (HR = 1.36; 95% CI: 1.28-1.44) and chronic obstructive pulmonary disease (COPD) mortality (HR = 1.24; 95% CI: 1.11-1.39) compared to HR for all non-accidental causes of death. For non-accidental, cardio-metabolic, ischemic heart disease, respiratory and COPD mortality, the shape of the concentration-response curve was supra-linear, with larger differences in relative risk for lower concentrations. For both pneumonia and lung cancer, there was some suggestion that the curves were sub-linear. CONCLUSIONS: Associations between ambient concentrations of fine particulate matter and several causes of death were non-linear for each cause of death examined.

The reduction of birth weight by fine particulate matter and its modification by maternal and neighbourhood-level factors: a multilevel analysis in British Columbia, Canada.

BACKGROUND: The purpose of this research was to determine the relationship between modeled particulate matter (PM2.5) exposure and birth weight, including the potential modification by maternal risk factors and indicators of socioeconomic status (SES). METHODS: Birth records from 2001 to 2006 (N = 231,929) were linked to modeled PM2.5 data from a national land-use regression model along with neighbourhood-level SES and socio-demographic data using 6-digit residential postal codes. Multilevel random coefficient models were used to estimate the effects of PM2.5, SES and other individual and neighbourhood-level covariates on continuous birth weight and test interactions. Gestational age was modeled with a random slope to assess potential neighbourhood-level differences of its effect on birth weight and whether any between-neighbourhood variability can be explained by cross-level interactions. RESULTS: Models adjusted for individual and neighbourhood-level covariates showed a significant non-linear negative association between PM2.5 and birth weight explaining 8.5 % of the between-neighbourhood differences in mean birth weight. A significant interaction between SES and PM2.5 was observed, revealing a more pronounced negative effect of PM2.5 on birth weight in lower SES neighbourhoods. Further positive and negative modification of the PM2.5 effect was observed with maternal smoking, maternal age, gestational diabetes, and suspected maternal drug or alcohol use. The random intercept variance indicating between-neighbourhood birth weight differences was reduced by 75 % in the final model, while the random slope variance for between-neighbourhood gestational age effects remained virtually unchanged. CONCLUSION: We provide evidence that neighbourhood-level SES variables and PM2.5 have both independent and interacting associations with birth weight, and together account for 49 % of the between-neighbourhood differences in birth weight. Evidence of effect modification of PM2.5 on birth weight across various maternal and neighbourhood-level factors suggests that certain sub-populations may be more or less vulnerable to relatively low doses PM2.5 exposure.

Air pollution, neighbourhood and maternal-level factors modify the effect of smoking on birth weight: a multilevel analysis in British Columbia, Canada.

BACKGROUND: Maternal smoking during pregnancy negatively impacts fetal growth, but the effect is not homogenous across the population. We sought to determine how the relationship between cigarette use and fetal growth is modified by the social and physical environment. METHODS: Birth records with covariates were obtained from the BC Perinatal Database Registry (N = 232,291). Maternal smoking status was self-reported as the number of cigarettes smoked per day usually at the first prenatal care visit. Census dissemination areas (DAs) were used as neighbourhood-level units and linked to individual births using residential postal codes to assign exposure to particulate air pollution (PM2.5) and neighbourhood-level attributes such as socioeconomic status (SES), proportion of post-secondary education, immigrant density and living in a rural place. Random coefficient models were used with cigarettes/day modeled with a random slope to estimate its between-DA variability and test cross-level interactions with the neighbourhood-level variables on continuous birth weight. RESULTS: A significant negative and non-linear association was found between maternal smoking and birth weight. There was significant between-DA intercept variability in birth weight as well as between-DA slope variability of maternal smoking on birth weight of which 68 and 30 % respectively was explained with the inclusion of DA-level variables and their cross-level interactions. High DA-level SES had a strong positive association with birth weight but the effect was moderated with increased cigarettes/day. Conversely, heavy smokers showed the largest increases in birth weight with rising neighbourhood education levels. Increased levels of PM2.5 and immigrant density were negatively associated with birth weight, but showed positive interactions with increased levels of smoking. Older maternal age and suspected drug or alcohol use both had negative interactions with increased levels of maternal smoking. CONCLUSION: Maternal smoking had a negative and non-linear dose-response association with birth weight which was highly variable between neighbourhoods and evidence of effect modification with neighbourhood-level factors. These results suggest that focusing exclusively on individual behaviours may have limited success in improving outcomes without addressing the contextual influences at the neighbourhood-level. Further studies are needed to corroborate our findings and to understand how neighbourhood-level attributes interact with smoking to affect birth outcomes.

Identifying potential exposure reduction priorities using regional rankings based on emissions of known and suspected carcinogens to outdoor air in Canada.

BACKGROUND: Emissions inventories aid in understanding the sources of hazardous air pollutants and how these vary regionally, supporting targeted reduction actions. Integrating information on the relative toxicity of emitted pollutants with respect to cancer in humans helps to further refine reduction actions or recommendations, but few national programs exist in North America that use emissions estimates in this way. The CAREX Canada Emissions Mapping Project provides key regional indicators of emissions (total annual and total annual toxic equivalent, circa 2011) of 21 selected known and suspected carcinogens. METHODS: The indicators were calculated from industrial emissions reported to the National Pollutant Release Inventory (NPRI) and estimates of emissions from transportation (airports, trains, and car and truck traffic) and residential heating (oil, gas and wood), in conjunction with human toxicity potential factors. We also include substance-specific annual emissions in toxic equivalent kilograms and annual emissions in kilograms, to allow for ranking substances within any region. RESULTS: For provinces and territories in Canada, the indicators suggest the top five substances contributing to the total toxic equivalent emissions in any region could be prioritized for further investigation. Residents of Quebec and New Brunswick may be more at risk of exposure to industrial emissions than those in other regions, suggesting that a more detailed study of exposure to industrial emissions in these provinces is warranted. Residential wood smoke may be an important emission to control, particularly in the north and eastern regions of Canada. Residential oil and gas heating, along with rail emissions contribute little to regional emissions and therefore may not be an immediate regional priority. CONCLUSIONS: The developed indicators support the identification of pollutants and sources for additional investigation when planning exposure reduction actions among Canadian provinces and territories, but have important limitations similar to other emissions inventory-based tools. Additional research is required to evaluate how the Emissions Mapping Project is used by different groups and organizations with respect to informing actions aimed at reducing Canadians' potential exposure to harmful air pollutants.

The Impact of Chronic Disease on the Corrected QT (QTc) Value in Women in a British Columbia First Nations Population.

BACKGROUND: Indigenous women have higher rates of chronic disease than Indigenous men and non-Indigenous women. Long QT syndrome (LQTS) can be inherited or acquired; the latter may occur with chronic disease. A prolonged corrected QT value (QTc) is an independent risk factor for ventricular arrhythmias and sudden death, but few studies have quantified the impact of chronic disease on the QTc. We assessed the association between chronic disease and QTc prolongation in a population of First Nations women previously ascertained to study a high rate of inherited LQTS due to a unique genetic (founder) variant in their community. METHODS: This substudy focusing on women expands on the original research where patients with clinical features of LQTS and their relatives were assessed for genetic variants discovered to affect the QTc. Medical records were retrospectively reviewed and chronic diseases documented. Using multivariate linear regression, adjusting for the effect of genetic variants, age, and QTc-prolonging medications, we evaluated the association between chronic disease and the QTc. RESULTS: In total, 275 women were included. After adjustments, a prolonged QTc was associated with coronary artery disease (26.5 ms, 95% confidence interval [CI] 9.0-44.1 ms; P = 0.003), conduction system disease (26.8 ms, 95% CI 2.2-51.4 ms; P = 0.033), rheumatoid arthritis (28.9 ms, 95% CI 12.7-45.1 ms; P = 0.001), and type 2 diabetes mellitus (17.9 ms, 95% CI 3.6-32.3 ms; P = 0.015). CONCLUSIONS: This quantification of the association between chronic disease and QTc prolongation in an Indigenous cohort provides insight into the nongenetic determinants of QTc prolongation. Corroboration in other populations will provide evidence for generalisability of these results.

Re-examining prophylactic cranial irradiation in small cell lung cancer: a systematic review and meta-analysis.

Background: Patients with small cell lung cancer (SCLC) are at high risk for brain metastases. Prophylactic cranial irradiation (PCI) is recommended in this population to reduce the incidence of brain metastases and prolong survival. We aimed to assesses the efficacy of PCI in this population in the era of routine brain imaging. To our knowledge, this is the first systematic review and meta-analysis to examine the use among patients who were radiographically confirmed not to have brain metastases after completion of first-line therapy. Methods: In this systematic review and meta-analysis, cohort studies and controlled trials reporting on the use of PCI for patients SCLC were identified in EMBASE, MEDLINE, CENTRAL, and grey literature sources. The literature search was conducted on November 12, 2023. Summary data were extracted. Random-effects meta-analyses pooled hazard ratios (HR) for the primary outcome of overall survival between PCI and no intervention groups. This study is registered with the Open Science Framework, DOI:10.17605/OSF.IO/BC359, and PROSPERO, CRD42021249466. Findings: Of 4318 identified records, 223 were eligible for inclusion. 109 reported on overall survival in formats amenable to meta-analysis; PCI was associated with longer survival in all patients with SCLC (HR 0.59; 95% CI, 0.55-0.63; p < 0.001; n = 56,770 patients), patients with limited stage disease (HR 0.60; 95% CI, 0.55-0.65; p < 0.001; n = 78 studies; n = 27,137 patients), and patients with extensive stage disease (HR 0.59; 95% CI, 0.51-0.70; p < 0.001; n = 28 studies; n = 26,467 patients). Between-study heterogeneity was significant when pooled amongst all studies (I2 = 73.6%; 95% CI 68.4%-77.9%). Subgroup analysis did not reveal sources of heterogeneity. In a subgroup analysis on studies that used magnetic resonance imaging to exclude presence of brain metastases at restaging among all patients, overall survival did not differ significantly between patients who did or did not receive PCI (HR 0.74; 95% CI, 0.52-1.05; p = 0.08; n = 9 studies; n = 1384 patients). Interpretation: Our findings suggested that administration of PCI is associated with a survival benefit, but not when considering studies that radiographically confirmed absence of brain metastases, suggesting that the survival benefit conferred by PCI might be therapeutic rather than prophylactic. Funding: No funding.

Estimating the impacts of nonoptimal temperatures on mortality: A study in British Columbia, Canada, 2001-2021.

Background: Studies show that more than 5.1 million deaths annually are attributed to nonoptimal temperatures, including extreme cold and extreme heat. However, those studies mostly report average estimates across large geographical areas. The health risks attributed to nonoptimal temperatures in British Columbia (BC) are reported incompletely or limit the study area to urban centers. In this study, we aim to estimate the attributable deaths linked to nonoptimal temperatures in all five regional health authorities (RHAs) of BC from 2001 to 2021. Methods: We applied the widely used distributed lag nonlinear modeling approach to estimate temperature-mortality association in the RHAs of BC, using daily all-cause deaths and 1 × 1 km gridded daily mean temperature. We evaluated the model by comparing the model-estimated attributable number of deaths during the 2021 heat dome to the number of heat-related deaths confirmed by the British Columbia Coroners Service. Results: Overall, between 2001 and 2021, we estimate that 7.17% (95% empirical confidence interval = 3.15, 10.32) of deaths in BC were attributed to nonoptimal temperatures, the majority of which are attributed to cold. On average, the mortality rates attributable to moderate cold, moderate heat, extreme cold, and extreme heat were 47.04 (95% confidence interval [CI] = 45.83, 48.26), 0.94 (95% CI = 0.81, 1.08), 2.88 (95% CI = 2.05, 3.71), and 3.10 (95% CI = 1.79, 4.4) per 100,000 population per year, respectively. Conclusions: Our results show significant spatial variability in deaths attributable to nonoptimal temperatures across BC. We find that the effect of extreme temperatures is significantly less compared to milder nonoptimal temperatures between 2001 and 2021. However, the increased contribution of extreme heat cannot be ruled out in the near future.

A mild phenotype associated with KCNQ1 p.V205M mediated long QT syndrome in First Nations children of Northern British Columbia: effect of additional variants and considerations for management.

Introduction: Congenital Long QT Syndrome (LQTS) is common in a First Nations community in Northern British Columbia due to the founder variant KCNQ1 p.V205M. Although well characterized molecularly and clinically in adults, no data have been previously reported on the pediatric population. The phenotype in adults has been shown to be modified by a splice site variant in KCNQ1 (p.L353L). The CPT1A p.P479L metabolic variant, also common in Northern Indigenous populations, is associated with hypoglycemia and infant death. Since hypoglycemia can affect the corrected QT interval (QTc) and may confer risk for seizures (also associated with LQTS), we sought to determine the effect of all three variants on the LQTS phenotype in children within our First Nations cohort. Methods: As part of a larger study assessing those with LQTS and their relatives in a Northern BC First Nation, we assessed those entering the study from birth to age 18 years. We compared the corrected peak QTc and potential cardiac events (syncope/seizures) of 186 children from birth to 18 years, with and without the KCNQ1 (p.V205M and p.L353L) and CPT1A variants, alone and in combination. Linear and logistic regression and student t-tests were applied as appropriate. Results: Only the KCNQ1 p.V205M variant conferred a significant increase in peak QTc 23.8 ms (p < 0.001) above baseline, with females increased by 30.1 ms (p < 0.001) and males by 18.9 ms (p < 0.01). There was no evidence of interaction effects with the other two variants studied. Although the p.V205M variant was not significantly associated with syncope/seizures, the odds of having a seizure/syncope were significantly increased for those homozygous for CPT1A p.P479L compared to homozygous wild type (Odds Ratio [OR]3.0 [95% confidence interval (CI) 1.2-7.7]; p = 0.019). Conclusion: While the KCNQ1 p.V205M variant prolongs the peak QTc, especially in females, the CPT1A p.P479L variant is more strongly associated with loss of consciousness events. These findings suggest that effect of the KCNQ1 p.V205M variant is mild in this cohort, which may have implications for standard management. Our findings also suggest the CPT1A p.P479L variant is a risk factor for seizures and possibly syncope, which may mimic a long QT phenotype.

Association of Brain Metastases With Survival in Patients With Limited or Stable Extracranial Disease: A Systematic Review and Meta-analysis.

Importance: Intracranial metastatic disease (IMD) is a severe complication of cancer with profound prognostic implications. Patients with IMD in the setting of limited or stable extracranial disease (IMD-SE) may represent a unique and understudied subset of patients with IMD with superior prognosis. Objective: To evaluate overall survival (OS), progression-free survival (PFS), and intracranial PFS (iPFS) in patients with IMD-SE secondary to any primary cancer. Data Sources: Records were identified from MEDLINE, EMBASE, CENTRAL, and gray literature sources from inception to June 21, 2021. Study Selection: Studies in English reporting OS, PFS, or iPFS in patients with IMD-SE (defined as IMD and ≤2 extracranial metastatic sites) and no prior second-line chemotherapy or brain-directed therapy were selected. Data Extraction and Synthesis: Author, year of publication, type of study, type of primary cancer, and outcome measures were extracted. Random-effects meta-analyses were performed to estimate effect sizes, and subgroup meta-analysis and metaregression were conducted to measure between-study differences in February 2022. Main Outcomes and Measures: The primary end point was OS described as hazard ratios (HRs) and medians for comparative and single-group studies, respectively. Secondary end points were PFS and iPFS. Results: Overall, 68 studies (5325 patients) were included. IMD-SE was associated with longer OS (HR, 0.52; 95% CI, 0.39-0.70) and iPFS (HR, 0.63; 95% CI, 0.52-0.76) compared with IMD in the setting of progressive extracranial disease. The weighted median OS estimate for patients with IMD-SE was 17.9 months (95% CI, 16.4-22.0 months), and for patients with IMD-PE it was 8.0 months (95% CI, 7.2-12.8 months). Pooled median OS for all patients with IMD-SE was 20.9 months (95% CI, 16.35-25.98 months); for the subgroup with breast cancer it was 20.2 months (95% CI, 10.43-38.20 months), and for non-small cell lung cancer it was 27.5 months (95% CI, 18.27-49.66 months). Between-study heterogeneity for OS and iPFS were moderate (I2 = 56.5%) and low (I2 = 0%), respectively. Conclusions and Relevance: In this systematic review and meta-analysis of patients with IMD-SE, limited systemic disease was associated with improved OS and iPFS. Future prospective trials should aim to collect granular information on the extent of extracranial disease to identify drivers of mortality and optimal treatment strategies in patients with brain metastases.