Care4Rare Canada: Outcomes from a decade of network science for rare disease gene discovery.

The past decade has witnessed a rapid evolution in rare disease (RD) research, fueled by the availability of genome-wide (exome and genome) sequencing. In 2011, as this transformative technology was introduced to the research community, the Care4Rare Canada Consortium was launched: initially as FORGE, followed by Care4Rare, and Care4Rare SOLVE. Over what amounted to three eras of diagnosis and discovery, the Care4Rare Consortium used exome sequencing and, more recently, genome and other 'omic technologies to identify the molecular cause of unsolved RDs. We achieved a diagnostic yield of 34% (623/1,806 of participating families), including the discovery of deleterious variants in 121 genes not previously associated with disease, and we continue to study candidate variants in novel genes for 145 families. The Consortium has made significant contributions to RD research, including development of platforms for data collection and sharing and instigating a Canadian network to catalyze functional characterization research of novel genes. The Consortium was instrumental to implementing genome-wide sequencing as a publicly funded test for RD diagnosis in Canada. Despite the successes of the past decade, the challenge of solving all RDs remains enormous, and the work is far from over. We must leverage clinical and 'omic data for secondary use, develop tools and policies to support safe data sharing, continue to explore the utility of new and emerging technologies, and optimize research protocols to delineate complex disease mechanisms. Successful approaches in each of these realms is required to offer diagnostic clarity to all families with RDs.

Impact of lowering fine particulate matter from major emission sources on mortality in Canada: A nationwide causal analysis.

Emissions of fine particulate matter (PM2.5) from human activities have been linked to substantial disease burdens, but evidence regarding how reducing PM2.5 at its sources would improve public health is sparse. We followed a population-based cohort of 2.7 million adults across Canada from 2007 through 2016. For each participant, we estimated annual mean concentrations of PM2.5 and the fractional contributions to PM2.5 from the five leading anthropogenic sources at their residential address using satellite observations in combination with a global atmospheric chemistry transport model. For each source, we estimated the causal effects of six hypothetical interventions on 10-y nonaccidental mortality risk using the parametric g-formula, a structural causal model. We conducted stratified analyses by age, sex, and income. This cohort would have experienced tangible health gains had contributions to PM2.5 from any of the five sources been reduced. Compared with no intervention, a 10% annual reduction in PM2.5 contributions from transportation and power generation, Canada's largest and fifth-largest anthropogenic sources, would have prevented approximately 175 (95%CI: 123-226) and 90 (95%CI: 63-117) deaths per million by 2016, respectively. A more intensive 50% reduction per year in PM2.5 contributions from the two sources would have averted 360 and 185 deaths per million, respectively, by 2016. The potential health benefits were greater among men, older adults, and low-income earners. In Canada, where PM2.5 levels are among the lowest worldwide, reducing PM2.5 contributions from anthropogenic sources by as little as 10% annually would yield meaningful health gains.

Powassan Virus Encephalitis after Tick Bite, Manitoba, Canada.

A case of Powassan encephalitis occurred in Manitoba, Canada, after the bite of a black-legged tick. Awareness of this emerging tickborne illness is needed because the number of vector tick species is growing. No specific treatment options exist, and cases with illness and death are high. Prevention is crucial.

Genomic Epidemiology of Large Blastomycosis Outbreak, Ontario, Canada, 2021.

Using phylogenomic analysis, we provide genomic epidemiology analysis of a large blastomycosis outbreak in Ontario, Canada, caused by Blastomyces gilchristii. The outbreak occurred in a locale where blastomycosis is rarely diagnosed, signaling a possible shift in geographically associated incidence patterns. Results elucidated fungal population genetic structure, enhancing understanding of the outbreak.

Salmonella Vitkin Outbreak Associated with Bearded Dragons, Canada and United States, 2020-2022.

We identified 2 cases of Salmonella enterica serovar Vitkin infection linked by whole-genome sequencing in infants in Ontario, Canada, during 2022. Both households of the infants reported having bearded dragons as pets. The outbreak strain was also isolated from an environmental sample collected from a patient's bearded dragon enclosure. Twelve cases were detected in the United States, and onset dates occurred during March 2021-September 2022 (isolates related to isolates from Canada within 0-9 allele differences by core-genome multilocus sequence typing). Most US patients (66.7%) were <1 year of age, and most (72.7%) had reported bearded dragon exposure. Hospitalization was reported for 5 (38.5%) of 13 patients. Traceback of bearded dragons identified at least 1 potential common supplier in Southeast Asia. Sharing rare serovar information and whole-genome sequencing data between Canada and the United States can assist in timely identification of outbreaks, including those that might not be detected through routine surveillance.

Body Louse Pathogen Surveillance among Persons Experiencing Homelessness, Canada, 2020-2021.

We analyzed body lice collected from persons experiencing homelessness in Winnipeg, Manitoba, Canada, during 2020-2021 to confirm vector species and ecotype and to identify louseborne pathogens. Of 556 lice analyzed from 7 persons, 17 louse pools (218 lice) from 1 person were positive for the louseborne bacterium Bartonella quintana.

SARS-CoV-2 Transmission in Alberta, British Columbia, and Ontario, Canada, January 2020-January 2022.

We estimated COVID-19 transmission potential and case burden by variant type in Alberta, British Columbia, and Ontario, Canada, during January 23, 2020-January 27, 2022; we also estimated the effectiveness of public health interventions to reduce transmission. We estimated time-varying reproduction number (Rt) over 7-day sliding windows and nonoverlapping time-windows determined by timing of policy changes. We calculated incidence rate ratios (IRRs) for each variant and compared rates to determine differences in burden among provinces. Rt corresponding with emergence of the Delta variant increased in all 3 provinces; British Columbia had the largest increase, 43.85% (95% credible interval [CrI] 40.71%-46.84%). Across the study period, IRR was highest for Omicron (8.74 [95% CrI 8.71-8.77]) and burden highest in Alberta (IRR 1.80 [95% CrI 1.79-1.81]). Initiating public health interventions was associated with lower Rt and relaxing restrictions and emergence of new variants associated with increases in Rt.

Wastewater Surveillance to Confirm Differences in Influenza A Infection between Michigan, USA, and Ontario, Canada, September 2022-March 2023.

Wastewater surveillance is an effective way to track the prevalence of infectious agents within a community and, potentially, the spread of pathogens between jurisdictions. We conducted a retrospective wastewater surveillance study of the 2022-23 influenza season in 2 communities, Detroit, Michigan, USA, and Windsor-Essex, Ontario, Canada, that form North America's largest cross-border conurbation. We observed a positive relationship between influenza-related hospitalizations and the influenza A virus (IAV) wastewater signal in Windsor-Essex (ρ = 0.785; p<0.001) and an association between influenza-related hospitalizations in Michigan and the IAV wastewater signal for Detroit (ρ = 0.769; p<0.001). Time-lagged cross correlation and qualitative examination of wastewater signal in the monitored sewersheds showed the peak of the IAV season in Detroit was delayed behind Windsor-Essex by 3 weeks. Wastewater surveillance for IAV reflects regional differences in infection dynamics which may be influenced by many factors, including the timing of vaccine administration between jurisdictions.

Case Series of Jamestown Canyon Virus Infections with Neurologic Outcomes, Canada, 2011-2016.

Jamestown Canyon virus (JCV) is a mosquitoborne orthobunyavirus in the California serogroup that circulates throughout Canada and the United States. Most JCV exposures result in asymptomatic infection or a mild febrile illness, but JCV can also cause neurologic diseases, such as meningitis and encephalitis. We describe a case series of confirmed JCV-mediated neuroinvasive disease among persons from the provinces of British Columbia, Alberta, Quebec, and Nova Scotia, Canada, during 2011-2016. We highlight the case definitions, epidemiology, unique features and clinical manifestations, disease seasonality, and outcomes for those cases. Two of the patients (from Quebec and Nova Scotia) might have acquired JCV infections during travel to the northeastern region of the United States. This case series collectively demonstrates JCV's wide distribution and indicates the need for increased awareness of JCV as the underlying cause of meningitis/meningoencephalitis during mosquito season.

Detection of OXA-181 Carbapenemase in Shigella flexneri.

We report the detection of OXA-181 carbapenemase in an azithromycin-resistant Shigella spp. bacteria in an immunocompromised patient. The emergence of OXA-181 in Shigella spp. bacteria raises concerns about the global dissemination of carbapenem resistance in Enterobacterales and its implications for the treatment of infections caused by Shigella bacteria.

Outbreak of Highly Pathogenic Avian Influenza A(H5N1) Virus in Seals, St. Lawrence Estuary, Quebec, Canada1.

We describe an unusual mortality event caused by a highly pathogenic avian influenza (HPAI) A(H5N1) virus clade 2.3.4.4b involving harbor (Phoca vitulina) and gray (Halichoerus grypus) seals in the St. Lawrence Estuary, Quebec, Canada, in 2022. Fifteen (56%) of the seals submitted for necropsy were considered to be fatally infected by HPAI H5N1 containing fully Eurasian or Eurasian/North American genome constellations. Concurrently, presence of large numbers of bird carcasses infected with HPAI H5N1 at seal haul-out sites most likely contributed to the spillover of infection to the seals. Histologic changes included meningoencephalitis (100%), fibrinosuppurative alveolitis, and multiorgan acute necrotizing inflammation. This report of fatal HPAI H5N1 infection in pinnipeds in Canada raises concerns about the expanding host of this virus, the potential for the establishment of a marine mammal reservoir, and the public health risks associated with spillover to mammals.Nous décrivons un événement de mortalité inhabituelle causé par un virus de l'influenza aviaire hautement pathogène A(H5N1) clade 2.3.4.4b chez des phoques communs (Phoca vitulina) et gris (Halichoerus grypus) dans l'estuaire du Saint-Laurent au Québec, Canada, en 2022. Quinze (56%) des phoques soumis pour nécropsie ont été considérés comme étant fatalement infectés par le virus H5N1 de lignées eurasiennes ou de réassortiment eurasiennes/nord-américaines. Un grand nombre simultané de carcasses d'oiseaux infectés par le H5N1 sur les sites d'échouement a probablement contribué à la contamination de ces phoques. Les changements histologiques associés à cette infection incluaient : méningo-encéphalite (100%), alvéolite fibrinosuppurée et inflammation nécrosante aiguë multi-organique. Cette documentation soulève des préoccupations quant à l'émergence de virus mortels, à la possibilité d'établissement de réservoirs chez les mammifères marins, et aux risques pour la santé publique associés aux propagations du virus chez les mammifères.

The association between neighborhood-level income and cancer stage at diagnosis and survival in Alberta.

BACKGROUND: Socioeconomic status (SES) is associated with a range of health outcomes, including cancer diagnosis and survival. However, the evidence for this association is inconsistent between countries with and without single-payer health care systems. In this study, the relationships between neighborhood-level income, cancer stage at diagnosis, and cancer-specific mortality in Alberta, Canada, were evaluated. METHODS: The Alberta Cancer Registry was used to identify all primary cancer diagnoses between 2010 and 2020. Average neighborhood income was determined by linking the Canadian census to postal codes and was categorized into quintiles on the basis of income distribution in Alberta. Multivariable multinomial logistic regression was used to model the association between income quintile and stage at diagnosis, and the Fine-Gray proportional subdistribution hazards model was used to estimate the association between SES and cancer-specific mortality. RESULTS: Out of the 143,818 patients with cancer included in the study, those in lower income quintiles were significantly more likely to be diagnosed at stage III (odds ratio [OR], 1.07; 95% CI [confidence interval], 1.06-1.09) or IV (OR, 1.12; 95% CI, 1.11-1.14) after adjusting for age and sex. Lower income quintiles also had significantly worse cancer-specific survival for breast, colorectal, liver, lung, non-Hodgkin lymphoma, oral cavity, pancreas, and prostate cancers. CONCLUSIONS: Disparities were observed in cancer outcomes across neighborhood-level income groups in Alberta, which demonstrates that health inequities by SES exist in countries with single-payer health care systems. Further research is needed to better understand the underlying causes and to develop strategies to mitigate these disparities.

Survival, treatment patterns, and costs of HER2+ metastatic breast cancer patients in Ontario between 2005 to 2020.

BACKGROUND: To enable the integration of novel therapies, it is critical to understand current long-term outcomes in HER2-positive metastatic breast cancer (mBC), including survival, treatment patterns, and costs. We sought to define these outcomes among patients with mBC in Ontario. METHODS: We conducted a retrospective population-level study in Ontario women diagnosed with breast cancer of any stage between January 1, 2005 and December 31, 2019, with follow-up until December 31, 2020. HER2-positivity was based on receipt of a HER2-targeted therapy (HER2-TT) in the first line (1L) metastatic setting. Administrative databases at ICES were used to assess outcomes. RESULTS: In Ontario, 2557 patients were diagnosed with mBC and received a HER2-TT, and of these 1606 were diagnosed with early-stage (stage I-III) that became metastatic (recurrent), while 951 were diagnosed with late stage/de novo mBC (stage IV). The average age of all patients was 54.8 years ± 12.7 years. Treatment regimens that included pertuzumab and trastuzumab (cohort name: pert_tras) were the most frequently used HER2-TT for 1L mBC (51.4%), while T-DM1 was the most frequent therapy (87.5%) in second line (2L). The median overall survival (mOS) from initiation of 1L pert_tras was not reached, whereas mOS from initiation of T-DM1 in 2L was 18.7 months. The overall mean cost per patient on pert_tras during 1L was $267,282. The main cost drivers were the cost of systemic therapy, followed by cancer clinic visits, with a mean cost per patient at $158,961 and $73,882, respectively. CONCLUSION: The baseline characteristics and treatment patterns for patients who received HER2-TT in our study align with previously reported results. However, the mOS observed for 2L T-DM1 was shorter than that found in pivotal, clinical trial literature. As expected, anti-cancer systemic therapy costs were the main contributor to the over quarter-million dollar mean cost per patient on pert_tras in 1L.

Trends in socioeconomic inequalities in breast cancer mortality in Canada: 1992-2019.

PURPOSE: Breast cancer is the second leading cause of death from cancer among Canadian females. This study aimed to quantify and assess trends in education and income inequalities in the mortality rate of breast cancer in Canada from 1992 to 2019. METHODS: We constructed a census division-level dataset pooled from the Canadian Vital Death Statistics Database (CVSD), the Canadian Census of the Population (CCP), and the National Household Survey (NHS) to examine trends in education and income inequalities in the mortality rate of breast cancer in Canada over the study period. The age-standardized Concentration index (C) was used to quantify income and education inequalities in breast cancer mortality over time. RESULTS: The national crude mortality rate of breast cancer has decreased in Canada from 1992 to 2019, with Alberta, British Columbia, Manitoba, Ontario, Prince Edward Island, and Quebec having the greatest decreases in mortality rate. The age-standardized C for education and income inequalities were always negative for all the study years, meaning that the mortality rate of breast cancer was higher among less-educated and poorer females. Moreover, the results indicate a growing trend in the concentration of breast cancer mortality among females with lower income and education from 1992 to 2019. CONCLUSION: The increasing concentration of breast cancer mortality among low socioeconomic status females remains a challenge in Canada. Continuous efforts are needed within Canadian healthcare system to improve the prevention and treatment of breast cancer for this population.

An updated assessment of hepatitis delta prevalence among adults in Canada: A meta-analysis.

Foreign-born (FB) persons represent a large proportion of adults with chronic hepatitis B (CHB) in Canada due to higher prevalence rates in countries of birth for FB persons. Suboptimal awareness and low rates of hepatitis delta virus (HDV) testing contribute to underdiagnosis and gaps in accurate estimates of Canada HDV prevalence. We aim to provide an assessment of CHB and HDV prevalence in Canada using a comprehensive literature review and meta-analysis. A comprehensive literature review of articles reporting HBsAg seroprevalence and anti-HDV prevalence was conducted to calculate country-specific rates and pooled prevalence of CHB and HDV using meta-analyses. Country-specific CHB and HDV rate estimates were combined with number of FB persons in Canada in 2021 from Statistics Canada to estimate total numbers of FB with CHB and HDV, respectively. These estimates were combined with estimates of Canada-born persons with CHB and HDV to yield the total number of persons with CHB and HDV. In 2021, we estimated 0.550 million (M) (95% CI 0.488-0.615) persons with CHB; 0.344 M (95% CI 0.288-0.401) were FB and 0.206 M (95% CI: 0.200-0.214) were Canada-born. The weighted average HDV prevalence among FB persons in Canada was 5.19% (17,848 [95% CI 9611-26,052] persons), among whom 50% emigrated from Asia and 31% from Africa. When combined with estimates of Canada-born persons with HDV, we estimate 35,059 (95% CI: 18,744-52,083) persons with HDV in Canada. In conclusion, we estimate 0.550 M and 35,059 persons living with CHB and HDV, respectively, in Canada in 2021.

Extreme wildfires in Canada and their contribution to global loss in tree cover and carbon emissions in 2023.

Canadian wildfires in 2023 were record breaking with wide-reaching impacts on people, nature, and climate. Extreme heat and low rainfall associated with climate change led to unprecedented forest fires that released enormous amounts of carbon as they burned. This study used data on fire-driven tree cover loss and forest carbon fluxes to estimate the total extent of stand-replacing forest fires and their associated carbon emissions. We found that the 2023 Canadian wildfires burned nearly 7.8 million hectares of forest and accounted for more than a quarter of all tree cover loss globally. Furthermore, forests impacted by wildfires emitted nearly 3 billion tons of CO2 or about 25% more carbon than all primary tropical tree cover loss that year. These results have important implications for global carbon budgets because emissions from these wildfires will largely be excluded from official greenhouse gas reporting.

Mapping the distance between fire hazard and disaster for communities in Canadian forests.

Communities interspersed throughout the Canadian wildland are threatened by fires that have become bigger and more frequent in some parts of the country in recent decades. Identifying the fireshed (source area) and pathways from which wildland fire may ignite and spread from the landscape to a community is crucial for risk-reduction strategy and planning. We used outputs from a fire simulation model, including fire polygons and rate of spread, to map firesheds, fire pathways and corridors and spread distances for 1980 communities in the forested areas of Canada. We found fireshed sizes are larger in the north, where the mean distances between ecumene and fireshed perimeters were greater than 10 km. The Rayleigh Z test indicated that simulated fires around a large proportion of communities show significant directional trends, and these trends are stronger in the Boreal Plains and Shields than in the Rocky Mountain area. The average distance from which fire, when spreading at the maximum simulated rate, could reach the community perimeter was approximately 5, 12 and 18 km in 1, 2 and 3 days, respectively. The average daily spread distances increased latitudinally, from south to north. Spread distances were the shortest in the Pacific Maritime, Atlantic Maritime and Boreal Plains Ecozones, implying lower rates of spread compared to the rest of the country. The fire corridors generated from random ignitions and from ignitions predicted from local fire history differ, indicating that factors other than fuel (e.g. fire weather, ignition pattern) play a significant role in determining the direction that fires burn into a community.

Adherence to Vitamin D Supplementation Recommendations for Breastfed Infants and Young Children: An Analysis of Canadian Community Health Survey Data Cycles From 2015 to 2018.

BACKGROUND: In Canada, nutrition policy, as outlined in the Nutrition for Healthy Term Infants recommendations, includes a daily vitamin D supplement of 10 µg (400 IU) for breastfed infants and young children to support adequate vitamin D status. OBJECTIVES: This study aimed to report on adherence to vitamin D supplementation recommendations for breastfed infants (≤12 months); and for children breastfed >12 mo. METHODS: Canadian Community Health Survey (paired-cycles 2015/2016 and 2017/2018) maternal experiences data for infants born 2012-2018 who received any breastmilk formed the sample (n = 7079). Whether the infant was given a vitamin D supplement (yes/no) and the frequency (daily/almost every day, 1-2/wk, or <1/wk) were surveyed. Weighted data (95% CI) were summarized according to breastfeeding history (exclusive to 6 mo and continuing; partial to 6 mo and continuing; and stopped ≤6 mo). Correlates of supplement adherence were explored using logistic regression. RESULTS: Overall, 87.1% (95% CI: 85.9%, 88.3%) of participants reported giving their infant (≤12 mo) a vitamin D supplement, and of these, 83.3% (95% CI: 81.9%, 84.7%) did so daily/almost every day, 12.4% (95% CI: 11.1%, 13.7%) did so 1-2/wk, and 4.3% (95% CI: 3.6%, 5.0%) did so <1/wk. Lower adjusted odds of adherence were observed among participants reporting: stopped breastfeeding ≤6 mo, lower education or income, recent immigration, and overweight prepregnancy body mass index; higher odds of adherence were observed in the western provinces. Regarding mothers of children >12 mo and breastfed (n = 2312), 58.0% (95% CI: 54.9%, 61.1%) gave a vitamin D supplement daily/almost every day. CONCLUSIONS: Adherence to providing a vitamin D supplement to breastfed infants is high in Canada. Nonetheless, we estimate that ∼27% of mothers are nonadherent to daily/almost every day administration of a vitamin D supplement and that adherence declines in children breastfed >12 mo. Further promotion to support uptake of the current guidance may be necessary, particularly for parents of recent immigration or lower socioeconomic status.

Qualitative analysis of Canadian blood and plasma donors' views on expanding donor screening eligibility for gay, bisexual, and other men who have sex with men.

BACKGROUND: In many countries, sexually active gay, bisexual and other men who have sex with men (gbMSM) continue to be screened based on their sex or gender and the sex or gender of their sexual partner. However, there is growing support that screening based on specific sexual behaviors that pose risk of transfusion transmissible infection is a better approach to donor screening. STUDY DESIGN AND METHODS: This paper reports results from Phase 1 (qualitative) of a mixed-methods study on Canadian blood and plasma donors' views on expanding eligibility for gbMSM by changing to sexual behavior-based screening. Semistructured interview data with 40 donors (whole blood = 20, plasma = 20; male = 21, female = 18, nonbinary = 1; mean age = 46.2; 10% participation rate) in Canada were analyzed using a thematic approach. RESULTS: All participants, except one, supported the change as they anticipated that at least one of three outcomes would be achieved: increasing blood supply, enhancing equity, and improving or maintaining the safety of blood supply. One donor who was more skeptical of the change questioned the scientific evidence for the change and indicated mistrust of state institutions. The discussion considers implications for blood operators' communication strategies that can be used to reduce donor discomfort with the changes to donor screening. CONCLUSION: In a nonrandom, purposive sample of 40 Canadian blood and plasma donors, most participants held favorable views regarding expanding the eligibility of gbMSM donors based on sexual risk behavior. Understanding donors' views on increasing eligibility may inform Canadian Blood Services and other blood operators as they develop their communications plans.

Prevalence and Temporal Trends of Epilepsy in Children: A Retrospective Birth Cohort Study.

OBJECTIVE: Epilepsy is one of the most common chronic neurologic diseases in children; however, few recent studies examine the prevalence of epilepsy and its evolution over time according to birth or maternal characteristics. The aim of the study was to examine the prevalence of epilepsy in children born between 2002 and 2020 and the temporal trends by year of birth, in Ontario, Canada, overall, and according to maternal and birth characteristics. METHODS: We included all in-hospital deliveries between 2002 and 2020 (N = 2,343,482) in Ontario, Canada, using linked administrative health dataset. We estimated the overall prevalence of epilepsy diagnosed before the age of 18 years, by birth and maternal characteristics. For temporal trend analyses, we restricted our population to children born up to 2012 (N = 1,405,271) and examined the prevalence of epilepsy diagnosed by age 8 by their year of birth, using Poisson regression. RESULTS: The overall prevalence of epilepsy in our cohort was 8.1 per 1,000 live births (95% CI: 8.0-8.2). Prevalence was higher for boys, for children born preterm, with congenital malformations, from multiple pregnancies, from mothers born in Canada, and for children living in deprived areas. Epilepsy prevalence diagnosed by age 8 increased slightly between 2002 and 2012 cohorts (6.9 [95% CI: 6.2-7.6] to 7.3 [95% CI: 6.6-8.1] per 1,000 live births, respectively). Differences by gestational age as gradient and socioeconomic characteristics were persistent and stable over time, while those by pregnancy plurality and sex decreased. SIGNIFICANCE: In a large population-based birth cohort in Canada, we observed a slight increase in epilepsy prevalence over time among children born in 2002 and those born in 2012 and persistent disparities by gestational age, socioeconomic position, and maternal immigration status. This study highlights the need for continued surveillance of rates to see if this increasing trend is persistent, to understand the potential causes behind it, and to understand the persistence of these disparities.