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Reducing treatment burden is a priority for people with cystic fibrosis, whose health has benefited from using new modulators that substantially increase CFTR protein function. The SIMPLIFY study aimed to assess the effects of discontinuing nebulised hypertonic saline or dornase alfa in individuals using the CFTR modulator elexacaftor plus tezacaftor plus ivacaftor (ETI).The SIMPLIFY study included two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials at 80 participating clinics across the USA in the Cystic Fibrosis Therapeutics Development Network. We included individuals with cystic fibrosis aged 12-17 years with percent predicted FEVFrom Aug 25, 2020, to May 25, 2022, a total of 672 unique participants were screened for eligibility for one or both trials, resulting in 847 total random assignments across both trials with 594 unique participants. 370 participants were randomly assigned in the hypertonic saline trial and 477 in the dornase alfa trial. Participants across both trials had an average ppFEVIn individuals with cystic fibrosis on ETI with relatively well preserved pulmonary function, discontinuing daily hypertonic saline or dornase alfa for 6 weeks did not result in clinically meaningful differences in pulmonary function when compared with continuing treatment.

ObjectivesGiven the impact of colonization and responding to Canada’s Truth and Reconciliation Commission, we aimed to provide baseline measures of First Nations children’s health and social outcomes in Manitoba, Canada. We also aimed to create a research process where Indigenous and non-Indigenous researchers work collaboratively and in culturally safe ways. ApproachWe formed a team consisting of members of First Nation organizations and academic researchers. Knowledge Keepers from Anishinaabe, Cree, Anishininew, Dakota and Dene Nations guided the study, interpreted results and ensured meaningful knowledge translation. This retrospective cohort study utilized population-based health, social services, education and justice administrative data that allowed de-identified individual-level linkages across all databases through a scrambled health number. Adjusted rates and rate ratios were calculated using a generalized liner modeling approach to compare First Nations children (n=61,726) and all other Manitoba children (n=279,087) and comparing First Nations children living on and off-reserve. ResultsLarge disparities between First Nations and other Manitoba children were found in birth outcomes, physical and mental health, health services, education, social services, justice system involvement and mortality. First Nations infants had higher rates of preterm births, large-for-gestational-age births, newborn readmissions to hospital and lower rates of breastfeeding initiation compared with other Manitoba infants. Suicide rates among First Nations adolescents were ten times higher than among other adolescents in Manitoba, yet we found few differences in diagnosis of mood and anxiety disorders between the groups. First Nations children were also seven times more likely to apprehended by child protection services and youth were ten times more likely to be criminally accused. Knowledge Keepers offered their perspectives on these findings. ConclusionThese findings demonstrate that an enormous amount of work is required in virtually every area – health, social, education and justice – to improve First Nations children’s lives. There is an urgent need for equitable access to services, and these services should be self-determined, planned and implemented by First Nations people.

ObjectivesPAX, a mental health promotion approach, has been shown to decrease negative mental health outcomes and improve academic achievement. These effects have yet to be shown among Indigenous children. We evaluated PAX for improving First Nations children’s outcomes following a research process wherein community members and researchers work more collaboratively. ApproachBuilding on a long-term relationship with Swampy Cree Tribal Council, community members, First Nations leaders and researchers worked together through all phases of the project. This cluster randomized controlled trial used population-based health, social services, and education administrative data that allowed de-identified individual-level linkages across all databases through a scrambled health number. Our cohort of 725 children from 20 First Nations schools were randomized to PAX (n=469, 11 schools) or wait-list control (n=256, 9 schools). We used propensity score weighting and multi-level modeling to estimate the differences over time (2011 up to 2020) between children exposed to PAX and those who were not. ResultsDifferences in baseline characteristics were found between the two groups of children, despite the cluster randomization. After applying propensity score weights, children in the PAX group had significantly greater decreases in conduct problems (β:-1.08, standard error(se):0.2505, p

ObjectivesOver three decades ago, the Aboriginal Justice Inquiry identified structural racism in Canada’s justice system. Although rates of youth criminal charges and incarcerations have declined substantially since then, it is unclear whether First Nations youth are treated differently than non-First Nations youth for similar offences. Our study addressed this question. ApproachThis retrospective cohort study of youth born 1991-2001 and living in Manitoba between ages 12-17 used whole-population linked administrative data to identify youth charged with a crime (N=13,543). First Nations youth (n=7,081) were compared with all other Manitoba (AOM) youth (n=6,462) on whether their criminal charge proceeded or was dropped, deferred or diverted. The study applied an intersectionality theoretical framework. Individual (age, type and severity of charge, ever in child protection care, youth and/or mother diagnosed mental disorder, maternal incarceration, number of siblings, urban/rural residence) and social strata (First Nations identity, income, sex) factors were adjusted for using multi-level models. ResultsAfter accounting for other factors, First Nations youth had a higher risk of a charge proceeding than AOM (adjusted Relative Risk (aRR) 1.16, 95% CI 1.12-1.20). There was no difference in charges proceeding for male First Nations youth compared with male AOM, whereas among females, the risk was greater for First Nations (aRR 1.31, 95% CI 1.26-1.36). Low income and a history of being in the care of the child protection system increased the risk of charges proceeding for AOM only (aRR 1.16, 95% CI 1.13-1.18; aRR 1.13, 95% CI 1.07-1.20); for First Nations, there was no increased risk of charges proceeding associated with these intersecting factors. ConclusionThese findings provide quantitative evidence of the intersecting structural racism in the youth criminal justice system previously identified by First Nations leaders. Future research will follow this cohort to determine whether more judicial sanctions are applied to First Nations youth throughout the justice process, including within criminal courts and corrections.

IntroductionRoutine health care information systems only capture a portion of violence against women because some victimized women may not seek health care and some events may not require medical attention. Population-based estimates of the risk of violent injury (VI) among women with a history of intimate partner victimization (IPV) are lacking. Objectives and ApproachTo determine the risk of violent injury following IPV among women living in Manitoba, Canada, 2004-2016. Linked administrative justice, healthcare, and social databases were used. Exposure began after a woman was first involved with the Manitoba Justice system as a victim of IPV, assessed through provincial prosecution and disposition records. IPV victims (n= 20,469) were matched to three non-victims (n= 61,407) on age, relationship status and place of residence at the date of the IPV incident. The main outcomes were first health care use for violent injury and violent death. Outcomes were assessed through emergency department, hospital and vital statistics records. Conditional Cox Regression was used to obtain Hazard Ratios with 95% confidence intervals (CI). ResultsThe crude risk of VI was 8.5 per 1000 women among non-victims and 55.8 among victims of IPV. Compared to non-victims, IPV victims were 3.8 [95% confidence interval (CI): 3.4, 4.3] times more likely to suffer IIIO and 4.5 [95% CI: 2.3, 9.0] times to have a violent death, after adjustment. Victims had approximately half the risk of VI if the accused is on probation. Conclusion / ImplicationsJustice System-identified victims of IPV are at higher risk of assault and violent death than women not exposed to IPV. Justice involvement represents an opportunity for prevention of violent injury and homicide among IPV victims.

IntroductionChildren who have a history of involvement in child protection services (CPS) are over-represented in the youth and adult criminal justice systems. There are significant health and socioeconomic implications for individuals involved in either or both CPS and the justice system. Understanding the ‘overlap’ between these two systems would provide insight into the health and social needs of this population. This protocol describes a research programme on the relationship between the child welfare and the youth justice systems, looking specifically at the population involved in both CPS and the youth justice system. We will examine the characteristics associated with involvement in these systems, justice system trajectories of individuals with a history of CPS involvement and early adult outcomes of children involved in both systems.Methods and analysisAdministrative data sets will be linked at the individual level for three cohorts born 1991, 1994 and 1998 in Manitoba, Canada. Involvement in CPS will be categorised as ‘placed in out-of-home care’, ‘received in-home services, but was not placed in care’ or ‘no involvement’. Involvement in the youth justice system will be examined through contacts with police between ages 12 and 17 that either led to charges or did not proceed. Individual, maternal and neighbourhood characteristics will be examined to identify individuals at greatest risk of involvement in one or both systems.Ethics and disseminationThe study was approved by the University of Manitoba Health Research Ethics Board and permission to access data sets has been granted by all data providers. We also received approval for the study from the First Nations Health and Social Secretariat of Manitoba’s Health Information Research Governance Committee and the Manitoba Metis Federation. Strategies to disseminate study results will include engagement of stakeholders and policymakers through meetings and workshops, scientific publications and presentations, and social media.

IntroductionManitoba Public Health Nurses (PHNs) attempt to visit all families with newborns shortly after discharge from birth hospitalizations. Since 2000, PHNs have completed the Families First Screen (FFS) at these visits, to identify families at risk for child maltreatment. The information captured in FFS is a valuable tool for research. Objectives and ApproachOur objective was to clean and validate FFS data and link to health data in the Manitoba repository in order to determine the percent of births in Manitoba hospitals that had FFS. We identified all babies born in Manitoba hospitals 2000-2015 using ICD-9-CM /ICD-10-CA codes. Mothers were identified through the Health Registry (Mom_Baby Link File) using scrambled Personal Health Identification Numbers (sPHINs). FFS data were linked to births via baby’s sPHIN. Determining which FFS records linked to babies required several steps of cleaning and validating the data to account for differences in birthdates between files, missing sPHINs, and multiple records. ResultsFor example, in 2014 there were 16,079 births and 14,002 FFS records; 13,524 FFS had mother and/or baby sPHIN. For those missing baby sPHIN (9,295), 99.8% were retrieved via the Mom_Baby Link File. Linking the FFS to the hospital births we found: 3,043 births didn’t have an FFS; 12,762 had a single FFS, and 274 births had multiple FFS (i.e., baby associated with more than one mother, FFS and/or form date). To ensure that the baby was only associated with one mother and one FFS the most current FFS was kept. We found that in 2014, 81.07% (13,036/16,079) of the births had an FFS. In the longitudinal analysis, the percent of births with an FFS ranged from 74.6% in 2000 to 81.1% in 2014. Conclusion/ImplicationsWe were able to achieve good linkage between FFS and health registry data, allowing this rich data source to be used for research on maternal and child health. Information on percent of births with FFS has been shared with policy-makers over the years and changes to screening practices implemented.

IntroductionManitoba has one of the highest rates of children taken into care of child welfare services (Child and Family Services; CFS) in the world, and also one of the highest youth incarceration rates in Canada. Policy-makers recognize there is overlap between these systems; the extent of that overlap is unknown. Objectives and ApproachWe linked CFS, Justice, and Population Health Registry data to quantify the overlap between having a history of CFS during childhood (0-17 years) and being charged with a crime as a youth (12-17 years). Using a cohort approach, we selected all individuals in Manitoba who were born in 1988 (N=28,178); those not in the province at any time from 12-17 years were excluded, leaving a final cohort of 18,182. The cohort was divided into 3 groups according to CFS involvement: CFS out-of-home care (1,148); CFS in-home services (3,395); no CFS (13,639). Criminal charges between 12-17 years were identified. Results6.3% of our cohort had CFS out-of-home care, 18.7% received CFS in-home services, and 75% had no CFS involvement. 10.5% of the cohort were charged of a crime between 12-17 years. Almost half (46.6%) of youth who had CFS out-of-home care had criminal charges, compared to 19.4% of youth who had CFS in-home services, and 5.3% of youth with no CFS. Despite accounting for only 6.3% of the cohort, youth who had out-of-home care accounted for 28.0% of youth with criminal charges. Indigenous (First Nations (FN) and Metis) children/youth were over-represented in both systems; for example, 24.5% of FN youth had been in care compared to 3.1% of non-Indigenous; and 32.2% of FN youth were charged with a crime compared to 6.6% of non-Indigenous youth. Conclusion/ImplicationsThere is substantial overlap between the child welfare and youth justice systems, with overrepresentation of Indigenous youth in both systems. Culturally appropriate programs and policies aimed at supporting parents, families and communities to care for their own children will likely have long-term positive impacts on the youth justice system.

Background Congenital anomalies of the kidney and urinary tract (CAKUT) are the primary cause of chronic kidney disease in children. The relevance of timing of diabetes mellitus (DM) exposure on risk of CAKUT in exposed children is unknown. Study Design Population-based nested case-control study. Setting & Participants Infants born between fiscal years 1996/1997 and 2009/2010 in Manitoba, Canada, identified using administrative data housed at the Manitoba Centre for Health Policy. Predictors Pregestational (including first 20 weeks' gestation) and gestational (>20 weeks) DM and relevant confounders (maternal age; renin-angiotensin-aldosterone system inhibitor use; low socioeconomic status; alcohol, illicit drug, and smoking use during pregnancy; region of residence; and size for gestational age [surrogate of glycemic control]). Outcome CAKUT identified by International Classification of Diseases codes. Results 945 case patients with CAKUT and 4,725 controls (matched for gestational age, sex, and birth year) were identified. Maternal pregestational DM occurred in 39 (4.1%) of the CAKUT group and 111 (2.3%) controls (P = 0.002), whereas gestational DM occurred in 40 (4.2%) of the CAKUT group and 157 (3.3%) controls (P = 0.2). In the conditional multivariable logistic regression model, pregestational DM was associated with CAKUT (OR, 1.67; 95% CI, 1.14-2.46), whereas gestational DM was not (OR, 1.29; 95% CI, 0.90-1.85). Both large (LGA) and small for gestational age (SGA) also were associated significantly with CAKUT (LGA: OR, 1.34 [95% CI, 1.11-1.63]; SGA: OR, 1.59 [95% CI, 1.26-2.01]). Limitations Lack of data for maternal glycemic control and body mass index. Conclusions This study suggests that DM in the first 20 weeks of pregnancy is associated with CAKUT in exposed infants. The association between CAKUT and LGA suggests that poor glycemic control increases risk. Screening and intervention studies in women of childbearing age with DM are warranted to determine whether the risk of chronic kidney disease in children can be modified.

ObjectivesManitoba has one of the highest rates of children in out-of-home care in the world. Our aims were to: 1) describe characteristics of children in care; 2) determine differences in educational outcomes for children in care, children receiving in-home protection services and children not involved with child welfare; and, 3) identify factors contributing to educational success for children in care. ApproachPopulation-level administrative data from the Population Health Research Data Repository at the Manitoba Centre for Health Policy, were used. Several data sources were linked together at an individual level: child welfare services (e.g., in care, in-home services; hospital birth records (e.g., birth weight, gestational age); health status (e.g., from hospitalizations, physician visits); family risk factors (e.g., maternal prenatal smoking and/or drinking, maternal education); family characteristics (e.g., number of children in family, receipt of income assistance); education assessments at kindergarten, grades 3, 7, 8, 9 and 12. Children in care from 1998 onward were included. Number of children analyzed differed depending on the educational outcome examined: e.g., analyses at kindergarten include 1,893 children in care, 4,229 children receiving in-home services, and 32,280 children not involved with child welfare services; for high school completion these numbers were 11,234, 40,671, and 162,265 respectively. Multivariate regressions identified characteristics associated with educational outcomes for children in care. ResultsOver one-third of children in care first entered care as infants, and of those, close to half were apprehended at birth. 5.5% of children in Manitoba spent some time in care before their 15th birthday, with an almost tenfold difference for Indigenous (16.6%) and non-Indigenous (1.7%) children. Across the range of educational outcomes, children in care did more poorly than children receiving in-home services, who in turn did more poorly than children with no child welfare involvement. For example, only 33.4% of children in care completed high school compared to 66.8% of children receiving in-home services and 89.3% of children with no child welfare involvement. Adjusting covariates reduced differences but all remained statistically significant. Factors associated with positive outcomes for children in care differed depending on the outcome and included measures like poverty (at Kindergarten, p

Motor vehicle collisions (MVCs) are the leading cause of death in young people in North America. The effects of such deaths on parents have not been systematically studied. Administrative data sets were used to identify all parents (n = 1,458) who had an offspring die in a MVC between 1996 and 2008 in the province of Manitoba, Canada. They were matched to general population control parents who had not had offspring die from any sudden cause during the study period. Generalized estimating equations were used to compare the rates of physician-diagnosed mental and physical disorders, social factors, and treatment utilization in the 2 parent groups in the 2 years before and after offspring death, with adjustment for confounding factors. The risk of depression among bereaved parents almost tripled (adjusted prevalence ratio = 2.85, 95% confidence interval: 2.44, 3.33; P0.001) during the 2 years after death of an offspring. Significant increases in the risk of anxiety disorders (adjusted prevalence ratio = 1.45, 95% confidence interval: 1.26, 1.67; P0.001) were also observed. When compared with nonbereaved parents, bereaved parents had significant increases in the risks of depression (P0.001), anxiety disorders (P0.001), marital break-up (P = 0.015), and physician visits for mental illness (P0.001) in the post-death period. In conclusion, parents who lose an offspring in a MVC experience considerable mental illness and marital disruption.

Objective To examine the association between the interpregnancy interval (IPI) and preterm birth, low birth weight, and SGA birth in a developed country with universal health coverage. Methods We conducted a secondary analysis of data housed at the Manitoba Centre for Health Policy. All live births in Manitoba hospitals over a 29-year period were identified and consecutive births to the same mother were grouped into sibling pairs to calculate the IPI for the younger siblings. Logistic regression models were fit to examine the association between the IPI and adverse perinatal outcomes, adjusted for potentially confounding sociodemographic and clinical factors. Results In a cohort of more than 171 000 births and relative to IPIs of 18 to 23 months, IPIs shorter than 12 and longer than 23 months were associated with significantly increased odds of preterm birth overall and both medically indicated and spontaneous preterm births, low birth weight, and SGA birth. The strongest association observed was for intervals shorter than 6 months and spontaneous preterm birth (adjusted OR 1.83, 95% CI 1.65-2.03). When the outcome was modelled as GA categories, the strongest association observed was for intervals shorter than 6 months and early preterm birth ( Conclusion If the associations observed between the IPI and adverse perinatal outcomes in this large, population-based cohort are causal, birth spacing could form an important target of public health messaging in Canada.

The objective of this study was to examine mental disorders and treatment use among bereaved siblings in the general population. Siblings (N=7243) of all deceased children in the population of Manitoba, Canada who died between 1984 and 2009 were matched 1:3 to control siblings (N=21,729) who did not have a sibling die in the study period. Generalized estimating equations were used to compare the two sibling groups in the two years before and after the index child's death on physician-diagnosed mental disorders and treatment utilization, with adjustment for confounding factors including pre-existing mental illness. Analyses were stratified by age of the bereaved (

Background: Few population studies have examined the psychiatric outcomes of children and adolescents in the child welfare system, and no studies have compared outcomes before and after entry into care. Our objective was to assess the relative rate (RR) of suicide, attempted suicide, admission to hospital and visits to physicians’ offices among children and adolescents in care compared with those not in care. We also examined these outcomes within the child welfare population before and after entry into care. Methods: We used population-level data to identify children and adolescents 5 to 17 years of age who were in care in Manitoba for the first time between Apr. 1, 1997, and Mar. 31, 2006, and a comparison cohort not in care. We compared the two cohorts to obtain RRs for the specified outcomes. We also determined RRs within the child welfare population relative to the same population two years before entry into care. Results: We identified 8279 children and adolescents in care for the first time and a comparison cohort of 353 050 children and adolescents not in care. Outcome rates were higher among those in care than in the comparison cohort for suicide (adjusted RR 3.54, 95% confidence interval [CI] 2.11–5.95), attempted suicide (adjusted RR 2.11, 95% CI 1.84–2.43) and all other outcomes. However, adjusted RRs for attempted suicide (RR 0.27, 95% CI 0.21–0.34), admissions to hospital and physician visits decreased after entry into care. Interpretation: Children and adolescents in care were at greater risk of suicide and attempting suicide than those who were not in care. Rates of suicide attempts and hospital admissions within this population were highest before entry into care and decreased thereafter.

CONTEXT Suicide bereavement remains understudied and poorly understood. OBJECTIVES To examine outcomes of parents bereaved by the suicide death of their offspring and to compare these with both nonbereaved parent controls and parents who had offspring die in a motor vehicle crash (MVC). DESIGN Population-based case-control study. Suicide-bereaved parents were compared with nonbereaved matched control parents in the general population (n = 1415) and with MVC-bereaved parents (n = 1132) on the rates of physician-diagnosed mental and physical disorders, social factors, and treatment use in the 2 years after death of the offspring. Adjusted relative rates (ARRs) were generated by generalized estimating equation models and adjusted for confounding factors. SETTING Manitoba, Canada. PARTICIPANTS All identifiable parents who had an offspring die by suicide between 1996 and 2007 (n = 1415). MAIN OUTCOME MEASURES Mental and physical disorders, social factors, and treatment use. RESULTS Suicide bereavement was associated with an increased rate of depression (ARR, 2.14; 95% CI, 1.88-2.43), anxiety disorders (ARR, 1.41; 95% CI, 1.24-1.60), and marital breakup (ARR, 1.18; 95% CI, 1.13-1.23) in the 2 years after the suicide of an offspring, as compared with the 2 years prior to the death. Suicide-bereaved and MVC-bereaved parents had very few differences on predeath to postdeath outcomes. Depression rate increases were greater for MVC-bereaved parents (19.9%) compared with suicide-bereaved parents (15.9%; P = .005), whereas suicide-bereaved parents had higher rate increases of hospitalization for mental illness (P = .049). Suicide-bereaved parents were more likely than their MVC-bereaved counterparts to have depression (ARR, 1.30; 95% CI, 1.06-1.61), physical disorders (ARR, 1.32; 95% CI, 1.19-1.45), and low income (ARR, 1.34; 95% CI, 1.18-1.51) before their offspring's death. CONCLUSIONS Suicide bereavement is associated with adverse mental health and social outcomes. These consequences appear similar to those associated with MVC bereavement. Parents who lose offspring to suicide appear to be a vulnerable group even prior to their offspring's death.

A newborn screen designed to predict family risk was examined to: (a) determine whether all families with newborns were screened; (b) evaluate its predictive validity for identifying risk of out-of-home placement, as a proxy for maltreatment; (c) determine which items were most predictive of out-of-home placement. All infants born in Manitoba, Canada from 2000 to 2002 were followed until March 31, 2004 ( N = 40,886) by linking four population-based data sets: (a) newborn screening data on biological, psychological, and social risks; (b) population registry data on demographics; (c) hospital discharge data on newborn birth records; (d) data on children entering out-of-home care. Of the study population, 18.4% were not screened and 3.0% were placed in out-of-home care at least once during the study period. Infants not screened were twice as likely to enter care compared to those screened (4.9% vs. 2.5%). Infants screening at risk were 15 times more likely to enter care than those screening “not at risk.” Sensitivity and specificity of the screen were 77.6% and 83.3%, respectively. Screening efforts to identify vulnerable families missed a substantial portion of families needing support. The screening tool demonstrated moderate predictive validity for identifying children at risk of entering care in the first years of life.

Ornithine decarboxylase (ODC) is the key enzyme in the polyamine synthesis pathway and is overexpressed in a variety of cancers. We have performed a detailed immunostaining analysis of the expression of ODC in normal, benign prostatic hyperplasia (BPH), and cancerous prostate tissues. We conclude that ODC is overexpressed in both BPH and neoplastic tissues and that ODC overexpression appears to be an early event in prostate carcinogenesis. The extent of overexpression decreases as cancer progresses. Interestingly, ODC overexpression was also detected in patients who underwent androgen ablation therapy, suggesting ODC overexpression may contribute to the androgen-independent survival of prostate cancer cells. ODC is perinuclear localized in BPH samples but is diffusely cytoplasmic in cancer samples. Having shown ODC overexpression in human prostate cancer, we developed prostate-specific ODC transgenic mice to further investigate whether ODC overexpression alone is a causal factor in prostate carcinogenesis. RT-PCR and immunostaining confirmed that ODC was overexpressed in a subset of prostate epithelial cells. Although minor nucleoli enlargements in some tissues were detected, gross morphological changes were not observed in transgenic prostates. Therefore, overexpression of ODC alone in this subset of prostate epithelial cells is not sufficient to induce prostate carcinogenesis.