Optimal Volume of Moderate-to-Vigorous Physical Activity Postconcussion in Children and Adolescents.

Importance: Determining the optimal volume of early moderate-to-vigorous-intensity physical activity (MVPA) after concussion and its association with subsequent symptom burden is important for early postinjury management recommendations. Objectives: To investigate the association between cumulative MVPA (cMVPA) over 2 weeks and subsequent symptom burden at 1 week, 2 weeks, and 4 weeks postinjury in children and examine the association between cMVPA and odds of persisting symptoms after concussion (PSAC) at 2 weeks and 4 weeks postinjury. Design, Setting, and Participants: This multicenter cohort study used data from a randomized clinical trial that was conducted from March 2017 to December 2019 at 3 Canadian pediatric emergency departments in participants aged 10.00 to 17.99 years with acute concussion of less than 48 hours. Data were analyzed from July 2022 to December 2023. Exposure: cMVPA postinjury was measured with accelerometers worn on the waist for 24 hours per day for 13 days postinjury, with measurements deemed valid if participants had 4 or more days of accelerometer data and 3 or fewer consecutive days of missing data. cMVPA at 1 week and 2 weeks postinjury was defined as cMVPA for 7 days and 13 days postinjury, respectively. Multiple imputations were carried out on missing MVPA days. Main Outcomes and measures: Self-reported postconcussion symptom burden at 1 week, 2 weeks, and 4 weeks postinjury using the Health and Behavior Inventory (HBI). PSAC was defined as reliable change on the HBI. A linear mixed-effect model was used for symptom burden at 1 week, 2 weeks, and 4 weeks postinjury with a time × cMVPA interaction. Logistic regressions assessed the association between cMVPA and PSAC. All models were adjusted for prognostically important variables. Results: In this study, 267 of 456 children (119 [44.6%] female; median [IQR] age, 12.9 [11.5 to 14.4] years) were included in the analysis. Participants with greater cMVPA had significantly lower HBI scores at 1 week (75th percentile [258.5 minutes] vs 25th percentile [90.0 minutes]; difference, -5.45 [95% CI, -7.67 to -3.24]) and 2 weeks postinjury (75th percentile [565.0 minutes] vs 25th percentile [237.0 minutes]; difference, -2.85 [95% CI, -4.74 to -0.97]) but not at 4 weeks postinjury (75th percentile [565.0 minutes] vs 25th percentile [237.0 minutes]; difference, -1.24 [95% CI, -3.13 to 0.64]) (P = .20). Symptom burden was not lower beyond the 75th percentile for cMVPA at 1 week or 2 weeks postinjury (1 week, 259 minutes; 2 weeks, 565 minutes) of cMVPA. The odds ratio for the association between 75th and 25th percentile of cMVPA and PSAC was 0.48 (95% CI, 0.24 to 0.94) at 2 weeks. Conclusions and Relevance: In children and adolescents with acute concussion, 259 minutes of cMVPA during the first week postinjury and 565 minutes of cMVPA during the second week postinjury were associated with lower symptom burden at 1 week and 2 weeks postinjury. At 2 weeks postinjury, higher cMVPA volume was associated with 48% reduced odds of PSAC compared with lower cMVPA volume.

Maternal exposure to metals and time-to-pregnancy: The MIREC cohort study.

OBJECTIVE: To study the association between maternal exposure to arsenic, cadmium, lead, manganese and mercury, time-to-pregnancy (TTP) and infertility. DESIGN: Pregnancy-based retrospective TTP cohort study. SETTING: Hospitals and clinics from ten cities across Canada. POPULATION: A total of 1784 pregnant women. METHODS: Concentrations of arsenic, cadmium, lead, manganese and mercury were measured in maternal whole blood during the first trimester of pregnancy as a proxy of preconception exposure. Discrete-time Cox proportional hazards models generated fecundability odds ratios (FOR) for the association between metals and TTP. Logistic regression generated odds ratios (OR) for the association between metals and infertility. Models were adjusted for maternal age, pre-pregnancy body mass index, education, income, recruitment site and plasma lipids. MAIN OUTCOME MEASURES: TTP was self-reported as the number of months of unprotected intercourse to become pregnant. Infertility was defined as TTP longer than 12 months. RESULTS: A total of 1784 women were eligible for the analysis. Mean ± SD maternal age and gestational age at interview were 32.2 ± 5.0 years, and 11.6 ± 1.6 weeks, respectively. Exposure to arsenic, cadmium, manganese or mercury was not associated with TTP or infertility. Increments of one standard deviation of lead concentrations resulted in a shorter TTP (adjusted FOR 1.09, 95% CI 1.02-1.16); however, the association was not linear when exposure was modelled in tertiles. CONCLUSION: Blood concentrations of metals at typical levels of exposure among Canadian pregnant women were not associated with TTP or infertility. Further studies are needed to assess the role of lead, if any, on TTP.

Cohort profile update: The Canadian Maternal-Infant Research on Environmental Chemicals Child Development study (MIREC-CD PLUS).

BACKGROUND: The pan-Canadian Maternal-Infant Research on Environmental Chemicals (MIREC) study was established to determine whether maternal environmental chemical exposures were associated with adverse pregnancy outcomes in 2001 pregnant women. OBJECTIVES: The MIREC-Child Development (CD PLUS) study followed this cohort with the goal of assessing the potential effects of prenatal exposures on anthropometry and neurodevelopment in early childhood. POPULATION: MIREC families with children between the ages of 15 months and 5 years who had agreed to be contacted for future research (n = 1459) were invited to participate in MIREC-CD PLUS which combines data collected from an online Maternal Self-Administered Questionnaire with biomonitoring and neurodevelopment data collected from two in-person visits. PRELIMINARY RESULTS: Between April 2013 and March 2015, 803 children participated in the Biomonitoring visit where we collected anthropometric measures, blood, and urine from the children. The Behavioural Assessment System for Children-2, Behaviour Rating Inventory of Executive Function, MacArthur-Bates Communicative Development Inventories and the Communication subscale of the Adaptive Behaviour Scale from the Bayley Scales of Infant and Toddler Development-III are available on close to 900 children. There were 610 singleton children who completed in-person visits for neurodevelopment assessments including the Social Responsiveness Scale, Wechsler Preschool Primary Scale of Intelligence-III and NEuroPSYchological assessments (NEPSY). Currently, we are following the cohort into early adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC-ENDO). CONCLUSIONS: Data collection for the MIREC-CD PLUS study is complete and analysis of the data continues. We are now extending the follow-up of the cohort into adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC-ENDO). MIREC-CD PLUS is limited by loss to follow-up and the fact that mothers are predominately of higher socioeconomic status and 'White' ethnicity, which limits our generalizability. However, the depth of biomonitoring and clinical measures in MIREC provides a platform to examine associations of prenatal, infancy and childhood exposures with child growth and development.

Prenatal exposure to perfluoroalkyl substances and inflammatory biomarker concentrations.

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants that induce immunotoxicity in experimental studies; however, epidemiological evidence-particularly during pregnancy-is scarce. We quantified associations between first trimester plasma perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorohexane sulfonate (PFHxS) concentrations and third trimester concentrations of inflammatory biomarkers and determined if these associations were modified by fetal sex. Methods: We analyzed data from 1411 participants, recruited between 2008 and 2011, in the Maternal-Infant Research on Environmental Chemicals study. Our primary outcome was a composite inflammatory index derived by summing the z-scores of eight proinflammatory biomarkers. Using multivariable linear regression models, we quantified associations between each PFAS and the inflammatory index and individual biomarkers. We quantified the effects of the PFAS mixture using weighted quantile sum regression, and evaluated effect modification using product terms and sex-stratified models. Results: Each doubling of PFOA and PFHxS was associated with a 0.38 (95% CI, 0.09, 0.67) and 0.21 (95% CI, 0.01, 0.41) SD increase in the proinflammatory index, respectively. A one-quartile increase in the PFAS mixture was associated with a 0.40 (95% CI, 0.09, 0.71) SD increase in the proinflammatory index. In individual models, we observed positive associations between PFAS and concentrations of monocyte chemoattractant protein-1, macrophage inflammatory protein-1ß, and matrix metalloproteinases-9; however, the magnitude and precision varied according to the specific PFAS. Sex-specific findings were identified in few PFAS-biomarker associations. Conclusions: PFOA, PFOS, and PFHxS, individually and as a mixture, were positively associated with proinflammatory biomarkers during pregnancy.

Measurement of 24 phthalate metabolites in 1st trimester urine samples: The MIREC study.

Phthalates are non-persistent chemicals measured as metabolites in urine. Over time, new metabolites have been identified. In the original Maternal-Infant Research on Environmental Chemicals (MIREC) study (2008-2011), we measured 11 phthalate metabolites in first trimester urine samples. The goal of the present study was to develop a method to measure new metabolites, to increase the sensitivity for some previously measured metabolites, and to measure these new metabolites in biobanked urine samples from MIREC participants. Using Ultra Performance Liquid Chromatography with a tandem mass spectrometer, we developed a method to measure 24 metabolites from 10 different parent phthalates. Chromatographic interpretation of some of the di-iso-decyl phthalate metabolites (mono-(2-propyl-6oxoheptyl) phthalate (MOiDP), mono-(2,7-methyl-7-carboxyheptyl) phthalate (MCiNP), mono-(2-propyl-6-hydroxy-heptyl) phthalate (MHiDP)) and di-iso-nonyl phthalate metabolites (mono(oxo-isononyl) phthalate (MOiNP), mono(carboxy-isooctyl) phthalate (MCiOP), mono(hydroxy-isononyl) phthalate (MHiNP) and mono-isononyl phthalate (MiNP)) was challenging as these are complex isomeric mixtures. To validate and confirm our quantitation peaks, an assay using a high-resolution detection technique was developed on a Quadrupole Time-of-Flight (QToF) system. This system has a mass resolution of at least 0.005 amu, compared to 0.5 amu for the MS/MS detector. Using the QToF system, the distinction between an isomer and possible interference was achieved with the use of the exact mass. In about 1800 MIREC samples, mono-cyclo-hexyl phthalate (MCHP), mono-(7-carboxy-n-heptyl) phthalate (MCHpP), mono-iso-decyl phthalate (MiDP), and mono-n-octyl phthalate (MnOP) were rarely detected, while detection of MMP was improved. MCiOP, MiNP and MCiNP had to be reported semi-quantitatively. Given the complexity of isomeric mixtures of some phthalates, researchers must be careful in their determination of the analytes and the approach used in their quantification when generating biomonitoring data. This study produced biomonitoring data for a large population of pregnant people that can be used in risk assessment of phthalates. Future work will examine associations with birth and child outcomes.

Individual, Independent, and Joint Associations of Toxic Metals and Manganese on Hypertensive Disorders of Pregnancy: Results from the MIREC Canadian Pregnancy Cohort.

BACKGROUND: Toxic metals, such as lead (Pb), cadmium (Cd), arsenic (As), and mercury (Hg), may be associated with a higher risk of gestational hypertension and preeclampsia, whereas manganese (Mn) is an essential metal that may be protective. OBJECTIVES: We estimated the individual, independent, and joint associations of Pb, Cd, As, Hg, and Mn on the risk of developing gestational hypertension and preeclampsia in a cohort of Canadian women. METHODS: Metal concentrations were analyzed in first and third trimester maternal blood (n=1,560). We measured blood pressure after 20 wk gestation to diagnose gestational hypertension, whereas proteinuria and other complications defined preeclampsia. We estimated individual and independent (adjusted for coexposure) relative risks (RRs) for each doubling of metal concentrations and examined interactions between toxic metals and Mn. We used quantile g-computation to estimate the joint effect of trimester-specific exposures. RESULTS: Each doubling of third trimester Pb (RR=1.54; 95% CI: 1.06, 2.22) and first trimester blood As (RR=1.25; 95% CI: 1.01, 1.58) was independently associated with a higher risk of developing preeclampsia. First trimester blood As (RR=3.40; 95% CI: 1.40, 8.28) and Mn (RR=0.63; 95% CI: 0.42, 0.94) concentrations were associated with a higher and lower risk, respectively, of developing gestational hypertension. Mn modified the association with As such that the deleterious association with As was stronger at lower concentrations of Mn. First trimester urinary dimethylarsinic acid concentrations were not associated with gestational hypertension (RR=1.31; 95% CI: 0.60, 2.85) or preeclampsia (RR=0.92; 95% CI: 0.68, 1.24). We did not observe overall joint effects for blood metals. DISCUSSION: Our results confirm that even low blood Pb concentrations are a risk factor for preeclampsia. Women with higher blood As concentrations combined with lower Mn in early pregnancy were more likely to develop gestational hypertension. These pregnancy complications impact maternal and neonatal health. Understanding the contribution of toxic metals and Mn is of public health importance. https://doi.org/10.1289/EHP10825.

Descriptive analysis of organophosphate ester metabolites in a pan-Canadian pregnancy cohort.

Organophosphate esters (OPEs) are widely used in numerous consumer products for their flame retardant and plasticizing properties. Despite potential widespread exposure, biomonitoring data during critical windows of development are scarce and limited to the most widely studied metabolites. We quantified urinary concentrations of multiple OPE metabolites in a vulnerable Canadian population. Using data and biobanked specimens from the Maternal-Infant Research on Environmental Chemicals (MIREC) study (2008-2011), we measured first trimester urinary concentrations of 15 OPE metabolites as well as one flame retardant metabolite and quantified associations with sociodemographic and sample collection characteristics in 1865 pregnant participants. We applied 2 different analytical methods to quantify OPEs, one using UItra-Performance Liquid Chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) and the other using Atmospheric Pressure Gas Chromatography coupled to mass spectrometry (APGC-MS/MS) with sensitive limits of detection (0.008-0.1 µg/L). We modelled associations between sociodemographic and sample collection characteristics and specific gravity-standardized chemical concentrations. Six OPE metabolites were detected in the majority (68.1-97.4 %) of participants. Bis-(2-chloroethyl) hydrogen phosphate had the highest detection rate (97.4 %). Diphenyl phosphate had the highest geometric mean concentration (0.657 µg/L). Metabolites of tricresyl phosphate were detected in few participants. Associations between sociodemographic characteristics varied according to each OPE metabolite. Pre-pregnancy body mass index tended to be positively associated with OPE metabolite concentrations whereas age tended to be inversely associated with OPE concentrations. OPE concentrations were, on average, higher in urine samples collected in the summer than other seasons the winter. We present the largest biomonitoring study of OPE metabolites in pregnant people to date. These findings demonstrate widespread exposure to OPEs and their metabolites and identify subpopulations who may experience heightened exposure.

Association between toxic metals, vitamin D and preterm birth in the Maternal-Infant research on environmental chemicals study.

BACKGROUND: Toxic metals, like lead, are risk factors for preterm birth (PTB), but few studies have examined low levels found in most Canadians. Vitamin D, which may have antioxidant activity, protects against PTB. OBJECTIVES: In this study, we investigated the impact of toxic metals (lead, mercury, cadmium and arsenic) on PTB and examined if maternal plasma vitamin D concentrations modify these associations. METHODS: We investigated whether concentrations of metals in whole blood measured in early and late pregnancy were associated with PTB (<37 weeks) and spontaneous PTB in 1851 live births from the Maternal-Infant Research on Environmental Chemicals Study using discrete time survival analysis. We also investigated whether the risk of PTB was modified by first-trimester plasma 25-hydroxyvitamin D (25OHD) concentrations. RESULTS: Of 1851 live births, 6.1% (n = 113) were PTBs and 4.9% (n = 89) were spontaneous PTB. A 1 µg/dL increase in blood lead concentrations during pregnancy was associated with an increased risk of PTB (relative risk [RR] 1.48, 95% confidence interval [CI] 1.00, 2.20) and spontaneous PTB (RR 1.71, 95% CI 1.13, 2.60). The risk was higher in women with insufficient vitamin D concentrations (25OHD <50 nmol/L) for both PTB (RR 2.42, 95% CI 1.01, 5.79) and spontaneous PTB (RR 3.04, 95% CI 1.15, 8.04). However, an interaction on the additive scale was not present. Arsenic was associated with a higher risk of PTB (RR 1.10, 95% CI 1.02, 1.19) and spontaneous PTB (RR 1.11, 95% CI 1.03, 1.20) per 1 µg/L. CONCLUSIONS: Gestational exposure to low levels of lead and arsenic may increase the risk of PTB and spontaneous PTB; individuals with insufficient vitamin D may be more susceptible to the adverse effects of lead. Given our relatively small number of cases, we encourage testing of this hypothesis in other cohorts, especially those with vitamin D-deficient populations.

Urinary concentrations and determinants of glyphosate and glufosinate in pregnant Canadian participants in the MIREC study.

BACKGROUND: Glyphosate is the most widely applied herbicide in agriculture. Glufosinate is a broad spectrum herbicide used to manage glyphosate-resistant weeds. Despite the widespread use of these herbicides, biomonitoring data - which inform risk assessment and management - are sparse. OBJECTIVES: To identify determinants of urinary concentrations of these herbicides and their metabolites in pregnancy. METHODS: We measured urinary concentrations of glyphosate, glufosinate, and their primary metabolites aminomethylphosphonic acid (AMPA) and 3-methylphosphinicopropionic acid (3-MPPA) in a single spot urine specimen collected during the first trimester of pregnancy from the Maternal-Infant Research on Environmental Chemicals (MIREC) study. MIREC recruited about 2000 pregnant women from 10 Canadian cities between 2008 and 2011. We used UItra-Performance Liquid Chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) with sensitive limits of detection to quantify analyte concentrations. We examined urinary concentrations according to maternal sociodemographics, sample collection characteristics, reported pesticide use, and consumption of fruits, vegetables, legumes, and grain products. We used ANOVA models with specific gravity-standardized chemical concentrations as the dependent variable to determine associations with maternal and sample determinants. RESULTS: Among women with biobanked urine samples (n = 1829-1854), 74% and 72% had detectable concentrations of glyphosate and AMPA, respectively. In contrast, one and six percent of women had detectable concentrations of glufosinate and 3-MPPA, respectively. The specific gravity-standardized geometric mean (95% CI) concentrations of glyphosate and AMPA were 0.112 (0.099-0.127) µg/L and 0.159 (0.147-0.172) µg/L, respectively. We observed a dose-response relationship between consumption of whole grain bread and higher urinary glyphosate concentrations. Season of urine collection and self-reported pesticide use were not associated with increased concentrations of any analyte. CONCLUSIONS: We detected glyphosate and AMPA in the majority of pregnant women from this predominantly urban Canadian cohort. Diet was a probable route of exposure.

Biomonitoring of DEET and DCBA in Canadian children following typical protective insect repellent use.

N,N-diethyl-m-toluamide (DEET) is an ingredient found in many consumer insect repellents and its use is recommended to Canadians by government agencies, including Health Canada, for protection against insect bites including mosquitos and ticks. The majority of research on DEET exposure and toxicokinetics in humans has focused on adult populations with little information from vulnerable populations, including children. We aimed to fill this knowledge gap by examining real-world exposure data for DEET and its metabolite 3-diethylcarbamoyl benzoic acid (DCBA) in a sample population of Canadian children. We conducted a 24-h observational exposure human biomonitoring study at three overnight summer camps in Ontario, Canada through July and August 2019. Participating children aged 7-13 years provided multiple spot urine samples over a 24-h period and completed a journal to document insect repellent use and factors that could influence absorption of DEET. Children were instructed to use insect repellent as they usually would while attending a summer camp. Exposure was quantified using the information from the participant's journal and the change in the mass of their insect repellent containers over the course of the study. A total of 389 urine samples were collected from 124 children. Among participants using insect repellent, urinary levels of DEET were elevated between 2 and 8 h post-application and decreased thereafter but remained qualitatively higher than concentrations in participants who did not use insect repellent on the study day, even at 18-22 h post-application. DCBA was the predominant metabolite of DEET exposure in urine. DCBA was elevated between 8 and 14 h post-application, and declined thereafter, but not to the level observed among those who did not use insect repellent on the study day. Children who used more insect repellent, or used higher concentration insect repellent (10%-30% DEET) excreted higher levels of DEET and DCBA. Excreted DEET and DCBA accounted for 0.001% (median) and 1.3% (median) of the estimated applied DEET, respectively. Children did not reach an undetectable level of DEET or DCBA in urine, even among those not using insect repellent during the study day, indicating a potentially complex multi-route exposure to insect repellents in a real world scenario. This work provides targeted biomonitoring data for children intentionally using DEET-based insect repellents for normal protective use, and will support the risk re-evaluation of DEET by Health Canada.

Individual and mixture associations of perfluoroalkyl substances on liver function biomarkers in the Canadian Health Measures Survey.

BACKGROUND: Perfluoroalkyl substances can disrupt hepatic metabolism and may be associated with liver function biomarkers. We examined individual and mixture associations of PFAS on liver function biomarkers in a representative sample of Canadian adults. We explored the potential for effect modification by sex and body mass index, as well as by physical activity level which may attenuate the deleterious effect of PFAS on metabolic disorders. METHODS: We analyzed data from participants aged 20-74 from the Canadian Health Measures Survey. We used linear regression to examine associations between plasma concentrations of PFOA, PFOS, PFHxS, PFNA, PFDA, and PFUDA on serum concentrations of aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), alanine aminotransferase (ALT) and total bilirubin. We used quantile g-computation to estimate associations with a PFAS mixture for each simultaneous, one-quartile change in PFAS concentrations. RESULTS: Each doubling of PFOA, PFOS, PFHxS, or PFNA concentrations was associated with higher AST, GGT, and ALP concentrations. Each doubling of PFOA concentrations was associated with 16.5% (95%CI: 10.4, 23.0) higher GGT concentrations among adults not meeting Canada's physical activity guidelines vs. 6.6% (95%CI: -1.6, 15.5) among those meeting these guidelines. Sex and BMI also modified some associations, though to a lesser extent. We did not observe associations between ALT and PFOA (1.2% change; 95%CI: -2.5, 4.9), PFOS (2.2% change; 95%CI: -0.8, 5.3), or PFHxS (1.5% change; 95%CI: -0.4, 3.4). We also did not observe consistent associations for PFDA and PFUDA or with total bilirubin. In quantile g-computation models, each simultaneous one-quartile increase in the PFAS mixture was positively associated with AST (7.5% higher; 95%CI: 4.0, 10.4), GGT (9.7% higher; 95%CI: 1.7, 17.0), and ALP (2.8% higher; 95%CI: 0.5, 5.4). CONCLUSION: Higher plasma concentrations of PFOA, PFOS, PFHxS, and PFNA - both individually and as a mixture - were associated with higher serum concentrations of liver function biomarkers. These results contribute to emerging evidence suggesting that higher levels of physical activity appear to be protective against the hepatotoxic effects of PFOA. This work contributes to a growing body of evidence supporting the hepatotoxic effects of PFAS.

Perspective: Human Milk Composition and Related Data for National Health and Nutrition Monitoring and Related Research.

National health and nutrition monitoring is an important federal effort in the United States and Canada, and the basis for many of their nutrition and health policies. Understanding of child exposures through human milk (HM) remains out of reach due to lack of current and representative data on HM's composition and intake volume. This article provides an overview of the current national health and nutrition monitoring activities for HM-fed children, HM composition (HMC) and volume data used for exposure assessment, categories of potential measures in HM, and associated variability factors. In this Perspective, we advocate for a framework for collection and reporting of HMC data for national health and nutrition monitoring and programmatic needs, including a shared vision for a publicly available Human Milk Composition Data Repository (HMCD-R) to include essential metadata associated with HMC. HMCD-R can provide a central, integrated platform for researchers and public health officials for compiling, evaluating, and sharing HMC data. The compiled compositional and metadata in HMCD-R would provide pertinent measures of central tendency and variability and allow use of modeling techniques to approximate compositional profiles for subgroups, providing more accurate exposure assessments for purposes of monitoring and surveillance. HMC and related metadata could facilitate understanding the complexity and variability of HM composition, provide crucial data for assessment of infant and maternal nutritional needs, and inform public health policies, food and nutrition programs, and clinical practice guidelines.

Development of an observational exposure human biomonitoring study to assess Canadian children's DEET exposure during protective use.

Biomonitoring data of N,N-diethyl-meta-toluamide (DEET) in children is scarce and limited to controlled exposure and surveillance studies. We conducted a 24-hour observational exposure and human biomonitoring study designed to estimate use of and exposure to DEET-based insect repellents by Canadian children in an overnight summer camp setting. Here, we present our study design and methodology. In 2019, children between the ages of 7 and 13 took part in the study (n = 126). Children controlled their use of DEET-based insect repellents, and provided an account of their activities at camp that could impact insect repellent absorption. Children provided a total of 389 urine samples throughout the study day, and reported the time that they applied insect repellent, which allowed us to contextualize urinary DEET and metabolite concentrations with respect to the timing of insect repellent application. DEET (2.3%

Blood metals and vitamin D status in a pregnancy cohort: A bidirectional biomarker analysis.

Low 25-hydroxyvitamin D (25OHD), a biomarker of vitamin D status, is associated with reduced immune function and adverse pregnancy outcomes, such as preterm birth. Observational studies indicate that long-term, high level exposure to metals such as cadmium (Cd) and lead (Pb) can impact a person's vitamin D status. However, the directionality of the association is uncertain, particularly for low-level exposures. We used three distinct longitudinal data analysis methods to investigate cross-sectional, longitudinal and bidirectional relationships of Cd and Pb biomarkers with 25-hydroxyvitamin D (25OHD) in a Canadian pregnancy cohort. Maternal whole blood Cd and Pb and plasma 25OHD concentrations were measured in the 1st (n = 1905) and 3rd (n = 1649) trimester and at delivery (25OHD only, n = 1542). Our multivariable linear regression analysis showed weak inverse associations between Cd and 25OHD concentrations cross-sectionally and longitudinally while the latent growth curve models showed weak associations with Pb on the 25OHD intercept. In the bidirectional analysis, using cross lagged panel models, we found no association between 1st trimester metals and 3rd trimester 25OHD. Instead, 1st trimester 25OHD was associated with 9% (-15%, -3%) lower 3rd trimester Cd and 3% (-7, 0.1%) lower Pb. These findings suggest the 25OHD may modify metal concentrations in pregnancy and demonstrates the value of controlling for contemporaneous effects and the persistence of a biomarker over time, in order to rule out reverse causation.

An exposure-response meta-analysis of ambient PM2.5 during pregnancy and preeclampsia.

Relationships between PM2.5 exposure and preeclampsia have been the focus of four recent systematic reviews and meta-analyses. We expand on knowledge gaps in these reviews by characterizing the shape of the exposure-outcome relationship, and by assessing the heterogeneity in these associations by study characteristics. Studies of PM2.5 and preeclampsia were identified from reviews, and confounder-adjusted estimates were extracted. Estimates were derived using a random-effects model. Potential non-linearity was evaluated using a one-stage dose-response meta-analysis. Contrary to previous meta-analyses reporting stronger relationships, the overall adjusted relative risk (RR) for a 10 µg/m3 average increase in PM2.5 during pregnancy and preeclampsia was modest and not statistically significant (RR: 1.07, 95% CI: 0.99-1.15). This was mainly attributable to inclusion/exclusion decisions for studies made during this review. In addition, there was no evidence of non-linearity, and no important sub-group differences by characteristics such as region, exposure assessment, participant exclusions, and early versus late-onset preeclampsia. Overall, our analysis suggests a modest relationship between ambient PM2.5 and preeclampsia. We provide details on inclusion and exclusion decisions that were lacking in previous studies, and report novel investigations of non-linearity and heterogeneity.

Is early activity resumption after paediatric concussion safe and does it reduce symptom burden at 2 weeks post injury? The Pediatric Concussion Assessment of Rest and Exertion (PedCARE) multicentre randomised clinical trial.

OBJECTIVE: Investigate whether resuming physical activity (PA) at 72 hours post concussion is safe and reduces symptoms at 2 weeks, compared with resting until asymptomatic. METHODS: Real-life conditions, multicentre, single-blinded randomised clinical trial, conducted in three Canadian paediatric emergency departments (ED). Children/youth aged 10-<18 years with acute concussion were recruited between March 2017 and December 2019, and randomly assigned to a 4-week stepwise return-to-PA protocol at 72 hours post concussion even if symptomatic (experimental group (EG)) or to a return-to-PA once asymptomatic protocol (control group (CG)). The primary outcome was self-reported symptoms at 2 weeks using the Health and Behaviour Inventory. Adherence was measured using accelerometers worn 24 hours/day for 14 days post injury. Adverse events (AE) (worsening of symptoms requiring unscheduled ED or primary care visit) were monitored. Multivariable intention-to-treat (ITT) and per-protocol analyses adjusting for prognostically important covariates were examined. Missing data were imputed for the ITT analysis. RESULTS: 456 randomised participants (EG: N=227; mean (SD) age=13.3 (2.1) years; 44.5% women; CG: N=229; mean (SD) age=13.3 (2.2) years; 43.7% women) were analysed. No AE were identified. ITT analysis showed no strong evidence of a group difference at 2 weeks (adjusted mean difference=-1.3 (95% CI:-3.6 to 1.1)). In adherent participants, initiating PA 72 hours post injury significantly reduced symptoms 2 weeks post injury, compared with rest (adjusted mean difference=-4.3 (95% CI:-8.4 to -0.2)). CONCLUSION: Symptoms at 2 weeks did not differ significantly between children/youth randomised to initiate PA 72 hours post injury versus resting until asymptomatic; however, many were non-adherent to the intervention. Among adherent participants, early PA was associated with reduced symptoms at 2 weeks. Resumption of PA is safe and may be associated with milder symptoms at 2 weeks. LEVEL OF EVIDENCE: 1b. TRIAL REGISTRATION NUMBER: NCT02893969. REGISTRY NAME: Pediatric Concussion Assessment of Rest and Exertion (PedCARE).

Ambient air pollution and inflammatory effects in a Canadian pregnancy cohort.

BACKGROUND: Epidemiologic studies have consistently reported associations between air pollution and pregnancy outcomes including preeclampsia and gestational diabetes. However, the biologic mechanisms underlying these relationships remain unclear as few studies have collected relevant biomarker data. We examined relationships between ambient PM2.5 and NO2 with markers of inflammation during pregnancy in a prospective cohort of Canadian women. METHODS: We analyzed data from 1170 women enrolled in the Maternal-Infant Research on Environmental Chemicals study. Daily residential PM2.5 and NO2 exposures during pregnancy were estimated using satellite-based and land-use regression models and used to create 14-day and 30-day exposure windows before blood-draw. Inflammatory markers C-reactive protein, interleukin-6, interleukin-8, and tumor necrosis factor-α were measured in third trimester plasma samples. Multivariable linear regression was used to estimate associations for an interquartile range (IQR) increase in PM2.5 and NO2 and markers of inflammation, while adjusting for individual-level confounders. RESULTS: Fourteen-day (IQR: 6.85 µg/m3) and 30-day (IQR: 6.15 µg/m3) average PM2.5 exposures before blood-draw were positively associated with C-reactive protein after adjustment for covariates (24.6% [95% CI = 9.4, 41.9] and 17.4% [95% CI = 1.0, 35.0] increases, respectively). This association was found to be robust in several sensitivity analyses. Neither PM2.5 nor NO2 exposures were associated with interleukin-6, interleukin-8, or tumor necrosis factor-α. CONCLUSION: Exposure to ambient PM2.5 is positively associated with maternal inflammatory pathways in late pregnancy. This may contribute to positive associations between ambient PM2.5 and risk of adverse pregnancy outcomes.

Which intensities, types, and patterns of movement behaviors are most strongly associated with cardiometabolic risk factors among children?

PURPOSE: The purpose of this study was to determine which intensities, patterns, and types of 24-h movement behaviors are most strongly associated with cardiometabolic risk factors among children. METHODS: A total of 369 children aged 10-13 years were studied. Participants wore an Actical accelerometer and a Garmin Forerunner 220 Global Positioning System logger and completed an activity and sleep log for 7 days. Data from these instruments were combined to estimate average minute per day spent in 14 intensities, 11 types, and 14 patterns of movement. Body mass index, resting heart rate, and systolic blood pressure values were combined to create a cardiometabolic risk factor score. Partial least squares regression analysis was used to examine associations between the 39 movement behavior characteristics and the cardiometabolic risk factor score. The variable importance in projection (VIP) values were used to determine and rank important movement behavior characteristics. There was evidence of interaction by biological maturity, and the analyses were conducted separately in the 50% least mature and 50% most mature participants. RESULTS: For the least biologically mature participants, fifteen of the 39 movement behavior characteristics had important VIP value scores; eight of these reflected movement intensities (particularly moderate and vigorous intensities), six reflected movement patterns, and one reflected a movement type. For the most mature participants, thirteen of the 39 movement behavior characteristics had important VIP value scores, with five reflecting intensities (particularly moderate and vigorous intensities), five reflecting patterns, and three reflecting types of movement. CONCLUSION: More than 12 movement behavior characteristics were associated with cardiometabolic risk factors within both the most and least mature participants. Movement intensities within the moderate and vigorous intensity ranges were the most consistent correlates of these risk factors.

Association of perfluoroalkyl substances with gestational hypertension and preeclampsia in the MIREC study.

BACKGROUND: Perfluoroalkyl substances (PFAS) have been linked with a number of developmental, reproductive, hepatic, and cardiovascular health outcomes. However, the evidence for an association between PFAS and hypertensive disorders of pregnancy (including gestational hypertension and preeclampsia) is equivocal and warrants further investigation. OBJECTIVES: To examine the relationship between background levels of perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorohexane sulfonate (PFHxS) and the development of gestational hypertension or preeclampsia in a Canadian pregnancy cohort. We also explored the potential for effect modification according to fetal sex. METHODS: Maternal plasma samples were collected in the first trimester from participants in the MIREC study and were analyzed for PFOA, PFOS, and PFHxS. Blood pressure was measured during each trimester. Gestational hypertension and preeclampsia were defined using the Society of Obstetricians and Gynaecologists of Canada guidelines. Logistic regression models were used to derive adjusted odds ratios (OR) and 95% confidence intervals (CI) for associations between PFAS concentrations (per doubling of concentration as well as according to tertiles) and gestational hypertension or preeclampsia. Linear mixed models were used to examine the association between PFAS concentrations and changes in blood pressure throughout pregnancy. RESULTS: Data from 1739 participants were analyzed. 90% of women were normotensive throughout pregnancy, 7% developed gestational hypertension without preeclampsia, and 3% developed preeclampsia. In the full analyses, neither PFOA nor PFOS were associated with gestational hypertension or preeclampsia. However, each doubling of PFHxS plasma concentration was associated with higher odds of developing preeclampsia (OR = 1.32; 95% CI: 1.03, 1.70). In addition, participants in the highest PFHxS tertile (1.4-40.0 µg/L) had higher odds of developing preeclampsia relative to those in the lowest tertile (OR = 3.06; 95% CI: 1.27, 7.39). In stratified analyses, this effect was only apparent among women carrying a female fetus (OR = 4.90; 95% CI: 1.02, 22.3). However, among women carrying a male fetus, both PFOS and PFHxS were associated with gestational hypertension, but not preeclampsia. Higher plasma concentrations of all three PFAS were associated with increases in diastolic blood pressure throughout pregnancy, and PFOA and PFHxS were also associated with systolic blood pressure. Discrepant findings were similarly revealed in analyses stratified by fetal sex. CONCLUSIONS: Higher levels of PFHxS were associated with the development of preeclampsia, but not gestational hypertension. Neither PFOA nor PFOS were associated with either outcome. However, we show, for the first time, that fetal sex may modify these associations, a finding which warrants replication and further study.

Is replacing time spent in 1 type of physical activity with another associated with health in children?

Altering the proportion of total physical activity time accumulated while participating in different types of physical activity may influence health. Our objective was to use observational data to estimate whether replacing time from 1 type of physical activity with another is associated with physical and mental health indicators among children. Participants were 385 children aged 10-13 years. They wore a Global Positioning System watch and accelerometer and completed an activity log for 7 days. Data from these instruments was used to estimate time spent in outdoor active play, organized sport, curriculum-based physical activity at school, and active transportation. A cardiometabolic risk factor score was created from body fat, resting heart rate, and resting blood pressure measures. An internalizing symptoms score was created using anxiety and depression symptom questionnaire items. Isotemporal substitution models estimated if health indicators changed when time in 1 type of physical activity was replaced with equivalent time from another. The results indicated that time spent in all types of physical activity combined was associated with the cardiometabolic risk factor and internalizing symptom scores. Replacing active transportation with outdoor active play was associated with an increase in the internalizing symptoms score but a decrease in the cardiometabolic risk factor score. The internalizing symptoms score decreased when active transportation was replaced by equivalent time in organized sport. Other time substitutions were not significant. In conclusion, the total time spent participating in physical activity and not a specific type of physical activity was the most consistent correlate of the health indicators.