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Objective: Characterizing the seroprevalence of SARS-CoV-2 antibodies in children is needed to optimize the COVID-19 public health response. We quantified the seroprevalence of SARS-CoV-2 infection-acquired antibodies and vaccine-acquired antibodies among children receiving primary care in Toronto, Canada., Methods: We conducted a longitudinal cohort study between January 2021 and November 2022 in healthy children aged 0-16 years receiving primary care in Toronto. The primary and secondary outcomes were seroprevalence of SARS-COV-2 infection-acquired antibodies and vaccine-acquired antibodies ascertained from finger-prick dried blood spots. Samples were tested using an enzyme-linked immunosorbent assay for antibodies to full-length spike trimer and nucleocapsid. We explored sociodemographic differences with Firth's penalized generalized estimating equations., Results: Of the 475 participants, 50.1% were girls and mean age was 6.4 years (SD = 3.2). We identified 103 children seropositive for infection-acquired antibodies, with a crude seroprevalence that rose from 2.6% (95%CI 1.39-4.92) from January to July 2021 to 50.7% (95%CI 39.5-61.8) by July to November 2022. Seroprevalence of vaccine-acquired antibodies was 45.2% by July to November 2022 (95%CI 34.3-56.58). No differences in sociodemographic factors (age, sex, income, or ethnicity) were identified for infection-acquired antibodies; however, children with vaccine-acquired antibodies were more likely to be older, have mothers with university education, and have mothers who had also been vaccinated., Conclusion: Our results provide a benchmark for seroprevalence of SARS-CoV-2 antibodies in children in Toronto. Ongoing monitoring of the serological status of children is important, particularly with the emergence of new variants of concern, low vaccine coverage, and discontinuation of PCR testing., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethics approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional (REB# 20–080 Unity Health Toronto Research Ethics) and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Consent to participate: Informed consent was obtained from all individual participants included in the study., (© 2024. The Author(s) under exclusive license to The Canadian Public Health Association.)

Objectives: This study aimed to investigate adverse events (AEs) in trauma resuscitation, evaluate contributing factors, and assess methods, such as trauma video review (TVR), to mitigate AEs., Background: Trauma remains a leading cause of global mortality and morbidity, necessitating effective trauma care. Despite progress, AEs during trauma resuscitation persist, impacting patient outcomes and the healthcare system. Identifying and analyzing AEs and their determinants are crucial for improving trauma care., Methods: This narrative review explored the definition, identification, and assessment of AEs associated with trauma resuscitation within the trauma system. It includes various studies and assessment tools such as STAT Taxonomy and T-NOTECHs. Additionally, it assessed the role of TVR in detecting AEs and strategies to enhance patient safety., Conclusion: Integrated with standardized tools, TVR shows promise for identifying AEs. Challenges include ensuring reporting consistency and integrating approaches into existing protocols. Future research should prioritize linking trauma team performance to patient outcomes, and develop sustainable TVR programs to enhance patient safety., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Vital signs are important factors in assessing injury severity and guiding trauma resuscitation, especially among severely injured patients. Despite this, physiological data are frequently missing from trauma registries. This study aimed to evaluate the extent of missing prehospital data in a hospital-based trauma registry and to assess the associations between prehospital physiological data completeness and indicators of injury severity., Methods: A retrospective review was conducted on all adult trauma patients brought directly to a level 1 trauma center in Toronto, Ontario by paramedics from January 1, 2015, to December 31, 2019. The proportion of missing data was evaluated for each variable and patterns of missingness were assessed. To investigate the associations between prehospital data completeness and injury severity factors, descriptive and unadjusted logistic regression analyses were performed., Results: A total of 3,528 patients were included. We considered prehospital data missing if any of heart rate, systolic blood pressure, respiratory rate or oxygen saturation were incomplete. Each individual variable was missing from the registry in approximately 20 % of patients, with oxygen saturation missing most frequently (n = 831; 23.6 %). Over 25 % (n = 909) of patients were missing at least one prehospital vital sign, of which 69.1 % (n = 628) were missing all four of these variables. Patients with incomplete data were more severely injured, had higher mortality, and more frequently received lifesaving interventions such as blood transfusion and intubation. Patients were most likely to have missing prehospital physiological data if they died in the trauma bay (unadjusted OR: 9.79; 95 % CI: 6.35-15.10), did not survive to discharge (unadjusted OR: 3.55; 95 % CI: 2.76-4.55), or had a prehospital GCS less than 9 (OR: 3.24; 95 % CI: 2.59-4.06)., Conclusion: In this single center trauma registry, key prehospital variables were frequently missing, particularly among more severely injured patients. Patients with missing data had higher mortality, more severe injury characteristics and received more life-saving interventions in the trauma bay, suggesting an injury severity bias in prehospital vital sign missingness. To ensure the validity of research based on trauma registry data, patterns of missingness must be carefully considered to ensure missing data is appropriately addressed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Aim: To assess the acceptability and explore the utility of a novel digital platform designed as a student-facing well-being and mental health support., Methods: An adapted version of i-spero® was piloted as a student-facing well-being support and as part of routine university-based mental health care. In both pathways, student participants completed baseline demographics and brief validated measures of well-being and mental health. Weekly measures of anxiety (GAD-7) and depression (PHQ-9) and a Week 8 Experience Survey were also scheduled. Integrated mixed methods analysis was used to assess acceptability and explore the utility of these platforms., Results: Students in the well-being (n = 120) and care pathways (n = 121) were mostly female and between 19 and 22 years of age. Baseline screen positive rates for anxiety and depression were high in both the well-being (68%) and care pathways (80%). There was a substantial drop in adherence over Week 1 (50% well-being; 40% care) followed by minor attrition up to Week 8. Anxiety and depressive symptom levels improved from baseline in students who dropped out after Week 1 (p ≤ .06). The student experience was that i-spero® improved their emotional self-awareness, understanding of progress in care, and knowledge about when to seek help. Most students agreed (>75%) that i-spero® should form part of regular university student wellness support., Conclusions: Digital well-being and mental health support seems acceptable to university students; however, engagement and persistence are areas for further development. Such digital tools could make a positive contribution to an evidence-based stepped approach to student well-being and mental health support., (© 2023 The Authors. Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

Objective: To investigate the regular use of xylitol, compared with sorbitol, to prevent acute otitis media (AOM), upper respiratory tract infections (URTIs) and dental caries., Design: Blinded randomised controlled trial with a 6-month study period., Setting: Enrolment took place at 11 primary care practices in Ontario, Canada., Patients: Children aged 1-5 years who did not use xylitol or sorbitol at enrolment., Interventions: Children were randomly assigned to use a placebo syrup with sorbitol or xylitol syrup two times per day for 6 months., Main Outcome Measures: Primary outcome was the number of clinician-diagnosed AOM episodes over 6 months. Secondary outcomes were caregiver-reported URTIs and dental caries., Results: Among the 250 randomised children, the mean (SD) age was 38±14 months and there were 124 girls (50%). There were three clinician-diagnosed AOM episodes in the 125 placebo group participants and six in the 125 xylitol group participants (OR 2.04; 95% CI 0.43, 12.92; p=0.50). There was no difference in number of caregiver-reported URTI episodes (rate ratio (RR) 0.88; 95% CI 0.70, 1.11) between the placebo (4.2 per participant over 6 months; 95% CI 3.6, 5.0) and xylitol (3.7; 95% CI 3.2, 4.4) groups. Dental caries were reported for four participants in the placebo group and two in the xylitol group (OR 0.42; 95% CI 0.04, 3.05; p=0.42). In a post-hoc analysis of URTIs during the COVID-19 pandemic, the rate among the 59 participants receiving placebo was 2.3 per participant over 6 months (95% CI 1.8, 3.0) and for the 55 receiving xylitol, 1.3 over 6 months (95% CI 0.92, 1.82; RR 0.56; 95% CI 0.36, 0.87). The most common adverse event was diarrhoea (28% with placebo; 34% with xylitol)., Conclusions: Regular use of xylitol did not prevent AOM, URTIs or dental caries in a trial with limited statistical power. A post-hoc analysis indicated that URTIs were less common with xylitol exposure during the COVID-19 pandemic, but this finding could be spurious., Trial Registration Number: NCT03055091., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This prospective longitudinal study measured sex-specific changes in depression, anxiety, and stress scores using, validated Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and the Perceived Stress Scale (PSS) in a cohort of 1445 post-secondary students (500 males, 945 females) assessed at three time points from December 2020 to January 2022. Participants were ascertained from a population of 15,585 students with in-person activities on campus at baseline and recruited from December 2020 to January 2021. We also assessed how sociodemographic characteristics influenced students' mental health outcomes. Inverse probability weighting was used to account for missing data and attrition. Linear mixed effects models were used to analyze the relationship between the mental health scores in each questionnaire, demographic and academic data, and public health stringency measured by the local stringency index. No change was observed in questionnaire scores over time for males and females, but the stringency index was significantly associated with increased stress. Being in a non-health-related-field or being white affected males and females differently for stress and anxiety, but not depression. Demographics tended to be more influential on females' mental health than males. In conclusion, mental health resource allocation in time of emerging pandemic could benefit from targeted interventions., Competing Interests: Declaration of Competing Interest We declare that we have no known competing interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: Antibiotic prescription for uncomplicated upper respiratory tract infection (URTI) in children is not recommended but remains common. The primary objective was to evaluate the relationship between antibiotic prescription for URTI prior to age 2 and antibiotic prescription for URTI after age 2. It was hypothesized that antibiotic prescription for URTI in early childhood may increase the risk of antibiotic use for subsequent URTIs. The secondary objective was to investigate whether this relationship was different for acute otitis media (AOM), for which antibiotics may be indicated., Methods: A prospective cohort study was conducted between December 2008 and March 2016 at 9 primary care practices in Toronto, Canada. Healthy children aged 0-5 years that met TARGet Kids! cohort eligibility criteria were included if they had at least one sick visit prior to age 2 and least one sick visit after age 2. Generalized Estimating Equation (GEE) models were used to evaluate this relationship while considering within-subject correlation., Results: Of 2380 participants followed for a mean duration of 4.6 years, children who received an antibiotic prescription for URTI prior to age 2 had higher odds of receiving an antibiotic prescription for URTI in later childhood (adjusted odds ratio: 1.39; 95% confidence interval: 1.19 to 1.63; P < .001). This relationship did not appear to be different for AOM compared to non-AOM URTI., Conclusion: Antibiotic prescription for URTI before age 2 was associated with antibiotic prescription for URTI in later childhood. Reducing early life antibiotic prescription for URTI may be associated with reduction in antibiotic prescription for subsequent URTIs., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: The long-term cardiometabolic consequences of late preterm birth (34-36 weeks' gestation) are not well understood., Objective: To assess whether late preterm birth and size for gestational age are associated with cardiometabolic risk (CMR) in childhood., Design, Setting, and Participants: This retrospective cohort study included 1742 children born in Ontario, Canada, between April 1, 2006, and September 30, 2014, and followed up until September 30, 2019. Data from children enrolled in The Applied Research Group for Kids (TARGet Kids!) primary care practice-based research network were linked to administrative health care data at ICES (formerly known as the Institute for Clinical Evaluative Sciences). Participants were excluded if they had conditions affecting growth (eg, failure to thrive or cystic fibrosis), any acute or chronic conditions (other than asthma and high-functioning autism), severe developmental delay, or families who were unable to communicate in English., Exposures: Late preterm birth, gestational age as a continuous measure, and size for gestational age., Main Outcomes and Measures: The primary outcome was composite CMR score (overall age- and sex-standardized z score of CMR components, including waist circumference, log triglyceride level, glucose level, systolic blood pressure, and high-density lipoprotein cholesterol level). Secondary outcomes were the individual CMR components. Multivariable linear regression analysis was used to separately evaluate the associations of late preterm birth, continuous gestational age, and size for gestational age with CMR at ages 3 to 12 years., Results: Among 2440 eligible children, 1742 (mean [SD] age, 5.6 [2.2] years; 951 boys [54.6%]) were included in the final cohort. Overall, 87 children (5.0%) were born moderately preterm (<34 weeks' gestation), 145 (8.3%) were born late preterm (34-36 weeks' gestation), 455 (26.1%) were born early term (37-38 weeks' gestation), and 1055 (60.6%) were born full term (≥39 weeks' gestation). Compared with children born full term, those born moderately preterm (adjusted β = 0.50; 95% CI, 0.24-0.75) and late preterm (adjusted β = 0.27; 95% CI, 0.06-0.47) had higher CMR scores. Each additional gestational week was associated with a 0.06 U (adjusted β; 95% CI, -0.08 to -0.03 U) decrease in CMR., Conclusions and Relevance: In this study, children born late preterm and moderately preterm had higher CMR. These results suggest that screening and early-life interventions for these children may prevent cardiometabolic outcomes.

Background: The effect of being born late preterm (34-36 weeks gestation) on cardiometabolic outcomes across the life course is unclear., Objectives: To systematically review the association between being born late preterm (spontaneous or indicated), compared to the term and cardiometabolic outcomes in children and adults., Data Sources: EMBASE(Ovid), MEDLINE(Ovid), CINAHL., Study Selection and Data Extraction: Observational studies up to July 2021 were included. Study characteristics, gestational age, cardiometabolic outcomes, risk ratios (RRs), odds ratios (ORs), hazard ratios (HRs), mean differences and 95% confidence intervals (CIs) were extracted., Synthesis: We pooled converted RRs using random-effects meta-analyses for diabetes, hypertension, ischemic heart disease (IHD) and body mass index (BMI) with subgroups for children and adults. The risk of bias was assessed using the Newcastle-Ottawa scale and certainty of the evidence was assessed using the grading of recommendations, assessment, development and evaluation (GRADE) approach., Results: Forty-one studies were included (41,203,468 total participants; median: 5.0% late preterm). Late preterm birth was associated with increased diabetes (RR 1.24, 95% CI 1.17, 1.32; nine studies; n = 6,056,511; incidence 0.9%; I 2 51%; low certainty) and hypertension (RR 1.21, 95% CI 1.13, 1.30; 11 studies; n = 3,983,141; incidence 3.4%; I 2 64%; low certainty) in children and adults combined. Late preterm birth was associated with decreased BMI z-scores in children (standard mean difference -0.38; 95% CI -0.67, -0.09; five studies; n = 32,602; proportion late preterm 8.3%; I 2 96%; very low certainty). There was insufficient evidence that late preterm birth was associated with increased IHD risk in adults (HR 1.20, 95% CI 0.89, 1.62; four studies; n = 2,706,806; incidence 0.3%; I 2 87%; very low certainty)., Conclusions: Late preterm birth was associated with an increased risk of diabetes and hypertension. The certainty of the evidence was low or very low. Inconsistencies in late preterm and term definitions, confounding variables and outcome age limited the comparability of studies., (© 2021 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Objectives: To examine the association between mealtime media use and non-HDL-cholesterol as well as other markers of cardiometabolic risk (CMR) in children., Design: A repeated measures study design was used to examine the association between mealtime media use and CMR outcomes. Multivariable linear regression with generalised estimating equations was used to examine the association between mealtime media use and CMR outcomes. Analyses were stratified a priori by age groups (1-4 and 5-13 years)., Setting: The TARGet Kids! Practice-based research network in Toronto, Canada., Participants: 2117 children aged 1-13 years were included in the analysis., Results: After adjusting for covariates, there was no evidence that total mealtime media use was associated with non-HDL-cholesterol in 1-4 year olds (P = 0·10) or 5-13 year olds (P = 0·29). Each additional meal with media per week was associated with decreased HDL-cholesterol in 5-13 year olds (-0·006 mmol/l; 95 % CI -0·009, -0·002; P = 0·003) and log-TAG in 1-4 year olds (β = -0·004; 95 % CI -0·008, -0·00009; P = 0·04). Media use during breakfast was associated with decreased HDL-cholesterol in 5-13 year olds (-0·012 mmol/l; 95 % CI -0·02, -0·004; P = 0·002), while media during lunch was associated with decreased log-TAG (-0·01 mmol/l; 95 % CI -0·03, -0·002; P = 0·03) in children aged 1-4 years. Total mealtime media use was not associated with total cholesterol, glucose or insulin in either age group., Conclusions: Mealtime media use may be associated with unfavourable lipid profiles through effects on HDL-cholesterol in school-aged children but likely not in pre-schoolers.

Background: Bipolar disorder onset peaks over early adulthood and confirmed family history is a robust risk factor. However, penetrance within families varies and most children of bipolar parents will not develop the illness. Individualized risk prediction would be helpful for identifying those young people most at risk and to inform targeted intervention. Using prospectively collected data from the Canadian Flourish High-risk Offspring cohort study available in routine practice, we explored the use of a neural network, known as the Partial Logistic Artificial Neural Network (PLANN) to predict the time to diagnosis of major mood disorders in 1, 3 and 5-year intervals., Results: Overall, for predictive performance, PLANN outperformed the more traditional discrete survival model for 3-year and 5-year predictions. PLANN was better able to discriminate or rank individuals based on their risk of developing a major mood disorder, better able to predict the probability of developing a major mood disorder and better able to identify individuals who would be diagnosed in future time intervals. The average AUC achieved by PLANN for 5-year prediction was 0.74, which indicates good discrimination., Conclusions: This evaluation of PLANN is a useful step in the investigation of using neural networks as tools in the prediction of mood disorders in at-risk individuals and the potential that neural networks have in this field. Future research is needed to replicate these findings in a separate high-risk offspring sample.

Aim: Transition to university is associated with unique stressors and coincides with the peak period of risk for onset of mental illness. Our objective in this analysis was to estimate the mental health need of students at entry to a major Canadian university., Methods: After a student-led engagement campaign, all first year students were sent a mental health survey, which included validated symptom rating scales for common mental disorders. Rates of self-reported lifetime mental illness, current clinically significant symptoms and treatment stratified by gender are reported. The likelihood of not receiving treatment among those symptomatic and/or with lifetime disorders was estimated., Results: Fifty-eight per cent of all first-year students (n = 3029) completed the baseline survey, of which 28% reported a lifetime mental disorder. Moreover, 30% of students screened positive for anxiety symptoms, 28% for depressive symptoms, and 18% for sleep problems with high rates (≅45%) of associated impairment. Only 8.5% of students indicated currently receiving any form of treatment. Females were more likely to report a lifetime diagnosis, anxiety and depressive symptoms, as well as current treatment. Over 25% of students reported lifetime suicidal thoughts and 6% suicide attempt(s). Current weekly binge drinking (25%) and cannabis use (11%) were common, especially in males., Conclusions: There is limited systematically collected data describing the mental health needs of young people at entry to university. Findings of this study underscore the importance of timely identification of significant mental health problems as part of a proactive system of effective student mental health care., (© 2020 John Wiley & Sons Australia, Ltd.)

Background: While bariatric surgery has proven to be effective to achieve significant weight loss and short-term improvements in both physical and mental (HRQoL), little is known about the factors associated with long-term decline in mental HRQoL after bariatric surgery., Objective: To examine differences in physical and mental HRQoL trajectories in a bariatric patient population 3 years after bariatric surgery and examine associated sociodemographic, weight, and mental health factors., Setting: A Canadian academic bariatric care center., Methods: A group-based trajectory model was used to examine physical and mental HRQoL trajectories 3 years after bariatric surgery. In a prospective cohort bariatric sample (n = 2270), demographic factors, body mass index, binge eating symptoms, anxiety symptoms (Generalized Anxiety Disorder-7), depressive symptoms (Patient Health Questionnaire-9), and physical and mental HRQoL (Short-form health survey-36 (SF-36)), were measured at baseline, 6 months, 1, 2, and 3 years respectively. The effect of time-varying covariates (body mass index, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7) were investigated to examine effects on physical and mental HRQoL trajectories., Results: Five distinct trajectories described changes in (n = 1939 of 2270) individuals' physical HRQoL outcomes (SF-36-physical health component summary score) and five other trajectories described changes in mental HRQoL (SF-36-mental health component summary score) outcomes from baseline to 3 years postsurgery. The group-based distribution for the 5 physical HRQoL trajectories were as follows: (1) low baseline-stable low (5.8%); (2) low baseline-moderate rise (12%); (3) low baseline-stable high (41.1%); (4) high baseline-stable high (33.2%); and (5) moderate baseline-decline (7.9%). The 5 mental HRQoL trajectories were as follows: (1) low baseline-slow decline (10%); (2) low baseline-stable high (25%); (3) high baseline-unstable rise (12%); (4) high baseline-stable high (48.9%); and (5) high baseline-transient decline (4.1%). Compared with physical HRQoL, mental HRQoL trajectories were not associated with changes in body mass index, yet strongly correlated with changes in binge eating symptoms, Generalized Anxiety Disorder-7, and Patient Health Questionnaire measures at all time points., Conclusion: This study demonstrates distinct patterns in physical and mental HRQoL trajectories after bariatric surgery. The decline in mental HRQoL trajectories was more heterogeneous and associated with several psychosocial predictors that may be useful to guide risk prediction of long-term physical and mental HRQoL outcomes postbariatric surgery., (Copyright © 2020 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: This study examined the relative impact of breastfeeding duration and timing of solids introduction on BMI z score (BMIz) trajectory in early childhood., Methods: This study conducted secondary analyses of data from the Melbourne Infant Feeding, Activity and Nutrition Trial (InFANT) Program (N = 542), a prospective cohort study with data collected at birth and 3, 9, 18, 42, and 60 months. Linear spline multilevel models were performed., Results: Differential growth rates were observed from birth to 3 months and from 9 to 18 months by breastfeeding duration (≥ 6 vs. < 6 months) and timing of solids introduction (before vs. after 6 months). Children who were breastfed for ≥ 6 versus < 6 months had lower BMIz at all ages from 3 to 60 months. The difference remained after adjusting for child and maternal factors, and the adjusted mean differences in BMIz at 3, 9, 18, 42, and 60 months were -0.34, -0.44, -0.13, -0.19, and -0.23, respectively. Children who received solids before versus after 6 months of age had higher BMIz at 18 and 42 months, but adjustment for child and maternal factors attenuated these differences., Conclusions: Longer breastfeeding duration was associated with lower BMIz to 5 years of age, providing further support for infant feeding guidelines to prolong breastfeeding duration for healthy growth., (© 2020 The Obesity Society.)

Objective: The authors sought to describe the emergent course of bipolar disorder in offspring of affected parents subgrouped by parental response to lithium prophylaxis., Methods: Parent bipolar disorder was confirmed by the best-estimate procedure and lithium response by research protocol. High-risk offspring (N=279) and control subjects (N=87) were blindly assessed, annually on average, with the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime version or the Schedule for Affective Disorders and Schizophrenia-Lifetime version. DSM-IV diagnoses were confirmed using the best-estimate procedure in blind consensus reviews. Cumulative incidence and median age at onset were determined for lifetime syndrome- and symptom-level data. Mixed models assessed the association between parent and offspring course. A multistate model was used to estimate the clinical trajectory into bipolar disorder., Results: The cumulative incidence of bipolar disorder was 24.5%, and the median age at onset was 20.7 years (range, 12.4 to 30.3). The clinical course of the affected parent was associated with that of the affected child. Depressive episodes predominated during the early bipolar course, especially among offspring of lithium responders. Childhood sleep and anxiety disorders significantly predicted 1.6-fold and 1.8-fold increases in risk of mood disorder, respectively, and depressive and manic symptoms predicted 2.7-fold and 2.3-fold increases in risk, respectively. The best-fit model of emerging bipolar disorder was a progressive sequence from nonspecific childhood antecedents to adolescent depression to index manic or hypomanic episode. Subthreshold sleep symptoms were significantly associated with transition from well to non-mood disorder, and psychotic symptoms in mood episodes were significantly associated with transition from unipolar to bipolar disorder., Conclusions: Bipolar disorder in individuals at familial risk typically unfolds in a progressive clinical sequence. Childhood sleep and anxiety disorders are important predictors, as are clinically significant mood symptoms and psychotic symptoms in depressive episodes.

Bipolar disorder is highly heritable and typically onsets in late adolescence or early adulthood. Evidence suggests that immune activation may be a mediating pathway between genetic predisposition and onset of mood disorders. Building on a prior study of mRNA and protein levels in high-risk offspring published in this Journal, we conducted a preliminary examination of methylation profiles in candidate immune genes from a subsample of well-characterized emergent adult (mean 20 years) offspring of bipolar parents from the Canadian Flourish high-risk cohort. Models were adjusted for variable age at DNA collection, sex and antidepressant and mood stabilizer use. On cross-sectional analysis, there was evidence of higher methylation rates for BDNF-1 in high-risk offspring affected (n = 27) and unaffected (n = 23) for mood disorder compared to controls (n = 24) and higher methylation rates in affected high-risk offspring for NR3C1 compared to controls. Longitudinal analyses (25 to 34 months) provided evidence of steeper decline in methylation rates in controls (n = 24) for NR3C1 compared to affected (n = 15) and unaffected (n = 11) high-risk offspring and for BDNF-2 compared to affected high-risk. There was insufficient evidence that changes in any of the candidate gene methylation rates were associated with illness recurrence in high-risk offspring. While preliminary, findings suggest that longitudinal investigation of epigenetic markers in well-characterized high-risk individuals over the peak period of risk may be informative to understand the emergence of bipolar disorder.

Background: Differences in cortisol secretion may differentiate individuals at high compared to low genetic risk for bipolar disorder (BD) and predict the onset or recurrence of mood episodes. The objectives of this study were to determine if salivary cortisol measures are: (1) different in high-risk offspring of parents with BD (HR) compared to control offspring of unaffected parents (C), (2) stable over time, (3) associated with the development of mood episode onset/recurrence, and (4) influenced by comorbid complications., Methods: Fifty-three HR and 22 C completed salivary cortisol sampling annually for up to 4 years in conjunction with semi-structured clinical interviews. The cortisol awakening response (CAR), daytime cortisol [area under the curve (AUC)], and evening cortisol (8:00 p.m.) were calculated., Results: There were no differences in baseline CAR, AUC and evening cortisol between HR and C (p = 0.38, p = 0.30 and p = 0.84), respectively. CAR, AUC and evening cortisol were stable over yearly assessments in HR, while in Cs, evening cortisol increased over time (p = 0.008), and CAR and AUC remained stable. In HR, AUC and evening cortisol increased the hazard of a new onset mood disorder/recurrence by 2.7 times (p = 0.01), and 3.5 times (p = 0.01), respectively, but this was no longer significant after accounting for multiple comparisons., Conclusions: Salivary cortisol is stable over time within HR offspring. However, between individuals, basal salivary cortisol is highly variable. More research is needed, with larger samples of prospectively studied HR youth using a more reliable method of cortisol measurement, to determine the potential role of cortisol in the development of mood disorders.

Bipolar disorder is a highly heritable illness that onsets in adolescence and young adulthood. We examined gene expression (mRNA) and protein levels of candidate immune and neurotrophic markers in well-characterized offspring of bipolar parents in order to identify reliable indicators of illness risk status and the early clinical stages of illness development. We measured mRNA expression and protein levels in candidate immune (TNF-α, IL-1β, IL-10, IFN-δ) and neurotrophic (brain-derived neurotrophic factor (BDNF)) markers from plasma. High-risk offspring were identified from families in which one parent had confirmed bipolar disorder. Control offspring were identified from families in which neither parent met lifetime criteria for a major psychiatric disorder. All parental Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnoses were based on Schedule for Affective Disorders - Lifetime Version (SADS-L) interviews and blind consensus review. As part of an ongoing study, all offspring were prospectively assessed using KSADS-PL format interviews and diagnoses confirmed on blind consensus review. High-risk offspring had significantly increased IL-6 (p = 0.050) and BDNF (p = 0.006) protein levels compared to controls. Those high-risk offspring in earlier compared to later clinical stages of illness development had higher IL-6 (p = 0.050) and BDNF (p = 0.045) protein levels. After adjustments, only differences in BDNF protein levels remained significant. There was a moderating effect of the BDNF genotype on both gene expression and protein levels in high-risk compared to control offspring. The BDNF genotype also moderated the association between clinical stage and gene expression levels in high-risk offspring. These findings provide support for detectable differences in candidate immune and neurotrophic markers in individuals at high risk of developing bipolar disorder and for detectable changes over the clinical stages of illness development. These associations appear to be moderated by genetic variants.

Background: Bipolar disorder is highly heritable and therefore longitudinal observation of children of affected parents is important to mapping the early natural history., Aims: To model the developmental trajectory of bipolar disorder based on the latest findings from an ongoing prospective study of the offspring of parents with well-characterised bipolar disorder., Method: A total of 229 offspring from families in which 1 parent had confirmed bipolar disorder and 86 control offspring were prospectively studied for up to 16 years. High-risk offspring were divided into subgroups based on the parental long-term response to lithium. Offspring were clinically assessed and DSM-IV diagnoses determined on masked consensus review using best estimate procedure. Adjusted survival analysis and generalised estimating equations were used to calculate differences in lifetime psychopathology. Multistate models were used to examine the progression through proposed clinical stages., Results: High-risk offspring had an increased lifetime risk of a broad spectrum of disorders including bipolar disorder (hazard ratio (HR) = 20.89; P = 0.04), major depressive disorder (HR = 17.16; P = 0.004), anxiety (HR = 2.20; P = 0.03), sleep (HR = 28.21; P = 0.02) and substance use disorders (HR = 2.60; P = 0.05) compared with controls. However, only offspring from lithium non-responsive parents developed psychotic disorders. Childhood anxiety disorder predicted an increased risk of major mood disorder and evidence supported a progressive transition through clinical stages, from non-specific psychopathology to depressive and then manic or psychotic episodes., Conclusions: Findings underscore the importance of a developmental approach in conjunction with an appreciation of familial risk to facilitate earlier accurate diagnosis in symptomatic youth.

Background: Anxiety disorders are common among the offspring of parents with bipolar disorder (BD). This study investigated the nature of the association between anxiety disorders and mood disorders in a prospectively studied high-risk cohort., Methods: High-risk offspring were identified from families in which one parent had confirmed BD based on SADS-L interviews and best estimate diagnostic procedures. All agreeable offspring aged 8-25 years were enrolled in a longitudinal study involving repeated KSADS-PL format clinical assessments. Control (C) offspring from families in which neither parent met lifetime criteria for a psychiatric disorder were similarly assessed. All DSM-IV diagnoses in the offspring were confirmed on blind consensus review. Cumulative incidence and adjusted Cox Proportional Hazards models were used to calculate the risk of anxiety disorders and the predictive association with mood disorders., Results: The cumulative incidence of anxiety disorders was higher (23.40% vs. 10.42%; HR=2.136; p=.0382) and occurred earlier (9.79 vs. 14.84 years; p=.0125) in high-risk compared to C offspring. In high-risk offspring generalized anxiety disorders (GAD) followed by social phobia were the most incident anxiety subtypes; while high emotionality (HR 1.111; p=.0096) and shyness (HR 1.144; p=.0053) increased the risk of anxiety disorders. Anxiety disorders increased the adjusted risk of mood disorders (HR 2.166; p=.0004), on average 8.49 years later (SD 5.97)., Limitations: The cumulative incidence of BD is relatively low, as the cohort is still in the period of risk., Conclusions: Findings highlight the need for longitudinal surveillance of symptomatic high-risk children and suggest anxiety disorders are an important early intervention target., (Copyright © 2013 Elsevier B.V. All rights reserved.)