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Aims: To evaluate associations between 24-h ambulatory blood pressure monitor (ABPM) data vs. single casual blood pressure (BP) and albuminuria in youth with type 2 diabetes., Methods: A cross-sectional analysis of youth with type 2 diabetes 10-<18 yrs. from the iCARE cohort., Main Exposures: daytime HTN (+/- nocturnal), isolated nocturnal HTN and single casual BP., Main Outcome: non-orthostatic urine albumin: creatinine ratio (ACR) ≥ 3 mg/mmol and log-transformed urine ACR. Regressions evaluated associations between 1. HTN status based on ABPM and log-transformed urine ACR (continuous) and 2. ABPM-derived BP z-scores and casual BPcentiles and albuminuria status (categorical)., Results: Of 281 youth included, 19.6 % had daytime HTN (+/- nocturnal), and 28.5 % isolated nocturnal HTN on 24-h ABPM. In multivariate linear regression, HTN (ABPM) (ß = 0.553; p = 0.001), duration of diabetes (ß = 0.857; p = 0.02), HbA1c (ß = 1.172; p ≤0.0001) and ACEI/ARB use (ß = 3.94; p < 0.0001) were positively associated with log-transformed ACR; (R 2  = 0.184). In logistic regression analysis, all ABPM LMS z-scores were positively associated with albuminuria; casual BPcentile was not significant., Conclusions: Youth with type 2 diabetes have high rates of HTN based on 24-ABPM data. ABPM-derived measures of BP are associated with albuminuria. These data support the routine use of ABPM devices to diagnose hypertension in youth with type 2 diabetes., Competing Interests: Declaration of competing interest All authors have no potential conflicts of interest to report., (Copyright © 2023. Published by Elsevier Inc.)

Background: Indigenous children in Canada have high rates of obesity and type 2 diabetes mellitus (T2DM). Culturally appropriate interventions, guided by an Indigenous knowledge-based view of health, are crucial to target these conditions. The objective of this systematic review was to assess the impact of indigenous Knowledge-based lifestyle interventions on the prevention of obesity and T2DM in Indigenous children in Canada., Methods: Database searches were conducted from inception until February 22, 2022. The main outcomes were changes in Body Mass Index (BMI) z-score and the development of T2DM. The other outcomes included adiposity, metabolic, and lifestyle determinants of health. The GRADE approach was used to assess confidence in the evidence., Results: Four non-randomized controlled trials (non-RCTs) and six uncontrolled studies were identified. Peer-led interventions led to a reduction in BMI z-score and waist circumference. GRADE assessment revealed very low quality of evidence due to a lack of randomization and small sample sizes. There were no diabetes-specific reported programs., Conclusion: Limited evidence from non-randomized studies suggest that peer-led indigenous Knowledge-based lifestyle interventions improve BMI z-score and central adiposity. There is a need for community-owned and adequately powered randomized studies for interventions that aim to treat and prevent obesity and T2DM in Indigenous children in Canada., Systematic Review Registration: PROSPERO CRD42017072781., Competing Interests: The authors declare no competing interests., (© 2023 Kshatriya et al.)

Importance: Type 2 diabetes (T2D) is increasing globally. Diabetic retinopathy (DR) is a leading cause of blindness in adults with T2D; however, the global burden of DR in pediatric T2D is unknown. This knowledge can inform retinopathy screening and treatments to preserve vision in this population., Objective: To estimate the global prevalence of DR in pediatric T2D., Data Sources: MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Cochrane Library, the Web of Science, and the gray literature (ie, literature containing information that is not available through traditional publishing and distribution channels) were searched for relevant records from the date of database inception to April 4, 2021, with updated searches conducted on May 17, 2022. Searches were limited to human studies. No language restrictions were applied. Search terms included diabetic retinopathy; diabetes mellitus, type 2; prevalence studies; and child, adolescent, teenage, youth, and pediatric., Study Selection: Three teams, each with 2 reviewers, independently screened for observational studies with 10 or more participants that reported the prevalence of DR. Among 1989 screened articles, 27 studies met the inclusion criteria for the pooled analysis., Data Extraction and Synthesis: This systematic review and meta-analysis followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines for systematic reviews and meta-analyses. Two independent reviewers performed the risk of bias and level of evidence analyses. The results were pooled using a random-effects model, and heterogeneity was reported using χ2 and I2 statistics., Main Outcomes and Measures: The main outcome was the estimated pooled global prevalence of DR in pediatric T2D. Other outcomes included DR severity and current DR assessment methods. The association of diabetes duration, sex, race, age, and obesity with DR prevalence was also assessed., Results: Among the 27 studies included in the pooled analysis (5924 unique patients; age range at T2D diagnosis, 6.5-21.0 years), the global prevalence of DR in pediatric T2D was 6.99% (95% CI, 3.75%-11.00%; I2 = 95%; 615 patients). Fundoscopy was less sensitive than 7-field stereoscopic fundus photography in detecting retinopathy (0.47% [95% CI, 0%-3.30%; I2 = 0%] vs 13.55% [95% CI, 5.43%-24.29%; I2 = 92%]). The prevalence of DR increased over time and was 1.11% (95% CI, 0.04%-3.06%; I2 = 5%) at less than 2.5 years after T2D diagnosis, 9.04% (95% CI, 2.24%-19.55%; I2 = 88%) at 2.5 to 5.0 years after T2D diagnosis, and 28.14% (95% CI, 12.84%-46.45%; I2 = 96%) at more than 5 years after T2D diagnosis. The prevalence of DR increased with age, and no differences were noted based on sex, race, or obesity. Heterogeneity was high among studies., Conclusions and Relevance: In this study, DR prevalence in pediatric T2D increased significantly at more than 5 years after diagnosis. These findings suggest that retinal microvasculature is an early target of T2D in children and adolescents, and annual screening with fundus photography beginning at diagnosis offers the best assessment method for early detection of DR in pediatric patients.

In children with diabetic ketoacidosis (DKA), insulin infusions are the mainstay of treatment; however, optimal dosing remains unclear. Our objective was to compare the efficacy and safety of different insulin infusion doses for the treatment of pediatric DKA., Data Sources: We searched MEDLINE, EMBASE, PubMed, and Cochrane from inception to April 1, 2022., Study Selection: We included randomized controlled trials (RCTs) of children with DKA comparing intravenous insulin infusion administered at 0.05 units/kg/hr (low dose) versus 0.1 units/kg/hr (standard dose)., Data Extraction: We extracted data independently and in duplicate and pooled using a random effects model. We assessed the overall certainty of evidence for each outcome using the Grading Recommendations Assessment, Development and Evaluation approach., Data Synthesis: We included four RCTs ( n = 190 participants). In children with DKA, low-dose compared with standard-dose insulin infusion probably has no effect on time to resolution of hyperglycemia (mean difference [MD], 0.22 hr fewer; 95% CI, 1.19 hr fewer to 0.75 hr more; moderate certainty), or time to resolution of acidosis (MD, 0.61 hr more; 95% CI, 1.81 hr fewer to 3.02 hr more; moderate certainty). Low-dose insulin infusion probably decreases the incidence of hypokalemia (relative risk [RR], 0.65; 95% CI, 0.47-0.89; moderate certainty) and hypoglycemia (RR, 0.37; 95% CI, 0.15-0.80; moderate certainty), but may have no effect on rate of change of blood glucose (MD, 0.42 mmol/L/hr slower; 95% CI, 1 mmol/L/hr slower to 0.18 mmol/L/hr faster; low certainty)., Conclusions: In children with DKA, the use of low-dose insulin infusion is probably as efficacious as standard-dose insulin, and probably reduces treatment-related adverse events. Imprecision limited the certainty in the outcomes of interest, and the generalizability of the results is limited by all studies being performed in a single country., Competing Interests: Dr. Sharif holds a McMaster University Department of Medicine Internal Career Research Award. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Type 2 diabetes (T2D) rates in children and adolescents are rising globally. T2D is a complex and aggressive disease in children with several comorbidities, high treatment failure rates, and insulin needs within a few years from diagnosis. While myriads of pharmacotherapies are licensed to treat adults with T2D, treatments accessible to children and adolescents have been limited until recently. Metformin is an old drug with multiple beneficial metabolic health effects beyond glycemic control. This review discusses Metformin's origins, its mechanisms of action, and evidence for its use in the pediatric population to treat and prevent T2D. We also explore the evidence for its use as an obesity therapy, which is the primary driver of T2D, and T2D-driven comorbidities. While emerging therapies create new horizons for managing pediatric T2D, Metformin remains an inexpensive and safe part of the treatment plans of many T2D children globally for its beneficial metabolic effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Alfaraidi and Samaan.)

Importance: The childhood obesity epidemic is presumed to drive pediatric type 2 diabetes (T2D); however, the global scale of obesity in children with T2D is unknown., Objectives: To evaluate the global prevalence of obesity in pediatric T2D, examine the association of sex and race with obesity risk, and assess the association of obesity with glycemic control and dyslipidemia., Data Sources: MEDLINE, Embase, CINAHL, Cochrane Library, and Web of Science were searched from database inception to June 16, 2022., Study Selection: Observational studies with at least 10 participants reporting the prevalence of obesity in patients with pediatric T2D were included., Data Extraction and Synthesis: Following the Meta-analysis of Observational Studies in Epidemiology reporting guideline, 2 independent reviewers in teams performed data extraction and risk of bias and level of evidence analyses. The meta-analysis was conducted using a random-effects model., Main Outcomes and Measures: The primary outcomes included the pooled prevalence rates of obesity in children with T2D. The secondary outcomes assessed pooled prevalence rates by sex and race and associations between obesity and glycemic control and dyslipidemia., Results: Of 57 articles included in the systematic review, 53 articles, with 8942 participants, were included in the meta-analysis. The overall prevalence of obesity among pediatric patients with T2D was 75.27% (95% CI, 70.47%-79.78%), and the prevalence of obesity at diabetes diagnosis among 4688 participants was 77.24% (95% CI, 70.55%-83.34%). While male participants had higher odds of obesity than female participants (odds ratio, 2.10; 95% CI, 1.33-3.31), Asian participants had the lowest prevalence of obesity (64.50%; 95% CI, 53.28%-74.99%), and White participants had the highest prevalence of obesity (89.86%; 95% CI, 71.50%-99.74%) compared with other racial groups. High heterogeneity across studies and varying degrees of glycemic control and dyslipidemia were noted., Conclusions and Relevance: The findings of this systematic review and meta-analysis suggest that obesity is not a universal phenotype in children with T2D. Further studies are needed to consider the role of obesity and other mechanisms in diabetes genesis in this population.

Background: The COVID-19 pandemic led to substantial shifts in pediatric diabetes care delivery to virtual and hybrid models. It is unclear if these changes in care delivery impacted short-term patient outcomes., Objectives: We aimed to explore glycemic control and other diabetes-related outcomes in children living with Type 1 Diabetes Mellitus (T1DM) during the first year of the COVID-19 pandemic at a tertiary pediatric academic center in Canada., Subjects: Patients <18 years of age with a confirmed diagnosis of T1DM for at least one year were included., Methods: This was a retrospective chart review. We compared data from two years pre-pandemic (March 15, 2018-March 14, 2020) to the first year of the pandemic (March 15, 2020-March 14, 2021). The data assessed included glycemic control [Hemoglobin A1c (HbA1c)], diabetic ketoacidosis (DKA), hospital attendance and hospitalizations, hypoglycemia, and hyperglycemia. The generalized estimating equation (GEE) analysis was used to model potential factors affecting the HbA1c and diabetes-related morbidities. Multiple imputations were conducted as a sensitivity analysis., Results: There were 346 eligible patients included in the study. The HbA1c remained stable during the pandemic compared to the pre-pandemic phase (MD-0.14, 95% CI, -0.28, 0.01; p  = 0.058). The pandemic saw an increase in the number of newly diagnosed patients (X 2  = 16.52, p  < 0.001) and a higher number of newly diagnosed patients presenting in DKA (X 2  = 12.94, p  < 0.001). In patients with established diabetes, there was an increase in hyperglycemia (OR1.38, 95% CI, 1.12,1.71; p  = 0.003) and reduced DKA (OR 0.30, 95% CI, 0.12,0.73; p  = 0.009) during the pandemic compared to the pre-pandemic phase. Stable rates of hospitalization (OR0.57, 95% CI, 0.31,1.04, p  = 0.068) and hypoglycemia (OR1.11, 95% CI, 0.83,1.49; p  = 0.484) were noted. These results were retained in the sensitivity analysis., Conclusions: Glycemic control in children with T1DM remained stable during the first year of the pandemic. There were more newly diagnosed patients during the pandemic compared to the pre-pandemic phase, and more of these new patients presented in DKA. The latter presentation was reduced in those with established diabetes during the same period.Further studies are needed to assess the ongoing impact of the COVID-19 pandemic on T1DM care pathways and outcomes to allow children, families, and diabetes teams to personalize choices of care models., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Rajan, Athale, Ewusie, McAssey, Thabane and Samaan.)

Introduction: The rates of type 2 diabetes mellitus (T2DM) in children and adolescents have risen globally over the past few years. While a few diabetes pharmacotherapies have been used in this population, their comparative benefits and harms are unclear. Thus, we will conduct a systematic review and network meta-analysis (NMA) of randomised controlled trials (RCTs) to compare the efficacy and safety of pharmacotherapies for managing paediatric T2DM., Methods and Analysis: We will include RCTs that enrolled T2DM patients ≤18 years of age and who were randomised to monotherapy or combination pharmacotherapies with or without lifestyle interventions. Comparator groups will include placebo or non-pharmacological treatments including lifestyle interventions.Treatment outcomes will include change from baseline in glycated haemoglobin A1c, body mass index z-score, weight, systolic/diastolic blood pressure, fasting plasma glucose, fasting insulin and lipid profiles, T2DM-related complications, as well as the incidence of treatment-related adverse events.Literature searches will be conducted in Medline, Embase, CINAHL, CENTRAL and Web of Science. We will also search the grey literature and the reference list of included trials and relevant reviews. Two reviewers will assess the eligibility of articles identified through our searches and will extract data from eligible studies independently. We will use a modified Cochrane instrument to evaluate the risk of bias. Disagreements will be resolved through consensus or arbitration by a third reviewer.A frequentist random-effects model will be used for conducting NMA. The quality of evidence will be assessed using the Confidence in Network Meta-Analysis platform. We will assess the effect modification through network meta-regression and subgroup analyses for sex, age at study inclusion, duration of T2DM, follow-up duration and risk of bias ratings., Ethics and Dissemination: This study will not require ethics approval. We will disseminate our findings through publication in a peer-reviewed journal and conference presentations., Prospero Registration Number: CRD42022310100., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Obesity is a global public health concern. Given the widespread disruption caused by the SARS-CoV-2 pandemic, it is important to evaluate its impact on children with chronic health conditions. This study examines the health of paediatric patients with obesity enrolled in a tertiary hospital weight management program, before and 1 year into the COVID-19 pandemic., Methods: This is a retrospective chart review of patients aged 2 to 17 years enrolled in a paediatric weight management clinic. Mental health outcomes (i.e., new referrals to psychologist, social work, eating disorder program, incidence of dysregulated eating, suicidal ideation, and/or self-harm) and physical health (anthropometric measures) were compared before and 1 year into the pandemic., Results: Among the 334 children seen in either period, there was an increase in referrals to psychologist (12.4% versus 26.5%; P=0.002) and the composite mental health outcome (17.2% versus 30.2%; P=0.005) during the pandemic compared with pre-pandemic. In a subset of children (n=30) with anthropometric measures in both periods, there was a lower rate of decline in BMIz score (-1.5 [2.00] versus -0.3 [0.73]/year; P=0.002) and an increase in adiposity (-0.8 [4.64] versus 2.7 [5.54]%/year; P=0.043) during the pandemic., Discussion: The pandemic has impacted the mental and physical health of children with obesity engaged in a weight management clinic. While our study provides evidence of a negative impact on mental health outcomes and less improvement in anthropometric measures, future research when patients return to in-person care will enable further examination of our findings with additional objective measures., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. 
For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Diabetes mellitus is the most common endocrine disorder in children, and the prevalence of paediatric type 1 and type 2 diabetes continue to rise globally. Diabetes clinical care programs pivoted to virtual care with the COVID-19 pandemic-driven social distancing measures. Yet, the impact of virtual care on health-related quality of life in children living with diabetes remains unclear. This protocol reports on the methods that will be implemented to conduct a systematic review to assess the health-related quality of life and metabolic health impacts of virtual diabetes care., Methods and Analysis: We will search MEDLINE, Embase, EMCare, PsycInfo, Web of Science, and the grey literature for eligible studies. We will screen title, abstract, and full-text papers for potential inclusion and assess the risk of bias and the overall confidence in the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. A meta-analysis will be conducted if two studies report similar populations, study designs, methods, and outcomes.This systematic review will summarise the health-related quality of life outcomes for virtual diabetes care delivery models., Ethics and Dissemination: No ethics approval is required for this systematic review protocol as it does not include patient data. The systematic review will be published in a peer-reviewed journal and presented at international conferences., Prospero Registration Number: CRD42021235646., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: The prevalence of pediatric type 2 diabetes (T2D) is increasing globally. Girls with T2D are at risk of developing polycystic ovary syndrome (PCOS), but the prevalence of PCOS among girls with T2D is unknown., Objective: To determine the prevalence of PCOS in girls with T2D and to assess the association of obesity and race with this prevalence., Data Sources: In this systematic review and meta-analysis, MEDLINE, Embase, CINAHL, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Science: Conference Proceedings Citation Index-Science, and the gray literature were searched from inception to April 4, 2021., Study Selection: Two reviewers independently screened for studies with observational study design that recruited 10 or more participants and reported the prevalence of PCOS in girls with T2D., Data Extraction and Synthesis: Risk of bias was evaluated using a validated tool, and level of evidence was assessed using the Oxford Centre for Evidence-Based Medicine criteria. A random-effects meta-analysis was performed. This study follows the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline., Main Outcomes and Measures: The main outcome of this systematic review was the prevalence of PCOS in girls with T2D. Secondary outcomes included assessing the associations of obesity and race with PCOS prevalence., Results: Of 722 screened studies, 6 studies involving 470 girls with T2D (mean age at diagnosis, 12.9-16.1 years) met the inclusion criteria. The prevalence (weighted percentage) of PCOS was 19.58% (95% CI, 12.02%-27.14%; I2 = 74%; P = .002). Heterogeneity was moderate to high; however, it was significantly reduced after excluding studies that did not report PCOS diagnostic criteria, leading to a calculated prevalence (weighted percentage) of 24.04% (95% CI, 15.07%-33.01%; I2 = 0%; P = .92). Associations with obesity and race could not be determined because of data paucity., Conclusions and Relevance: In this meta-analysis, approximately 1 in 5 girls with T2D had PCOS, but the results of this meta-analysis should be considered with caution because studies including the larger numbers of girls did not report the criteria used to diagnose PCOS, which is a challenge during adolescence. The associations of obesity and race with PCOS prevalence among girls with T2D need further evaluation to help define at-risk subgroups and implement early assessment and treatment strategies to improve management of this T2D-related comorbidity.

Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer. Treatments of ALL predispose survivors to obesity, which increases the risk of cardiovascular disease and diabetes. The hallmark of obesity is excess fat mass, and adiposity is a superior predictor of cardiometabolic risk when compared to Body Mass Index (BMI), yet clinical measures of adiposity in children are lacking. The Tri-Ponderal Mass Index (TMI) (kg/m 3 ) is a more accurate adiposity measure compared to BMI z-score in the general pediatric population. This cross-sectional study aimed to validate TMI as an adiposity measure against DEXA scan-derived adiposity, and to compare it to BMI z-score, in pediatric ALL survivors. This study was a retrospective chart review of pediatric ALL survivors diagnosed between 2004 and 2015 at McMaster Children's Hospital, a tertiary pediatric center in Ontario, Canada. One hundred and thirteen patients (Female n = 55, 48.70%) were included, and adiposity was measured using DEXA scans. Exploratory partial correlations and linear regression analyses were adjusted for age, sex, ethnicity, and ALL risk status. Both TMI and BMI z-score correlated with the DEXA-measured fat mass percentage (FM%) (partial correlation TMI versus FM% r = 0.56; p value < 0.0001; BMI z-score versus FM% r = 0.55; p value < 0.0001). In regression analyses, the association of TMI was not inferior to BMI z-score in assessing adiposity (TMI versus FM% estimated unstandardized B 0.80, 95% CI 0.56, 1.02; p value < 0.0001; BMI z-score versus FM% (unstandardized B 0.37, 95% CI 0.26, 0.49; p value < 0.0001). The TMI is a useful clinical adiposity-specific measure in survivors of pediatric ALL., (© 2022. The Author(s).)

Abstract: Primary adrenal insufficiency is a potentially life-threatening condition that provides a diagnostic challenge because many patients have months to years of insidious symptomatology. Adrenal crisis is the extreme acute manifestation of primary adrenal insufficiency, presenting with any, or all, of severe weakness, altered mental status, hypotension, and rarely cardiorespiratory arrest. Primary adrenal insufficiency should be considered in patients with clinical features of glucocorticoid and/or mineralocorticoid deficiency. These features however, such as hyperpigmentation, may be subtle, and so a degree of suspicion is needed to make the diagnosis. In extremis, children may present with fluid and catecholamine refractory shock. The management of an adrenal crisis includes prompt delivery of stress-dose corticosteroids together with aggressive organ support and correction of metabolic and electrolyte disturbances. We report the case of a previously healthy 10-year-old child that presented to a community emergency department in pulseless arrest, in whom adrenal crisis was suspected as well as treated early, and was subsequently successfully resuscitated., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: This study aims to better understand factors that impact management of patients with diabetic ketoacidosis (DKA) in the pediatric emergency department (ED) by novel application of the threat-and-error model, commonly used in the aviation industry., Methods: This study was a retrospective chart review of all patients diagnosed with DKA and managed in our pediatric ED during a 1-year period. A "flight plan" was created for each patient's ED visit, from triage to final disposition. Each flight was analyzed with the goal of identifying threats and errors that may impact patients' clinical status or management. Particular focus was placed on physicians' adherence to hospital and provincial DKA protocols. Unintended patient states or outcomes were also noted., Results: A total of 46 patient flights were outlined and analyzed. A total of 146 threats were identified, affecting 43 (93%) patient flights. No flight was error-free. Errors in communication and lack of adherence to protocol were the most common types of errors. Unintended patient states occurred in 30 cases (65%), some of which were preceded by at least 1 error. There were no cases of cerebral edema or death., Conclusions: It is important to identify and appropriately mitigate threats and errors that commonly occur during initial management of DKA in the ED to prevent unintended states and patient morbidity. This study demonstrates the threat-and-error model as a potentially useful tool for focusing quality improvement initiatives in the pediatric ED setting., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Our aim in this study was to describe the clinical and social characteristics of 2 Canadian cohorts of adolescents with diabetes., Methods: Participants from the Improving renal Complications in Adolescents with type 2 diabetes through REsearch (iCARE) study (n=322) and the Early Determinants of Cardio-Renal Disease in Youth With Type 1 Diabetes (n=199) study were compared., Results: Adolescents were 10 to 18 years of age (mean ± standard deviation: 14.8±2.4 years). The T2DM cohort had a shorter duration of diabetes. Both groups had glycated hemoglobin levels above target. The type 2 diabetes (T2D) cohort was comprised of predominantly Indigenous youth. The type 1 diabetes (T1D) cohort was 58.3% European/Caucasian, with a high proportion (41.7%) of visible minority groups (Afro-Caribbean, Asian/Pacific Islander, Hispanic). The prevalence of obesity, hypertension, left ventricular hypertrophy, albuminuria and hyperfiltration was higher in the T2D cohort. The T1D cohort was more socially and economically advantaged in all 4 dimensions of health inequality., Conclusions: There are significant differences in clinical and social characteristics of adolescents with T2D and T1D in Canada. Both have inadequate glycemic control with evidence of onset and progression of diabetes-related complications., (Copyright © 2021 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Pediatric type 2 diabetes mellitus (T2DM) patients are often overweight or obese, yet there are no validated clinical measures of adiposity to stratify cardiometabolic risk in this population. The tri-ponderal mass index (TMI, kg/m 3 ) has recently been reported as a measure of adiposity in children, but there has been no validation of the association of TMI with adiposity in pediatric T2DM. We hypothesized that in children with T2DM, the TMI can serve as a more accurate measure of adiposity when compared to BMI z-score, and that it is associated with components of the metabolic syndrome. This is a cross-sectional secondary data analysis from the Improving Renal Complications in Adolescents with Type 2 Diabetes Through REsearch (iCARE) study (n = 116, age 10.20-17.90 years). Spearman's correlations and multivariable regression were used in the analyses. When compared to DXA, TMI demonstrated significant correlation with total adiposity versus BMI z-score (TMI r = 0.74, p-value < 0.0001; BMI z-score r = - 0.08, p-value 0.403). In regression analyses, TMI was associated with WHtR (B = 35.54, 95% CI 28.81, 42.27, p-value < 0.0001), MAP dipping (B = 1.73, 95% CI 0.12, 3.33, p-value = 0.035), and HDL (B = - 5.83, 95% CI - 10.13, - 1.54, p-value = 0.008). In conclusion, TMI is associated with adiposity and components of the metabolic syndrome in pediatric T2DM patients.

Importance: Hypertension and albuminuria are markers of diabetes-related nephropathy and important factors associated with kidney outcomes in pediatric type 2 diabetes. However, their prevalence in these patients is unknown., Objective: To measure the prevalence of hypertension and albuminuria in pediatric patients with type 2 diabetes and to evaluate the association of sex and race/ethnicity with these conditions., Data Sources: MEDLINE, Embase, CINAHL, Cochrane Library, Web of Science, the gray literature, and references of the screened articles were searched for human studies from date of database inception to February 20, 2020., Study Selection: Observational studies with at least 10 participants reporting the prevalence of hypertension and/or albuminuria in pediatric patients with type 2 diabetes were included. Three teams of 2 independent reviewers screened 7614 papers, of which 60 fulfilled the eligibility criteria., Data Extraction and Synthesis: Three teams of 2 independent reviewers performed data extraction, risk of bias analysis, and level of evidence analyses. The meta-analysis was conducted using a random-effects model and followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines., Main Outcomes and Measures: The primary outcomes included the pooled prevalence rates (percentages with 95% CI) for hypertension and albuminuria. The secondary outcomes assessed pooled prevalence rates by sex and racial/ethnic group., Results: Sixty studies were included in the systematic review. Diabetes duration varied from inclusion at diagnosis to 15.0 years after diagnosis, and the reported mean age at diagnosis ranged from 6.5 to 21.0 years. Hypertension prevalence among 3463 participants was 25.33% (95% CI, 19.57%-31.53%). Male participants had higher hypertension risk than female participants (odds ratio [OR], 1.42 [95% CI, 1.10-1.83]), with Pacific Islander and Indigenous youth having the highest prevalence of all racial/ethnic groups (Pacific Islander youth: 26.71% [95% CI, 14.54%-40.72%]; Indigenous youth: 26.48% [95% CI, 17.34%-36.74%]; White youth: 20.95% [95% CI, 12.65%-30.57%]; African American youth: 19.04% [95% CI, 12.01%-27.23%]; Hispanic/Latino youth: 15.11% [95% CI, 6.56%-26.30%]; Asian youth: 18.37% [95% CI, 9.49%-29.23%]). Albuminuria prevalence among 2250 participants was 22.17% (95% CI, 17.34%-27.38%). Pacific Islander youth, Indigenous youth, and Asian youth had higher prevalence rates than White youth (Pacific Islander youth: 31.84% [95% CI, 11.90%-55.47%]; Indigenous youth: 24.27% [95% CI, 14.39%-35.73%]; Asian youth: 23.00% [95% CI, 18.85%-27.41%]; White youth: 12.59% [95% CI, 7.75%-18.33%]), with no sex differences (OR for male vs female participants, 0.68 [95% CI, 0.46-1.01]). Heterogeneity was high among studies, with a low to moderate risk of bias., Conclusions and Relevance: In this study, markers of diabetes-related nephropathy were commonly detected in pediatric patients with type 2 diabetes, with a disproportionate burden noted among Pacific Islander and Indigenous youth. Personalized management strategies to target kidney outcomes are urgently needed in pediatric patients with type 2 diabetes to alleviate the burden of this condition on the kidneys.

Background: Obesity is characterized by the disproportionate expansion of the fat mass and is most commonly diagnosed using the Body Mass Index (BMI) z-score or percentile in children. However, these measures associate poorly with the fat mass. This is important, as adiposity is a more robust predictor of cardiometabolic risk than BMI-based measures, but there are limited clinical measures of adiposity in children. A new measure, the Tri-ponderal Mass Index (TMI, kg/m 3 ) has recently demonstrated robust prediction of adiposity in children. The aim of this study is to explore the association of leptin, a validated biomarker of the fat mass, with TMI., Methods: One hundred and eight children and adolescents were included in this cross-sectional study. Height and weight were used to calculate TMI. Plasma leptin was measured using ELISA. Multivariable regression analysis was applied to determine the predictors of TMI., Results: The age range of participants included in this study was 8.00-16.90 years (female n=48, 44%). Leptin correlated with BMI percentile (r=0.64, p-value <0.0001) and TMI (r=0.71, p-value <0.0001). The multivariable regression analysis revealed that BMI percentile (Estimated Beta-coefficient 0.002, 95% CI 0.002-0.003, p-value <0.0001) and Leptin (Estimated Beta-coefficient 0.05, 95% CI 0.02-0.07, p-value 0.013) were associated with TMI., Conclusion: Leptin is associated with TMI in healthy children. The TMI is a feasible clinical measure of adiposity that may be used to stratify children and adolescents for further assessments and interventions to manage and attempt to prevent cardiometabolic comorbidities., Competing Interests: M.C.S. was funded by the Pediatric Oncology Group of Ontario Research Unit and Hamilton Health Sciences and Foundation. B.E. received funding from Regional Medical Associates (RMA) Hamilton. The funding agencies had no participation in the conception of the research question, study design, data collection and analysis or conclusions. The authors report no other conflicts of interest in this work., (© 2021 Empringham et al.)

Opioid use has reached an epidemic proportion in Canada and the United States that is mostly attributed to excess availability of prescribed opioids for pain. This excess in opioid use led to an increase in the prevalence of opioid use disorder (OUD) requiring treatment. The most common treatment recommendations include medication-assisted treatment (MAT) combined with psychosocial interventions. Clinical trials investigating the effectiveness of MAT, however, have a limited focus on effectiveness measures that overlook patient-important outcomes. Despite MAT, patients with OUD continue to suffer negative consequences of opioid use. Patient goals and personalized medicine are overlooked in clinical trials and guidelines, thus missing an opportunity to improve prognosis of OUD by considering precision medicine in addiction trials. In this mixed-methods study, patients with OUD receiving MAT (n=2,031, mean age 39.1 years [SD 10.7], 44% female) were interviewed to identify patient goals for MAT. The most frequently reported patient-important outcomes were to stop treatment (39%) and to avoid all drugs (25%). These results are inconsistent with treatment recommendations and trial outcome measures. We discuss theses inconsistencies and make recommendations to incorporate these outcomes to achieve patient-centered and personalized treatment strategies.

Introduction: Vaping behaviour has increased in popularity and is particularly important to examine how it effects health outcomes in vulnerable populations, including those with opioid use disorder (OUD). With polysubstance use including cigarette and cannabis use being highly prevalent in the OUD population and cannabis/nicotine increasingly being consumed by vaping, vaping may have an important contribution to health outcomes in these individuals. The primary objective of this review is to systematically assess the literature related to patients with OUD and the effects vaping has shown on their physical and mental health., Method and Analysis: A systematic search of databases including MEDLINE, Embase, PsycINFO, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, Cochrane Clinical Trials Registry, the National Institutes for Health Clinical Trials Registry and the WHO International Clinical Trials Registry Platform from inception to 31 December 2020 will be conducted. Identified citations will be screened by two reviewers to determine eligibility at the title and abstract level, and then at the full text and data extraction phases. Any disagreements in inclusion will be resolved through unblinded discussion by these reviewers, with any remaining disagreements being resolved by a third reviewer. Data collection from eligible studies will be conducted according to the data extraction form tested prior to abstraction. Included studies will be examined for quality and bias and will be meta-analysed where applicable. This protocol is reported in keeping with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines., Ethics and Dissemination: The results for this review will be disseminated through publications in peer-reviewed journals, posters and presentations at scientific conferences. Additionally, we are collaborating with the Canadian Addiction Treatment Centre clinics to help disseminate the findings for this review. As this is a systematic review, no ethics approval is needed., Review Registration Number: CRD42020178441., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

While children with brain tumors are surviving at record rates, survivors are at risk of cardiovascular disease and type 2 diabetes mellitus; these conditions may be driven by excess body fat. Adiponectin in an adipokine that is inversely associated with the fat mass, and has been linked to cardiometabolic risk stratification in the general population. However, adiponectin's profile and determinants in SCBT have not been established. We tested the hypothesis that high molecular weight (HMW) adiponectin levels, the more biologically active form of adiponectin, were associated with adiposity in SCBT similarly to non-cancer controls. Seventy-four SCBT (n = 32 female) and 126 controls (n = 59 female) who were 5-17 years old were included. Partial correlations and multivariable regression analyses assessed the relationship between HMW adiponectin and adiposity. HMW adiponectin was inversely associated with total and central adiposity (FM%: β - 0.21, 95% CI - 0.15, - 0.08; p value < 0.0001; WHR: β - 0.14, 95% CI - 0.02, - 0.01; p value < 0.0001 ;WHtR: β - 0.21, 95% CI - 0.05, - 0.03; p value < 0.0001). In conclusion, HMW adiponectin is inversely correlated with adiposity in SCBT. Adiponectin may serve as a biomarker of cardiometabolic risk and response to interventions to prevent and manage obesity and its comorbidities in SCBT.

Survivors of Childhood Brain Tumors (SCBT) are at a higher risk of developing cardiovascular disease and type 2 diabetes compared to the general population. Adiposity is an important risk factor for the development of these outcomes, and identifying biomarkers of adiposity may help the stratification of survivors based on their cardiovascular risk or allow for early screening and interventions to improve cardiometabolic outcomes. Leptin is an adipokine that positively correlates with the adipose mass in the general population and is a predictor of adverse cardiometabolic outcomes, yet its association with adiposity in SCBT has not been studied. The aim of this study was to determine if leptin levels are associated with the adipose mass in SCBT, and to define its predictors. This cross-sectional study included 74 SCBT (n = 32 females) with 126 non-cancer controls (n = 59 females). Total adiposity was measured using Bioelectrical Impendence Analysis (BIA) and central adiposity was measured using waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR). We used multivariable linear regression analysis to determine if leptin predicts adiposity in SCBT and adjusted for age, sex, puberty, and cancer status. Leptin correlated strongly with total (p < 0.001) and central (WHR p = 0.001; WHtR p < 0.001) adiposity in SCBT and non-cancer controls. In conclusion, leptin is a potential biomarker for adiposity in SCBT, and further investigation is needed to clarify if leptin is a predictor of future cardiometabolic risk in SCBT.

Most children are surviving acute lymphoblastic leukemia (ALL) today. Yet, the emergence of cardiometabolic comorbidities in this population may impact long-term outcomes including the quality of life and lifespan. Obesity is a major driver of cardiometabolic disorders in the general population, and in ALL patients it is associated with increased risk of hypertension, dysglycemia, and febrile neutropenia when compared with lean ALL patients undergoing therapy. This systematic review aims to assess the current evidence for bariatric interventions to manage obesity in children with ALL. The primary outcome for this systematic review was the change in BMI z-score with implementation of the interventions studied. Literature searches were conducted in several databases. Ten publications addressing the study question were included in this review, and five studies were used in the meta-analysis to assess the impact of the bariatric interventions on obesity. The BMI z-score did not change significantly with the interventions. However, the quality of evidence was low, which precluded the recommendation of their use. In conclusion, prospective, rigorous, adequately powered, and high-quality longitudinal studies are urgently needed to deliver effective lifestyle interventions to children with ALL to treat and prevent obesity. These interventions, if successful, may improves cardiometabolic health outcomes and enhance the quality of life and life expectancy in children with ALL.

Background: Type 2 diabetes mellitus (T2DM) is a worldwide epidemic, and while its etiology is polygenic, the role of environmental contaminant exposure in T2DM pathogenesis is of increasing importance. However, the evidence presented in systematic reviews on the relationship between cadmium exposure and T2DM development is inconsistent. This overview aims to assess existing evidence from systematic reviews linking cadmium exposure to T2DM and select metabolic disorders in humans., Methods: Searches will be conducted in Medline, Embase, Web of Science, GEOBASE, BIOSIS Previews, and Cochrane Database of Systematic Reviews. Two reviewers (J.H and S.T.) will independently complete screening, data abstraction, risk of bias evaluation, and quality assessment. The primary outcome will be the association between cadmium exposure and T2DM prevalence. Secondary outcomes will include prediabetes, obesity, dyslipidemia, hypertension, and non-alcoholic fatty liver disease. We will perform a meta-analysis if two or more studies assess similar populations, utilize analogous methods, have related study designs, and evaluate similar outcomes., Discussion: This overview will assess current evidence from systematic reviews for the association between cadmium exposure and risk of T2DM and other metabolic morbidities. This overview may be helpful for policy-makers and healthcare teams aiming to mitigate T2DM risk in populations at risk of cadmium exposure., Systematic Review Registration: PROSPERO CRD42019125956.

Background Context: Adolescent idiopathic scoliosis (AIS) is the leading cause of spinal deformity in adolescents globally. Recent evidence from genome-wide association studies has implicated variants in or near the ladybird homeobox 1 (LBX1) gene, encoding the ladybird homeobox 1 transcription factor, in AIS development. This gene plays a critical role in guiding embryonic neurogenesis and myogenesis and is vital in muscle mass determination. Despite the confirmation of the role for LBX1 gene variants in the development of AIS, the biological basis of LBX1 contribution to AIS remains mostly unknown., Purpose: To investigate the potential role of LBX1 in driving spinal curving, curve laterality, and progression through muscle-based mechanisms in AIS patients by analyzing its gene and protein expression., Study Design: This is a cross-sectional study using clinical data and biological samples from the Immunometabolic CONnections to Scoliosis study (ICONS study)., Patient Sample: Twenty-five patients with AIS provided informed consent. Paraspinal muscle biopsies from the maximal points of concavity and convexity for gene expression and protein analysis were obtained at the start of corrective spinal surgery., Outcome Measures: The outcome measures included the detection of paraspinal muscle LBX1 mRNA abundance and LBX1 protein expression and the correlation of the latter with age, sex, and curve severity., Methods: The measurement of mRNA abundance was done using quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, protein lysates from the biopsied muscle samples were probed with a monoclonal LBX1 antibody to compare the muscle protein levels on either side of the scoliotic curve by western blot. This study received funding from the Division of Orthopedics, Department of Surgery, McMaster University, Hamilton, Ontario, Canada ($39,900 CAN for 2 years). The authors have no conflicts of interest to disclose., Results: LBX1 mRNA abundance (concave 2.98±0.87, convex 3.40±1.10, p value 0.73) and protein expression (concave 1.20±0.13, convex 1.21±0.10, p value 0.43) were detected on both sides of the scoliotic curve at equivalent levels. The expression of LBX1 protein did not correlate with age (concave: correlation coefficient 0.32, p value 0.12; convex: correlation coefficient 0.08, p value 0.69), sex (concave: correlation coefficient -0.03, p value 0.08; convex: correlation coefficient 0.07, p value 0.72), or the severity of spinal curving measured using the Cobb angle (concave: correlation coefficient -0.16, p value 0.45; convex: correlation coefficient -0.08, p value 0.69)., Conclusions: LBX1 is expressed in erector spinae muscles, and its levels are equal in muscles on both sides of the scoliotic curve in AIS. The expression of LBX1 on the convex and concave sides of the scoliotic curve did not correlate with age, sex, or the severity of spinal curving. The molecular mechanisms by which LBX1contributes to the development and propagation of AIS need to be explored further in muscle and other tissues., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Obesity is associated with the production of inflammatory cytokines that are implicated in insulin resistance (IR), and if not addressed, can lead to type 2 diabetes (T2D). The role of the immune system in skeletal muscle (SM) inflammation and insulin sensitivity is not yet well characterized. As SM IR is an important determinant of glycaemia, it is critical that the muscle-immune phenotype is mapped to help design interventions to target T2D. This systematic review synthesized the evidence for SM macrophage content and phenotype in humans and murine models of obesity, and the association of muscle macrophage content and phenotype with IR. Results were synthesized narratively, as we were unable to conduct a meta-analysis. We included 28 studies (n=10 human, n=18 murine), and all studies detected macrophage markers in SM. Macrophage content was positively associated with IR. In humans and mice, there was variability in muscle macrophage content and phenotype in obesity. Overall certainty in the evidence was low due to heterogeneity in detection methods and incompleteness of data reporting. Macrophages are detected in human and murine SM in obesity and a positive association between macrophage content and IR is noted; however, the standardization of markers, detection methods, and reporting of study details is warranted to accurately characterize macrophages and improve the potential for creating specific and targeted immune-based therapies in obesity., (© 2019 World Obesity Federation.)

Introduction: Chronic Myeloid Leukaemia (CML) constitutes 15% of new adult leukaemia cases as well as 2%-3% of leukaemia in children under 15% and 9% of leukaemias in adolescents 15-19 years of age annually. The introduction of Tyrosine Kinase Inhibitors (TKI) therapy has dramatically improved survival in these patients, yet the off-target effects of this treatment may have long-term health impacts on CML survivors. The risk of adverse health outcomes is especially important in children, where TKI exposure may occur during critical windows of growth and puberty, and patients require treatment for prolonged periods of time. The aim of this systematic review protocol is to report on the methods used to conduct a systematic review to investigate the endometabolic and bone health effects of TKI therapy in CML., Methods and Analysis: Searches will be conducted in the Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE from inception on August 1st, 2019. Searches may be updated while performing the systematic review to ensure new evidence is included if applicable. Grey literature search will include ClinicalTrials.gov and ProQuest Dissertations and Theses A&I. We will perform a meta-analysis if there are at least two studies reporting similar populations, interventions, methods and tracking the same outcome measures. The studies should also have similar age and sex distributions., Ethics and Dissemination: As this is a systematic review protocol, it does not include patient data; therefore, Research Ethics Board approval is not indicated. The systematic review will be published in a peer-reviewed journal and presented at international conferences., Prospero Registration Number: CRD42018091175., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The obesity and Type 2 Diabetes Mellitus (T2DM) rates are at an all-time high globally. This diabesity epidemic is increasingly impacting children and adolescents, and there is scarce evidence of interventions with favourable long-term outcomes., Purpose: In order to understand the determinants of diabesity and how to address them, multiple stakeholders were invited to a meeting to discuss current state of knowledge and to help design a program to prevent pediatric and adolescent diabesity., Participants and Methods: The meeting was held at McMaster University on March 4th, 2015. The event involved presentations to deliver state-of-the-art knowledge about diabesity, and roundtable discussions of several domains including nutrition, physical activity, sleep, and mental health. Discussion transcripts were analyzed using NVivo., Results: Forty-nine participants took part in the workshop. They included clinical healthcare professionals, public health, Aboriginal Patient Navigator, research scientists, students, and patients with family members. A total of 628 reference counts from the roundtable discussions were coded under 20 emerging themes. Participants believed that the most important elements of the program involve the provision of knowledge and education, family involvement, patient motivation, location of program delivery, and use of surveys and questionnaires for outcome measurement., Conclusion: Effective pediatric and adolescent diabesity prevention programs should be conceptualized by multidisciplinary stakeholders and embrace the complexity of diabesity with multiprong interventions. This meeting provided a framework for developing such interventions., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Balakumaran et al.)

Introduction: Children diagnosed with medulloblastoma (MB) who are refractory to upfront therapy or experience recurrence have very poor prognoses. Although phase I and phase II trials exist, these treatments bear significant treatment-related morbidity and mortality., Methods: A retrospective review of children diagnosed with a recurrence of MB from 2002 to 2015 at McMaster University was undertaken., Results: Recurrent disease in 10 patients involved leptomeningeal dissemination, with 3 experiencing local recurrence. In three recurrent patients the disease significantly progressed, and the children were palliated. The remaining 10 children underwent some form of salvage therapy, including surgical re-resection, radiation, and chemotherapy, either in isolation or in varying combinations. Of the 13 children experiencing treatment-refractory or recurrent disease, 4 are currently alive with a median follow-up of 38.5 months (75.5 months). Of the eight patients with molecular subgrouping data, none of the Wnt MB experienced recurrence., Conclusion: Recurrent MB carried a poor prognosis with a 5-year overall survival (OS) of 18.2% despite the administration of salvage therapy. The upfront therapy received, available treatment, and tolerability of the proposed salvage therapy resulted in significant heterogeneity in the treatment of our recurrent cohort.

Objectives: The number of children who survive cancer is reaching new record levels, thanks to improved management strategies. However, this population is predisposed to chronic health conditions including cardiovascular disease and type 2 diabetes, yet the full scale of these diagnoses in this population is unclear. This protocol describes the conduct of a systematic review to report on the prevalence of diabetes mellitus (DM) subtypes in childhood cancer survivors. Methods: Searches will be conducted in MEDLINE, Embase, CINAHL, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials. We will also search gray literature in Theses A&I, ProQuest Dissertations, and Web of Science as well as clinicaltrials.gov. Screening search results and data abstraction will be done independently by two reviewers. We will conduct a meta-analysis if two studies have similar designs, populations, methods, and outcome measures reported. Results: The findings of this systematic review will provide insights into the scale of diabetes in childhood cancer survivors to allow the prioritization of subpopulations that need specific interventions to screen, prevent, and treat DM. This will likely lead to improved outcomes in childhood cancer survivors., Competing Interests: The authors declare that they have no competing interests in this work.

Background: Approximately 50% of all youth-onset type 2 diabetes mellitus (T2DM) in Canada occurs in Indigenous children. In adults, cardiovascular disease is one of the leading causes of mortality in First Nations communities, and diabetes is a significant contributor to the risk of developing this disorder. The early onset of diabetes may predispose these children to premature cardiovascular disease and influence their longevity and quality of life. As a result, the implementation of culturally tailored obesity and T2DM primary prevention programs is vital. This systematic review aims to assess the effectiveness of existing traditional knowledge-based lifestyle intervention programs on preventing obesity and T2DM in Indigenous children in Canada., Methods: We will conduct database searches in MEDLINE, Embase, PsycINFO, SPORTDiscus, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, and the Cochrane Controlled Register of Trials. We will also conduct grey literature searches of central repository of trials ( ClinicalTrials.gov ), ProQuest Dissertations, Theses A&I, and Indigenous studies portal research tools. Reviewers will independently review titles, abstracts, and full-text articles retrieved from databases to assess potentially eligible studies, and relevant articles will be assessed for risk of bias and quality. The primary outcomes include the change in body mass index z-scores or a diagnosis of diabetes. The secondary outcomes include the change in measures of adiposity as well as lifestyle and metabolic profiles. A meta-analysis will be performed if two or more studies have used similar study designs, comparable intervention techniques , similar populations and measured similar outcomes., Discussion: This review will provide a summary of current interventions to prevent obesity and T2DM in Indigenous children in Canada and help determine the gaps in the literature so that interventions can be developed to control the surge in pediatric T2DM in Indigenous communities., Systematic Review Registration: PROSPERO CRD42017072781.

Background: Acute low back pain (ALBP) is a common clinical complaint that can last anywhere from 24 hours to 12 weeks. In recent years, there has been an opioid epidemic which is linked to the increased availability of prescription opioids. Though guidelines recommend that in the treatment of ALBP, opioids should be used when other treatments fail, we have seen an increase in opioid prescriptions for ALBP. With this crisis, it is important to examine if there are any adverse outcomes associated with prescribing opioids for ALBP., Objective: We aim to review the published literature to examine the adverse outcomes associated with opioid use for ALBP., Study Design: We performed a systematic review with meta-analysis in accordance with our published protocol and PRISMA guidelines., Setting: The review was conducted at McMaster University., Methods: Various electronic databases for articles published from inception to September 30, 2017, inclusive. Both randomized clinical trials and observational studies on the impact of opioid use in ALBP in the adult population were included. Eight pairs of independent reviewers performed screening, data extraction, and assessment of methodological quality. The identified articles were assessed for risk of bias using sensitivity analysis. Trials with comparative outcomes were reported in a meta-analysis using a fixed effects model., Results: A total of 13,889 studies were initially screened for the review and a total of 4 studies were included in the full review, of which 2 studies were meta-analyzed. Our results showed that prescribing opioids for ALBP was significantly associated with long-term continued opioid use (1.57, 95% CI, 1.06-2.33). There was no significant association found between unemployment duration and prescribing opioids for ALBP (3.54, 95% CI, -7.57 to 14.66)., Limitations: Due to the limited number of studies that considered unemployment, only an unpooled analysis was conducted. Among the included studies there was both statistical and clinical heterogeneity due to differences in methodology, study design, risk of selection or performance bias. Most of the studies had an unclear or high risk of bias and poorly defined side effects., Conclusions: Due to the lack of literature examining long-term adverse outcomes associated with prescribing opioids for ALBP, no definitive conclusions can be made. However, with the literature available, there does seem to be risk associated with prescribing opioids for ALBP so there is a great need to conduct further investigations examining these adverse outcomes for ALBP patients., Key Words: Acute low back pain, opioids, prescriptions, low back pain, long-term use, opioid use disorder.

In this report, we document the discussions and recommendations of a national conference designed to create a coalition to tackle adolescent idiopathic scoliosis (AIS) held on June 6 and 7, 2017 in Hamilton, ON, Canada. The goal of the establishment of this coalition is to join the efforts of patients, parents, physicians, researchers and other stakeholders to identify stakeholders' perspectives and to categorize gaps in knowledge and target further AIS research and clinical care priorities. The participants' main priorities included focus on shared decision making regarding clinical and research priorities between the stakeholders on the clinical, research and policy sides with patients and families. In addition, improvements in the dissemination of information via digital platforms and identification of cost-effective screening strategies that may help early identification and intervention were also recognized as a priority. Commitment was reached to form a national coalition to understand the determinants of this condition and enhance patient outcomes through improved clinical care and research efforts., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Introduction: Illicit opioid use has become a national crisis in Canada, with over 65 000 people seeking treatment for opioid use disorder (OUD) in Ontario and British Columbia alone. Medication-assisted treatment (MAT) is a common treatment for OUD. There is substantial variability in treatment outcomes used to evaluate effectiveness of MAT, making it difficult to establish clinically and scientifically relevant treatment effect. Furthermore, patients are often excluded from the process of determining these outcomes. The primary objective of this review is to examine outcomes currently used to measure MAT effectiveness and to identify patient-relevant outcomes to enhance effectiveness of treatment options. This review refers to patient-important outcomes as those outcomes patients consider important to or markers of treatment success., Methods and Analysis: MEDLINE, EMBASE, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Cochrane Library, Cochrane Clinical Trials Registry, National Institutes for Health Clinical Trials Registry and WHO International Clinical Trials Registry Platform databases will be searched. We will search databases from inception to the date the search is ran. Studies of interest include those evaluating the effectiveness of MAT for patients with OUD, with or without consultation with patients regarding what they consider to be important as an indicator of treatment success. Results will be analysed using thematic analysis and qualitative analysis where possible. This will result in comprehensive synthesis of all outcomes and measures found related to OUD treatment effectiveness., Ethics and Dissemination: We are collaborating with Canadian Addiction Treatment Centres which provide MAT to patients with OUD who will participate in disseminating study results. Dissemination strategies will involve sharing study results through workshops, presentations, peer-reviewed publications, study reports, community presentations and resources in primary care settings., Prospero Registration Number: CRD42018095553., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Pediatric type 2 diabetes mellitus (T2DM) is a relatively new disease with increasing incidence corresponding to the obesity epidemic among youth. It is important for clinicians to have access to high-quality clinical practice guidelines (CPGs) for appropriate management of pediatric patients with T2DM. The objective of this systematic review was to evaluate overall quality of CPGs for the management of pediatric T2DM using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool., Methods: We searched MEDLINE, Embase, CINAHL, Trip, National Guideline Clearinghouse, and grey literature to identify eligible CPGs. We also searched the webpages of national and international diabetes and pediatric organizations globally. We included CPGs from national and international diabetes and pediatric associations that were published as standalone guidelines for T2DM in children and adolescents (2-18 years of age). We also included pediatric and adult guidelines for type 1 diabetes if they included a section addressing T2DM management in children and adolescents. We retrieved the two most recent guidelines from each organization when available to assess change in quality over time. We excluded individual studies and systematic reviews that made treatment recommendations as well as CPGs that were developed for a single institution., Results: We included 21 unique CPGs in this systematic review. Of the included guidelines, 12 were developed or updated between 2012 and 2014. Five of all included CPGs were specific to pediatric populations. The analysis revealed that "Rigour of Development" (mean 45%, SD 28.68) and "Editorial Independence" (mean 45%, SD 35.19) were the lowest scoring domains on the AGREE II for the majority of guidelines, whereas "Clarity of Presentation" was the highest scoring domain (mean 72%, SD 18.89)., Conclusions: Overall, two thirds of the pediatric T2DM guidelines were moderate to low quality and the remaining third ranked higher in quality. Low quality was especially due to the scores for the "Rigour of Development" domain, which directly measures guideline development methodology. It is important that future guidelines and updates of existing guidelines improve the methodology of development and quality of reporting in order to appropriately guide physicians managing children and adolescents with T2DM., Systematic Review Registration: PROSPERO CRD42016034187.

Survivors of childhood brain tumors (SCBT) face a higher risk of cardiometabolic disorders and premature mortality compared to the general population. Excess adiposity is a known risk factor for these comorbidities. However, while SCBT have higher adiposity compared to healthy controls, measuring adiposity in clinical practice involves access to specialized equipment and may impact busy clinical services. Tri-ponderal Mass Index (TMI; kg/m 3 ) may be a superior measure of adiposity when compared to Body Mass Index (BMI; kg/m 2 ). However, its use in determining adiposity in SCBT has not been assessed. This study aims to validate TMI as a clinical measure of adiposity in SCBT. This was a cross-sectional study including 44 SCBT (n = 20 female) and 137 (n = 64 female) non-cancer control children, 5-17 years of age. BMI and TMI were calculated from height and weight measurements. Fat mass percentage was assessed using bioelectrical impedance analysis and waist to hip and waist to height ratios were used to assess central adiposity. Regression analyses were adjusted for age, sex, puberty and treatment. TMI demonstrated strong correlations to measures of total and central adiposity and predicted adiposity in SCBT and non-cancer controls, with stronger trends in the latter group. TMI may serve as a reliable clinical measure of adiposity in both SCBT and healthy children.

Background: Prescription opioid misuse in Canada has become a serious public health concern and has contributed to Canada's opioid crisis. There are thousands of Canadians who are currently receiving treatment for opioid use disorder, which is a chronic relapsing disorder with enormous impact on individuals and society., Objectives: The aim of this study was to compare the clinical and demographic differences between cohorts of patients who were introduced to opioids through a prescription and those introduced to opioids for non-medical purposes., Study Design: This was an observational, prospective cohort study., Setting: The study took place in 19 Canadian Addiction Treatment Centres across Ontario., Methods: We included a total of 976 participants who were diagnosed with Opioid Use Disorder and currently receiving methadone maintenance treatment. We excluded participants who were on any other type of prescription opioid or who were missing their 6-month follow-up urine screens. We measured the participants' initial source of introduction to opioids along with other variables using the Maudsley Addiction Profile. We also measured illicit opioid use using urine screens at baseline and at 6-months follow-up., Results: Almost half the sample (n = 469) were initiated to opioids via prescription. Women were more likely to be initiated to opioids via a prescription (OR = 1.385, 95% CI 1.027-1.866, P = .033). Those initiated via prescription were also more likely to have post-secondary education, older age of onset of opioid use, less likely to have hepatitis C and less likely to have use cannabis. Chronic pain was significantly associated with initiation to opioids through prescription (OR = 2.720, 95% CI 1.998-3.722, P < .0001). Analyses by gender revealed that men initiated by prescription were less likely to have liver disease and less likely to use cannabis, while women initiated by prescription had a higher methadone dose., Limitations: This project was limited by its study design being observational in nature; no causal relationships can be inferred. Also, the data did not allow determination of the role that the prescribed opioids played in developing opioid use disorder., Conclusions: Our results have revealed that almost half of this methadone maintenance treatment (MMT) population has been introduced to opioids through a prescription. Given that the increasing prescribing rates of opioids has an impact on this at-risk population, alternative treatments for pain should be considered to help decrease this opioid epidemic in Canada., Key Words: Opioid use disorder, chronic pain relief, methadone maintenance treatment, prescriptions, male, female.

Purpose: Several countries are legalizing the use of medicinal cannabis and easing restrictions on its recreational use. While adults have been the primary target of these initiatives, expanding access to cannabis will likely lead to increased use by children. While the effects of cannabis on pediatric neuropsychological and mental health outcomes have been broadly studied, there are limited data on the physical health effects of cannabis, including endocrine health. Animal studies have shown that chronic cannabis use leads to delayed sexual maturation; however, its effects on pubertal outcomes in children are not well studied. This systematic review aimed to assess the effect of cannabis use on pubertal timing and tempo in children., Methods: We conducted a systematic review with literature searches in MEDLINE, Embase, Cochrane Database of Systematic Reviews, Central, PsycINFO, CINAHL, Web of Science, and SPORTDiscus from inception to February 2018. A gray literature search was also completed in Clinicaltrials.gov and ProQuest Dissertations and Theses A&I. The primary outcome was pubertal timing, while secondary outcomes included pubertal tempo and final height and weight. We had no restrictions on date or language of publication of papers. Two reviewers independently assessed records for eligibility, with a third reviewer resolving disagreements., Results: Our database and gray literature searches identified 759 records. A total of 29 full-text papers were assessed for eligibility. However, all studies were ultimately excluded as they did not meet the eligibility criteria., Conclusion: Our results highlight a significant gap in existing literature regarding the effects of cannabis use on puberty. Adequately powered longitudinal studies are urgently needed to provide pediatricians and other health care providers with high-quality information on the potential effects of cannabis on the physical health of children., Prospective Registrar of Systematic Reviews Registration: PROSPERO no.: CRD42018089397., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Introduction: Acute lymphoblastic leukaemia is the most common paediatric cancer. Survivors of childhood acute lymphoblastic leukaemia (SALL) are at risk of obesity and related cardiometabolic diseases including type 2 diabetes, hypertension, stroke and cardiovascular events. Therefore, it is important to address obesity in this population as this may help mitigate future cardiometabolic comorbidities. In this systematic review, we aim to assess current treatment strategies including lifestyle interventions, pharmacotherapy and bariatric surgery to manage overweight and obesity in SALL., Methods and Analysis: We will search the following databases for primary studies: CINAHL, SPORTDiscus, EMBASE, MEDLINE, PsycINFO, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. In addition, unpublished primary studies will be searched in ClinicalTrials.gov as well as conference proceedings, presentations, abstracts, editorials and ProQuest Dissertations and Theses A&I. Reviewers will perform title, abstract, and full-text screening as well as data abstraction and risk of bias assessment independently with a third reviewer to be consulted to resolve disagreements. Searches will be run and updated through May 1st, 2018. The overall quality of the evidence will be determined using the Grading of Recommendations, Assessment, Development, and Evaluation criteria for each outcome. A meta-analysis will be performed if two studies deploying similar interventions, populations, and design and outcomes are identified., Ethics and Dissemination: As individual patient data will not be included, we do not require ethics approval. This review will be published in a peer-reviewed journal., Prospero Registration Number: CRD42016051031., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Children with brain tumors (CBT) are at higher risk of cardiovascular disease and type 2 diabetes compared to the general population, in which birth weight is a risk factor for these diseases. However, this is not known in CBT. The primary aim of this study was to explore the association between birth weight and body mass measures in CBT, compared to non-cancer controls. This is a secondary data analysis using cross-sectional data from the CanDECIDE study (n = 78 CBT and n = 133 non-cancer controls). Age, sex, and birth weight (grams) were self-reported, and confirmed through examination of the medical records. Body mass index (BMI) was calculated from height and weight measures and reported as kg/m 2 . BMI z-scores were obtained for subjects under the age of 20 years. Multivariable linear regression was used to evaluate the relationship between birth weight and BMI and BMI z-score, adjusted for age, sex, puberty, and fat mass percentage. Higher birth weight was associated with higher BMI and BMI z-score among CBT and controls. In conclusion, birth weight is a risk factor for higher body mass during childhood in CBT, and this may help the identification of children at risk of future obesity and cardiometabolic risk.

Background: In North America, opioid use has become a public health crisis with policy makers declaring it a state of emergency. Opioid substitution therapy (OST) is a harm-reduction method used in treating opioid use disorder. While OST has shown to be successful in improving treatment outcomes, there is still a great degree of variability among patients. This cohort of patients has shifted from young males using heroin to a greater number of older people and women using prescription opioids. The primary objective of this review is to examine the literature on the association between the first exposure to opioids through prescription versus illicit use and OST treatment outcomes., Method: An electronic search will be conducted on the EMBASE, MEDLINE, PsycINFO, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases. Two independent reviewers will conduct the initial title and abstract screenings using predetermined criteria for inclusion and exclusion. Reviewers will then conduct full-text data extraction using a pilot-tested data extraction form in duplicate. A third author will resolve disagreements if consensus cannot be reached. Quality and risk of bias assessment will be conducted along with a sensitivity analysis for all included studies. Qualitative summary of the evidence will be provided, and when possible, a meta-analysis will be conducted, along with heterogeneity calculation. The reporting of this protocol follows the PRISMA-P., Discussion: We expect that this review will help determine whether patients that were initially exposed to opioids through a prescription differ in OST treatment outcomes in comparison to people who used opioids through illicit means. We hope that this review will provide evidence related to prescription opioids exposure and future treatment outcomes, which will aid clinicians in their decisions to prescribe opioids or not for specific populations at risk., Systematic Review Registration: PROSPERO CRD42017058143.

Background: Adolescent idiopathic scoliosis (AIS) is the most common form of scoliosis in children, and its cause remains unknown. The Immune-metabolic CONnections to Scoliosis (ICONS) Study was designed to elucidate the potential mechanisms by which immune system-paraspinal muscle crosstalk contributes to the development of AIS. In this report, we document the evaluation of ICONS Study feasibility., Methods: This study was conducted at a tertiary pediatric academic center in Hamilton, Ontario, Canada. We included boys and girls, aged 10-17 years with a diagnosis of AIS requiring corrective spinal surgery. Exclusion criteria included patients on high-dose steroids, immunosuppressive therapy, anti-thrombotic medications, those with an active infection for 15 days before participation , autoimmune disease, pregnancy, and patients who were unwilling to consent.Pre-determined feasibility criteria included permission to approach participants and recruitment rates of 80%, consenting of at least 80% of participants to provide biological samples, 90% or higher case report form and questionnaire completion, resources to be sufficient in at least 80% of recruitments, and the ability to successfully collect and process 80% or more of the biological samples needed for this study., Results: Between August 2013 and October 2014, we identified 32 potential participants with AIS, but had the resources to approach only 16, of which 12 (75%) agreed to be approached by the research team, and all consented to participate. Of the 12 participants recruited, 11 questionnaire packages and muscle biopsies (91.7% for each objective) were collected, while other biological samples (serum, plasma, whole blood for DNA and RNA processing, urine) were collected from all participants., Conclusions: The ICONS study protocols and procedures are feasible. However, recruitment rates were less than predicted. For the full study, we plan on prolonging the recruitment phase and the inclusion of additional centers to achieve recruitment targets.

Objectives: The current global rates of obesity and type 2 diabetes are staggering. In order to implement effective management strategies, it is imperative to understand the mechanisms of obesity-induced insulin resistance and diabetes. Macrophage infiltration and inflammation of the adipose tissue in obesity is a well-established paradigm, yet the role of macrophages in muscle inflammation, insulin resistance and diabetes is not adequately studied. In this systematic review, we will examine the evidence for the presence of macrophages in skeletal muscle of obese humans and mice, and will assess the association between muscle macrophages and insulin resistance. We will identify published studies that address muscle macrophage content and phenotype, and its association with insulin resistance. We will search MEDLINE/PubMed, EMBASE, and Web of Science for eligible studies. Grey literature will be searched in ProQuest. Quality assessment will be conducted using the Systematic Review Centre for Laboratory Animal Experimentation risk of bias Tool for animal studies., Results: The findings of this systematic review will shed light on immune-metabolic crosstalk in obesity, and allow the consideration of targeted therapies to modulate muscle macrophages in the treatment and prevention of diabetes. The review will be published in a peer-reviewed journal and presented at conferences.

The surgical risk factors and neuro-imaging characteristics associated with cerebellar mutism (CM) remain unclear and require further investigation. Therefore, we aimed to examine surgical and MRI findings associated with CM in children following posterior fossa tumor resection. Using our data registry, we retrospectively collected data from pediatric patients who acquired CM and were matched based on age and pathology type with individuals who did not acquire CM after posterior fossa surgery. The strength of association between surgical and MRI variables and CM were examined using odds ratios (ORs) and corresponding 95% confidence intervals (CIs). A total of 22 patients (11 with and 11 without CM) were included. Medulloblastoma was the most common pathology among CM patients (91%); the remaining 9% were diagnosed with a pilocytic astrocytoma. Tumor attachment to the floor of the fourth ventricle (OR 6; 95% CI 0.7-276), calcification/hemosiderin deposition (OR 7; 95% CI 0.9-315.5), and post-operative peri-ventricular ischemia on MRI (OR 5; 95% CI 0.5-236.5) were found to have the highest measures of association with CM. Our results may suggest that tumor attachment to the floor of the fourth ventricle, pathological calcification, and post-operative ischemia have a relatively higher prevalence in patients with CM. Collectively, our work calls for a larger multi-institutional cohort study of CM patients to encourage further investigation of the determinants and management of CM in order to potentially minimize its development and predict onset.

Children with brain tumors (CBT) are at high risk of cardiovascular diseases and type 2 diabetes compared to the general population. Recently, adiposity has been reported to be more informative for cardiometabolic risk stratification than body mass index (BMI) in the general population. The goal of this study is to describe the adiposity phenotype in CBT, and to establish adiposity determinants. We recruited CBT (n = 56) and non-cancer controls (n = 106). Percent body fat (%FM), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) were measured to determine total and central adiposity, respectively. Regression analyses were used to evaluate adiposity determinants. CBT had higher total and central adiposity compared to non-cancer controls despite having similar BMI measurements. Those with tumors at the supratentorial region had increased total and central adiposity, while those who received radiotherapy had increased total adiposity. In conclusion, CBT have increased total and central adiposity in the presence of similar BMI levels when compared to non-cancer controls. Adiposity, especially central adiposity, is a potential cardiometabolic risk factor present relatively early in life in CBT. Defining interventions to target adiposity may improve long-term outcomes by preventing cardiometabolic disorders in CBT.

Background: Overweight and obesity are well-known risk factors for cardiometabolic diseases including hypertension, myocardial infarction, stroke, and type 2 diabetes in the general population. Survivors of childhood brain tumors (SCBT) are at risk of premature mortality, and recent evidence suggests that these cardiometabolic diseases are potential emerging determinants of survival and quality of life. Therefore, the rates of overweight and obesity in this population need to be examined to assess their impact on outcomes. The objective of this systematic review is to examine the prevalence of overweight and obesity in SCBT. The secondary aim of this review is to evaluate whether SCBT have higher adiposity compared to the general population., Methods: Searches will be conducted in MEDLINE, CINAHL, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, PubMed, and Database of Abstracts of Reviews of Effect. For gray literature, we will search ProQuest Dissertations and Theses A&I and Web of Science. Two reviewers will independently screen all articles against predetermined eligibility criteria and complete data abstraction, risk of bias, and quality assessments. The primary outcome includes the prevalence of overweight or obesity. The secondary outcomes involve waist-to-hip ratio, waist-to-height ratio, body fat percentage, and skinfold thickness. Meta-analysis will be performed when two or more studies with similar design, populations, and outcomes are available., Discussion: This review will summarize current data on the prevalence of overweight and obesity in SCBT. This will help the development of an understanding of the scale of overweight and obesity in this population and guide the design of interventions that will improve outcomes., Systematic Review Registration: PROSPERO CRD42016051035.

Background: The prevalence of type 2 diabetes mellitus (T2DM) in children and adolescents is increasing. This has spurred the development and publication of clinical practice guidelines (CPGs) for the management of paediatric T2DM. Given the long-term complications of T2DM, optimal management is important to prevent or delay these complications. However, the quality of published CPGs has not yet been empirically evaluated. Our objective is to systematically appraise all published CPGs for the management of T2DM in children and adolescents., Methods: We will identify all published CPGs that address T2DM in children and adolescents through MEDLINE, Embase, CINAHL, Trip, and the National Guideline Clearinghouse and will screen diabetes and paediatric societies and associations' websites. Search records will be screened in duplicate for inclusion. Grey literature will be covered by systematically searching publications of all relevant diabetes societies and associations and other health organizations for CPGs that meet our inclusion criteria. CPGs deemed eligible for inclusion will be retrieved. Quality assessment will be conducted using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool by a team of four appraisers. Scaled scores of the AGREE II will be used to gauge the overall quality of CPGs., Discussion: The results of this review will be disseminated through presentations at local, national, and international conferences and publication in a peer-reviewed journal. The results of this review can help improve the reporting of future guidelines, inform decisions of policy-makers to endorse CPGs, and affect the choice of guideline use in clinical practice., Systematic Review Registration: PROSPERO CRD42016034187.

Introduction: Adolescent idiopathic scoliosis (AIS) affects up to 3% of children around the world. There is limited knowledge of AIS aetiopathogenesis, and this evidence is needed to develop new management strategies. Paraspinal muscle in AIS demonstrates evidence of differential fibrosis based on curve sidedness. Fibrosis is the hallmark of macrophage-driven inflammation and tissue remodelling, yet the mechanisms of fibrosis in paraspinal muscle in AIS are poorly understood., Objectives: The primary objective of this study is to determine the influence of curve sidedness on paraspinal muscle inflammation. Secondary objectives include defining the mechanisms of macrophage homing to muscle, and determining muscle-macrophage crosstalk in muscle fibrosis in AIS., Methods and Analysis: This is a cross-sectional study conducted in a tertiary paediatric centre in Hamilton, Ontario, Canada. We will recruit boys and girls, 10-17 years of age, who are having surgery to correct AIS. We will exclude children who have an active infection or are on immunosuppressive therapies within 2 weeks of surgery, smokers and pregnant girls. Paraspinal muscle biopsies will be obtained at the start of surgery. Also, blood and urine samples will be collected from participants, who will fill questionnaires about their lifestyle. Anthropometric measures will also be collected including height, weight, waist and hip circumferences., Ethics and Dissemination: This study has received ethics authorisation by the institutional review board. This work will be published in peer-reviewed journals and will be presented in oral and poster formats at scientific meetings., Discussion: This study will explore the mechanisms of paraspinal muscle inflammation, remodelling and fibrosis in AIS. This will help identify pathways and molecules as potential therapeutic targets to treat and prevent AIS. It may also yield markers that predict scoliosis progression and response to treatment in these children., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)