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Background: Chronic pain is the most commonly reported comorbidity among patients with opioid addiction receiving methadone maintenance treatment (MMT), with an estimated prevalence ranging between 30% and 55%. Evidence suggests that patients with comorbid pain are at high risk for poor treatment response, including continued illicit substance use. Due to the important relationship between the presence of pain and illicit substance abuse within the MMT setting, it is imperative that we target our efforts toward understanding the characteristics of this patient population. Methods: The primary objective of this study was to explore the clinical and inflammatory profile of MMT patients reporting comorbid pain. This multicenter study enrolled patients (n=235) on MMT for the treatment of opioid dependence. Clinical history and blood and urine data were collected. Blood samples were obtained for estimating the serum levels of inflammatory markers (tumor necrosis factor [TNF]-α, interleukin-1 receptor antagonist [IL-1ra], IL-6, IL-8, IL-10, interferon [IFN]-γ and chemokine (C–C motif) ligand 2 [CCL2]). The study objectives were addressed using a descriptive statistical summary and a multivariable logistic regression model constructed in STATA version 12. Results: Among the participants eligible for inclusion (n=235), serum IFN-γ level and substance abuse behavior proved to be important delineating characteristics for the detection of comorbid pain. Analysis of inflammatory profile showed IFN-γ to be significantly elevated among patients reporting comorbid pain (odds ratio [OR]: 2.02; 95% confidence interval [CI]: 1.17, 3.50; P=0.01). Patients reporting comorbid pain were also found to have an increase in positive opioid urine screens (OR: 1.02; 95% CI: 1.00, 1.03; P=0.01), indicating an increase in illicit opioid consumption. Conclusion: MMT patients with comorbid pain were shown to have elevated IFN-γ and higher rates of continued opioid abuse. The ability to objectively distinguish between patients with comorbid pain may help to both improve the prediction of poor responders to MMT as well as identify treatment approaches such as anti-inflammatory medications as safe alternatives for MMT patients with comorbid pain. [ABSTRACT FROM AUTHOR]

Obesity is associated with chronic low-grade inflammation that involves infiltration of macrophages into metabolic organs such as skeletal muscle. Exercise enhances skeletal muscle insulin sensitivity independently of weight loss; but its role in regulating muscle inflammation is not fully understood. We hypothesized that exercise training would inhibit skeletal muscle inflammation and alter macrophage infiltration into muscle independently of weight loss. Wild type C57BL/6 male mice were fed a chow diet or a high-fat diet (HFD, 45% calories fat) for 6 weeks. Then, mice maintained on the HFD either remained sedentary (HFD Sed) or exercised (HFD Ex) on a treadmill for another 6 weeks. The exercise training protocol involved conducting intervals of 2 min in duration followed by 2 min of rest for 60 min thrice weekly. Chow-fed control mice remained sedentary for the entire 12 weeks. Muscle cytokine and macrophage gene expression analysis were conducted using qRT- PCR, and muscle macrophage content was also measured using immunohistochemistry. Muscle cytokine protein content was quantified using a cytokine array. The HFD increased adiposity and weight gain compared to chow-fed controls. HFD Sed and HFD Ex mice had similar body mass as well as total and visceral adiposity. However, despite similar adiposity, exercise reduced inflammation and muscle macrophage infiltration. We conclude that Endurance exercise training modulates the immune-metabolic crosstalk in obesity independently of weight loss, and may have potential benefits in reducing obesity-related muscle inflammation. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) was an adult disease until recently, but the rising rates of obesity around the world have resulted in a younger age at presentation. Children who have T2D have several comorbidities and complications reminiscent of adult diabetes, but these are appearing in teens instead of midlife. In this review, we discuss the clinical presentation andmanagement options for youth with T2D. We discuss the elements of lifestyle intervention programs and allude to pharmacotherapeutic options used in the treatment of T2D youth.We also discuss comorbidities and complications seen in T2D in children and adolescents. [ABSTRACT FROM AUTHOR]

A 10-year-old boy known to have type 1 diabetes presented to the emergency department with history of sudden onset of rightsided hemiplegia after exercise. He did not respond to oral glucose administration, but had an almost immediate resolution of symptoms with intravenous bolus of dextrose. Hemiplegic hypoglycemia is a rare complication in diabetic children, mostly affects the right side of the body, and is rarely recurrent. Children have normal brain imaging and angiography testing, and electroencephalogram may show slow-wave activity. The recovery takes place within 24 hours, and the prognosis is excellent with no focal neurological deficits noted. Our patient responded within minutes to intravenous dextrose, which is unusual and has not been reported previously. The mechanisms leading to development of hypoglycemic hemiplegia are unclear, but may involve effects of hypoglycemia on intracellular signaling pathways or molecules on motor neurons, as recent studies have shown normal brain cell glucose uptake and metabolism in hypoglycemia. While hypoglycemic hemiplegia is rare, it is a frightening experience to caregivers, and efforts should concentrate on its prevention by preventing hypoglycemia. [ABSTRACT FROM AUTHOR]

Women have higher adiposity but maintain insulin sensitivity when compared to men. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibits insulin signaling, but it is not known if PTEN regulate insulin resistance in a sex-specific manner. In this cross-sectional study, muscle biopsies from participants in the Molecular Study of Health and Risk in Ethnic Groups (Mol-SHARE) were used to test for sex differences in PTEN expression. Quantitative real-time PCR was performed to determine PTEN gene expression (n = 53), and western blotting detected total and phosphorylated PTEN protein (n = 36). Study participants were comparable in age and body mass index. Women had higher fat mass percentage compared to men (40.25 ± 9.9% in women versus 27.6 ± 8.8% in men; mean difference −0.18, 95%CI (−0.24, −0.11), p-value <0.0001), with similar HOMA-IR (2.46 ± 2.05 in men versus 2.34 ± 3.06 in women; mean difference 0.04; 95% CI (−0.12, 0.21), p-value 0.59). Women had significant downregulation of PTEN gene expression (p-value 0.01) and upregulation of PTEN protein phosphorylation (inactivation) (p-value 0.001) when compared to men after correction for age, ethnicity, HOMA-IR, fat mass and sex. We conclude that the downregulation of muscle PTEN may explain the retention of insulin sensitivity with higher adiposity in women compared to men. [ABSTRACT FROM AUTHOR]

Historique L'obésité est un problème sanitaire mondial. Étant donné la perturbation généralisée causée par la pandémie de COVID-19, il est important d'en évaluer l'effet chez les enfants ayant des troubles de santé chroniques. La présente étude évalue la santé des patients pédiatriques obèses inscrits à un programme de gestion du poids d'un hôpital de soins tertiaires avant la pandémie de COVID-19, puis un an après le début de la pandémie. Méthodologie Les chercheurs ont mené une analyse rétrospective des dossiers de patients de deux à 17 ans inscrits à une clinique pédiatrique de gestion du poids. Ils ont comparé les effets en matière de santé mentale (nouvelles orientations en psychologie, en travail social, dans un programme de troubles alimentaires, incidence de dysrégulation de l'alimentation, idéation suicidaire ou automutilation) et de santé physique (mesures anthropométriques) avant la pandémie, puis un an après le début de la pandémie. Résultats Chez les 334 enfants vus pendant l'une ou l'autre période, le nombre d'orientations en psychologie (12,4 % par rapport à 26, 5 %; p=0,002) et le résultat composite sur la santé mentale (17,2 % par rapport à 30,2 %; p=0,005) se sont creusés pendant la pandémie comparativement à auparavant. Dans un sous-groupe d'enfants (n=30) dont ils connaissaient les mesures anthropométriques au cours des deux périodes, le taux de diminution du score z de l'indice de masse corporelle était plus faible (−1,5 [2,00] par rapport à −0,3 [0,73]/année; p=0,002) et l'adiposité, plus élevée (−0,8 [4,64] par rapport à 2,7 [5,54] %/année; p=0,043) pendant la pandémie. Exposé La pandémie a influé sur la santé mentale et physique des enfants obèses inscrits à une clinique de gestion du poids. L'étude démontre un effet négatif sur la santé mentale et une amélioration moins marquée des mesures anthropométriques, mais les futures recherches, lorsque les patients auront repris les soins en clinique, permettront d'examiner nos résultats à la lumière de nouvelles mesures objectives. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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/m3) 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. [ABSTRACT FROM AUTHOR]

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/m3) 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. [ABSTRACT FROM AUTHOR]

Objective: 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. Methods: 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. Results: The most frequently reported patient-important outcomes were to stop treatment (39%) and to avoid all drugs (25%). Conclusion: 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. [ABSTRACT FROM AUTHOR]

Growth hormone deficiency (GHD) in children has significant impacts on growth and metabolism. Two-agent GH stimulation tests are commonly used to diagnose GHD, and these tests are generally considered safe. We report the case of a 5-year 5-month-old boy with a history of anaplastic ependymoma who underwent GH stimulation testing for growth deceleration using clonidine and arginine. He developed bilateral calf myalgia and gross hematuria within 24 hours of the tests. Myalgia and hematuria resolved spontaneously. Importantly, the literature review and database searches for hematuria identified 6 cases with clonidine and 20 cases with arginine. This case highlights an unusual combination of adverse reactions to clonidine and arginine in children undergoing GH stimulation testing to assess for GHD. Pediatric endocrinologists need to be aware of the potential for these side effects to allow appropriate management, and further studies are needed to clarify the mechanisms and frequency of these side effects. We recommend that patients and families need to be counselled about hematuria as an association of GH testing with these medications. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

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. 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). 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; (R2 = 0.184). In logistic regression analysis, all ABPM LMS z-scores were positively associated with albuminuria; casual BPcentile was not significant. 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. • 24-h ABPMs are recommended for screening in at risk children, but not often used in youth with type 2 diabetes in practice. • Daytime and nocturnal hypertension are common in youth with type 2 diabetes and associated with albuminuria. • Physicians should consider implementing screening with 24-hour ABPMs into routine care of youth living with type 2 diabetes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A 19-month-old boy was referred for progressive weight gain. His past medical history included congenital hypothyroidism and developmental delay. Physical examination revealed characteristics of Albright Hereditary Osteodystrophy, macrocephaly, and calcinosis cutis. He had hypocalcemia, hyperphosphatemia, and elevated Parathyroid Hormone levels. Genetic testing revealed a known mutation of GNAS gene, confirming the diagnosis of Pseudohypoparathyroidism Type Ia (PHP-Ia) (c.34C>T (p.G1n12X)). He had a normal brain MRI at three months, but developmental delay prompted a repeat MRI that revealed Chiari Malformation Type I (CM-I) with hydrocephalus requiring neurosurgical intervention. This was followed by improvement in attaining developmental milestones. Recently, he was diagnosed with growth hormone deficiency. This case suggests the potential association of CM-I with PHP-Ia. Larger studies are needed to assess whether CM-I with hydrocephalus are common associations with PHP-Ia and to define potential genetic links between these conditions. We propose a low threshold in performing brain MRI on PHP-1a patients, especially those with persistent developmental delay to rule out CM-I. Early intervention may improve neurodevelopmental outcomes and prevent neurosurgical emergencies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Pediatric brain tumors are the most common solid tumors in children. Advances in understanding the hallmarks of cancer biology and novel therapies have led to an increasing number of survivors of childhood brain tumors (SCBT). However, these survivors are at an increased risk of obesity and cardiometabolic disorders that affect their quality of life and lifespan. It is important to define effective strategies to treat and prevent obesity in this population. This systematic review aims to investigate the effectiveness of lifestyle interventions, pharmacotherapy, and bariatric surgery on treating obesity in SCBT. Methods: Searches will be conducted in PubMed, MEDLINE, EMBASE, PsycINFO, SPORTDiscus, CINAHL, Cochrane Database of Systematic Review, Cochrane Central Register of Controlled Trials (CENTRAL), and Database of Abstracts of Reviews of Effect (DARE). In addition, ClinicalTrials.gov and ProQuest Dissertations and Theses A&I will be searched to identify relevant gray literature. The reference lists of eligible articles will be searched for additional studies. All screening, quality assessment, and data abstraction will be done independently by two reviewers. We will perform meta-analysis if there are sufficient studies. Discussion: This review will summarize evidence for the effectiveness of interventions used to reduce obesity risk in SCBT. This has significant implications for SCBT, as it can identify gaps in knowledge and provide insights into the development of new interventions to manage obesity in survivors, which may improve their outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Adipose tissue hypoxia is an early phenotype in obesity, associated with macrophage infiltration and local inflammation. Here we test the hypothesis that adipocytes in culture respond to a hypoxic environment with the release of pro-inflammatory factors that stimulate macrophage migration and cause muscle insulin resistance. 3T3-L1 adipocytes cultured in a 1% O2 atmosphere responded with a classic hypoxia response by elevating protein expression of HIF-1α. This was associated with elevated mRNA expression and peptide release of cytokines TNFα, IL-6 and the chemokine monocyte chemoattractant protein-1 (MCP-1). The mRNA and protein expression of the anti-inflammatory adipokine adiponectin was reduced. Conditioned medium from hypoxia-treated adipocytes (CM-H), inhibited insulin-stimulated and raised basal cell surface levels of GLUT4myc stably expressed in C2C12 myotubes. Insulin stimulation of Akt and AS160 phosphorylation, key regulators of GLUT4myc exocytosis, was markedly impaired. CM-H also caused activation of JNK and S6K, and elevated serine phosphorylation of IRS1 in the C2C12 myotubes. These effects were implicated in reducing propagation of insulin signaling to Akt and AS160. Heat inactivation of CM-H reversed its dual effects on GLUT4myc traffic in muscle cells. Interestingly, antibody-mediated neutralization of IL-6 in CM-H lowered its effect on both the basal and insulin-stimulated cell surface GLUT4myc compared to unmodified CM-H. IL-6 may have regulated GLUT4myc traffic through its action on AMPK. Additionally, antibody-mediated neutralization of MCP-1 partly reversed the inhibition of insulin-stimulated GLUT4myc exocytosis caused by unmodified CM-H. In Transwell co-culture, hypoxia-challenged adipocytes attracted RAW 264.7 macrophages, consistent with elevated release of MCP-1 from adipocytes during hypoxia. Neutralization of MCP-1 in adipocyte CM-H prevented macrophage migration towards it and partly reversed the effect of CM-H on insulin response in muscle cells. We conclude that adipose tissue hypoxia may be an important trigger of its inflammatory response observed in obesity, and the elevated chemokine MCP-1 may contribute to increased macrophage migration towards adipose tissue and subsequent decreased insulin responsiveness of glucose uptake in muscle. [Copyright &y& Elsevier]

Obesity is associated with insulin resistance and increased risk for developing type 2 diabetes. Enlarged adipocytes develop resistance to the anti-lipolytic action of insulin. Elevated levels of fatty acids in the plasma and interstitial fluids lead to whole-body insulin resistance by disrupting normal insulin-regulated glucose uptake and glycogen storage in skeletal muscle. A new understanding has been cultivated in the past 5 to 10 years that adipocytes and macrophages (resident or bone marrow-derived) in adipose tissue of obese animals and humans are activated in a pro-inflammatory capacity and secrete insulin resistance-inducing factors. However, only recently have fatty acids themselves been identified as agents that engage toll-like receptors of the innate immunity systems of macrophages, adipocytes and muscle cells to trigger pro-inflammatory responses. This review summarizes our observations that fatty acids evoke the release of pro-inflammatory factors from macrophages that consequently induce insulin resistance in muscle cells. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

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/m3) may be a superior measure of adiposity when compared to Body Mass Index (BMI; kg/m2). 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]