Health Care Utilization and Direct Costs Prior to Subspecialty Care in Children with Chronic Pain Compared with Other Chronic Childhood Diseases: A Cohort Study.

OBJECTIVES: To understand the burden associated with pediatric chronic pain (CP) on the health care system compared with other costly chronic diseases prior to subspecialty care. STUDY DESIGN: In this retrospective cohort study, we assessed all-cause health care utilization and direct health care costs associated with pediatric CP (n = 91) compared with juvenile arthritis (n = 135), inflammatory bowel disease (n = 90), type 1 diabetes (n = 475) or type 2 diabetes (n = 289), anxiety (n = 7193), and controls (n = 273) 2 and 5 years prior to patients entering subspecialty care in Manitoba, Canada. Linked data from physician encounters, emergency department visits, hospitalizations, and prescriptions were extracted from administrative databases. Differences in health care utilization and direct health care costs associated with CP vs the other conditions were tested using negative binomial and zero-inflated negative binomial regression models, respectively. RESULTS: After adjustment for age at diagnosis, sex, location of residence, and socioeconomic status, CP continued to be associated with the highest number of consulted physicians and subspecialists and the highest number of physician billings compared with all other conditions (P < .01, respectively). CP was significantly associated with higher physician costs than juvenile arthritis, inflammatory bowel disease, type 1 diabetes, type 2 diabetes, or controls (P < .01, respectively); anxiety was associated with the highest physician and prescription costs among all cohorts (P < .01, respectively). CONCLUSION: Compared with chronic inflammatory and endocrinologic conditions, pediatric CP and anxiety were associated with substantial burden on the health care system prior to subspecialty care, suggesting a need to assess gaps and resources in the management of CP and mental health conditions in the primary care setting.

Youth perceptions and experiences of type 2 diabetes: Protocol for a collaborative knowledge translation approach and qualitative study.

AIMS: The aim of this study is to generate an in-depth understanding of youth perceptions and experiences of living with type 2 diabetes to inform knowledge translation, research and intervention development. DESIGN: Interpretive descriptive qualitative study. METHODS: Twenty to 25 youth aged 10-18 years with a diagnosis of type 2 diabetes will be purposively recruited through the Diabetes Education Resource for Children and Adolescents in Winnipeg, Manitoba, and through the Improving Renal Complications in Adolescents With Type 2 Diabetes Through the REsearch [iCARE] cohort. Socio-demographic information will be collected. Semi-structured interviews will occur iteratively with inductive thematic analysis. Data will be professionally transcribed and managed using NVivo 1.0 software. The University Ethics Committee approved this study (May 2020). DISCUSSION: There is a critical gap in understanding youth experiences of type 2 diabetes. Research involving youth with type 2 diabetes is predominantly quantitative in nature, largely reflecting risk factors, underlying mechanisms and treatment outcomes associated with diabetes management. In-depth qualitative research on youth experiences can help identify youth priorities, provide insight into critical misalignments between stakeholder perspectives, and drive forward a more consolidated youth-centred research agenda. IMPACT: Understanding and applying knowledge of youth experiences is critical as the prevalence of, and challenges associated with, youth onset type 2 diabetes continues to increase worldwide. This research will generate a robust interpretive description of youth lived experiences and perceptions of type 2 diabetes where such research is lacking, to inform basic and applied research within an interdisciplinary investigative and clinical research team with relevance to other jurisdictions. In response to calls for youth-oriented research in type 2 diabetes, this work will catalyse collaborative knowledge translation using creative and youth-directed initiatives.

Management and Appropriate Use of Diazoxide in Infants and Children with Hyperinsulinism.

BACKGROUND: The diagnosis of hypoglycemia and the use of diazoxide have risen in the last decade. Diazoxide is the only Food and Drug Agency-approved pharmacologic treatment for neonatal hypoglycemia caused by hyperinsulinism (HI). Recent publications have highlighted that diazoxide has serious adverse effects (AEs) such as pulmonary hypertension (2-3%) and neutropenia (15%). Despite its increasing use, there is little information regarding dosing of diazoxide and/or monitoring for AEs. METHODS: We convened a working group of pediatric endocrinologists who were members of the Drug and Therapeutics Committee of the Pediatric Endocrine Society (PES) to review the available literature. Our committee sent a survey to its PES members regarding the use of diazoxide in their endocrine practices. Our review of the results concluded that there was substantial heterogeneity in usage and monitoring for AEs for diazoxide among pediatric endocrinologists. CONCLUSIONS: Based on our extensive literature review and on the lack of consensus regarding use of diazoxide noted in our PES survey, our group graded the evidence using the framework of the Grading of Recommendations, Assessment, Development and Evaluation Working Group, and has proposed expert consensus practice guidelines for the appropriate use of diazoxide in infants and children with HI. We summarized the information on AEs reported to date and have provided practical ideas for dosing and monitoring for AEs in infants treated with diazoxide.

Filling gaps in type 1 diabetes and exercise research: a scoping review and priority-setting project.

Our team examined the characteristics of patient engagement (PE) practices in exercise-based randomized trials in type 1 diabetes (T1D), and facilitated T1D stakeholders in determining the top 10 list of priorities for exercise research. Two methodological approaches were employed: a scoping review and a modified James Lind Alliance priority-setting partnership. Published (Medline, Embase, CINAHL and Central databases) and grey literature (www.clinicaltrials.gov) were searched to identify randomized controlled trials of exercise interventions lasting minimum 4 weeks and available in English. We extracted information on PE and patient-reported outcomes (PROs) to identify if patient perspectives had been implemented. Based on results, we set out to determine exercise research priorities as a first step towards a patient-engaged research agenda. An online survey was distributed across Canada to collect research questions from patients, caregivers and healthcare providers. We qualitatively analyzed submitted questions and compiled a long list that a 12-person stakeholder steering committee used to identify the top 10 priority research questions. Of 9962 identified sources, 19 published trials and 4 trial registrations fulfilled inclusion criteria. No evidence of PE existed in any included study. Most commonly measured PROs were frequency of hypoglycemia (n=7) and quality of life (n=4). The priority-setting survey yielded 194 submitted research questions. Steering committee rankings identified 10 priorities focused on lifestyle factors and exercise modifications to maintain short-term glycemic control. Recent exercise-based randomized trials in T1D have not included PE and PROs. Patient priorities for exercise research have yet to be addressed with adequately designed clinical trials.

Marked phenotypic variable expression among brothers with duplication of Xq27.1 involving the SOX3 gene.

We describe four phenotypically different brothers who share the same microduplication of Xq27.1, which contains the SOX3 gene. SOX3 mutations have been associated with growth hormone deficiency, variable degrees of additional pituitary hormone deficiencies, and mental retardation. SOX3 also appears to play an important role in pharyngeal arch segmentation that gives rise to craniofacial structures. While these four brothers have inherited the same mutation, they manifest a spectrum of phenotypes, ranging from complete, multiple pituitary hormone deficiencies to no apparent pituitary hormone deficiency with or without craniopharyngeal/facial dysmorphisms. We look to the literature to provide putative explanations for the variable expression of the brothers' shared SOX3 mutation.

The screening and management of newborns at risk for low blood glucose.

Hypoglycemia in the first hours to days after birth remains one of the most common conditions facing practitioners across Canada who care for newborns. Many cases represent normal physiologic transition to extrauterine life, but another group experiences hypoglycemia of longer duration. This statement addresses key issues for providers of neonatal care, including the definition of hypoglycemia, risk factors, screening protocols, blood glucose levels requiring intervention, and managing care for this condition. Screening, monitoring, and intervention protocols have been revised to better identify, manage, and treat infants who are at risk for persistent, recurrent, or severe hypoglycemia. The role of dextrose gels in raising glucose levels or preventing more persistent hypoglycemia, and precautions to reduce risk for recurrence after leaving hospital, are also addressed. This statement differentiates between approaches to care for hypoglycemia during the 'transitional' phase-the first 72 hours post-birth-and persistent hypoglycemia, which occurs or presents for the first time past that point.

Frequency and etiology of persistent neonatal hypoglycemia using the more stringent 2015 Pediatric Endocrine Society hypoglycemia guidelines.

OBJECTIVE: To determine if there was a significant increase in Endocrine consultations postinitiation of the more stringent 2015 guidelines for persistent neonatal hypoglycemia. METHODS: A retrospective chart review was conducted using data from November 2011 to October 2016. All infants with persistent hypoglycemia past 72 hours of life were included. Data included age, critical sample values, anthropometric measures, and maternal health. Descriptive statistical analyses were performed as was an interrupted time series analysis assuming a Poisson distribution. RESULTS: Fifty-eight infants were evaluated. Postintervention, there was a significant increase in the number of consults (P<0.03, 95% confidence interval [CI]: 1.14 to 8.93). Most infants with hypoglycemia persisting >72 hours were hypoglycemic shortly after birth. Half had intrauterine growth restriction; 75% were male. The median age for investigation was 8.3 days. Hyperinsulinism was the most common etiology (52/58 infants); diazoxide treatment was utilized in roughly half (29/52 to 56%) with a median duration of treatment for 91 days. The phenotype of the infants and duration of diazoxide pre- and post-Pediatric Endocrine Society protocol did not differ; two infants on diazoxide developed pulmonary hypertension. Mothers were typically of lower socioeconomic status. CONCLUSION: Not surprisingly, there was significant increase in the number of infants with persistent hypoglycemia using the 2015 guidelines. Prolonged hyperinsulinism was the major cause; medical management was typically sufficient and typically well tolerated. Care to reduce adverse effects of diazoxide is advised. We postulate that infants diagnosed using the more stringent 2015 guidelines have real disease based on the protracted medical management required.

Vigorous Intervals and Hypoglycemia in Type 1 Diabetes: A Randomized Cross Over Trial.

Adding vigorous-intensity intervals (VII) to moderate-intensity exercise prevents immediate declines in blood glucose in type 1 diabetes (T1D) however the intensity required to minimize post-exercise hypoglycemia is unknown. To examine this question, ten sedentary T1D individuals completed four treadmill exercise sessions: a control session of 45 minutes of walking at 45-55% of heart rate reserve (HRR) and three sessions consisting of 60 seconds (VII) at 70%, 80%, or 90% of HRR every 4 minutes during exercise at 45-55% of HRR. We used continuous glucose monitoring (CGM) to measure time ≤3.9 mmol/L, glucose variability, hypoglycemia frequency and area under the curve (AUC) for hypoglycemia and hyperglycemia for 12 hours post-exercise. We also examined growth hormone and cortisol responses during and following exercise. In the 12 hours post-exercise, the percentage of time ≤3.9 mmol/L, glucose variability, and AUC for hypoglycemia and hyperglycemia were similar across conditions. The frequency of hypoglycemic events was highest after the 90% intervals compared to the control arm (12 vs 3 events, p = 0.03). There was a trend towards elevated growth hormone with increasing exercise intensity but cortisol levels were similar across conditions. Adding VII to moderate intensity exercise may increase hypoglycemia risk at higher intensities.

Growth hormone treatment of Canadian children: results from the GeNeSIS phase IV prospective observational study.

BACKGROUND: Country-specific data on outcomes of treatment with recombinant human growth hormone are lacking. We present such data for children treated with growth hormone in Canada. METHODS: We describe characteristics and outcomes of 850 children (mean age at baseline 8.5 yr) treated with growth hormone constituting the Canadian cohort of the multinational phase IV prospective observational Genetics and Neuroendocrinology of Short-stature International Study (GeNeSIS). The diagnosis associated with short stature was as determined by the investigator. Auxological data were evaluated yearly until near-adult height. Adverse events were assessed in all growth-hormone-treated patients. RESULTS: The diagnosis ascribed as the cause of short stature was growth hormone deficiency in 526 children (61.9%), predominantly organic rather than idiopathic, particularly congenital pituitary abnormalities and intracranial tumours. All diagnostic groups with sufficient patients for analysis had increased height velocity standard deviation score (SDS) and height SDS during growth hormone treatment. For patients who reached near-adult height (n = 293), the mean height SDS was within the normal range for about 80% of patients with organic growth hormone deficiency (n = 131) or idiopathic growth hormone deficiency (n = 50), 50% of patients with idiopathic short stature (n = 10) and 46% of patients with Turner syndrome (n = 79). Eleven deaths were reported, 7 in patients with organic growth hormone deficiency. Serious adverse events considered related to growth hormone treatment (n = 19) were isolated except for medulloblastoma recurrence (n = 2) and adenoidal hypertrophy (n = 2). INTERPRETATION: Growth hormone treatment was effective and had a good safety profile in Canadian children. Growth hormone dosages were lower than in the US and global GeNeSIS cohorts, and a greater proportion of treated Canadian children had organic growth hormone deficiency. STUDY REGISTRATION: ClinicalTrials.gov, no. NCT01088412.

A systematic review and meta-analysis of exercise interventions in adults with type 1 diabetes.

AIMS: Conflicting evidence exists regarding the benefits of physical activity for long-term blood glucose control in adults with type 1 diabetes (T1D). The object of this systematic review was to determine the effects of physical activity on long-term blood glucose control in T1D adults. METHODS: PubMed/Medline, Embase, CENTRAL, SPORTdiscus, Global Health and ICTRP were searched up to October 2013 for randomized trials of aerobic or resistance exercise training in T1D adults. Exercises had to be performed at least twice weekly for a minimum of two months. The primary outcome was glycated hemoglobin (HbA1c). Secondary outcomes included cardiorespiratory fitness and insulin dose. RESULTS: Six randomized trials were identified (323 adults); sample sizes ranged from n=6 to n=148 participants receiving the intervention. Five trials had an unknown risk of bias; one trial was deemed to be at high risk of bias. Exercise frequency varied from twice weekly to daily, with intensities (50-90% VO2peak), and session durations (20-120 min) varying widely. Four trials reported HbA1c, which decreased with exercise training (mean difference [MD] -0.78% (-9 mmol/mol), 95% CI -1.14 (-13 mmol/mol) to -0.41 (-5 mmol/mol); p<0.0001; I(2) 0%) compared with controls. Exercise training improved cardiorespiratory fitness by 3.45 ml/kg/min (95% CI 0.59 to 6.31, p=0.02, I(2) 0%) compared with controls. One trial reported an effect on insulin dose (MD -0.4U/kg, 95% CI -0.53 to -0.27, p<0.00001) compared to controls. CONCLUSION: There are currently insufficient well-designed studies to ascertain the true effect of exercise training on HbA1c in individuals with T1D, but current results are promising.

Nonthyroidal illness syndrome in children.

Neuroendocrine changes in the hypothalamic-pituitary-thyroid axis during critical illness result in nonthyroidal illness syndrome (NTIS) characterized by abnormal thyrotropin (TSH) and thyroid hormone levels. Studies looking at the natural history of neuroendocrine changes during critical illness have revealed the presence of NTIS. NTIS has been described in a variety of patient settings. Many studies have tried to uncover the pathophysiology behind NTIS and several theories are proposed. Whether NTIS requires treatment or intervention is still controversial and the results of the treatment studies are arguably mixed. Whether implicitly stated or not, the underlying purpose of all the natural history, pathophysiology, or treatment studies is to determine whether NTIS is adaptive or maladaptive. Some studies have illustrated a correlation between illness severity and the degree of NTIS but a cause and effect relationship is still elusive. The human studies can be divided between those with either adult or pediatric subjects, with much less data available in the latter. This review examines the available literature on NTIS with an emphasis on the pediatric literature.

Hypothalamic-pituitary-thyroid axis changes in children after cardiac surgery.

INTRODUCTION: Hypothalamic-pituitary-thyroid axis changes in critical illness result in nonthyroidal illness syndrome (NTIS) characterized by abnormal TSH and thyroid hormone levels. It is unclear whether NTIS is adaptive or maladaptive. Some have suggested that NTIS adversely affects outcome, but there are limited data in children. OBJECTIVE: Our objective was to determine the natural history of NTIS in children undergoing cardiac bypass surgery and to correlate these changes with outcome and illness severity. METHODS: Thyroid function was measured in 21 patients, aged 1-11 yr, preoperatively and postoperatively twice daily on postoperative days (POD) 0-3 and daily thereafter until POD 7. Pediatric Logistic Organ Dysfunction and inotrope scores and pediatric intensive care unit, hospital, and ventilation days were measured and statistically analyzed in relation to thyroid function. RESULTS: All patients exhibited NTIS within the first day postoperatively. TSH recovered by POD 4. Total T(3), free T(3) index, and T(3) uptake were still below preoperative levels on POD 7. NTIS changes correlated to prolonged hospital stays with increased pediatric intensive care unit and mechanical ventilation days and also showed strong relations with Pediatric Logistic Organ Dysfunction and inotrope scores. The T(3) measures drawn within 6-14 h from surgery were predictive of clinical outcome. Alterations in illness severity preceded changes in thyroid function. CONCLUSION: NTIS was present in this population of critically ill children with some of the biochemical changes not corrected by 8 d postoperatively. The degree of NTIS was related to and predictive of clinical outcome and illness severity.

Childhood onset demyelination and Graves' disease: shared antigen or autoimmune clustering?

We describe a case of concomitant Graves' disease and demyelination, with optic neuritis and cerebellar dysfunction, in an adolescent girl. Autoimmune thyroid disease with encephalopathy is the hallmark of Hashimoto's encephalopathy, linking thyroid and central nervous system dysfunction. However, to our knowledge, Graves' disease has not been previously reported in association with clinically isolated demyelinating disease in childhood.