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Magnetic Resonance Imaging (MRI) is well‐suited for imaging peripheral blood flow due to its non‐invasive nature and excellent spatial resolution. Although MRI is routinely used in adults to assess physiological changes in chronic diseases, there are currently no MRI‐based data quantifying arterial flow in pediatric or adolescent populations during exercise. Therefore the current research sought to document femoral arterial blood flow at rest and following exercise in a pediatric‐adolescent population using phase contrast MRI, and to present test‐retest reliability data for this method. Ten healthy children and adolescents (4 male; mean age 14.8 ± 2.4 years) completed bloodwork and resting and exercise MRI. Baseline images consisted of PC‐MRI of the femoral artery at rest and following a 5 × 30 s of in‐magnet exercise. To evaluate test‐retest reliability, five participants returned for repeat testing. All participants successfully completed exercise testing in the MRI. Baseline flow demonstrated excellent reliability (ICC = 0.93, p = 0.006), and peak exercise and delta rest‐peak flow demonstrated good reliability (peak exercise ICC = 0.89, p = 0.002, delta rest‐peak ICC = 0.87, p = 0.003) between‐visits. All three flow measurements demonstrated excellent reliability when assessed with coefficients of variance (CV's) (rest: CV = 6.2%; peak exercise: CV = 7.3%; delta rest‐peak: CV = 7.1%). The mean bias was small for femoral arterial flow. There was no significant mean bias between femoral artery flow visits 1 and 2 at peak exercise. There were no correlations between age or height and any of the flow measurements. There were no significant differences between male and female participants for any of the flow measurements. The current study determined that peripheral arterial blood flow in children and adolescents can be evaluated using non‐invasive phase contrast MRI. The MRI‐based techniques that were used in the current study for measuring arterial flow in pediatric and adolescent patients demonstrated acceptable test‐retest reliability both at rest and immediately post‐exercise. [ABSTRACT FROM AUTHOR]

Thrombosis remains an important complication for children with single‐ventricle physiology following the Fontan procedure, and effective thromboprophylaxis is an important unmet medical need. To obviate conventional dose‐finding studies and expedite clinical development, a rivaroxaban dose regimen for this indication was determined using a model‐informed drug development approach. A physiologically based pharmacokinetic rivaroxaban model was used to predict a pediatric dosing regimen that would produce drug exposures similar to that of 10 mg once daily in adults. This regimen was used in an open‐label, multicenter phase III study, which investigated the use of rivaroxaban for thromboprophylaxis in post‐Fontan patients 2 to 8 years of age. The pharmacokinetics (PK) of rivaroxaban was assessed in part A (n = 12) and in part B (n = 64) of the UNIVERSE study. The safety and efficacy in the rivaroxaban group were compared to those in the acetylsalicylic acid group for 12 months. Pharmacodynamic end points were assessed in both parts of the study. Rivaroxaban exposures achieved in parts A and B were similar to the adult reference exposures. Prothrombin time also showed similarity to the adult reference. Exposure‐response analysis did not identify a quantitative relationship between rivaroxaban exposures and efficacy/safety outcomes within the observed exposure ranges. A body weight–based dose regimen selected by physiologically based pharmacokinetic modeling was shown in the UNIVERSE study to be appropriate for thromboprophylaxis in the post‐Fontan pediatric population. Model‐based dose selection can support pediatric drug development and bridge adult dose data to pediatrics, thereby obviating the need for dose‐finding studies in pediatric programs. [ABSTRACT FROM AUTHOR]

Objective: Abnormal blood lipid levels are common in bipolar disorder (BD) and correlate with mood symptoms and neurocognition. However, studies have not examined the lipid–brain structure association in BD or youth. Methods: This study examined low‐density lipoprotein (LDL‐C), high‐density lipoprotein (HDL‐C), triglycerides, and total cholesterol (TC) levels in relation to brain structure utilizing T1‐weighted images, among participants ages 13–20 with BD (n = 55) and healthy controls (HC; n = 47). General linear models investigated group differences in the association of lipids with anterior cingulate cortex (ACC), hippocampus, and inferior parietal lobe structure, controlling for age, sex, body mass index, and intracranial volume. For significant associations, post hoc within‐group analyses were undertaken. Exploratory vertex‐wise analyses further investigated group differences in the lipid–brain structure association. Results: There were significant group differences in the association of LDL‐C (β = −0.29 p = 0.001), and TC (β = −0.21 p = 0.016), with hippocampal volume, and triglycerides with ACC volume (β = −0.25 p = 0.01) and area (β = −0.26 p = 0.004). Elevated lipids were associated with smaller brain structure to a significantly greater extent in BD vs HC. Post hoc analyses revealed that elevated LDL‐C (β = −0.27 p = 0.007) and reduced HDL‐C (β = 0.24 p = 0.01) were associated with smaller hippocampal volume in the BD group. Exclusion of BD second‐generation antipsychotic users did not alter these results. Vertex‐wise analyses further showed that elevated lipids were associated with smaller brain structure to a significantly greater extent in BD vs HC, across the cortex. Conclusion: Elevated lipids are associated with smaller brain structure in BD. Research evaluating lipid–brain structure associations prospectively and whether lipid optimization has salutary effects on brain structure is necessary. [ABSTRACT FROM AUTHOR]

Summary: Background: Rapid growth is associated with increased cardiometabolic risk (CMR) in adolescence and adulthood. Little is known about whether the association between rapid growth and increased CMR originates in early childhood. Objectives: To identify age and sex standardized body mass index (zBMI) trajectories and to examine the association between zBMI trajectories and CMR outcomes in children 0 to 60 months. Study design A longitudinal cohort study was conducted through The Applied Research Group for Kids (TARGet Kids!) in Toronto, Canada. Participants had repeated measures of weight and length or height performed from birth to 60 months of age. Latent class mixed modelling was used to identify the zBMI trajectories. Linear regressions were performed to determine the association between zBMI trajectories and the primary outcome, a CMR score, quantified as the sum of age‐ and sex‐ standardized waist circumference, systolic blood pressure, glucose, log‐triglycerides and negative high‐density lipoprotein cholesterol (HDL‐C), divided by √5. Secondary outcomes were the individual components of the CMR formula as well as diastolic blood pressure and non‐HDL‐C. Results: Four BMI trajectories were identified among the 1166 children. After adjusting for all covariates, children in the rapidly accelerating trajectory had increased total CMR score (β = 1.38, 95% CI 0.77; 1.99, P <.001) and increased waist circumference score (β = 2.39, 95% CI 1.92; 2.86, P <.001) compared to the stable low group. Conclusions: Rapid growth during early childhood is associated with increased CMR in preschool children, largely driven by larger waist circumference. [ABSTRACT FROM AUTHOR]

Background: Hyperglycemia is common following cardiopulmonary bypass (CPB) surgery and is associated with poor outcomes, often attributed to hyperinsulinemia and an acquired state of insulin resistance. This study examined the underpinnings of hyperglycemia and the effects of nutrition on the association with inflammation and clinical outcomes.Methods: This prospective, observational cohort study enrolled consecutive children (<18 years) undergoing CPB. Serial measurements of inflammatory cytokines, glucose, insulin, and nutrition delivery were obtained. Glucose-insulin ratio (G:I) was calculated for each time point as a measure of insulin resistance (lower G:I reflects higher resistance). Clinical outcomes were recorded using a composite morbidity score.Results: The 200 subjects studied were predominantly females (58%) undergoing biventricular repair (85%) at a median (interquartile range) age of 0.58 years (0.28, 3.4) and weight of 7.0 kg (3.1, 59.5). Hyperglycemia was common (49% of patients), coinciding with peak cytokine concentrations. Insulin levels were highest and G:I lowest immediately following separation from CPB but had no consistent relationship with cytokines. The morbidity outcome was reached by 23% of patients, with increased odds associated with higher interleukin (IL)6 and IL8 levels but not by glucose, insulin, or G:I. Providing higher feeding volumes attenuated this association between inflammation and morbidity. Higher feeds were not associated with G:I but appeared to decrease the strength of the relationship between cytokines and glycemic indices.Conclusion: Postoperative morbidity is independently associated with increased inflammation but not with hyperglycemia or markers of insulin resistance. Higher feeding volume may modify these relationships and have a protective role. [ABSTRACT FROM AUTHOR]

Abstract: Infants listed for heart transplantation experience high waitlist and early post‐transplant mortality, and thus, optimal allocation of scarce donor organs is required. Unfortunately, the creation and validation of multivariable regression models to identify risk factors and generate individual‐level predictions are challenging. We sought to explore the use of data mining methods to generate a prediction model. CART analysis was used to create a model which, at the time of listing, would predict which infants listed for heart transplantation would survive at least 3 months post‐transplantation. A total of 48 infants were included; 13 died while waiting, and six died within 3 months of heart transplant. CART analysis identified RRT, blood urea nitrogen, and hematocrit as terminal nodes with alanine transaminase as an intermediate node predicting death. No patients listed on RRT (n = 10) survived and only three of 12 (25%) patients listed on ECLS survived >3 months post‐transplant. CART analysis overall accuracy was 83%, with sensitivity of 95% and specificity 76%. This study shows that CART analysis can be used to generate accurate prediction models in small patient populations. Model validation will be necessary before incorporation into decision‐making algorithms used to determine transplant candidacy. [ABSTRACT FROM AUTHOR]

Abstract: Kawasaki disease (KD) is an acute, self‐limited vasculitis affecting young children. It can result in coronary artery abnormalities in a significant proportion of patients, especially if the diagnosis is missed or treatment gets delayed. Echocardiography is the imaging modality of choice for detection of coronary artery abnormalities and assessment of myocardial function. It is also useful for characterization and risk stratification of patients with KD. Echocardiography should be performed at the time of diagnosis and then again at 1–2 weeks and 4–6 weeks after treatment, for uncomplicated cases who do not have significant coronary artery involvement. Use of a standardized imaging protocol is necessary to detect and characterize coronary artery abnormalities, including standardization of measurements (Z scores). For patients with evolving abnormalities, more frequent assessment is necessary in order to detect thromboses in aneurysms. Long‐term prognosis and management is dependent on both the maximal and current Z scores of aneurysms. Patients with large or giant aneurysms (i.e., Z score ≥ 10) are at the highest risk of both thrombosis and stenosis. Such patients need careful follow‐up for subsequent cardiovascular events. Many of them would be candidates for advanced cardiovascular imaging and may require revascularization therapy. Serial echocardiography plays a key role in surveillance. In addition, stress echocardiography has proven useful as a modality to assess for inducible myocardial ischemia. Intravascular ultrasound has been recommended for functional and structural assessment of coronary arteries in children with KD. [ABSTRACT FROM AUTHOR]

This study aimed to determine the validity of the Habitual Activity Estimation Scale (HAES) for assessing physical activity (PA) in children and adolescents with severe obesity. Data were obtained from participants ( n = 17) in the High Impact Strategies Toward Overweight Reduction in Youth study at the Hospital for Sick Children in Toronto. Objective measurement of PA was recorded with accelerometers and interpreted using counts-per-minute (CPM) cut­points developed for children and adolescents. Self-report measurement of PA was collected using the HAES questionnaire. Pearson correlations revealed HAES significantly overestimated average daily duration of vigorous (+48 ± 64 min, p < 0.001) and moderate-light activity (+114 ± 129 min, p < 0.001) but not inactivity (+38 ± 158 min, p = 0.17). This disagreement may be explained by increased perceived exertion in obese participants when performing PA. Thus, the HAES should not be used to assess PA in obese youth. Further work to validate accelerometer CPM cut-points for obese children and adolescents calibrated to energy consumption and perceived exertion during PA in this group is warranted [ABSTRACT FROM AUTHOR]

Background: Obesity is associated with cardiometabolic disturbances, which may have significant implications for musculoskeletal health and exercise tolerance. Objective: We sought to determine the association between muscle structure, function, and metabolism in adolescents across the weight spectrum. Methods: This cross‐sectional case–control study included overweight and obese participants (n = 24) 8–18 years of age with a body mass index (BMI) ≥ 85th percentile for age and gender, and non‐obese participants (n = 24) with a BMI < 85th percentile. Body composition, physical activity, peak aerobic capacity, cardiometabolic blood markers and insulin resistance (measured by the homeostatic model assessment of insulin resistance, HOMA‐IR), skeletal muscle mitochondrial oxidative capacity (via 31Phosphorous‐Magnetic Resonance Spectroscopy, 31P‐MRS, to assess phosphocreatine (PCr) recovery after exercise), and extramyocellular and intramyocellular lipid (IMCL) levels (via 1Hydrogen‐MRS) were assessed. Stepwise regression was performed to examine the factors associated with oxidative capacity. Results: bese and overweight patients had similar age, height, and physical activity to non‐obese controls, but obese and overweight participants exhibited higher insulin resistance. Obese and overweight participants had longer PCr recovery than non‐obese controls following 5x30s of moderate‐intensity exercise (51.2 ± 20.1 s vs. 23.9 ± 7.5 s, p = 0.004). In univariate correlation analysis, impaired PCr recovery was associated with a higher BMI z‐score (rs = 0.51, p < 0.001), circulating triglycerides (rs = 0.41, p = 0.005), and HOMA‐IR (rs = 0.46, p = 0.001). In stepwise multivariate regression analysis, impaired PCr recovery was associated with a higher BMI z‐score (β = 0.47, p = 0.002), but not insulin resistance (β = 0.07, p = 0.07) or circulating triglycerides (β = 0.16 p = 0.33). Conclusion: A slower phosphocreatine recovery following aerobic exercise is strongly associated with increasing adiposity. A slower metabolic recovery following aerobic exercise stress suggests that endurance exercise training in obese adolescents may be an optimal strategy to target exercise intolerance in this cohort. [ABSTRACT FROM AUTHOR]

CV disease is a major cause of morbidity and mortality following solid organ transplantation in adults. While the prevalence of multiple cardiometabolic risk factors is increased in pediatric solid organ transplant recipients, it is not clear whether they have subclinical CV changes. c IMT, central p WV, and CAC are indicative of subclinical CV disease, and, in adults, predict future CV events. The objective of this systematic review and meta-analysis was to investigate the prevalence of subclinical CV changes, as measured by c IMT, p WV, and CAC among pediatric solid organ transplant recipients. We searched MEDLINE® and EMBASE and conducted meta-analysis for studies that evaluated c IMT, central p WV, and CAC among pediatric solid organ transplant recipients (kidney, lung, intestine and liver). The search identified nine eligible studies that included a total of 259 patients and 685 healthy controls. Eight studies reported on kidney transplant recipients and one study on a combined cohort of kidney and liver transplant recipients. The mean c IMT of transplant recipients was significantly higher than that of healthy controls (mean difference = 0.05 mm, 95% CI 0.02-0.07; p < 0.0001) with an estimated pooled prevalence of elevated c IMT of 56.0% (95% CI 17.0-95.0). The one study that assessed p WV showed increased vascular stiffness in transplant recipients compared to healthy controls. No studies assessing for CAC were found. There were limited data regarding subclinical CV disease following pediatric solid organ transplantation. In conclusion, kidney transplantation in childhood is associated with a higher prevalence of subclinical CV changes compared to healthy children. Longitudinal studies are needed to determine whether children have increased CV morbidity and mortality after transplantation. [ABSTRACT FROM AUTHOR]

Background: Obesity has its origins in early childhood; however, there is limited evidence of the association between anthropometric indicators and cardiometabolic risk factors in young children. Our aim was to evaluate the associations between body mass index (BMI) and waist circumference (WC) in relation to cardiometabolic risk factors and to explore the clustering of these factors.Methods: A cross-sectional study was conducted in children aged 1-5 years through TARGet Kids! (n = 2917). Logistic regression was used to evaluate associations between BMI and WC z-scores and individual traditional and possible non-traditional cardiometabolic risk factors. The underlying clustering of these measures was evaluated using principal components analysis (PCA).Results: Child obesity (BMI z-score >2) was associated with high (>90th percentile) leptin [odds ratio (OR) 8.15, 95% confidence interval (CI) 4.56, 14.58] and insulin (OR = 1.76; 95% CI 1.05, 2.94). WC z-score >1 was associated with high insulin (OR 1.59, 95% CI 1.11, 2.28), leptin (OR 5.48, 95% CI 3.48, 8.63) and 25-hydroxyvitamin D < 75 nmol/L (OR 1.39, 95% CI 1.08, 1.79). BMI and WC were not associated with other traditional cardiometabolic risk factors, including non-High Density Lipoprotein (HDL) cholesterol, and glucose. Among children 3-5 years (n = 1035) the PCA of traditional risk factors identified three components: adiposity/blood pressure, metabolic, and lipids. The inclusion of non-traditional risk factors identified four additional components but contributed minimally to the total variation explained.Conclusions: Anthropometric indicators are associated with selected cardiometabolic risk factors in early childhood, although the clustering of risk factors suggests that adiposity is only one distinct component of cardiometabolic risk. The measurement of other risk factors beyond BMI and WC may be important in defining cardiometabolic risk in early childhood. [ABSTRACT FROM AUTHOR]

Background and objectives Delayed puberty and lower levels of testosterone (T) have been observed in adult obese males and some adolescent males. In adult men, enteral glucose ingestion results in acute lowering of serum testosterone levels; however, this has not been studied in adolescents. We aimed to examine the acute effect of a glucose/protein beverage on serum T concentration changes in obese peripubertal males. A second objective was to determine whether change in T concentration was related to appetite hormone levels. Patients and methods Twenty-three overweight and obese males aged 8-17 in pre-early (Tanner stage 1-2) and mid-late (Tanner stage 3-5) puberty were included in this cross-sectional study at the Clinical investigative unit at the Hospital for Sick Children. Participants consumed a beverage containing glucose and protein, and blood samples measuring pubertal hormones, ghrelin and glucagon-like peptide-1 ( GLP-1) were taken over 60 min. Results Across pubertal stages, there was a significant decrease in T levels in adolescent boys (−18·6 ± 3·1%, P < 0·01) with no proportional differences between pre-early and mid-late puberty ( P = 0·09). Decrease in T was associated with a decrease in LH ( r = 0·52, P = 0·02), and fasting T was inversely correlated with fasting ghrelin ( r = −0·51, P = 0·03) with no correlation with GLP-1. Conclusions Intake of a mixed glucose/protein beverage acutely decreases T levels in overweight and obese peripubertal boys. A potential mechanism for this decrease may be secondary to an acute decrease in LH, but this requires further evaluation. [ABSTRACT FROM AUTHOR]

Background and Objectives Little information is available on how food intake regulatory hormones may be altered during pubertal development and across the weight spectrum in adolescents. Therefore, the effect of obesity, sex and pubertal status on subjective appetite and appetite hormones in response to a mixed glucose and whey protein drink was determined in 8-18 year old adolescents. Patients and Methods A cross-sectional cohort study was conducted at the Hospital for Sick Children, Toronto. After a 12 h fast, normal weight ( n = 5 female, 4 male) and obese ( n = 5 female, 4 male) adolescents (Experiment 1), and pre-early pubertal ( n = 10) and mid-late pubertal ( n = 10) obese male adolescents (Experiment 2) consumed a 250 ml glucose (30 g) and whey protein (30 g) beverage. Insulin, PYY, ghrelin and subjective appetite were measured over 120 min. Results Obese adolescents (Experiment 1) have higher insulin, PYY and lower ghrelin ( P < 0·006) than normal weight controls, with a more pronounced effect in males ( P < 0·037). Puberty (Experiment 2) did not affect insulin ( P = 0·305), but the change in PYY in response to the drink was greater ( P = 0·032) and ghrelin was lower ( P = 0·026) in mid-late pubertal than pre-early pubertal obese males. Average appetite 60 min post-drink was higher in obese and mid-late pubertal adolescents, but not related to hormone changes. Conclusions Obesity, sex and pubertal status affect macronutrient-stimulated appetite hormone secretion and these factors may alter food intake in obese children during pubertal development. [ABSTRACT FROM AUTHOR]

Banks L, Dipchand AI, Manlhiot C, Millar K, McCrindle BW. Factors associated with low physical activity levels following pediatric cardiac transplantation. Abstract: Background: Objectively measured MVPA levels following pediatric cardiac transplantation are unknown despite physical health implications. We sought to determine factors associated with MVPA in a pediatric cohort who had undergone cardiac transplantation. Methods: Study assessments included maximal exercise testing (VO2max), accelerometry, and physical activity (HAES) and functional health status (CHQ-PF50) questionnaires. Results: Participants (n = 20, 60% male, age: 11.8 ± 3.0 yr old) had a VO2max of 28.5 ± 6.8 mL/kg/min (%-predicted: 65 ± 14%) and maximal heart rate of 154 ± 16 beats/min (%-predicted: 73 ± 7.5%). Participants performed a median of 7.6 min/day (Q1 4.0 min/day, Q3 11.0 min/day) of MVPA. Each additional year of age at transplantation was associated with a decrease of 1.9 [1.0] min/day of MVPA (p = 0.07). Predicted VO2max, maximal power output, male sex, and age at study enrollment were not associated with an increase in MVPA. Parents' perception of their child's functional health status (CHQ-PF50) was lower on general health (p < 0.01) and family activity (p < 0.01) domains relative to a population-based cohort of parents reporting on healthy children. Conclusion: Pediatric cardiac transplantation recipients may be indicated to participate in cardiac rehabilitation to optimize physical activity levels. [ABSTRACT FROM AUTHOR]

Objective: Pediatric arterial ischemic stroke (AIS) carries an important morbidity and mortality burden. Congenital heart disease (CHD) is among the most important risk factors for pediatric AIS. Data on stroke recurrence in childhood CHD are lacking, resulting in uncertainty regarding optimal strategies for preventing recurrence. Methods: In the Canadian Pediatric Ischemic Stroke Registry-Toronto site, we identified children (birth to 18 years) with CHD diagnosed with AIS during 1992-2008. Data were abstracted from both stroke and cardiac surgery databases. Time-dependent outcomes (death and recurrent stroke) following sentinel stroke were parametrically modeled in competing risk analysis. Factors predicting stroke recurrence in parametric survival models were sought in parametric survival model analyses using backward variable selection of variables. Results: A total of 135 patients (19 with recurrence, 116 without recurrence) were studied. In competing risk analysis, 10 years following sentinel stoke, 27% had experienced a stroke recurrence, 26% had died, and 47% were alive and free from recurrence. Stroke recurrence risk decreased over time from sentinel stroke. Approximately 50% of patients were receiving anticoagulation at recurrence. Significant factors associated with recurrence included the presence of a mechanical valve, prothrombotic condition, and an acute infection at the time of sentinel stroke. Hazard of mortality after recurrence was similar to mortality after sentinel stroke (hazard ratio, 1.3; p = 0.75). Interpretation: Stroke recurrence was relatively common in neonates and children with CHD. Identified groups of patients at increased risk may require more aggressive secondary prophylaxis, especially in the early poststroke period. ANN NEUROL 2012;72:103-111 [ABSTRACT FROM AUTHOR]

Background: Previous studies on recurrence of Kawasaki disease (KD) have mostly been limited to Japan, which has an incidence of KD 8-10-fold higher than North America. The aim of the present study was to determine the rate of KD recurrence for patients in Ontario, to identify factors potentially associated with increased odds of recurrence, and to compare the clinical course and outcomes of index and recurrent KD episodes. Methods: Review was undertaken of all patients with recurrence of KD identified in Ontario, Canada, from 1995 to 2006. All patients with recurrence of KD (defined as at least three clinical signs of KD in addition to fever ≥5 days), presenting ≥14 days after the return to baseline from the index episode were included. Results: A total of 1010 patients were followed for 5786 patient-years. During this period a total of 17 recurrent episodes in 16 patients were identified at a median of 1.5 years after the initial episode (2 weeks-5 years). Rate of recurrence of KD was 2.9 episodes/1000 patient-years, which is higher than the expected annual incidence of KD in the same age group (26.2/100 000 per year). No factors associated with increased risk of recurrence were identified, perhaps due to the small number of events. Clinical course and outcomes of the index and recurrent KD episodes were similar. Conclusions: A previous history of KD should increase the index of suspicion for future episodes of KD to allow for rapid recognition, treatment and to achieve optimal outcomes. [ABSTRACT FROM AUTHOR]

Pollock-BarZiv SM, Finkelstein Y, Manlhiot C, Dipchand AI, Hebert D, Ng VL, Solomon M, McCrindle BW, Grant D. Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children. Pediatr Transplantation 2010: 14:968-975. © 2010 John Wiley & Sons A/S. Late graft rejection impairs the long-term function of organ transplants in children. Previous studies suggest patients with wide variation in tacrolimus levels may have higher rates of late kidney and liver graft rejection. The reproducibility of this finding and impact on graft and recipient survival have not been reported. We investigated factors associated with late rejection >6 months post-transplant in 144 heart, kidney, liver, and lung transplant recipients (ages 8-18, ≥1-yr survivors, receiving tacrolimus-based immunosuppression), comparing late rejectors (n = 61, 42%) to non-rejectors (no rejection >6 months); groups had similar mean tacrolimus concentrations ≤6 months post-transplant. For all organ types, increased standard deviation in intrapatient tacrolimus blood levels was an independent risk factor for late rejection (OR 1.6 [CI 1.1-2.1]; p = 0.02). Each 1-point increase in s.d. > 2 of tacrolimus level >6 months post-transplant associated with 1.58 increase in hazard of graft loss (p = 0.003). Graft survival (conditional on one-yr survival) was significantly better for those with s.d. < 2 at >6 months post-transplant: 98% at three and five yr, versus 88%, 70%, at three and five yr, in patients with s.d. > 2 (p = 0.003). In conclusion, high s.d. in serial tacrolimus concentrations associated with increased risk of late rejection and graft loss in pediatric organ transplant recipients, providing opportunities for screening and interventions. [ABSTRACT FROM AUTHOR]

Extracorporeal membrane oxygenation (ECMO) has long been the sole means of mechanical support for pediatric patients with end-stage cardiac failure, but has a high waitlist mortality and a reported survival to hospital discharge of less than 50%. The purpose of this study was to compare waitlist mortality and survival for ECMO versus ventricular assist device (VAD) support. A review was conducted of all patients listed for heart transplantation (HTx) since 2002 and requiring mechanical support. VAD support has been available from 2004 (Berlin Heart Excor Pediatrics). Competing risks analysis was used to model survival to one of four outcomes (HTx, death on waitlist, delisting, improvement). Thirty-six patients were on mechanical support while awaiting HTx (21 ECMO, 12 VAD, three both). Median age at listing was 1.2 years (birth-16.6 years) for ECMO and 11.3 years (0.3-14.6 years) for VAD. Diagnosis was cardiomyopathy in 33% for ECMO and 93% for VAD. Median time to HTx was 37 days (1-930) overall, 20 days (1-85) for ECMO, and 39 days (5-108) for VAD. Mechanical support was associated with increased odds of HTx (hazard ratio [HR] 2.4 [1.7-3.3], P < 0.0001) but also delisting or death waiting (HR 3.0 [1.1-7.8], P = 0.03). Waitlist mortality of 38% on ECMO was reduced to 13% with VAD use. Survival post-HTx to hospital discharge was better in the group on VAD support (92 vs. 80%). Pediatric patients requiring mechanical support as a bridge to HTx have short wait times but high waitlist mortality. Those patients who survived to be put on the Berlin Heart Excor Pediatric device based on individualized clinical decision making then had a lower waitlist mortality, a longer duration of support, and a higher survival to transplantation and hospital discharge. [ABSTRACT FROM AUTHOR]

Bannister L, Manlhiot C, Pollock-BarZiv S, Stone T, McCrindle BW, Dipchand AI. Anthropometric growth and utilization of enteral feeding support in pediatric heart transplant recipients. Pediatr Transplantation 2010: 14:879-886. © 2010 John Wiley & Sons A/S. We sought to outline trends in anthropometric growth before and after cardiac transplantation and to document our experience with the use of EFS in this population. A total of 130 patients (59% male) were enrolled and followed for a median of 4.4 yr after transplantation. Negative changes over time in weight z-score (EST: −0.256 [0.160] z/yr, p = 0.01), height z-score (EST: −0.214 [0.096] z/yr, p = 0.03), and BMI z-score (EST: −0.287 [0.161] z/yr, p = 0.07) were observed prior to transplantation. Significant increases in weight z-score (EST: +0.342 [0.143] z/yr, p < 0.001) and BMI z-score (EST: +0.396 [0.140] z/yr, p = 0.005) were seen in the first 18 months following transplantation. No further increases in height, weight, or BMI z-score were seen beyond this. Forty-two (32%) patients received EFS. Prior to transplantation, it was not found to be associated with change in anthropomorphic growth. Post-transplantation exposure to EFS was associated with a faster increase in weight z-score (EST: +0.480 [0.231] z/yr, p = 0.04) and height z-score over time (EST: +0.366 [0.141] z/yr, p = 0.01). Normalization of weight and height z-scores was not achieved during the study follow-up period. This study suggests that further investigation into the role of EFS is warranted to identify strategies to improve growth in pediatric heart transplant recipients. [ABSTRACT FROM AUTHOR]

Manlhiot C, Yeung RSM, Chahal N, McCrindle BW. Intravenous immunoglobulin preparation type: Association with outcomes for patients with acute Kawasaki disease. Pediatr Allergy Immunol 2010: 21: 515–521. © 2010 John Wiley & Sons A/S To determine whether two different intravenous immunoglobulin (IVIG) preparations were equally efficacious in the treatment of Kawasaki disease (KD). Single centre retrospective review of all patients treated with IVIG for KD between January 1990 and April 2007. Comparison of IVIG (dose 2 g/kg) from two commercial preparations; Iveegam® stabilized with sugar (lyophilized, 5 g/ml glucose, pH 6.4–7.2, IgA 10 μg/ml, 5% IgG/ml) and Gamimune® stabilized through acidification (no sugar, pH 4.0–4.5, IgA 270 μg/ml, 5% 1990–1999, 10% 1999–2007 IgG/ml). Propensity-adjusted differences in duration of fever after treatment initiation, frequency of retreatment with IVIG, hospital stay and maximum coronary artery z-score. A total of 954 patients were included, 862 (90%) were treated with Iveegam® and 92 (10%) were treated with Gamimune®. Patients’ demographic, clinical and laboratory characteristics were similar between the two groups. In propensity-adjusted models, Iveegam® was found to be associated with higher probability of non-response to IVIG (12% vs. 5%, p = 0.05) and longer median duration of fever after IVIG [1 (1–27) vs. 1 (1–8) days, p = 0.02] than Gamimune®. Nevertheless, Gamimune® was found to be associated with longer median duration of hospital stay [5 (2–49) vs. 4 (2–76) days, p < 0.0001] and higher median maximum coronary artery z-score both at the end of the acute phase (+1.4 vs. +0.8, p < 0.0001) and 6–8 weeks after the acute phase (+0.7 vs. +0.4, p < 0.0001). IVIG preparations with lower IgA content and stabilized with glucose appear to be associated with improved coronary artery outcomes for patients with KD. [ABSTRACT FROM AUTHOR]

Minimal data exist on the perioperative use of TG for induction in pediatric HTx recipients. We report our experience using continuous infusion of TG on (i) perioperative adverse events, (ii) rejection, (iii) CAV, and (iv) PTLD. TG was infused via peripheral intravenous intra- and perioperatively as a continuous infusion (24 h/day). Starting dose was 1.5 mg/kg/day titrated to achieve target lymphocyte count of 0.1–0.3 × 109/L. Fifty-five patients received TG; mean age at HTx was 4.4 yr (1 day–17.8 yr). The mean duration of TG was three and a half days (2–7 days). Median platelet count during TG infusion was 95 × 109/L (28–228). Five patients had TG stopped for low platelets (at 4–6 days post-HTx) – all started maintenance immunosuppression. There was no perioperative mortality due to infection. Mean follow-up of 46 survivors was 2.3 yr (0.6–5.8 yr). Fifty-one percent had ≥ ISHLT 2R rejection at a median time of 33 days post-HTx (7 days–2 yr). One patient developed PTLD 1.4 yr post-HTx; three patients developed mild-moderate CAV. TG as a continuous infusion appears to have a good safety profile. Though mild thrombocytopenia was prevalent, there was no bleeding attributable solely to TG. Whether early depletion of T-cell function will translate into long-term benefits remains to be determined. [ABSTRACT FROM AUTHOR]

To assess the burden over time of renal dysfunction in pediatric heart transplant patients using an objective measure on an annual basis for serial comparison. GFR was measured at regular interval by nuclear medicine scintigraphy. Results were analyzed in relation to age, time post-transplantation, gender, and average calcineurin-inhibitor dose for the first two months post-transplantation. Results were compared with cGFR using the Schwartz equation. A total of 91 patients (56 males) transplanted between 1990 and 2004 underwent 373 GFR measurements. Median age at transplantation was 3.3 yr (birth – 17.8). Median first GFR at 0.7 yr (0.1–4.1) post-transplant was normal (94 mL/kg/1.73 m2). Freedom from at least mild renal insufficiency was 84% and 33% at one and five years post-transplant. Females had better renal function early post-transplant (GFR 105 mL/min/1.73 m2) but an increased probability of an abnormal GFR over time. Higher calcineurin inhibitor dose in the first two months post-transplantation was associated with an increasing probability of an abnormal GFR over time. The cGFR overestimated the measured GFR by 33 ± 26 mL/kg/1.73 m2. Renal insufficiency is an important morbidity after pediatric transplantation with the majority of patients experiencing at least mild renal dysfunction. Calculated GFR significantly underestimates the burden of renal insufficiency in this patient population. [ABSTRACT FROM AUTHOR]

Transplant CAV is the leading cause of graft loss beyond one yr post-heart transplant. Diagnosis can be challenging and the previous “gold standard,” coronary ANG, tends to underestimate disease. The purpose of this study was to relate DSE to ANG for the diagnosis of CAV. Prospective annual DSE at a single centre on all heart transplant patients (1999–2006) were compared with results from routine coronary angiograms. Progression of CAV over time as determined by DSE and ANG and associated factors were sought through logistic regression models adjusted for repeated measures. There were 102 heart transplant patients (54 males) transplanted between 1989 and 2006. Median age at transplant was 17 months (0–16.6 yr). The initial DSE was at a median of 10-months post-transplantation. There was a high correlation between an abnormal DSE and an abnormality on ANG (p = 0.002). There was an increased probability of an abnormal DSE with increasing grade of CAV as assessed by ANG (p < 0.001). Factors associated with an abnormal DSE included older age at transplant (p = 0.04), higher grade of rejection (p = 0.002), higher total cholesterol (p = 0.04), higher LDL (p < 0.05), and older age at the time of DSE (p = 0.002). DSE result was not related to HDL, triglyceride or homocysteine levels, or to steroid or statin use. The probability of an abnormal DSE result increases with increasing angiographic grade of CAV, and thus DSE may be used for initial screening for CAV with ANG reserved for confirmation and grading. Patients transplanted at an older age and those with a greater history of rejection were at higher risk of a positive DSE and may require increased surveillance for CAV. [ABSTRACT FROM AUTHOR]

CHIU, C.C.,et al.: Usability Assessment of Pacemaker Programmers. There is a perception among clinicians of usability differences in the user interface of pacemaker programmers, but there is an absence of literature in this area. The purpose of this study was to describe usability differences in pacemaker programmers. Forty-two programmer users completed self-administered questionnaires and two usability experts independently performed heuristic evaluation to identify features that violated general usability principles. Programmers from seven manufacturers (coded A–G) were evaluated. There was a balanced representation of users: nurses (58%) versus technologists (40%) who are employed in community (50%) versus academic (45%) hospitals, novice versus expert users based on the median users' programming experience of 60 months (range 1–300 months). Significant differences between programmers were found in overall user satisfaction and ease of programmer use (P<0.0001) in the display, controls, operation, and physical dimension of the programmers (P<0.05). Heuristic evaluations showed frequent violations of usability principles in all programmers. Problematic areas include reliance on user recall, inconsistency in operation of critical controls, poor readability, and not anticipating user wants or action. Programmer interface designs do not consistently meet user needs or general usability principles. This impacts on the safe and effective use of programmers. Guidelines in programmer design should be established, particularly with respect to labeling, location, and operation of critical controls.(PACE 2004; 27:1388–1398) [ABSTRACT FROM AUTHOR]

The use of the implanted atrial-based pacemaker to overdrive postsurgical intraatrial reentry tachycardia (IART) was evaluated in a large group of pediatric patients over a 14-year study period. The authors sought to determine the feasibility of this noninvasive technique in the management of this specialized population and to determine factors associated with successful conversion. They examined 128 manual overdrive attempts performed on 22 consecutive patients. There were 10 patients with post-Fontan repair, 7 with post-Mustard/Senning procedure, and 5 with miscellaneous lesion types. The number of IAHT episodes for overdrive pacing per patient ranged from 1 to 15. The first overdrive pacing attempt was successful in 63% (14/22) of the patients. The mean IART cycle length was 278 ± 59 ms. The mean pacing rate for effective conversion of IABT was 66 ± 10% faster than the I ART rate. By controlling for repeated measures for individual patients, three factors were found to be independently associated with a successful outcome: (1) lesion type other than Fontan surgery (P = 0.007), (2) lack of acceleration of IART with the overdrive attempt (P < 0.001), and (3) patient use of amiodarone with attempt (P = 0.005). There were three procedural complications: two inadvertent overdrive pacing episodes, and one episode of acceleration of IART cycle length and conduction resulting in need for cardioversion. Manual pacemaker overdrive conversion of IART is a useful adjunct in the management of postsurgical IART in the pediatric population and should be considered as an initial treatment option. [ABSTRACT FROM AUTHOR]

Abstract: Mycophenolate mofetil (MMF) is emerging as an effective agent for the treatment of both established rejection and primary rejection prophylaxis in solid-organ transplantation (Tx). However, little data is available on the use of MMF in the pediatric population. We therefore report on our experience with MMF in 21 pediatric heart transplant recipients. Data were obtained by retrospective chart review. Median age at time of review was 12.3 yr (range 11 months to 16.9 yr). Median age at Tx was 10.7 yr (range 55 days to 16.7 yr). MMF was started at a median of 4.3 months after Tx (range 1 day to 4.5 yr). At the time of MMF institution, all patients were concurrently on prednisone and azathioprine; 20 of these patients were also undergoing treatment with tacrolimus (median dose 0.18 mg/kg, range 0.03–0.64 mg/kg) and one with cyclo-sporin A (10 mg/kg). Azathioprine was discontinued at the time of commencing MMF. The average MMF dose was 40 ± 14 mg/kg. The rationale for switching to MMF included rejection (International Society for Heart and Lung Transplantation [ISHLT] 3A/B), 66%; inability to wean steroids, 14%; ABO blood group donor–recipient mismatch, 10%; coronary artery disease (CAD), 5%; and side-effects of immuno-suppression, 5%. Of the patients switched for rejection, 93% demonstrated resolved or improving rejection. Both ABO donor–recipient mismatch patients were started on tacrolimus/MMF as primary therapy and had no significant episodes of rejection. Two patients had rejection classified as unchanged (one with CAD, one treated with addition of sirolimus prior to improvement). Corticosteroids were successfully discontinued in 28% of patients, and 20% are currently on a reduced dose. Fourteen per cent developed significant rejection while attempting to reduce the steroid dose. Steroid reduction has not yet been attempted in 38% of patients. The following side-effects were reported in 38% of the patients: diarrhea, 10%;... [ABSTRACT FROM AUTHOR]

The relationship between the pacemaker sensitivity safety factor (PSSF) and atrial under- or oversensing as documented by 24-hour Holter monitoring was examined. Our study comprised 78 transvenous fixed atrial leads implanted between 1983-1995 in 71 children. Overall, 210 Holter reports identified 143 (68%) Holters with normal atrial sensing function, 31 (15%) with undersensing, 32 (15%) with oversensing, and 4 (2%) with both problems. From 161 Holter reports in which the PSSF was available, the incidence of undersensing at a PSSF of 2.0 (range 1.5-2.4) was 25% (14/57). There was a dramatic decline in undersensing when the PSSF was > 3 (3%) compared to a FSSF < 3 (21 %) (P < 0.001). A PSSF cut-off point of 2.0 best predicted occurrence of undersensing with a sensitivity of 79% and a specificity of 67%. Other variable were also examined by multiple logistic regression analysis, but only PSSF remained highly associated with undersensing (odds ratio [OR] = 0.6, P = 0.03). In contrast, PSSF did not have a significant role in predicting oversensing, but presence of sick sinus syndrome (OR = 10.5) or unipolar lead (OR = 5.6) were significantly associated with oversensing (P = 0.0001). The majority of undersensing problems can be avoided by routinely allowing for at least a threefold or more programmed sensitivity margin. Other factors may increase the risk of oversensing, regardless of the PSSF. [ABSTRACT FROM AUTHOR]

To determine the incidence and risk factors for venous obstruction in children with transvenous pacing leads, 63 children were evaluated clinically and echocardiographically. Patients with abnormal clinical and/or echocardiographic findings were further investigated by venography. Thirteen patients (21%) had evidence of venous obstruction. Venography in 11 (2 refused) showed that severity of obstruction (as defined by percentage of luminal narrowing) was complete (100%) in 3, severe (> 90%) in 4. and moderate (60%-90%) in 5 (1 patient having 2 sites of obstruction). Risk factors for obstruction in 55 patients with single implantation procedures (10 with ohstruction: 18%) were sought. Total cross-sectional area of lead(s) was indexed to body surface area at implantation (INDEX). Patients with obstruction had a higher mean INDEX (7.6 ± 1.6 mm²/m²) than patients without obstruction (4.9 ± 2.0 mm²/m²); P < 0.0002). Receiver-operator characteristic curves showed an INDEX > 6.6 mm²/m² to best predict obstruction, with a sensitivity of 90% and specificity of 84%. Since pacing is lifelong, sizing of transvenous leads to the child is important to prevent obstruction and preserve venous access. [ABSTRACT FROM AUTHOR]

To obtain normative data for the childhood signal-averaged ECG (SAECG), we obtained SAECGs in 155 volunteers, aged 5-15 years, using Frank leads and a Fourier transform filter. Unfiltered QRS duration (QRSDU) and filtered QRS duration (QRSDF) were significantly longer in males, and the root mean square of the terminal 40 ms {RMS40) was significantly higher in females. There were no gender differences in the duration of high frequency low amplitude signals < 40 µV (DHFLA). All SAEGG variables were significantly related to body surface area (BSA). Regression models were established for SAECG variables. For males, the predicted mean + 1.96 standard deviations (SD) for QRSDF (97.5th centile) ranged from 114 ms at BSA 0.70 m² to 123 ms at 1.90 m². For females, the predicted mean -h 1.96 SD for QRSDF ranged from 110 ms at RSA 0.70 m² to 119 ms at 1.90 m². For males and females, the predicted mean + 1.96 SD for DHFLA ranged from 34 ms at 0.70 m² to 38 ms at 1.90 m². For males, the predicted mean - 1.96 SD (2.5th centile) for RMS40 (based on natural logarithm model) ranged from 30 µV at 0.70 m² to 15 µV at 1.90 m². For females, the predicted mean - 1.96 SD for RMS40 ranged from 42 µV at 0.70 m² to 20 µV at 1.90 nf. In children 5-15 years of age, both gender and BSA need to be taken into account when interpreting the SAEGG. [ABSTRACT FROM AUTHOR]

Background: The healthcare burden related to congenital heart disease (CHD) is increasing with improving survival. We assessed changing trends in prenatal risk factors for CHD in the current era in a Canadian cohort., Methods and Results: CHD patients <18 years old (n=2339) and controls without structural heart disease (n=199) were prospectively enrolled in an Ontario province-wide biobank registry from 2008-2011. Family history, frequency of extra-cardiac anomalies (ECAs), and antenatal risk factors were assessed. Temporal trends were analyzed and associations with CHD were measured using linear and logistic regression. Family history of CHD and frequency of major ECAs was higher in cases versus controls (P<0.001). Despite an increase in genetic testing in the recent era, only 9.5% of cases with CHD had a confirmed genetic diagnosis. Yield of genetic testing (ie, frequency of abnormal results) was higher in familial and syndromic cases. There was an increase in parental age at conception, maternal prepregnancy body mass index, maternal urinary tract infections, type 1 diabetes, and exposure to nonfertility medications during pregnancy from 1990-2011. Later year of birth, family history of CHD, presence of major ECAs, maternal smoking during pregnancy, and maternal medication exposure were associated with increased odds of CHD (P<0.05 for all). Advanced parental age was associated with increased odds of CHD caused by genetic abnormalities., Conclusions: The increase in prenatal risk factors for CHD highlights the need for more rigorous ascertainment of genetic and environmental factors including gene-environment interactions that contribute to CHD.