QTc Interval Prolongation and Its Association With Electrolyte Abnormalities and Psychotropic Drug Use Among Patients With Eating Disorders.

Background: Eating disorders (EDs) often develop during adolescence with high mortality rates. Sudden cardiac death in these patients has been associated with corrected QT (QTc) interval prolongation. The significance of extrinsic factors on QTc prolongation in populations with EDs remains controversial. This study assessed the relationship between QTc prolongation in paediatric patients with EDs and extrinsic factors, such as QTc-prolonging medications and electrolyte abnormalities to investigate whether an ED alone is associated with an increased prevalence of QTc prolongation. Methods: Electrocardiograms, electrolytes, and psychopharmaceutical usage were retrospectively analysed from the charts of 264 paediatric patients with EDs. Descriptive statistics were used to assess QTc prolongation and its relationship with electrolyte abnormalities and psychopharmaceuticals. Results: Of 264 patients, 227 had normal QTc intervals (<440 ms), whereas 37 had borderline prolonged (440-460 ms) or prolonged (>460 ms) intervals. The prevalence of QTc intervals exceeding 440 ms in patients with normal electrolytes and not using QTc-prolonging psychotropics mirrored that of the general population (P = 0.59). Of the 23 patients taking psychotropics, 8 had abnormal QTc intervals. The average QTc was greater for patients using QTc-prolonging psychotropics (P = 0.05) with a correlation between interval length and psychotropic usage (P < 0.01). Average potassium (P = 0.08), calcium (P = 0.18), and magnesium (P = 0.08) levels did not significantly differ between those with normal and abnormal QTc intervals. Conclusions: This study suggests that EDs alone may not prolong QTc intervals in paediatric patients with EDs, but psychotropics appear to be a salient external factor in QTc prolongation.

Contexte: Les troubles des conduites alimentaires (TCA) surviennent surtout au cours de l'adolescence et entraînent un taux de mortalité élevé. Chez ces patients, la mort subite d'origine cardiaque a été associée à un allongement de l'intervalle QT corrigé (QTc). La portée des facteurs extrinsèques sur l'allongement de cet intervalle chez les patients atteints de TCA demeure un sujet controversé. La présente étude visait à évaluer la relation entre l'allongement de l'intervalle QTc chez les enfants atteints de TCA et des facteurs extrinsèques, comme la prise de médicaments causant l'allongement de l'intervalle QTc et les anomalies électrolytiques, pour déterminer si la présence d'un TCA est à elle seule associée à une prévalence élevée d'allongement de l'intervalle QTc. Méthodologie: Nous avons analysé rétrospectivement les électrocardiogrammes, les valeurs d'électrolytes et l'utilisation de médicaments psychotropes dans les dossiers de 264 enfants atteints de TCA. Des techniques de statistique descriptive ont été utilisées pour analyser l'allongement de l'intervalle QTc et les liens avec les anomalies électrolytiques et les médicaments psychotropes. Résultats: Parmi les 264 patients, 227 présentaient un intervalle QTc normal (< 440 ms) et 37 présentaient des résultats limites (440 à 460 ms) ou un allongement de l'intervalle (> 460 ms). La prévalence d'un intervalle QTc de 440 ms ou plus chez les patients présentant des taux d'électrolytes normaux et non traités par des médicaments psychotropes causant l'allongement de l'intervalle QTc était semblable à la prévalence dans la population générale (p = 0,59). Huit des 23 patients traités par des médicaments psychotropes présentaient un intervalle QTc anormal. La moyenne des intervalles QTc était supérieure dans le groupe des patients recevant des médicaments psychotropes causant un allongement de l'intervalle QTc (p = 0,05), et il existait une corrélation entre la durée de l'intervalle et de l'usage de médicaments psychotropes (p < 0,01). Les taux moyens de potassium (p = 0,08), de calcium (p = 0,18) et de magnésium (p = 0,08) ne différaient pas de façon significative entre les groupes présentant des intervalles QTc normaux et anormaux. Conclusions: Les résultats de notre étude donnent à penser que le TCA à lui seul ne provoque pas l'allongement de l'intervalle QTc chez les enfants qui en sont atteints, mais que l'utilisation de médicaments psychotropes constitue un facteur externe important dans l'allongement de l'intervalle QTc.

Genome-wide enhancer-associated tandem repeats are expanded in cardiomyopathy.

BACKGROUND: Cardiomyopathy is a clinically and genetically heterogeneous heart condition that can lead to heart failure and sudden cardiac death in childhood. While it has a strong genetic basis, the genetic aetiology for over 50% of cardiomyopathy cases remains unknown. METHODS: In this study, we analyse the characteristics of tandem repeats from genome sequence data of unrelated individuals diagnosed with cardiomyopathy from Canada and the United Kingdom (n = 1216) and compare them to those found in the general population. We perform burden analysis to identify genomic and epigenomic features that are impacted by rare tandem repeat expansions (TREs), and enrichment analysis to identify functional pathways that are involved in the TRE-associated genes in cardiomyopathy. We use Oxford Nanopore targeted long-read sequencing to validate repeat size and methylation status of one of the most recurrent TREs. We also compare the TRE-associated genes to those that are dysregulated in the heart tissues of individuals with cardiomyopathy. FINDINGS: We demonstrate that tandem repeats that are rarely expanded in the general population are predominantly expanded in cardiomyopathy. We find that rare TREs are disproportionately present in constrained genes near transcriptional start sites, have high GC content, and frequently overlap active enhancer H3K27ac marks, where expansion-related DNA methylation may reduce gene expression. We demonstrate the gene silencing effect of expanded CGG tandem repeats in DIP2B through promoter hypermethylation. We show that the enhancer-associated loci are found in genes that are highly expressed in human cardiomyocytes and are differentially expressed in the left ventricle of the heart in individuals with cardiomyopathy. INTERPRETATION: Our findings highlight the underrecognized contribution of rare tandem repeat expansions to the risk of cardiomyopathy and suggest that rare TREs contribute to ∼4% of cardiomyopathy risk. FUNDING: Government of Ontario (RKCY), The Canadian Institutes of Health Research PJT 175329 (RKCY), The Azrieli Foundation (RKCY), SickKids Catalyst Scholar in Genetics (RKCY), The University of Toronto McLaughlin Centre (RKCY, SM), Ted Rogers Centre for Heart Research (SM), Data Sciences Institute at the University of Toronto (SM), The Canadian Institutes of Health Research PJT 175034 (SM), The Canadian Institutes of Health Research ENP 161429 under the frame of ERA PerMed (SM, RL), Heart and Stroke Foundation of Ontario & Robert M Freedom Chair in Cardiovascular Science (SM), Bitove Family Professorship of Adult Congenital Heart Disease (EO), Canada Foundation for Innovation (SWS, JR), Canada Research Chair (PS), Genome Canada (PS, JR), The Canadian Institutes of Health Research (PS).

Systematic Development of a Simple Human Gait Index.

Human gait analysis aims to assess gait mechanics and to identify the deviations from "normal" gait patterns by using meaningful parameters extracted from gait data. As each parameter indicates different gait characteristics, a proper combination of key parameters is required to perform an overall gait assessment. Therefore, in this study, we introduced a simple gait index derived from the most important gait parameters (walking speed, maximum knee flexion angle, stride length, and stance-swing phase ratio) to quantify overall gait quality. We performed a systematic review to select the parameters and analyzed a gait dataset (120 healthy subjects) to develop the index and to determine the healthy range (0.50 - 0.67). To validate the parameter selection and to justify the defined index range, we applied a support vector machine algorithm to classify the dataset based on the selected parameters and achieved a high classification accuracy (∼95%). Also, we explored other published datasets that are in good agreement with the proposed index prediction, reinforcing the reliability and effectiveness of the developed gait index. The gait index can be used as a reference for preliminary assessment of human gait conditions and to quickly identify abnormal gait patterns and possible relation to health issues.

Age and Sex Differences in the Genetics of Cardiomyopathy.

Cardiomyopathy has variable penetrance. We analyzed age and sex-related genetic differences in 1,397 cardiomyopathy patients (Ontario, UK) with whole genome sequencing. Pediatric cases (n = 471) harbored more deleterious protein-coding variants in Tier 1 cardiomyopathy genes compared to adults (n = 926) (34.6% vs 25.9% respectively, p = 0.0015), with variant enrichment in constrained coding regions. Pediatric patients had a higher burden of sarcomere and lower burden of channelopathy gene variants compared to adults. Specifically, pediatric patients had more MYH7 and MYL3 variants in hypertrophic cardiomyopathy, and fewer TTN truncating variants in dilated cardiomyopathy. MYH7 variants clustered in the myosin head and neck domains in children. OBSCN was a top mutated gene in adults, enriched for protein-truncating variants. In dilated cardiomyopathy, female patients had a higher burden of z-disc gene variants compared to males. Genetic differences may explain age and sex-related variability in cardiomyopathy penetrance. Genotype-guided predictions of age of onset can inform pre-test genetic counseling. Pediatric cardiomyopathy patients were more likely to be genotype-positive than adults with a higher burden of variants in MYH7, MYL3, TNNT2, VCL. Adults had a higher burden of OBSCN and TTN variants. Females with dilated cardiomyopathy (DCM) had a higher burden of z-disc gene variants compared to males.

Cardiovascular outcomes in children with Kawasaki disease: a population-based cohort study.

BACKGROUND: The risk of cardiovascular events after Kawasaki disease (KD) remains uncertain. Our objective was to determine the risk of cardiovascular events and mortality after KD. METHODS: Population-based retrospective cohort study using Ontario health administrative databases (0-18 years; 1995-2018). EXPOSURE: pediatric KD hospitalizations. Each case was matched to 100 non-exposed controls. PRIMARY OUTCOME: major adverse cardiac events (MACE; cardiovascular death, myocardial infarction, or stroke composite). SECONDARY OUTCOMES: composite cardiovascular events and mortality. We determined incidence rates and adjusted hazard ratios (aHR) using multivariable Cox models. RESULTS: Among 4597 KD survivors, 79 (1.7%) experienced MACE, 632 (13.8%) composite cardiovascular events, and 9 (0.2%) died during 11-year median follow-up. The most frequent cardiovascular events among KD survivors were ischemic heart disease (4.6 events/1000 person-years) and arrhythmias (4.5/1000 person-years). KD survivors were at increased risk of MACE between 0-1 and 5-10 years, and composite cardiovascular events at all time periods post-discharge. KD survivors had a lower mortality risk throughout follow-up (aHR 0.36, 95% CI 0.19-0.70). CONCLUSION: KD survivors are at increased risk of post-discharge cardiovascular events but have a lower risk of death, which justifies enhanced cardiovascular disease surveillance in these patients. IMPACT: Among 4597 Kawasaki disease (KD) survivors, 79 (1.7%) experienced major adverse cardiac events (MACE) and 632 (13.8%) had composite cardiovascular events during 11-year median follow-up. KD survivors had significantly higher risks of post-discharge MACE and cardiovascular events versus non-exposed children. Only nine KD survivors (0.2%) died during follow-up, and the risk of mortality was significantly lower among KD survivors versus non-exposed children. Childhood KD survivors should receive preventative counseling and cardiovascular surveillance, aiming to mitigate adult cardiovascular disease.

Cardiovascular Outcomes During Index Hospitalization in Children with Kawasaki Disease in Ontario, Canada.

Kawasaki disease (KD) is a common childhood vasculitis associated with coronary artery aneurysms (CAA). However, there is limited published data on other cardiovascular events diagnosed during acute KD hospitalizations. Our objectives were to determine the incidence of cardiovascular events during acute KD hospitalizations, stratified by age at admission, CAA status, and pediatric intensive care unit (PICU) admission status. We identified all children (0-18 year) hospitalized with a new KD diagnosis in Ontario, between 1995 and 2018, through validated algorithms using population health administrative databases. We excluded children previously diagnosed with KD and non-Ontario residents. We evaluated for cardiovascular events that occurred during the acute KD hospitalizations, defined by administrative coding. Among 4597 children hospitalized with KD, 3307 (71.9%) were aged 0-4 years, median length of stay was 3 days (IQR 2-4), 113 children (2.5%) had PICU admissions, and 119 (2.6%) were diagnosed with CAA. During acute hospitalization, 75 children were diagnosed with myocarditis or pericarditis (1.6%), 47 with arrhythmias (1.0%), 25 with heart failure (0.5%), and ≤ 5 with acute MI (≤ 0.1%). Seven children underwent cardiovascular procedures (0.2%). Older children (10-18 years), children with CAA, and children admitted to the PICU were more likely to experience cardiovascular events, compared with children aged 0-4 years, without CAA or non-PICU admissions, respectively. The frequency of non-CAA cardiovascular events during acute KD hospitalizations did not change significantly between 1995 and 2018. During acute KD hospitalizations, older children, children with CAA, and PICU admissions are at higher risk of cardiovascular complications, justifying closer monitoring of these high-risk individuals.

A rare paediatric case of possible infective endocarditis caused by Streptococcus anginosus.

Infective endocarditis in children is a rare but serious condition that requires prompt management. We present a case of an 11-year-old boy with subacute bacterial endocarditis caused by Streptococcus anginosus, an unusual causative microorganism for infective endocarditis. The patient presented with a history of malaise, fatigue, and one subjective tactile fever. To the best of our knowledge, this is the first paediatric case of possible infective endocarditis caused by Streptococcus anginosus.

Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy.

Cardiomyopathy (CMP) is a heritable disorder. Over 50% of cases are gene-elusive on clinical gene panel testing. The contribution of variants in non-coding DNA elements that result in cryptic splicing and regulate gene expression has not been explored. We analyzed whole-genome sequencing (WGS) data in a discovery cohort of 209 pediatric CMP patients and 1953 independent replication genomes and exomes. We searched for protein-coding variants, and non-coding variants predicted to affect the function or expression of genes. Thirty-nine percent of cases harbored pathogenic coding variants in known CMP genes, and 5% harbored high-risk loss-of-function (LoF) variants in additional candidate CMP genes. Fifteen percent harbored high-risk regulatory variants in promoters and enhancers of CMP genes (odds ratio 2.25, p = 6.70 × 10-7 versus controls). Genes involved in α-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) were most highly enriched for regulatory variants (odds ratio 6.7-58.1). Functional effects were confirmed in patient myocardium and reporter assays in human cardiomyocytes, and in zebrafish CRISPR knockouts. We provide strong evidence for the genomic contribution of functionally active variants in new genes and in regulatory elements of known CMP genes to early onset CMP.

Cord-Blood High-Sensitivity Troponin-I Reference Interval and Association with Early Neonatal Outcomes.

OBJECTIVE: This study was aimed to establish a reference interval for high-sensitivity cardiac troponin I (hs-cTnI) in umbilical cord blood of infants and to assess its association with the risk of predetermined early neonatal outcomes in a high-acuity tertiary care hospital. STUDY DESIGN: Umbilical cord-blood samples were collected and hs-cTnI was measured in all infants born between August 2015 and September 2015 at McMaster Children's Hospital (n = 256). Gestational age, birth weight, Apgar's scores, age in days at which feeding was established, neonatal intensive care unit (NICU) admission, and discharge in days after birth were recorded. RESULTS: The 90th, 95th, and 99th percentiles for the term infant subcohort were 19.75, 41.45, and 166.30 ng/L, respectively. We observed decreased mean gestational ages and birth weights in both the 90th (37.7 weeks; 2,961.4 g) and 95th percentiles (37.1 weeks; 2,709.9 g) when compared with the remaining infants. Moreover, levels of hs-cTnI were significantly higher in infants with respiratory distress requiring intervention (p < 0.05), low birth weight infants (p < 0.01), preterm infants (p < 0.001), and those requiring NICU admission (p < 0.01). Multiple linear regression of the recorded demographic factors revealed prematurity (gestational age <35 weeks: coefficient 0.346 ± 0.160, p < 0.05; gestational age <37 weeks: coefficient 0.253 ± 0.105, p < 0.05) and male sex (coefficient 0.138 ± 0.047; p < 0.01) to be most predictive of log-hs-cTnI levels. CONCLUSION: This study establishes the reference values for cord-blood hs-cTnI in infants at a tertiary care center. Premature and sick infants requiring NICU admission had significantly higher levels of hs-cTnI. KEY POINTS: · Established the 90th, 95th, and 99th percentiles of neonatal cord-blood hs-cTnI in term infants as 19.75, 41.45, and 166.30 ng/L, respectively.. · Infants with hs-cTnI levels exceeding the 90th percentile had lower gestational ages and birth weights with higher rates of NICU admissions.. · Infants with respiratory distress or requiring NICU admission were found to have higher levels of hs-cTnI..

A Wearable Tele-Health System towards Monitoring COVID-19 and Chronic Diseases.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic since early 2020. The coronavirus disease 2019 (COVID-19) has already caused more than three million deaths worldwide and affected people's physical and mental health. COVID-19 patients with mild symptoms are generally required to self-isolate and monitor for symptoms at least for 14 days in the case the disease turns towards severe complications. In this work, we overviewed the impact of COVID-19 on the patients' general health with a focus on their cardiovascular, respiratory and mental health, and investigated several existing patient monitoring systems. We addressed the limitations of these systems and proposed a wearable telehealth solution for monitoring a set of physiological parameters that are critical for COVID-19 patients such as body temperature, heart rate, heart rate variability, blood oxygen saturation, respiratory rate, blood pressure, and cough. This physiological information can be further combined to potentially estimate the lung function using artificial intelligence (AI) and sensor fusion techniques. The prototype, which includes the hardware and a smartphone app, showed promising results with performance comparable to or better than similar commercial devices, thus potentially making the proposed system an ideal wearable solution for long-term monitoring of COVID-19 patients and other chronic diseases.

Inactive Lifestyles Among Young Children With Innocent Murmurs or Congenital Heart Disease, Regardless of Disease Severity or Treatment.

BACKGROUND: Sedentary lifestyle morbidities are common among children with congenital heart disease (CHD). Understanding the physical activity trajectory from early childhood could enhance timing and effectiveness of interventions. METHODS: We recruited 154 children (56% male) at 12 to 47 months of age for this prospective, longitudinal, observational study. Physical activity and sedentary behaviour (7-day accelerometry) and motor skill (Peabody Developmental Motor Scales-2) were assessed every 8 months until 5 years of age and then annually. Mixed-effect repeated measures regression models described outcome trajectories across study assessments. RESULTS: Children had innocent heart murmurs (n = 28), CHD with insignificant hemodynamics not requiring treatment (n = 47), CHD treated by catheterization or surgery without cardiopulmonary bypass (n = 31), or CHD treated surgically with bypass (n = 48). Motor skill was age appropriate (Peabody 49.0 ± 8.4), but participants had lower physical activity (143 ± 41 minutes per day) and higher sedentary time (598 ± 89 minutes per day) than healthy peers, starting at 18 months of age. Movement behaviours were not related to treatment group (P > 0.10), and physical activity was below the recommended 180 minutes per day. Over time, physical activity, sedentary time, and motor skills were primarily related to the baseline measure of each outcome (P < 0.001). CONCLUSIONS: Children with simple or complex CHD or innocent heart murmurs have increased risk for sedentary lifestyles. Their physical activity and sedentary behaviours are established before 2 years of age, persist until school age, and are unrelated to motor skills. These results emphasize the need for interventions targeting the youngest children seen in cardiac clinics, regardless of diagnoses of CHD or innocent murmur.

High CPAP vs. NIPPV in preterm neonates - A physiological cross-over study.

OBJECTIVE: To evaluate the physiological impact of high CPAP (≥9 cmH2O) vs. NIPPV at equivalent mean airway pressures. STUDY DESIGN: In this cross-over study, preterm neonates on high CPAP or NIPPV were placed on the alternate mode. After 30 min, left and right ventricular cardiac output and work of breathing indices were assessed, following which patients were placed back on the original mode and a similar procedure ensued. RESULTS: Fifteen infants with mean (SD) postmenstrual age 32.7 (3.0) weeks, and weight 1569 (564) grams were included. No differences in LVO [320 (63) vs. 331 (86) mL/kg/min, P = 0.46] or RVO [420 (135) vs. 437 (141) mL/kg/min, P = 0.19] were noted during high CPAP vs. NIPPV, along with no differences in work of breathing indices. CONCLUSION: High CPAP pressures did not adversely impact cardiac output or work of breathing compared to NIPPV at equivalent mean airway pressure.

Management of COVID-19-associated multisystem inflammatory syndrome in children: A comprehensive literature review.

BACKGROUND: The prevalence and severity of COVID-19 are greatly reduced in children, yet some pediatric patients develop a syndrome resembling Kawasaki Disease (KD), termed Multisystem Inflammatory Syndrome in Children (MIS-C). With an estimated incidence of 2/100,000 children, MIS-C is relatively rare but can be fatal. Clinical features can include fever, hyperinflammatory state, gastrointestinal symptoms, myocardial dysfunction, and shock. The pathogenesis of MIS-C, although yet to be completely elucidated, appears to be distinct from KD in terms of epidemiology, severity, and biochemical signature. AIM OF REVIEW: Although efficacy of treatments for MIS-C have largely not yet been investigated, we aim to conduct a comprehensive literature search of numerous medical databases (AMED, EBM Reviews, Embase, Healthstar, MEDLINE, ERIC, and Cochrane) to highlight treatments used around the world, their rationale, and outcomes to better inform guidelines in the future. Using the findings, an approach to MIS-C management will be outlined. KEY SCIENTIFIC CONCEPTS OF REVIEW: •MIS-C appears to be a SARS-CoV-2 related post-infection phenomenon that is distinct from Kawasaki disease.•Although outcomes are largely favorable, there is significant variation in MIS-C treatment. Most management regimens reported to date mirror that of KD; however, targeted therapy based on specific MIS-C phenotypes may have the potential to improve outcomes.•We recommend close monitoring by a multidisciplinary team, symptomatic treatment (e.g., intravenous immunoglobulin for KD-like symptoms, steroids/immunotherapy for multisystem inflammation), and long-term follow-up.•Further research is required to evaluate the effectiveness of current MIS-C treatments and to determine more refined therapies.

Incidence and short-term outcomes of Kawasaki disease.

OBJECTIVE: Kawasaki disease (KD) is a childhood vasculitis with conflicting reported North American trends in incidence and patient characteristics. OBJECTIVES: (1) determine KD incidence between 1995 and 2017; (2) compare patient characteristics by era and age group; (3) determine complication and cardiovascular follow-up rates. METHODS: We used population-based health administrative data to identify children (0-18 yr) hospitalized with KD in Ontario, Canada between 1995 and 2017. We excluded children with prior KD diagnosis or incomplete records. We determined the annualized incidence and follow-up trends. RESULTS: KD was diagnosed in 4,346 children between 1995 and 2017. Annual KD incidence was 22.0 (<5 yr), 6.1 (5-9 yr), and 0.6 (10-18 yr) per 100,000 children. KD incidence increased significantly for all age groups, including from 18.4 to 25.0 cases per 100,000 children <5 yr. Ninety-day mortality occurred in ≤5 children (≤0.1%). Coronary artery aneurysm (CAA) occurred in 106 children (2.4%, 95% confidence interval 2.0-2.9) during admission and 151 (3.5%, 95% confidence interval 3.0-4.1) during 11-year median follow-up. Children 10-18 yr had longer hospitalizations (4.3 vs. 3.5 days, p = 0.003) and more CAA (7.4% vs. 3.4%, p = 0.007). By 1-year post-diagnosis, 3970 (91.3%) and 2576 (59.3%) children had echocardiography and cardiology follow-up, respectively. CONCLUSIONS: KD incidence is increasing in Ontario, with greater healthcare utilization from hospitalizations and subsequent follow-up. IMPACT: 4346 children were hospitalized for Kawasaki disease over 22 years in Ontario, and Kawasaki disease incidence increased significantly for all age groups, males and females. Older children (10-18 years) had longer hospital length of stay, more PICU admissions and more frequent coronary artery aneurysms. Nearly all children with Kawasaki disease had follow-up echocardiography within 1 year.

Comparison Between Currently Recommended Long-Term Medical Management of Coronary Artery Aneurysms After Kawasaki Disease and Actual Reported Management in the Last Two Decades.

In the 2017 American Heart Association (AHA) Kawasaki disease (KD) guidelines, risk levels (RLs) for long-term management are defined by both maximal and current coronary artery (CA) dimensions normalized as z-scores. We sought to determine the degree to which current recommended practice differs from past actual practice, highlighting areas for knowledge translation efforts. The International KD Registry (IKDR) included 1651 patients with CA aneurysms (z-score > 2.5) from 1999 to 2016. Patients were classified by AHA RL using maximum CA z-score (RL 3 = small, RL 4 = medium, RL 5 = large/giant) and subcategorized based on decreases over time. Medical management provided was compared to recommendations. Low-dose acetylsalicylic acid (ASA) use ranged from 86 (RL 3.1) to 95% (RL 5.1) for RLs where use was "indicated." Dual antiplatelet therapy (ASA + clopidogrel) use ranged from 16% for RL 5.2 to 9% for RL 5.4. Recommended anticoagulation (warfarin or low molecular weight heparin) use was 65% for RL 5.1, while 12% were on triple therapy (anticoagulation + dual antiplatelet). Optional statin use ranged from 2 to 8% depending on RL. Optional beta-blocker use was 2-25% for RL 5, and 0-5% for RLs 3 and 4 where it is not recommended. Generally, past practice was consistent with the latest AHA guidelines, taking into account the flexible wording of recommendations based on the limited evidence, as well as unmeasured patient-specific factors. In addition to strengthening the overall evidence base, knowledge translation efforts may be needed to address variation in thromboprophylaxis management.

The Impact of beta blockade on the cardio-respiratory system and symptoms during exercise.

BACKGROUND: Beta blockers prolong life in patients with cardiovascular diseases. Negative chronotropic and inotropic effects carry the potential to adversely effect peripheral skeletal and airway smooth muscle contributing to further fatigue, dyspnea and exercise intolerance. RESEARCH QUESTIONS: Do beta-blockers reduce maximal power output (MPO), VO2 max, cardiorespiratory responses, increase the perceived effort required to cycle and breath during cardiopulmonary exercise tests (CPET) and limit the capacity to exercise? METHODS: Retrospective observational study of subjects performing CPET to capacity from 1988 to 2012. Subjects with and without beta-blockers were compared: baseline physiological characteristics, MPO, VO2 max, heart rate max, ventilation responses and perceived exertion required to cycle and breathe (modified Borg scale). Forward stepwise linear additive regression was performed with MPO as the dependent factor with height, age, gender, muscle strength, FEV1 and DLCO as independent contributors. RESULTS: 42,771 subjects were included 7,787 were receiving beta-blocker [mean age 61 yrs, BMI 28.40 kg/m2, 9% airflow obstruction (FEV1/FVC<0.7)] and 34,984 were not [mean age 51yrs, BMI 27.40 kg/m2, 11% airflow obstruction]. Heart rate was lower by 18.2% (95% C.I. 18.15-18.38) (p<0.0001) while Oxygen pulse (VO2/HR) was higher by 19.5% (95% C.I. 19.3-19.7) in those receiving beta blockers. Maximum power output (MPO) was 3.3% lower in those taking beta-blockers. The perceived effort required to cycle and breathe (mBorg) was 8% lower in those taking beta-blockers. INTERPRETATION: Increases in oxygen pulse minimize the reduction in exercise intolerance and symptom handicap associated with beta-blockers.

Central venous catheters are an important factor in paediatric thrombosis.

AIM: To establish the incidence and characteristics of paediatric thrombosis (PT) in a Canadian tertiary care centre during the era of low molecular weight heparin (LMWH). METHODS: A retrospective observational case study of all patients <18 years of age evaluated for arterial and venous thrombosis from May 2008 to July 2018 at McMaster Children's Hospital was conducted through the electronic medical record. RESULTS: The incidence of PT was 52.2 per 10 000 hospital admissions (n = 477/91 462). Provoked thrombosis was more prevalent (88.9%, n = 424/477) than unprovoked (2.9%, n = 14/477) or idiopathic thrombosis (4%, n = 19/477). Half of PT were in children <2 years (51.2%, n = 244/477). Central vascular catheterisation was a contributory factor in more than half of thrombotic events (56.2%, n = 268/477), while trauma (1.1%, n = 5/477), oral contraceptives (4%, n = 19/477), infection (4%, n = 19/477), surgery (6.9%, n = 33/477) and malignancy (8.4%, n = 40/477) were also risk factors. Arterial ischaemic stroke was diagnosed in 11.1% of cases (n = 53/477), while pulmonary embolism was identified in 7.1% (n = 34/477) and 1.7% of cases were fatal (n = 8/477). LMWH was the first-line therapeutic of choice (47.8%, n = 228/477), with 28.1% (n = 134/477) requiring no intervention. CONCLUSION: These data reiterate the elevated thrombosis risk to which infants and children with central vascular access are exposed.

Prenatal Diagnosis of Transposition of the Great Arteries Reduces Postnatal Mortality: A Population-Based Study.

BACKGROUND: Transposition of the great arteries (TGA) may present as a life-threatening neonatal malformation. Although prenatal detection facilitates the perinatal management, the impact on outcome is controversial. METHODS: This study reviewed the differences in prenatal diagnosis of TGA from 2009 to 2014 among the 5 geographic areas in Ontario and compared the management, morbidity, and mortality among neonates with a prenatal (prenatal cohort; n = 70) vs a postnatal (postnatal cohort; n = 76) anomaly diagnosis. Cases were identified from prospective databases of the provincial cardiac tertiary centres and the coroner's office. RESULTS: Prenatal TGA detection rates varied significantly among areas (median: 50%; range: 14% to 72%; P = 0.03). Compared with the postnatal cohort, time from birth to tertiary care admission (1.4 vs 10.4 hours, P < 0.001), prostaglandin therapy (0.1 vs 5.3 hours; P < 0.001), balloon atrial septostomy (5.3 vs 14.9 hours; P <0.001), and arterial switch operation (6 vs 9 days, P = 0.002) was significantly shorter in the prenatal cohort. Although other preoperative variables-including the need of ventilation and mechanical support, morbidity score, and lowest pH and preductal oxygen saturations-were comparable, a prenatal diagnosis was associated with improved 1-year survival (odds ratio: 0.108; 95% confidence interval, 0.013-0.88; P = 0.0184). CONCLUSIONS: Prenatal diagnosis of TGA significantly shortened time intervals from birth to neonatal care and surgery and was associated with improved survival. The prenatal detection rate of TGA in Ontario was low (50% or less) outside of Metropolitan Toronto, suggesting the need for new strategies to further improve intraprovincial detection rates.

Low-Molecular-Weight Heparin vs Warfarin for Thromboprophylaxis in Children With Coronary Artery Aneurysms After Kawasaki Disease: A Pragmatic Registry Trial.

BACKGROUND: The substantial risk of thrombosis in large coronary artery aneurysms (CAAs) (maximum z-score ≥ 10) after Kawasaki disease (KD) mandates effective thromboprophylaxis. We sought to determine the effectiveness of anticoagulation (low-molecular-weight heparin [LMWH] or warfarin) for thromboprophylaxis in large CAAs. METHODS: Data from 383 patients enrolled in the International KD Registry (IKDR) were used. Time-to-event analysis was used to account for differences in treatment duration and follow-up. RESULTS: From diagnosis onward (96% received acetylsalicylic acid concomitantly), 114 patients received LMWH (median duration 6.2 months, interquartile range [IQR] 2.5-12.7), 80 warfarin (median duration 2.2 years, IQR 0.9-7.1), and 189 no anticoagulation. Cumulative incidence of coronary artery thrombosis with LMWH was 5.7 ± 3.0%, with warfarin 6.7 ± 3.7%, and with no anticoagulation 20.6 ± 3.0% (P < 0.001) at 2.5 years after the start of thromboprophylaxis (LMWH vs warfarin HR 1.5, 95% confidence interval [CI] 0.4-5.1; P = 0.56). A total of 51/63 patients with coronary artery thrombosis received secondary thromboprophylaxis (ie, thromboprophylaxis after a previous thrombus): 27 LMWH, 24 warfarin. There were no differences in incidence of further coronary artery thrombosis between strategies (HR 2.9, 95% CI 0.6-13.5; P = 0.19). Severe bleeding complications were generally rare (1.6 events per 100 patient-years) and were noted equally for patients on LMWH and warfarin (HR 2.3, 95% CI 0.6-8.9; P = 0.25). CONCLUSIONS: LMWH and warfarin appear to have equivalent effectiveness for preventing thrombosis in large CAAs after KD, although event rates for secondary thromboprophylaxis and safety outcomes were low. Based on our findings, all patients with CAA z-score ≥ 10 should receive anticoagulation, but the choice of agent might be informed by secondary risk factors and patient preferences.