Actionability and familial uptake following opportunistic genomic screening in a pediatric cancer cohort.

The care for patients with serious conditions is increasingly guided by genomic medicine, and genomic medicine may equally transform care for healthy individual if genomic population screening is implemented. This study examines the medical impact of opportunistic genomic screening (OGS) in a cohort of patients undergoing comprehensive genomic germline DNA testing for childhood cancer, including the impact on their relatives. Medical actionability and uptake after cascade testing in the period following disclosure of OGS results was quantified. A secondary finding was reported to 19/595 (3.2%) probands primarily in genes related to cardiovascular and lipid disorders. After a mean follow up time of 1.6 years (Interquartile range (IQR): 0.57-1.92 yrs.) only 12 (63%) of these variants were found to be medically actionable. Clinical follow up or treatment was planned in 16 relatives, and as in the probands, the prescribed treatment was primarily betablockers or cholesterol lowering therapy. No invasive procedures or implantation of medical devices were performed in probands or relatives, and no reproductive counseling was requested. After an average of 1.6 years of follow-up 2.25 relatives per family with an actionable finding had been tested. This real-world experience of OGS grants new insight into the practical implementation effects and derived health care demands of genotype-first screening. The resulting health care effect and impact on demand for genetic counseling and workup in relatives extends beyond the effect in the probands.

Pulmonary Valve Replacement in Tetralogy of Fallot: Procedural Volume and Durability of Bioprosthetic Pulmonary Valves.

BACKGROUND: Robust data on changes in pulmonary valve replacement (PVR) procedural volume and predictors of bioprosthetic pulmonary valve (BPV) durability in patients with tetralogy of Fallot (TOF) are scarce. OBJECTIVES: This study sought to assess temporal trends in PVR procedural volume and BPV durability in a nationwide, retrospective TOF cohort. METHODS: Data were obtained from patient records. Robust linear regression was used to assess temporal trends in PVR procedural volume. Piecewise exponential additive mixed models were used to estimate BPV durability, defined as the time from implantation to redo PVR with death as a competing risk, and to assess risk factors for reduced durability. RESULTS: In total, 546 PVR were performed in 384 patients from 1976 to 2021. The annual number of PVR increased from 0.4 to 6.0 per million population (P < 0.001). In the last decade, the transcatheter PVR volume increased by 20% annually (P < 0.001), whereas the surgical PVR volume did not change significantly. The median BPV durability was 17 years (Q1: 10-Q3: 10 years-not applicable). There was no significant difference in the durability of different BPV after adjustment for confounders. Age at PVR (HR: 0.78 per 10 years from <1 year; 95% CI: 0.63-0.96; P = 0.02) and true inner valve diameter (9-17 mm vs 18-22 mm HR: 0.40; 95% CI: 0.22-0.73; P = 0.003 and 18-22 mm vs 23-30 mm HR: 0.59; 95% CI: 0.25-1.39; P = 0.23) were associated with reduced BPV durability in multivariate models. CONCLUSIONS: The PVR procedural volume has increased over time, with a greater increment in transcatheter than surgical PVR during the last decade. Younger patient age at PVR and a smaller true inner valve diameter predicted reduced BPV durability.

Postoperative free water administration is associated with dysnatremia after congenital heart disease surgery in infants.

Dysnatremia after congenital heart disease (CHD) surgery is common. European guidelines on intraoperative fluid therapy in children recommend isotonic solutions to avoid hyponatremia, but prolonged cardiopulmonary bypass and administration of high sodium-containing solutions (i.e., blood products and sodium bicarbonate) are associated with postoperative hypernatremia. The aim of the study was to describe fluid composition prior to and during the development of postoperative dysnatremia. A retrospective observational, single-center study including infants undergoing CHD surgery. Demographics and clinical characteristics were registered. Highest and lowest plasma sodium values were recorded and associations with perioperative fluid administration, blood products, crystalloids, and colloids were explored in relation to three perioperative periods. Postoperative dysnatremia occurred in nearly 50% of infants within 48 h after surgery. Hypernatremia was mainly associated with administration of blood products (median [IQR]: 50.5 [28.4-95.5] vs. 34.5 [18.5-61.1] mL/kg; p = 0.001), and lower free water load (1.6 [1.1-2.2] mL/kg/h; p = 0.01). Hyponatremia was associated with a higher free water load (2.3 [1.7-3.3] vs. 1.8 [1.4-2.5] mL/kg/h; p = 0.001) and positive fluid balance. On postoperative day 1, hyponatremia was associated with higher volumes of free water (2.0 [1.5-2.8] vs. 1.3 [1.1-1.8] mL/kg/h; p < 0.001) and human albumin, despite a larger diuresis and more negative daily fluid balance. Postoperative hyponatremia occurred in 30% of infants despite restrictive volumes of hypotonic maintenance fluid, whereas hypernatremia was mainly associated with blood product transfusion. Individualized fluid therapy, with continuous reassessment to reduce the occurrence of postoperative dysnatremia is mandatory in pediatric cardiac surgery. Prospective studies to evaluate fluid therapy in pediatric cardiac surgery patients are warranted.

Temporal changes in the surgical management of patients with tetralogy of Fallot in Denmark: a nationwide cohort study.

OBJECTIVES: To assess temporal changes in the surgical management of patients with tetralogy of Fallot including the timing of interventions, surgical techniques, reinterventions and survival in a nationwide cohort. METHODS: Patients with tetralogy of Fallot in Denmark were divided into 3 eras based on their year of birth: early (1977-1991), intermediate (1992-2006) and late (2007-2021). RESULTS: The cohort consisted of 745 patients. Median follow-up was 21.2 years (13.7-30.5). There was a temporal trend towards less shunt palliation (-0.3% per year, 95% CI -0.05 to -0.1). Median age at intracardiac repair was 2.9 years (1.8-5.0), 0.8 years (0.5-1.3) and 0.5 years (0.4-0.7) (P < 0.001) in the early, intermediate and late era, respectively. There was a temporal trend towards less valve-sparing repair (-0.7% per year, 95% CI -0.5 to -1.0) and more repair with transannular patches (0.7% per year, 95% CI 0.5-1.0). Survival at 10 years was 79% (64-76), 90% (87-93) and 95% (92-98) (P < 0.001) and pulmonary valve replacement within the first 10 years after intracardiac repair was performed in 3% (1-6), 12% (8-16) and 21% (13-29) (P < 0.001) in the early, intermediate and late era, respectively. CONCLUSIONS: There was a temporal trend towards less shunt palliation and intracardiac repair at a younger age with more use of transannular patches. While survival throughout childhood and adolescence has improved, more patients undergo pulmonary valve replacement during the first 10 years after intracardiac repair.

Heart disease among Greenlandic children and young adults: a nationwide cohort study.

BACKGROUND: The incidences of heart disease (HD) and congenital heart disease (CHD) among Inuit in Greenland (GL) and Denmark (DK) are unknown. This study aims to estimate incidence rates (IRs) of HD and CHD among the young Inuit populations in Greenland and Denmark compared with rates among young non-Inuit populations in the same countries. METHODS: A register-based nationwide cohort including all individuals living in Greenland and Denmark from birth to age <40 years through 1989-2014 was formed. Ethnicity was considered Inuit/mixed if at least one parent was registered as being born in Greenland. Information on HD and CHD hospitalization was obtained from national inpatient registers using ICD-8 and ICD-10 codes. RESULTS: HD IR was lower among individuals living in Greenland compared with those living in Denmark, [73.35GL (95% confidence interval (CI) 68.07 to 79.03)] vs [88.07DK (95% CI 87.38 to 88.76)], whereas CHD IRs were almost similar in the two countries [IR 34.44GL (95% CI 30.89 to 38.40) vs IR 34.67DK (95% CI 34.24 to 35.10)]. Being of Inuit/mixed ethnicity was associated with an increased risk of both HD and CHD compared with non-Inuit in Greenland and Denmark [adjusted hazard ratio HD 2.07GL (95% CI 1.25 to 3.42)] and CHD [2.92GL (95% CI 1.34 to 6.38)]. CONCLUSION: HD IR was lower in individuals living in Greenland compared with individuals living in Denmark, whereas the CHD IRs were almost the same for both countries. However, the risk of HD including CHD was higher among individuals of Inuit/mixed ethnicity compared with non-Inuit in both countries, suggesting a role of ethnicity among children and younger adults.

Cohort profile: the vitamin A and D and nitric oxide (AD-ON) observational cohort on lung development and symptoms in premature and mature children in North Zealand, Denmark.

PURPOSE: The risk of developing asthma-like symptoms and asthma in childhood is influenced by genetics, environmental exposures, prenatal and early postnatal events, and their interactions. The cohort name refers to vitamins A and D, and nitric oxide (NO) spelt backwards and this cohort profile paper aims to present the data collection and aim of the cohort.The overall aim when establishing this cohort was to investigate if childhood lung function can be traced back to early neonatal lung function and fractional exhaled NO (FeNO) and investigate prenatal and postnatal risk factors including maternal and neonatal vitamin A and D levels in preterm and term born children. PARTICIPANTS: One thousand five hundred women and their babies born at Nordsjaellands Hospital in Denmark from 2013 to 2014 were included in the AD-ON research biobank prior to birth.Neonates from the AD-ON research biobank, admitted to the Neonatal Intensive Care Unit at Nordsjaellands Hospital, were included in the AD-ON neonatal cohort. The neonatal cohort consisted of 149 neonates hereof 63 preterm and 86 term born. The children in the cohort have been invited to follow-up visits at age 1 and 6 years. FINDINGS TO DATE: Published data from this cohort includes a validated and clinically applicable method to measure FeNO in neonates. We found an age-specific pattern of association between respiratory symptoms at age 1 and neonatal FeNO in preterm children. Moreover, we found that the respiratory symptoms risk was associated with postnatal factors (Respiratory Syncytial Virus infection and parental smoking) in preterm infants and prenatal factors (parental asthma and maternal infection during pregnancy) in term born infants. FUTURE PLANS: In the future, the children will be examined continuously with 3-year to 5-year intervals until the age of 18. Lung function, allergy tests, environmental exposure measurements and questionnaires will be collected at each follow-up visit.

Clinical assessment of blood pressure in 60 girls with Turner syndrome compared to 1888 healthy Danish girls.

OBJECTIVE: Hypertension contributes to increased risk of cardiovascular disease in patients with Turner syndrome (TS). Our objective was to evaluate blood pressure (BP) in girls with TS followed longitudinally through childhood and adolescence compared to a newly established BP reference material. DESIGN: Cohort study with data collected from 1991 to 2019 consisting of a population-based reference cohort and a group of girls with TS followed at a single tertiary centre. PATIENTS/PARTICIPANTS: Reference population of 1888 healthy girls with 4890 BP recordings and 60 girls with TS with 365 BP recordings. MEASUREMENTS: Difference in diastolic BP (DBP) and systolic BP (SBP), expressed in standard deviation scores (SDS), between girls with TS and the reference population, unadjusted and adjusted for BMI. Difference in BP (SDS) between TS subgroups (karyotype, oestrogen treatment, cardiac diagnosis). RESULTS: The girls with TS had significantly higher DBP (mean ± SD, 0.72 SDS ± 0.95; p < .001) and SBP (0.53 SDS ± 1.11; p = .001) than the reference population. Adjusted for BMI, girls with TS had significantly higher DBP (mean ± SE, 0.71 SDS ± 0.12; p < .001) but not SBP (0.17 SDS ± 0.16; p = .29). There was no significant difference in DBP (median, IQR: 0.97 SDS, 0.30-1.58 vs. 0.76 SDS, 0.10-1.20; p = .31) or SBP (0.51 SDS, 0.15-1.30 vs. 0.57 SDS, -0.30 to 1.05; p = .67) between individuals with or without a cardiac diagnosis. In the TS population, 55% (31/56) had at least one BP recording above the hypertension threshold. CONCLUSIONS: Our findings indicate that standardised longitudinal routine monitoring of BP in girls with TS already in childhood is of utmost importance.

Postoperative dysnatremia in infants after open-heart surgery occurs frequently and is associated with prolonged intensive care length of stay.

BACKGROUND: Dysnatremia after surgery for congenital heart disease (CHD) is well known and has been associated with prolonged pediatric intensive care unit length of stay (PICU-LOS). Fluctuations in plasma sodium levels occur perioperatively. The primary aim of the study was to evaluate the occurrence of dysnatremia during the first 48 h after surgery and whether it was associated with PICU-LOS. The secondary aim was to evaluate if the degree of sodium fluctuations was associated with PICU-LOS. METHODS: A retrospective observational, single-center study including infants undergoing surgery for CHD. The highest and lowest plasma sodium value was registered for the prespecified time periods. PICU-LOS was analyzed in relation to the occurrence of dysnatremia and the degree of plasma sodium fluctuations. The occurrence of dysnatremia was evaluated in relation to surgical procedure and fluid administration. RESULTS: Two hundred and thirty infants who underwent 249 surgical procedures were included. Dysnatremia developed in more than 60% within 48 h after surgery. Infants with normonatremia had a 40%-50% shorter PICU-LOS among children in RACHS-1 category 3-6, compared with infants developing either hypo- or hyper-/hyponatremia within 48 h after surgery (p = .006). Infants who had a decline of plasma sodium >11 mmol/L had almost double the PICU-LOS compared to those with a decline of <8 mmol/L. CONCLUSION: Dysnatremias were common after surgery for CHD and associated with prolonged PICU-LOS. The degree of decline in plasma sodium was significantly associated with PICU-LOS. Fluid administration both in terms of volume and components (blood products and crystalloids) as well as diuresis were related to the occurrence of dysnatremias.

Left ventricular thrombus in multisystem inflammatory syndrome in children associated with COVID-19.

A 17-year-old adolescent with severe multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease-2019 developed reduced left ventricular function and left ventricular thrombus. With treatment, his condition improved and the thrombus was dissolved. This case illustrates the risk of severe intra-cardiac thrombotic complications in patients with MIS-C.

Population-based Incidence of Myopericarditis After COVID-19 Vaccination in Danish Adolescents.

In this prospective nationwide multicenter study from Denmark, myopericarditis after Pfizer-BioNTech mRNA COVID-19 vaccination was identified in 13 males and 2 females between May 15 and September 15, 2021, among 133,477 vaccinated males and 127,857 vaccinated females 12-17 years of age, equaling 97 males and 16 females per million. In conclusion, the incidence of myopericarditis after COVID-19 vaccination among males appears higher than reports from the United States.

Transthoracic Vector Flow Imaging in Pediatric Patients with Valvular Stenosis - A Proof of Concept Study.

Purpose Continuous wave Doppler ultrasound is routinely used to detect cardiac valve stenoses. Vector flow imaging (VFI) is an angle-independent real-time ultrasound method that can quantify flow complexity. We aimed to evaluate if quantification of flow complexity could reliably assess valvular stenosis in pediatric patients. Materials and Methods Nine pediatric patients with echocardiographically confirmed valvular stenosis were included in the study. VFI and Doppler measurements were compared with transvalvular peak-to-peak pressure differences derived from invasive endovascular catheterization. Results Vector concentration correlated with the catheter measurements before intervention after exclusion of one outlier (r=-0.83, p=0.01), whereas the Doppler method did not (r=0.49, p=0.22). The change in vector concentration after intervention correlated strongly with the change in the measured catheter pressure difference (r=-0.86, p=0.003), while Doppler showed a tendency for a moderate correlation (r=0.63, p=0.07). Conclusion Transthoracic flow complexity quantification calculated from VFI data is feasible and may be useful for assessing valvular stenosis severity in pediatric patients.

[Preoperative risk assessment of patients with congenital heart disease in non-cardiac surgery].

Over the last decades, remarkable advances in survival in patients with congenital heart disease (CHD) have been reported. Currently, 90% of infants born with CHD can expect to reach adulthood. Moderate and severe CHD is associated with increased perioperative mortality. To ensure optimal management of CHD patients undergoing non-cardiac surgery, preoperative risk assessment is pivotal, along with a multidisciplinary approach and collaboration across hospitals. The objective of this review is to provide a simple model to identify CHD patients at risk prior to non-cardiac surgery.

Liver fibrosis in patients with tetralogy of Fallot, an unrecognised complication?

OBJECTIVES: Improved survival has led to a growing population of adults with congenital heart disease (CHD), followed by numerous reports of late complications. Liver disease is a known complication in some patients, with most studies focusing on Fontan associated liver disease. Whether liver disease also exists in other patients with CHD is not fully investigated. Elevated central venous pressure is considered pivotal in the development of liver disease in Fontan associated liver disease, and other patients with alterations in central venous pressure may also be at risk for developing liver fibrosis. We wanted to see if liver fibrosis is present in patients with tetralogy of Fallot. Many patients with tetralogy of Fallot have severe pulmonary regurgitation, which can lead to elevated central venous pressure. Patients with tetralogy of Fallot may be at risk of developing liver fibrosis. MATERIALS AND METHODS: Ten patients (24-56 years) with tetralogy of Fallot and pulmonary regurgitation were investigated for liver fibrosis. All patients were examined with magnetic resonance elastography of liver, hepatobiliary iminodiacetic acid scan, indocyanine green elimination by pulse spectrophotometry, elastography via FibroScan, abdominal ultrasound including liver elastography, and blood samples including liver markers. RESULTS: Three out of ten patients had findings indicating possible liver fibrosis. Two of these had a liver biopsy performed, which revealed fibrosis stage 1 and 2, respectively. The same three patients had an estimated elevated central venous pressure in previous echocardiograms. CONCLUSIONS: Mild liver fibrosis was present in selected patients with tetralogy of Fallot and may be related to elevated central venous pressure.

Attention-deficit/hyperactivity disorder symptoms in children with surgically corrected Ventricular Septal Defect, Transposition of the Great Arteries, and Tetralogy of Fallot.

BACKGROUND: Children with complex CHD are at risk for psychopathology such as severe attention-deficit/hyperactivity disorder symptoms after congenital heart surgery. OBJECTIVE: The aim of this study was to investigate if children with Ventricular Septal Defect, Transposition of Great Arteries, or Tetralogy of Fallot have an increased occurrence of attention-deficit/hyperactivity disorder symptoms compared with the background population and to investigate differences between the three CHDs in terms of occurrence and appearance of attention-deficit/hyperactivity disorder symptoms. METHOD: A national register-based survey was conducted, including children aged 10-16 years with surgically corrected CHDs without genetic abnormalities and syndromes. The Attention-Deficit/Hyperactivity Disorder-Rating Scale questionnaires were filled in by parents and school teachers. RESULTS: In total, 159 out of 283 questionnaires were completed among children with CHDs and compared with age- and sex-matched controls. Children with CHDs had significantly increased inattention scores (p = 0.009) and total attention-deficit/hyperactivity disorder scores (p = 0.008) compared with controls. Post hoc analyses revealed that children with Tetralogy of Fallot had significantly higher inattention scores compared with children both with Ventricular Septal Defect (p = 0.043) and controls (p = 0.004). CONCLUSION: Attention-deficit/hyperactivity disorder symptoms and inattention symptoms were significantly more frequent among children aged 10-16 years with CHDs, in particular in children with corrected Tetralogy of Fallot.

Impact of congenital heart surgery on quality of life in children and adolescents with surgically corrected Ventricular Septal Defect, Tetralogy of Fallot, and Transposition of the Great Arteries.

OBJECTIVE: To describe the impact of CHD surgery in early childhood on quality of life in children aged 10-16 years with surgically corrected Ventricular Septal Defect, Transposition of the Great Arteries, and Tetralogy of Fallot. METHOD: A cross-sectional survey study of quality of life survey on 161 children and adolescents aged 10-16 years with surgically corrected Ventricular Septal Defect, Transposition of the Great Arteries, and Tetralogy of Fallot. The international Paediatric Quality of Life 4.0 quality of life questionnaires were applied and collected for assessment from patients and parents. The endpoints were total, physical, emotional, social, and school quality of life scores. RESULTS: The quality of life total and school scores was significantly lower in children with CHD than their healthy peers. There was no significant difference in quality of life between the three CHD groups. All three CHD groups had a significantly lower total (7.7-13.2%, p<0.001) and school scores (21.1-31.6%, p<0.001) than the control group. The tetralogy of Fallot group was the only group that had significantly lower scores in the physical subscale (p<0.001) than the controls. CONCLUSION: Children and adolescents with surgically corrected CHD show losses in quality of life in total and school scores compared to healthy controls. The tetralogy of Fallot group was the only CHD group that had significantly lower physical score than the controls.

Pediatric Transthoracic Cardiac Vector Flow Imaging - A Preliminary Pictorial Study.

Purpose Conventional pediatric echocardiography is crucial for diagnosing congenital heart disease (CHD), but the technique is impaired by angle dependency. Vector flow imaging (VFI) is an angle-independent noninvasive ultrasound alternative for blood flow assessment and can assess complex flow patterns not visible on conventional Doppler ultrasound. Materials and Methods 12 healthy newborns and 3 infants with CHD were examined with transthoracic cardiac VFI using a conventional ultrasound scanner and a linear array. Results VFI examinations revealed common cardiac flow patterns among the healthy newborns, and flow changes among the infants with CHD not previously reported with conventional echocardiography. Conclusion For assessment of cardiac flow in the normal and diseased pediatric heart, VFI may provide additional information compared to conventional echocardiography and become a useful diagnostic tool.

Change and dispersion of QT interval during treatment with quetiapine extended release versus aripiprazole in children and adolescents with first-episode psychosis: results from the TEA trial.

OBJECTIVE: The aim of this study was to compare the effect of quetiapine extended release (ER) versus aripiprazole on corrected QT interval (QTc) and QT dispersion (QTd) in youths with first-episode psychosis. METHODS: Youths 12-17 years were randomized to quetiapine ER (daily dose range = 50 to 800 mg) or aripiprazole (daily dose range = 2.5 to 30 mg) in a 12-week double-blinded trial and examined at weeks 0, 4, and 12. Primary outcome was QTc change using Hodges formula (QTcH); secondary outcomes included QTcH > 450 ms, QTcH > 500 ms, QTcH change > 60 ms, QTd, and heart rate (HR). RESULTS: Among 113 randomized youths, follow-up ECG was available for 93 patients (82.3%) (age = 15.8 ± 1.3 years, males = 34.4%, schizophrenia = 67.7%). Quetiapine ER treatment (n = 47) was associated with a significant increase in QTcH of + 6.8 ± 20.2 ms (p = 0.025), while the change from baseline in patients receiving aripiprazole (n = 46) was non-significant (- 3.4 ± 18.9 ms, p = 0.225). One patient in the quetiapine ER group had a QTcH change of + 62.3 ms. Age, sex, smoking, body mass index, and concomitant medication were not significantly associated with QTcH change, but higher baseline potassium was correlated to higher QTcH change in the quetiapine ER group. The HR increased significantly with quetiapine ER (+ 11.0 ± 14.2 bpm, p < 0.001) but not with aripiprazole (- 0.8 ± 12.0 bpm, p = 0.643). QTd did not significantly change with quetiapine ER or aripiprazole. CONCLUSION: QTcH and HR increased significantly with quetiapine ER, although changes were small and likely not clinically significant in otherwise healthy patients. QTcH and HR were unchanged with aripiprazole. No significant change in QTd was seen. ClinicalTrials.gov: NCT01119014, EudraCT: 2009-016715-38.

Corrected QT changes during antipsychotic treatment of children and adolescents: a systematic review and meta-analysis of clinical trials.

OBJECTIVE: To evaluate the effect of antipsychotics on the corrected QT (QTc) interval in youth. METHOD: We searched PubMed (http://www.ncbi.nlm.nih.gov/pubmed) for randomized or open clinical trials of antipsychotics in youth <18 years with QTc data, meta-analyzing the results. Meta-regression analyses evaluated the effect of age, sex, dose, and study duration on QTc. Incidences of study-defined QTc prolongation (>440-470 milliseconds), QTc >500 milliseconds, and QTc change >60 milliseconds were also evaluated. RESULTS: A total of 55 studies were meta-analyzed, evaluating 108 treatment arms covering 9 antipsychotics and including 5,423 patients with QTc data (mean age = 12.8 ± 3.6 years, female = 32.1%). Treatments included aripiprazole: studies = 14; n = 814; haloperidol: studies = 1; n = 15; molindone: studies = 3; n = 125; olanzapine: studies = 5; n = 212; paliperidone: studies = 3; n = 177; pimozide: studies = 1; n = 25; quetiapine: studies = 5; n = 336; risperidone: studies = 23; n = 2,234; ziprasidone: studies = 10, n = 523; and placebo: studies = 19, n = 962. Within group, from baseline to endpoint, aripiprazole significantly decreased the QTc interval (-1.44 milliseconds, CI = -2.63 to -0.26, p = .017), whereas risperidone (+1.68, CI = +0.67 to +2.70, p = .001) and especially ziprasidone (+8.74, CI = +5.19 to +12.30, p < .001) significantly increased QTc. Compared to pooled placebo arms, aripiprazole decreased QTc (p = .007), whereas ziprasidone increased QTc (p < .001). Compared to placebo, none of the investigated antipsychotics caused a significant increase in the incidence of the 3 studied QTc prolongation measures, but there was significant reporting bias. CONCLUSION: Based on these data, the risk of pathological QTc prolongation seems low during treatment with the 9 studied antipsychotics in otherwise healthy youth. Nevertheless, because individual risk factors interact with medication-related QTc effects, both medication and patient factors need to be considered when choosing antipsychotic treatment.

Quetiapine versus aripiprazole in children and adolescents with psychosis--protocol for the randomised, blinded clinical Tolerability and Efficacy of Antipsychotics (TEA) trial.

BACKGROUND: The evidence for choices between antipsychotics for children and adolescents with schizophrenia and other psychotic disorders is limited. The main objective of the Tolerability and Efficacy of Antipsychotics (TEA) trial is to compare the benefits and harms of quetiapine versus aripiprazole in children and adolescents with psychosis in order to inform rational, effective and safe treatment selections. METHODS/DESIGN: The TEA trial is a Danish investigator-initiated, independently funded, multi-centre, randomised, blinded clinical trial. Based on sample size estimation, 112 patients aged 12-17 years with psychosis, antipsychotic-naïve or treated for a limited period are, 1:1 randomised to a 12- week, double-blind intervention with quetiapine versus aripiprazole. Effects on psychopathology, cognition, health-related quality of life, and adverse events are assessed 2, 4, and 12 weeks after randomisation. The primary outcome is change in the positive symptom score of the Positive and Negative Syndrome Scale. The recruitment period is 2010-2014. DISCUSSION: Antipsychotics are currently the only available pharmacologic treatments for psychotic disorders. However, information about head-to-head differences in efficacy and tolerability of antipsychotics are scarce in children and adolescents. The TEA trial aims at expanding the evidence base for the use of antipsychotics in early onset psychosis in order to inform more rational treatment decisions in this vulnerable population. Here, we account for the trial design, address methodological challenges, and discuss the estimation of sample size. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01119014.