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Showing papers by "Hospital for Sick Children published in 2014"


Journal ArticleDOI
TL;DR: Gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, as an alternative to further chemotherapy dose escalation improved EFS through a reduction in RR for children and adolescents with AML.
Abstract: Purpose To improve survival rates in children with acute myeloid leukemia (AML), we evaluated gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, as an alternative to further chemotherapy dose escalation. Our primary objective was to determine whether adding GO to standard chemotherapy improved event-free survival (EFS) and overall survival (OS) in children with newly diagnosed AML. Our secondary objectives examined outcomes by risk group and method of intensification. Patients and Methods Children, adolescents, and young adults ages 0 to 29 years with newly diagnosed AML were enrolled onto Children's Oncology Group trial AAML0531 and then were randomly assigned to either standard five-course chemotherapy alone or to the same chemotherapy with two doses of GO (3 mg/m2/dose) administered once in induction course 1 and once in intensification course 2 (two of three). Results There were 1,022 evaluable patients enrolled. GO significantly improved EFS (3 years: 53.1% v 46.9%; hazard...

319 citations


Journal ArticleDOI
TL;DR: Remote ischaemic conditioning before primary percutaneous coronary intervention seemed to improve long-term clinical outcomes in patients with ST-elevation myocardial infarction.
Abstract: Aims Remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction increases myocardial salvage. We investigated the effect of remote ischaemic conditioning on long-term clinical outcome. Methods and results From February 2007 to November 2008, 333 patients with a suspected first acute ST-elevation myocardial infarction were randomized to receive primary percutaneous coronary intervention with ( n = 166) or without ( n = 167) remote ischaemic conditioning (intermittent arm ischaemia through four cycles of 5-min inflation followed by 5-min deflation of a blood-pressure cuff). Patient follow-up extended from the randomization date until an outcome, emigration or January 2012 (median follow-up = 3.8 years). The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE)—a composite of all-cause mortality, myocardial infarction, readmission for heart failure, and ischaemic stroke/transient ischaemic attack. The individual components of the primary endpoint comprised the secondary endpoints. Outcomes were obtained from Danish nationwide medical registries and validated by medical record review and contact to patients' general practitioner. In the per-protocol analysis of 251 patient fulfilling trial criteria, MACCE occurred for 17 (13.5%) patients in the intervention group compared with 32 (25.6%) patients in the control group, yielding a hazard ratio (HR) of 0.49 (95% confidence interval: 0.27–0.89, P = 0.018). The HR for all-cause mortality was 0.32 (95% confidence interval: 0.12–0.88, P = 0.027). Although lower precision, the HRs were also directionally lower for all other secondary endpoints. Conclusion Remote ischaemic conditioning before primary percutaneous coronary intervention seemed to improve long-term clinical outcomes in patients with ST-elevation myocardial infarction.

265 citations


Journal ArticleDOI
TL;DR: It is shown that clinically classic DIPGs represent a diverse histologic spectrum, including multiple cases which would fit WHO criteria of grade II astrocytoma which nevertheless behave clinically as high-grade astroCytomas and harbour the histone K27M-H3.3 mutation, suggesting that the current WHO astro Cytoma grading scheme may not appropriately predict outcome for paediatric brainstem gliomas.
Abstract: Diffuse intrinsic pontine glioma (DIPG) is the main cause of brain tumour-related death in children. In the majority of cases diagnosis is based on clinical and MRI findings, resulting in the scarcity of pre-treatment specimens available to study. Our group has developed an autopsy-based protocol to investigate the histologic and biologic spectrum of DIPG. This has also allowed us to investigate the terminal pattern of disease and gain a better understanding of what challenges we are facing in treating DIPG. Here, we review 72 DIPG cases with well documented clinical history and molecular data and describe the pathological features of this disease in relation to clinical and genetic features. Fifty-three of the samples were autopsy material (7 pre-treatment) and 19 were pre-treatment biopsy/surgical specimens. Upon histological review, 62 patients had high-grade astrocytomas (18 WHO grade III and 44 WHO grade IV patients), 8 had WHO grade II astrocytomas, and 2 had features of primitive neuroectodermal tumour (PNET). K27M-H3 mutations were exclusively found in tumours with WHO grade II–IV astrocytoma histology. K27M-H3.1 and ACVR1 mutations as well as ALT phenotype were only found in WHO grade III–IV astrocytomas, while PIK3CA mutations and PDGFRA gains/amplifications were found in WHO grade II–IV astrocytomas. Approximately 1/3 of DIPG patients had leptomeningeal spread of their tumour. Further, diffuse invasion of the brainstem, spinal cord and thalamus was common with some cases showing spread as distant as the frontal lobes. These findings suggest that focal radiation may be inadequate for some of these patients. Importantly, we show that clinically classic DIPGs represent a diverse histologic spectrum, including multiple cases which would fit WHO criteria of grade II astrocytoma which nevertheless behave clinically as high-grade astrocytomas and harbour the histone K27M-H3.3 mutation. This suggests that the current WHO astrocytoma grading scheme may not appropriately predict outcome for paediatric brainstem gliomas.

233 citations


Journal ArticleDOI
TL;DR: Systemic release of microRNA 144 plays a pivotal role in the cardioprotection induced by rIPC, and the potential for plasma miR-144 as a biomarker of the effectiveness of r IPC induced by limb ischemia is assessed.
Abstract: Remote ischemic preconditioning (rIPC) induced by cycles of transient limb ischemia and reperfusion is a powerful cardioprotective strategy with additional pleiotropic effects. However, our understanding of its underlying mediators and mechanisms remains incomplete. We examined the role of miR-144 in the cardioprotection induced by rIPC. Microarray studies first established that rIPC increases, and IR injury decreases miR-144 levels in mouse myocardium, the latter being rescued by both rIPC and intravenous administration of miR-144. Going along with this systemic treatment with miR-144 increased P-Akt, P-GSK3β and P-p44/42 MAPK, decreased p-mTOR level and induced autophagy signaling, and induced early and delayed cardioprotection with improved functional recovery and reduction in infarct size similar to that achieved by rIPC. Conversely, systemic administration of a specific antisense oligonucleotide reduced myocardial levels of miR-144 and abrogated cardioprotection by rIPC. We then showed that rIPC increases plasma miR-144 levels in mice and humans, but there was no change in plasma microparticle (50-400 nM) numbers or their miR-144 content. However, there was an almost fourfold increase in miR-144 precursor in the exosome pellet, and a significant increase in miR-144 levels in exosome-poor serum which, in turn, was associated with increased levels of the miR carriage protein Argonaute-2. Systemic release of microRNA 144 plays a pivotal role in the cardioprotection induced by rIPC. Future studies should assess the potential for plasma miR-144 as a biomarker of the effectiveness of rIPC induced by limb ischemia, and whether miR-144 itself may represent a novel therapy to reduce clinical ischemia-reperfusion injury.

212 citations


Journal ArticleDOI
01 May 2014-Diabetes
TL;DR: Results suggest an association between HbA1c level and H3K9Ac, and a possible epigenetic explanation for metabolic memory in humans.
Abstract: We assessed whether epigenetic histone posttranslational modifications are associated with the prolonged beneficial effects (metabolic memory) of intensive versus conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term Epidemiology of Diabetes Interventions and Complications (EDIC) study. We performed chromatin immunoprecipitation linked to promoter tiling arrays to profile H3 lysine-9 acetylation (H3K9Ac), H3 lysine-4 trimethylation (H3K4Me3), and H3K9Me2 in blood monocytes and lymphocytes obtained from 30 DCCT conventional treatment group subjects (case subjects: mean DCCT HbA1c level >9.1% [76 mmol/mol] and progression of retinopathy or nephropathy by EDIC year 10 of follow-up) versus 30 DCCT intensive treatment subjects (control subjects: mean DCCT HbA1c level 15 genes related to the nuclear factor-κB inflammatory pathway and were enriched in genes related to diabetes complications. These results suggest an association between HbA1c level and H3K9Ac, and a possible epigenetic explanation for metabolic memory in humans.

200 citations


Journal ArticleDOI
TL;DR: Evidence from two large high quality studies suggests that omega 3 fatty acids are probably ineffective for maintenance of remission in CD, although they may cause diarrhea and upper gastrointestinal tract symptoms.
Abstract: Background The anti-inflammatory effects of n-3 (omega-3 fatty acids, fish oil) have been suggested to be beneficial in chronic inflammatory disorders such as inflammatory bowel disease. Objectives To systematically review the efficacy and safety of n-3 for maintenance of remission in Crohn's disease (CD). Search strategy The following databases were searched from their inception without language restriction: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Healthstar, PubMed, and ACP journal club. Experts were contacted for unpublished data. Selection criteria Randomized placebo-controlled trials (RCT) of n-3 for maintenance of remission in CD were included. Studies must have enrolled patients of any age group, who were in remission at the time of recruitment, and were followed for at least six months. The intervention must have been fish oil or n-3 given in pre-defined dosage. Co-interventions were allowed only if they were balanced between the study groups. The primary outcome was the relapse rate and secondary outcomes included change in disease activity scores, time to first relapse and adverse events. Data collection and analysis Two independent investigators reviewed studies for eligibility, extracted the data and assessed study quality using Jadad's criteria. Meta-analyses were performed using RevMan 4.2 software weighted by the Mantel-Haenszel method. Random or fixed effect models were used according to degree of heterogeneity and subgroup analyses were performed in an attempt to explore possible sources of heterogeneity. Main results Six studies were eligible for inclusion. There was a marginal significant benefit of n-3 therapy for maintaining remission (RR 0.77 0.; 95%CI 0.61 to 0.98; P = 0.03). However, the studies were both clinically and statistically heterogeneous (P = 0.03, I(2) = 58%). Two large studies showed negative results. When considering the estimated rather than the observed 1-year relapse rate of these two studies, the benefit was no longer statistically significant (RR 0.59; 95% CI 0.34 to 1.03; P=0.06). A funnel plot suggested publication bias. No serious adverse events were recorded in any of the studies but in a pooled analyses there was a significantly higher rate of diarrhea (RR 1.36 95% CI 1.01 to 1.84) and symptoms of the upper gastrointestinal tract (RR 1.98 95% CI 1.38 to 2.85) in the n-3 treatment group. Authors' conclusions Omega 3 fatty acids are safe but probably ineffective for maintenance of remission in CD. The existing data do not support routine maintenance treatment of Crohn's disease with omega 3 fatty acids.

189 citations


Journal ArticleDOI
TL;DR: By 3 years, the Norwood procedure with RVPAS compared with MBTS was no longer associated with superior transplantation-free survival, andRVPAS subjects had slightly worse right ventricular ejection fraction and underwent more catheter interventions with increasing hazard ratio over time.
Abstract: Background— In the Single Ventricle Reconstruction (SVR) trial, 1-year transplantation-free survival was better for the Norwood procedure with right ventricle–to–pulmonary artery shunt (RVPAS) compared with a modified Blalock-Taussig shunt (MBTS). At 3 years, we compared transplantation-free survival, echocardiographic right ventricular ejection fraction, and unplanned interventions in the treatment groups. Methods and Results— Vital status and medical history were ascertained from annual medical records, death indexes, and phone interviews. The cohort included 549 patients randomized and treated in the SVR trial. Transplantation-free survival for the RVPAS versus MBTS groups did not differ at 3 years (67% versus 61%; P =0.15) or with all available follow-up of 4.8±1.1 years (log-rank P =0.14). Pre-Fontan right ventricular ejection fraction was lower in the RVPAS group than in the MBTS group (41.7 ± 5.1% versus 44.7 ± 6.0%; P =0.007), and right ventricular ejection fraction deteriorated in RVPAS ( P =0.004) but not MBTS ( P =0.40) subjects (pre-Fontan minus 14-month mean, −3.25±8.24% versus 0.99±8.80%; P =0.009). The RVPAS versus MBTS treatment effect had nonproportional hazards ( P =0.004); the hazard ratio favored the RVPAS before 5 months (hazard ratio=0.63; 95% confidence interval, 0.45–0.88) but the MBTS beyond 1 year (hazard ratio=2.22; 95% confidence interval, 1.07–4.62). By 3 years, RVPAS subjects had a higher incidence of catheter interventions ( P P =0.005): 1 year, 2.48 (95% confidence interval, 1.28–4.80). Conclusions— By 3 years, the Norwood procedure with RVPAS compared with MBTS was no longer associated with superior transplantation-free survival. Moreover, RVPAS subjects had slightly worse right ventricular ejection fraction and underwent more catheter interventions with increasing hazard ratio over time. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00115934.

182 citations


Journal ArticleDOI
TL;DR: Sleep duration in children with ASD is reduced from 30 months of age and persists until adolescence, and age-specific decreases of >1SD within individuals in sleep duration across adjacent time points was a predictor of ASD.
Abstract: Objective To investigate longitudinal sleep patterns in children with autistic spectrum disorders (ASDs). Study design Prospective longitudinal study using Avon Longitudinal Study of Parents and Children, an English cohort born in 1991–1992. Parental reports of sleep duration were collected by questionnaires at 8 time points from 6 months to 11 years. Children with an ASD diagnosis at age 11 years (n=73) were identified from health and education records. Results From aged 30 months to 11 years old, children with ASD slept for 17–43 min less each day than contemporary controls. No significant difference in total sleep duration was found in infancy, but from 30 months of age children with ASD slept less than their peers, a difference that remained significant after adjusting for sex, ethnicity, high parity and epilepsy. The reduction in total sleep was wholly due to changes in night rather than daytime sleep duration. Night-time sleep duration was shortened by later bedtimes and earlier waking times. Frequent waking (3 or more times a night) was also evident among the children with ASD from 30 months of age. Age-specific decreases of >1SD within individuals in sleep duration across adjacent time points was a predictor of ASD between 18 months and 30 months of age (p=0.04) and from 30 months to 42 months (p=0.02). Conclusions Sleep duration in children with ASD is reduced from 30 months of age and persists until adolescence.

146 citations


Journal ArticleDOI
TL;DR: Budesonide is a glucocorticoid with limited systemic bioavailability due to extensive first-pass hepatic metabolism and is effective for induction of remission in Crohn's disease as mentioned in this paper.
Abstract: Background Corticosteroids are effective for induction, but not maintenance of remission in Crohn's disease. Significant concerns exist regarding the risk for adverse events, particularly when corticosteroids are used for long treatment courses. Budesonide is a glucocorticoid with limited systemic bioavailability due to extensive first-pass hepatic metabolism and is effective for induction of remission in Crohn's disease. Objectives To evaluate the efficacy and safety of oral budesonide for maintenance of remission in Crohn's disease. Search methods The following databases were searched from inception to 12 June 2014: PubMed, MEDLINE, EMBASE, CENTRAL, the Cochrane IBD/FBD Group Specialised Trial Register, and ClinicalTrials.gov. Reference lists of articles, as well as conference proceedings were manually searched. Selection criteria Randomized controlled trials comparing budesonide to a control treatment, or comparing two doses of budesonide, were included. The study population included patients of any age with quiescent Crohn's disease. Data collection and analysis Two independent investigators reviewed studies for eligibility, extracted data and assessed study quality using the Cochrane risk of bias tool. The primary outcome was maintenance of remission at various reported follow-up times during the study. Secondary outcomes included: time to relapse, mean change in CDAI, clinical, histological, improvement in quality of life, adverse events and study withdrawal. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes and the mean difference (MD) and 95% CI for continuous outcomes. Data were analysed on an intention-to-treat basis. The Chi2 and I2 statistics were used to assess heterogeneity. Random-effects models were used to allow for expected clinical and statistical heterogeneity. The overall quality of the evidence supporting the primary outcome was assessed using the GRADE criteria. Main results Twelve studies (n = 1273 patients) were included in the review: eight studies compared budesonide to placebo, one compared budesonide to 5-aminosalicylates, one compared budesonide to traditional systemic corticosteroids, one compared budesonide to azathioprine, and one compared two doses of budesonide. Nine studies used a controlled ileal release form of budesonide, while three used a pH-modified release formulation. Nine studies were judged to be at low risk of bias. Three studies were judged to be at high risk of bias due to blinding and one of these studies also had inadequate allocation concealment. Budesonide 6 mg daily was no more effective than placebo for maintenance of remission at 3 months, 6 months or 12 months. At three months 64% of budesonide 6 mg patients remained in remission compared to 52% of placebo patients (RR 1.25, 95% CI 1.00 to 1.58; 6 studies, 540 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to moderate heterogeneity (I2 = 56%) and sparse data (315 events). At six months 61% of budesonide 6 mg patients remained in remission compared to 52% of placebo patients (RR 1.15, 95% CI 0.95 to 1.39; 5 studies, 420 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate due to sparse data (238 events). At 12 months 55% of budesonide 6 mg patients remained in remission compared to 48% of placebo patients (RR 1.13; 95% CI 0.94 to 1.35; 5 studies, 420 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate due to sparse data (215 events). Similarly, there was no significant benefit for budesonide 3 mg compared to placebo at 6 and 12 months. There was no statistically significant difference in continued remission at 12 months between budesonide and weaning doses of prednisolone (RR 0.79; 95% CI 0.55 to 1.13; 1 study, 90 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (51 events) and high risk of bias (no blinding). Budesonide 6 mg was better than mesalamine 3 g/day at 12 months (RR 2.51, 95% CI 1.03 to 6.12; 1 study, 57 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to very sparse data (18 events) and high risk of bias (no blinding). There was no statistically significant difference in continued remission at 12 months between budesonide and azathioprine (RR 0.81; 95% CI 0.61 to 1.08; 1 study 77 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to sparse data (55 events) and high risk of bias (single-blind and no allocation concealment). The use of budesonide 6 mg resulted in slight improvements in CDAI scores when assessed at 6 months (MD -24.30, 95% CI -46.31 to -2.29) and 12 months (MD -23.49, 95% CI -46.65 to -0.32) and mean time to relapse of disease (MD 59.93 days, 95% CI 19.02 to 100.84). Mean time to relapse was significantly shorter for patients receiving budesonide than for those receiving azathioprine (MD -58.00, 95% CI -96.68 to -19.32). Adverse events were not more common in patients treated with budesonide compared to placebo (6 mg: RR 1.51, 95% CI 0.90 to 2.52; 3 mg: RR 1.19, 95% CI 0.63 to 2.24). These events were relatively minor and did not result in increased rates of study withdrawal. Commonly reported treatment-related adverse effects included acne, moon facies, hirsutism, mood swings, insomnia, weight gain, striae, and hair loss. Abnormal adrenocorticoid stimulation tests were seen more frequently in patients receiving both 6 mg (RR 2.88, 95% CI 1.72 to 4.82) and 3 mg daily (RR 2.73, 95% CI 1.34 to 5.57) compared to placebo. Authors' conclusions These data suggest budesonide is not effective for maintenance of remission in CD, particularly when used beyond three months following induction of remission. Budesonide does have minor benefits in terms of lower CDAI scores and longer time to relapse of disease. However, these benefits are offset by higher treatment-related adverse event rates and more frequent adrenocorticoid suppression in patients receiving budesonide.

134 citations


Journal ArticleDOI
TL;DR: The authors report their progress in the development of an Internet- and smartphone-based application for chronic pain self-management and the potential of Internet-based cognitive behavioural therapy in treating chronic pain.
Abstract: BACKGROUND: While there are emerging web-based self-management programs for children and adolescents with chronic pain, there is currently not an integrated web- and smartphone-based app that specifically addresses the needs of adolescents with chronic pain.

121 citations


Journal ArticleDOI
TL;DR: The findings suggest that while the shift sub-scale of the self-report version of the BRIEF is a promising clinical marker, clinical performance measures of cognitive flexibility may lack ecological validity and reinforces that impairments in cognitive flexibility do not uniformly characterize all persons with ASD.
Abstract: Impairments in cognitive flexibility have been used to characterize the neuropsychological presentation of persons with autism spectrum disorders (ASDs). Previous studies have yielded mixed results. Our objective was to systematically review the sensitivity of cognitive flexibility measures in ASD using quantitative methods employed by meta-analytic statistical techniques. Seventy-two studies met inclusion criteria for analysis and included a total of 2,137 individuals with ASD and 2,185 healthy controls. Our findings demonstrate that while the shift sub-scale of the self-report version of the Behavioral Rating Inventory of Executive Function (BRIEF) showed approximate absolute discriminability, of all the performance measures that were systematically reviewed and evaluated, none could reliably differentiate between individuals with ASD and controls; this is not surprising given that cognitive flexibility is not a core deficit of ASD. Our findings suggest that while the shift sub-scale of the self-report version of the BRIEF is a promising clinical marker, clinical performance measures of cognitive flexibility may lack ecological validity and lastly, reinforces that impairments in cognitive flexibility do not uniformly characterize all persons with ASD.

Journal ArticleDOI
TL;DR: Increases in HPA are feasible despite progression of lung disease and are associated with a slower rate of decline in FEV1, highlighting the benefit of regular physical activity, and its positive impact on lung function in patients with CF.
Abstract: Exercise is beneficial for patients with cystic fibrosis (CF) but long-term effects of physical activity on lung function evolution are unknown. We evaluated the longitudinal relationship between changes in habitual physical activity (HPA) and rate of decline in lung function in patients with CF. We tracked HPA using the Habitual Activity Estimation Scale, forced expiratory volume in 1 s (FEV₁) and Stage I exercise tests in 212 patients with CF over a 9-year period. Adjusting for sex, baseline age and FEV₁, mucoid Pseudomonas aeruginosa and CF-related diabetes, mean ± sd FEV₁ % predicted decreased by 1.63 ± 0.08% per year (p<0.0001) while mean ± sd HPA increased by 0.28 ± 0.03 h·day(-1) per year (p<0.0001) over the study period. A greater increase in HPA was associated with a slower rate of decline in FEV₁ (r=0.19, p<0.0069). Dividing subjects into "high" and "low" activity (above or below the mean rate of change of activity, respectively), a steeper rate of FEV₁ decline was observed for low (-1.90% per year) compared to high (-1.39% per year) (p=0.002). Increases in HPA are feasible despite progression of lung disease and are associated with a slower rate of decline in FEV₁, highlighting the benefit of regular physical activity, and its positive impact on lung function in patients with CF.

Journal ArticleDOI
TL;DR: The existence of pleiotropic effects within this single disorder suggests that complementary therapeutic strategies to augment solute transport will benefit multiple CF-associated tissues.
Abstract: The existence of pleiotropy in disorders with multi-organ involvement can suggest therapeutic targets that could ameliorate overall disease severity. Here we assessed pleiotropy of modifier genes in cystic fibrosis (CF). CF, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, affects the lungs, liver, pancreas and intestines. However, modifier genes contribute to variable disease severity across affected organs, even in individuals with the same CFTR genotype. We sought to determine whether SLC26A9, SLC9A3 and SLC6A14, that contribute to meconium ileus in CF, are pleiotropic for other early-affecting CF co-morbidities. In the Canadian CF population, we assessed evidence for pleiotropic effects on (1) pediatric lung disease severity (n = 815), (2) age at first acquisition of Pseudomonas aeruginosa (P. aeruginosa) (n = 730), and (3) prenatal pancreatic damage measured by immunoreactive trypsinogen (n = 126). A multiple-phenotype analytic strategy assessed evidence for pleiotropy in the presence of phenotypic correlation. We required the same alleles to be associated with detrimental effects. SLC26A9 was pleiotropic for meconium ileus and pancreatic damage (p = 0.002 at rs7512462), SLC9A3 for meconium ileus and lung disease (p = 1.5 × 10(-6) at rs17563161), and SLC6A14 for meconium ileus and both lung disease and age at first P. aeruginosa infection (p = 0.0002 and p = 0.006 at rs3788766, respectively). The meconium ileus risk alleles in SLC26A9, SLC9A3 and SLC6A14 are pleiotropic, increasing risk for other early CF co-morbidities. Furthermore, co-morbidities affecting the same organ tended to associate with the same genes. The existence of pleiotropy within this single disorder suggests that complementary therapeutic strategies to augment solute transport will benefit multiple CF-associated tissues.

Journal ArticleDOI
TL;DR: Twenty-two CNVs were validated from this set, many of which appear likely to disrupt genes that may be considered as good candidates for neuropsychiatric disorders, including DLG2, S100B, ARX, DIP2A, HPCAL1, and GPHN.
Abstract: Autism or autism spectrum disorder (ASD) is a range of neurodevelopmental disorders starting in early childhood and is characterized by impairments in communication and reciprocal social interaction and presence of restricted and repetitive patterns of behavior. The contribution of genetic factors to autism is clear in twin and family studies. It is apparent that, overall, ASD is a complex non-Mendelian disorder. Recent studies suggest that copy number variations (CNVs) play a significant role in the etiology of ASD. For the current work, we recruited 245 family members from 73 ASD families from Styria, Austria. The DNA from probands was genotyped with Affymetrix single nucleotide polymorphism (SNP) 6.0 microarrays to screen for CNVs in their genomes. Analysis of the microarray data was performed using three different algorithms, and a list of stringent calls was compared to existing CNV data from over 2,357 controls of European ancestry. For stringent calls not present in controls, quantitative real-time PCR (qRT-PCR) was used to validate the CNVs in the probands and in their family members. Twenty-two CNVs were validated from this set (five of which are apparently de novo), many of which appear likely to disrupt genes that may be considered as good candidates for neuropsychiatric disorders, including DLG2, S100B, ARX, DIP2A, HPCAL1, and GPHN. Several others disrupt genes that have previously been implicated in autism, such as BDNF, AUTS2, DPP6, and C18orf22, and our data add to the growing evidence of their involvement in ASD.

Journal ArticleDOI
TL;DR: There is no evidence that fibre supplements, lactose free diets or lactobacillus supplementation are effective in the management of children with RAP, and a lack of high quality evidence on the effectiveness of dietary interventions is provided.
Abstract: Background Between 4% and 25% of school-age children complain of recurrent abdominal pain (RAP) of sufficient severity to interfere with daily activities. It is unclear whether the diagnosis includes children with different aetiologies for their pain. For the majority no organic cause for their pain can be found on physical examination or investigation. Although most children are likely managed by reassurance and simple measures, a large range of interventions have been recommended. Objectives To determine the effectiveness of dietary interventions for recurrent abdominal pain in school-age children. Search strategy The Cochrane Library (CENTRAL) 2006 (Issue 4), MEDLINE (1966 to Dec 2006), EMBASE (1980 to Dec 2006), CINAHL (1982 to Dec 2007), ERIC (1966 to Dec 2006), PsycINFO (1872 to Dec 2006), LILACS (1982 to Dec 2006), SIGLE (1980 to March 2005), and JICST (1985 to 06/2000) were searched . Where appropriate, search filters were employed. In addition, researchers working in this area were asked to identify relevant studies. Selection criteria Randomised or quasi-randomised studies of any dietary treatment versus placebo or no treatment in school-age children with a diagnosis of RAP or functional gastrointestinal disorder based on the Rome II criteria. Data collection and analysis Two authors independently assessed trials for inclusion, assessed quality and extracted data. Where appropriate studies were pooled using a random effects meta-analysis. Main results Seven trials were included in this review. Two trials, including 83 participants, compared fibre supplements with placebo (Christensen 1982, Feldman 1985), with data from one study reported in two papers (Christensen 1982, Christensen 1986). The pooled odds ratio for improvement in the frequency of abdominal pain was 1.16 (95% CI 0.45-2.87). Two trials, including 90 participants (Lebenthal 1981, Dearlove 1983) compared lactose-containing with lactose-free diets. Neither reported data in a form which could be used in the meta-analysis and the former trial had a loss to follow-up of 45%. We were not able to obtain further data for either trial. Three trials (Bausserman 2005, Gavronska 2007, Young 1997) comparing supplementation with Lactobacillus with placebo met the inclusion criteria but only two (Bausserman 2005, Gavronska 2007), including a total of 168 children, provided analysable data. The pooled odds ratio for improvement of symptoms was 1.17 (95% CI 0.62, 2.21). Authors' conclusions There is a lack of high quality evidence on the effectiveness of dietary interventions. This review provides no evidence that fibre supplements, lactose free diets or lactobacillus supplementation are effective in the management of children with RAP.

Journal ArticleDOI
TL;DR: Given that the main causes of maternal and perinatal deaths are generally consistent across low resource settings, the specific avoidable factors identified in this review can help to inform the rational design of health systems with the aim of achieving continued progress towards Millennium Development Goals Four and Five.
Abstract: Audits provide a rational framework for quality improvement by systematically assessing clinical practices against accepted standards with the aim to develop recommendations and interventions that target modifiable deficiencies in care. Most childbirth-associated mortality audits in developing countries are focused on a single facility and, up to now, the avoidable factors in maternal and perinatal deaths cataloged in these reports have not been pooled and analyzed. We sought to identity the most frequent avoidable factors in childbirth-related deaths globally through a systematic review of all published mortality audits in low and lower-middle income countries. We performed a systematic review of published literature from 1965 to November 2011 in Pubmed, Embase, CINAHL, POPLINE, LILACS and African Index Medicus. Inclusion criteria were audits from low and lower-middle income countries that identified at least one avoidable factor in maternal or perinatal mortality. Each study included in the analysis was assigned a quality score using a previously published instrument. A meta-analysis was performed for each avoidable factor taking into account the sample sizes and quality score from each individual audit. The study was conducted and reported according to PRISMA guidelines for systematic reviews. Thirty-nine studies comprising 44 datasets and a total of 6,205 audited deaths met inclusion criteria. The analysis yielded 42 different avoidable factors, which fell into four categories: health worker-oriented factors, patient-oriented factors, transport/referral factors, and administrative/supply factors. The top three factors by attributable deaths were substandard care by a health worker, patient delay, and deficiencies in blood transfusion capacity (accounting for 688, 665, and 634 deaths attributable, respectively). Health worker-oriented factors accounted for two-thirds of the avoidable factors identified. Audits provide insight into where systematic deficiencies in clinical care occur and can therefore provide crucial direction for the targeting of interventions to mitigate or eliminate health system failures. Given that the main causes of maternal and perinatal deaths are generally consistent across low resource settings, the specific avoidable factors identified in this review can help to inform the rational design of health systems with the aim of achieving continued progress towards Millennium Development Goals Four and Five.

Journal ArticleDOI
TL;DR: This audit provides a snapshot of the early outcome of a group of children with aHUS in the months prior to more widespread use of eculizumab.
Abstract: Background In 2009, the European Paediatric Study Group for Haemolytic Uraemic Syndrome (HUS) published a clinical practice guideline for the investigation and initial therapy of diarrhea-negative HUS (now more widely referred to as atypical HUS, aHUS). The therapeutic component of the guideline (comprising early, high-volume plasmapheresis) was derived from anecdotal evidence and expert consensus, and the authors committed to auditing outcome.

Journal ArticleDOI
TL;DR: This systematic review and proposed model represent a useful starting point in the critical appraisal of the conceptual underpinnings of PRO instruments used in pediatric oncology and contribute to the need to place such tools under a critical, yet reflective and analytical lens.
Abstract: Objectives An appraisal of pediatric cancer-specific quality-of-life (QOL) instruments revealed a lack of clarity about what constitutes QOL in this population. This study addresses this concern by identifying the concepts that underpin the construct of QOL as determined by a content analysis of all patient-reported outcome (PRO) instruments used in childhood cancer research. Methods A systematic review was performed of key databases (i.e., MEDLINE, CINAHL, PsychINFO) to identify studies of QOL in children with cancer. A content analysis process was used to code and categorize all items from generic and cancer-specified PRO instruments. Our objective was to provide clarification regarding the conceptual underpinnings of these instruments, as well as to help inform the development of theory and contribute to building a conceptual framework of QOL for children with cancer. Results A total of 6,013 English language articles were screened, identifying 148 studies. Ten generic and ten cancer-specific PRO instruments provided 957 items. Content analysis led to the identification of four major domains of QOL (physical, psychological, social, and general health), with 11 subdomains covering 98 different concepts. While all instruments reflected items relating to the broader domains of QOL, there was substantial heterogeneity in terms of the content and variability in the distribution of items. Conclusions This systematic review and the proposed model represent a useful starting point in the critical appraisal of the conceptual underpinnings of PRO instruments used in pediatric oncology and contribute to the need to place such tools under a critical, yet reflective and analytical lens.

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TL;DR: Only traffic calming and presence of playgrounds/recreation areas were consistently associated with more walking and less pedestrian injury, and the importance of incorporating safety into the conversation about creating more walkable cities is highlighted.
Abstract: Background The child active transportation literature has focused on walking, with little attention to risk associated with increased traffic exposure. This paper reviews the literature related to built environment correlates of walking and pedestrian injury in children together, to broaden the current conceptualization of walkability to include injury prevention. Methods Two independent searches were conducted focused on walking in children and child pedestrian injury within nine electronic databases until March, 2012. Studies were included which: 1) were quantitative 2) set in motorized countries 3) were either urban or suburban 4) investigated specific built environment risk factors 5) had outcomes of either walking in children and/or child pedestrian roadway collisions (ages 0-12). Built environment features were categorized according to those related to density, land use diversity or roadway design. Results were cross-tabulated to identify how built environment features associate with walking and injury. Results Fifty walking and 35 child pedestrian injury studies were identified. Only traffic calming and presence of playgrounds/recreation areas were consistently associated with more walking and less pedestrian injury. Several built environment features were associated with more walking, but with increased injury. Many features had inconsistent results or had not been investigated for either outcome. Conclusions The findings emphasise the importance of incorporating safety into the conversation about creating more walkable cities.

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TL;DR: Therapeutic neonatal caffeine administration has no long-term effects on sleep duration or sleep apnea during childhood, and ex-preterm infants, regardless of caffeine status, are at risk for obstructiveSleep apnea and periodic limb movements in later childhood.
Abstract: Rationale: Apnea of prematurity is a common condition that is usually treated with caffeine, an adenosine receptor blocker that has powerful influences on the central nervous system. However, little is known about the long-term effects of caffeine on sleep in the developing brain.Objectives: We hypothesized that neonatal caffeine use resulted in long-term abnormalities in sleep architecture and breathing during sleep.Methods: A total of 201 ex-preterm children aged 5–12 years who participated as neonates in a double-blind, randomized, controlled clinical trial of caffeine versus placebo underwent actigraphy, polysomnography, and parental sleep questionnaires. Coprimary outcomes were total sleep time on actigraphy and apnea–hypopnea index on polysomnography.Measurements and Main Results: There were no significant differences in primary outcomes between the caffeine group and the placebo (adjusted mean difference of −6.7 [95% confidence interval (CI) = −15.3 to 2.0 min]; P = 0.13 for actigraphic total sleep...

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TL;DR: To truly inform health and healthcare, toolkits should include comprehensive descriptions of their content, be explicit regarding content that is evidence-based, and include an evaluation of the their effectiveness as a KT strategy, addressing both clinical and implementation outcomes.
Abstract: Background: Significant resources are invested in the production of research knowledge with the ultimate objective of integrating research evidence into practice. Toolkits are becoming increasingly popular as a knowledge translation (KT) strategy for disseminating health information, to build awareness, inform, and change public and healthcare provider behavior. Toolkits communicate messages aimed at improving health and changing practice to diverse audiences, including healthcare practitioners, patients, community and health organizations, and policy makers. This scoping review explores the use of toolkits in health and healthcare. Methods: Using Arksey and O’Malley’s scoping review framework, health-based toolkits were identified through a search of electronic databases and grey literature for relevant articles and toolkits published between 2004 and 2011. Two reviewers independently extracted data on toolkit topic, format, target audience, content, evidence underlying toolkit content, and evaluation of the toolkit as a KT strategy. Results: Among the 253 sources identified, 139 met initial inclusion criteria and 83 toolkits were included in the final sample. Fewer than half of the sources fully described the toolkit content and about 70% made some mention of the evidence underlying the content. Of 83 toolkits, only 31 (37%) had been evaluated at any level (27 toolkits were evaluated overall relative to their purpose or KT goal, and 4 toolkits evaluated the effectiveness of certain elements contained within them). Conclusions: Toolkits used to disseminate health knowledge or support practice change often do not specify the evidence base from which they draw, and their effectiveness as a knowledge translation strategy is rarely assessed. To truly inform health and healthcare, toolkits should include comprehensive descriptions of their content, be explicit regarding content that is evidence-based, and include an evaluation of the their effectiveness as a KT strategy, addressing both clinical and implementation outcomes.

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TL;DR: How a cost-effectiveness analysis may be applied to simulation training is introduced; a method that medical educators may use to investment decisions (e.g., purchasing cost-effective and educationally sound simulators).
Abstract: While the ultimate goal of simulation training is to enhance learning, cost-effectiveness is a critical factor. Research that compares simulation training in terms of educational- and cost-effectiveness will lead to better-informed curricular decisions. Using previously published data we conducted a cost-effectiveness analysis of three simulation-based programs. Medical students (n = 15 per group) practiced in one of three 2-h intravenous catheterization skills training programs: low-fidelity (virtual reality), high-fidelity (mannequin), or progressive (consisting of virtual reality, task trainer, and mannequin simulator). One week later, all performed a transfer test on a hybrid simulation (standardized patient with a task trainer). We used a net benefit regression model to identify the most cost-effective training program via paired comparisons. We also created a cost-effectiveness acceptability curve to visually represent the probability that one program is more cost-effective when compared to its comparator at various ‘willingness-to-pay’ values. We conducted separate analyses for implementation and total costs. The results showed that the progressive program had the highest total cost (p < 0.001) whereas the high-fidelity program had the highest implementation cost (p < 0.001). While the most cost-effective program depended on the decision makers’ willingness-to-pay value, the progressive training program was generally most educationally- and cost-effective. Our analyses suggest that a progressive program that strategically combines simulation modalities provides a cost-effective solution. More generally, we have introduced how a cost-effectiveness analysis may be applied to simulation training; a method that medical educators may use to investment decisions (e.g., purchasing cost-effective and educationally sound simulators).

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TL;DR: Children born ≥ 37 weeks and exposed to multiple ACS therapy may have an increased risk of neurodevelopmental/neurosensory impairment by 5 years of age.
Abstract: The Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study (MACS) showed no benefit in the reduction of major neonatal mortality/morbidity or neurodevelopment at 2 and 5 years of age. Using the data from the randomized controlled trial and its follow-up, the aim of this study was to evaluate the association between gestational ages at birth in children exposed to single versus multiple courses of antenatal corticosteroid (ACS) therapy in utero and outcomes at 5 years of age. A total of 1719 children, with the breakdown into groupings of <30, 30–36, and ≥ 37 weeks gestation at birth, contributed to the primary outcome: death or survival with a disability in one of the following domains: neuromotor, neurosensory, and neurobehavioral/emotional disability and were included in this analysis. Gestational age at birth was strongly associated with the primary outcome, p < 0.001. Overall, the interaction between ACS groups and gestational age at birth was not significant, p = 0.064. Specifically, in the 2 preterm categories, there was no difference in the primary outcome between single vs. multiple ACS therapy. However, for infants born ≥37 weeks gestation, there was a statistically significant increase in the risk of the primary outcome in multiple ACS therapy, 48/213 (22.5%) compared to 38/249 (15.3%) in the single ACS therapy; OR = 1.69 [95% CI: 1.04, 2.77]; p = 0.037. Preterm birth (<37 weeks gestation) remained the primary factor contributing to an adverse outcome regardless of the number of courses of ACS therapy. Children born ≥ 37 weeks and exposed to multiple ACS therapy may have an increased risk of neurodevelopmental/neurosensory impairment by 5 years of age. To optimize outcomes for infants/children, efforts in reducing the incidence of preterm birth should remain the primary focus in perinatal research. This study has been registered at (identifier NCT00187382 )

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TL;DR: Examination of psychological and behavioral responses in children aged 3 to 12 years over a three year period following PICU hospitalization, and compare them to children who have undergone ear, nose and/or throat (ENT) day surgery is conducted.
Abstract: Pediatric intensive care unit (PICU) hospitalization places children at increased risk of persistent psychological and behavioral difficulties following discharge. Despite tremendous advances in medical technology and treatment regimes, approximately 25% of children demonstrate negative psychological and behavioral outcomes within the first year post-discharge. It is imperative that a broader array of risk factors and outcome indicators be explored in examining long-term psychological morbidity to identify areas for future health promotion and clinical intervention. This study aims to examine psychological and behavioral responses in children aged 3 to 12 years over a three year period following PICU hospitalization, and compare them to children who have undergone ear, nose and/or throat (ENT) day surgery. This mixed-methods prospective cohort study will enrol 220 children aged 3 to 12 years during PICU hospitalization (study group, n = 110) and ENT day surgery hospitalization (comparison group, n = 110). Participants will be recruited from 3 Canadian pediatric hospitals, and followed for 3 years with data collection points at 6 weeks, 6 months, 1 year, 2 years and 3 years post-discharge. Psychological and behavioral characteristics of the child, and parent anxiety and parenting stress, will be assessed prior to hospital discharge, and again at each of the 5 subsequent time points, using standardized measures. Psychological and behavioral response scores for both groups will be compared at each follow-up time point. Multivariate regression analysis will be used to adjust for demographic and clinical variables at baseline. To explore baseline factors predictive of poor psychological and behavioral scores at 3 years among PICU patients, correlation analysis and multivariate linear regression will be used. A subgroup of 40 parents of study group children will be interviewed at years 1 and 3 post-discharge to explore their perceptions of the impact of PICU hospitalization on their children and enhance our understanding of findings generated from standardized measures in the larger cohort study. An interpretive descriptive approach will guide qualitative data collection and analysis. This study aims to generate new information regarding the magnitude and duration of psychological and behavioral disturbances among children admitted to PICUs, potentially leading to remedial or preventive interventions.

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TL;DR: Changes of the coronary microcirculation in the first day after PPCI are associated with 6-month ejection fraction and myocardial salvage and CMR imaging indices of MVO and haemorrhage and elevated endothelin levels.
Abstract: Aims Predicting the likely success of primary PCI to salvage potential infarcted myocardium is desirable. We compared early invasive parameters of coronary microcirculation function with the levels of circulating endothelin (ET-1) and 6-month ejection fraction after STEMI. Methods and results Forty-four STEMI patients underwent assessment of coronary flow reserve (CFR) and index of myocardial resistance (IMR) on completion of PPCI and one day later. Cardiac magnetic resonance (CMR) at 24 h and 6 months assessed ejection fraction, oedema, late gadolinium enhancement, and salvage. In patients with depressed EF, there was no difference in IMR or CFR measured immediately after PPCI compared with those with preserved EF. However, by Day 1, CFR was significantly lower in those with depressed EF [2.0(1.5–2.3) vs. 2.6(2.1–3.3), P = 0.008]. In multivariable models, higher CFR post-PPCI [EST: +8.9 (SE 3.7) per 1 CFR unit, P = 0.03] and greater increase in CFR between post-PPCI and Day 1 [EST: +8.5 (SE 3.4) per 1 CFR unit, P = 0.01] were associated with higher salvage index. Circulating endothelin levels were significantly elevated in the low EF group at both 6 and 24 h, and 24 h levels correlated with CFR. Conclusion Changes of the coronary microcirculation in the first day after PPCI are associated with 6-month ejection fraction and myocardial salvage. Depressed CFR at 24 h is associated with CMR imaging indices of MVO and haemorrhage and elevated endothelin levels.

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TL;DR: Cellular mechanisms of hematopoietic cell feedback in HSC fate regulation are uncovers, insight is provided into the design principles of the human hematoietIC system, and intercellular regulation in multicellular systems is provided.
Abstract: The hematopoietic system is a distributed tissue that consists of functionally distinct cell types continuously produced through hematopoietic stem cell (HSC) differentiation. Combining genomic and phenotypic data with high-content experiments, we have built a directional cell–cell communication network between 12 cell types isolated from human umbilical cord blood. Network structure analysis revealed that ligand production is cell type dependent, whereas ligand binding is promiscuous. Consequently, additional control strategies such as cell frequency modulation and compartmentalization were needed to achieve specificity in HSC fate regulation. Incorporating the in vitro effects (quiescence, self-renewal, proliferation, or differentiation) of 27 HSC binding ligands into the topology of the cell–cell communication network allowed coding of cell type-dependent feedback regulation of HSC fate. Pathway enrichment analysis identified intracellular regulatory motifs enriched in these cell type- and ligand-coupled responses. This study uncovers cellular mechanisms of hematopoietic cell feedback in HSC fate regulation, provides insight into the design principles of the human hematopoietic system, and serves as a foundation for the analysis of intercellular regulation in multicellular systems.

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TL;DR: In this article, a real-time smartphone-based pain management app for adolescents with cancer was developed using a user-centered approach to develop the decision algorithm and system requirements that will inform the pain management advice provided by a realtime smartphone based pain management application.
Abstract: Background: Pain that occurs both within and outside of the hospital setting is a common and distressing problem for adolescents with cancer. The use of smartphone technology may facilitate rapid, in-the-moment pain support for this population. To ensure the best possible pain management advice is given, evidence-based and expert-vetted care algorithms and system design features, which are designed using user-centered methods, are required. Objective: To develop the decision algorithm and system requirements that will inform the pain management advice provided by a real-time smartphone-based pain management app for adolescents with cancer. Methods: A systematic approach to algorithm development and system design was utilized. Initially, a comprehensive literature review was undertaken to understand the current body of knowledge pertaining to pediatric cancer pain management. A user-centered approach to development was used as the results of the review were disseminated to 15 international experts (clinicians, scientists, and a consumer) in pediatric pain, pediatric oncology and mHealth design, who participated in a 2-day consensus conference. This conference used nominal group technique to develop consensus on important pain inputs, pain management advice, and system design requirements. Using data generated at the conference, a prototype algorithm was developed. Iterative qualitative testing was conducted with adolescents with cancer, as well as pediatric oncology and pain health care providers to vet and refine the developed algorithm and system requirements for the real-time smartphone app. Results: The systematic literature review established the current state of research related to nonpharmacological pediatric cancer pain management. The 2-day consensus conference established which clinically important pain inputs by adolescents would require action (pain management advice) from the app, the appropriate advice the app should provide to adolescents in pain, and the functional requirements of the app. These results were used to build a detailed prototype algorithm capable of providing adolescents with pain management support based on their individual pain. Analysis of qualitative interviews with 9 multidisciplinary health care professionals and 10 adolescents resulted in 4 themes that helped to adapt the algorithm and requirements to the needs of adolescents. Specifically, themes were overall endorsement of the system, the need for a clinical expert, the need to individualize the system, and changes to the algorithm to improve potential clinical effectiveness. Conclusions: This study used a phased and user-centered approach to develop a pain management algorithm for adolescents with cancer and the system requirements of an associated app. The smartphone software is currently being created and subsequent work will focus on the usability, feasibility, and effectiveness testing of the app for adolescents with cancer pain.

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TL;DR: This review highlights the current understanding of both primary and secondary triadopathies, and identifies important concepts yet to be fully addressed in the field.

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TL;DR: ABBREVIATIONS CIED = cardiovascular implantable electronic device; CT=computed tomography; EP=electrophysiology; FDA= U.S. Food and Drug Administration; ICD=implantable cardioverterdefibrillator; MRI = magnetic resonance imaging; QA = quality assurance; QI = quality improvement; RF = radiofrequency; VT = ventricular tachycardia.

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TL;DR: It is suggested that propranolol has activity against NB and thus should be considered in combination treatments for patients with relapsed and refractory NB.
Abstract: Neuroblastoma (NB) is a pediatric tumor of the sympathetic nervous system, which is often associated with elevated catecholamines. More than half of patients with metastatic NB relapse and survival is extremely poor with current therapies. In a high-throughput screen of FDA-approved drugs we identified anti-NB activity for the nonselective β-adrenergic receptor antagonist propranolol hydrochloride. Propranolol inhibited growth of a panel of fifteen NB cell lines irrespective of MYCN status, and treatment induced apoptosis and decreased proliferation. Activity was dependent on inhibition of the β2, and not β1, adrenergic receptor, and treatment resulted in activation of p53 and p73 signaling in vitro. The majority of NB cell lines and primary tumors express β2 adrenergic receptor and higher mRNA levels correlate with improved patient survival, but expression levels did not correlate with in vitro sensitivity to propranolol. Furthermore, propranolol is synergistic with the topoisomerase I inhibitor SN-38 and propranolol inhibits growth of NB xenografts in vivo at doses similar to those used to treat infants with hemangiomas and hypertension. Taken together, our results suggest that propranolol has activity against NB and thus should be considered in combination treatments for patients with relapsed and refractory NB.