Hospital for Sick Children

About: Hospital for Sick Children is a healthcare organization based out in Toronto, Ontario, Canada. It is known for research contribution in the topics: Population & Medicine. The organization has 4097 authors who have published 3746 publications receiving 129066 citations. The organization is also known as: Sick Kids Hospital & SickKids.

Orkambi® and amplifier co‐therapy improves function from a rare CFTR mutation in gene‐edited cells and patient tissue

Abstract: The combination therapy of lumacaftor and ivacaftor (Orkambi ® ) is approved for patients bearing the major cystic fibrosis (CF) mutation: ΔF508 . It has been predicted that Orkambi ® could treat patients with rarer mutations of similar “theratype”; however, a standardized approach confirming efficacy in these cohorts has not been reported. Here, we demonstrate that patients bearing the rare mutation: c.3700 A>G, causing protein misprocessing and altered channel function—similar to ΔF508‐CFTR, are unlikely to yield a robust Orkambi ® response. While in silico and biochemical studies confirmed that this mutation could be corrected and potentiated by lumacaftor and ivacaftor, respectively, this combination led to a minor in vitro response in patient‐derived tissue. A CRISPR/Cas9‐edited bronchial epithelial cell line bearing this mutation enabled studies showing that an “amplifier” compound, effective in increasing the levels of immature CFTR protein, augmented the Orkambi ® response. Importantly, this “amplifier” effect was recapitulated in patient‐derived nasal cultures—providing the first evidence for its efficacy in augmenting Orkambi ® in tissues harboring a rare CF‐causing mutation. We propose that this multi‐disciplinary approach, including creation of CRISPR/Cas9‐edited cells to profile modulators together with validation using primary tissue, will facilitate therapy development for patients with rare CF mutations.

Genome-wide association study identifies loci on 12q24 and 13q32 associated with Tetralogy of Fallot

Abstract: We conducted a genome-wide association study to search for risk alleles associated with Tetralogy of Fallot (TOF), using a northern European discovery set of 835 cases and 5159 controls. A region on chromosome 12q24 was associated (P = 1.4 × 10(-7)) and replicated convincingly (P = 3.9 × 10(-5)) in 798 cases and 2931 controls [per allele odds ratio (OR) = 1.27 in replication cohort, P = 7.7 × 10(-11) in combined populations]. Single nucleotide polymorphisms in the glypican 5 gene on chromosome 13q32 were also associated (P = 1.7 × 10(-7)) and replicated convincingly (P = 1.2 × 10(-5)) in 789 cases and 2927 controls (per allele OR = 1.31 in replication cohort, P = 3.03 × 10(-11) in combined populations). Four additional regions on chromosomes 10, 15 and 16 showed suggestive association accompanied by nominal replication. This study, the first genome-wide association study of a congenital heart malformation phenotype, provides evidence that common genetic variation influences the risk of TOF.

Cardiovascular magnetic resonance demonstration of the spectrum of morphological phenotypes and patterns of myocardial scarring in Anderson-Fabry disease

Abstract: Although it is known that Anderson-Fabry Disease (AFD) can mimic the morphologic manifestations of hypertrophic cardiomyopathy (HCM) on echocardiography, there is a lack of cardiovascular magnetic resonance (CMR) literature on this. There is limited information in the published literature on the distribution of myocardial fibrosis in patients with AFD, with scar reported principally in the basal inferolateral midwall. All patients with confirmed AFD undergoing CMR at our center were included. Left ventricular (LV) volumes, wall thicknesses and scar were analyzed offline. Patients were categorized into 4 groups: 1) no wall thickening; 2) concentric hypertrophy; 3) asymmetric septal hypertrophy (ASH); and 4) apical hypertrophy. Charts were reviewed for clinical information. Thirty-nine patients were included (20 males [51 %], median age 45.2 years [range 22.3–64.4]). Almost half (17/39) had concentric wall thickening. Almost half (17/39) had pathologic LV scar; three quarters of these (13/17) had typical inferolateral midwall scar. A quarter (9/39) had both concentric wall thickening and typical inferolateral scar. A subgroup with ASH and apical hypertrophy (n = 5) had greater maximum wall thickness, total LV scar, apical scar and mid-ventricular scar than those with concentric hypertrophy (n = 17, p < 0.05). Patients with elevated LVMI had more overall arrhythmia (p = 0.007) more ventricular arrhythmia (p = 0.007) and sustained ventricular tachycardia (p = 0.008). Concentric thickening and inferolateral mid-myocardial scar are the most common manifestations of AFD, but the spectrum includes cases morphologically identical to apical and ASH subtypes of HCM and these have more apical and mid-ventricular LV scar. Significant LVH is associated with ventricular arrhythmia.

Vitamin D supplementation for preventing infections in children under five years of age.

Abstract: Background Vitamin D is a micronutrient important for bone growth and immune function. Deficiency can lead to rickets and has been linked to various infections, including respiratory infections. The evidence on the effects of supplementation on infections in children has not been assessed systematically. Objectives To evaluate the role of vitamin D supplementation in preventing pneumonia, tuberculosis (TB), diarrhoea, and malaria in children under five years of age. This includes high-, middle-, and low-income countries. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Library, MEDLINE, EMBASE, LILACS, the WHO International Clinical Trials Registry Platform (ICTRP; http://www.who.int/ictrp/en/) , ClinicalTrials.gov and the ISRCTN registry (http://www.isrctn.com/) up to 16 June 2016. Selection criteria We included randomized controlled trials (RCTs) that evaluated preventive supplementation of vitamin D (versus placebo or no intervention) in children under five years of age. Data collection and analysis Two review authors independently screened the titles and abstracts, extracted the data, and assessed the risk of bias of included trials. Main results Four trials met the inclusion criteria, with a total of 3198 children under five years of age, and were conducted in Afghanistan, Spain, and the USA. Prevalence of vitamin D deficiency varied widely in these populations (range: 73.1% in Afghanistan, 10 to 12% in USA, and 6.2% in Spain). The included trials evaluated mortality (two trials), pneumonia incidence (two trials), diarrhoea incidence (two trials), hospitalization (two trials), and mean serum vitamin D concentrations (four trials). We do not know whether vitamin D supplementation impacts on all-cause mortality because this outcome was underpowered due to few events (risk ratio (RR) 1.43, 95% confidence interval (CI) 0.54 to 3.74; one trial, 3046 participants, low quality evidence). For pneumonia, episodes of 'radiologically confirmed' first or only episode of pneumonia were little different in the supplemented and unsupplemented group (Rate Ratio: 1.06, 95% confidence interval (CI) 0.89 to 1.26; two trials, 3134 participants, moderate quality evidence), and similarly for children with confirmed or unconfirmed pneumonia (RR 0.95, 95% CI 0.87 to 1.04; one trial, 3046 participants). In these two trials there were no obvious differences between supplemented and unsupplemented children regarding episodes of diarrhoea. In the single large trial from Afghanistan, the trial authors reported that vitamin D supplementation was associated with an increase in repeat episodes of pneumonia confirmed by chest radiograph (RR 1.69, 95% CI 1.28 to 2.21; one trial, 3046 participants), but not reflected in the outcome of confirmed or unconfirmed pneumonia (RR 1.06, 95% CI 1.00 to 1.13; one trial, 3046 participants). For hospital admission measured in one small trial, there was no difference detected (RR 0.86, 95% CI 0.20 to 3.62; one trial, 88 participants; very low quality evidence). The mean serum vitamin D concentrations were higher in supplemented compared to unsupplemented children at the end of supplementation (MD 7.72 ng/mL, 95% CI 0.50 to 14.93; four trials, 266 participants, low quality evidence). These results were driven primarily by two smaller trials with large magnitudes of effect. In the other two bigger trials, serum vitamin D concentrations were elevated in the intervention group for most of the trial duration but not at the end of supplementation. This may be due to time elapsed at measurement from the last dose, incomplete compliance, or increased need of vitamin D with infant age. We did not find any trial that reported on the incidence of TB, malaria or febrile illness, duration of pneumonia, duration of diarrhoea, severity of infection, and cause-specific mortality (due to TB, diarrhoea, or malaria). Authors' conclusions Evidence from one large trial did not demonstrate benefit of vitamin D supplementation on the incidence of pneumonia or diarrhoea in children under five years. To our knowledge, trials that evaluated supplementation for preventing other infections, including TB and malaria, have not been performed.