Showing papers by "Hospital for Sick Children published in 2016"

A century of trends in adult human height

Abstract: Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3–19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8–144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.

High-throughput discovery of novel developmental phenotypes

Abstract: Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.

A contribution of novel CNVs to schizophrenia from a genome-wide study of 41,321 subjects

Abstract: Genomic copy number variants (CNVs) have been strongly implicated in the etiology of schizophrenia (SCZ). However, apart from a small number of risk variants, elucidation of the CNV contribution to risk has been difficult due to the rarity of risk alleles, all occurring in less than 1% of cases. We sought to address this obstacle through a collaborative effort in which we applied a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. We observed a global enrichment of CNV burden in cases (OR=1.11, P=5.7e-15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7e-6). CNV burden is also enriched for genes associated with synaptic function (OR = 1.68, P = 2.8e-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3e-5). We identified genome-wide significant support for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. We find support at a suggestive level for nine additional candidate susceptibility and protective loci, which consist predominantly of CNVs mediated by non-allelic homologous recombination (NAHR).

Sucrose for analgesia in newborn infants undergoing painful procedures

Abstract: Background Administration of oral sucrose with and without non-nutritive sucking is the most frequently studied non-pharmacological intervention for procedural pain relief in neonates. Objectives To determine the efficacy, effect of dose, method of administration and safety of sucrose for relieving procedural pain in neonates as assessed by validated composite pain scores, physiological pain indicators (heart rate, respiratory rate, saturation of peripheral oxygen in the blood, transcutaneous oxygen and carbon dioxide (gas exchange measured across the skin - TcpO2, TcpCO2), near infrared spectroscopy (NIRS), electroencephalogram (EEG), or behavioural pain indicators (cry duration, proportion of time crying, proportion of time facial actions (e.g. grimace) are present), or a combination of these and long-term neurodevelopmental outcomes. Search methods We used the standard methods of the Cochrane Neonatal. We performed electronic and manual literature searches in February 2016 for published randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library, Issue 1, 2016), MEDLINE (1950 to 2016), EMBASE (1980 to 2016), and CINAHL (1982 to 2016). We did not impose language restrictions. Selection criteria RCTs in which term or preterm neonates (postnatal age maximum of 28 days after reaching 40 weeks' postmenstrual age), or both, received sucrose for procedural pain. Control interventions included no treatment, water, glucose, breast milk, breastfeeding, local anaesthetic, pacifier, positioning/containing or acupuncture. Data collection and analysis Our main outcome measures were composite pain scores (including a combination of behavioural, physiological and contextual indicators). Secondary outcomes included separate physiological and behavioural pain indicators. We reported a mean difference (MD) or weighted MD (WMD) with 95% confidence intervals (CI) using the fixed-effect model for continuous outcome measures. For categorical data we used risk ratio (RR) and risk difference. We assessed heterogeneity by the I2 test. We assessed the risk of bias of included trials using the Cochrane 'Risk of bias' tool, and assessed the quality of the evidence using the GRADE system. Main results Seventy-four studies enrolling 7049 infants were included. Results from only a few studies could be combined in meta-analyses and for most analyses the GRADE assessments indicated low- or moderate-quality evidence. There was high-quality evidence for the beneficial effect of sucrose (24%) with non-nutritive sucking (pacifier dipped in sucrose) or 0.5 mL of sucrose orally in preterm and term infants: Premature Infant Pain Profile (PIPP) 30 s after heel lance WMD -1.70 (95% CI -2.13 to -1.26; I2 = 0% (no heterogeneity); 3 studies, n = 278); PIPP 60 s after heel lance WMD -2.14 (95% CI -3.34 to -0.94; I2 = 0% (no heterogeneity; 2 studies, n = 164). There was high-quality evidence for the use of 2 mL 24% sucrose prior to venipuncture: PIPP during venipuncture WMD -2.79 (95% CI -3.76 to -1.83; I2 = 0% (no heterogeneity; 2 groups in 1 study, n = 213); and intramuscular injections: PIPP during intramuscular injection WMD -1.05 (95% CI -1.98 to -0.12; I2 = 0% (2 groups in 1 study, n = 232). Evidence from studies that could not be included in RevMan-analyses supported these findings. Reported adverse effects were minor and similar in the sucrose and control groups. Sucrose is not effective in reducing pain from circumcision. The effectiveness of sucrose for reducing pain/stress from other interventions such as arterial puncture, subcutaneous injection, insertion of nasogastric or orogastric tubes, bladder catherization, eye examinations and echocardiography examinations are inconclusive. Most trials indicated some benefit of sucrose use but that the evidence for other painful procedures is of lower quality as it is based on few studies of small sample sizes. The effects of sucrose on long-term neurodevelopmental outcomes are unknown. Authors' conclusions Sucrose is effective for reducing procedural pain from single events such as heel lance, venipuncture and intramuscular injection in both preterm and term infants. No serious side effects or harms have been documented with this intervention. We could not identify an optimal dose due to inconsistency in effective sucrose dosage among studies. Further investigation of repeated administration of sucrose in neonates is needed. There is some moderate-quality evidence that sucrose in combination with other non-pharmacological interventions such as non-nutritive sucking is more effective than sucrose alone, but more research of this and sucrose in combination with pharmacological interventions is needed. Sucrose use in extremely preterm, unstable, ventilated (or a combination of these) neonates needs to be addressed. Additional research is needed to determine the minimally effective dose of sucrose during a single painful procedure and the effect of repeated sucrose administration on immediate (pain intensity) and long-term (neurodevelopmental) outcomes.

Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency

Abstract: PurposeRecurrent glioblastoma multiforme (GBM) is incurable with current therapies. Biallelic mismatch repair deficiency (bMMRD) is a highly penetrant childhood cancer syndrome often resulting in GBM characterized by a high mutational burden. Evidence suggests that high mutation and neoantigen loads are associated with response to immune checkpoint inhibition.Patients and MethodsWe performed exome sequencing and neoantigen prediction on 37 bMMRD cancers and compared them with childhood and adult brain neoplasms. Neoantigen prediction bMMRD GBM was compared with responsive adult cancers from multiple tissues. Two siblings with recurrent multifocal bMMRD GBM were treated with the immune checkpoint inhibitor nivolumab.ResultsAll malignant tumors (n = 32) were hypermutant. Although bMMRD brain tumors had the highest mutational load because of secondary polymerase mutations (mean, 17,740 ± standard deviation, 7,703), all other high-grade tumors were hypermutant (mean, 1,589 ± standard deviation, 1,043), simila...

An international consensus approach to the management of atypical hemolytic uremic syndrome in children.

Abstract: Atypical hemolytic uremic syndrome (aHUS) emerged during the last decade as a disease largely of complement dysregulation. This advance facilitated the development of novel, rational treatment options targeting terminal complement activation, e.g., using an anti-C5 antibody (eculizumab). We review treatment and patient management issues related to this therapeutic approach. We present consensus clinical practice recommendations generated by HUS International, an international expert group of clinicians and basic scientists with a focused interest in HUS. We aim to address the following questions of high relevance to daily clinical practice: Which complement investigations should be done and when? What is the importance of anti-factor H antibody detection? Who should be treated with eculizumab? Is plasma exchange therapy still needed? When should eculizumab therapy be initiated? How and when should complement blockade be monitored? Can the approved treatment schedule be modified? What approach should be taken to kidney and/or combined liver-kidney transplantation? How should we limit the risk of meningococcal infection under complement blockade therapy? A pressing question today regards the treatment duration. We discuss the need for prospective studies to establish evidence-based criteria for the continuation or cessation of anticomplement therapy in patients with and without identified complement mutations.

Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

Abstract: Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.

Spatial genomic heterogeneity in diffuse intrinsic pontine and midline high-grade glioma: implications for diagnostic biopsy and targeted therapeutics

Abstract: Diffuse intrinsic pontine glioma (DIPG) and midline high-grade glioma (mHGG) are lethal childhood brain tumors. Spatial genomic heterogeneity has been well-described in adult HGG but has not been comprehensively characterized in pediatric HGG. We performed whole exome sequencing on 38-matched primary, contiguous, and metastatic tumor sites from eight children with DIPG (n = 7) or mHGG (n = 1) collected using a unique MRI-guided autopsy protocol. Validation was performed using Sanger sequencing, Droplet Digital polymerase-chain reaction, immunohistochemistry, and fluorescent in-situ hybridization. Median age at diagnosis was 6.1 years (range: 2.9–23.3 years). Median overall survival was 13.2 months (range: 11.2–32.2 months). Contiguous tumor infiltration and distant metastases were observed in seven and six patients, respectively, including leptomeningeal dissemination in three DIPGs. Histopathological heterogeneity was evident in seven patients, including intra-pontine heterogeneity in two DIPGs, ranging from World Health Organization grade II to IV astrocytoma. We found conservation of heterozygous K27M mutations in H3F3A (n = 4) or HIST1H3B (n = 3) across all primary, contiguous, and metastatic tumor sites in all DIPGs. ACVR1 (n = 2), PIK3CA (n = 2), FGFR1 (n = 2), and MET (n = 1) were also intra-tumorally conserved. ACVR1 was co-mutated with HIST1H3B (n = 2). In contrast, PDGFRA amplification and mutation were spatially heterogeneous, as were mutations in BCOR (n = 1), ATRX (n = 2), and MYC (n = 1). TP53 aberrations (n = 3 patients) varied by type and location between primary and metastatic tumors sites but were intra-tumorally conserved. Spatial conservation of prognostically-relevant and therapeutically-targetable somatic mutations in DIPG and mHGG contrasts the significant heterogeneity of driver mutations seen in adult HGG and supports uniform implementation of diagnostic biopsy in DIPG and mHGG to classify molecular risk groups and guide therapeutic strategy.

Pediatric emergency medicine point-of-care ultrasound: summary of the evidence

Abstract: The utility of point-of-care ultrasound is well supported by the medical literature. Consequently, pediatric emergency medicine providers have embraced this technology in everyday practice. Recently, the American Academy of Pediatrics published a policy statement endorsing the use of point-of-care ultrasound by pediatric emergency medicine providers. To date, there is no standard guideline for the practice of point-of-care ultrasound for this specialty. This document serves as an initial step in the detailed “how to” and description of individual point-of-care ultrasound examinations. Pediatric emergency medicine providers should refer to this paper as reference for published research, objectives for learners, and standardized reporting guidelines.

Stomach development, stem cells and disease.

Abstract: The stomach, an organ derived from foregut endoderm, secretes acid and enzymes and plays a key role in digestion. During development, mesenchymal-epithelial interactions drive stomach specification, patterning, differentiation and growth through selected signaling pathways and transcription factors. After birth, the gastric epithelium is maintained by the activity of stem cells. Developmental signals are aberrantly activated and stem cell functions are disrupted in gastric cancer and other disorders. Therefore, a better understanding of stomach development and stem cells can inform approaches to treating these conditions. This Review highlights the molecular mechanisms of stomach development and discusses recent findings regarding stomach stem cells and organoid cultures, and their roles in investigating disease mechanisms.

Oral non-steroidal anti-inflammatory drug therapy for lung disease in cystic fibrosis

Abstract: Background Progressive lung damage causes most deaths in cystic fibrosis. Non-steroidal anti-inflammatory drugs (such as ibuprofen) may prevent progressive pulmonary deterioration and morbidity in cystic fibrosis. Objectives To assess the effectiveness of treatment with non-steroidal anti-inflammatory drugs in cystic fibrosis. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, hand searches of relevant journals and abstract books of conference proceedings. We contacted manufacturers of non-steroidal anti-inflammatory drugs. Latest search of the Group's Trials Register: 04 February 2016. Selection criteria Randomized controlled trials comparing oral non-steroidal anti-inflammatory drugs, at any dose for at least two months, to placebo in people with cystic fibrosis. Data collection and analysis Two authors independently assessed trials for inclusion the review and their potential risk of bias. Main results The searches identified 10 trials; four are included (287 participants aged five to 39 years; maximum follow up of four years) and one is currently awaiting classification pending publication of the full trial report. Three trials compared ibuprofen to placebo (two from the same centre with some of the same participants); one trial assessed piroxicam versus placebo. The three ibuprofen trials were deemed to have good or adequate methodological quality, but used various outcomes and summary measures. Reviewers considered measures of lung function, nutritional status, radiological assessment of pulmonary involvement, intravenous antibiotic usage, hospital admissions, survival and adverse effects. Combined data from the two largest ibuprofen trials showed a significantly lower annual rate of decline for lung function, percent predicted forced expiratory volume in one second mean difference 1.32 (95% confidence interval 0.21 to 2.42); forced vital capacity mean difference 1.27 (95% confidence interval 0.26 to 2.28); forced expiratory flow (25-75%) mean difference 1.80 (95% confidence interval 0.15 to 3.45). The post-hoc analysis of data from two trials split by age showed a statistically significant slower rate of annual decline of percent predicted forced expiratory volume in one second and forced vital capacity in the ibuprofen group in younger children, mean difference 1.41% (95% confidence interval 0.03 to 2.80) and mean difference 1.32% (95% confidence interval 0.04 to 2.60) respectively. In one trial, long-term use of high-dose ibuprofen was associated with reduced intravenous antibiotic usage, improved nutritional and radiological pulmonary status. No major adverse effects were reported, but the power of the trials to identify clinically important differences in the incidence of adverse effects was low. We did not have any concerns with regards to risk of bias for the trial comparing piroxicam to placebo. However, the trial did not report many data in a form that we could analyse in this review. No data were available for the review's primary outcome of lung function; available data for hospital admissions showed no difference between the groups. No analysable data were available for any other review outcome. Authors' conclusions High-dose ibuprofen can slow the progression of lung disease in people with cystic fibrosis, especially in children, which suggests that strategies to modulate lung inflammation can be beneficial for people with cystic fibrosis.

Ketamine added to morphine or hydromorphone patient-controlled analgesia for acute postoperative pain in adults: a systematic review and meta-analysis of randomized trials.

Abstract: To determine whether ketamine added to morphine or hydromorphone patient-controlled analgesia (PCA) provides clinically relevant reductions in postoperative pain, opioid requirements, and adverse events when compared with morphine or hydromorphone PCA in adults undergoing surgery. We systematically searched six databases up to June 2, 2015 for randomized controlled trials (RCTs) comparing ketamine plus morphine/hydromorphone PCA vs morphine/hydromorphone PCA for postoperative pain in adults. Thirty-six RCTs including 2,502 patients proved eligible, and 22 of these were at low risk of bias. The addition of ketamine to morphine/hydromorphone PCA decreased postoperative pain intensity at six to 72 hr when measured at rest (weighted mean difference [WMD] on a 10-cm visual analogue scale ranged from −0.4 to −1.3 cm) and during mobilization (WMD ranged from −0.4 to −0.5 cm). Adjunctive ketamine also significantly reduced cumulative morphine consumption at 24-72 hr by approximately 5-20 mg. Predefined subgroup analyses and meta-regression did not detect significant differences across subgroups, including a dose-response relationship. There was no significant difference in patient satisfaction scores at 24 and 48 hr. Nevertheless, the addition of ketamine to morphine/hydromorphone PCA significantly reduced postoperative nausea and vomiting (relative risk, 0.71; 95% confidence interval [CI], 0.60 to 0.85; absolute risk reduction, 8.9%; 95% CI, 4.6 to 12.2). Significant effects on other adverse events (e.g., hallucinations, vivid dreams) were not detected, though only a few studies reported on them. Adding ketamine to morphine/hydromorphone PCA provides a small improvement in postoperative analgesia while reducing opioid requirements. Adjunctive ketamine also reduces postoperative nausea and vomiting without a detected increase in other adverse effects; however, adverse events were probably underreported.

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.

Behavioral and Electrophysiological Differences in Executive Control Between Monolingual and Bilingual Children.

Abstract: This study examined executive control in sixty-two 5-year-old children who were monolingual or bilingual using behavioral and event-related potentials (ERPs) measures. All children performed equivalently on simple response inhibition (gift delay), but bilingual children outperformed monolinguals on interference suppression and complex response inhibition (go/no-go task). On the go/no-go task, ERPs showed larger P3 amplitudes and shorter N2 and P3 latencies for bilingual children than for monolinguals. These latency and amplitude data were associated with better behavioral performance and better discrimination between stimuli for bilingual children but not for monolingual children. These results clarify the conditions that lead to advantages for bilingual children in executive control and provide the first evidence linking those performance differences to electrophysiological brain differences in children.

Herpesvirus Infections and Childhood Arterial Ischemic Stroke: Results of the VIPS Study.

Abstract: Background— Epidemiological studies demonstrate that childhood infections, including varicella zoster virus, are associated with an increased risk of arterial ischemic stroke (AIS). Other herpesviruses have been linked to childhood AIS in case reports. We sought to determine whether herpesvirus infections, which are potentially treatable, increase the risk of childhood AIS. Methods and Results— We enrolled 326 centrally confirmed cases of AIS and 115 stroke-free controls with trauma (29 days to 18 years of age) with acute blood samples (≤3 weeks after stroke/trauma); cases had convalescent samples (7–28 days later) when feasible. Samples were tested by commercial enzyme-linked immunosorbent assay kits for immunoglobulin M/immunoglobulin G antibodies to herpes simplex virus 1 and 2, cytomegalovirus, Epstein-Barr virus, and varicella zoster virus. An algorithm developed a priori classified serological evidence of past and acute herpesvirus infection as dichotomous variables. The median (quartiles) age was 7.7 (3.1–14.3) years for cases and 10.7 (6.9–13.2) years for controls ( P =0.03). Serological evidence of past infection did not differ between cases and controls. However, serological evidence of acute herpesvirus infection doubled the odds of childhood AIS, even after adjusting for age, race, and socioeconomic status (odds ratio, 2.2; 95% confidence interval, 1.2–4.0; P =0.007). Among 187 cases with acute and convalescent blood samples, 85 (45%) showed evidence of acute herpesvirus infection; herpes simplex virus 1 was found most often. Most infections were asymptomatic. Conclusions— Herpesviruses may act as a trigger for childhood AIS, even if the infection is subclinical. Antivirals like acyclovir might have a role in the prevention of recurrent stroke if further studies confirm a causal relationship. # CLINICAL PERSPECTIVE {#article-title-48}

Shifts in Lachnospira and Clostridium sp. in the 3-month stool microbiome are associated with preschool age asthma

Abstract: Asthma is a chronic disease of the airways affecting one in ten children in Westernized countries. Recently, our group showed that specific bacterial genera in early life are associated with atopy and wheezing in 1-year-old children. However, little is known about the link between the early life gut microbiome and the diagnosis of asthma in preschool age children. To determine the role of the gut microbiota in preschool age asthma, children up to 4 years of age enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) study were classified as asthmatic (n=39) or matched healthy controls (n=37). 16S rRNA sequencing and quantitative PCR (qPCR) were used to analyse the composition of the 3-month and 1-year gut microbiome of these children. At 3 months the abundance of the genus, Lachnospira (L), was decreased (P=0.008), whereas the abundance of the species, Clostridium neonatale (C), was increased (P=0.07) in asthmatics. Quartile analysis of stool composition at 3-months revealed a negative association between the ratio of these two bacteria (L/C) and asthma risk by 4 years of age [quartile 1: odds ratio (OR)=15, P=0.02, CI (confidence interval)= 1.8-124.7; quartile 2: OR=1.0, ns; quartile 3: OR=0.37, ns]. We conclude that opposing shifts in the relative abundances of Lachnospira and C. neonatale in the first 3 months of life are associated with preschool age asthma, and that the L/C ratio may serve as a potential early life biomarker to predict asthma development.

Closed Reduction for Developmental Dysplasia of the Hip: Early-term Results From a Prospective, Multicenter Cohort.

Abstract: Closed reduction (CR) is a common treatment for infantile developmental dysplasia of the hip. The purpose of this observational, prospective, multicenter study was to determine the early outcomes following CR. Prospectively collected data from an international multicenter study group was analyzed for patients treated from 2010 to 2014. Baseline demographics, clinical exam, radiographic/ultrasonographic data, and history of previous orthotic treatment were assessed. At minimum 1-year follow-up, failure was defined as an IHDI grade 3 or 4 hip and/or need for open reduction. The incidence of avascular necrosis (AVN), residual dysplasia, and need for further surgery was assessed. A total of 78 patients undergoing CR for 87 hips were evaluated with a median age at initial reduction of 8 months (range, 1 to 20 mo). Of these, 8 hips (9%) were unable to be closed reduced initially. At most recent follow-up (median 22 mo; range, 12 to 36 mo), 72/79 initially successful CRs (91%) remained stable. The likelihood of failure was unaffected by initial clinical reducibility of the hip (P=0.434), age at initial CR (P=0.897), or previous treatment in brace (P=0.222). Excluding those hips that failed initial CR, 18/72 hips (25%) developed AVN, and the risk of osteonecrosis was unaffected by prereduction reducibility of the hip (P=0.586), age at CR (P=0.745), presence of an ossific nucleus (P=0.496), or previous treatment in brace (P=0.662). Mean acetabular index on most recent radiographs was 25 degrees (±6 degrees), and was also unaffected by any of the above variables. During the follow-up period, 8/72 successfully closed reduced hips (11%) underwent acetabular and/or femoral osteotomy for residual dysplasia. Following an initially successful CR, 9% of hips failed reduction and 25% developed radiographic AVN at early-term follow-up. History of femoral head reducibility, previous orthotic bracing, and age at CR did not correlate with success or chances of developing AVN. Further follow-up of this prospective, multicenter cohort will be necessary to establish definitive success and complication rates following CR for infantile developmental dysplasia of the hip. Level II—prospective observational cohort. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/

Results of the randomized Intergroup trial Inter-B-NHL Ritux 2010 for children and adolescents with high-risk B-cell non-Hodgkin lymphoma (B-NHL) and mature acute leukemia (B-AL): Evaluation of rituximab (R) efficacy in addition to standard LMB chemotherapy (CT) regimen.

Abstract: 10507Background: R with CT improves survival of adult B-cell malignancies. Beyond pilot studies, no randomized trial evaluated efficacy and safety of R added to CT in childhood B-NHL/AL. Methods: T...

Neonatal deaths: prospective exploration of the causes and process of end-of-life decisions.

Abstract: Objective To determine the causes and process of death in neonates in Canada. Design Prospective observational study. Setting Nineteen tertiary level neonatal units in Canada. Participants 942 neonatal deaths (215 full-term and 727 preterm). Exposure and outcome Explored the causes and process of death using data on: (1) the rates of withdrawal of life-sustaining treatment (WLST); (2) the reasons for raising the issue of WLST; (3) the extent of consensus with parents; (4) the consensual decision-making process both with parents and the multidisciplinary team; (5) the elements of WLST; and (6) the age at death and time between WLST and actual death. Results The main reasons for deaths in preterm infants were extreme immaturity, intraventricular haemorrhage and pulmonary causes; in full-term infants asphyxia, chromosomal anomalies and syndromic malformations. In 84% of deaths there was discussion regarding WLST. WLST was agreed to by parents with relative ease in the majority of cases. Physicians mainly offered WLST for the purpose of avoiding pain and suffering in imminent death or survival with a predicted poor quality of life. Consensus with multidisciplinary team members was relatively easily obtained. There was marked variation between centres in offering WLST for severe neurological injury in preterm (10%–86%) and severe hypoxic-ischaemic encephalopathy in full-term infants (5%–100%). Conclusions and relevance In Canada, the majority of physicians offered WLST to avoid pain and suffering or survival with a poor quality of life. Variation between units in offering WLST for similar diagnoses requires further exploration.

Do clinicians understand the size of treatment effects? A randomized survey across 8 countries

Abstract: Background: Meta-analyses of continuous outcomes typically provide enough information for decision-makers to evaluate the extent to which chance can explain apparent differences between interventions. The interpretation of the magnitude of these differences — from trivial to large — can, however, be challenging. We investigated clinicians’ understanding and perceptions of usefulness of 6 statistical formats for presenting continuous outcomes from meta-analyses (standardized mean difference, minimal important difference units, mean difference in natural units, ratio of means, relative risk and risk difference). Methods: We invited 610 staff and trainees in internal medicine and family medicine programs in 8 countries to participate. Paper-based, self-administered questionnaires presented summary estimates of hypothetical interventions versus placebo for chronic pain. The estimates showed either a small or a large effect for each of the 6 statistical formats for presenting continuous outcomes. Questions addressed participants’ understanding of the magnitude of treatment effects and their perception of the usefulness of the presentation format. We randomly assigned participants 1 of 4 versions of the questionnaire, each with a different effect size (large or small) and presentation order for the 6 formats (1 to 6, or 6 to 1). Results: Overall, 531 (87.0%) of the clinicians responded. Respondents best understood risk difference, followed by relative risk and ratio of means. Similarly, they perceived the dichotomous presentation of continuous outcomes (relative risk and risk difference) to be most useful. Presenting results as a standardized mean difference, the longest standing and most widely used approach, was poorly understood and perceived as least useful. Interpretation: None of the presentation formats were well understood or perceived as extremely useful. Clinicians best understood the dichotomous presentations of continuous outcomes and perceived them to be the most useful. Further initiatives to help clinicians better grasp the magnitude of the treatment effect are needed.

Separate effects of sex hormones and sex chromosomes on brain structure and function revealed by high-resolution magnetic resonance imaging and spatial navigation assessment of the Four Core Genotype mouse model.

Abstract: Males and females exhibit several differences in brain structure and function. To examine the basis for these sex differences, we investigated the influences of sex hormones and sex chromosomes on brain structure and function in mice. We used the Four Core Genotype (4CG) mice, which can generate both male and female mice with XX or XY sex chromosome complement, allowing the decoupling of sex chromosomes from hormonal milieu. To examine whole brain structure, high-resolution ex vivo MRI was performed, and to assess differences in cognitive function, mice were trained on a radial arm maze. Voxel-wise and volumetric analyses of MRI data uncovered a striking independence of hormonal versus chromosomal influences in 30 sexually dimorphic brain regions. For example, the bed nucleus of the stria terminalis and the parieto-temporal lobe of the cerebral cortex displayed steroid-dependence while the cerebellar cortex, corpus callosum, and olfactory bulbs were influenced by sex chromosomes. Spatial learning and memory demonstrated strict hormone-dependency with no apparent influence of sex chromosomes. Understanding the influences of chromosomes and hormones on brain structure and function is important for understanding sex differences in brain structure and function, an endeavor that has eventual implications for understanding sex biases observed in the prevalence of psychiatric disorders.

Primary care interventions to improve transition of youth with chronic health conditions from paediatric to adult healthcare: a systematic review

Abstract: Objective To determine effective interventions to improve primary care provider involvement in transitioning youth with chronic conditions from paediatric to adult care. Design Systematic review. Multiple electronic databases were searched including Ovid MEDLINE, EMBASE and Web of Science (from 1 January 1947 to 5 August 2015). Evidence quality was assessed using a 36-point scoring system for disparate study designs. Setting Studies with paediatric-to-adult transition programmes and interventions involving primary care providers or in primary care settings. Participants Youth aged 16 years and over. Outcomes Relevant outcomes were grouped into 3 main domains based on the Triple Aim Framework: experience of care, population health, cost. Results A total of 1888 unique citations were identified, yielding 3 studies for inclusion. Overall, primary care provider roles were not well defined. 2 studies used case managers to facilitate referrals to primary care, and the remaining study was the only 1 situated in a primary care setting. None of the studies examined transition in all 3 Triple Aim Framework domains. The most commonly reported outcomes were in the cost domain. Conclusions There is limited empiric evidence to guide primary care interventions to improve transition outcomes for youth with chronic conditions. Future research and policy should focus on developing and evaluating coordinated transition interventions to better integrate primary care for high need populations.