Showing papers by "Montreal Children's Hospital published in 2015"
Alberta Children's Hospital1, Brown University2, University of Alberta3, University of Alabama at Birmingham4, Montreal Children's Hospital5, Northwestern University6, Children's Medical Center of Dallas7, Bristol Royal Hospital for Children8, Yale University9, Tufts University10, Johns Hopkins University School of Medicine11, Columbia University12, University of British Columbia13, Children's Hospital of Philadelphia14
TL;DR: Using novel and practical technology, JIT training before CPA or real-time VisF during CPA, alone or in combination, improves compliance with American Heart Association guidelines for CPR that are associated with better outcomes.
Abstract: Importance The quality of cardiopulmonary resuscitation (CPR) affects hemodynamics, survival, and neurological outcomes following pediatric cardiopulmonary arrest (CPA). Most health care professionals fail to perform CPR within established American Heart Association guidelines. Objective To determine whether “just-in-time” (JIT) CPR training with visual feedback (VisF) before CPA or real-time VisF during CPA improves the quality of chest compressions (CCs) during simulated CPA. Design, Setting, and Participants Prospective, randomized, 2 × 2 factorial-design trial with explicit methods (July 1, 2012, to April 15, 2014) at 10 International Network for Simulation-Based Pediatric Innovation, Research, & Education (INSPIRE) institutions running a standardized simulated CPA scenario, including 324 CPR-certified health care professionals assigned to 3-person resuscitation teams (108 teams). Interventions Each team was randomized to 1 of 4 permutations, including JIT training vs no JIT training before CPA and real-time VisF vs no real-time VisF during simulated CPA. Main Outcomes and Measures The proportion of CCs with depth exceeding 50 mm, the proportion of CPR time with a CC rate of 100 to 120 per minute, and CC fraction (percentage CPR time) during simulated CPA. Results The quality of CPR was poor in the control group, with 12.7% (95% CI, 5.2%-20.1%) mean depth compliance and 27.1% (95% CI, 14.2%-40.1%) mean rate compliance. JIT training compared with no JIT training improved depth compliance by 19.9% (95% CI, 11.1%-28.7%; P P = .037). Visual feedback compared with no VisF improved depth compliance by 15.4% (95% CI, 6.6%-24.2%; P = .001) and rate compliance by 40.1% (95% CI, 28.8%-51.3%; P 89.0%) in all groups. Combining both interventions showed the highest compliance with American Heart Association guidelines but was not significantly better than either intervention in isolation. Conclusions and Relevance The quality of CPR provided by health care professionals is poor. Using novel and practical technology, JIT training before CPA or real-time VisF during CPA, alone or in combination, improves compliance with American Heart Association guidelines for CPR that are associated with better outcomes. Trial Registration clinicaltrials.gov Identifier:NCT02075450
174 citations
TL;DR: The results suggest that the poor sensitivity of RSV RADTs in adults may preclude their use in this population, and industry-sponsored studies and those that did not use RT-PCR as a reference standard likely overestimated test sensitivity.
Abstract: Respiratory syncytial virus (RSV) rapid antigen detection tests (RADT) are extensively used in clinical laboratories. We performed a systematic review and meta-analysis to evaluate the accuracy of RADTs for diagnosis of RSV infection and to determine factors associated with accuracy estimates. We searched EMBASE and PubMed for diagnostic-accuracy studies of commercialized RSV RADTs. Studies reporting sensitivity and specificity data compared to a reference standard (reverse transcriptase PCR [RT-PCR], immunofluorescence, or viral culture) were considered. Two reviewers independently extracted data on study characteristics, diagnostic-accuracy estimates, and study quality. Accuracy estimates were pooled using bivariate random-effects regression models. Heterogeneity was investigated with prespecified subgroup analyses. Seventy-one articles met inclusion criteria. Overall, RSV RADT pooled sensitivity and specificity were 80% (95% confidence interval [CI], 76% to 83%) and 97% (95% CI, 96% to 98%), respectively. Positive- and negative-likelihood ratios were 25.5 (95% CI, 18.3 to 35.5) and 0.21 (95% CI, 0.18 to 0.24), respectively. Sensitivity was higher in children (81% [95% CI, 78%, 84%]) than in adults (29% [95% CI, 11% to 48%]). Because of this disparity, further subgroup analyses were restricted to pediatric data (63 studies). Test sensitivity was poorest using RT-PCR as a reference standard and highest using immunofluorescence (74% versus 88%; P < 0.001). Industry-sponsored studies reported significantly higher sensitivity (87% versus 78%; P = 0.01). Our results suggest that the poor sensitivity of RSV RADTs in adults may preclude their use in this population. Furthermore, industry-sponsored studies and those that did not use RT-PCR as a reference standard likely overestimated test sensitivity.
149 citations
Boston Children's Hospital1, Montreal Children's Hospital2, Royal Children's Hospital3, VU University Medical Center4, University of Colorado Boulder5, Baylor University Medical Center6, University of Queensland7, University of Nebraska Medical Center8, George Washington University9, Illumina10, Mayo Clinic11
TL;DR: A workflow detailing the Global Leukodystrophy Initiative (GLIA) consensus recommendations for an approach to clinical diagnosis is presented, including salient clinical features suggesting a specific diagnosis, neuroimaging features and molecular genetic testing.
141 citations
University of Minnesota1, University of Pittsburgh2, University of Iowa3, University of Texas Southwestern Medical Center4, University of Toronto5, Baylor College of Medicine6, Harvard University7, Nationwide Children's Hospital8, Boston Children's Hospital9, University of California, San Francisco10, Montreal Children's Hospital11, University of New South Wales12, University of Utah13, Medical College of Wisconsin14, Hebrew University of Jerusalem15
TL;DR: The authors performed a cross-sectional study of data from the International Study Group of Pediatric Pancreatitis: In Search for a Cure, a registry of children with acute recurrent pancreatitis and chronic pancreatitis.
137 citations
Johns Hopkins University1, Duke University2, University of Michigan3, University of Pennsylvania4, Harvard University5, University of California, San Francisco6, University of Illinois at Chicago7, Baylor University Medical Center8, Society of Thoracic Surgeons9, Dupont Hospital10, Montreal Children's Hospital11, Johns Hopkins University School of Medicine12, Northwestern University13, University of Louisville14, Baylor College of Medicine15, Children's Hospital of Wisconsin16, Children's National Medical Center17, University of Florida18, University of Colorado Denver19
TL;DR: The empirically derived 2014 Society of Thoracic Surgeons Congenital Heart Surgery Database Mortality Risk Model facilitates description of outcomes (mortality) adjusted for procedural and for patient-level factors.
123 citations
Children's Mercy Hospital1, Montreal Children's Hospital2, Centre Hospitalier Universitaire Sainte-Justine3, VU University Medical Center4, Montreal Neurological Institute and Hospital5, Scripps Research Institute6, University of Toronto7, University of Szeged8, Children's Hospital at Westmead9, University of Duisburg-Essen10, Radboud University Nijmegen11, The Chinese University of Hong Kong12, French Institute of Health and Medical Research13, University of Bordeaux14, George Washington University15, University of Queensland16, Université de Montréal17
TL;DR: This study is the first to show that distinct mutations in a gene coding for a shared subunit of two RNA polymerases lead to selective modification of the enzymes' availability leading to two different clinical conditions and to shed some light on the pathophysiological mechanism of one of the most common hypomyelinating leukodystrophies, POLR3-related leukODYstrophy.
Abstract: A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B. Here we report eight of these cases carrying recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, also mutated in some Treacher Collins syndrome (TCS) cases. Using shotgun proteomics and ChIP sequencing, we demonstrate that leukodystrophy-causative mutations, but not TCS mutations, in POLR1C impair assembly and nuclear import of POLR3, but not POLR1, leading to decreased binding to POLR3 target genes. This study is the first to show that distinct mutations in a gene coding for a shared subunit of two RNA polymerases lead to selective modification of the enzymes' availability leading to two different clinical conditions and to shed some light on the pathophysiological mechanism of one of the most common hypomyelinating leukodystrophies, POLR3-related leukodystrophy.
121 citations
Alberta Children's Hospital1, University of Toronto2, Seoul National University3, McGill University4, Asan Medical Center5, Vancouver General Hospital6, The Chinese University of Hong Kong7, University of Alberta Hospital8, Montreal Children's Hospital9, University of Calgary10, Instituto de Medicina Molecular11, Uppsala University Hospital12, University of Colorado Denver13, University of Debrecen14, Semmelweis University15, University of Szeged16, University of Alberta17, University of British Columbia18, Centre Hospitalier Universitaire Sainte-Justine19, Virginia Commonwealth University20, Kumamoto University21, Hebrew University of Jerusalem22, University of Utah23, Boston Children's Hospital24, McMaster University25, University of Ottawa26, Children's Hospital of Eastern Ontario27, University of Western Ontario28, London Health Sciences Centre29, Children's Memorial Hospital30, Mahidol University31, Aga Khan University Hospital32, Services Hospital33, University of Nottingham34, Ludwig Maximilian University of Munich35, University of California, San Francisco36, University of Würzburg37, University of Hamburg38, University of Bonn39, Children's Hospital Los Angeles40
TL;DR: An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours.
Abstract: Summary Background Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5 . Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. Methods We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. Findings Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13–57, and 20%, 6–34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7–61, and 9%, 0–21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04–3·85; p=0·038) and 3·98 (1·71–9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. Interpretation An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. Funding C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.
121 citations
TL;DR: The use of high fidelity manikins for advanced life support training is associated with moderate benefits for improving skills performance at course conclusion and future research should define the optimal means of tailoring fidelity to enhance short and long term educational goals and clinical outcomes.
102 citations
Alberta Children's Hospital1, Brown University2, Columbia University3, Children's Hospital of Philadelphia4, University of British Columbia5, University of Alberta6, University of Alabama at Birmingham7, Montreal Children's Hospital8, Northwestern University9, Johns Hopkins University School of Medicine10
TL;DR: Healthcare providers' visual perception of CPR quality is poor, but perceptions of CPR depth are improved by using real-time visual feedback and with prior JIT CPR training.
99 citations
TL;DR: It is reported that vesiculomes differ between known GBM subtypes, and the GBM/GSC subtype-specific differentials in EV cargo of proteins, transcripts, microRNA and DNA may enable detection of the dynamics of the stem cell compartment and result in biological effects that remain to be fully characterized.
96 citations
TL;DR: Advantages in operative time appear outweighed by the increased safety profile of laparoscopic gastrostomy insertion, and the number needed to treat to reduce one major complication by abandoning PEG is 45.
TL;DR: The proposed set of ICD-10 codes encompasses the codes used in different countries for most SUDI cases and will allow for better international comparisons and tracking of trends over time.
Abstract: Background Comparing rates of sudden unexpected death in infancy (SUDI) in different countries and over time is difficult, as these deaths are certified differently in different countries, and, even within the same jurisdiction, changes in this death certification process have occurred over time. Aims To identify if International Classification of Diseases-10 (ICD-10) codes are being applied differently in different countries, and to develop a more robust tool for international comparison of these types of deaths. Methods Usage of six ICD-10 codes, which code for the majority of SUDI, was compared for the years 2002–2010 in eight high-income countries. Results There was a great variability in how each country codes SUDI. For example, the proportion of SUDI coded as sudden infant death syndrome (R95) ranged from 32.6% in Japan to 72.5% in Germany. The proportion of deaths coded as accidental suffocation and strangulation in bed (W75) ranged from 1.1% in Germany to 31.7% in New Zealand. Japan was the only country to consistently use the R96 code, with 44.8% of SUDI attributed to that code. The lowest, overall, SUDI rate was seen in the Netherlands (0.19/1000 live births (LB)), and the highest in New Zealand (1.00/1000 LB). SUDI accounted for one-third to half of postneonatal mortality in 2002–2010 for all of the countries except for the Netherlands. Conclusions The proposed set of ICD-10 codes encompasses the codes used in different countries for most SUDI cases. Use of these codes will allow for better international comparisons and tracking of trends over time.
TL;DR: This observational study reports the use of triple therapy, which combines three effective components in this rare condition, and suggests that early diagnosis and treatment with this new triple therapy may ameliorate the cognitive impairment in PDE.
TL;DR: The results show that phosphatidylethanolamine (PE), a diacyl glycerophospholipid, which like ethanolamine plasmalogens carries the head group ethanolamine, is the main player in the adaptation toPlasmalogen insufficiency, and the amount of total ethanolamine phospholipids is precisely maintained by a rise in PE.
Children's Hospital of Eastern Ontario1, University of Toronto2, Montreal Children's Hospital3, University of Alberta4, Memorial University of Newfoundland5, Dalhousie University6, McMaster Children's Hospital7, University of Saskatchewan8, University of Western Ontario9, University of Manitoba10, University of British Columbia11, Alberta Children's Hospital12, Centre Hospitalier Universitaire Sainte-Justine13
TL;DR: Most patients respond well to conventional therapy, diminishing the need for liver transplantation, and AIH is uncommon in children and adolescents in Canada.
Abstract: BACKGROUND AND OBJECTIVES: Autoimmune hepatitis (AIH) is a progressive inflammatory liver disease of unknown etiology, with limited population-based estimates of pediatric incidence. We reported the incidence of pediatric AIH in Canada and described its clinical characteristics. METHODS: We conducted a retrospective cohort study of patients aged RESULTS: A total of 159 children with AIH (60.3% female, 13.2% type 2 AIH) were identified. Annual incidence was 0.23 per 100000 children. Median age at presentation for type 1 was 12 years (interquartile range: 11–14) versus 10 years for type 2 (interquartile range: 4.5–13) ( P = .03). Fatigue (58%), jaundice (54%), and abdominal pain (49%) were the most common presenting symptoms. Serum albumin (33 vs 38 g/L; P = .03) and platelet count (187 000 vs 249 000; P P CONCLUSIONS: AIH is uncommon in children and adolescents in Canada. Type 1 AIH was diagnosed 5.5 times more frequently than type 2 AIH. Most patients respond well to conventional therapy, diminishing the need for liver transplantation.
TL;DR: The present review will highlight the different challenges that remain today in the global evaluation of infants afflicted with Pierre Robin sequence through a thorough review of the medical literature, giving the clinician a full scope of the disease and of the various management options.
Journal Article•
TL;DR: In this paper, the utility of motivation and emotion variables to account for persistence and achievement in science in male and female students transitioning from high school to junior college was examined to address continually decreasing enrollment and rising attrition in post-secondary STEM degree (science, technology, engineering, and mathematics) programs, particularly for women.
Abstract: To address continually decreasing enrollment and rising attrition in post-secondary STEM degree (science, technology, engineering, and mathematics) programs, particularly for women, the present study examines the utility of motivation and emotion variables to account for persistence and achievement in science in male and female students transitioning from high school to junior college. Consistent with self-determination theory (Deci & Ryan, 2012) and achievement-goal theory (Senko, Hulleman, & Harackiewicz, 2011), structural equation modelling based on data from 1,309 students from four English-language CEGEPs showed students’ achievement goals, self-efficacy, and perceived autonomy support to impact intrinsic motivation, emotions, and achievement that, in turn, predicted persistence in the science domain.
TL;DR: Lung volume recruitment and avoidance of excessive tidal volume are key elements of lung-protective ventilation strategies, as well as avoidance of oxidative stress, less invasive methods of surfactant administration, and high-frequency ventilation, in lung injury prevention.
TL;DR: Knowledge derived from this review provides preliminary understanding of and justifies greater attention towards the concept of participation in this population of children with Autism Spectrum Disorder.
Abstract: Participation in leisure activities is beneficial for children’s health and development, including those living with Autism Spectrum Disorder (ASD). Available syntheses of knowledge about participation have focused primarily on children with physical disabilities; however, little attention is directed to children with ASD. The purpose of this study was therefore to synthesize research evidence regarding the patterns and determinants of leisure participation in this population. A scoping review of peer-reviewed studies published between 2000 and 2013 was performed. Two reviewers independently selected studies based on a systematic procedure. Inclusion criteria for studies were participants with ASD, aged 5–17 years, and description of participation in leisure activities outside of school. Data were organized and synthesized based on domains of the International Classification of Functioning, Disability and Health (ICF): Body Functions, Activity Limitations, and Environmental factors. Sixteen articles (out of 920) met the inclusion criteria and majority of those were descriptive in nature (69 %), whereas information about the factors that affect participation was reported in only 31 %. Overall, children with ASD participate in fewer leisure activities, mostly in the home setting, either with adults or on their own. Factors identified as associated with participation involved family support and social attitudes (environmental factors), sensitivity and behavioral challenges (body functions), and communication and interpersonal relationships problems (activity limitations). Knowledge derived from this review provides preliminary understanding of and justifies greater attention towards the concept of participation in this population. Further research directions are suggested to address the identified gaps in the literature.
John Radcliffe Hospital1, University of Birmingham2, Lund University3, University of Amsterdam4, University of Padua5, University of California, San Diego6, University of Leicester7, University of Hull8, Harvard University9, University of North Carolina at Chapel Hill10, Medical University of Vienna11, Montreal Children's Hospital12
TL;DR: This review discusses the themes of that event and the ISEV 2014 meeting that followed, and proposes a possible explanation for the increased risk of VTE observed in some types of cancer.
Abstract: Although the association between cancer and venous thromboembolism (VTE) has long been known, the mechanisms are poorly understood. Circulating tissue factor-bearing extracellular vesicles have been proposed as a possible explanation for the increased risk of VTE observed in some types of cancer. The International Society for Extracellular Vesicles (ISEV) and International Society on Thrombosis and Haemostasis (ISTH) held a joint Educational Day in April 2014 to discuss the latest developments in this field. This review discusses the themes of that event and the ISEV 2014 meeting that followed.
Children's Hospital of Eastern Ontario1, Halifax2, University of British Columbia3, Queen's University4, Montreal Children's Hospital5, Alberta Children's Hospital6, University of Saskatchewan7, University of Alberta8, McMaster Children's Hospital9, London Health Sciences Centre10, St. John's University11, University of Toronto12, McMaster University13
TL;DR: A next-generation sequencing assay to analyse a panel of 72 known IBMFS genes is developed and detected mutant genes that had not previously been reported to be associated with the patient phenotypes and has a major impact on patient care.
Abstract: Background Phenotypic overlap among the inherited bone marrow failure syndromes (IBMFSs) frequently limits the ability to establish a diagnosis based solely on clinical features. >70 IBMFS genes have been identified, which often renders genetic testing prolonged and costly. Since correct diagnosis, treatment and cancer surveillance often depend on identifying the mutated gene, strategies that enable timely genotyping are essential. Methods To overcome these challenges, we developed a next-generation sequencing assay to analyse a panel of 72 known IBMFS genes. Cases fulfilling the clinical diagnostic criteria of an IBMFS but without identified causal genotypes were included. Results The assay was validated by detecting 52 variants previously found by Sanger sequencing. A total of 158 patients with unknown mutations were studied. Of 75 patients with known IBMFS categories (eg, Fanconi anaemia), 59% had causal mutations. Among 83 patients with unclassified IBMFSs, we found causal mutations and established the diagnosis in 18% of the patients. The assay detected mutant genes that had not previously been reported to be associated with the patient phenotypes. In other cases, the assay led to amendments of diagnoses. In 20% of genotype cases, the results indicated a cancer surveillance programme. Conclusions The novel assay is efficient, accurate and has a major impact on patient care.
TL;DR: There was a lack of consensus on the time frame for definition of extubation failure (EF), the majority proposing a period between 24 and 72 h; 43% believed that EF is an independent risk factor for increased mortality and morbidity.
Abstract: Objective To determine periextubation practices in extremely preterm infants ( Design A survey consisting of 13 questions related to weaning from mechanical ventilation, assessment of extubation readiness and postextubation respiratory support was developed and sent to clinical directors of level III NICUs in Australia, Canada, Ireland, New Zealand and USA. A descriptive analysis of the results was performed. Results 112/162 (69%) units responded; 36% reported having a guideline (31%) or written protocol (5%) for ventilator weaning. Extubation readiness was assessed based on ventilatory settings (98%), blood gases (92%) and the presence of clinical stability (86%). Only 54% ensured that infants received caffeine ≤24 h prior to extubation. 16% of units systematically extubated infants on the premise that they passed a Spontaneous Breathing Test with a duration ranging from 3 min (25%) to more than 10 min (35%). Nasal continuous positive airway pressure was the most common type of respiratory support used (84%) followed by nasal intermittent positive pressure ventilation (55%) and high-flow nasal cannula (33%). Reintubation was mainly based on clinical judgement of the responsible physician (88%). There was a lack of consensus on the time frame for definition of extubation failure (EF), the majority proposing a period between 24 and 72 h; 43% believed that EF is an independent risk factor for increased mortality and morbidity. Conclusions Periextubation practices vary considerably; decisions are frequently physician dependent and not evidence based. The definition of EF is variable and well-defined criteria for reintubation are rarely used. High-quality trials are required to inform guidelines and standardise periextubation practices.
St. Jude Children's Research Hospital1, Tel Aviv Sourasky Medical Center2, Rambam Health Care Campus3, Georgetown University Medical Center4, Children's National Medical Center5, Children's Memorial Hospital6, German Cancer Research Center7, Montreal Children's Hospital8, Children's Hospital Los Angeles9, University of Toronto10
TL;DR: The data demonstrate that differences in CN, gene expression, and DNA methylation signatures distinguish CPCs from CPPs and aCPPs; however, molecular similarities among the papillomas suggest that these two histologic subgroups are indeed a single molecular entity.
Abstract: Purpose To investigate molecular alterations in choroid plexus tumors (CPT) using a genome-wide high-throughput approach to identify diagnostic and prognostic signatures that will refine tumor stratification and guide therapeutic options. Experimental design One hundred CPTs were obtained from a multi-institutional tissue and clinical database. Copy-number (CN), DNA methylation, and gene expression signatures were assessed for 74, 36, and 40 samples, respectively. Molecular subgroups were correlated with clinical parameters and outcomes. Results Unique molecular signatures distinguished choroid plexus carcinomas (CPC) from choroid plexus papillomas (CPP) and atypical choroid plexus papillomas (aCPP); however, no significantly distinct molecular alterations between CPPs and aCPPs were observed. Allele-specific CN analysis of CPCs revealed two novel subgroups according to DNA content: hypodiploid and hyperdiploid CPCs. Hyperdiploid CPCs exhibited recurrent acquired uniparental disomy events. Somatic mutations in TP53 were observed in 60% of CPCs. Investigating the number of mutated copies of p53 per sample revealed a high-risk group of patients with CPC carrying two copies of mutant p53, who exhibited poor 5-year event-free (EFS) and overall survival (OS) compared with patients with CPC carrying one copy of mutant p53 (OS: 14.3%, 95% confidence interval, 0.71%-46.5% vs. 66.7%, 28.2%-87.8%, respectively, P = 0.04; EFS: 0% vs. 44.4%, 13.6%-71.9%, respectively, P = 0.03). CPPs and aCPPs exhibited favorable survival. Discussion Our data demonstrate that differences in CN, gene expression, and DNA methylation signatures distinguish CPCs from CPPs and aCPPs; however, molecular similarities among the papillomas suggest that these two histologic subgroups are indeed a single molecular entity. A greater number of copies of mutated TP53 were significantly associated to increased tumor aggressiveness and a worse survival outcome in CPCs. Collectively, these findings will facilitate stratified approaches to the clinical management of CPTs.
TL;DR: A novel pattern of chemotherapy-induced mitochondrial dysfunction in skeletal muscle that persists because of an acquired defect in mitophagy signaling is suggested and could explain the observed functional impairments in adult survivors of childhood ALL and may be relevant to long-term survivors of other cancers treated with similar regimes.
Abstract: Anticancer treatments for childhood acute lymphoblastic leukaemia (ALL) are highly effective but are now implicated in causing impaired muscle function in long-term survivors. However, no comprehensive assessment of skeletal muscle mitochondrial functions in long-term survivors has been performed and the presence of persistent chemotherapy-induced skeletal muscle mitochondrial dysfunction remains a strong possibility. Non-tumour-bearing mice were treated with two drugs that have been used frequently in ALL treatment (doxorubicin and dexamethasone) for up to 4 cycles at 3-week intervals and euthanized 3 months after the 4th cycle. Treated animals had impaired growth and lower muscle mass as well as reduced mitochondrial respiration and increased reactive oxygen species production per unit oxygen consumption. Mitochondrial DNA content and protein levels of key mitochondrial membrane proteins and markers of mitochondrial biogenesis were unchanged, but protein levels of Parkin were reduced. This suggests a novel pattern of chemotherapy-induced mitochondrial dysfunction in skeletal muscle that persists because of an acquired defect in mitophagy signaling. The results could explain the observed functional impairments in adult survivors of childhood ALL and may also be relevant to long-term survivors of other cancers treated with similar regimes.
TL;DR: The findings indicate that the bilingual treatment created through collaboration with parents was not effective in creating a sufficiently intense bilingual context to make it significantly different from the monolingual treatment.
Abstract: Purpose This study investigated the clinical effectiveness of monolingual versus bilingual language intervention, the latter involving speech-language pathologist–parent collaboration. The study focuses on methods that are currently being recommended and that are feasible within current clinical contexts. Method Bilingual children with primary language impairment who speak a minority language as their home language and French as their second (n = 29, mean age = 5 years) were randomly assigned to monolingual treatment, bilingual treatment, and no-treatment (delayed-treatment) conditions. Sixteen sessions of individual language intervention were offered, targeting vocabulary and syntactic skills in French only or bilingually, through parent collaboration during the clinical sessions. Language evaluations were conducted before and after treatment by blinded examiners; these evaluations targeted French as well as the home languages. An additional evaluation was conducted 2 months after completion of treatment...
TL;DR: The findings do not support replacing SCr by CysC to define AKI and combined SCr-CysC-AKI definition leads to stronger AKI biomarker associations.
Abstract: Early acute kidney injury (AKI) diagnosis is needed to pursue treatment trials. We evaluated cystatin C (CysC) as an early biomarker of serum creatinine (SCr)-AKI and an alternative to define AKI. We studied 160 non-cardiac children in the intensive care unit (ICU). We measured daily CysC and SCr. AKI was staged by KDIGO (Kidney Disease: Improving Global Outcomes) guidelines using SCr and CysC (CysC-AKI). We calculated area under the curve (AUC) for (1) neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1) and urine CysC to diagnose SCr- and CysC-AKI; and (2) for CysC to diagnose SCr-AKI. We evaluated AKI associations with length of stay and ventilation duration. We found that 44 % of patients developed SCr-AKI; 32 % developed CysC-AKI. Early ICU NGAL was most diagnostic of CysC-AKI (AUC 0.69, 95% CI 0.54–0.84); IL-18 was most diagnostic for SCr-AKI (AUC 0.69 95% CI 0.55–0.82). Combining SCr and CysC-AKI definition led to higher biomarker diagnostic AUC’s. CysC-AKI was not more strongly associated with clinical outcomes. Early ICU CysC predicted SCr-AKI development (AUC 0.70, 95 % CI 0.53–0.89). Our findings do not support replacing SCr by CysC to define AKI. Early ICU CysC predicts SCr-AKI development and combined SCr-CysC-AKI definition leads to stronger AKI biomarker associations.
TL;DR: Diffusion tensor imaging and tractography were used to analyze white matter (WM) development in 11 newborns whose mothers were recruited during pregnancy, the first DTI‐tractography study of prenatally alcohol exposed newborns.
Abstract: Prenatal alcohol exposure (PAE) is known to have severe, long-term consequences for brain and behavioral development already detectable in infancy and childhood. Resulting features of fetal alcohol spectrum disorders include cognitive and behavioral effects, as well as facial anomalies and growth deficits. Diffusion tensor imaging (DTI) and tractography were used to analyze white matter (WM) development in 11 newborns (age since conception <45 weeks) whose mothers were recruited during pregnancy. Comparisons were made with nine age-matched controls born to abstainers or light drinkers from the same Cape Coloured (mixed ancestry) community near Cape Town, South Africa. DTI parameters, T1 relaxation time, proton density and volumes were used to quantify and investigate group differences in WM in the newborn brains. Probabilistic tractography was used to estimate and to delineate similar tract locations among the subjects for transcallosal pathways, cortico-spinal projection fibers, and cortico-cortical association fibers. In each of these WM networks, the axial diffusivity was the parameter that showed the strongest association with maternal drinking. The strongest relations were observed in medial and inferior WM, regions in which the myelination process typically begins. In contrast to studies of older individuals with PAE, fractional anisotropy did not exhibit a consistent and significant relation with alcohol exposure. To our knowledge, this is the first DTI-tractography study of prenatally alcohol exposed newborns. Hum Brain Mapp, 36:170–186, 2015. © 2014 Wiley Periodicals, Inc.
TL;DR: Delayed osteotomy healing occurred less frequently in children with moderate to severe osteogenesis imperfecta who were treated with intravenous pamidronate infusions in the past 10 years than in the decade before that.
Abstract: A decade ago our group had reported that osteotomy healing was commonly delayed in children with moderate to severe osteogenesis imperfecta (OI) who were treated with intravenous pamidronate infusions. We subsequently maintained a bisphosphonate infusion–free interval of 4 months after osteotomy and changed the surgical approach (use of an osteotome instead of a power saw). In addition, zoledronic acid has become the standard intravenous bisphosphonate for treatment of OI at our institution. In the present study, we compared osteotomy healing before and after these changes were instituted. We evaluated bone healing post-osteotomy on standard radiographs after 261 intramedullary rodding procedures involving osteotomies (139 femur, 112 tibia) in 110 patients (age at surgery 1.2 to 20.4 years). Delayed healing was diagnosed when the osteotomy line was visible 12 months after the event. We observed delayed bone healing after 48 of the 114 osteotomies (42%) performed with the new approach, and in 106 of the 147 osteotomies (72%) using the previous approach (p = 0.001). The odds for delayed osteotomy healing were significantly lower with the new approach even after adjustment for age, sex, height Z-score, weight Z-score, OI type, and bone involved (odds ratio = 0.17; 95% confidence interval 0.16–0.47). Thus, delayed osteotomy healing occurred less frequently in the past 10 years than in the decade before that. It is likely that this improved result is attributable to the implemented changes in both medical and surgical management. © 2015 American Society for Bone and Mineral Research.
TL;DR: The challenge for future research is to find effective ways to improve primary care physician and general community awareness of T1DM to reduce DKA at presentation and develop practical, cost-effective programs to reduce recurrent DKA.
TL;DR: In this paper, the authors used whole-exome sequencing to identify disease-causing variants in four patients with basal ganglia abnormalities and clinical presentations consistent with Leigh syndrome (LS) and reported a clear clinical overlap between their patients and the reported cases with ECHS1 or HIBCH deficiency.
Abstract: Leigh syndrome (LS) is a rare heterogeneous progressive neurodegenerative disorder usually presenting in infancy or early childhood. Clinical presentation is variable and includes psychomotor delay or regression, acute neurological or acidotic episodes, hypotonia, ataxia, spasticity, movement disorders, and corresponding anomalies of the basal ganglia and brain stem on magnetic resonance imaging. To date, 35 genes have been associated with LS, mostly involved in mitochondrial respiratory chain function and encoded in either nuclear or mitochondrial DNA. We used whole-exome sequencing to identify disease-causing variants in four patients with basal ganglia abnormalities and clinical presentations consistent with LS. Compound heterozygote variants in ECHS1, encoding the enzyme enoyl-CoA hydratase were identified. One missense variant (p.Thr180Ala) was common to all four patients and the haplotype surrounding this variant was also shared, suggesting a common ancestor of French-Canadian origin. Rare mutations in ECHS1 as well as in HIBCH, the enzyme downstream in the valine degradation pathway, have been associated with LS or LS-like disorders. A clear clinical overlap is observed between our patients and the reported cases with ECHS1 or HIBCH deficiency. The main clinical features observed in our cohort are T2-hyperintense signal in the globus pallidus and putamen, failure to thrive, developmental delay or regression, and nystagmus. Respiratory chain studies are not strikingly abnormal in our patients: one patient had a mild reduction of complex I and III and another of complex IV. The identification of four additional patients with mutations in ECHS1 highlights the emerging importance of this pathway in LS.