Showing papers by "Children's Memorial Hospital published in 2017"
Richard S. Finkel1, Eugenio Mercuri2, Basil T. Darras3, Anne M. Connolly4 +394 more•Institutions (13)
TL;DR: Those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group and infants with a shorter disease duration at screening wereMore likely than those with a longer disease duration to benefit from nusineren.
Abstract: BackgroundSpinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonu...
1,342 citations
TL;DR: Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive‐seizure frequency than placebo and was associated with higher rates of adverse events.
Abstract: BackgroundThe Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome MethodsIn this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period ResultsThe median frequency of convulsive seizures per month decreased from 124 to 59 with cannabidiol, as compared with a decrease from 149 to 141 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, −228 percentage points; 95% confidence i
1,060 citations
23 Feb 2017
TL;DR: Although considerable progress has been made in understanding this condition, numerous challenges remain; a collaborative and interdisciplinary approach is required to manage individuals with neurofibromatosis type1 and to develop effective treatments.
Abstract: Neurofibromatosis type 1 is a complex autosomal dominant disorder caused by germline mutations in the NF1 tumour suppressor gene. Nearly all individuals with neurofibromatosis type 1 develop pigmentary lesions (cafe-au-lait macules, skinfold freckling and Lisch nodules) and dermal neurofibromas. Some individuals develop skeletal abnormalities (scoliosis, tibial pseudarthrosis and orbital dysplasia), brain tumours (optic pathway gliomas and glioblastoma), peripheral nerve tumours (spinal neurofibromas, plexiform neurofibromas and malignant peripheral nerve sheath tumours), learning disabilities, attention deficits, and social and behavioural problems, which can negatively affect quality of life. With the identification of NF1 and the generation of accurate preclinical mouse strains that model some of these clinical features, therapies that target the underlying molecular and cellular pathophysiology for neurofibromatosis type 1 are becoming available. Although no single treatment exists, current clinical management strategies include early detection of disease phenotypes (risk assessment) and biologically targeted therapies. Similarly, new medical and behavioural interventions are emerging to improve the quality of life of patients. Although considerable progress has been made in understanding this condition, numerous challenges remain; a collaborative and interdisciplinary approach is required to manage individuals with neurofibromatosis type1 and to develop effective treatments.
639 citations
TL;DR: This study is the first assessment, to date, of the Sepsis-3 definitions in critically ill children and demonstrates use of these definitions in children is feasible and shows promising results.
Abstract: Importance The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) uses the Sequential Organ Failure Assessment (SOFA) score to grade organ dysfunction in adult patients with suspected infection. However, the SOFA score is not adjusted for age and therefore not suitable for children. Objectives To adapt and validate a pediatric version of the SOFA score (pSOFA) in critically ill children and to evaluate the Sepsis-3 definitions in patients with confirmed or suspected infection. Design, Setting, and Participants This retrospective observational cohort study included all critically ill children 21 years or younger admitted to a 20-bed, multidisciplinary, tertiary pediatric intensive care unit between January 1, 2009 and August 1, 2016. Data on these children were obtained from an electronic health record database. The pSOFA score was developed by adapting the original SOFA score with age-adjusted cutoffs for the cardiovascular and renal systems and by expanding the respiratory criteria to include noninvasive surrogates of lung injury. Daily pSOFA scores were calculated from admission until day 28 of hospitalization, discharge, or death (whichever came first). Three additional pediatric organ dysfunction scores were calculated for comparison. Exposures Organ dysfunction measured by the pSOFA score, and sepsis and septic shock according to the Sepsis-3 definitions. Main Outcomes and Measures The primary outcome was in-hospital mortality. The daily pSOFA scores and additional pediatric organ dysfunction scores were compared. Performance was evaluated using the area under the curve. The pSOFA score was then used to assess the Sepsis-3 definitions in the subgroup of children with confirmed or suspected infection. Results In all, 6303 patients with 8711 encounters met inclusion criteria. Each encounter was treated independently. Of the 8482 survivors of hospital encounters, 4644 (54.7%) were male and the median (interquartile range [IQR]) age was 69 (17-156) months. Among the 229 nonsurvivors, 127 (55.4%) were male with a median (IQR) age of 43 (8-144) months. In-hospital mortality was 2.6%. The maximum pSOFA score had excellent discrimination for in-hospital mortality, with an area under the curve of 0.94 (95% CI, 0.92-0.95). The pSOFA score had a similar or better performance than other pediatric organ dysfunction scores. According to the Sepsis-3 definitions, 1231 patients (14.1%) were classified as having sepsis and had a mortality rate of 12.1%, and 347 (4.0%) had septic shock and a mortality rate of 32.3%. Patients with sepsis were more likely to die than patients with confirmed or suspected infection but no sepsis (odds ratio, 18; 95% CI, 11-28). Of the 229 patients who died during their hospitalization, 149 (65.0%) had sepsis or septic shock during their course. Conclusions and Relevance The pSOFA score was adapted and validated with age-adjusted variables in critically ill children. Using the pSOFA score, the Sepsis-3 definitions were assessed in children with confirmed or suspected infection. This study is the first assessment, to date, of the Sepsis-3 definitions in critically ill children. Use of these definitions in children is feasible and shows promising results.
366 citations
TL;DR: To examine the therapeutic potential of blocking the recruitment of bromodomain proteins by heterotypic H3K27M-K27ac nucleosomes in DIPG cells, treatments in vivo with BET bromidomain inhibitors are performed and demonstrate that they efficiently inhibit tumor progression, thus identifying this class of compounds as potential therapeutics in DipG.
Abstract: Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor characterized by rapid and uniform patient demise. A heterozygous point mutation of histone H3 occurs in more than 80% of these tumors and results in a lysine-to-methionine substitution (H3K27M). Expression of this histone mutant is accompanied by a reduction in the levels of polycomb repressive complex 2 (PRC2)-mediated H3K27 trimethylation (H3K27me3), and this is hypothesized to be a driving event of DIPG oncogenesis. Despite a major loss of H3K27me3, PRC2 activity is still detected in DIPG cells positive for H3K27M. To investigate the functional roles of H3K27M and PRC2 in DIPG pathogenesis, we profiled the epigenome of H3K27M-mutant DIPG cells and found that H3K27M associates with increased H3K27 acetylation (H3K27ac). In accordance with previous biochemical data, the majority of the heterotypic H3K27M-K27ac nucleosomes colocalize with bromodomain proteins at the loci of actively transcribed genes, whereas PRC2 is excluded from these regions; this suggests that H3K27M does not sequester PRC2 on chromatin. Residual PRC2 activity is required to maintain DIPG proliferative potential, by repressing neuronal differentiation and function. Finally, to examine the therapeutic potential of blocking the recruitment of bromodomain proteins by heterotypic H3K27M-K27ac nucleosomes in DIPG cells, we performed treatments in vivo with BET bromodomain inhibitors and demonstrate that they efficiently inhibit tumor progression, thus identifying this class of compounds as potential therapeutics in DIPG.
317 citations
Ohio State University1, American Physical Therapy Association2, State University of New York Upstate Medical University3, Children's Memorial Hospital4, University of Texas Southwestern Medical Center5, University of Colorado Boulder6, Washington University in St. Louis7, University of California, Berkeley8, Vanderbilt University9, Nemours Foundation10
TL;DR: Clinical trials in infantile‐onset spinal muscular atrophy require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes.
Abstract: OBJECTIVE Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death preceding age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. METHODS A longitudinal, multicenter, prospective natural history study enrolled 26 SMA infants and 27 control infants aged <6 months. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT (National Network for Excellence in Neuroscience Clinical Trials) Network. Infant motor function scales (Test of Infant Motor Performance Screening Items [TIMPSI], The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders, and Alberta Infant Motor Score) and putative physiological and molecular biomarkers were assessed preceding age 6 months and at 6, 9, 12, 18, and 24 months with progression, correlations between motor function and biomarkers, and hazard ratios analyzed. RESULTS Motor function scores (MFS) and compound muscle action potential (CMAP) decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post-hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95% confidence interval, 6, 17). INTERPRETATION These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide "real-world," prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. Ann Neurol 2017;82:883-891.
230 citations
TL;DR: Selumetinib has promising antitumor activity in children with LGG and the recommended phase II dose (RP2D) and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumet inib inChildren with progressive LGG are determined.
Abstract: Background Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG. Methods Selumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed during the first course. BRAF aberrations in tumor tissue were determined by real-time polymerase chain reaction and fluorescence in situ hybridization. Results Thirty-eight eligible subjects were enrolled. Dose levels 1 and 2 (33 and 43 mg/m2/dose b.i.d.) were excessively toxic. DLTs included grade 3 elevated amylase/lipase (n = 1), headache (n = 1), mucositis (n = 2), and grades 2-3 rash (n = 6). At dose level 0 (25 mg/m2/dose b.i.d, the RP2D), only 3 of 24 subjects experienced DLTs (elevated amylase/lipase, rash, and mucositis). At the R2PD, the median (range) area under the curve (AUC0-∞) and apparent oral clearance of selumetinib were 3855 ng*h/mL (1780 to 7250 ng × h/mL) and 6.5 L × h-1 × m-2 (3.4 to 14.0 L × h-1 × m-2), respectively. Thirteen of 19 tumors had BRAF abnormalities. Among the 5 (20%) of 25 subjects with sustained partial responses, all at the RP2D, 4 had BRAF aberrations, 1 had insufficient tissue. Subjects received a median of 13 cycles (range: 1-26). Fourteen (37%) completed all protocol treatment (26 cycles [n = 13], 13 cycles [n = 1]) with at least stable disease; 2-year progression-free survival at the RP2D was 69 ± SE 9.8%. Conclusion Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.
222 citations
TL;DR: Strong consensus was reached regarding typical clinical presentation of Dravet syndrome, range of electroencephalography and magnetic resonance imaging findings, need for genetic testing, critical information that should be conveyed to families at diagnosis, priorities for seizure control and typical degree of control, and recommendations for avoidance.
198 citations
University of Wisconsin-Madison1, National Institutes of Health2, University of Texas Southwestern Medical Center3, Columbia University4, Cincinnati Children's Hospital Medical Center5, Henry Ford Health System6, University of Colorado Denver7, Children's National Medical Center8, Boston University9, Children's Memorial Hospital10
TL;DR: In children with allergic asthma, treatment with omalizumab decreased the duration of RV infections, viral shedding, and the risk of RV illnesses, providing direct evidence that blocking IgE decreases susceptibility to RV infections and illness.
Abstract: Rationale: Allergic inflammation has been linked to increased susceptibility to viral illnesses, but it is unclear whether this association is causal.Objectives: To test whether omalizumab treatmen...
185 citations
Cornell University1, University of Utah2, University of Pennsylvania3, Children's Memorial Hospital4, Nationwide Children's Hospital5, University of Washington6, University of Arizona7, Johns Hopkins University8, Harvard University9, Washington University in St. Louis10, Emory University11, Erasmus University Rotterdam12, Boston Children's Hospital13, University of Michigan14, Duke University15, University of North Carolina at Chapel Hill16, University of Wisconsin-Madison17, Virginia Commonwealth University18, University of Pittsburgh19
TL;DR: In this article, a multi-institutional point prevalence study was conducted to determine prevalence of delirium in critically ill children and explore associated risk factors, including age less than 2 years, mechanical ventilation, benzodiazepines, narcotics, use of physical restraints, and exposure to vasopressors and antiepileptics.
Abstract: Objectives: To determine prevalence of delirium in critically ill children and explore associated risk factors. Design: Multi-institutional point prevalence study. Setting: Twenty-five pediatric critical care units in the United States, the Netherlands, New Zealand, Australia, and Saudi Arabia. Patients: All children admitted to the pediatric critical care units on designated study days (n = 994). Intervention: Children were screened for delirium using the Cornell Assessment of Pediatric Delirium by the bedside nurse. Demographic and treatment-related variables were collected. Measurements and Main Results: Primary study outcome measure was prevalence of delirium. In 159 children, a final determination of mental status could not be ascertained. Of the 835 remaining subjects, 25% screened positive for delirium, 13% were classified as comatose, and 62% were delirium-free and coma-free. Delirium prevalence rates varied significantly with reason for ICU admission, with highest delirium rates found in children admitted with an infectious or inflammatory disorder. For children who were in the PICU for 6 or more days, delirium prevalence rate was 38%. In a multivariate model, risk factors independently associated with development of delirium included age less than 2 years, mechanical ventilation, benzodiazepines, narcotics, use of physical restraints, and exposure to vasopressors and antiepileptics. Conclusions: Delirium is a prevalent complication of critical illness in children, with identifiable risk factors. Further multi-institutional, longitudinal studies are required to investigate effect of delirium on long-term outcomes and possible preventive and treatment measures. Universal delirium screening is practical and can be implemented in pediatric critical care units.
180 citations
TL;DR: In this paper, the authors describe fertility preservation (FP) utilization by transgender adolescents within a pediatric gender clinic between July 2013 and July 2016, using a retrospective chart review to abstract demographic and clinical information among adolescents initiating gender-affirming hormones, including patient age at initial FP consultation, birth-assigned sex, race/ethnicity, and outcome of FP consultation.
Boston Children's Hospital1, Children's Hospital of Wisconsin2, Children's Memorial Hospital3, Cincinnati Children's Hospital Medical Center4, Children's Hospital of Philadelphia5, Hospital for Sick Children6, Riley Hospital for Children7, Children's Hospital of Orange County8, Seattle Children's9, Vanderbilt University Medical Center10, Mount Sinai Hospital11, Medical University of South Carolina12, University of Utah13
TL;DR: In this article, published nomograms of pediatric echocardiographic measurements are limited by insufficient sample size to assess the effects of age, sex, race, and ethnicity on the outcome.
Abstract: Background—Published nomograms of pediatric echocardiographic measurements are limited by insufficient sample size to assess the effects of age, sex, race, and ethnicity. Variable methodologies hav...
TL;DR: The use of text messaging and mobile phone app interventions to improve medication adherence among adolescents with CHCs has shown promising feasibility and acceptability, and there is modest evidence to support the efficacy of these interventions.
Abstract: Background: The number of adolescents with chronic health conditions (CHCs) continues to increase Medication nonadherence is a global challenge among adolescents across chronic conditions and is associated with poor health outcomes While there has been growing interest in the use of mHealth technology to improve medication adherence among adolescents with CHCs, particularly text messaging and mobile phone apps, there has been no prior systematic review of their efficacy Objective: The purpose of this review was to systematically evaluate the most recent evidence for the efficacy of text messaging and mobile phone apps as interventions to promote medication adherence among adolescents with CHCs Methods: PubMed, Embase, CENTRAL, PsycINFO, Web of Science, Google Scholar, and additional databases were searched from 1995 until November 2015 An additional hand search of related themes in the Journal of Medical Internet Research was also conducted The Preferred Reporting Results of Systematic Reviews and Meta-Analyses guidelines were followed Two reviewers independently screened titles/abstracts, assessed full-text articles, extracted data from included articles, and assessed their quality using Grades of Recommendation, Assessment, Development, and Evaluation criteria Included studies were described in original research articles that targeted adherence in adolescents with CHCs (12-24 years-old) Results: Of the 1423 records examined, 15 met predefined criteria: text messaging (n=12) and mobile phone apps (n=3) Most studies were performed in the United States (11/15, 73%), were randomized-controlled trials (8/15, 53%), had a sample size <50 (11/15, 73%), and included adherence self-report and/or biomarkers (9/15, 60%) Only four studies were designed based on a theoretical framework Approaches for text messaging and mobile phone app interventions varied across studies Seven articles (7/15, 47%) reported significant improvement in adherence with moderate to large standardized mean differences Most of the included studies were of low or moderate quality Studies varied in sample size, methods of adherence assessment, and definition of adherence, which prohibited performing a meta-analysis Conclusions: The use of text messaging and mobile phone app interventions to improve medication adherence among adolescents with CHCs has shown promising feasibility and acceptability, and there is modest evidence to support the efficacy of these interventions Further evaluation of short- and long-term efficacy and cost-effectiveness of these interventions is warranted given the early and evolving state of the science [JMIR Mhealth Uhealth 2017;5(5):e66]
Icahn School of Medicine at Mount Sinai1, DBV Technologies2, Harvard University3, University of Ottawa4, University of Toronto5, Children's Hospital of Philadelphia6, Stanford University7, University of California, San Diego8, Children's Memorial Hospital9, Cincinnati Children's Hospital Medical Center10, University of Texas Southwestern Medical Center11, University of Pittsburgh12, Erasmus University Rotterdam13, Utrecht University14, University of Lorraine15, Boston Children's Hospital16, Medical University of Łódź17, Necker-Enfants Malades Hospital18, Paris Descartes University19
TL;DR: A dose-ranging trial of a peanut patch in peanut-allergic patients and a double-blind, placebo-controlled food challenge to establish changes in eliciting dose to determine the optimal dose, adverse events (AEs), and efficacy of aanut patch for peanut allergy treatment.
Abstract: IMPORTANCE: Epicutaneous immunotherapy may have potential for treating peanut allergy but has been assessed only in preclinical and early human trials. OBJECTIVE: To determine the optimal dose, adverse events (AEs), and efficacy of a peanut patch for peanut allergy treatment. DESIGN, SETTING, AND PARTICIPANTS: Phase 2b double-blind, placebo-controlled, dose-ranging trial of a peanut patch in peanut-allergic patients (6-55 years) from 22 centers, with a 2-year, open-label extension (July 31, 2012-July 31, 2014; extension completed September 29, 2016). Patients (n = 221) had peanut sensitivity and positive double-blind, placebo-controlled food challenges to an eliciting dose of 300 mg or less of peanut protein. INTERVENTIONS: Randomly assigned patients (1:1:1:1) received an epicutaneous peanut patch containing 50 μg (n = 53), 100 μg (n = 56), or 250 μg (n = 56) of peanut protein or a placebo patch (n = 56). Following daily patch application for 12 months, patients underwent a double-blind, placebo-controlled food challenge to establish changes in eliciting dose. MAIN OUTCOMES AND MEASURES: The primary efficacy end point was percentage of treatment responders (eliciting dose: 10-times increase and/or reaching 1000 mg of peanut protein) in each group vs placebo patch after 12 months. Secondary end points included percentage of responders by age strata and treatment-emergent adverse events (TEAEs). RESULTS: Of 221 patients randomized (median age, 11 years [quartile 1, quartile 3: 8, 16]; 37.6% female), 93.7% completed the trial. A significant absolute difference in response rates was observed at month 12 between the 250-μg (n = 28; 50.0%) and placebo (n = 14; 25.0%) patches (difference, 25.0%; 95% CI, 7.7%-42.3%; P = .01). No significant difference was seen between the placebo patch vs the 100-μg patch. Because of statistical testing hierarchical rules, the 50-μg patch was not compared with placebo. Interaction by age group was only significant for the 250-μg patch (P = .04). In the 6- to 11-year stratum, the response rate difference between the 250-μg (n = 15; 53.6%) and placebo (n = 6; 19.4%) patches was 34.2% (95% CI, 11.1%-57.3%; P = .008); adolescents/adults showed no difference between the 250-μg (n = 13; 46.4%) and placebo (n = 8; 32.0%) patches: 14.4% (95% CI, −11.6% to 40.4%; P = .40). No dose-related serious AEs were observed. The percentage of patients with 1 or more TEAEs (largely local skin reactions) was similar across all groups in year 1: 50-μg patch = 100%, 100-μg patch = 98.2%, 250-μg patch = 100%, and placebo patch = 92.9%. The overall median adherence was 97.6% after 1 year; the dropout rate for treatment-related AEs was 0.9%. CONCLUSIONS AND RELEVANCE: In this dose-ranging trial of peanut-allergic patients, the 250-μg peanut patch resulted in significant treatment response vs placebo patch following 12 months of therapy. These findings warrant a phase 3 trial. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01675882.
University of Michigan1, University of Toronto2, University of Southern California3, University of British Columbia4, German Cancer Research Center5, University of California, San Francisco6, University of Pennsylvania7, Johns Hopkins University School of Medicine8, New York University9, Memorial Sloan Kettering Cancer Center10, Northwestern University11, Children's Memorial Hospital12, Centre Hospitalier Universitaire Sainte-Justine13, University of Alberta14, University of Ottawa15, Alberta Children's Hospital16, University of Western Ontario17, Queen's University18, University of Basel19, McMaster University20, McGill University21, Dalhousie University22, Heidelberg University23
TL;DR: In conclusion, immunohistochemical evaluation of H3K27me3 global reduction is an economic, easily available and readily adaptable method for defining high-risk EPN_PFA from low-risk posterior fossa EPN-PFB tumors to inform prognosis and to enable the design of future clinical trials.
Abstract: Posterior fossa ependymomas (EPN_PF) in children comprise two morphologically identical, but biologically distinct tumor entities. Group-A (EPN_PFA) tumors have a poor prognosis and require intensive therapy. In contrast, group-B tumors (EPN_PFB) exhibit excellent prognosis and the current consensus opinion recommends future clinical trials to test the possibility of treatment de-escalation in these patients. Therefore, distinguishing these two tumor subtypes is critical. EPN_PFA and EPN_PFB can be distinguished based on DNA methylation signatures, but these assays are not routinely available. We have previously shown that a subset of poorly prognostic childhood EPN_PF exhibits global reduction in H3K27me3. Therefore, we set out to determine whether a simple immunohistochemical assay for H3K27me3 could be used to segregate EPN_PFA from EPN_PFB tumors. We assembled a cohort of 230 childhood ependymomas and H3K27me3 immunohistochemistry was assessed as positive or negative in a blinded manner. H3K27me3 staining results were compared with DNA methylation-based subgroup information available in 112 samples [EPN_PFA (n = 72) and EPN_PFB tumors (n = 40)]. H3K27me3 staining was globally reduced in EPN_PFA tumors and immunohistochemistry showed 99% sensitivity and 100% specificity in segregating EPN_PFA from EPN_PFB tumors. Moreover, H3K27me3 immunostaining was sufficient to delineate patients with worse prognosis in two independent, non-overlapping cohorts (n = 133 and n = 97). In conclusion, immunohistochemical evaluation of H3K27me3 global reduction is an economic, easily available and readily adaptable method for defining high-risk EPN_PFA from low-risk posterior fossa EPN_PFB tumors to inform prognosis and to enable the design of future clinical trials.
TL;DR: It is concluded that differential methylation between ethnic groups is partially explained by the shared genetic ancestry but that environmental factors not captured by ancestry significantly contribute to variation in methylation.
Abstract: Populations are often divided categorically into distinct racial/ethnic groups based on social rather than biological constructs. Genetic ancestry has been suggested as an alternative to this categorization. Herein, we typed over 450,000 CpG sites in whole blood of 573 individuals of diverse Hispanic origin who also had high-density genotype data. We found that both self-identified ethnicity and genetically determined ancestry were each significantly associated with methylation levels at 916 and 194 CpGs, respectively, and that shared genomic ancestry accounted for a median of 75.7% (IQR 45.8% to 92%) of the variance in methylation associated with ethnicity. There was a significant enrichment (p=4.2×10-64) of ethnicity-associated sites amongst loci previously associated environmental exposures, particularly maternal smoking during pregnancy. We conclude that differential methylation between ethnic groups is partially explained by the shared genetic ancestry but that environmental factors not captured by ancestry significantly contribute to variation in methylation.
TL;DR: This is the first controlled trial examining video-teleconferencing to remotely deliver behavioral parent training to the home setting with a live therapist, and findings build on the small but growing literature supporting the promising role of new technologies for expanding the delivery of Behavioral parent training.
Abstract: Objective Remote technologies are increasingly being leveraged to expand the reach of supported care, but applications to early child-behavior problems have been limited. This is the first controlled trial examining video-teleconferencing to remotely deliver behavioral parent training to the home setting with a live therapist. Method Racially/ethnically diverse children ages 3-5 years with disruptive behavior disorders, and their caregiver(s), using webcams and parent-worn Bluetooth earpieces, participated in a randomized trial comparing Internet-delivered parent-child interaction therapy (I-PCIT) versus standard clinic-based PCIT (N = 40). Major assessments were conducted at baseline, midtreatment, posttreatment, and 6-month follow-up. Linear regressions and hierarchical linear modeling using maximum-likelihood estimation were used to analyze treatment satisfaction, diagnoses, symptoms, functioning, and burden to parents across conditions. Results Intent-to-treat analyses found 70% and 55% of children treated with I-PCIT and clinic-based PCIT, respectively, showed "treatment response" after treatment, and 55% and 40% of children treated with I-PCIT and clinic-based PCIT, respectively, continued to show "treatment response" at 6-month follow-up. Both treatments had significant effects on children's symptoms and burden to parents, and many effects were very large in magnitude. Most outcomes were comparable across conditions, except that the rate of posttreatment "excellent response" was significantly higher in I-PCIT than in clinic-based PCIT, and I-PCIT was associated with significantly fewer parent-perceived barriers to treatment than clinic-based PCIT. Both treatments were associated with positive engagement, treatment retention, and very high treatment satisfaction. Conclusion Findings build on the small but growing literature supporting the promising role of new technologies for expanding the delivery of behavioral parent training. (PsycINFO Database Record
Oregon Health & Science University1, Utrecht University2, King's College London3, University of Southampton4, Aarhus University Hospital5, University of Bonn6, Ninewells Hospital7, University of Dundee8, University of Sheffield9, Brown University10, University of California, San Diego11, Boston Children's Hospital12, Icahn School of Medicine at Mount Sinai13, Newcastle University14, Royal Victoria Infirmary15, Northwestern University16, Dresden University of Technology17, Radboud University Nijmegen Medical Centre18, University of Melbourne19, University of São Paulo20, Technische Universität München21, University of Copenhagen22, Ludwig Maximilian University of Munich23, Trinity College, Dublin24, Children's Memorial Hospital25
TL;DR: The decision to start systemic medication should include assessment of severity and quality of life while considering the individual's general health status, psychologic needs, and personal attitudes toward systemic therapies.
Abstract: Background Although most patients with atopic dermatitis (AD) are effectively managed with topical medication, a significant minority require systemic therapy. Guidelines for decision making about advancement to systemic therapy are lacking. Objective To guide those considering use of systemic therapy in AD and provide a framework for evaluation before making this therapeutic decision with the patient. Methods A subgroup of the International Eczema Council determined aspects to consider before prescribing systemic therapy. Topics were assigned to expert reviewers who performed a topic-specific literature review, referred to guidelines when available, and provided interpretation and expert opinion. Results We recommend a systematic and holistic approach to assess patients with severe signs and symptoms of AD and impact on quality of life before systemic therapy. Steps taken before commencing systemic therapy include considering alternate or concomitant diagnoses, avoiding trigger factors, optimizing topical therapy, ensuring adequate patient/caregiver education, treating coexistent infection, assessing the impact on quality of life, and considering phototherapy. Limitations Our work is a consensus statement, not a systematic review. Conclusion The decision to start systemic medication should include assessment of severity and quality of life while considering the individual's general health status, psychologic needs, and personal attitudes toward systemic therapies.
TL;DR: 8 weeks of 4‐food elimination diet induced clinical, endoscopic, and histologic remission in more than 60% of children with EoE, and can be recommended as a treatment for children withEoE.
TL;DR: Women are underrepresented as authors and editors, although the gap is closing, and junior women are less likely to co‐author with senior men, which may be a disservice given current gender disparities in promotion and leadership.
TL;DR: Intestinal rehabilitation programs provide integrated interdisciplinary care, more discussion of patient management by involved specialists, continuity of care through various treatment interventions, close follow-up of outpatients, improved patient and family education, earlier treatment of complications, and learning from the accumulated patient databases.
Abstract: Intestinal failure is a rare, debilitating condition that presents both acute and chronic medical management challenges. The condition is incompatible with life in the absence of the safe application of specialized and individualized medical therapy that includes surgery, medical equipment, nutritional products, and standard nursing care. Intestinal rehabilitation programs are best suited to provide such complex care with the goal of achieving enteral autonomy and oral feeding with or without intestinal transplantation. These programs almost all include pediatric surgeons, pediatric gastroenterologists, specialized nurses, and dietitians; many also include a variety of other medical and allied medical specialists. Intestinal rehabilitation programs provide integrated interdisciplinary care, more discussion of patient management by involved specialists, continuity of care through various treatment interventions, close follow-up of outpatients, improved patient and family education, earlier treatment of complications, and learning from the accumulated patient databases. Quality assurance and research collaboration among centers are also goals of many of these programs. The combined and coordinated talents and skills of multiple types of health care practitioners have the potential to ameliorate the impact of intestinal failure and improve health outcomes and quality of life.
TL;DR: AS significantly alters aortic hemodynamics and WSS independent of aortIC valve phenotype and over‐rides previously described flow patterns associated with BAV and tricuspid aorti valve with aortsic dilatation.
Abstract: Background Wall shear stress (WSS) is a stimulus for vessel wall remodeling. Differences in ascending aorta (AAo) hemodynamics have been reported between bicuspid aortic valve (BAV) and tricuspid aortic valve patients with aortic dilatation, but the confounding impact of aortic valve stenosis (AS) is unknown. Methods and Results Five hundred seventy‐one subjects underwent 4‐dimensional flow magnetic resonance imaging in the thoracic aorta (210 right‐left BAV cusp fusions, 60 right‐noncoronary BAV cusp fusions, 245 tricuspid aortic valve patients with aortic dilatation, and 56 healthy controls). There were 166 of 515 (32%) patients with AS. WSS atlases were created to quantify group‐specific WSS patterns in the AAo as a function of AS severity. In BAV patients without AS, the different cusp fusion phenotypes resulted in distinct differences in eccentric WSS elevation: right‐left BAV patients exhibited increased WSS by 9% to 34% ( P P P P Conclusions AS significantly alters aortic hemodynamics and WSS independent of aortic valve phenotype and over‐rides previously described flow patterns associated with BAV and tricuspid aortic valve with aortic dilatation. Severity of AS must be considered when investigating valve‐mediated aortopathy.
TL;DR: The results indicate that histone H3 gene mutation is detectable in CSF-derived tumor DNA from children with brain tumors, including diffuse midline glioma, and suggest the feasibility of “liquid biopsy” in lieu of, or to complement, tissue diagnosis, which may prove valuable for stratification to targeted therapies and monitoring treatment response.
Abstract: Diffuse midline gliomas (including diffuse intrinsic pontine glioma, DIPG) are highly morbid glial neoplasms of the thalamus or brainstem that typically arise in young children and are not surgically resectable. These tumors are characterized by a high rate of histone H3 mutation, resulting in replacement of lysine 27 with methionine (K27M) in genes encoding H3 variants H3.3 (H3F3A) and H3.1 (HIST1H3B). Detection of these gain-of-function mutations has clinical utility, as they are associated with distinct tumor biology and clinical outcomes. Given the paucity of tumor tissue available for molecular analysis and relative morbidity of midline tumor biopsy, CSF-derived tumor DNA from patients with diffuse midline glioma may serve as a viable alternative for clinical detection of histone H3 mutation. We demonstrate the feasibility of two strategies to detect H3 mutations in CSF-derived tumor DNA from children with brain tumors (n = 11) via either targeted Sanger sequencing of H3F3A and HIST1H3B, or H3F3A c.83 A > T detection via nested PCR with mutation-specific primers. Of the six CSF specimens from children with diffuse midline glioma in our cohort, tumor DNA sufficient in quantity and quality for analysis was isolated from five (83%), with H3.3K27M detected in four (66.7%). In addition, H3.3G34V was identified in tumor DNA from a patient with supratentorial glioblastoma. Test sensitivity (87.5%) and specificity (100%) was validated via immunohistochemical staining and Sanger sequencing in available matched tumor tissue specimens (n = 8). Our results indicate that histone H3 gene mutation is detectable in CSF-derived tumor DNA from children with brain tumors, including diffuse midline glioma, and suggest the feasibility of “liquid biopsy” in lieu of, or to complement, tissue diagnosis, which may prove valuable for stratification to targeted therapies and monitoring treatment response.
TL;DR: In a multivariable regression model, having an HIV positive sex partner, reporting recent group sex, peer network size, and city (Chicago) were significantly and positively associated with use of PrEP, while Black race was negatively associated with it.
Abstract: Pre-exposure prophylaxis (PrEP) is efficacious to prevent HIV infection, however, uptake among young men who have sex with men (YMSM) is relatively low. The purpose of this study was to describe PrEP use and related factors in a representative sample of YMSM in two cities, Chicago and Houston. YMSM, ages 16-29, were recruited via respondent-driven sampling (RDS) from 2014 to 2016. Correlates of PrEP uptake were assessed in weighted multivariable logistic regression models. A total of 12.2% of participants (of 394) reported ever taking PrEP; Black YMSM had the lowest rates of uptake (4.7%) and Whites the highest (29.5%). In a multivariable regression model, having an HIV positive sex partner, reporting recent group sex, peer network size, and city (Chicago) were significantly and positively associated with use of PrEP, while Black race was negatively associated with it. Given evidence of racial/ethnic disparities in PrEP uptake in this study, further research is needed to identify potential mechanisms of action and points of intervention.
Northwestern University1, Children's Memorial Hospital2, Oregon Health & Science University3, University of Washington4, NewYork–Presbyterian Hospital5, Cornell University6, Emory University7, University of California, San Francisco8, Mayo Clinic9, University of Michigan10, Nationwide Children's Hospital11, Ohio State University12, George Washington University13, Johns Hopkins University14, Drexel University15, Anschutz Medical Campus16, Stanford University17, University of Pennsylvania18, Harvard University19, Boston Children's Hospital20
TL;DR: Thorough genetic investigation emphasizing sequencing tests should be incorporated into the initial evaluation of newly presenting early-life epilepsies and not just reserved for those with severe presentations and poor outcomes.
Abstract: Importance Early-life epilepsies are often a consequence of numerous neurodevelopmental disorders, most of which are proving to have genetic origins. The role of genetic testing in the initial evaluation of these epilepsies is not established. Objective To provide a contemporary account of the patterns of use and diagnostic yield of genetic testing for early-life epilepsies. Design, Setting, and Participants In this prospective cohort, children with newly diagnosed epilepsy with an onset at less than 3 years of age were recruited from March 1, 2012, to April 30, 2015, from 17 US pediatric hospitals and followed up for 1 year. Of 795 families approached, 775 agreed to participate. Clinical diagnosis of the etiology of epilepsy were characterized based on information available before genetic testing was performed. Added contributions of cytogenetic and gene sequencing investigations were determined. Exposures Genetic diagnostic testing. Main Outcomes and Measures Laboratory-confirmed pathogenic variant. Results Of the 775 patients in the study (367 girls and 408 boys; median age of onset, 7.5 months [interquartile range, 4.2-16.5 months]), 95 (12.3%) had acquired brain injuries. Of the remaining 680 patients, 327 (48.1%) underwent various forms of genetic testing, which identified pathogenic variants in 132 of 327 children (40.4%; 95% CI, 37%-44%): 26 of 59 (44.1%) with karyotyping, 32 of 188 (17.0%) with microarrays, 31 of 114 (27.2%) with epilepsy panels, 11 of 33 (33.3%) with whole exomes, 4 of 20 (20.0%) with mitochondrial panels, and 28 of 94 (29.8%) with other tests. Forty-four variants were identified before initial epilepsy presentation. Apart from dysmorphic syndromes, pathogenic yields were highest for children with tuberous sclerosis complex (9 of 11 [81.8%]), metabolic diseases (11 of 14 [78.6%]), and brain malformations (20 of 61 [32.8%]). A total of 180 of 446 children (40.4%), whose etiology would have remained unknown without genetic testing, underwent some testing. Pathogenic variants were identified in 48 of 180 children (26.7%; 95% CI, 18%-34%). Diagnostic yields were greater than 15% regardless of delay, spasms, and young age. Yields were greater for epilepsy panels (28 of 96 [29.2%]; P P = .02) than for chromosomal microarray (8 of 101 [7.9%]). Conclusions and Relevance Genetic investigations, particularly broad sequencing methods, have high diagnostic yields in newly diagnosed early-life epilepsies regardless of key clinical features. Thorough genetic investigation emphasizing sequencing tests should be incorporated into the initial evaluation of newly presenting early-life epilepsies and not just reserved for those with severe presentations and poor outcomes.
TL;DR: Lactobacillus sp.
Abstract: Necrotizing enterocolitis (NEC) is a serious intestinal disease that occurs in newborn infants. It is associated with major morbidity and affects 5% of all infants admitted to neonatal intensive care units. Probiotics have variable efficacy in preventing necrotizing enterocolitis. Tight junctions (TJ) are protein complexes that maintain epithelial barrier integrity. We hypothesized that the probiotics Lactobacillus rhamnosus and Lactobacillus plantarum strengthen intestinal barrier function, promote TJ integrity, and protect against experimental NEC. Both an in vitro and an in vivo experimental model of NEC were studied. Cultured human intestinal Caco-2 cells were pretreated with L. rhamnosus and L. plantarum probiotics. TJ were then disrupted by EGTA calcium switch or LPS to mimic NEC in vitro. Trans-epithelial resistance (TER) and flux of fluorescein isothiocynate dextran was measured. TJ structure was evaluated by ZO-1 immunofluorescence. in vivo effects of ingested probiotics on intestinal injury and ZO-1 expression were assessed in a rat model of NEC infected with Cronobacter sakazaki (CS). Caco-2 cells treated with individual probiotics demonstrated higher TER and lower permeability compared to untreated cells (p<0.0001). ZO-1 immunofluorescence confirmed TJ stability in treated cells. Rat pups fed probiotics alone had more intestinal injury compared with controls (p=0.0106). Probiotics were protective against injury when given in combination with CS, with no difference in intestinal injury compared to controls (p=0.21). Increased permeability was observed in the probiotic and CS groups (p=0.03, p=0.05), but not in the probiotic plus CS group (p=0.79). Lactobacillus sp. strengthened intestinal barrier function and preserved TJ integrity in an in vitro experimental model of NEC. in vivo, probiotic bacteria were not beneficial when given alone, but were protective in the presence of CS in a rat model of NEC.
TL;DR: This review focuses on the preclinical and clinical development of GSK-3 inhibitors and the potential therapeutic impact of targeting G SK-3β in human cancer.
Abstract: Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, is a complex regulator of numerous cellular functions. GSK-3β is a unique kinase which is constitutively active in resting and nonstimulated cells. GSK-3β has been implicated in a wide range of diseases including neurodegeneration, inflammation and fibrosis, noninsulin-dependent diabetes mellitus, and cancer. It is a regulator of NF-κB–mediated survival of cancer cells, which provided a rationale for the development of GSK-3 inhibitors targeting malignant tumors. Recent studies, many of them reported over the past decade, have identified GSK-3β as a potential therapeutic target in more than 15 different types of cancer. Whereas only active GSK-3β is expressed in cancer cell nucleus, aberrant nuclear accumulation of GSK-3β has been identified as a hallmark of cancer cells in malignant tumors of different origin. This review focuses on the preclinical and clinical development of GSK-3 inhibitors and the potential therapeutic impact of targeting GSK-3β in human cancer. Clin Cancer Res; 23(8); 1–7. ©2017 AACR.
TL;DR: Among African Americans from 2 large, well-established cohorts, participants with SCT had lower levels of HbA1c at any given concentration of fasting or 2-hour glucose compared with participants without SCT, suggesting that Hb a1c may systematically underestimate past glycemia in black patients with S CT.
Abstract: Importance Hemoglobin A 1c (HbA 1c ) reflects past glucose concentrations, but this relationship may differ between those with sickle cell trait (SCT) and those without it. Objective To evaluate the association between SCT and HbA 1c for given levels of fasting or 2-hour glucose levels among African Americans. Design, Setting, and Participants Retrospective cohort study using data collected from 7938 participants in 2 community-based cohorts, the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson Heart Study (JHS). From the CARDIA study, 2637 patients contributed a maximum of 2 visits (2005-2011); from the JHS, 5301 participants contributed a maximum of 3 visits (2000-2013). All visits were scheduled at approximately 5-year intervals. Participants without SCT data, those without any concurrent HbA 1c and glucose measurements, and those with hemoglobin variants HbSS, HbCC, or HbAC were excluded. Analysis of the primary outcome was conducted using generalized estimating equations (GEE) to examine the association of SCT with HbA 1c levels, controlling for fasting or 2-hour glucose measures. Exposures Presence of SCT. Main Outcomes and Measures Hemoglobin A 1c stratified by the presence or absence of SCT was the primary outcome measure. Results The analytic sample included 4620 participants (mean age, 52.3 [SD, 11.8] years; 2835 women [61.3%]; 367 [7.9%] with SCT) with 9062 concurrent measures of fasting glucose and HbA 1c levels. In unadjusted GEE analyses, for a given fasting glucose, HbA 1c values were statistically significantly lower in those with (5.72%) vs those without (6.01%) SCT (mean HbA 1c difference, −0.29%; 95% CI, −0.35% to −0.23%). Findings were similar in models adjusted for key risk factors and in analyses using 2001 concurrent measures of 2-hour glucose and HbA 1c concentration for those with SCT (mean, 5.35%) vs those without SCT (mean, 5.65%) for a mean HbA 1c difference of −0.30% (95% CI, −0.39% to −0.21%). The HbA 1c difference by SCT was greater at higher fasting ( P = .02 for interaction) and 2-hour ( P = .03) glucose concentrations. The prevalence of prediabetes and diabetes was statistically significantly lower among participants with SCT when defined using HbA 1c values (29.2% vs 48.6% for prediabetes and 3.8% vs 7.3% for diabetes in 572 observations from participants with SCT and 6877 observations from participants without SCT; P Conclusions and Relevance Among African Americans from 2 large, well-established cohorts, participants with SCT had lower levels of HbA 1c at any given concentration of fasting or 2-hour glucose compared with participants without SCT. These findings suggest that HbA 1c may systematically underestimate past glycemia in black patients with SCT and may require further evaluation.
TL;DR: The data show that MYO5B deficiency may lead to isolated cholestasis and that Myosin 5B should be considered as an additional progressive familial intrahepatic cholESTasis gene.
TL;DR: Athletes in individual sports may be more likely to specialize in a single sport than team sport athletes, with higher training volumes and greater rates of overuse injuries than single-sport specialized athletes in team sports.
Abstract: Objectives: Current trends among young athletes towards earlier specialization age and year-round training on multiple teams has raised concern for increased injury risk. Our previous analyses showed higher risk for injury in highly specialized young athletes. The goal of this research was to determine whether sports specialization and injury patterns vary by sports type.Methods: In this clinical case-control study, injured athletes (aged 7–18 years) were recruited from sports medicine clinics and compared to similarly aged uninjured athletes recruited from primary care clinics. Participants completed a survey reporting age, gender, sport type, specialization patterns, and details regarding sports-related injuries in the previous 6 months. Clinical diagnoses were collected from patients’ medical records. Injuries were classified as acute, overuse, or serious overuse.Results: Of 1,190 athletes enrolled, 26% (313) were single-sport specialized (reported participation in one sport and trained >8 mont...