A population-based study of communicative participation in preschool children with speech-language impairments

Aim. To develop statistical models of preschoolers’ communicative participation development and explore variations by level of function. Methods. This was a secondary analysis of data from a longitudinal study of preschoolers with speech and language delays (N = 46,872, M age = 41.76, SD age = 11.92; 67% male) accessing publicly-funded services in Ontario Canada. Two measures were used: Focus on the Outcomes of Communication Under Six (FOCUS), measuring changes in communicative participation skills, and the Communication Function Classification System (CFCS), classifying communication function into one of five levels. We used mixed effects modeling to fit growth curves for each CFCS level. Models allowed for variation in initial FOCUS scores at 18 months, rate of growth with age, and rate of acceleration/deceleration with age. Results. Starting FOCUS score (18 months) varied inversely with CFCS level at entry to the program. Growth was initially rapid and then levelled off for children in levels I-III. Growth was less rapid for children in level IV, but levelled off, and was slow but continual for children in level V. Interpretation. This work can help us to move beyond traditional impairment-based thinking and shows that children can make meaningful communicative changes regardless of their function

Factors Contributing to Preschoolers\u27 Communicative Participation Outcomes: Findings From a Population-Based Longitudinal Cohort Study in Ontario, Canada

Purpose. To identify predictors of communicative participation outcomes for a large cohort of preschoolers with communication disorders. Method. A secondary analysis of longitudinal program evaluation data from Ontario Canada’s Preschool Speech and Language Program (PSLP). Data available for 46,872 children 18-67 months of age (M = 41.76 mo, SD = 11.92, 68% male) were previously used to predict children’s communicative participation skill development in five levels of function. Demographic and intervention-based variables were added to the models to identify new predictors of growth. Results. Three demographic and three intervention-based variables were statistically significant predictors of children’s communicative participation outcomes. Clinically significant predictors included participation in an early learning environment, receipt of speech-language interventions, and the amount of time spent in intervention. These variables impacted predicted outcomes differently depending on a child’s level of communicative function. Conclusions. This population-based study of preschoolers with speech and language disorders identified predictors of growth in communicative participation skills – an outcome important and meaningful to families but, not often explored. A broad picture emerged of factors that may influence the development of communicative participation skills, and may be used to predict outcomes for preschoolers. Given the large sample size, these robust findings may be used to predict outcomes outside the PSLP as well

Prognosis of West Nile virus associated acute flaccid paralysis: a case series

Introduction: Little is known about the long-term health related quality of life outcomes in patients with West Nile virus associated acute flaccid paralysis. We describe the quality of life scores of seven patients with acute flaccid paralysis who presented to hospital between 2003 and 2006, and were followed for up to two years. Case presentations: Between 2003 and 2006, 157 symptomatic patients with West Nile virus were enrolled in a longitudinal cohort study of West Nile virus in Canada. Seven patients (4%) had acute flaccid paralysis. The firs

Developmental Trajectories for the Early Clinical Assessment of Balance by Gross Motor Function Classification System Level for Children With Cerebral Palsy.

Background: Children with cerebral palsy (CP) characteristically present with impairments in balance. Currently, the pattern and timing of the development of balance ability have not been described for children with CP of varying Gross Motor Function Classification System (GMFCS) levels. Objective: The purpose of this study was to document longitudinal developmental trajectories in a measure of balance, the Early Clinical Assessment of Balance (ECAB) scores, along with age-specific reference percentiles and the amount of change typical over a 1-year period for children within different GMFCS levels. Design: The design was a longitudinal cohort study. Methods: Participants included 708 children with CP, aged 18 months through their 12th birthday, and their families. Children participated in 2 to 5 assessments using the GMFCS and ECAB. Results: Longitudinal trajectories describing the average change in the ECAB score with respect to age were created by fitting separate nonlinear mixed-effect models for children in each GMFCS level. Reference percentiles were constructed using quantile regression of ECAB data from the first visit (baseline) and 12-month and 24-month visits. Using these reference points, the amount of change in percentiles was calculated for all children by subtracting the baseline percentile score from the 12-month percentile score. Children whose percentile changes are within the 80% limits can usually be described as developing as expected for their age and GMFCS levels. Limitations: Limitations of this study included use of a convenience sample, a ceiling effect of the ECAB for some children in GMFCS levels I and II, and the use of both a 12-month and 24-month study protocol that impacted the number of children available for each assessment session. Conclusions: When used appropriately to monitor development and change over time for children with CP, the ECAB longitudinal trajectories, reference percentiles, and the associated change scores presented here should assist therapists and families in collaborative interaction to proactively plan services and interventions relative to balance ability

Longitudinal trajectories and reference centiles for the impact of health conditions on daily activities of children with cerebral palsy.

AIM: First, to describe the impact of health conditions on daily activities over time in children with cerebral palsy (CP) and to create age-specific reference centiles. Second, to determine the amount of change typical over a 1-year period, across Gross Motor Function Classification System (GMFCS) levels. METHOD: A prospective, cohort design, with five assessments over 2 years, involved 708 children with a confirmed diagnosis of CP participating in the On Track Study (396 males, 312 females; mean age 6y [SD 2y 7mo]; range 18mo-12y at first assessment; 32.1% in GMFCS level I, 22.7% in GMFCS level II, 11.2% in GMFCS level III, 18.2% in GMFCS level IV, 15.7% in GMFCS level V). The impact of health conditions on daily activities was assessed using the Child Health Conditions Questionnaire. Data were analyzed using mixed-effects models and quantile regression. RESULTS: Linear longitudinal trajectories describe the relatively stable impact of health conditions over time for each functional level for children aged 2 years to 12 years, with the lowest scores (least impact) in GMFCS level I and the highest scores (highest impact) in GMFCS level V. Centiles were created for children in each GMFCS level. A system to interpret the magnitude of change over time in centiles was developed. INTERPRETATION: Longitudinal trajectories of co-occurring health conditions assist with understanding children\u27s prognoses. Centiles assist in understanding a child\u27s experience relative to children in similar GMFCS levels. Guidelines are provided to determine if children are progressing \u27as expected\u27, \u27better than expected\u27 or \u27more poorly than expected\u27 in regard to the impact of health conditions on daily activities. WHAT THIS PAPER ADDS: For children with cerebral palsy, the mean impact of health conditions on daily activities is relatively stable. Significant intraindividual and interindividual variability for the impact of health conditions exists, which complicates prognosis. Centiles enable interpretation of the impact of health conditions relative to Gross Motor Function Classification System level

Intermediate stable states in substance use

Many people across the world use potentially addictive legal and illegal substances, but evidence suggests that not all use leads to heavy use and dependence, as some substances are used moderately for long periods of time. Here, we empirically examine, the stability of and transitions between three substance use states: zero-use, moderate use, and heavy use. We investigate two large datasets from the US and the Netherlands on yearly usage and change of alcohol, nicotine, and cannabis. Results, which we make available through an extensive interactive tool, suggests that there are stable moderate use states, even after meeting criteria for a positive diagnosis of substance abuse or dependency, for both alcohol and cannabis use. Moderate use of tobacco, however, was rare. We discuss implications of recognizing three states rather than two states as a modeling target, in which the moderate use state can both act as an intervention target or as a gateway between zero use and heavy use

FOXO1 controls protein synthesis and transcript abundance of mutant polyglutamine proteins, preventing protein aggregation

FOXO1, a transcription factor downstream of the insulin/insulin like growth factor axis, has been linked to protein degradation. Elevated expression of FOXO orthologs can also prevent the aggregation of cytosine adenine guanine (CAG)-repeat disease causing polyglutamine (polyQ) proteins but whether FOXO1 targets mutant proteins for degradation is unclear. Here, we show that increased expression of FOXO1 prevents toxic polyQ aggregation in human cells while reducing FOXO1 levels has the opposite effect and accelerates it. Although FOXO1 indeed stimulates autophagy, its effect on polyQ aggregation is independent of autophagy, ubiquitin–proteasome system (UPS) mediated protein degradation and is not due to a change in mutant polyQ protein turnover. Instead, FOXO1 specifically downregulates protein synthesis rates from expanded pathogenic CAG repeat transcripts. FOXO1 orchestrates a change in the composition of proteins that occupy mutant expanded CAG transcripts, including the recruitment of IGF2BP3. This mRNA binding protein enables a FOXO1 driven decrease in pathogenic expanded CAG transcript- and protein levels, thereby reducing the initiation of amyloidogenesis. Our data thus demonstrate that FOXO1 not only preserves protein homeostasis at multiple levels, but also reduces the accumulation of aberrant RNA species that may co-contribute to the toxicity in CAG-repeat diseases

Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases

Despite their apparent lack of catalytic activity, pseudokinases are essential signaling molecules. Here, we describe the structural and dynamic properties of pseudokinase domains from the Wnt-binding receptor tyrosine kinases (PTK7, ROR1, ROR2, and RYK), which play important roles in development. We determined structures of all pseudokinase domains in this family and found that they share a conserved inactive conformation in their activation loop that resembles the autoinhibited insulin receptor kinase (IRK). They also have inaccessible ATP-binding pockets, occluded by aromatic residues that mimic a cofactor-bound state. Structural comparisons revealed significant domain plasticity and alternative interactions that substitute for absent conserved motifs. The pseudokinases also showed dynamic properties that were strikingly similar to those of IRK. Despite the inaccessible ATP site, screening identified ATP-competitive type-II inhibitors for ROR1. Our results set the stage for an emerging therapeutic modality of "conformational disruptors" to inhibit or modulate non-catalytic functions of pseudokinases deregulated in disease.Peer reviewe

Interleukin-4 activated macrophages mediate immunity to filarial helminth infection by sustaining CCR3-dependent eosinophilia

Eosinophils are effectors in immunity to tissue helminths but also induce allergic immunopathology. Mechanisms of eosinophilia in non-mucosal tissues during infection remain unresolved. Here we identify a pivotal function of tissue macrophages (Mϕ) in eosinophil anti-helminth immunity using a BALB/c mouse intra-peritoneal Brugia malayi filarial infection model. Eosinophilia, via C-C motif chemokine receptor (CCR)3, was necessary for immunity as CCR3 and eosinophil impairments rendered mice susceptible to chronic filarial infection. Post-infection, peritoneal Mϕ populations proliferated and became alternatively-activated (AAMϕ). Filarial AAMϕ development required adaptive immunity and interleukin-4 receptor-alpha. Depletion of Mϕ prior to infection suppressed eosinophilia and facilitated worm survival. Add back of filarial AAMϕ in Mϕ-depleted mice recapitulated a vigorous eosinophilia. Transfer of filarial AAMϕ into Severe-Combined Immune Deficient mice mediated immunological resistance in an eosinophil-dependent manner. Exogenous IL-4 delivery recapitulated tissue AAMϕ expansions, sustained eosinophilia and mediated immunological resistance in Mϕ-intact SCID mice. Co-culturing Brugia with filarial AAMϕ and/or filarial-recruited eosinophils confirmed eosinophils as the larvicidal cell type. Our data demonstrates that IL-4/IL-4Rα activated AAMϕ orchestrate eosinophil immunity to filarial tissue helminth infection