Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Functional communication training and prelinguistic communication behaviour of children with autism

Many idiosyncratic and subtle behaviours of children with autism are now seen as having potential communicative significance, even though they may begin as reflexive or nonpurposeful responses. the study of these prelinguistic communicative behaviours in normally developing children has been of interest for some time. There is growing interest in the communicative potential of prelinguistic behaviours in children with developmental disabilities. the present article reviews some of the behaviourally based research in this area and discusses the links between prelinguistic communication development and functional communica-tion training in children with autism. Theoretical and practical implica-tions are considered and areas for future research are highlighted

Behaviour state analysis in Rett syndrome: Continuous data reliability measurement

Awareness of optimal behaviour states of children with profound intellectual disability has been reported in the literature as a potentially useful tool for planning intervention within this population. Some arguments have been raised, however, which question the reliability and validity of previously published work on behaviour state analysis. This article sheds light on the debate by presenting two stages of a study of behaviour state analysis for eight girls with Rett syndrome. The results support Mudford, Hogg, and Roberts' (1997, 1999) concerns with the pooling of participant data. The results of Stage 2 also suggest, however, that most categories of behaviour state can be reliably distinguished once definitions of behaviours for each state are clearly defined

Investigating adult language input and young children's responses in naturalistic environments: An Observational Framework

This paper reports the design and trial of an original Observational Framework for quantitative investigation of young children's responses to adult language in their typical language learning environments. The Framework permits recording of both the response expectation of the adult utterances, and the degree of compliance in the child's responses. The former are evaluated under the categories of Response Required (RR), Response Not Required (RNR), and Other Directed (OD) spoken to a child other than the one who responds); the latter, based on both verbal and non-verbal behaviours, as Compliance (correct in the context), Valid (correct in another context), Ambiguous (unable to be classified), Acknowledgement, Inappropriate and No Response. Details are given for the initial application of the Observational Framework with 10 children in two- or three-year-old childcare centre classrooms. The findings that RR utterances in the adult input were more frequently addressed to younger children, while RNR utterances were more prevalent in the older classroom are discussed in terms of both adult and child communicative behaviours and the practicality of using the Observational Framework in naturalistic conditions

Phonological awareness skills in young boys with Duchenne muscular dystrophy

Substantial research has detailed the reading deficits experienced by children with Duchenne muscular dystrophy (DMD). Although phonological awareness (PA) is vital in reading development, little is known about PA in the DMD population. This pilot study describes the PA abilities of a group of five young children with DMD, comparing the results with those of a group of children with spinal muscular atrophy and with those of a group of typically developing children. The Preschool and Primary Inventory of Phonological Awareness was used to assess the PA skills of the participants. Results indicated that the children with DMD performed significantly poorer than the typically developing group on tests of Syllable Segmentation, Rhyme Awareness, Alliteration Awareness and Phoneme Isolation and significantly poorer than the spinal muscular atrophy group on Rhyme Awareness. The findings of this pilot study indicate that children with DMD may have an increased risk of having PA difficulties, thus requiring early PA training

Linguistic abilities in children with autism spectrum disorder.

Background: Two broad approaches have been used to examine linguistic skills in Asperger syndrome (AS) and high functioning autism (HFA). One approach has aimed at determining the external validity of each diagnosis by investigating whether developmental language history, which differentiates AS from HFA, is relevant in long-term linguistic outcomes. An alternative approach, viewing AS and HFA as presentations on an autism spectrum (ASD), has investigated subgroups within the spectrum based on linguistic performance. Neither approach, however, has provided an in-depth description of the linguistic difficulties experienced in ASD necessary for therapy planning. Purpose: To provide clinically applicable research findings to extend the clinical understanding of the linguistic difficulties in ASD by: (1) comparing the linguistic skills in ASD with those of normally developing controls; (2) comparing the linguistic skills of children with ASD re-classified as AS and HFA using DSM-IV language criterion; (3) documenting the heterogeneity within a group of children with ASD by investigating within-group differences. Methods and procedures: Twenty children (aged 9; 0-17; 1 years) with a diagnosis of ASD were assessed using the Clinical Evaluation of Language Fundamentals-Fourth Edition (CELF-4) and the Test of Nonverbal Intelligence-Second Edition (TONI-2). Performance by ASD participants was compared to typically developing peers. Re-classification of individuals with ASD as AS or HFA was undertaken using DSM-IV language criterion to determine between-group differences on linguistic measures. Hierarchical cluster analysis was undertaken using the ASD performance on the CELF-4 to examine within-group differences based on linguistic abilities. Outcomes and results: There were significant differences between the ASD children and normally developing peers on a range of linguistic measures. There were no significant differences between the children re-classified as AS and HFA on the comprehensive linguistic assessment. Subgroups within ASD, based on linguistic performance, could be identified. Conclusions and implications: Collectively, the children with ASD in the study had a range of compromised linguistic skills relative to their peers. Children re-classified as AS could not be differentiated from children re-classified as HFA on current linguistic performance. An examination of subgroups of ASD participants revealed the heterogeneous nature of the linguistic skills associated with ASD, where linguistic proficiency ranged from above average performance to severe difficulties. The results of the study are discussed in terms of the clinical applicability of the findings