The use of eye-tracking to explore social difficulties in cognitively able students with autism spectrum disorder: A pilot study

Individuals with autism spectrum disorder do not just 'grow out of' their early difficulties in understanding the social world. Even for those who are cognitively able, autism-related difficulties continue into adulthood. Atypicalities attending to and interpreting communicative signals from others can provide barriers to success in education, employment and relationships. In the current study, we use eye-tracking during real social interaction to explore attention to social cues (e.g. face, eyes, mouth) and links to social awareness in a group of cognitively able University students with autism spectrum disorder and typically developing students from the same University. During the interaction, students with autism spectrum disorder showed less eye fixation and more mouth fixation than typically developing students. Importantly, while 63% of typically developing participants reported thinking they were deceived about the true nature of the interaction, only 9% of autism spectrum disorder participants picked up this subtle social signal. We argue that understanding how these social attentional and social awareness difficulties manifest during adulthood is important given the growing number of adults with autism spectrum disorder who are attending higher level education. These adults may be particularly susceptible to drop-out due to demands of coping in situations where social awareness is so important.

Motor deficits in children with autism spectrum disorder: A cross-syndrome study

Recent research suggests that children with autism spectrum disorder (ASD) experience some level of motor difficulty, and that this may be associated with social communication skills. However, other studies show that children with language impairments, but without the social communication problems, are at risk of motor difficulties as well. The aim of the present study was to determine if children with ASD have syndrome specific motor deficits in comparison to children with specific language impairment (SLI). We used an independent groups design with three groups of children (8-10 years old) matched on age and nonverbal IQ; an ASD group, an SLI group, and a typically developing (TD) group. All of the children completed an individually administered, standardized motor assessment battery. We found that the TD group demonstrated significantly better motor skills than either the ASD or SLI groups. Detailed analyses of the motor subtests revealed that the ASD and SLI groups had very similar motor profiles across a range of fine and gross motor skills, with one exception. We conclude that children with ASD, and SLI, are at risk of clinically significant motor deficits. However, future behavioural and neurological studies of motor skills in children with ASD should include an SLI comparison group in order to identify possible autism specific deficits.

Reliability of reports of childhood trauma in bipolar disorder: A test–retest study over 18 months

This study aimed to explore the reliability of self-reported trauma histories in a population with a diagnosis of Bipolar Disorder using the Childhood Trauma Questionnaire. Previous studies in other populations suggest high reliability of trauma histories over time and it was postulated that a similar high reliability would be demonstrated in this population. Thirty-nine patients with a confirmed diagnosis (DSM-IV criteria) were followed-up and re-administered the Childhood Trauma Questionnaire after 18 months. Cohen's kappa scores and intraclass correlations suggest reasonable test-retest reliability over the 18-month time period of the study for all types of childhood abuse, namely emotional, physical, sexual, and physical abuse and emotional neglect. Intraclass correlations ranged from r = .50 to (sexual abuse) to r = .96 (physical abuse). Cohen's kappas ranged from .44 (sexual abuse) to .76 (physical abuse). Retrospective reports of childhood trauma can be seen as reliable and are in keeping with results found with other mental health populations.

INVESTIGATING THE ROLE OF NOX NADPH OXIDASE SIGNALLING IN CELL MIGRATION AND ANGIOGENESIS OF ENDOTHELIAL COLONY-FORMING CELLS

Introduction. Endothelial colony-forming cells (ECFCs) hold great cytotherapeutic potential for ischaemic disease. Emerging evidence supports a key role for NADPH oxidases in underlying angiogenic processes of these and other endothelial cells. Aims. To study the influence of Nox NADPH oxidases on the pro-angiogenic function of ECFCs. Methods. Human ECFCs isolated from umbilical cord blood were treated with pro-oxidant PMA and assessed in vitro, both under basal conditions and after siRNA knockdown of Nox4, a key endothelial NADPH oxidase isoform, alongside primary mature human aortic endothelial cells (HAoECs) for comparison, using an established scratch-wound assay as the functional end-point. Results. PMA (500nM for 8h) increased cell migration (control 18.6±2.8, PMA 32.7±6.6% wound closure; n=6, P<0.05) in a superoxide-dependent manner, as indicated by attenuation of this effect in the presence of PEG-SOD. Although HAoEC migration in response to PMA also tended to increase, this did not reach statistical significance. Notably, cell migration at 16h was reduced by Nox4 knockdown in ECFCs (control siRNA 53.4±3.5, Nox4 siRNA 35.1±4.9% closure; n=3, P<0.05), but not in HAoECs, whilst the pro-migratory effect of PMA in ECFCs was potentiated after Nox4 knockdown (control siRNA 53.4±3.5, +PMA 61.5±3.2% closure; n=3, P=NS; Nox4 siRNA 35.1±4.9, +PMA 53.0±4.9% closure; n=3, P<0.05). Conclusion. ECFC migration is enhanced by low concentrations of superoxide, to a greater extent compared to mature endothelial cells, and appears to be at least partly dependent upon NADPH oxidase, including a specific role for Nox4. Although, the precise contribution of endothelial Nox NADPH oxidases isoforms remains to be determined, it is clear that these findings may have significant implications for potential ECFC-based therapies for ischaemic disease, which is associated with an oxidative microenvironment.

EFFECTS OF ENVIRONMENTAL ANTIOXIDANTS ON PRO-ANGIOGENIC ROS SIGNALLING IN ENDOTHELIAL COLONY FORMING CELLS IN VITRO

Introduction. Endothelial colony-forming cells (ECFCs) hold great cytotherapeutic potential for ischaemic disease. Whilst increasing evidence supports a key role for reactive oxygen species (ROS), specifically those derived from Nox NADPH oxidases, in the underlying angiogenic processes of these and other endothelial cells, such studies investigating the role of redox signalling may be hampered by the standard inclusion of antioxidant agents in endothelial cell media, such as phenol red. Aims. To study the effects of antioxidants present in culture media on pro-angiogenic function of ECFCs in vitro. Methods. Human ECFCs isolated from umbilical cord blood were maintained in media with and without antioxidant components (EGM2 and phenol red-free DMEM, respectively) prior to treatment with pro-oxidant PMA and assessment of their in vitro migratory capacity using a scratch-wound assay to measure pro-angiogenic activity. Results. Our previous work in our group indicated that PMA (500nM) increased ECFC migration in a both a superoxide and NADPH oxidase-dependent manner (control 18.6±2.8, PMA 32.7±6.6% wound closure; n=6, P<0.05), as indicated by attenuation with PEG-SOD and VAS2870. However, inconsistencies in the data generated under varying experimental conditions led us to hypothesise that antioxidant agents in the standard ECFC media may be influencing these effects. Indeed, a direct comparison of cell migration between ECFCs incubated in EGM2 DMEM demonstrated a clear trend towards higher migration in the latter (EGM2 9.0±4.5, DMEM 22.7±6.4%; n=3, P=NS). Similar to our previous EGM2 studies, cell migration was potentiated by PMA (control 11.6±1.6, PMA 25.1±2.8%; n=3, P<0.05), but at a lower dose (100nM), which is consistent with a reduction in media antioxidants. Notably, this response was attenuated by VAS2870 (PMA 37.6±7.3, PMA+VAS2870 10.3±2.9%; n=6, P<0.05), underlining a likely role for Nox NADPH oxidases. Conclusion. Taken together, these data indicate that ECFC migration is sensitive to different endothelial cell growth media, which appears to be dependent upon their antioxidant content. Although further experiments, such as quantification of cellular superoxide generation by dihydroethidium fluorescence may be required to confirm a specific role for antioxidants, such blunting of ROS signalling in vitro is clearly an important consideration which may significantly impact upon data interpretation.

Applied behaviour analysis: What do teachers of students with autism spectrum disorder know

With rising numbers of school-aged children with autism educated in mainstream classrooms and applied behaviour analysis (ABA) considered the basis of best practice, teachers’ knowledge in this field has become a key concern for inclusion. Self-reported knowledge of ABA of special needs teachers (n=165) was measured and compared to their actual knowledge of ABA demonstrated in accurate responses to a multiple-choice test. Findings reported here show that teachers’ self-perceived knowledge exceeded actual knowledge and that actual knowledge of ABA was not related to training received by government agency. Implications for teacher training are discussed.

Systematic review of tools to measure outcomes for young children with autism spectrum disorder

BACKGROUND: The needs of children with autism spectrum disorder (ASD) are complex and this is reflected in the number and diversity of outcomes assessed and measurement tools used to collect evidence about children's progress. Relevant outcomes include improvement in core ASD impairments, such as communication, social awareness, sensory sensitivities and repetitiveness; skills such as social functioning and play; participation outcomes such as social inclusion; and parent and family impact.

OBJECTIVES: To examine the measurement properties of tools used to measure progress and outcomes in children with ASD up to the age of 6 years. To identify outcome areas regarded as important by people with ASD and parents.

METHODS: The MeASURe (Measurement in Autism Spectrum disorder Under Review) research collaboration included ASD experts and review methodologists. We undertook systematic review of tools used in ASD early intervention and observational studies from 1992 to 2013; systematic review, using the COSMIN checklist (Consensus-based Standards for the selection of health Measurement Instruments) of papers addressing the measurement properties of identified tools in children with ASD; and synthesis of evidence and gaps. The review design and process was informed throughout by consultation with stakeholders including parents, young people with ASD, clinicians and researchers.

RESULTS: The conceptual framework developed for the review was drawn from the International Classification of Functioning, Disability and Health, including the domains 'Impairments', 'Activity Level Indicators', 'Participation', and 'Family Measures'. In review 1, 10,154 papers were sifted - 3091 by full text - and data extracted from 184; in total, 131 tools were identified, excluding observational coding, study-specific measures and those not in English. In review 2, 2665 papers were sifted and data concerning measurement properties of 57 (43%) tools were extracted from 128 papers. Evidence for the measurement properties of the reviewed tools was combined with information about their accessibility and presentation. Twelve tools were identified as having the strongest supporting evidence, the majority measuring autism characteristics and problem behaviour. The patchy evidence and limited scope of outcomes measured mean these tools do not constitute a 'recommended battery' for use. In particular, there is little evidence that the identified tools would be good at detecting change in intervention studies. The obvious gaps in available outcome measurement include well-being and participation outcomes for children, and family quality-of-life outcomes, domains particularly valued by our informants (young people with ASD and parents).

CONCLUSIONS: This is the first systematic review of the quality and appropriateness of tools designed to monitor progress and outcomes of young children with ASD. Although it was not possible to recommend fully robust tools at this stage, the review consolidates what is known about the field and will act as a benchmark for future developments. With input from parents and other stakeholders, recommendations are made about priority targets for research.

FUTURE WORK: Priorities include development of a tool to measure child quality of life in ASD, and validation of a potential primary outcome tool for trials of early social communication intervention.

STUDY REGISTRATION: This study is registered as PROSPERO CRD42012002223.

FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Aims of education and well-being as absence of disorder

This thesis offers an original account of what personal well-being can be. Any account of education, it is believed, has to do with and aims at personal well-being. I approach this view on well-being not in a positive but in a negative way. I put forward some items that in certain circumstances can be taken by and called sources or forms of disorder. In the absence of such forms or sources of disorder, I assume that a certain order, prudential or moral, takes place and that constitutes the well-being of the person. The concept of ‘absence of disorder’ is introduced and argued as an educationally appropriate view of personal well-being which is the central educational aim. Therefore, ‘absence of disorder’ is positioned as the central aim of education. This concept is illuminated, for practical reasoning, by a list of seven possible forms of disorder: Comparison, Corruption, Dependency, Division, Fear, Self-disintegration and Violence. As a view of personal well-being, ‘absence of disorder’ is initially rooted in informed desire satisfaction, via the introduction of the concept of entropy. Prudentially, the agent’s informed desire is satisfied by living a life with low build up of entropy or disorder. But, in a second move such a base is also provided by the Levinasinian concept of ‘disinterest’ as a root for ‘what is to be a human’. Such ‘disinterest’ is related to the concepts of love and of ‘action for its own sake’. It is at this final approach that an attempt is made towards the approximation of the ethical and the prudential aspects of social practices. Even if only to some extent successful, the argument is directed to the following conclusion: an education aiming at ‘absence of disorder’ may promote prudential well-being and give us some confidence in simultaneously favouring moral education.

Impact of an evidence-based online module on best practice in physical therapy for children with developmental coordination disorder: a mixed methods study

Aims : This study evaluates the impact of a Developmental Coordination Disorder (DCD) evidence-based online module including synthesized resources, practical strategies, and interactive component on self-reported physical therapist (PT) knowledge, skills, and practice. Methods : PTs from across Canada completed questionnaires before, immediately after, and 2 months following completion of the module. Questionnaires used 7-point Likert scale items and short open-ended questions; analyzes used paired t-tests and a thematic approach. Results : Fifty PTs completed both pre- and post-questionnaires; 41 of these completed the follow-up questionnaire. Most items (79%) evaluating self-reported knowledge and skills increased significantly following module completion and this increase was maintained two months later. Most participants (92%) reported an increase in their confidence to provide DCD evidence-based services. Participants plan to modify their evaluative practices (e.g., involving children in goal setting) and their management of DCD (e.g., using best practice principles, providing resources to families and physicians). At the 2- month follow-up, 46% of participants had returned to the module to review information (e.g., video, resources) or to download handouts. Conclusion : An online module developed collaboratively with PTs has the potential not only to increase PTs’ knowledge, but also to support them in implementing evidence-based services for children with DCD.

Working with physical therapists to develop and evaluate an evidence-based online module for Developmental Coordination Disorder (DCD): bridging the knowledge-to-practice gap

Aims: Developmental Coordination Disorder (DCD) is a chronic condition with potential negative health consequences. Clinicians working with children with DCD need access to tailored, synthesized, evidence-based DCD information; however a knowledge-to-practice gap exists. The aim of this study was to develop and evaluate an evidence-based online DCD module tailored to physical therapists’ (PTs) identified needs. Methods: Guided by the Knowledge to Action framework, we interviewed PTs working with children with DCD (n=9) to identify their information needs. Their recommendations, along with synthesized DCD research evidence, informed module development. PTs (n=50) responded to scaled items and open-ended questions to evaluate module usefulness. Results: The module incorporated important PT DCD content areas including: 1) Identification; 2) Planning Interventions and Goals; 3) Evidence-Based Practice; 4) Management; and, 5) Resources. Case scenarios, clinical applications, interactive media, links to resources, and interactive learning opportunities were also embedded. PTs perceived the module to be comprehensive and useful and provided feedback to improve module navigation. Conclusions: Involving end-users throughout the development and evaluation of an online PT DCD module contributed to its relevance, applicability, and utility. The ongoing clinical use of this module may have the potential to improve the quality of PT DCD services.

Genome-wide Association Study Identifies SESTD1 as a Novel Risk Gene for Lithium Responsive Bipolar Disorder

Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10-8). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.

A Retrospective Claims Analysis of Medication Adherence and Persistence Among Patients Taking Antidepressants for the Treatment of Major Depressive Disorder (MDD)

Thesis (Master's)--University of Washington, 2015