A systematic review of interventions for echolalia in autistic children.

INTRODUCTION: Echolalia, the repetition of others' speech, is a common observation in autistic people. Research has established that echolalia is functional and meaningful for many; however, some clinicians and researchers continue to characterise it as pathological and in need of reduction. The aim of this systematic review was to understand the range and impact of interventions for echolalia in autistic children. METHOD: A systematic search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 15 studies met predetermined inclusion criteria. Screening, data extraction and quality rating using the Scientific Merit Rating Scale (SMRS) were performed in duplicate. RESULTS: Ten interventions across 15 papers were found. Results indicated that interventions generally decreased levels of echolalia. However, there were considerable inconsistencies in the definitions and conceptualisations of echolalia, administration, generalisation techniques and the measures used. The quality of the studies was very low. CONCLUSION: Interventions for echolalia vary widely in terms of administration and measurement. There is limited consensus on the definition of echolalia among the reviewed studies, and no evidence that echolalia is recognised as functional or meaningful to the autistic children. Further, the lack of methodological rigour makes it difficult to draw clinical conclusions about the interventions. WHAT THIS PAPER ADDS: What is already known Echolalia is the immediate or delayed repetition of others' speech and is a common observation in autistic children and in some older autistic people. While research and practice has established that echolalia is a functional and meaningful form of communication, particularly for those first developing spoken communication, some clinicians and researchers continue to characterise it as problematic and suggest that echolalia should be reduced or eliminated. What this study adds We systematically searched the literature about echolalia interventions to try to find out about the types of interventions that aim to reduce or eliminate echolalia. We found 15 studies on this topic. The way they defined echolalia was varied, and there was a range of interventions researched. None of the research papers recognised echolalia as functional or meaningful and the quality of the research was very low. What are the potential or actual clinical implications of this work? Clinicians, families and researchers should think carefully and critically about suggesting any programs or supports that aim to reduce echolalia as no recommendations can be drawn from the research we studied. Echolalia should be considered functional, and efforts made to understand the meaning and purpose of echolalic speech.

The identification of exceptional skills in school-age autistic children: Prevalence, misconceptions and the alignment of informant perspectives.

BACKGROUND: Although autism is commonly described in terms of deficits, many autistic individuals have been found to demonstrate exceptional skills. The shift to a strengths-based approach in the field of autism necessitates increased understanding of these skills. AIMS: This study examined (1) rates of exceptional skills in autistic school-age children as reported by parents and teachers, (2) associations between exceptional skills, autism severity and intellectual disability and (3) correlations between parent and teacher reports of exceptional skills. METHOD: Parents and teachers of 76 children attending autism-specific schools in Australia completed online questionnaires. Thereafter, 35 parents and teachers who identified their child as having one or more exceptional skills were interviewed by a clinical psychologist. RESULTS: Forty parents (53%) and 16 (21%) teachers reported that their child had at least one exceptional skill (agreement between the parent and teacher reports was low; κ = .03, p = .74). In comparison, clinical psychologist assessments identified 22 children (29%) as having at least one such skill. No statistically significant relationships were identified between exceptional skills, autism severity and intellectual disability. CONCLUSION: While different exceptional skills were identified, regardless of children's intellectual functioning or autism severity, parents and teachers varied substantially in their evaluations of these skills. Furthermore, the identified prevalence rates of exceptional skills did not always align with the rates identified in previous studies. The study findings highlight the need for definitional consensus on different types of exceptional skills, and the importance of multiple criteria/multi-instrument approaches in the identification of exceptional skills in autistic children.

Jarid2 promotes temporal progression of retinal progenitors via repression of Foxp1.

Transitions in competence underlie the ability of CNS progenitors to generate a diversity of neurons and glia. Retinal progenitor cells in mouse generate early-born cell types embryonically and late-born cell types largely postnatally. We find that the transition from early to late progenitor competence is regulated by Jarid2. Loss of Jarid2 results in extended production of early cell types and extended expression of early progenitor genes. Jarid2 can regulate histone modifications, and we find reduction of repressive mark H3K27me3 on a subset of early progenitor genes with loss of Jarid2, most notably Foxp1. We show that Foxp1 regulates the competence to generate early-born retinal cell types, promotes early and represses late progenitor gene expression, and is required for extending early retinal cell production after loss of Jarid2. We conclude that Jarid2 facilitates progression of retinal progenitor temporal identity by repressing Foxp1, which is a primary regulator of early temporal patterning.

Non-pharmacological interventions for autistic children: An umbrella review.

LAY ABSTRACT: What is already known about the topic?The delivery of evidence-based interventions is an important part of the clinical pathway for many autistic children and their families. However, parents, practitioners, and policymakers face challenges making evidence informed decisions, due to the wide variety of interventions available and the large, and often inconsistent, body of evidence regarding their effectiveness.What this paper adds?This is a comprehensive umbrella review, also known as a 'review of reviews', which examined the range of interventions available, the evidence for their effectiveness, and whether effects were influenced by factors relating to individual children (e.g. chronological age, core autism characteristics, and related skills) or the ways interventions were delivered (by whom and in what setting, format, mode, and amount). There was evidence for positive therapeutic effects for some, but not all, interventions. No single intervention had a positive effect for all child and family outcomes of interest. The influence of child and delivery characteristics on effects was unclear.Implications for practice, research, and policyThe findings provide parents, practitioners, and policymakers with a synthesis of the research evidence to inform decision-making and highlight the importance of individualised approaches in the absence of clear and consistent evidence. The findings also highlight the need to improve consistency and completeness in reporting of research studies, so that the same questions may be answered more comprehensively in the future.

Neuronal apoptosis drives remodeling states of microglia and shifts in survival pathway dependence.

Microglia serve critical remodeling roles that shape the developing nervous system, responding to the changing neural environment with phagocytosis or soluble factor secretion. Recent single-cell sequencing (scRNAseq) studies have revealed the context-dependent diversity in microglial properties and gene expression, but the cues promoting this diversity are not well defined. Here, we ask how interactions with apoptotic neurons shape microglial state, including lysosomal and lipid metabolism gene expression and dependence on Colony-stimulating factor 1 receptor (CSF1R) for survival. Using early postnatal mouse retina, a CNS region undergoing significant developmental remodeling, we performed scRNAseq on microglia from mice that are wild-type, lack neuronal apoptosis (Bax KO), or are treated with CSF1R inhibitor (PLX3397). We find that interactions with apoptotic neurons drive multiple microglial remodeling states, subsets of which are resistant to CSF1R inhibition. We find that TAM receptor Mer and complement receptor 3 are required for clearance of apoptotic neurons, but that Mer does not drive expression of remodeling genes. We show TAM receptor Axl is negligible for phagocytosis or remodeling gene expression but is consequential for microglial survival in the absence of CSF1R signaling. Thus, interactions with apoptotic neurons shift microglia toward distinct remodeling states and through Axl, alter microglial dependence on survival pathway, CSF1R.

Herpes zoster and Janus kinase inhibition in rheumatology and gastroenterology patients: managing risk and vaccination.

Patients with chronic inflammatory diseases, such as rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis (UC), have an increased risk of herpes zoster (HZ) infection, compared with the general population. This risk is further increased by the use of immunomodulatory therapies, with a higher incidence of HZ reported in patients receiving Janus kinase (JAK) inhibitors, compared with those receiving other immunomodulatory or biological therapies. Tofacitinib is an oral JAK inhibitor for the treatment of RA, PsA and UC. In this narrative review, we discuss the effects of tofacitinib and other JAK inhibitors on HZ risk in patients with RA, PsA and UC, and strategies for risk management. We also discuss current UK guidelines for HZ vaccination in healthy individuals and patients with chronic inflammatory diseases, consider selected international guidelines, and review current HZ vaccination strategies.

The 2018 Global Point Prevalence Survey of antimicrobial consumption and resistance in 47 Canadian hospitals: a cross-sectional survey.

BACKGROUND: Patient-level surveillance of antimicrobial use (AMU) in Canadian hospitals empowers the reduction of inappropriate AMU and was piloted in 2017 among 14 hospitals in Canada. We aimed to describe AMU on the basis of patient-level data in Canadian hospitals in 2018 in terms of antimicrobial prescribing prevalence and proportions, antimicrobial indications, and agent selection in medical, surgical and intensive care wards. METHODS: Canadian adult, pediatric and neonatal hospitals were invited to participate in the standardized web-based cross-sectional Global Point Prevalence Survey of Antimicrobial Consumption and Resistance (Global-PPS) conducted in 2018. An identified site administrator assigned all wards admitting inpatients to specific surveyors. A physician, pharmacist or nurse with infectious disease training performed the survey. The primary outcomes were point prevalence rates for AMU over the study period regarding prescriptions, indications and agent selection in medical, surgical and intensive care wards. The secondary outcomes were AMU for resistant organisms and practice appropriateness evaluated on the basis of quality indicators. Antimicrobial consumption is presented in terms of prevalence and proportions. RESULTS: Forty-seven of 118 (39.8%) hospitals participated in the survey; 9 hospitals were primary care centres, 15 were secondary care centres and 23 were tertiary or specialized care centres. Of 13 272 patients included, 33.5% (n = 4447) received a total of 6525 antimicrobials. Overall, 74.1% (4832/6525) of antimicrobials were for therapeutic use, 12.6% (n = 825) were for medical prophylaxis, 8.9% (n = 578) were for surgical prophylaxis, 2.2% (n = 143) were for other use and 2.3% (n = 147) were for unidentified reasons. A diagnosis or indication was documented in the patient's file at the initiation for 87.3% (n = 5699) of antimicrobials; 62.9% (n = 4106) of antimicrobials had a stop or review date; and 72.0% (n = 4697) of prescriptions were guided by local guidelines. INTERPRETATION: Overall, three-quarters of AMU was for therapeutic use across participating hospitals. Canadian hospitals should be further incentivized to create and adapt local guidelines on the basis of recent antimicrobial resistance data.

Transcriptional repression by FEZF2 restricts alternative identities of cortical projection neurons.

Projection neuron subtype identities in the cerebral cortex are established by expressing pan-cortical and subtype-specific effector genes that execute terminal differentiation programs bestowing neurons with a glutamatergic neuron phenotype and subtype-specific morphology, physiology, and axonal projections. Whether pan-cortical glutamatergic and subtype-specific characteristics are regulated by the same genes or controlled by distinct programs remains largely unknown. Here, we show that FEZF2 functions as a transcriptional repressor, and it regulates subtype-specific identities of both corticothalamic and subcerebral neurons by selectively repressing expression of genes inappropriate for each neuronal subtype. We report that TLE4, specifically expressed in layer 6 corticothalamic neurons, is recruited by FEZF2 to inhibit layer 5 subcerebral neuronal genes. Together with previous studies, our results indicate that a cortical glutamatergic identity is specified by multiple parallel pathways active in progenitor cells, whereas projection neuron subtype-specific identity is achieved through selectively repressing genes associated with alternate identities in differentiating neurons.

Prognostic value of comorbidity indices and lung diseases in early rheumatoid arthritis: a UK population-based study.

OBJECTIVES: We assessed comorbidity burden in people with RA at diagnosis and early disease (3 years) and its association with early mortality and joint destruction. The association between lung disease and mortality in RA is not well studied; we also explored this relationship. METHODS: From a contemporary UK-based population (n = 1, 475 762) we identified a cohort with incident RA (n = 6591). The prevalence of comorbidities at diagnosis of RA and at 3 years was compared with age- and gender-matched controls (n = 6591). In individuals with RA we assessed the prognostic value of the Charlson Comorbidity Index and Rheumatic Disease Comorbidity Index calculated at diagnosis for all-cause mortality and joint destruction (with joint surgery as a surrogate marker). We separately evaluated the association between individual lung diseases [chronic obstructive pulmonary disease (COPD), asthma and interstitial lung disease] and mortality. RESULTS: Respiratory disease, cardiovascular disease, stroke, diabetes, previous fracture and depression were more common (P < 0.05) in patients with RA at diagnosis than controls. Comorbidity (assessed using RDCI) was associated with all-cause mortality in RA [adjusted hazard ratio (HR) 1.26, 95% CI 1.00-1.60]. There was no association with joint destruction. COPD, but not asthma, was associated with mortality (COPD HR 2.84, 95% CI 1.13-7.12). CONCLUSION: There is an excess burden of comorbidity at diagnosis of RA including COPD, asthma and interstitial lung disease. COPD is a major predictor of early mortality in early RA. Early assessment of comorbidity including lung disease should form part of the routine management of RA patients.

Haematological abnormalities in new-onset rheumatoid arthritis and risk of common infections: a population-based study.

OBJECTIVES: To describe the prevalence of haematological abnormalities in individuals with RA at the point of diagnosis in primary care and the associations between haematological abnormalities, vaccinations and subsequent risk of common infections. METHODS: We studied 6591 individuals with newly diagnosed RA between 2004 and 2016 inclusive using the UK Royal College of General Practitioners Research and Surveillance Centre primary care database. The prevalence of haematological abnormalities at diagnosis (anaemia, neutropenia and lymphopenia) was established. Cox proportional hazards models were used to evaluate the association between each haematological abnormality and time to common infections and the influence of vaccination status (influenza and pneumococcal vaccine) on time to common infections in individuals with RA compared with a matched cohort of individuals without RA. RESULTS: Anaemia was common at RA diagnosis (16.1% of individuals), with neutropenia (0.6%) and lymphopenia (1.4%) less so. Lymphopenia and anaemia were associated with increased infection risk [hazard ratio (HR) 1.18 (95% CI 1.08, 1.29) and HR 1.37 (95% CI 1.08, 1.73), respectively]. There was no evidence of an association between neutropenia and infection risk [HR 0.94 (95% CI 0.60, 1.47)]. Pneumonia was much more common in individuals with early RA compared with controls. Influenza vaccination was associated with reduced risk of influenza-like illness only for individuals with RA [HR 0.58 (95% CI 0.37, 0.90)]. CONCLUSION: At diagnosis, anaemia and lymphopenia, but not neutropenia, increase the risk of common infections in individuals with RA. Our data support the effectiveness of the influenza vaccination in individuals with RA.

Systematic review of factors that may influence the outcomes and generalizability of parent-mediated interventions for young children with autism spectrum disorder.

Parent mediated interventions have the potential to positively influence the interactions and developmental outcomes of children with autism spectrum disorder (ASD). However, a range of factors relating to children, parents and caregivers, and study design may impact on outcomes and thus the generalizability of these interventions to the broader community. The objective of this review was to examine factors that may influence the feasibility, appropriateness, effectiveness, and generalizability of parent mediated interventions for children with ASD. We conducted a systematic review, yielding 41 articles. There was substantial variability in the intervention type, intensity, and study quality. Notably, 46 different inclusion/exclusion criteria were reported across studies including factors relating to children's development, access to other services, comorbidities, parental factors, and access to the intervention. Fifteen articles included examination of 45 different factors potentially associated with, or influencing, intervention outcomes including child (e.g., language skills, ASD severity, cognition) and parent (e.g., adherence and fidelity, education) factors. Although there is clear evidence for an increasingly sophisticated (e.g., systematic phased research for some interventions) and diverse (e.g., studies in geographical diverse contexts including low-resource communities) approach to research examining parent mediated interventions, there remains a need for improved study quality and measurement consistency in research, including a detailed examination of factors that may predict, moderate, and mediate intervention effectiveness for children and their parents. Autism Res 2019, 12: 1304-1321. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Parent mediated interventions-in which parents adapt their own behavior or deliver interventions to help their children learn-appear to be effective for some children with autism spectrum disorder. In this review, we identified a range of child, parent, and study design factors that may influence intervention outcomes and ultimately the uptake of these approaches in the community. We suggest that research in this area could be further improved by ensuring that studies include diverse groups of children and parents, and by using study designs that help to establish not only if interventions work, but for whom they work best and why.

The Developmental Behaviour Checklist (DBC) Profile in Young Children on the Autism Spectrum: The Impact of Child and Family Factors.

High levels of emotional/behavioural difficulties are frequently reported in children on the autism spectrum. However, given the diversity in profiles, there is a need to explore such behaviours in relation to individual factors. Parents of 130 children aged 4-5 on the autism spectrum completed measures of behaviour and adaptive behaviour. Hierarchical multiple regressions explored child and family characteristics in relation to children's emotional/behavioural presentation. Different aspects of the behavioural profile were associated with different factors, with child autism characteristics, medication use, and parent mental health making significant unique contributions to a range of behavioural subscales. Understanding individual profiles beyond total scores is therefore needed to truly understand the emotional and behavioural profile of specific subgroups.

Developmental Apoptosis Promotes a Disease-Related Gene Signature and Independence from CSF1R Signaling in Retinal Microglia.

Microglia have important remodeling functions in neurodevelopment, aging, and disease, with evidence for molecular diversity. However, the signaling pathways and environmental cues that drive diverse states of microglia are incompletely understood. We profiled microglia of a discrete developing CNS region, the murine retina. We found distinct transcriptional signatures for retinal microglia across development and peak postnatal density of a population that resembles aging and disease-associated microglia (DAM) and CD11c+ microglia of developing white matter. While TREM2 signaling modulates the expression of select genes, the DAM-related signature is significantly reduced in retinas lacking Bax, a proapoptotic factor required for neuronal death. Furthermore, we found postnatal retinal microglia highly expressing CD11c are resistant to loss or inhibition of colony stimulating factor 1 receptor (CSF1R), while most microglia can be eliminated in Bax knockout retina. Thus, developmental apoptosis promotes a microglia gene signature linked to CSF1R independence that shares features with microglia in developing white matter and in disease.

Telehealth and autism: Are telehealth language assessments reliable and feasible for children with autism?

BACKGROUND: Access to timely and appropriate speech-language pathology (SLP) services is a significant challenge for many families. Telehealth has been used successfully to treat a range of communication disorders in children and adults. Research examining the use of telehealth for children with autism has focused largely on diagnosis, parent-implemented interventions, and behavioural interventions involving interactions between clinicians and parents. There is, however, very limited research into the use of telehealth directly to assess or intervene with children with autism. This paper reports the outcomes of a study of telehealth language assessments with primary school-aged children with autism. AIMS: To evaluate the reliability and feasibility of telehealth language assessments for school-aged children with autism. METHODS & PROCEDURES: The language skills of 13 children with autism aged 9-12 who attended mainstream schools or support classes were assessed using the Clinical Evaluation of Language Fundamentals-4th Edition. An SLP delivered and scored four subtests of the assessment via telehealth from a remote location. A second SLP at the same location as the child co-scored the online subtests to provide a measure of reliability and delivered the remaining subtests. The local SLP completed checklists in both conditions to provide observations regarding behaviour. Parent feedback was elicited via survey. OUTCOMES & RESULTS: There was strong interrater reliability between the telehealth and face-to-face conditions (correlation coefficients ranged from r = 0.919 to 0.990 across the subtests and Core Language Score) and good agreement between clinicians on all measures. Analysis using the Wilcoxon Signed Rank test indicated no significant differences in children's behaviour between the telehealth and face-to-face conditions, although variation between individuals was observed. Parents provided generally positive feedback about the use of telehealth for the assessments. CONCLUSIONS & IMPLICATIONS: The findings of this study provide preliminary support the use of telehealth assessments of school-aged children with autism. Comparison of telehealth and face-to-face assessment scores showed high agreement and correlation, and while the children showed individual differences in their behaviour during the telehealth sessions, there was no clear difference between the conditions at the group level. The findings suggest that telehealth may present a reliable and feasible approach to the assessment of language for children with autism in some circumstances as a primary or adjunct service model, while acknowledging that individual differences among these children may be important to consider when planning both assessment and intervention via telehealth.

Anxiety-related symptomatology in young children on the autism spectrum.

Anxiety symptomatology is frequently reported in autistic children, and the prevalence of anxiety disorder is estimated at around 40%. However, most studies have focused upon children of age 8 years or above, so little is known about early signs of anxiety in younger children with autism. This study sought to describe anxiety-related symptomatology in 95 5- to 6-year-old autistic children using the Anxiety Scale for Children with Autism Spectrum Disorder. Wide variability was found in levels of symptomatology with the most frequently reported items within the 'uncertainty' subscale and the least frequently reported items in the 'anxious arousal' subscale. Comparisons of those with scores less than or greater than 70 on adaptive behaviour suggests some influence of ability on presentation of anxiety-related symptomatology.

Telehealth and autism: A systematic search and review of the literature.

PURPOSE: Research interest in telehealth and autism spectrum disorder (ASD) has grown. There is a need to review the literature to allow speech-language pathologists (SLPs) and other service providers to consider applicability to their settings. The aim of this review was to examine the nature and outcomes of studies examining telehealth assessment and/or intervention in ASD. METHOD: A systematic search of the literature was undertaken, with 14 studies meeting inclusion criteria. The authors extracted information from each included article, including participant characteristics, technology used, measures and reported outcomes. Quality review of articles was undertaken. RESULT: The 284 participants with ASD across the 14 included studies ranged in age from 19 months to adulthood. The quality of the studies varied. A range of services were provided via telehealth, including diagnostic assessments, early intervention and language therapy. Results suggested that services delivered via telehealth were equivalent to services delivered face to face, and superior to comparison groups without telehealth sessions. CONCLUSION: The findings suggest there may be a range of benefits in using telehealth with individuals with ASD, their families, and teachers. Further research, however, is required particularly regarding the use of telehealth directly with children with ASD for assessment and intervention.

From Retina to Stem Cell and Back Again: Memories of a Chromatin Journey.

The use of retinal organoids requires efficient differentiation from induced pluripotent stem cells (iPSCs). In this issue of Cell Reports, Wang et al. (2018) examine how the chromatin landscape after iPSC programming predicts their ability to differentiate into retinal tissue.

C8orf46 homolog encodes a novel protein Vexin that is required for neurogenesis in Xenopus laevis.

Neural basic helix-loop helix (bHLH) transcription factors promote progenitor cell differentiation by activation of downstream target genes that coordinate neuronal differentiation. Here we characterize a neural bHLH target gene in Xenopus laevis, vexin (vxn; previously sbt1), that is homologous to human c8orf46 and is conserved across vertebrate species. C8orf46 has been implicated in cancer progression, but its function is unknown. Vxn is transiently expressed in differentiating progenitors in the developing central nervous system (CNS), and is required for neurogenesis in the neural plate and retina. Its function is conserved, since overexpression of either Xenopus or mouse vxn expands primary neurogenesis and promotes early retinal cell differentiation in cooperation with neural bHLH factors. Vxn protein is localized to the cell membrane and the nucleus, but functions in the nucleus to promote neural differentiation. Vxn inhibits cell proliferation, and works with the cyclin-dependent kinase inhibitor p27Xic1 (cdkn1b) to enhance neurogenesis and increase levels of the proneural protein Neurog2. We propose that vxn provides a key link between neural bHLH activity and execution of the neurogenic program.

Protocol for a prospective longitudinal study investigating the participation and educational trajectories of Australian students with autism.

INTRODUCTION: Autism is associated with high cost to individuals, families, communities and government. Understanding educational and participation trajectories during the school years, and factors influencing these, is fundamental to reducing financial and personal costs. The primary aim of this study is to document the trajectories of Australian students with autism during their education. The secondary aim is to examine personal (eg, student skills) and environmental (eg, school setting) factors associated with differing trajectories and outcomes. METHODS AND ANALYSIS: The cross-sequential longitudinal study will recruit two cohorts of 120 parents/caregivers of children with autism. Cohort 1 aged between 4 and 5 years and cohort 2 between 9 and 10 years to start the study. Information will be gathered from parents, teachers and school principals at six annual time points (T1 to T6). Parents will be emailed a link to an online initial questionnaire (T1) and then contacted annually and asked to complete either an extended questionnaire (T3, T5 and T6) or an abbreviated questionnaire (T2, T4). Where consent is given, the child's current school will be contacted annually (T1 to T6) and teacher and school principal asked to complete questionnaires about the child and school. Parent and school questionnaires are comprised of questions about demographic and school factors that could influence trajectories and a battery of developmental and behavioural assessment tools designed to assess educational and participation trajectories and outcomes. Surveys will provide longitudinal data on educational and participation trajectories for children and adolescents with autism. In addition cross-sectional comparisons (within or between age groups) at each time point and cohort effects will be explored. ETHICS AND DISSEMINATION: Ethics approvals have been granted for this study by all recruiting sites and universities in the project. Study findings will inform policy and practice to promote successful inclusion and participation of children with autism in education. Results will be disseminated through journal publication, conference and seminar presentation.