The effectiveness and tolerability of pharmacotherapy for psychosis in 22q11.2 Deletion Syndrome: A systematic review.

OBJECTIVE: The 22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion in humans with over 180 phenotypic expressions. Approximately 30-40% of affected individuals will develop psychosis and 25% meet the criteria for schizophrenia. Despite this, pharmacotherapy for managing psychosis in 22q11.2DS is poorly understood and 22q11.2DS psychosis is frequently labelled as treatment resistant. The objectives of this paper are to evaluate the effectiveness and tolerability of pharmacotherapy for 22q11.2DS psychosis and evaluate the evidence for treatment resistance. METHOD: A systematic search was performed using CINAHL, The Cochrane Library (Cochrane Database of Systematic Reviews; Cochrane Central Register of Controlled Trials and Cochrane Clinical Answers), EMBASE, PsycINFO, PubMed, Scopus and Web of Science Core Collection from inception to December 2022. It yielded 39 case reports, 6 case series and 1 retrospective study which met the inclusion criteria. RESULTS: Based on the current literature, individuals with 22q11.2DS psychosis experience a greater rate of medical co-morbidities such as cardiac arrhythmias, seizures and movement disorders, which complicate pharmacotherapy. Poor tolerability rather than poor clinical response motivates the switching of antipsychotics, which may explain the labelling of treatment resistance in the literature. CONCLUSION: There are insufficient data to recommend a single antipsychotic for 22q11.2DS psychosis. Nonetheless, with proactive management of co-morbidities, antipsychotic medication in 22q11.2DS psychosis is an effective treatment commonly resulting in improvement in quality of life.

Exploring the experience of service users following attendance at a student-led interprofessional neurodevelopmental clinic.

PURPOSE: The aim of the current study was to understand service users' experiences at a recently established student-led interprofessional neurodevelopmental clinic for children and adolescents with suspected or confirmed prenatal alcohol exposure. METHOD: Semi-structured interviews were completed at 3-months post-clinic attendance with 10 service users: eight parents/caregivers and two youth workers/case managers. Interview data were analysed thematically using NVivo12. RESULTS: Four main themes were developed: (1) clinic attendance seen as a positive event; (2) validation, clarification, and relief, but also challenges post-assessment; (3) need for further support and importance of advocacy; and (4) drawing on lived experiences for future service improvements. CONCLUSIONS: The current study demonstrated that service users reported benefits from tailored services delivered by student practitioners that were validating, supportive, and holistic. Findings from the current study can inform the development and implementation of future innovative service delivery models for individuals with suspected or confirmed prenatal alcohol exposure.

People with fetal alcohol spectrum disorder (FASD) can experience a range of neurocognitive impairments that impact their day-to-day living.Access to assessment, early diagnosis, and appropriate supports are important protective factors associated with improved outcomes for individuals with FASD.Results highlighted the benefits to rehabilitation professionals of listening to service users to understand the complexity of their lived experiences, including how this information can be used to improve service design and delivery.Results also highlighted the potential role of incorporating student-led clinics within models of healthcare and rehabilitation service delivery.Utilising student-led clinics can help to increase access to specialised services for underserved groups in our community, combat shortages in the health workforce, reduce burden on the public health system, and educate the future of rehabilitation professionals.

Longitudinal change in sleep, functional, and behavioural characteristics in a cohort of children with Down syndrome.

This paper describes the longitudinal change in sleep, functional, and behavioural characteristics in a cohort of children with Down syndrome, including the effect of sleep interventions in a subset. A prospective longitudinal cohort study was undertaken in children with Down syndrome aged 3-16 years comparing (1) children referred to a tertiary sleep medicine clinic who received sleep hygiene advice and an additional sleep treatment (DSref_I) with (2) children attending the same clinic who only received sleep hygiene advice (DSref_N) and (3) children recruited from the community who, were not receiving any treatment (DScomm). Data collected included demographic and medical history information, Child Sleep Habits Questionnaire-Abbreviated (CSHQ-A), Life-Habits Questionnaire (Life-H) and Child Behaviour Checklist (CBCL) at baseline and then 6-monthly for a total of 18 months. Any sleep interventions during this time were recorded. A total of 57 children were included (DSref_I, n = 16; DSref_N, n = 25; DScomm, n = 16). At recruitment, the median CSHQ-A total score was high (>41) in all three subgroups, but highest in the DSref_I subgroup (median [interquartile range] Dsref_I score 58 [53-66] versus DSref_N score 49 [43-53], p = 0.019). Although improved, 80% of participants in the DSref_I subgroup still had a CSHQ-A total score >41 at the last assessment point. The median total Life-H and total CBCL scores were not significantly different between groups at baseline and there was no significant time, group, or interaction effect seen through the study. Over an 18-month period, sleep problems were seen to persist in children with Down syndrome. Treatment resulted in only modest improvements in sleep.

Does the registry speak your language? A case study of the Global Angelman Syndrome Registry.

Global disease registries are critical to capturing common patient related information on rare illnesses, allowing patients and their families to provide information about their condition in a safe, accessible, and engaging manner that enables researchers to undertake critical research aimed at improving outcomes. Typically, English is the default language of choice for these global digital health platforms. Unfortunately, language barriers can significantly inhibit participation from non-English speaking participants. In addition, there is potential for compromises in data quality and completeness. In contrast, multinational commercial entities provide access to their websites in the local language of the country they are operating in, and often provide multiple options reflecting ethnic diversity. This paper presents a case study of how the Global Angelman Syndrome Registry (GASR) has used a novel approach to enable multiple language translations for its website. Using a "semi-automated language translation" approach, the GASR, which was originally launched in English in September 2016, is now available in several other languages. In 2020, the GASR adopted a novel approach using crowd-sourcing and machine translation tools leading to the availability of the GASR in Spanish, Traditional Chinese, Italian, and Hindi. As a result, enrolments increased by 124% percent for Spain, 67% percent for Latin America, 46% percent for Asia, 24% for Italy, and 43% for India. We describe our approach here, which we believe presents an opportunity for cost-effective and timely translations responsive to changes to the registry and helps build and maintain engagement with global disease communities.

Gaboxadol in angelman syndrome: A double-blind, parallel-group, randomized placebo-controlled phase 3 study.

PURPOSE: To evaluate efficacy and safety of gaboxadol for treatment of children with Angelman syndrome (AS). METHOD: In this international, double-blind, phase 3 trial, we randomized children 4-12 years old with a molecular diagnosis of AS and a Clinical Global Impression (CGI)-severity score ≥3 to either daily administration of weight-based gaboxadol or matching placebo for 12 weeks. The primary endpoint was the CGI-Improvement-AS (CGI-I-AS) score at week 12. Secondary endpoints included the proportion of participants with CGI-I-AS response of ≤3 (i.e., at least "minimal improvement") and ≤2 (i.e., at least "much improvement") at week 12. Safety and tolerability were monitored throughout the study. Weight based dosing of study drug ranged from 0.125 mg/kg to 0.24 mg/kg depending on weight range. RESULTS: Between August 2019 and November 2020, 104 participants were enrolled: participants 4-12 years old were randomly (1:1) assigned to gaboxadol (n = 47) or placebo (n = 50), and 7 other participants 2─3 years old who received gaboxadol and were assessed for safety only. All gaboxadol-treated participants and 48 of 50 placebo-treated participants completed treatment. There was no significant difference in CGI-I-AS between groups: at week 12, mean CGI-I-AS score was 3.3 (SD, 1.00) and 3.2 (SD, 1.05) in the gaboxadol and placebo groups, respectively, yielding a least squares mean difference of zero (p = 0.83). There were no between-group significant differences with respect to CGI-I-AS responses. Gaboxadol was well tolerated in all age groups of this study. CONCLUSIONS: There was no significant difference in CGI-I-AS between gaboxadol and placebo after 12 weeks of study treatment in pediatric AS participants. CLINICALTRIALS: GOV: NCT04106557.

Understanding the Perspective of Youths on Undergoing Metabolic Monitoring While on Second-Generation Antipsychotics: Challenges, Insight, and Implications.

Introduction: Prescription of second-generation antipsychotics (SGAs) in youths is rapidly increasing globally, despite the potential for significant adverse effects and long-term health consequences. A known adverse reaction resulting from SGAs is metabolic syndrome (MS). Youths exposed to antipsychotics are at higher risk than adults for adverse drug reactions, including adverse events such as MS (with weight gain as the most significant adverse outcome) and other long-term endocrinological abnormalities. This study aimed to explore the experiences of young patients on factors impacting barriers to metabolic monitoring of SGAs and the strategies to address those barriers thereby providing further guidance on policy and service delivery. Methods: Semi-structured interviews were conducted with patients (youths who were prescribed SGAs) who attended Child and Youth Mental Health Services. The interviews focused on barriers to monitoring and strategies to enhance rates of monitoring that could be customized across study sites. Results: Young patients revealed that none of them had any concerns or objections to receiving anthropometric metabolic measurements. However, they seemed concerned to undergo blood tests as part of the metabolic monitoring process. Specifically, youths cited their fear of the needles as barrier to undergo the required blood tests. Youths have also reported that their dislike to healthy foods and exercise being the most common challenge they face while trying to engage in a healthy lifestyle to manage the SGAs resulted weight gain. Conclusion: Prescribers are recommended to actively engage young patients about the expected SGAs-induced adverse effects, the importance of conducting metabolic monitoring, and how to prevent and minimize the expected adverse effects from the start of initiating SGAs. This could be a vital step toward a successful treatment as the insight of youths into the details of the chosen treatment can play a significant role into treatment adherence and recovery.

Interactions between the lipidome and genetic and environmental factors in autism.

Autism omics research has historically been reductionist and diagnosis centric, with little attention paid to common co-occurring conditions (for example, sleep and feeding disorders) and the complex interplay between molecular profiles and neurodevelopment, genetics, environmental factors and health. Here we explored the plasma lipidome (783 lipid species) in 765 children (485 diagnosed with autism spectrum disorder (ASD)) within the Australian Autism Biobank. We identified lipids associated with ASD diagnosis (n = 8), sleep disturbances (n = 20) and cognitive function (n = 8) and found that long-chain polyunsaturated fatty acids may causally contribute to sleep disturbances mediated by the FADS gene cluster. We explored the interplay of environmental factors with neurodevelopment and the lipidome, finding that sleep disturbances and unhealthy diet have a convergent lipidome profile (with potential mediation by the microbiome) that is also independently associated with poorer adaptive function. In contrast, ASD lipidome differences were accounted for by dietary differences and sleep disturbances. We identified a large chr19p13.2 copy number variant genetic deletion spanning the LDLR gene and two high-confidence ASD genes (ELAVL3 and SMARCA4) in one child with an ASD diagnosis and widespread low-density lipoprotein-related lipidome derangements. Lipidomics captures the complexity of neurodevelopment, as well as the biological effects of conditions that commonly affect quality of life among autistic people.

Impact of adenotonsillectomy on growth trajectories in preschool children with mild-moderate obstructive sleep apnea.

STUDY OBJECTIVES: Adenotonsillectomy (AT) forms part of first-line management for pediatric obstructive sleep apnea. In nonrandomized studies of preschool-aged children, postoperative weight gain has been seen following AT, raising concerns regarding later obesity. Using longitudinal data from a multicenter randomized controlled trial, we assessed the impact of AT on growth trajectories in preschool-aged children with mild-moderate obstructive sleep apnea. METHODS: A total of 190 children (aged 3-5 years) with obstructive apnea-hypopnea index ≤ 10 events/h were randomly assigned to early (within 2 months) or routine (12-month wait) AT. Anthropometry and polysomnography were performed at baseline, 12-month, and 24-month time points for 126 children. Baseline characteristics were compared using a Mann-Whitney or t test for continuous variables and Fisher's exact test for categorical variables. Longitudinal data underwent linear mixed modeling. RESULTS: For body mass index (BMI) z-score there was a significant increase in the early surgery group between 0 and 12 months (0.4, 95% confidence interval 0.1-0.8) but not from 12-24 months. For the routine surgery group there was an identical significant BMI z-score increase in the first 12 months following surgery, ie, between 12- and 24-month time points (0.45, 95% confidence interval 0.1-0.8) but not from 0-12 months (preoperative time). Final BMI z-score was similar between groups. Findings for weight-for-age z-score were similar to the findings for BMI z-score. Height-for-age z-score was not significantly different between different time points or intervention groups. CONCLUSIONS: This study provides randomized controlled trial evidence of notable, but time-limited, increase in the BMI and weight of preschool children with mild-moderate obstructive sleep apnea in the months immediately following AT. CLINICAL TRIAL REGISTRATION: Registry: Australian New Zealand Clinical Trials Registry; Name: POSTA Child Study (Preschool Obstructive Sleep Apnea Tonsillectomy Adenoidectomy Study); URL: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336273&isReview=true; Identifier: ACTRN12611000021976. CITATION: Kevat A, Bernard A, Harris M-A, et al. Impact of adenotonsillectomy on growth trajectories in preschool children with mild-moderate obstructive sleep apnea. J Clin Sleep Med. 2023;19(1):55-62.

A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX).

BACKGROUND: Fragile X syndrome (FXS) is associated with dysregulated endocannabinoid signaling and may therefore respond to cannabidiol therapy. DESIGN: CONNECT-FX was a double-blind, randomized phase 3 trial assessing efficacy and safety of ZYN002, transdermal cannabidiol gel, for the treatment of behavioral symptoms in children and adolescents with FXS. METHODS: Patients were randomized to 12 weeks of ZYN002 (250 mg or 500 mg daily [weight-based]) or placebo, as add-on to standard of care. The primary endpoint assessed change in social avoidance (SA) measured by the Aberrant Behavior Checklist-Community Edition FXS (ABC-CFXS) SA subscale in a full cohort of patients with a FXS full mutation, regardless of the FMR1 methylation status. Ad hoc analyses assessed efficacy in patients with ≥ 90% and 100% methylation of the promoter region of the FMR1 gene, in whom FMR1 gene silencing is most likely. RESULTS: A total of 212 patients, mean age 9.7 years, 75% males, were enrolled. A total of 169 (79.7%) patients presented with ≥ 90% methylation of the FMR1 promoter and full mutation of FMR1. Although statistical significance for the primary endpoint was not achieved in the full cohort, significant improvement was demonstrated in patients with ≥ 90% methylation of FMR1 (nominal P = 0.020). This group also achieved statistically significant improvements in Caregiver Global Impression-Change in SA and isolation, irritable and disruptive behaviors, and social interactions (nominal P-values: P = 0.038, P = 0.028, and P = 0.002). Similar results were seen in patients with 100% methylation of FMR1. ZYN002 was safe and well tolerated. All treatment-emergent adverse events (TEAEs) were mild or moderate. The most common treatment-related TEAE was application site pain (ZYN002: 6.4%; placebo: 1.0%). CONCLUSIONS: In CONNECT-FX, ZYN002 was well tolerated in patients with FXS and demonstrated evidence of efficacy with a favorable benefit risk relationship in patients with ≥ 90% methylation of the FMR1 gene, in whom gene silencing is most likely, and the impact of FXS is typically most severe. TRIAL REGISTRATION: The CONNECT-FX trial is registered on Clinicaltrials.gov (NCT03614663).

Specialist care of children with complex needs: Insights from comparison of child development and child mental health clinics.

AIM: Paediatricians and child psychiatrists review children with complex comorbidity, noting similarities between tertiary Child Development Service (CDS) and Child and Youth Mental Health Service (CYMHS) cohorts. Mental health comorbidity is common in developmental services. Developmental comorbidity in mental health cohorts is uncharacterised. The study aimed to describe CDS and CYMHS cohorts using measures of child development, mental health, physical health and psychosocial risk. METHODS: A questionnaire was completed by parents of CDS and CYMHS new clients aged 4-11. It included measures of mental health symptoms, child development, physical health, stressful life events, family functioning, parent mental health and socio-economic variables. Sample rates were compared to population norms. CDS and CYMHS cohorts were compared. RESULTS: The study population had elevated rates of psychosocial risk, family dysfunction, physical illness, developmental risk and mental health symptoms. CDS had higher levels of developmental risk and family dysfunction. Most CDS clients (81%) had mental health difficulties. CYMHS clients were older, and had more mental health symptoms, stressful life events and child safety contact; 81% of CYMHS clients demonstrated developmental risk. CDS and CYMHS had similar socio-demographic profiles and parent mental health difficulties, and similarly high rates of physical health problems. CONCLUSIONS: Consideration should be given to mental health screening and support in CDS, and to developmental screening in CYMHS. Both services support at-risk children with complex developmental, mental health and physical co-morbidity necessitating shared approaches to clinical and population health, including care integration, and collaborative cross-disciplinary models of service provision and training, and advocacy.

Watch me grow integrated (WMG-I): protocol for a cluster randomised controlled trial of a web-based surveillance approach for developmental screening in primary care settings.

INTRODUCTION: The increasing prevalence of developmental disorders in early childhood poses a significant global health burden. Early detection of developmental problems is vital to ensure timely access to early intervention, and universal developmental surveillance is recommended best practice for identifying issues. Despite this, there is currently considerable variation in developmental surveillance and screening between Australian states and territories and low rates of developmental screening uptake by parents. This study aims to evaluate an innovative web-based developmental surveillance programme and a sustainable approach to referral and care pathways, linking primary care general practice (GP) services that fall under federal policy responsibility and state government-funded child health services. METHODS AND ANALYSIS: The proposed study describes a longitudinal cluster randomised controlled trial (c-RCT) comparing a 'Watch Me Grow Integrated' (WMG-I) approach for developmental screening, to Surveillance as Usual (SaU) in GPs. Forty practices will be recruited across New South Wales and Queensland, and randomly allocated into either the (1) WMG-I or (2) SaU group. A cohort of 2000 children will be recruited during their 18-month vaccination visit or opportunistic visit to GP. At the end of the c-RCT, a qualitative study using focus groups/interviews will evaluate parent and practitioner views of the WMG-I programme and inform national and state policy recommendations. ETHICS AND DISSEMINATION: The South Western Sydney Local Health District (2020/ETH01625), UNSW Sydney (2020/ETH01625) and University of Queensland (2021/HE000667) Human Research Ethics Committees independently reviewed and approved this study. Findings will be reported to the funding bodies, study institutes and partners; families and peer-reviewed conferences/publications. TRIAL REGISTRATION NUMBER: ANZCTR12621000680864.

Practitioners' Perspective on Metabolic Monitoring of Second-Generation Antipsychotics: Existing Gaps in Knowledge, Barriers to Monitoring, and Strategies.

Introduction: Prescription of second-generation antipsychotics (SGAs) in youth is rapidly increasing globally and in Australia. Lack of timely metabolic monitoring for potential adverse effects puts youth at greater risk for lifelong adverse health impact. Metabolic monitoring is recommended as best practice to prevent and/or manage SGA-induced weight gain/metabolic syndrome. The adherence to clinical guidelines remains suboptimal. It is crucial to gauge insight to challenges and strategies from the perspective of prescribers and to recommend strategies in promoting quality use of SGAs and adherence to pharmacovigilance standards. Methods: Psychiatrists participated through semistructured interviews within the community mental health clinics in the Queensland State of Australia. The interviews focused on barriers to monitoring and strategies to enhance rate of monitoring with key focus on practical strategies for future implications in community setting. Results: Ten participants completed the interviews. Barriers were specified such as lack of adequate resources to conduct monitoring, carers' disengagement in their youth's treatments, and patients' refusal to undergo blood tests. Strategies to enhance metabolic monitoring heavily relied on organizational support, provision of training, and education opportunities. Conclusions: Clinical recommendations require mental health providers to facilitate conduction of metabolic monitoring among youth prescribed SGA/s. However, they are not provided with enough support and there are challenges that prevent such care. It is crucial to understand the challenges in managing a complex and vulnerable patient cohort. This research has thrown light on these key aspects of existing gap between best practice standards and clinical practice in youth prescribed SGAs.

Clinical and behavioral attributes leading to sleep disorders in children on the autism spectrum.

Sleep disorders are a common comorbid condition in children diagnosed with autism spectrum disorder ("autism"). However, the relationship between the clinical features of autism and sleep disorders remains unclear. A better understanding of the inherent autism-related characteristics linked to comorbid sleep disorders would improve comprehensive assessment and management. This study examined the relationship between sociodemographics, autism symptoms, sleep problems, cognitive status, behavioral attributes, and sensory profiles. Using data from 1268 participants who took part in the Australian Autism Biobank, sleep-related measurements using the Child Sleep Habits Questionnaire (CSHQ) were compared between autistic children aged 2 to 17 (N = 969), their siblings (N = 188), and unrelated children without an autism diagnosis (N = 111). The known relationship between sleep problems and autism was further explored by including scores from the Autism Diagnostic Observation Schedule-2, Mullen Scales of Early Learning, Vineland Adaptive Behavioral Scale-II and the Short Sensory Profile-2; which were included in analyses for autistic participants who had a completed CSHQ. Multiple regression models were used to identify clinical/behavioral variables associated with CSHQ subscales. The autism group had a significantly higher total CSHQ score than the sibling and comparison groups (p < 0.001), indicating worse sleep quality. Within the autism group, lower adaptive behaviors (i.e., VABS-II) and sensory issues (i.e., SSP-2 subclass scores) were positively associated with the severity of sleep problems (i.e., the CSHQ subclass scores) (p < 0.001). The significant functional impact of poor sleep on autistic children warrants an assessment of sleep as a critical part of a holistic approach to supporting autistic children and their families. LAY SUMMARY: Autistic children generally have co-occurring conditions. Sleep disorders impact approximately 50%-80% of autistic children. The impact on the quality of life for both the children and their families can be significant. This study compares sleep problems in autistic children and adolescents with their siblings and children without a diagnosis of autism, and investigates the relationship between specific autistic traits, daily life behaviors and sleep problems. The findings highlight the importance of a holistic assessment for autistic children and matching appropriate sleep intervention and supports where indicated.

Safety and target engagement of an oral small-molecule sequestrant in adolescents with autism spectrum disorder: an open-label phase 1b/2a trial.

Autism spectrum disorder (ASD) is defined by hallmark behaviors involving reduced communication and social interaction as well as repetitive activities and restricted interests. ASD represents a broad spectrum, from minimally affected individuals to those requiring intense support, with additional manifestations often including anxiety, irritability/aggression and altered sensory processing. Gastrointestinal (GI) issues are also common in ASD, and studies have identified changes in the gut microbiome of individuals with ASD compared to control populations, complementing recent findings of differences in gut-derived metabolites in feces and circulation. However, a role for the GI tract or microbiome in ASD remains controversial. Here we report that an oral GI-restricted adsorbent (AB-2004) that has affinity for small aromatic or phenolic molecules relieves anxiety-like behaviors that are driven by a gut microbial metabolite in mice. Accordingly, a pilot human study was designed and completed to evaluate the safety of AB-2004 in an open-label, single-cohort, multiple-ascending-dose clinical trial that enrolled 30 adolescents with ASD and GI symptoms in New Zealand and Australia. AB-2004 was shown to have good safety and tolerability across all dose levels, and no drug-related serious adverse events were identified. Significant reductions in specific urinary and plasma levels of gut bacterial metabolites were observed between baseline and end of AB-2004 treatment, demonstrating likely target engagement. Furthermore, we observed improvements in multiple exploratory behavioral endpoints, most significantly in post hoc analysis of anxiety and irritability, as well as GI health, after 8 weeks of treatment. These results from an open-label study (trial registration no. ACTRN12618001956291) suggest that targeting gut-derived metabolites with an oral adsorbent is a safe and well-tolerated approach to improving symptoms associated with ASD, thereby emboldening larger placebo-controlled trials.

A multidisciplinary approach and consensus statement to establish standards of care for Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a rare neurogenetic disorder present in approximately 1/12,000 individuals and characterized by developmental delay, cognitive impairment, motor dysfunction, seizures, gastrointestinal concerns, and abnormal electroencephalographic background. AS is caused by absent expression of the paternally imprinted gene UBE3A in the central nervous system. Disparities in the management of AS are a major problem in preparing for precision therapies and occur even in patients with access to experts and recognized clinics. AS patients receive care based on collective provider experience due to limited evidence-based literature. We present a consensus statement and comprehensive literature review that proposes a standard of care practices for the management of AS at a critical time when therapeutics to alter the natural history of the disease are on the horizon. METHODS: We compiled the key recognized clinical features of AS based on consensus from a team of specialists managing patients with AS. Working groups were established to address each focus area with committees comprised of providers who manage >5 individuals. Committees developed management guidelines for their area of expertise. These were compiled into a final document to provide a framework for standardizing management. Evidence from the medical literature was also comprehensively reviewed. RESULTS: Areas covered by working groups in the consensus document include genetics, developmental medicine, psychology, general health concerns, neurology (including movement disorders), sleep, psychiatry, orthopedics, ophthalmology, communication, early intervention and therapies, and caregiver health. Working groups created frameworks, including flowcharts and tables, to help with quick access for providers. Data from the literature were incorporated to ensure providers had review of experiential versus evidence-based care guidelines. CONCLUSION: Standards of care in the management of AS are keys to ensure optimal care at a critical time when new disease-modifying therapies are emerging. This document is a framework for providers of all familiarity levels.

Autism-related dietary preferences mediate autism-gut microbiome associations.

There is increasing interest in the potential contribution of the gut microbiome to autism spectrum disorder (ASD). However, previous studies have been underpowered and have not been designed to address potential confounding factors in a comprehensive way. We performed a large autism stool metagenomics study (n = 247) based on participants from the Australian Autism Biobank and the Queensland Twin Adolescent Brain project. We found negligible direct associations between ASD diagnosis and the gut microbiome. Instead, our data support a model whereby ASD-related restricted interests are associated with less-diverse diet, and in turn reduced microbial taxonomic diversity and looser stool consistency. In contrast to ASD diagnosis, our dataset was well powered to detect microbiome associations with traits such as age, dietary intake, and stool consistency. Overall, microbiome differences in ASD may reflect dietary preferences that relate to diagnostic features, and we caution against claims that the microbiome has a driving role in ASD.

Sleep, Function, Behaviour and Cognition in a Cohort of Children with Down Syndrome.

OBJECTIVE: To describe the sleep problems experienced by children with Down syndrome attending a tertiary sleep clinic and relationship with behaviour, function and cognition. METHODS: Data were collected from children with Down syndrome aged 3-18 years old. Carers completed the Abbreviated Child Sleep Habits Questionnaire, Child Behaviour Checklist and Life-Habits Questionnaire at enrolment. Cognitive assessment (Stanford-Binet 5) was undertaken by a trained psychologist. Children received management for their sleep problem as clinically indicated. RESULTS: Forty-two subjects with a median age of 6.8 years (Interquartile Range-IQR 4.5, 9.8) were enrolled. A total of 92% were referred with snoring or symptoms of Obstructive Sleep Apnoea (OSA), with 79% of those referred having had previous ENT surgery. Thus, 85% of all participants underwent a sleep study and 61% were diagnosed with OSA (OAHI ≥ 1/h). Based on questionnaires, 86% of respondents indicated that their child had a significant sleep disorder and non-respiratory sleep problems were common. Non-respiratory problems included: trouble going to sleep independently (45%), restless sleep (76%), night-time waking (24%) and bedtime resistance (22%). No significant correlations were found between sleep measures (behavioural and medical sleep problems) and the behavioural, functional or cognitive parameters. CONCLUSION: Sleep disorders were very common, especially non-respiratory sleep problems. OSA was common despite previous surgery. No association was found between sleep-related problems (snoring, sleep-study-confirmed OSA or non-respiratory sleep problem) and parent-reported behavioural problems, functional impairments or intellectual performance. This may reflect limitations of the measures used in this study, that in this population ongoing problems with daytime function are not sleep related or that a cross-sectional assessment does not adequately take into account the impacts of past disease/treatments. Further research is required to further evaluate the tools used to evaluate sleep disorders, the impact of those disorder on children with Down syndrome and interventions which improve both sleep and daytime function.

Clinical outcomes and associated predictors of early intervention in autism spectrum disorder: a study protocol.

INTRODUCTION: Research highlights the importance of early intervention for children with autism spectrum disorder with better outcomes associated with earlier access to early intensive intervention (EII) programmes. However, there is significant variability in response to EII despite children receiving the same programmes. METHODS AND ANALYSIS: A prospective, multisite cohort study using a pre-post design assesses the predictors of early intervention outcomes for children who receive EII through six early intervention services (Autism Specific Early Learning and Care Centres, ASELCCs) across Australia. Child and family characteristics at entry to and exit from ASELCCs are ascertained using measures of autism symptoms (Autism Diagnostic Observation Schedule-2; Social Communication Questionnaire); cognitive, language and developmental skills (Mullen Scale of Early Learning); adaptive function (Vineland Adaptive Behaviour Scale-second Edition); behaviours (Child Behaviour Checklist-1.5 to 5 years; Restricted Repetitive Behaviour Scale); parental stress (Parent Stress Index-4 Short Form); quality of life (Quality of Life in Autism Scale) and a semistructured family history questionnaire for sociodemographic, family and psychosocial characteristics. Characteristics at entry are used as predictors of outcome at exit following EII approximately 12 months later. The change in score from baseline to exit will be the primary outcome of interest. The mediating role of family and psychosocial factors will also be considered. ETHICS APPROVAL: University of New South Wales Human Research Ethics Committee (HC14267). DISSEMINATION OF RESULTS: Findings will be published in peer-reviewed journals and presented at conferences. A report summarising data and the interpretation of data will be published.

Repetitive transcranial magnetic stimulation (rTMS) in autism spectrum disorder: protocol for a multicentre randomised controlled clinical trial.

INTRODUCTION: There are no well-established biomedical treatments for the core symptoms of autism spectrum disorder (ASD). A small number of studies suggest that repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique, may improve clinical and cognitive outcomes in ASD. We describe here the protocol for a funded multicentre randomised controlled clinical trial to investigate whether a course of rTMS to the right temporoparietal junction (rTPJ), which has demonstrated abnormal brain activation in ASD, can improve social communication in adolescents and young adults with ASD. METHODS AND ANALYSIS: This study will evaluate the safety and efficacy of a 4-week course of intermittent theta burst stimulation (iTBS, a variant of rTMS) in ASD. Participants meeting criteria for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ASD (n=150, aged 14-40 years) will receive 20 sessions of either active iTBS (600 pulses) or sham iTBS (in which a sham coil mimics the sensation of iTBS, but no active stimulation is delivered) to the rTPJ. Participants will undergo a range of clinical, cognitive, epi/genetic, and neurophysiological assessments before and at multiple time points up to 6 months after iTBS. Safety will be assessed via a structured questionnaire and adverse event reporting. The study will be conducted from November 2020 to October 2024. ETHICS AND DISSEMINATION: The study was approved by the Human Research Ethics Committee of Monash Health (Melbourne, Australia) under Australia's National Mutual Acceptance scheme. The trial will be conducted according to Good Clinical Practice, and findings will be written up for scholarly publication. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12620000890932).