Legacy benefits of blood pressure treatment on cardiovascular events are primarily mediated by improved blood pressure variability: the ASCOT trial.

BACKGROUND AND AIMS: Visit-to-visit systolic blood pressure variability (BPV) is an important predictor of cardiovascular (CV) outcomes. The long-term effect of a period of blood pressure (BP) control, but with differential BPV, is uncertain. Morbidity and mortality follow-up of UK participants in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure-Lowering Arm has been extended for up to 21 years to determine the CV impact of mean systolic blood pressure (SBP) control and BPV during the trial, and amongst those allocated to amlodipine- and atenolol-based treatment. METHODS: Eight thousand five hundred and eighty hypertensive participants (4305 assigned to amlodipine ± perindopril-based and 4275 to atenolol ± diuretic-based treatment during the in-trial period (median 5.5 years) were followed for up to 21 years (median 17.4 years), using linked hospital and mortality records. A subgroup of participants (n = 2156) was followed up 6 years after the trial closure with a self-administered questionnaire and a clinic visit. In-trial mean SBP and standard deviation of visit-to-visit SBP as a measure of BPV, were measured using >100 000 BP measurements. Cox proportional hazard models were used to estimate the risk [hazard ratios (HRs)], associated with (i) mean with SBP and BPV during the in-trial period, for the CV endpoints occurring after the end of the trial and (ii) randomly assigned treatment to events following randomization, for the first occurrence of pre-specified CV outcomes. RESULTS: Using BP data from the in-trial period, in the post-trial period, although mean SBP was a predictor of CV outcomes {HR per 10 mmHg, 1.14 [95% confidence interval (CI) 1.10-1.17], P < .001}, systolic BPV independent of mean SBP was a strong predictor of CV events [HR per 5 mmHg 1.22 (95% CI 1.18-1.26), P < .001] and predicted events even in participants with well-controlled BP. During 21-year follow-up, those on amlodipine-based compared with atenolol-based in-trial treatment had significantly reduced risk of stroke [HR 0.82 (95% CI 0.72-0.93), P = .003], total CV events [HR 0.93 (95% CI 0.88-0.98), P = .008], total coronary events [HR 0.92 (95% CI 0.86-0.99), P = .024], and atrial fibrillation [HR 0.91 (95% CI 0.83-0.99), P = .030], with weaker evidence of a difference in CV mortality [HR 0.91 (95% CI 0.82-1.01), P = .073]. There was no significant difference in the incidence of non-fatal myocardial infarction and fatal coronary heart disease, heart failure, and all-cause mortality. CONCLUSIONS: Systolic BPV is a strong predictor of CV outcome, even in those with controlled SBP. The long-term benefits of amlodipine-based treatment compared with atenolol-based treatment in reducing CV events appear to be primarily mediated by an effect on systolic BPV during the trial period.

Behavioural and neuropsychological outcomes in children exposed in utero to maternal labour epidural analgesia.

BACKGROUND: Recent studies report conflicting results regarding the relationship between labour epidural analgesia (LEA) in mothers and neurodevelopmental disorders in their offspring. We evaluated behavioural and neuropsychological test scores in children of mothers who used LEA. METHODS: Children enrolled in the Raine Study from Western Australia and delivered vaginally from a singleton pregnancy between 1989 and 1992 were evaluated. Children exposed to LEA were compared with unexposed children. The primary outcome was the parent-reported Child Behaviour Checklist (CBCL) reporting total, internalising, and externalising behavioural problem scores at age 10 yr. Score differences, an increased risk of clinical deficit, and a dose-response based on the duration of LEA exposure were assessed. Secondary outcomes included language, motor function, cognition, and autistic traits. RESULTS: Of 2180 children, 850 (39.0%) were exposed to LEA. After adjustment for covariates, exposed children had minimally increased CBCL total scores (+1.41 points; 95% confidence interval [CI] 0.09 to 2.73; P=0.037), but not internalising (+1.13 points; 95% CI -0.08 to 2.34; P=0.066) or externalising (+1.08 points; 95% CI -0.08 to 2.24; P=0.068) subscale subscores. Increased risk of clinical deficit was not observed for any CBCL score. For secondary outcomes, score differences were inconsistently observed in motor function and cognition. Increased exposure duration was not associated with worse scores in any outcomes. CONCLUSIONS: Although LEA exposure was associated with slightly higher total behavioural scores, there was no difference in subscores, increased risk of clinical deficits, or dose-response relationship. These results argue against LEA exposure being associated with consistent, clinically significant neurodevelopmental deficits in children.

Utilising Behavioural and Sensory Profiles and Associated Perinatal Factors to Identify Meaningful Subgroups in Autism Spectrum Disorder.

The heterogeneity of autism spectrum disorder (ASD) clinically and aetiologically hinders intervention matching and prediction of outcomes. This study investigated if the behavioural, sensory, and perinatal factor profiles of autistic children could be used to identify distinct subgroups. Participants on the autism spectrum aged 2 to 17 years and their families were sourced via the Australian Autism Biobank (AAB). Latent class analysis was used to identify subgroups within this cohort, utilising twenty-six latent variables representing child's behavioural and sensory features and perinatal factors. Four distinct subgroups within the sample (n = 1168) distinguished by sensory and behavioural autism traits and exposure to perinatal determinants were identified. Class 2 and Class 4, which displayed the greatest behavioural and sensory impairment respectively, were associated with the highest perinatal factor exposure. Class 1, labelled "Most behavioural concerns and moderate sensory and behavioural skills concerns" had mixed exposure to perinatal determinants while Class 3, named "Least sensory and behavioural skills concerns" had the least perinatal determinant exposure, indicating a directly proportional correlation between severity of clinical features and perinatal factor exposure. Additionally, association between specific exposures such as maternal mental illness in Class 1 and significant behavioural concerns was recognised. Identifying distinct subgroups among autistic children can lead to development of targeted interventions and supports. Close monitoring of children exposed to specific perinatal determinants for developmental differences could assist early intervention and supports.

The use of psychotropic medications in autistic individuals (21 years and younger) in Western Australia: A preliminary investigation.

LAY ABSTRACT: Prescriptions and use of medications to treat mental health conditions in young autistic populations are inconsistent worldwide. This makes it hard to compare findings from international studies to the Australian autistic population, where there are limited relevant studies. Apart from risperidone, there are no other medications specified for direct use in autistic persons. This study aims to gain initial broad understanding of the use of medications, commonly prescribed for mental health conditions, specifically by autistics under the age of 21 years. We analysed data that were previously collected as part of the Western Australian Autism Biological Registry between 2011 and 2015 which amounted to 239 surveys completed on young persons with diagnosed autism. The questionnaires included information on co-occurring conditions, current or previous use of medications and reasons for use of the medications. Only one-quarter of the participants in this study reported using at least one mental health-related medication in their lifetime. The most reported medications were stimulants, antidepressants and antiepileptics. The reasons for using medication included managing attention deficit hyperactivity disorder, challenging behaviours, seizures, sleep difficulties and symptoms of anxiety and depression. The number of individuals reporting medication use in this study was lower compared to other developed countries. Nevertheless, these medications should be monitored due to limited understanding of their use to manage co-occurring symptoms in young autistic persons. The findings highlight the importance of ongoing research to better understand mental health-related medications and inform best practice.

Harmonizing the CBCL and SDQ ADHD scores by using linear equating, kernel equating, item response theory and machine learning methods.

Introduction: A problem that applied researchers and practitioners often face is the fact that different institutions within research consortia use different scales to evaluate the same construct which makes comparison of the results and pooling challenging. In order to meaningfully pool and compare the scores, the scales should be harmonized. The aim of this paper is to use different test equating methods to harmonize the ADHD scores from Child Behavior Checklist (CBCL) and Strengths and Difficulties Questionnaire (SDQ) and to see which method leads to the result. Methods: Sample consists of 1551 parent reports of children aged 10-11.5 years from Raine study on both CBCL and SDQ (common persons design). We used linear equating, kernel equating, Item Response Theory (IRT), and the following machine learning methods: regression (linear and ordinal), random forest (regression and classification) and Support Vector Machine (regression and classification). Efficacy of the methods is operationalized in terms of the root-mean-square error (RMSE) of differences between predicted and observed scores in cross-validation. Results and discussion: Results showed that with single group design, it is the best to use the methods that use item level information and that treat the outcome as interval measurement level (regression approach).

Investigating Parental Observations of Early Autism Development in Simplex and Multiplex Families.

Past research has highlighted the importance of early identification of developmental differences to improve targeted access to early interventions or supports. As such, it is of particular importance in the context of children at elevated likelihood of autism (such as where an older sibling has a diagnosis of autism), to better understand when and which early concerns are important as predictors of which children will benefit from pre-diagnostic supports. This study explored the number and frequency of retrospective parent reported concerns within the first year of life for children diagnosed with autism, both those who had an older sibling diagnosed with autism and those who did not, as well as for undiagnosed siblings. We found that at both 0-6 and 7-12 months, the only factor related to the presence or absence of early parent reported concerns was child diagnostic status, with the presence of reported early concerns more likely for children with a diagnosis of autism. These findings suggest that for children at elevated likelihood of autism, parents' concerns are driven primarily by developmental differences, with child's birth order and sibling diagnostic status not impacting on parent early concerns.

Absence of association between maternal adverse events and long-term gut microbiome outcomes in the Australian autism biobank.

Introduction: Maternal immune activation (MIA) and prenatal maternal stress (MatS) are well-studied risk factors for psychiatric conditions such as autism and schizophrenia. Animal studies have proposed the gut microbiome as a mechanism underlying this association and have found that risk factor-related gut microbiome alterations persist in the adult offspring. In this cross-sectional study, we assessed whether maternal immune activation and prenatal maternal stress were associated with long-term gut microbiome alterations in children using shotgun metagenomics. Methods: This cross-sectional study included children diagnosed with autism (N = 92), siblings without a diagnosis (N = 42), and unrelated children (N = 40) without a diagnosis who were recruited into the Australian Autism Biobank and provided a faecal sample. MIA exposure was inferred from self-reported data and included asthma/allergies, complications during pregnancy triggering an immune response, auto-immune conditions, and acute inflammation. Maternal stress included any of up to 9 stressful life events during pregnancy, such as divorce, job loss, and money problems. Data were analysed for a total of 174 children, of whom 63 (36%) were born to mothers with MIA and 84 (48%) were born to mothers who experienced maternal stress during pregnancy (where 33 [19%] experienced both). Gut microbiome data was assessed using shotgun metagenomic sequencing of the children's faecal samples. Results: In our cohort, MIA, but not MatS, was associated with ASD. Variance component analysis revealed no associations between any of the gut microbiome datasets and neither MIA nor MatS. After adjusting for age, sex, diet and autism diagnosis, there was no significant difference between groups for bacterial richness, α-diversity or ß-diversity. We found no significant differences in species abundance in the main analyses. However, when stratifying the cohort by age, we found that Faecalibacterium prausnitzii E was significantly decreased in MIA children aged 11-17. Discussion: Consistent with previous findings, we found that children who were born to mothers with MIA were more likely to be diagnosed with autism. Unlike within animal studies, we found negligible microbiome differences associated with MIA and maternal stress. Given the current interest in the microbiome-gut-brain axis, researchers should exercise caution in translating microbiome findings from animal models to human contexts and the clinical setting.

Empathy and Autism: Establishing the Structure and Different Manifestations of Empathy in Autistic Individuals Using the Perth Empathy Scale.

PURPOSE: There is a common mischaracterisation that autistic individuals have reduced or absent empathy. Measurement issues may have influenced existing findings on the relationships between autism and empathy, and the structure of the empathy construct in autism remains unclear. METHODS: The present study sought to address these gaps by examining the structure and psychometric properties of the Perth Empathy Scale (PES) in autistic individuals (N = 239) compared to non-autistic individuals (N = 690). RESULTS: Our moderated non-linear factor analysis revealed that the multidimensional empathy construct manifested similarly in autistic and non-autistic individuals, with the PES displaying good validity and reliability. Moreover, the results revealed that autistic individuals reported reduced cognitive empathy and reduced affective empathy for positive and negative emotions. However, there was greater heterogeneity of empathic tendencies in the autistic sample, indicating that these mean differences may not be generalisable for all autistic individuals. CONCLUSION: The present study highlights that the PES is suitable for assessing empathy across autistic and non-autistic individuals. This work with the PES also provides greater nuance to our understanding of empathy and autism, and based on these findings, we propose the empathy heterogeneity hypothesis of autism as a new way of describing empathy in autism.

Feasibility of a 2-minute eye-tracking protocol to support the early identification of autism.

We tested the potential for Gazefinder eye-tracking to support early autism identification, including feasible use with infants, and preliminary concurrent validity of trial-level gaze data against clinical assessment scores. We embedded the ~ 2-min 'Scene 1S4' protocol within a comprehensive clinical assessment for 54 consecutively-referred, clinically-indicated infants (prematurity-corrected age 9-14 months). Alongside % tracking rate as a broad indicator of feasible assessment/data capture, we report infant gaze data to pre-specified regions of interest (ROI) across four trial types and associations with scores on established clinical/behavioural tools. Most infants tolerated Gazefinder eye-tracking well, returning high overall % tracking rate. As a group, infants directed more gaze towards social vs. non-social (or more vs. less socially-salient) ROIs within trials. Behavioural autism features were correlated with increased gaze towards non-social/geometry (vs. social/people) scenes. No associations were found for gaze directed to ROIs within other stimulus types. Notably, there were no associations between developmental/cognitive ability or adaptive behaviour with gaze towards any ROI. Gazefinder assessment seems highly feasible with clinically-indicated infants, and the people vs. geometry stimuli show concurrent predictive validity for behavioural autism features. Aggregating data across the ~ 2-min autism identification protocol might plausibly offer greater utility than stimulus-level analysis alone.

Reliability, Validity and Acceptability of the PEDI-CAT with ASD Scales for Australian Children and Youth on the Autism Spectrum.

PURPOSE: The PEDI-CAT (ASD) is used to assess functioning of children and youth on the autism spectrum; however, current psychometric evidence is limited. This study aimed to explore the reliability, validity and acceptability of the PEDI-CAT (ASD) using a large Australian sample. METHODS: Caregivers of 134 children and youth on the spectrum participated in clinical assessments involving the administration of the PEDI-CAT (ASD), Vineland-3, PEDI-CAT (Original) and a feedback instrument. The PEDI-CAT (ASD) content was compared to the ICF Core Sets for ASD to summarize areas of functioning assessed and relevance to autism. RESULTS: The PEDI-CAT (ASD) demonstrated good to excellent internal consistency and test-re-test reliability. Parallel forms reliability with the PEDI-CAT (Original) included significant correlations (good to excellent), however, t-tests showed significantly higher Social/Cognitive scores for the ASD version. Convergent validity results demonstrated that most PEDI-CAT (ASD) and Vineland-3 core domains were significantly correlated (poor to good). Content analysis revealed that the PEDI-CAT (ASD) covered less than half of the ICF Core Sets for ASD (mostly Activities and Participation codes). Just over half the codes assigned to the PEDI-CAT (ASD) were represented in the ICF Core Sets for ASD. Feedback on the acceptability of the measure was mixed, but overall was it was considered user-friendly and efficient. CONCLUSION: The PEDI-CAT (ASD) had adequate psychometric properties and acceptability as a measure of Activities and Participation codes. However, it lacks comprehensiveness and relevance when compared to the ICF Core Sets for ASD and has the potential to overestimate functioning.

Validating the International Classification of Functioning, Disability and Health Core Sets for Autism in a Sample of Australian School-Aged Children on the Spectrum.

Assessing functioning of children on the autism spectrum is necessary to determine the level of support they require to participate in everyday activities across contexts. The International Classification of Functioning, Disability and Health (ICF) is a comprehensive biopsychosocial framework recommended for classifying health-related functioning in a holistic manner, across the components of body functions, activities and participation, and environmental factors. The ICF Core Sets (ICF-CSs) are sub-sets of relevant codes from the broader framework that provide a basis for developing condition-specific measures. This study combined the ICF-CSs for autism, attention deficit hyperactivity disorder (ADHD) and cerebral palsy (CP) to validate the ICF-CSs for autism in an Australian sample of school-aged children. This cross-sectional study involved caregivers of school-aged children on the spectrum (n = 70) completing an online survey and being visited in their homes by an occupational therapist to complete the proxy-report measure based on the ICF-CSs for autism, ADHD and CP. Absolute and relative frequencies of ratings for each of the codes included in the measure were calculated and reported, along with the number of participants who required clarification to understand the terminology used. Findings indicate that the body functions and activities and participation represented in the ICF-CSs for autism were the most applicable for the sample. However, findings relating to environmental factors were less conclusive. Some codes not currently included in the ICF-CSs for autism may warrant further investigation, and the language used in measures based on the ICF-CSs should be revised to ensure clarity.

Investigating the impact of developmental coordination difficulties across home, school, and community settings: Findings from the Australian Impact for DCD survey.

AIM: To evaluate the participation difficulties experienced by children with developmental coordination disorder (DCD) in home, school, and community environments. METHODS: The Impact for DCD survey was completed by primary caregivers of 4-18-year-old children with DCD (or synonymous diagnosis) (n = 429). OUTCOMES AND RESULTS: The greatest participation difficulties experienced at home included dressing, eating with utensils, self-care tasks and drawing/writing reported by over 70% of families. At school, fine motor difficulties were also frequently reported, with additional difficulties keeping up or completing tasks, and not feeling supported at school. Socialisation challenges and bullying were also commonly reported (34.9%). As a result of participation difficulties at school, 5.4% were home schooled. Many children engaged in community activity, with 72.0% currently engaged in at least one organised sports-based activity. CONCLUSIONS AND IMPLICATIONS: Increased recognition of the widespread impact of DCD in a child's life is crucial at an individual and societal level. Parents reported their children experiencing significant participation restrictions and difficulties. The findings of this large-scale study have revealed that most children with DCD are not receiving the support they need to thrive, especially at school. This largely reflects a lack of understanding and recognition of the condition and its associated challenges.

Characterising Insistence on Sameness and Circumscribed Interests: A Qualitative Study of Parent Perspectives.

Manifestations of insistence on sameness (IS) and circumscribed interests (CI) are complex, with individuals varying considerably, not only in the types of behaviours they express, but also in terms of a behaviour's frequency, intensity, trajectory, adaptive benefits, and impacts. However, current quantitative RRB instruments capture only certain aspects of these behaviours (e.g., mostly frequency or general "severity"). Thus, the current study utilised a semi-structured caregiver interview to provide an in-depth, qualitative characterization of different aspects of IS and CI presentation. Caregivers of 27 autistic children and adolescents displaying IS and/or CI behaviours (3-16 years; 18 males; 9 females) participated in a semi-structured interview. Responses were analysed using thematic framework analysis. Framework analysis identified nine different aspects of IS and CI presentation: (1) intensity, (2) frequency, (3) emergence of behaviour, (4) changes over time, (5) day-to-day fluctuations, (6) purpose/adaptive benefit, (7) experiences of distress, (8) challenges for the individual, their family, and their socialisation, and (9) management strategies and their effectiveness. Autistic children and adolescents were reported to vary greatly on each of these dimensions. Findings demonstrate the complexity of IS and CI presentations and highlight the need for more comprehensive quantitative assessments that independently assess the frequency, intensity, and impact of behaviours. Further, findings reported here emphasize the need for ecologically valid measures that assess the contexts in which these behaviours occur and how their presentations can change within and across days.

Autistic and autism community perspectives on infant and family support in the first two years of life: Findings from a community consultation survey.

LAY ABSTRACT: Most support programmes for Autistic children are available only after they are diagnosed. Research suggests that parenting supports may be helpful for parents and their infants, when provided in the first 2 years of life - before a formal diagnosis is given, but when information suggests an infant is more likely to be Autistic. However, we do not know how acceptable these types of supports might be to the Autistic and autism communities. We asked 238 Autistic and non-autistic people - some of whom were parents, and some of whom were professionals working in research, health and education - about their perspectives on very-early supports. People generally agreed that it could be acceptable to work with parents to help them understand and support their child's specific needs and unique ways of communicating. People suggested a variety of support strategies could be acceptable, including parent education, changing the environment to meet an infant's needs, and creating opportunities for infants' to make choices and exercise control. People preferred respectful and accurate language - including the term 'support' (rather than 'intervention') and 'early-in-life' (rather than 'at-risk' of autism, or 'pre-emptive' when describing developmental stage). Continuing to work with community members will help to make sure autism support programmes are relevant and helpful.