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Early supports to enhance social development in children with autism are widely promoted. While oxytocin has a crucial role in mammalian social development, its potential role as a medication to enhance social development in humans remains unclear. We investigated the efficacy, tolerability, and safety of intranasal oxytocin in young children with autism using a double-blind, randomized, placebo-controlled, clinical trial, following a placebo lead-in phase. A total of 87 children (aged between 3 and 12 years) with autism received 16 International Units (IU) of oxytocin (n = 45) or placebo (n = 42) nasal spray, morning and night (32 IU per day) for twelve weeks, following a 3-week placebo lead-in phase. Overall, there was no effect of oxytocin treatment over time on the caregiver-rated Social Responsiveness Scale (SRS-2) (p = 0.686). However, a significant interaction with age (p = 0.028) showed that for younger children, aged 3–5 years, there was some indication of a treatment effect. Younger children who received oxytocin showed improvement on caregiver-rated social responsiveness ( SRS-2). There was no other evidence of benefit in the sample as a whole, or in the younger age group, on the clinician-rated Clinical Global Improvement Scale (CGI-S), or any secondary measure. Importantly, placebo effects in the lead-in phase were evident and there was support for washout of the placebo response in the randomised phase. Oxytocin was well tolerated, with more adverse side effects reported in the placebo group. This study suggests the need for further clinical trials to test the benefits of oxytocin treatment in younger populations with autism.Trial registration www.anzctr.org.au (ACTRN12617000441314).

Patients with depression and bipolar disorder have previously been shown to have impaired white matter (WM) integrity compared with healthy controls. This study aimed to investigate potential sex differences that may provide further insight into the pathophysiology of these highly debilitating mood disorders.Participants aged 17 to 30 years (168 with depression [60% females], 107 with bipolar disorder [74% females], and 61 controls [64% females]) completed clinical assessment, self-report measures, and a neuropsychological assessment battery. Participants also underwent magnetic resonance imaging from which diffusion tensor imaging data were collected among five fronto-limbic WM tracts: cingulum bundle (cingulate gyrus and hippocampus subsections), fornix, stria terminalis, and the uncinate fasciculus. Mean fractional anisotropy (FA) scores were compared between groups using analyses of variance with sex and diagnosis as fixed factors.Among the nine WM tracts analyzed, one revealed a significant interaction between sex and diagnosis, controlling for age. Male patients with bipolar disorder had significantly lower FA scores in the fornix compared with the other groups. Furthermore, partial correlations revealed a significant positive association between FA scores for the fornix and psychomotor speed.Our findings suggest that males with bipolar disorder may be at increased risk of disruptions in WM integrity, especially in the fornix, which is thought to be responsible for a range of cognitive functions. More broadly, our findings suggest that sex differences may exist in WM integrity and thereby alter our understanding of the pathophysiology of mood disorders.

Atypical sensory processing occurs in up to 97% of children on the autism spectrum. Children who are on the autism spectrum also commonly demonstrate challenging behaviors, and their caregivers report increased levels of strain in daily life. The aim of this study was to explore four sensory processing features; seeking, avoiding, sensitivity, and registration, and their relationships with maladaptive behaviors in children with autism, as well as with caregiver strain. Participants comprised 75 children with autism aged 7-12 years (M = 7.81). Caregivers completed three questionnaire measures examining child sensory processing, maladaptive behaviors, and perceptions of caregiver strain. We found avoiding significantly associated with irritability. Avoiding also displayed the strongest relationship with global caregiver strain. Avoiding and seeking were strongly related to hyperactivity/noncompliance (components of maladaptive behavior). A multiple regression was performed to explore how atypical sensory processing features and maladaptive behaviors together predicted caregiver strain. Together, maladaptive behaviors and sensory features accounted for 58% of the variance in total caregiver strain. The only significant individual predictor of total caregiver strain was sensory avoiding, which uniquely accounted for 5.76% of the variation. The findings suggest that atypical sensory processing is associated with overall caregiver strain, above that explained by maladaptive behaviors. Implications for targeted support for the benefit of the child, parents and family unit are discussed. LAY SUMMARY: Children who are on the autism spectrum often have differences in sensory processing. These children also tend to show challenging behaviors, and their caregivers can experience increased stress. This study looked at how sensory processing difficulties relate to such behaviors and caregiver stress. We found that both sensory processing and challenging behaviors were related to the amount of stress caregivers felt. This suggests that interventions may benefit from looking at sensory processing features when considering how to help reduce challenging behaviors and caregiver stress.

Routinely collected data help estimate the prevalence of autism spectrum disorder (ASD) in jurisdictions without active autism surveillance. We created a population-based cohort of 1,211,834 children born in 2002–2015 in New South Wales, Australia using data linkage. Children with ASD were identified in three datasets – disability services, hospital admissions, and ambulatory mental health data. The prevalence of ASD in the cohort was 1.3% by age 12 and prevalence at age 6 increased an average of 4.1% per year (95% Confidence Interval, 3.3%, 4.8%). Most children with ASD were identified in disability services data (87%), although data linkage identified 1,711 additional cases that were more likely female, older at first contact, and living in major cities and less disadvantaged areas.

There is significant interest in the possible influence of chronotype on clinical states in young people with emerging mental disorders. We apply a dynamic approach (bivariate latent change score modelling) to examine the possible prospective influence of chronotype on depressive and hypo/manic symptoms in a youth cohort with predominantly depressive, bipolar, and psychotic disorders (N = 118; 14–30-years), who completed a baseline and follow-up assessment of these constructs (mean interval = 1.8-years). Our primary hypotheses were that greater baseline eveningness would predict increases in depressive but not hypo/manic symptoms. We found moderate to strong autoregressive effects for chronotype (β = -0.447 to −0.448, p < 0.001), depressive (β = -0.650, p < 0.001) and hypo/manic symptoms (β = -0.819, p < 0.001). Against our predictions, baseline chronotypes did not predict change in depressive (β = -0.016, p = 0.810) or hypo/manic symptoms (β = 0.077, p = 0.104). Similarly, the change in chronotype did not correlate with the change in depressive symptoms (β = -0.096, p = 0.295) nor did the change in chronotype and the change in hypo/manic symptoms (β = -0.166, p = 0.070). These data suggest that chronotypes may have low utility for predicting future hypo/manic and depressive symptoms in the short term, or that more frequent assessments over longer periods are needed to observe these associations. Future studies should test whether other circadian phenotypes (e.g. sleep-wake variability) are better indicators of illness course.

Objective To identify trajectories of social and occupational functioning in young people during the two years after presenting for early intervention mental health care; to identify demographic and clinical factors that influence these trajectories. Design Longitudinal, observational study of young people presenting for mental health care. Setting Two primary care-based early intervention mental health services at the Brain and Mind Centre (University of Sydney), 1 June 2008 - 31 July 2018. Participants 1510 people aged 12-25 years who had presented with anxiety, mood, or psychotic disorders, for whom two years' follow-up data were available for analysis. Main outcome measures Latent class trajectories of social and occupational functioning based on growth mixture modelling of Social and Occupational Assessment Scale (SOFAS) scores. Results We identified four trajectories of functioning during the first two years of care: deteriorating and volatile (733 participants, 49%); persistent impairment (237, 16%); stable good functioning (291, 19%); and improving, but late recurrence (249, 16%). The less favourable trajectories (deteriorating and volatile; persistent impairment) were associated with physical comorbidity, not being in education, employment, or training, having substance-related disorders, having been hospitalised, and having a childhood onset mental disorder, psychosis-like experiences, or a history of self-harm or suicidality. Conclusions Two in three young people with emerging mental disorders did not experience meaningful improvement in social and occupational functioning during two years of early intervention care. Most functional trajectories were also quite volatile, indicating the need for dynamic service models that emphasise multidisciplinary interventions and measurement-based care.

Reduced social attention is characteristic of Autism Spectrum Disorder (ASD). It has been suggested to result from an early onset and excessive influence of circumscribed interests (CIs) on gaze behaviour, compared to typically developing (TYP) individuals. To date, these findings have been mixed. The current eye-tracking study utilised a visual preference paradigm to investigate the influence of CI versus non-CI objects on attention patterns in children with ASD (aged 3–12 years, n = 37) and their age-matched TYP peers (n = 30). Compared to TYP, social and object attention was reduced in the ASD group irrespective of the presence of CIs. Results suggest a reduced role for CIs and extend recent evidence of atypical attention patterns across social and non-social domains in ASD.

An ongoing need exists for innovation in service delivery to ensure that mental health services deliver high-quality treatment and prevention in the population. This Special Article proposes the adoption of “staged care” as a population health–oriented service delivery model for packages of specialized services delivered largely in ambulatory care settings for individuals with common affective disorders. Staged care integrates measures of clinical need alongside clinical stage and personal choice to select hierarchically arranged service packages for individuals. Packages then vary according to the intensity, duration, and mix of treatment options. This Special Article describes five levels of care in staged care: self- or family-directed monitoring and management, low-intensity services, moderate-intensity services, high-intensity services, and acute and specialist community mental health services. The care environment, treatment team, and length of treatment are also described, and provisional criteria are specified for assigning individuals to different care levels on the basis of current clinical need and clinical stage. Staged care is presented as a model that guides treatment selection and health service delivery to ensure that the high-quality care aims of “right care first time” and prevention are achieved and optimal use of available resources is considered.

The aim of this study was to examine potential synergistic effects between maternal autoimmune disease and early childhood infections and their association with autism spectrum disorder (ASD) in offspring. Both exposures have been associated with increased risk of ASD in previous studies, but potential synergistic effects remain underexplored. We conducted a population-based cohort study of singleton children born at term gestation (37-41 weeks) in New South Wales, Australia from January 2002 to December 2008. Maternal autoimmune diagnoses and childhood infections before age 2 years were identified from linked maternal and child hospital admissions, and ASD diagnoses by age 9 years were identified from linked disability services data. Multivariable logistic regression assessed the association between each exposure and ASD and additive interaction between exposures, controlling for potential confounders. A total of 18,451 children exposed to maternal autoimmune disease were propensity score matched (1:2) to 36,902 unexposed children. Any maternal autoimmune disease (adjusted odds ratio (aOR) 1.25, 95% confidence interval (CI) 1.07-1.47) and any childhood infection before age 2 years (aOR 1.38, 95% CI 1.15-1.67) were each associated with ASD. However, there was no evidence of additive interaction between the two exposures (relative excess risk due to interaction [RERI] 0.128, 95% CI -0.418-0.675) resulting in increased odds of ASD in offspring. Future studies could examine potential interactions between other sources of maternal immune activation and childhood infection and impact on ASD and other neurodevelopmental disorders.

GABA is the primary inhibitory neurotransmitter in the brain, and is essential to the balance of cortical excitation and inhibition. Reductions in GABA are proposed to result in an overly excitatory cortex that may cause, or contribute to, symptoms of autism spectrum disorder (ASD). This study employed a cross-sectional design to explore GABA+ differences in ASD and the impact of age, comparing 4-12 year olds with ASD (N = 24) to typically developing children (N = 35). GABA+ concentration was measured using edited magnetic resonance spectroscopy in the left parietal lobe. This study used a mixed model to investigate group differences between children with ASD and typically developing children. There was a significant difference in GABA+ levels between the groups, a significant effect of age and interaction between age and diagnostic group. The ASD group showed an association between GABA+ and age, with GABA+ levels gradually increasing with age (r = 0.59, p = 0.003). Typically developing children did not show age-related change in GABA+ concentration (r = 0.09, p = 0.60). By the age of 9, children with ASD showed GABA+ levels that were comparable to their typically developing peers. This study suggests that children with ASD have initially lower levels of GABA+ in the left parietal lobe compared to typically developing children, and that these initially lower levels of GABA+ increase with age in ASD within this region. It is suggested that this developmental shift of GABA+ levels within the left parietal lobe provides a possible explanation for the previously found reductions in childhood that does not persist in adults. LAY SUMMARY: This study measured levels of GABA in the left parietal lobe using magnetic resonance spectroscopy in children with ASD and typically developing children. GABA levels were initially lower in the ASD group, and increased with age, while GABA did not change with age in the typically developing group. This suggests that alterations in GABA signaling may be associated with ASD in childhood. Autism Res 2021, 14: 859-872. © 2021 International Society for Autism Research, Wiley Periodicals LLC.

BACKGROUND: Paediatric hospital length of stay (LoS) is often used as a benchmark for resource use of hospitalisations. Previous studies have mostly focused on LoS of admissions for specific conditions or medical specialties. We aimed to conduct an evaluation of LoS of all paediatric hospitalisations exploring the frequency and characteristics; and associated childhood conditions. METHODS: This population-based cross-sectional study included all hospital admissions in children aged 7 days represented 2.8% of total admissions, they accounted for 27% of total bed days. Children aged 1–4 years had the highest proportion of admissions (35%), with a majority lasting ≤7 days, whereas 45.6% of admissions ≥22 days were for children aged ≥12 years. Respiratory conditions, diseases of the digestive system and traumatic injuries were the most common reasons for hospitalization. LoS >7 days were more common in children from most disadvantaged backgrounds, residing further from hospital and those aged ≥12 years with mental health conditions. INTERPRETATION: The majority of paediatric hospitalizations are for short stay and require programs that target acute conditions that can be managed in primary care. Interventions such as care coordination, tailored models of care and enhanced outpatient/community treatment programs for high-risk groups will help reduce extended LoS and improving child health and well-being. FUNDING: 10.13039/501100000925Australian National Health and Medical Research Council.

Recent years have seen remarkable progress in our scientific understanding of early childhood social, emotional, and cognitive development, as well as our capacity to widely disseminate health information by using digital technologies. Together, these scientific and technological advances offer exciting opportunities to deliver high-quality information about early childhood development (ECD) to parents and families globally, which may ultimately lead to greater knowledge and confidence among parents and better outcomes among children (particularly in lower- and middle-income countries). With these potential benefits in mind, we set out to design, develop, implement, and evaluate a new parenting app—Thrive by Five—that will be available in 30 countries. The app will provide caregivers and families with evidence-based and culturally appropriate information about ECD, accompanied by sets of collective actions that go beyond mere tips for parenting practices. Herein, we describe this ongoing global project and discuss the components of our scientific framework for developing and prototyping the app’s content. Specifically, we describe (1) 5 domains that are used to organize the content and goals of the app’s information and associated practices; (2) 5 neurobiological systems that are relevant to ECD and can be behaviorally targeted to potentially influence social, emotional, and cognitive development; (3) our anthropological and cultural framework for learning about local contexts and appreciating decolonization perspectives; and (4) our approach to tailoring the app’s content to local contexts, which involves collaboration with in-country partner organizations and local and international subject matter experts in ECD, education, medicine, psychology, and anthropology, among others. Finally, we provide examples of the content that was incorporated in Thrive by Five when it launched globally.

ObjectivesEarly developmental assessment is crucial for effective support and intervention. This study examined factors that contribute to (a) older child age when caregivers first became concerned about their child’s development and (b) older child age at the point of entry into developmental and diagnostic assessment. We also quantified how factors contributed to risk of children not receiving an assessment by 5 years and considered the acceptability of electronic data capture for families.DesignThis cross-sectional study collected information about caregiver developmental concerns, family history and child characteristics.SettingChildren and families entered a large, publicly funded hospital-based paediatric developmental assessment service.ParticipantsConsecutively enrolled children (N=916) aged 6 months to 17 years with neurodevelopmental concerns and their caregivers.Main outcomes and measuresA developmental history questionnaire completed by caregivers.ResultsThe average age that caregivers identified developmental concerns was 3.0 years of age but the average age of a receiving a developmental assessment was 6.6 years. Only 46.4% of children received a diagnostic assessment by 5 years of age, even though 88.0% of caregivers were concerned about their child’s development by that age. Parental age, relationship status, education level, prior use of support services and being from a culturally and linguistically diverse background contributed to age at identification of concern, age at diagnostic assessment and the likelihood of receiving a diagnostic assessment by 5 years. Electronic data capture had high acceptability, with 88.2% of caregivers reporting a preference for electronic completion of questionnaires.ConclusionsThe study shows a substantial delay in diagnostic assessments that leaves most vulnerable children without an assessment by school age and highlights contributors to delays. These delays highlight the complexity of delivering early intervention and support policies that rely on swift and appropriate developmental assessment to vulnerable families.

Epidemiological and animal research shows that maternal immune activation increases the risk of autism spectrum disorders (ASD) in offspring. Emerging evidence suggests that maternal immune conditions may play a role in the phenotypic expression of neurodevelopmental difficulties in children with ASD and this may be moderated by offspring sex. This study aimed to investigate whether maternal immune conditions were associated with increased severity of adverse neurodevelopmental outcomes in children with ASD. Maternal immune conditions were examined as predictors of ASD severity, behavioural and emotional well-being, and cognitive functioning in a cohort of 363 children with ASD (n = 363; 252 males, 111 females; median age 3.07 [interquartile range 2.64–3.36 years]). We also explored whether these outcomes varied between male and female children. Results showed that maternal asthma was the most common immune condition reported in mothers of children with ASD. A history of maternal immune conditions (p = 0.009) was more common in male children with ASD, compared to female children. Maternal immune conditions were associated with increased behavioural and emotional problems in male and female children. By contrast, maternal immune conditions were not associated with decreased cognitive function. The findings demonstrate that MIA may influence the expression of symptoms in children with ASD and outcomes may vary between males and females.

Neurocognitive impairment is commonly associated with functional disability in established depressive, bipolar and psychotic disorders. However, little is known about the longer-term functional implications of these impairments in early phase transdiagnostic cohorts. We aimed to examine associations between neurocognition and functioning at baseline and over time. We used mixed effects models to investigate associations between neurocognitive test scores and longitudinal social and occupational functioning (“Social and Occupational Functioning Assessment Scale”) at 1–7 timepoints over five-years in 767 individuals accessing youth mental health services. Analyses were adjusted for age, sex, premorbid IQ, and symptom severity. Lower baseline functioning was associated with male sex (coefficient −3.78, 95% CI −5.22 to −2.34 p

Early life social experiences shape neural pathways in infants to develop lifelong social skills. This review presents the first unified circuit-based model of social learning that can be applied to early life social development, drawing together unique human developmental milestones, sensitive learning periods, and behavioral and neural scaffolds. Circuit domains for social learning are identified governing Activation, Integration, Discrimination, Response and Reward (AIDRR) to sculpt and drive human social learning. This unified model can be used to identify social delays earlier in development. We propose social impairments observed in Autism Spectrum Disorder are underpinned by early mistimed sensitive periods in brain development and alterations in amygdala development to disrupt the AIDRR circuits. This model directs how interventions can target neural circuits for social development and be applied early in life. To illustrate, the role of oxytocin and its use as an intervention is explored. The AIDRR model shifts focus away from delivering broad treatments based only on diagnostic classifications, to specifying and targeting the relevant circuits, at the right time of development, to optimize social learning.

Background Deficient extinction learning and threat adaptation in the ventromedial prefrontal cortex (vmPFC)-amygdala circuitry strongly impede the efficacy of exposure-based interventions in anxiety disorders. Recent animal models suggest a regulatory role of the renin-angiotensin system in both these processes. Against this background, the present randomized placebo-controlled pharmacologic functional magnetic resonance imaging experiment aimed at determining the extinction enhancing potential of the angiotensin II type 1 receptor antagonist losartan (LT) in humans. Methods Seventy healthy male subjects underwent Pavlovian threat conditioning and received single-dose LT (50 mg) or placebo administration before extinction. Psychophysiological threat reactivity (skin conductance response) and neural activity during extinction served as primary outcomes. Psychophysiological interaction, voxelwise mediation, and novel multivariate pattern classification analyses were used to determine the underlying neural mechanisms. Results LT significantly accelerated the decline of the psychophysiological threat response during within-session extinction learning. On the neural level, the acceleration was accompanied and critically mediated by threat-specific enhancement of vmPFC activation. Furthermore, LT enhanced vmPFC-basolateral amygdala coupling and attenuated the neural threat expression, particularly in the vmPFC, during early extinction. Conclusions Overall the results indicate that LT facilitates within-session threat memory extinction by augmenting threat-specific encoding in the vmPFC and its regulatory control over the amygdala. The findings document a pivotal role of angiotensin regulation of extinction learning in humans and suggest that adjunct LT administration has the potential to facilitate the efficacy of exposure-based interventions in anxiety disorders.

Background Children with neurodevelopmental disorders share common phenotypes, support needs and comorbidities. Such overlap suggests the value of transdiagnostic assessment pathways that contribute to knowledge about research and clinical needs of these children and their families. Despite this, large transdiagnostic data collection networks for neurodevelopmental disorders are not well developed. This paper describes the development of a nationally supported transdiagnostic clinical and research assessment protocol across Australia. The vision is to establish a harmonised network for data collection and collaboration that promotes transdiagnostic clinical practice and research. Methods Clinicians, researchers and community groups across Australia were consulted using surveys and national summits to identify assessment instruments and unmet needs. A national research committee was formed and, using a consensus approach, selected assessment instruments according to pre‐determined criteria to form a harmonised transdiagnostic assessment protocol. Results Identified assessment instruments were clustered into domains of transdiagnostic assessment needs, which included child functioning/quality of life, child mental health, caregiver mental health, and family background information. From this, the research committee identified a core set of nine measures and an extended set of 14 measures that capture these domains with potential for further modifications as recommended by clinicians, researchers and community members. Conclusion The protocol proposed here was established through a strong partnership between clinicians, researchers and the community. It will enable (i) consensus driven transdiagnostic clinical assessments for children with neurodevelopmental disorders, and (ii) research studies that will inform large transdiagnostic datasets across neurodevelopmental disorders and that can be used to inform research and policy beyond narrow diagnostic groups. The long‐term vision is to use this framework to facilitate collaboration across clinics to enable large‐scale data collection and research. Ultimately, the transdiagnostic assessment data can be used to inform practice and improve the lives of children with neurodevelopmental disorders and their families.

IntroductionAttention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder which affects 5% of children globally. In Australia, it is estimated that 4.1% of children and adolescents have ADHD. While research has examined the treatment and outcomes of children with ADHD attending public mental health services during their time in the public system in Australia, it is not known what treatment they received before and after these treatment episodes, which will provide a more complete understanding of these children’s treatment journey.Methods and analysisWe will link clinical data from cohorts of children and adolescents treated in the public child and youth mental health and/or child development services in Brisbane, Melbourne and Sydney to the Medicare Benefits Schedule (MBS), Pharmaceutical Benefits Scheme (PBS) and National Death Index. MBS data will demonstrate the treatment journey with respect to clinicians seen, and treatment episodes from the public health service data sets will be examined to assess if the type and intensity of treatment are related to treatment outcomes. PBS data will reveal all psychotropic medications prescribed, allowing an examination of not just ADHD medications, but also other psychotropics which may indicate co-occurring conditions (eg, anxiety and mood disorders). Statistical analyses will include descriptive statistics to describe the rates of specific medications and clinician specialties seen. Linear and logistic regression will be used to model how treatment and sociodemographic variables relate to routinely collected outcome measures in the public health system while controlling for covarying factors.Ethics and disseminationThis study has been approved by the following institutional ethics committees: (1) Children’s Health Queensland Hospital and Health Service (HREC/21/QCHQ/76260), (2) The University of Queensland (2021/HE002143) and (3) The Australian Institute of Health and Welfare (EO2021/4/1300). Findings will be disseminated through peer-reviewed journals, conferences, professional associations and to public mental health services that treat ADHD.

IntroductionThere 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 analysisThis 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 disseminationThe 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 numberAustralian New Zealand Clinical Trials Registry (ACTRN12620000890932).

IntroductionApproximately 75% of major mental illness occurs before the age of 25 years. Despite this, our capacity to provide effective, early and personalised interventions is limited by insufficient evidence for characterising early-stage, and less specific, presentations of major mental disorders in youth populations. This article describes the protocol for setting up a large-scale database that will collect longitudinal, prospective data that incorporate clinical, social and occupational function, neuropsychological, circadian, metabolic, family history and genetic metrics. By collecting data in a research-purposed, standardised manner, the ‘Neurobiology Youth Follow-up Study’ should improve identification, characterisation and profiling of youth attending mental healthcare, to better inform diagnosis and treatment at critical time points. The overall goal is enhanced long-term clinical and functional outcomes.Methods and analysisThis longitudinal clinical cohort study will invite participation from youth (12–30 years) who seek help for mental health-related issues at an early intervention service (headspace Camperdown) and linked services. Participants will be prospectively tracked over 3 years with a series of standardised multimodal assessments at baseline, 6, 12, 24 and 36 months. Evaluations will include: (1) clinician-administered and self-report assessments determining clinical stage, pathophysiological pathways to illness, diagnosis, symptomatology, social and occupational function; (2) neuropsychological profile; (3) sleep–wake patterns and circadian rhythms; (4) metabolic markers and (5) genetics. These data will be used to: (1) model the impact of demographic, phenomenological and treatment variables, on clinical and functional outcomes; (2) map neurobiological profiles and changes onto a transdiagnostic clinical stage and pathophysiological mechanisms framework.Ethics and disseminationThis study protocol has been approved by the Human Research Ethics Committee of the Sydney Local Health District (2020/ETH01272, protocol V.1.3, 14 October 2020). Research findings will be disseminated through peer-reviewed journals and presentations at scientific conferences and to user and advocacy groups. Participant data will be de-identified.

The World Health Organization Disability Assessment Schedule II (WHODAS-II) is one of the most widely used generic assessments for measuring disability levels in both clinical and nonclinical populations, with sound psychometrics that is also aligned with the International Classification of Functioning framework. However, its psychometric properties have not been explored extensively in individuals with autism spectrum disorder (ASD). This study examined the psychometric properties of the 36-item and 12-item Self-Report WHODAS-II from 109 individuals diagnosed with ASD and without intellectual disability (IQ ≥ 70). Participants were consecutively recruited from the Brain and Mind Centre in New South Wales, Australia. The WHODAS-II showed adequate internal consistency for all domain scores (α = 0.78-0.97 for 36-item) and for the summary scale (α = 0.95 for 36-item; 0.86 for 12-item). All items also exhibited satisfactory correlations with their respective domain (r = 0.39-0.94 for 36-item) and summary scores (r = 0.42-0.71 for 36-item; 0.42-0.67 for 12-item), except item 4.5 "sexual activity" from the 36-item WHODAS-II (r = 0.19). Concurrent validity was shown by moderate correlations between similar constructs across the WHODAS-II and the World Health Organization Quality of Life BREF (Ps < 0.05). The second-order 7-factor model showed the best fit for the 36-item WHODAS-II, while the second-order 6-factor model demonstrated an acceptable fit for the 12-item WHODAS-II. The model fit could be improved with some modifications. The Schmid-Leiman transformation further confirmed the appropriateness of the second-order factor structure. Overall, the results indicated that the WHODAS-II is a viable generic self-report measure for disability in autistic individuals without ID. Autism Res 2019, 12: 1101-1111. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The majority of autistic people have a disability with a profound or severe limitation in their core activities. However, there is currently limited research identifying reliable and valid self-report measures for disability in the autistic population. This study examined the psychometric properties of the World Health Organization Disability Assessment Schedule II (WHODAS-II) from 109 autistic individuals without intellectual disability. Our results suggest that the WHODAS-II is a viable generic self-report measure for disability in autistic individuals.

Reduced cardiac autonomic function is associated with increased risk of cardiovascular disease (CVD), with heart rate variability (HRV) providing an accessible index of cardiac autonomic function. HRV may provide a candidate physiological mechanism linking reduced cardiac autonomic function to increased risk for CVD in schizophrenia illness. This study examines whether HRV is also reduced in a community sample of treatment-seeking participants experiencing early psychosis (n = 48) compared to healthy volunteers (n = 48) and social anxiety control groups (n = 48) matched by gender and age. HRV was assessed during a five-minute interbeat interval recording at rest. Participants also completed self-report psychiatric symptom measures. Early psychosis participants showed significant reductions in HRV compared to social anxiety and healthy control groups. Reductions in HRV were also observed in early psychosis participants taking anticholinergic medications compared to both control groups taking cardio-benign medications or who were non-medicated. Lastly, whether or not early psychosis participants were taking anticholinergic medications was not associated with reductions in HRV. Findings provide preliminary evidence that early psychosis is associated with reduced HRV. This study supports further research with larger sample sizes to precisely determine the influence of anticholinergic drugs on HRV in early psychosis populations.

Importance Maternal autoimmune disease has been associated with increased risk of neurodevelopmental disorders in offspring, but few studies have assessed the association with attention-deficit/hyperactivity disorder (ADHD). Objective To examine the association between maternal autoimmune disease and ADHD within a population-based cohort and combine results in a subsequent systematic review and meta-analysis. Design, setting, and participants A cohort study was conducted of singleton children born at term gestation (37-41 weeks) in New South Wales, Australia, from July 1, 2000, to December 31, 2010, and followed up until the end of 2014; and a systematic review evaluated articles from the MEDLINE, Embase, and Web of Science databases to identify all studies published before November 20, 2019. A total of 12 610 children exposed to maternal autoimmune disease were propensity score matched (1:4) to 50 440 unexposed children, for a total cohort of 63 050. A child was considered to have ADHD if they had (1) an authorization or filled prescription for stimulant treatment for ADHD or (2) a hospital diagnosis of ADHD. Children linked to a first ADHD event before 3 years of age were excluded. Data were analyzed from January 13 to April 20, 2020. Exposures One or more maternal autoimmune diagnoses in linked hospital admission records between July 1, 2000, and December 31, 2012. Thirty-five conditions were considered together and individually. Main outcomes and measures The main outcome was child ADHD identified from stimulant authorization or prescription data and diagnoses in linked hospital admission records. Multivariable Cox regression was used to assess the association between maternal autoimmune disease and ADHD adjusted for child sex. Pooled hazard ratios (HRs) were calculated using random-effects meta-analysis with inverse-variance weights for each exposure reported by 2 or more studies. Results In the population-based cohort analysis, 831 718 singleton, term infants born to 831 718 mothers (mean [SD] age, 29.8 [5.6] years) were assessed. Of 12 767 infants (1.5%) who were linked to a maternal autoimmune diagnosis, 12 610 were propensity score matched to 50 440 control infants, for a total study cohort of 63 050 infants. In this cohort, any autoimmune disease was associated with ADHD in offspring (HR, 1.30; 95% CI 1.15-1.46), as was type 1 diabetes (HR, 2.23; 95% CI, 1.66-3.00), psoriasis (HR, 1.66; 95% CI, 1.02-2.70), and rheumatic fever or rheumatic carditis (HR, 1.75; 95% CI, 1.06-2.89). Five studies (including the present study) were included in the meta-analysis. Any autoimmune disease (2 studies: HR, 1.20; 95% CI, 1.03-1.38), type 1 diabetes (4 studies: HR, 1.53; 95% CI, 1.27-1.85), hyperthyroidism (3 studies: HR, 1.15; 95% CI, 1.06-1.26), and psoriasis (2 studies: HR, 1.31; 95% CI, 1.10-1.56) were associated with ADHD. Conclusions and relevance In this cohort study, maternal autoimmune diseases were associated with increased ADHD among children. These findings suggest possible shared genetic vulnerability between autoimmune disease and ADHD or a potential role for maternal immune activation in the expression of neurodevelopmental disorders in children. Future studies measuring disease activity, modifiers, and medication use are required to better understand the mechanisms underlying this association.

BackgroundA priority for health services is to reduce self-harm in young people. Predicting self-harm is challenging due to their rarity and complexity, however this does not preclude the utility of prediction models to improve decision-making regarding a service response in terms of more detailed assessments and/or intervention. The aim of this study was to predict self-harm within six-months after initial presentation.MethodThe study included 1962 young people (12–30 years) presenting to youth mental health services in Australia. Six machine learning algorithms were trained and tested with ten repeats of ten-fold cross-validation. The net benefit of these models were evaluated using decision curve analysis.ResultsOut of 1962 young people, 320 (16%) engaged in self-harm in the six months after first assessment and 1642 (84%) did not. The top 25% of young people as ranked by mean predicted probability accounted for 51.6% - 56.2% of all who engaged in self-harm. By the top 50%, this increased to 82.1%-84.4%. Models demonstrated fair overall prediction (AUROCs; 0.744–0.755) and calibration which indicates that predicted probabilities were close to the true probabilities (brier scores; 0.185–0.196). The net benefit of these models were positive and superior to the ‘treat everyone’ strategy. The strongest predictors were (in ranked order); a history of self-harm, age, social and occupational functioning, sex, bipolar disorder, psychosis-like experiences, treatment with antipsychotics, and a history of suicide ideation.ConclusionPrediction models for self-harm may have utility to identify a large sub population who would benefit from further assessment and targeted (low intensity) interventions. Such models could enhance health service approaches to identify and reduce self-harm, a considerable source of distress, morbidity, ongoing health care utilisation and mortality.

Background There is a strong research imperative to investigate effective treatment options for adolescents and adults with autism spectrum disorder (ASD). Elevated social anxiety, difficulties with social functioning and poor mental health have all been identified as core treatment targets for this group. While theoretical models posit a strong bidirectionality between social anxiety and ASD social functioning deficits, few interventions have targeted both domains concurrently. Of the two group interventions previously conducted with adolescents and adults with ASD, significant results have only been observed in either social anxiety or social functioning, and have not generalised to changes in overall mood. The aim of this study was to evaluate the potential benefit, tolerability and acceptability of a group cognitive-behaviour therapy (CBT) intervention in young adults with ASD. Primary treatment outcomes were social anxiety symptoms and social functioning difficulties; secondary outcomes were self-reported mood and overall distress. Method Ten groups of participants completed an eight-week, modified group CBT intervention targeting both social anxiety and social functioning, that included social skills training, exposure tasks and behavioural experiment components. Seventy-eight adolescents and young adults with ASD, without intellectual impairment, aged between 16 and 38 (M = 22.77; SD = 5.31), were recruited from the community, Headspace centres and the Autism Clinic for Translational Research at the Brain and Mind Centre, University of Sydney. Outcomes (social anxiety, social functioning and mood) were measured pre- and post-intervention via self-report questionnaires (administered either online or through the return of hard-copy booklets), and participants were invited to provide anonymous feedback on the intervention (at the mid-point and end of the intervention). Results Participants demonstrated statistically significant improvements on all outcome measures in response to the intervention. Specifically, social anxiety symptoms decreased (p p = .032) and restricted interests and repetitive behaviours (p = .025). Self-reported symptom improvements also generalised to mood (depression, anxiety and stress; p Limitations The absence of a control group and follow-up measures, reliance on self-report instruments as outcome measures and the exclusion of those with intellectual disability represent significant limitations to this study. Conclusions These findings indicate that a group CBT intervention appears to be a beneficial intervention for self-reported social anxiety, social functioning and overall mental health in adolescents and young adults with ASD. The stand-alone nature of the intervention combined with positive participant feedback indicates it was well tolerated, has potential clinical utility and warrants further study in a randomised-controlled, follow-up design.

Purpose The Brain and Mind Centre (BMC) Optymise cohort assesses multiple clinical and functional domains longitudinally in young people presenting for mental health care and treatment. Longitudinal tracking of this cohort will allow investigation of the relationships between multiple outcome domains across the course of care. Subsets of Optymise have completed detailed neuropsychological and neurobiological assessments, permitting investigation of associations between these measures and longitudinal course. Participants Young people (aged 12–30) presenting to clinics coordinated by the BMC were recruited to a research register (n=6743) progressively between June 2008 and July 2018. To date, 2767 individuals have been included in Optymise based on the availability of at least one detailed clinical assessment. Measures Trained researchers use a clinical research proforma to extract key data from clinical files to detail social and occupational functioning, clinical presentation, self-harm and suicidal thoughts and behaviours, alcohol and other substance use, physical health comorbidities, personal and family history of mental illness, and treatment utilisation at the following time points: baseline, 3, 6, 12, 24, 36, 48, and 60 months, and time last seen. Findings to date There is moderate to substantial agreement between raters for data collected via the proforma. While wide variations in individual illness course are clear, social and occupational outcomes suggest that the majority of cohort members show no improvement in functioning over time. Differential rates of longitudinal transition are reported between early and late stages of illness, with a number of baseline factors associated with these transitions. Furthermore, there are longitudinal associations between prior suicide attempts and inferior clinical and functional outcomes. Future plans Future reports will detail the longitudinal course of each outcome domain and examine multidirectional relationships between these domains both cross-sectionally and longitudinally, and explore in subsets the associations between detailed neurobiological measures and clinical, social and functional outcomes.

PurposeThe Brain and Mind Centre (BMC)Optymisecohort assesses multiple clinical and functional domains longitudinally in young people presenting for mental health care and treatment. Longitudinal tracking of this cohort will allow investigation of the relationships between multiple outcome domains across the course of care. Subsets ofOptymisehave completed detailed neuropsychological and neurobiological assessments, permitting investigation of associations between these measures and longitudinal course.ParticipantsYoung people (aged 12–30) presenting to clinics coordinated by the BMC were recruited to a research register (n=6743) progressively between June 2008 and July 2018. To date, 2767 individuals have been included inOptymisebased on the availability of at least one detailed clinical assessment.MeasuresTrained researchers use a clinical research proforma to extract key data from clinical files to detail social and occupational functioning, clinical presentation, self-harm and suicidal thoughts and behaviours, alcohol and other substance use, physical health comorbidities, personal and family history of mental illness, and treatment utilisation at the following time points: baseline, 3, 6, 12, 24, 36, 48, and 60 months, and time last seen.Findings to dateThere is moderate to substantial agreement between raters for data collected via the proforma. While wide variations in individual illness course are clear, social and occupational outcomes suggest that the majority of cohort members show no improvement in functioning over time. Differential rates of longitudinal transition are reported between early and late stages of illness, with a number of baseline factors associated with these transitions. Furthermore, there are longitudinal associations between prior suicide attempts and inferior clinical and functional outcomes.Future plansFuture reports will detail the longitudinal course of each outcome domain and examine multidirectional relationships between these domains both cross-sectionally and longitudinally, and explore in subsets the associations between detailed neurobiological measures and clinical, social and functional outcomes.

There is an increasing push to identify the neurobiology associated with Autism Spectrum Disorder (ASD) including via Magnetic Resonance Imaging (MRI). Much of the previous research, however, has used behavioral or intelligence score criteria to increase feasibility of such assessments, particularly in studies investigating the effects of intervention on the brain. Such restrictions, however, exclude a significant proportion of potential participants with ASD, potentially biasing the development of subtypes and treatments. To address the need for inclusive clinical trials that include neurobiological measures, this study investigated the feasibility of MRI scanning in a comprehensive, inclusive clinical trial for children (aged 3-12 years) with ASD. No adaptive functioning or IQ score criteria were required for enrollment into the trial. Of the 71 participants who consented to the MRI component of the protocol, 24 successfully completed the scan at baseline. At post-treatment, 22 participants returned, with 21 successful scan completions. This study illustrates the possibility of MRI inclusion in comprehensive clinical trials that include a number of measures for children with ASD and highlights limitations evident when MRI is not the focus of the trial.

Oxytocin has garnered considerable interest for its role in social behavior, as well as for the potential of intranasal administration to treat social difficulties. However, current theoretical models for the role of oxytocin in social behavior pay little consideration to its evolutionary and developmental history. This article aims to broaden our understanding of the role of oxytocin in social behavior by adopting an ethological approach through the lens of Nikolaas Tinbergen's 'four questions' - how does oxytocin work; how does the role of oxytocin change during development; how does oxytocin enhance survival; and how did the oxytocin system evolve? We argue that oxytocin is most accurately described as an allostatic hormone that modulates both social and non-social behavior by maintaining stability through changing environments.

Background For people with disabilities to live a good life, it is essential that funded research in health and social care addresses their interests, meets their needs, and fills gaps in our understanding of the impact that services, systems, and policies may have on them. Decisions about research funding should be based on an understanding of the research priorities of people with disabilities, their supporters and allies, disability researchers, service providers, and policy makers working in the field. Objective The aim of this protocol is to describe the research design and methods of a large-scale, disability research agenda–setting exercise conducted in 2021 in Australia. Methods The research agenda–setting exercise involves 3 integrated phases of work. In the first phase, a previous audit of disability research in Australia is updated to understand previous research and continuing gaps in the research. Building on this, the second phase involves consultation with stakeholders—people with disabilities and their supporters and family members, the disability workforce, and people working within services and connected sectors (eg, aging, employment, education, and housing), academia, and public policy. Data for the second phase will be gathered as follows: a national web-based survey; a consultation process undertaken through the government and nongovernment sector; and targeted consultation with Aboriginal and Torres Strait Islander people, children with disabilities and their families, people with cognitive disability, and people with complex communication needs. The third phase involves a web-based survey to develop a research agenda based on the outcomes of all phases. Results We have started working on 2 parts of the research prioritization exercise. Through the research-mapping exercise we identified 1241 journal articles and book chapters (referred to as research papers) and 225 publicly available reports (referred to as research reports) produced over the 2018-2020 period. Data collection for the national survey has also been completed. We received 973 fully completed responses to the survey. Analysis of these data is currently underway. Conclusions This multi-method research agenda–setting study will be the first to provide an indication of the areas of health and social research that people across the Australian disability community consider should be prioritized in disability research funding decisions. Project results from all phases will be made publicly available through reports, open-access journal publications, and Easy Read documents. International Registered Report Identifier (IRRID) DERR1-10.2196/31126

Impairments in social cognition are believed contribute to disability, particularly for disorders characterized by difficulties in social interaction. There has been little transdiagnostic investigation of this across social cognition domains in young adults. A total of 199 young adults diagnosed with autism spectrum disorder (ASD; N = 53), early psychosis (EP; N = 51), and social anxiety disorder (SAD; N = 64) were compared against neurotypical controls (NT; N = 31) on a battery of lower and higher-order and self-report social cognition measures. For both ASD and EP, participants showed impaired performance on all lower-order emotion recognition tasks and one higher-order social cognition test. Self-reports of empathy were reduced in all clinical groups and particularly in ASD. For SAD, despite showing no objective social cognition impairment, self-reported empathy was reduced to the same level as EP. Discriminant analysis revealed that self-reported empathy and lower-order emotion recognition tests provide best capacity to differentiate groups. Regressions predicting disability revealed depression as the strongest predictor across all disability measures. Empathy provided additional predictive value for social disability and social interaction anxiety. Overall, results support a similar social-cognitive development profile across ASD and EP. While self-reported empathy differentiated between groups, discrepancy between objective social cognition test performance and self-reported empathy in the SAD group suggests probable threat-related self-monitoring report biases that likely further influence all group outcomes. As depression and empathy were the most important predictors of disability, regardless of diagnostic group, research is required to explore targeted interventions for difficulties in these domains to reduce disability.

This review presents an outline of executive function (EF) and its application to autism spectrum disorder (ASD). The development of the EF construct, theoretical models of EF, and limitations in the study of EF are outlined. The potential of EF as a cognitive endophenotype for ASD is reviewed, and the Research Domain Criteria (RDoC) framework is discussed for researching EF in ASD given the multifaceted factors that influence EF performance. A number of executive-focused cognitive models have been proposed to explain the symptom clusters observed in ASD. Empirical studies suggest a broad impairment in EF, although there is significant inter-individual variability in EF performance. The observed heterogeneity of EF performance is considered a limiting factor in establishing EF as a cognitive endophenotype in ASD. We propose, however, that this variability in EF performance presents an opportunity for subtyping within the spectrum that can contribute to targeted diagnostic and intervention strategies. Enhanced understanding of the neurobiological basis that underpins EF performance, such as the excitation/inhibition hypothesis, will likely be important. Application of the RDoC framework could provide clarity on the nature of EF impairment in ASD with potential for greater understanding of, and improved interventions for, this disorder.

Mood and psychotic syndromes most often emerge during adolescence and young adulthood, a period characterised by major physical and social change. Consequently, the effects of adolescent-onset mood and psychotic syndromes can have long term consequences. A key clinical challenge for youth mental health is to develop and test new systems that align with current evidence for comorbid presentations and underlying neurobiology, and are useful for predicting outcomes and guiding decisions regarding the provision of appropriate and effective care. Our highly personalised and measurement-based care model includes three core concepts: ▶ A multidimensional assessment and outcomes framework that includes: social and occupational function; self-harm, suicidal thoughts and behaviour; alcohol or other substance misuse; physical health; and illness trajectory. ▶ Clinical stage. ▶ Three common illness subtypes (psychosis, anxious depression, bipolar spectrum) based on proposed pathophysiological mechanisms (neurodevelopmental, hyperarousal, circadian). The model explicitly aims to prevent progression to more complex and severe forms of illness and is better aligned to contemporary models of the patterns of emergence of psychopathology. Inherent within this highly personalised approach is the incorporation of other evidence-based processes, including real-time measurement-based care as well as utilisation of multidisciplinary teams of health professionals. Data-driven local system modelling and personalised health information technologies provide crucial infrastructure support to these processes for better access to, and higher quality, mental health care for young people. CHAPTER 1: MULTIDIMENSIONAL OUTCOMES IN YOUTH MENTAL HEALTH CARE: WHAT MATTERS AND WHY?: Mood and psychotic syndromes present one of the most serious public health challenges that we face in the 21st century. Factors including prevalence, age of onset, and chronicity contribute to substantial burden and secondary risks such as alcohol or other substance misuse. Mood and psychotic syndromes most often emerge during adolescence and young adulthood, a period characterised by major physical and social change; thus, effects can have long term consequences. We propose five key domains which make up a multidimensional outcomes framework that aims to address the specific needs of young people presenting to health services with emerging mental illness. These include social and occupational function; self-harm, suicidal thoughts and behaviours; alcohol or other substance misuse; physical health; and illness type, stage and trajectory. Impairment and concurrent morbidity are well established in young people by the time they present for mental health care. Despite this, services and health professionals tend to focus on only one aspect of the presentation - illness type, stage and trajectory - and are often at odds with the preferences of young people and their families. There is a need to address the disconnect between mental health, physical health and social services and interventions, to ensure that youth mental health care focuses on the outcomes that matter to young people. CHAPTER 2: COMBINING CLINICAL STAGE AND PATHOPHYSIOLOGICAL MECHANISMS TO UNDERSTAND ILLNESS TRAJECTORIES IN YOUNG PEOPLE WITH EMERGING MOOD AND PSYCHOTIC SYNDROMES: Traditional diagnostic classification systems for mental disorders map poorly onto the early stages of illness experienced by young people, and purport categorical distinctions that are not readily supported by research into genetic, environmental and neurobiological risk factors. Consequently, a key clinical challenge in youth mental health is to develop and test new classification systems that align with current evidence on comorbid presentations, are consistent with current understanding of underlying neurobiology, and provide utility for predicting outcomes and guiding decisions regarding the provision of appropriate and effective care. This chapter outlines a transdiagnostic framework for classifying common adolescent-onset mood and psychotic syndromes, combining two independent but complementary dimensions: clinical staging, and three proposed pathophysiological mechanisms. Clinical staging reflects the progression of mental disorders and is in line with the concept used in general medicine, where more advanced stages are associated with a poorer prognosis and a need for more intensive interventions with a higher risk-to-benefit ratio. The three proposed pathophysiological mechanisms are neurodevelopmental abnormalities, hyperarousal and circadian dysfunction, which, over time, have illness trajectories (or pathways) to psychosis, anxious depression and bipolar spectrum disorders, respectively. The transdiagnostic framework has been evaluated in young people presenting to youth mental health clinics of the University of Sydney's Brain and Mind Centre, alongside a range of clinical and objective measures. Our research to date provides support for this framework, and we are now exploring its application to the development of more personalised models of care. CHAPTER 3: A COMPREHENSIVE ASSESSMENT FRAMEWORK FOR YOUTH MENTAL HEALTH: GUIDING HIGHLY PERSONALISED AND MEASUREMENT-BASED CARE USING MULTIDIMENSIONAL AND OBJECTIVE MEASURES: There is an urgent need for improved care for young people with mental health problems, in particular those with subthreshold mental disorders that are not sufficiently severe to meet traditional diagnostic criteria. New comprehensive assessment frameworks are needed to capture the biopsychosocial profile of a young person to drive highly personalised and measurement-based mental health care. We present a range of multidimensional measures involving five key domains: social and occupational function; self-harm, suicidal thoughts and behaviours; alcohol or other substance misuse; physical health; and illness type, stage and trajectory. Objective measures include: neuropsychological function; sleep-wake behaviours and circadian rhythms; metabolic and immune markers; and brain structure and function. The recommended multidimensional measures facilitate the development of a comprehensive clinical picture. The objective measures help to further develop informative and novel insights into underlying pathophysiological mechanisms and illness trajectories to guide personalised care plans. A panel of specific multidimensional and objective measures are recommended as standard clinical practice, while others are recommended secondarily to provide deeper insights with the aim of revealing alternative clinical paths for targeted interventions and treatments matched to the clinical stage and proposed pathophysiological mechanisms of the young person. CHAPTER 4: PERSONALISING CARE OPTIONS IN YOUTH MENTAL HEALTH: USING MULTIDIMENSIONAL ASSESSMENT, CLINICAL STAGE, PATHOPHYSIOLOGICAL MECHANISMS, AND INDIVIDUAL ILLNESS TRAJECTORIES TO GUIDE TREATMENT SELECTION: New models of mental health care for young people require that interventions be matched to illness type, clinical stage, underlying pathophysiological mechanisms and individual illness trajectories. Narrow syndrome-focused classifications often direct clinical attention away from other key factors such as functional impairment, self-harm and suicidality, alcohol or other substance misuse, and poor physical health. By contrast, we outline a treatment selection guide for early intervention for adolescent-onset mood and psychotic syndromes (ie, active treatments and indicated and more specific secondary prevention strategies). This guide is based on experiences with the Brain and Mind Centre's highly personalised and measurement-based care model to manage youth mental health. The model incorporates three complementary core concepts: ▶A multidimensional assessment and outcomes framework including: social and occupational function; self-harm, suicidal thoughts and behaviours; alcohol or other substance misuse; physical health; and illness trajectory. ▶Clinical stage. ▶Three common illness subtypes (psychosis, anxious depression, bipolar spectrum) based on three underlying pathophysiological mechanisms (neurodevelopmental, hyperarousal, circadian). These core concepts are not mutually exclusive and together may facilitate improved outcomes through a clinical stage-appropriate and transdiagnostic framework that helps guide decisions regarding the provision of appropriate and effective care options. Given its emphasis on adolescent-onset mood and psychotic syndromes, the Brain and Mind Centre's model of care also respects a fundamental developmental perspective - categorising childhood problems (eg, anxiety and neurodevelopmental difficulties) as risk factors and respecting the fact that young people are in a period of major biological and social transition. Based on these factors, a range of social, psychological and pharmacological interventions are recommended, with an emphasis on balancing the personal benefit-to-cost ratio. CHAPTER 5: A SERVICE DELIVERY MODEL TO SUPPORT HIGHLY PERSONALISED AND MEASUREMENT-BASED CARE IN YOUTH MENTAL HEALTH: Over the past decade, we have seen a growing focus on creating mental health service delivery models that better meet the unique needs of young Australians. Recent policy directives from the Australian Government recommend the adoption of stepped-care services to improve the appropriateness of care, determined by severity of need. Here, we propose that a highly personalised approach enhances stepped-care models by incorporating clinical staging and a young person's current and multidimensional needs. It explicitly aims to prevent progression to more complex and severe forms of illness and is better aligned to contemporary models of the patterns of emergence of psychopathology. Inherent within a highly personalised approach is the incorporation of other evidence-based processes, including real-time measurement-based care and use of multidisciplinary teams of health professionals. Data-driven local system modelling and personalised health information technologies provide crucial infrastructure support to these processes for better access to, and higher quality of, mental health care for young people.

Fluorine-18 labelled prosthetic groups (PGs) are often necessary for radiolabelling sensitive biological molecules such as peptides and proteins. Several shortcomings, however, often diminish the final yield of radiotracer. In an attempt to provide higher yielding and operationally efficient tools for radiolabelling biological molecules, we describe herein the first radiochemical synthesis of [18 F]ethenesulfonyl fluoride ([18 F]ESF) and its Michael conjugation with amino acids and proteins. The synthesis of [18 F]ESF was optimised using a microfluidic reactor under both carrier-added (c.a.) and no-carrier-added (n.c.a.) conditions, affording, in a straightforward procedure, 30-50% radiochemical yield (RCY) for c.a. [18 F]ESF and 60-70% RCY for n.c.a. [18 F]ESF. The conjugation reactions were performed at room temperature using 10 mg/mL precursor in aqueous/organic solvent mixtures for 15 min. The radiochemical stability of the final conjugates was evaluated in injectable formulation and rat serum, and resulted strongly substrate dependent and generally poor in rat serum. Therefore, in this work we have optimised a straightforward synthesis of [18 F]ESF and its Michael conjugation with model compounds, without requiring chromatographic purification. However, given the general low stability of the final products, further studies will be required for improving conjugate stability, before assessing the use of this PG for PET imaging.

Background Autism spectrum disorders (ASDs) are complex, pervasive, and heterogeneous neurodevelopmental conditions with varying trajectories, significant male bias and largely unknown etiology. However, an understanding of the biological mechanisms driving pathophysiology is evolving. Immune system aberrations, as identified through cytokine profiles, are believed to have a role in ASD. Altered cytokine levels may facilitate identification of ASD subtypes as well as provide biological markers of response to effective treatments. Research exploring the relationship between cytokine profiles and ASD symptoms is, however, in its infancy. The objective of this study was to explore relationships between cytokine levels and the severity of ASD and other clinical traits. Methods Multiplex assay techniques were used to measure levels of 27 cytokines in plasma samples from a cohort of 144 children diagnosed with ASD. Results Overall, results showed a significant negative association between platelet-derived growth factor (PDGF)-BB, and the severity of ASD symptoms. Furthermore, a significant interaction with sex suggested a different immune profile for females compared to males. ASD symptom severity was negatively associated with levels of 4 cytokines, IL-1β, IL-8, MIP-1β, and VEGF, in females, but not in males. Conclusions Results of the present study suggest that an altered cytokine response or profile is associated with the severity of ASD-related symptoms, with sex a potential modifier of this relationship. Further research in larger populations which recognizes the importance of sex comparisons and longitudinal assessments are now required to extend and further describe the role of the immune system in ASD. Electronic supplementary material The online version of this article (10.1186/s13229-017-0176-2) contains supplementary material, which is available to authorized users.

Maternal immune activation has been highlighted as a factor that might increase the risk and severity of autism spectrum disorder (ASD) in children. Preclinical animal evidence shows that immune activation in mothers during pregnancy causes ASD-like behavioural traits in offspring. To this point, there has been no investigation of whether immune system activation in human mothers during pregnancy is associated with more severe symptoms in children with ASD. In this study, data from an existing ASD cohort (N=220) were analysed to investigate whether immune conditions in the mother were associated with greater severity of autism-related symptoms. Results showed that children whose mothers reported a history of immune activation (allergies and asthma) had significantly higher scores on the Social Responsiveness Scale (SRS; P=0.016), suggesting more severe social impairment symptoms in these children. This increasing severity of social impairment symptoms was further shown on the SRS cognition (P=0.007) and mannerisms (P=0.002) subscales. While immune history was associated with an increase in the severity of social impairment symptoms, history of autoimmune conditions in the mother did not have any effect in this cohort. To the best of our knowledge, this study is the first to show an association between immune activation history in the mother and increased ASD symptom severity in children with ASD. These findings support the idea of an immune system-mediated subtype in ASD, where the immune history of the mother may be an important factor.