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Abstract Background Chimeric antigen receptor (CAR) T-cell therapy has proven to be a valuable new treatment option for patients with B-cell malignancies. However, by applying selective pressure, outgrowth of antigen-negative tumor cells can occur, eventually resulting in relapse. Subsequent rescue by administration of CAR-T cells with different antigen-specificity indicates that those tumor cells are still sensitive to CAR-T treatment and points towards a multi-target strategy. Due to their natural tumor sensitivity and highly cytotoxic nature, natural killer (NK) cells are a compelling alternative to T cells, especially considering the availability of an off-the-shelf unlimited supply in the form of the clinically validated NK-92 cell line. Methods Given our goal to develop a flexible system whereby the CAR expression repertoire of the effector cells can be rapidly adapted to the changing antigen expression profile of the target cells, electrotransfection with CD19-/BCMA-CAR mRNA was chosen as CAR loading method in this study. We evaluated the functionality of mRNA-engineered dual-CAR NK-92 against tumor B-cell lines and primary patient samples. In order to test the clinical applicability of the proposed cell therapy product, the effect of irradiation on the proliferative rate and functionality of dual-CAR NK-92 cells was investigated. Results Co-electroporation of CD19 and BMCA CAR mRNA was highly efficient, resulting in 88.1% dual-CAR NK-92 cells. In terms of CD107a degranulation, and secretion of interferon (IFN)-γ and granzyme B, dual-CAR NK-92 significantly outperformed single-CAR NK-92. More importantly, the killing capacity of dual-CAR NK-92 exceeded 60% of single and dual antigen-expressing cell lines, as well as primary tumor cells, in a 4h co-culture assay at low effector to target ratios, matching that of single-CAR counterparts. Furthermore, our results confirm that dual-CAR NK-92 irradiated with 10 Gy cease to proliferate and are gradually cleared while maintaining their killing capacity. Conclusions Here, using the clinically validated NK-92 cell line as a therapeutic cell source, we established a readily accessible and flexible platform for the generation of highly functional dual-targeted CAR-NK cells.

Objectives: The rate of mental health services provided to children and young people is increasing worldwide, including in Australia. The aim of this study was to describe patterns of hospital and ambulatory mental health service use among a large population cohort of adolescents followed from birth, with consideration of variation by age, sex and diagnosis., Methods: Characteristics of services provided for children with mental disorder diagnoses between birth and age 17.5 years were ascertained for a population cohort of 85,642 children (52.0% male) born between 2002 and 2005, from 'Admitted Patients', 'Emergency Department' and 'Mental Health Ambulatory' records provided by the New South Wales and Australian Capital Territory Health Departments., Results: A total of 11,205 (~13.1%) children received at least one hospital or ambulatory health occasion of service for a mental health condition in the observation period. More than two-fifths of children with mental disorders had diagnoses spanning multiple categories of disorder over time. Ambulatory services were the most heavily used and the most common point of first contact. The rate of mental health service contact increased with age across all services, and for most categories of mental disorder. Girls were more likely to receive services for mental disorders than boys, but boys generally had an earlier age of first service contact. Finally, 3.1% of children presenting to mental health services experienced involuntary psychiatric inpatient admission., Conclusions: The extent of hospital and ambulatory-based mental healthcare service among children emphasises the need for primary prevention and early intervention., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Identification of youth presenting early risk factors for psychosis may facilitate preventive intervention. Through school-based screening, we recruited 112 children aged 9-12 years who presented multiple putative antecedents of schizophrenia (ASz), a family history of schizophrenia (FHx), or neither of these risk factors (typically-developing; TD). Clinical and functional outcomes were assessed at age 17-21 years (N = 93). Compared to the TD group, the ASz group had higher total Prodromal Questionnaire (PQ) scores (β = 10.59, 95% CI = 3.76, 17.42) and total psychopathology scores (β = 6.13, 95% CI: 1.03, 11.23), were more likely to score above-threshold on the PQ positive symptoms scale (OR = 4.00, 95% CI = 1.08, 14.83), and had lower scores on the Social and Occupational Functioning Scale (β = -9.43, 95% CI = -15.08, -3.77) at follow-up. The FHx and TD groups did not differ on any outcome. Findings suggest that population screening for putative antecedents of schizophrenia may identify children who would benefit from preventative intervention., (© 2024. The Author(s).)

Cumulative comorbidity of mental disorders is common, but the extent and patterns of comorbid psychopathology in childhood are not well established. The current study aimed to elucidate the emergent patterns of cumulative mental disorder comorbidity in children using network analysis of diagnoses recorded between birth and age 12 years. Participants were 90,269 children (mean age 12.7 years; 51.8% male) within the New South Wales Child Development Study (NSW-CDS)-a longitudinal record-linkage cohort study of Australian children born in NSW between 2002 and 2005. Binary indicators for eight types of mental disorder were derived from administrative health records. Patterns of conditional association between mental disorders were assessed utilising network analysis. Of 90,269 children, 2268 (2.5%) had at least one mental disorder by age 12 years; of the 2268 children who had at least one mental disorder by age 12 years, 461 (20.3%) were diagnosed with two or more different disorders out of the eight disorder types included in analyses. All disorders were either directly or indirectly interconnected, with childhood affective and emotional disorders and developmental disorders being most central to the network overall. Mental disorder nodes aggregated weakly (modularity = 0.185) into two communities, representative of internalising and externalising disorders, and neurodevelopmental and sleep disorders. Considerable sex differences in the structure of the mental disorder comorbidity networks were also observed. Developmental and childhood affective and emotional disorders appear to be key to mental disorder comorbidity in childhood, potentially reflecting that these disorders share symptoms in common with many other disorders., (© 2023. The Author(s).)

The relationship between childhood maltreatment and subsequent offending/victimization is well established. However, the magnitude of this relationship for different levels of child protection services (CPS) involvement is poorly understood, due to measurement issues, lack of longitudinal data, and reliance on reports of substantiated maltreatment, which can underestimate the impact of maltreatment. This study examined associations between CPS involvement during childhood (ages 0 to <11 years) and police services contact (as a victim and/or a person of interest) for criminal incidents in early adolescence (11 to ~14 years), differentiated according to levels of CPS involvement (i.e., no risk of significant harm [non-ROSH], unsubstantiated ROSH, substantiated ROSH, and out-of-home care; each examined relative to no CPS contact). Data for 71,465 children were drawn from the New South Wales Child Development Study, an intergenerational, longitudinal investigation that uses administrative records from CPS and police alongside other health, justice, and education data. Multinomial regression analyses were conducted to determine associations between increasing levels of CPS involvement and police contact as a victim only, a person of interest only, and as both victim and person of interest while accounting for covariates (i.e., child's sex, Aboriginal, and/or Torres Strait Islander background, socioeconomic status, maternal age at child's birth, and parental offending history). Children exposed to any of the four levels of CPS involvement had higher odds of police contact, relative to children with no CPS involvement. Odds ratios were higher for contact with police as both a victim and a person of interest, compared to police contact as a victim or a person of interest only. These findings highlight that children with even unsubstantiated CPS reports (i.e., non-ROSH and unsubstantiated ROSH reports) are at heightened risk of police contact compared to children who are unknown to CPS, underlining the need to support all families in contact with CPS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interests with respect to the authorship and/or publication of this article.

Background: Air pollution has been linked to a variety of childhood mental health problems, but results are inconsistent across studies and the effect of exposure timing is unclear. We examined the associations between air pollution exposure at two time-points in early development and psychotic-like experiences (PLEs), and emotional and conduct symptoms, assessed in middle childhood (mean age 11.5 years)., Methods: Participants were 19,932 children selected from the NSW Child Development Study (NSW-CDS) with available linked multi-agency data from birth, and self-reported psychotic-like experiences (PLEs) and psychopathology at age 11-12 years (middle childhood). We used binomial logistic regression to examine associations between exposure to nitrogen dioxide (NO 2 ) and particulate matter less than 2.5 μm (PM 2.5 ) at two time-points (birth and middle childhood) and middle childhood PLEs, and emotional and conduct symptoms, with consideration of socioeconomic status and other potential confounding factors in adjusted models., Results: In fully adjusted models, NO 2 exposure in middle childhood was associated with concurrent PLEs (OR = 1.10, 95% CI = 1.02-1.20). Similar associations with PLEs were found for middle childhood exposure to PM 2.5 (OR = 1.05, 95% CI = 1.01-1.09). Neither NO 2 nor PM 2.5 exposure was associated with emotional symptoms or conduct problems in this study., Conclusions: This study highlights the need for a better understanding of potential mechanisms of action of NO 2 in the brain during childhood., (© 2023. The Author(s).)

Background and Hypothesis: Schizotypy provides a framework for understanding the developmental nature of psychotic disorders and a means of identifying "at-risk" individuals early in the lifespan. However, there is a lack of prospective longitudinal research examining the relationship between schizotypy in childhood and later psychotic and other mental disorders. We hypothesized that distinct profiles of schizotypy in childhood would be differentially associated with psychotic and other mental disorders emerging later in adolescence., Study Design: In a large population cohort of Australian young people (n = 26 837), we prospectively examined the relationship between person-centered profiles of schizotypy identified in middle childhood (age ~11 years) and adolescent diagnoses (age ~13-18 years) across 7 types of mental disorders using multinomial logistic regression., Results: Membership in any of 3 childhood schizotypy profiles (true schizotypy, affective schizotypy, or introverted schizotypy) was associated with an increased likelihood of being diagnosed with any type of mental disorder in adolescence; effects were strongest for the true schizotypy group (aOR = 3.07, 95% CI = 2.64, 3.57), followed by the introverted (aOR = 1.94, 95% CI = 1.75, 2.15) and affective (aOR = 1.29, 95% CI = 1.13, 1.47) schizotypy groups. Six of the 7 types of mental disorders measured (including psychotic disorders) were associated with at least 1 schizotypy group., Conclusions: Schizotypy in middle childhood is an important correlate of mental disorders in adolescence; however, it does not appear to be specifically associated with psychotic disorders in this age group., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: The current study aimed to assess the measurement invariance of the 9-item self-report Psychotic-Like Experiences Questionnaire for Children (PLEQ-C) across various demographic (age, gender, ethnicity) and psychopathology profiles in a community sample of children., Methods: Children aged 9-11 years (n = 613; M age = 10.4 years [SD = 0.8]; 50.9% female) completed questionnaire screening at school, with primary caregivers returning questionnaires by mail from home. Configural, metric, scalar, and residual invariance of the PLEQ-C scores were investigated across groups differentiated by age (9; 10; 11 years), gender (female; male), ethnicity (white; black; other), and by child-reported and caregiver-reported psychopathology (abnormal rating; not abnormal)., Results: The PLEQ-C scores demonstrated good unidimensional model fit. Full configural, metric, scalar, and residual invariance were demonstrated across gender, ethnicity, and psychopathology (both child- and caregiver-reported). Across age groups, the PLEQ-C scores showed full configural and metric invariance, but only partial scalar and residual invariance (with a single item measuring differently among 11-year-olds)., Conclusions: In this community sample, the PLEQ-C was robust to age, gender, ethnicity, and psychopathology profiles, providing evidence of its capacity to identify children in the general population who might benefit from further assessment to determine the clinical significance of their psychotic experiences., (© 2023 The Authors. International Journal of Methods in Psychiatric Research published by John Wiley & Sons Ltd.)

Objective: We investigated patterns of service contact for self-harm and suicidal ideation recorded by a range of human service agencies - including health, police and child protection - with specific focus on overlap and sequences of contacts, age of first contact and demographic and intergenerational characteristics associated with different service responses to self-harm., Methods: Participants were 91,597 adolescents for whom multi-agency linked data were available in a longitudinal study of a population cohort in New South Wales, Australia. Self-harm and suicide-related incidents from birth to 18 years of age were derived from emergency department, inpatient hospital admission, mental health ambulatory, child protection and police administrative records. Descriptive statistics and binomial logistic regression were used to examine patterns of service contacts., Results: Child protection services recorded the largest proportion of youth with reported self-harm and suicidal ideation, in which the age of first contact for self-harm was younger relative to other incidents of self-harm recorded by other agencies. Nearly 40% of youth with a health service contact for self-harm also had contact with child protection and/or police services for self-harm. Girls were more likely to access health services for self-harm than boys, but not child protection or police services., Conclusion: Suicide prevention is not solely the responsibility of health services; police and child protection services also respond to a significant proportion of self-harm and suicide-related incidents. High rates of overlap among different services responding to self-harm suggest the need for cross-agency strategies to prevent suicide in young people., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Purpose: To investigate relationships between distinct schizotypy risk profiles in childhood and the full spectrum of parental mental disorders., Methods: Participants were 22,137 children drawn from the New South Wales Child Development Study, for whom profiles of risk for schizophrenia-spectrum disorders in middle childhood (age ~ 11 years) were derived in a previous study. A series of multinomial logistic regression analyses examined the likelihood of child membership in one of three schizotypy profiles (true schizotypy, introverted schizotypy, and affective schizotypy) relative to the children showing no risk, according to maternal and paternal diagnoses of seven types of mental disorders., Results: All types of parental mental disorders were associated with membership in all childhood schizotypy profiles. Children in the true schizotypy group were more than twice as likely as children in the no risk group to have a parent with any type of mental disorder (unadjusted odds ratio [OR] = 2.27, 95% confidence intervals [CI] = 2.01-2.56); those in the affective (OR = 1.54, 95% CI = 1.42-1.67) and introverted schizotypy profiles (OR = 1.39, 95% CI = 1.29-1.51) were also more likely to have been exposed to any parental mental disorder, relative to children showing no risk., Conclusion: Childhood schizotypy risk profiles appear not to be related specifically to familial liability for schizophrenia-spectrum disorders; this is consistent with a model where liability for psychopathology is largely general rather than specific to particular diagnostic categories., (© 2023. The Author(s).)

Objectives: Parental mental health has a profound influence on the mental health and well-being of their offspring. With comorbid mental disorders generally the rule rather than the exception, increased knowledge of the impact of parental mental disorder comorbidity on early child development may facilitate improved targeting and delivery of early intervention for vulnerable offspring., Methods: Participants were 66,154 children and their parents in the New South Wales Child Development Study - a prospective, longitudinal, record-linkage study of a population cohort of children born in NSW between 2002 and 2004. Early childhood developmental vulnerability was assessed at age ~5 years using the Australian Early Development Census, and information on parental mental disorders was obtained from administrative health records. Binomial and multinomial logistic regression were used to assess the relationship between parental mental disorders and early childhood developmental vulnerability on emotional and behavioural domains, as well as membership of latent developmental risk classes reflecting particular classes of vulnerability., Results: Multiple diagnoses of mental disorders in mothers and fathers were associated with an increased likelihood of early childhood emotional and behavioural developmental vulnerability in offspring, relative to parents without mental disorder. The likelihood of offspring vulnerability increased with the number of parental comorbidities, particularly maternal comorbidities., Conclusion: Early childhood developmental vulnerability was strongly associated with parental mental ill-health, with the strength of associations increasing in line with a greater number of mental disorder diagnoses among mothers and fathers. New and expectant parents diagnosed with multiple mental disorders should be prioritised for intervention, including attention to the developmental well-being of their offspring.

This study examined the influence of stigma, psychopathology, and sociodemographic characteristics on mental health-related service use and costs related to service use in a cohort of young people in the UK. Using data from a community sample of young people aged 9-17 years and their caregivers, we assessed 407 young people's use of services due to mental health problems, young people's psychopathology, demographic characteristics, maternal education and caregivers' stigma-related beliefs. Unit costs related to services were gathered from national annual compendia and other widely used sources. We assessed predictors of service use through logistic regression analysis and developed generalised linear models to identify factors associated with costs of mental health-related service utilisation. Persistent psychopathology, socioeconomic disadvantage, and low caregiver intended stigma-related behaviour were associated with increased likelihood of service use among young people. Older age and socioeconomic disadvantage were associated with increased costs. Different factors influenced contact with services and the cost associated with their use - persistent psychopathology and socioeconomic disadvantage increased, and caregivers' intended stigma-related behaviour decreased the likelihood of using services, whereas socioeconomic disadvantage and older age were associated with increased costs. Social determinants of mental health problems play an important role in the use and costs of different types of mental health-related services for young people. Discordance between drivers of service use and costs implies that young people who are more likely to access services due to mental health problems do not necessarily receive care at the intensity they need., (© 2022. The Author(s).)

Objective: The processes facilitating resilience are likely to be influenced by individual, familial and contextual factors that are dynamic across the life-course. These factors have been less studied in relation to resilience profiles evident in the developmental period between early to middle childhood, relative to later periods of adolescence or adulthood., Method: This study examined factors associated with resilience in a cohort of 4,716 children known to child protection services by age 13 years, in the Australian State of New South Wales. Latent profile and transition analyses were used to identify multi-dimensional profiles of resilience as evident in social, emotional and cognitive functioning when assessed in early childhood (time 1 [T1], age 5-6 years) and middle childhood (time 2 [T2], age 10-11 years). Logistic regression models were used to investigate factors associated with two types of resilience identified: a transition profile of stress-resistance (i.e., represented by a typically developing profile at both T1 and T2) delineated in the largest subgroup (54%) of children, and a smaller subgroup (13%) with a profile of emergent resilience (i.e., typically developing at T2 following a vulnerable profile at T1)., Results: Factors associated with resilience profiles included being female, and personality characteristics of openness and extraversion; other factors associated with stress-resistance , specifically, included higher socioeconomic status, non-Indigenous background, higher perceived port at home and at school, and not having a parent with a history of criminal offending., Conclusions: Resilience processes appear to involve a complex interplay between individual, family, and community characteristics requiring interagency support.

Background: No single environmental factor is a necessary or sufficient cause of mental disorder; multifactorial and transdiagnostic approaches are needed to understand the impact of the environment on the development of mental disorders across the life course., Method: Using linked multi-agency administrative data for 71 932 children from the New South Wales Child Developmental Study, using logistic regression, we examined associations between 16 environmental risk factors in early life (prenatal period to <6 years of age) and later diagnoses of mental disorder recorded in health service data (from age 6 to 13 years), both individually and summed as an environmental risk score (ERS)., Results: The ERS was associated with all types of mental disorder diagnoses in a dose-response fashion, such that 2.8% of children with no exposure to any of the environmental factors (ERS = 0), compared to 18.3% of children with an ERS of 8 or more indicating exposure to 8 or more environmental factors (ERS ⩾ 8), had been diagnosed with any type of mental disorder up to age 13-14 years. Thirteen of the 16 environmental factors measured (including prenatal factors, neighbourhood characteristics and more proximal experiences of trauma or neglect) were positively associated with at least one category of mental disorder., Conclusion: Exposure to cumulative environmental risk factors in early life is associated with an increased likelihood of presenting to health services in childhood for any kind of mental disorder. In many instances, these factors are preventable or capable of mitigation by appropriate public policy settings.

Childhood social and emotional competencies are recognized as teachable skills affecting well-being and developmental outcomes across the life span. This study sought to develop and validate a brief self-report measure of social-emotional competencies in middle childhood. The study used items from the 2015 Middle Childhood Survey, administered to a representative subsample of the New South Wales Child Development Study cohort, comprising sixth grade students ( n = 26,837; aged 11-12 years) attending primary school in New South Wales, Australia. Exploratory and confirmatory factor analyses assessed the latent structure of social-emotional competencies, and item response theory and construct validity analyses evaluated the reliability, validity, and psychometric properties of the derived measure. A correlated five-factor model outperformed other latent structures (one-factor, higher order, and bifactor models) and was consistent with the framework developed by the Collaborative for Academic, Social, and Emotional Learning that informs the Australian school-based social-emotional learning curriculum, incorporating the following: Self-Awareness; Self-Management; Social Awareness; Relationship Skills; and Responsible Decision-Making. This brief (20-item), psychometrically sound, self-report measure of social-emotional competencies in middle childhood provides capacity for exploration of these skills as mediators and moderators of developmental outcomes across the life span. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Distinct classes of children in the general population are at increased odds of later mental illness and other adverse outcomes according to patterns of early childhood developmental vulnerability. If certain risk factors known at the time of birth are reliably associated with membership in early childhood risk classes, then preventative interventions could be initiated in the earliest years of life. Associations between 14 factors known at the time of birth and membership in early childhood risk classes were examined in 66,464 children. Risk class membership was associated with maternal mental illness, parental criminal charges and being male; distinct patterns of association were shown for some conditions, for example, prenatal child protection notification was uniquely associated with misconduct risk'. These findings suggest that risk factors known at the time of birth could assist in very early detection of children who may benefit from early intervention in the first 2000 days., (© 2023. The Author(s).)

Background: Children in out-of-home care (OOHC) are generally at increased risk of health and social adversities compared to their peers. However, the experiences of children in OOHC are not uniform and their associated health and social indices may vary in relation to characteristics of OOHC placements and child protection contact., Objective: To examine associations between a range of characteristics of OOHC placements and child protection contact (e.g., number, type, and age of placement) with educational underachievement, mental disorder, and police contact (as a victim, witness, or person of interest) in childhood., Participants and Setting: Participants were Australian children drawn from the New South Wales Child Development Study cohort who had been placed in OOHC at least once between the ages of 0-13 years (n = 2082)., Methods: Logistic regression was used to examine prospective associations of OOHC placement and child protection contact characteristics (type of carer, placement instability, duration and frequency of maltreatment, and amount of time in care) with educational underachievement, mental disorder diagnosis and any type of police contact., Results: Placements with foster carers, greater placement instability, longer and more frequent exposure to maltreatment, and longer time spent in care were each associated with greater likelihood of consequences in all domains of functioning., Conclusions: Children with certain placement characteristics are at higher risk of adverse consequences and should be prioritised for support services. The magnitude of relationships was not uniform across different health and social indices, highlighting the need for holistic, multiagency approaches to support children placed in care., Competing Interests: Declaration of competing interest No conflict to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Child maltreatment rates remain unacceptably high and rates are likely to escalate as COVID-related economic problems continue. A comprehensive and evidence-building approach is needed to prevent, detect and intervene where child maltreatment occurs. This review identifies key challenges in definitions, overviews the latest data on prevalence rates, reviews risk and protective factors, and examines common long-term mental health outcomes for children who experience maltreatment. The review takes a systems approach to child maltreatment outcomes through its focus on the overall burden of disease, gene-environment interactions, neurobiological mechanisms and social ecologies linking maltreatment to mental ill-health. Five recommendations relating to the accurate measurement of trends, research on brain structures and processes, improving the reach and impact of teleservices for detecting, preventing and treating child maladjustment, community-based approaches, and building population-focused multidisciplinary alliances and think tanks are presented., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Hypothesis: Psychotic disorders are associated with a growing number of recognized environmental exposures. Cumulative exposure to multiple environmental risk factors in childhood may contribute to the development of different patterns of schizotypy evident in early life. Hypotheses were that distinct profiles of schizotypy would have differential associations with a cumulative score of environmental risk factors., Study Design: We prospectively examined the relationship between 19 environmental exposures (which had demonstrated replicated associations with psychosis) measured from the prenatal period through to age 11 years, and 3 profiles of schizotypy in children (mean age = 11.9 years, n = 20 599) that have been established in population data from the New South Wales-Child Development Study. Multinomial logistic regression was used to examine associations between membership in each of 3 schizotypy profiles (true schizotypy, introverted schizotypy, and affective schizotypy) and exposure to a range of 19 environmental risk factors for psychosis (both individually and summed as a cumulative environmental risk score [ERS]), relative to children showing no risk., Results: Almost all environmental factors were associated with at least 1 schizotypy profile. The cumulative ERS was most strongly associated with the true schizotypy profile (OR = 1.61, 95% CI = 1.52-1.70), followed by the affective (OR = 1.33, 95% CI = 1.28-1.38), and introverted (OR = 1.32, 95% CI = 1.28-1.37) schizotypy profiles., Conclusions: Consistent with the cumulative risk hypothesis, results indicate that an increased number of risk exposures is associated with an increased likelihood of membership in the 3 schizotypy profiles identified in middle childhood, relative to children with no schizotypy profile., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Childhood disturbances in social, emotional, language, motor and cognitive functioning, and schizotypy have each been implicated as precursors of schizophrenia-spectrum disorders. We investigated whether relationships between early childhood developmental vulnerabilities and childhood schizotypy are mediated by educational underachievement in middle childhood., Methods: Participants were members of a large Australian (n = 19,216) population cohort followed longitudinally. Path analyses were used to model relationships between developmental vulnerabilities at age ~5 years, educational underachievement from ages ~8 to 10 years and three distinct profiles of schizotypy at age ~11 years (true, introverted and affective schizotypy)., Results: Early childhood developmental vulnerabilities on five broad domains (related to physical, emotional, social, cognitive and communication development) were associated with schizotypy profiles in middle childhood. Educational underachievement in middle childhood was associated with all schizotypy profiles, but most strongly with the true schizotypy profile (OR = 3.92, 95% CI = 3.12, 4.91). The relationships between schizotypy profiles and early childhood developmental vulnerabilities in 'language and cognitive skills (school-based)' and 'communication skills and general knowledge' domains were fully mediated by educational underachievement in middle childhood, and the relationships with early childhood 'physical health and well-being' and 'emotional maturity' domains were partially mediated., Conclusion: Developmental continuity from early childhood developmental vulnerabilities to schizotypy in middle childhood is mediated by educational underachievement in middle childhood. While some domains of early developmental functioning showed differential relationships with distinct schizotypy profiles, these findings support a developmental pathway to schizotypy in which cognitive vulnerability operates from early childhood through to middle childhood., (© 2022 The Authors. British Journal of Clinical Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

Among children with psychotic-like experiences (PLEs), the presence of co-occurring psychopathology may distinguish children's self-report of clinically significant experiences (i.e., PLEs that are distressing and/or impairing of daily functioning) from reports of more benign experiences. The aim of this study was to examine whether the likelihood of distressing or impairing PLEs differed according to type of co-occurring psychopathology symptoms. A community sample of 5268 children aged 9-12 years were recruited from Greater London, UK. Participants completed the Psychotic-Like Experiences Questionnaire for Children, and the Strengths and Difficulties Questionnaire to measure internalising and externalising problems. Multinomial logistic regressions were used to determine the likelihood of PLEs being distressing and/or impairing (vs. not) among children with different co-occurring symptom profiles (PLEs only; PLEs with internalising problems only - PLE-I; PLEs with externalising problems only - PLE-E; and PLEs with both internalising and externalising problems - PLE-IE). Children with co-occurring internalising and/or externalising problems had greater odds of distressing and/or impairing PLEs compared to children without co-occurring psychopathology (PLEs only). These associations were moderate for PLE-E and strong for PLE-I and PLE-IE, with the greatest odds of distressing and impairing PLEs evident in the presence of internalising plus externalising comorbidities (odds ratios [with 99 % confidence intervals] for PLE-IE relative to PLE-I = 2.00 [1.34-2.99]; PLE-IE relative to PLE-E = 5.46 [3.78-7.90]). These results affirm the importance of screening for the presence and type of co-occurring psychopathology among children with PLEs to demarcate potentially different treatment needs., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Parental offending and mental illness are associated with an increased risk of criminal behaviour in offspring during adolescence and adulthood, but the impact of such problems on younger children, including children's experiences of victimisation, is less well known., Aim: To investigate the associations between parental offending and mental illness recorded prior to their offspring's age of 5 years and their offspring's contact with police as a 'person of interest', 'victim' or 'witness' between ages 5 and 13 years., Methods: Our sample consisted of 72,771 children and their parents drawn from the New South Wales Child Development Study, an Australian longitudinal population-based record linkage study. Logistic regression analyses were conducted to examine associations between parental factors and offspring's police contact. Separate models examined the relationships between maternal or paternal offending and mental illness, as well as the combination among either or both parents, as the independent variables, and their child's police contact as the dependent variable., Results: Parental offending and mental illness were each individually associated with indices of police contact among offspring. Stronger associations were observed when both offending and mental illness were present together (in either parent, or when one parent had both exposures). Stronger associations were evident for mothers with both factors across all offspring police contact types, relative to fathers with both factors, in fully adjusted models; that is, children of mothers with both factors were over four times as likely to have contact with police as a 'person of interest' (OR = 4.29; 95% CI = 3.75-4.92) and over three times as likely to have contact as a victim (OR = 3.35; 95% CI = 3.01-3.74) or witness (OR = 3.58; 95% CI = 3.03-4.24), than children whose mothers had no history of offending or mental illness., Conclusions: Children with a parental history of offending and mental illness in early life are at an increased likelihood of early police contact as young as 5-13 years of age; it is vital that this is taken as a signal to help them and their affected families according to need., (© 2023 The Authors. Criminal Behaviour and Mental Health published by John Wiley & Sons Ltd.)

This study aimed to systematically review and synthesise the available evidence on the prevalence and associations between psychotic-like experiences (PLEs) and substance use in children and adolescents aged ⩽17 years, prior to the typical age of development of prodromal symptoms of psychosis. As substance use has been associated with earlier age of psychosis onset and more severe illness, identifying risk processes in the premorbid phase of the illness may offer opportunities to prevent the development of prodromal symptoms and psychotic illness. MEDLINE, PsycINFO, and CINAHL databases were searched for chart review, case-control, cohort, twin, and cross-sectional studies. Study reporting was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist, and pooled evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Searches identified 55 studies that met inclusion criteria. Around two-in-five substance users reported PLEs [rate = 0.41, 95% confidence interval (CI) 0.32-0.51; low quality evidence], and one-in-five with PLEs reported using substances (rate = 0.19, 95% CI 0.12-0.28; moderate-to-high quality evidence). Substance users were nearly twice as likely to report PLEs than non-users [odds ratio (OR) 1.77, 95% CI 1.55-2.02; moderate quality evidence], and those with PLEs were twice as likely to use substances than those not reporting PLEs (OR 1.93, 95% CI 1.55-2.41; very low quality evidence). Younger age was associated with greater odds of PLEs in substance users compared to non-users. Young substance users may represent a subclinical at-risk group for psychosis. Developing early detection and intervention for both substance use and PLEs may reduce long-term adverse outcomes.

Maltreated children are vulnerable to adverse mental health outcomes. Information about how children's mental health needs vary according to different levels of child protection contact (potentially culminating in out-of-home care [OOHC]) is valuable for the effective provision of services. This study aimed to examine associations between different levels of contact with child protection services before the age of 10 years and self-reported mental health difficulties at age 11 years. Participants (n = 26,960) were drawn from the New South Wales Child Development Study, a multiagency, multigenerational, longitudinal record linkage study that combines administrative records with cross-sectional survey data. We examined associations between four levels of child protection response (non-threshold reports, unsubstantiated reports, substantiated reports, OOHC; each relative to no report) and six domains of self-reported mental health difficulties (including internalising and externalising symptoms, and psychotic-like experiences). All levels of contact with child protection services were associated with increased odds of mental health difficulties in all domains. Children who had been placed in OOHC and children with substantiated reports had the highest odds of reporting clinical levels of mental health difficulties; 48.1% of children with an OOHC placement and 45.6% of those with substantiated child protection reports showed clinical levels of mental health difficulties in at least one domain. Children with child protection reports that were unsubstantiated, or determined not to meet the threshold for risk-of-significant harm, were also at increased risk of mental health difficulties in middle childhood. These findings underscore the importance of early detection and intervention for all children at risk of maltreatment., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: Population-level profiles of risk for later childhood mental disorders have been identified in patterns of early developmental vulnerabilities using Australian Early Developmental Census. We sought to demonstrate the geographical distribution of these early childhood risk profiles for mental illness, to inform policy decisions for place-sensitive provision of health and allied services., Methods: Using geographic information system techniques, we mapped the regional percentage of children at highest risk for mental disorders across the state of New South Wales (NSW), according to Local Government Areas, for 82 891 children in the NSW Child Development Study., Results: A high proportion (>10%) of children at risk of later mental disorders were located in regional and socioeconomically disadvantaged areas, with a few metropolitan regions showing similarly high proportions of the population at risk., Conclusions: These findings highlight the potential to identify place-sensitive needs for early intervention and prevention programs for emerging mental health problems in children., (© 2022 The Authors. Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

There is substantial evidence confirming that children who begin school with strong developmental skills tend to maintain positive academic trajectories across the elementary school years. Much less is known about children who begin school with poorer developmental competencies yet go on to achieve academically on par with, or above, their initially more competent peers, demonstrating academic resilience. This study used a large population dataset, the Longitudinal Study of Australian Children (n = 2,118) to identify children who demonstrated academic resilience between school entry and third grade, and the child, parenting, and school characteristics associated with this resilience. Findings show that two in five children who were initially identified as academically vulnerable on a school entry measure of language and cognitive skills were classified as academically resilient by Grade 3. In multivariate analysis, higher attentional regulation and receptive vocabulary skills were key factors associated with academic resilience in reading and numeracy, along with paternal consistency (for reading resilience) and fewer sleep problems (for numeracy resilience). Bivariate relations (ANOVAs) showed that resilient children, when compared to children who remained vulnerable, also showed fewer peer problems, fewer behavioral sleep problems, higher levels of parenting consistency and lower levels of parenting anger by mothers and fathers, higher levels of parental engagement in children's school, and higher levels of teacher self-efficacy. Supporting resilient pathways for children who are identified as vulnerable at school entry should include a particular focus on vocabulary development and attentional regulation, along with social skills and peer relationships, school-based parental engagement, and positive parenting support., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Williams et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: The detection of young people at high risk for psychotic disorders has been somewhat narrowly focused on overt symptom-based markers that reflect mild reality distortion (e.g., psychotic-like experiences), or prodromal syndromes that are proximal to psychosis onset. The concept of schizotypy represents a broader framework for investigating risk for schizophrenia (and other disorders) in childhood, before the onset of prodromal or overt symptoms. We sought to detect profiles of risk for psychosis (schizotypy) in a general population sample of 22,137 Australian children aged 11-12 years, and to determine early life risk factors associated with these profiles from data available in linked records (registers)., Methods: Fifty-nine self-reported items were used as indicators of schizotypy across six broad domains; z-scores for each domain were subjected to latent profile analyses (LPA). A series of multinomial logistic regressions was used to examine the association between resulting profile (class) membership and several childhood and parental risk factors, and the proportion of children with mental disorders among each schizotypy profile was examined., Results: The LPA revealed three person-centred profiles referred to as True Schizotypy (n = 1,323; 6.0%), Introverted Schizotypy (n = 4,473; 20.2%), and Affective Schizotypy (n = 4,261; 19.2%), as well as a group of children showing no risk (n = 12,080; 54.6%). Prior exposure to perinatal and familial adversities including childhood maltreatment, as well as poor early childhood development and academic functioning, was variously associated with all risk groups. There was a higher proportion of childhood mental disorder diagnoses among children in the True Schizotypy group, relative to other profiles., Conclusion: Subtle differences in the pattern of exposures and antecedents among schizophrenia liability profiles in childhood may reflect distinct pathogenic pathways to psychotic or other mental illness., Practitioner Points: Children aged 11-12 years report characteristics of schizotypy which can be classified into three distinct profiles that may represent different pathological processes towards later mental ill-health. Early life exposure to perinatal and familial adversities including childhood maltreatment, early childhood developmental vulnerability, and poor academic functioning predict membership in all three childhood schizotypy profiles. Latent liability for schizophrenia (and potentially other mental disorders) may be represented by different profiles of functioning observable in childhood., (© 2022 The Authors. British Journal of Clinical Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

Early life exposure to Domestic Violence and Abuse (DVA) is associated with poor psychosocial and cognitive development in childhood. However, most prior research uses mother-reported involvement in DVA as a proxy indicator of child exposure; studies using direct measures of child exposure to DVA are scarce, especially among representative population-based samples. We address this gap by using longitudinal, population-based data from an Australian record linkage study of children to examine the associations between early life exposure to DVA and early childhood developmental vulnerability. Exposure to DVA was measured using police contact records for children involved in a DVA incident either as a victim or witness. Developmental vulnerability at school entry was measured using the Australian Early Development Census, providing indices of five broad domains of function and person-centred classes of developmental risk (referred to as 'mild generalized risk', 'misconduct risk', and 'pervasive risk', each compared to a group showing 'no risk'). Children exposed to DVA showed significantly greater odds of developmental vulnerability on all five domains and were more likely to be members of the three developmental risk classes. Girls who were victims of DVA (OR = 1.65) had significantly poorer developmental outcomes than boys who were victims (OR = 1.26) within the domain of communication skills and general knowledge (d = 0.29 [SE = 0.16], p = .04). No other sex differences were found. These preliminary findings hold important implications for policy regarding the early intervention and implementation of support services for young children exposed to DVA., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Childhood self-harm is rare but increasing in frequency. Little is known about risk factors specifically for self-harm in preteen children., Methods: We examined self-harm thoughts and behaviours in children aged 3-14 years in association with parental and community-level risk factors, using a large general population-based record linkage sample (n = 74,479)., Results: Parental factors were strongly associated with childhood self-harm, with over three-quarters of children with self-harm having a parent with a history of mental disorder and/or criminal offending. Community-level factors (socioeconomic deprivation, remote or regional location, and neighbourhood crime rate) were not associated with childhood self-harm after adjustment for confounding factors., Limitations: Measures of self-harm thoughts and behaviours derived from administrative data likely underestimate the prevalence of self-harm in the population., Conclusions: Intergenerational transmission of risk factors is likely an important contributor to childhood self-harm., (Copyright © 2022. Published by Elsevier B.V.)

Objective: To identify classes of children exposed to distinct clusters of perinatal and familial risk factors at the time of birth, and examine relationships between class membership and a variety of adverse outcomes in childhood., Design: A prospective longitudinal study of children (and their parents) born between 2002 and 2004 and who have been followed-up until 12-13 years of age. A combination of latent class analysis and logistic regression analyses were used., Results: Adverse developmental, social, and mental health outcomes in early and middle childhood were greatest for children with 'pervasive familial risk' (i.e., parental mental illness, parental criminality, and perinatal risk factors) at the time of birth; some associations were stronger among girls., Conclusion: Pervasive exposure to multiple risk factors in the pre- and perinatal period increases the risk of adverse outcomes in childhood. Future interventions should tailor strategies to address unique combinations of adverse risk exposures in vulnerable families., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Childbirth presents an optimal time for identifying high-risk families to commence intervention that could avert various childhood health and social adversities., Objective: We sought to establish the minimum set of exposures required to accurately predict a range of adverse childhood outcomes up to the age of 13 years, from a set of 14 individual and familial risk exposures evident at the time of birth., Methods: Participants were 72,059 Australian children and their parents drawn from a multi-register population cohort study (data spanning 1994-2018). Risk exposures included male sex, young mother (aged ≤21 years), no (or late first; >16 weeks) antenatal visit, maternal smoking during pregnancy, small for gestational age, preterm birth, pregnancy complications (any of hypertension, diabetes mellitus, gestational diabetes or pre-eclampsia), >2 previous pregnancies of ≥20 weeks, socio-economic disadvantage, prenatal child protection notification, and maternal or paternal mental disorder or criminal offending history. Individual outcomes included early childhood developmental vulnerability (age 5 years), sustained educational underachievement (age 8 and 10 years), mental disorder diagnoses, substantiated childhood maltreatment, and contact with the police as a victim or person-of-interest up to age 13-14 years., Results: Risk exposures at birth predicted individual childhood outcomes with fair to excellent accuracy: the area under the receiver operating characteristic curves ranged between 0.60 (95% CI 0.58, 0.62) for childhood mental disorder and 0.83 (95% CI 0.82, 0.85) for substantiated child maltreatment. The presence of five or more exposures characterised 12-25% of children with one or more adverse outcomes and showed high predictive certainty for models predicting multiple outcomes, which were apparent in 9% of the population., Conclusions: Up to a quarter of the neonatal population at risk of multiple adverse outcomes can be detected at birth, with implications for population health screening. However, cautious implementation of these models is warranted, given their relatively low positive predictive values., (© 2021 John Wiley & Sons Ltd.)

Purpose: Neurocognitive difficulties and early childhood speech/motor delays are well documented amongst older adolescents and young adults considered at risk for psychosis-spectrum diagnoses. We aimed to test associations between unusual or psychotic-like experiences (PLEs), co-occurring distress/emotional symptoms, current cognitive functioning and developmental delays/difficulties in young people (aged 8-18 years) referred to Child and Adolescent Mental Health Services in South London, UK., Methods: Study 1 examined receptive language, verbal learning and caregiver-reported speech and motor delays/difficulties in a sample of 101 clinically-referred children aged 8-14 years, comparing those reporting no PLEs (n = 19), PLEs without distress (n = 16), and PLEs with distress (n = 66). Study 2 tested associations of severity of distressing PLEs with vocabulary, perceptual reasoning, word reading and developmental delays/difficulties in a second sample of 122 adolescents aged 12-18 years with distressing PLEs., Results: In Study 1, children with distressing PLEs had lower receptive language and delayed recall and higher rates of developmental delays/difficulties than the no-PLE and non-distressing PLE groups (F values: 2.3-2.8; p values: < 0.005). Receptive language (β = 0.24, p = 0.03) and delayed recall (β = - 0.17, p = 0.02) predicted PLE distress severity. In Study 2, the cognitive-developmental variables did not significantly predict PLE distress severity (β values = 0.01-0.22, p values: > 0.05)., Conclusion: Findings may be consistent with a cognitive-developmental model relating distressing PLEs in youth with difficulties in cognitive functioning. This highlights the potential utility of adjunctive cognitive strategies which target mechanisms associated with PLE distress. These could be included in cognitive-behavioural interventions offered prior to the development of an at-risk mental state in mental health, educational or public health settings., (© 2021. The Author(s).)

Poor verbal learning and memory function is well-documented among individuals with schizophrenia and those at clinical high-risk for psychosis. This study aimed to identify these impairments among children aged 9-12 years with different schizophrenia risk profiles (family history or antecedents of schizophrenia, each of higher [H] or lower [L] risk load) relative to typically developing peers. These three groups were recruited via community-screening, and differentiated for analysis into: typically developing children (TD = 45); children who had 1 first- or ≥2 second-degree affected relatives (FHx H  = 16) or one second-degree relative (FHx L  = 15); and children presenting multiple replicated antecedents of schizophrenia whose clinical symptoms persisted at 2- and/or 4-year follow-up (ASz H  = 16) or remitted during follow-up (ASz L  = 16). Verbal learning/memory measures assessed at baseline (age 9-12 years) included: (i) total recall; (ii) trial 1 recall; (iii) learning score; (iv) intrusions; (v) total words lost; and (vi) serial position patterns. Analyses of variance indicated that FHx H and ASz H youth demonstrated impaired total recall compared to TD and ASz L children and lost significantly more words between trials than TD and FHx L children. Learning score was impaired among both FHx H and FHx L relative to TD and ASz L children. Thus, among putatively at-risk children, total words recalled and lost distinguished those with higher risk load (by family history or persistent antecedent symptomology), whereas learning score indexed familial vulnerability. Follow-up of the sample is needed to determine the capacity of verbal learning deficits to predict later illness and provide a potential avenue for early remediation to improve clinical or functional outcomes., Competing Interests: None., (© 2022 The Authors.)

Background: In individuals at clinical high-risk for psychosis, elevated cortisol levels predict subsequent onset of psychotic disorder. However, it is unclear whether cortisol alterations are evident at an earlier clinical stage and promote progression of psychosis expression. This study aimed to address this issue by investigating whether cortisol levels in childhood were associated with the emergence of attenuated psychotic symptoms in early adulthood. In exploratory analyses, we examined whether cortisol and psychosocial stress measures interacted in predicting attenuated psychotic symptoms., Methods: A sample of children (N = 109) enriched for psychosis risk factors were recruited at age 9-12 years and assessed at age 11-14 years (T1) and 17-21 years (T2). Measures of psychopathology, psychosocial stressors, and salivary cortisol were obtained at T1. Attenuated psychotic symptoms were assessed at T2 using the Prodromal Questionnaire., Results: Diurnal cortisol (β = 0.915, 95% CI: 0.062-1.769) and daily stressors (β = 0.379, 95% CI: 0.034-0.723) at T1 were independently associated with total Prodromal Questionnaire scores at T2 after accounting for demographic factors and T1 psychopathology. Exploratory analyses indicated a significant interaction between T1 diurnal cortisol and daily stressors (β = 0.743, 95% CI: 0.081-1.405), with the highest predicted T2 total Prodromal Questionnaire scores occurring when both diurnal cortisol and daily stressors were increased., Conclusions: Our findings suggest that daily stressors and elevations in diurnal cortisol in late childhood/early adolescence increases risk for developing attenuated psychotic symptoms. These findings emphasize the importance of assessing environmental and biological risk factors for psychosis during neurodevelopmentally vulnerable time periods., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: For adults with psychosis, international guidelines recommend individual and family based cognitive behavioural therapy interventions. Recommendations are extended to children and adolescents, based on adult research. It is also recommended that psychological interventions are offered for childhood presentations of psychotic-like or Unusual Experiences (UE), in the absence of a formal diagnosis, when these are Distressing (UEDs). Cognitive models underpinning these interventions require testing in adolescent populations, to further refine therapies. We address this need, by testing for the first time, the application of the adult cognitive model of psychosis to adolescent UEDs., Methods: We used baseline data from the Coping with Unusual ExperienceS (CUES+) randomised controlled trial for 122 clinically referred adolescents (12-18 years) with self-reported UEDs. Known psychological mechanisms of adult cognitive models of psychosis; negative life events, affect (anxiety and depression), reasoning (jumping to conclusions bias), and schemas were investigated using multiple linear regression models, alongside variables particularly associated with the development and severity of adolescent UEDs and UE type (dissociation, externalising/behavioural problems, managing emotions)., Results: The psychological mechanisms of adult cognitive models of psychosis explained 89% of the total variance of adolescent UED severity, F (10, 106) = 99.34, p < .0005, r 2  = 0.89, with schemas as the principal significant contributor. Variance explained 40 - 72% across each of the UE types (paranoia, hallucinations, delusions, paranormal thinking and grandiosity)., Conclusions: Findings suggest that the psychological components of adult cognitive models of psychosis, particularly schemas, are also implicated in adolescent UEDs., (Copyright © 2021 Elsevier B.V. All rights reserved.)