Initial Validation of a Brief Pictorial Measure of Caregiver Aggression: The Family Aggression Screening Tool

In the present study, we report on the development and initial psychometric properties of the Family Aggression Screening Tool (FAST). The FAST is a brief, self-report tool that makes use of pictorial representations to assess experiences of caregiver aggression, including direct victimization and exposure to intimate partner violence. It is freely available on request and takes under 5 minutes to complete. Psychometric properties of the FAST were investigated in a sample of 168 high-risk youth aged 16 to 24 years. For validation purposes, maltreatment history was assessed using the Childhood Trauma Questionnaire; levels of current psychiatric symptoms were also assessed. Internal consistency of the FAST was good. Convergent validity was supported by strong and discriminative associations with corresponding Childhood Trauma Questionnaire subscales. The FAST also correlated significantly with multi-informant reports of psychiatric symptomatology. Initial findings provide support for the reliability and validity of the FAST as a brief, pictorial screening tool of caregiver aggression

The Impact of Childhood Maltreatment in a Community Sample of High-Risk Youth

Childhood maltreatment represents a global phenomenon and a major public health concern. Despite considerable advances in the field, a number of important gaps have yet to be fully addressed. The current thesis set out to empirically address four outstanding research questions using data drawn from a community sample of high-risk youth. First, we examined whether childhood maltreatment and community violence exposure exert independent, additive or interactive effects on mental health (Chapter 2). Findings point to the existence of both common and distinct effects. While maltreatment predicted symptoms across a broad range of mental health domains, the impact of community violence was more constrained. Typically, these forms of adversity additively affected mental health. Second, we explored whether distinct forms of maltreatment uniquely impact mental health functioning (Chapter 3). Maltreatment types were highly interrelated and frequently co-occurring. We identified both shared and unique effects of maltreatment types on mental health. Emotional abuse emerged as the sole unique contributor to internalizing difficulties and trauma symptoms. Third, we investigated whether variants of callous-unemotional traits in youth are differentially associated with maltreatment history and markers of individual functioning (Chapter 4). Maltreatment was a key discriminating factor between variants. The combination of high anxiety and high callous-unemotional traits indexed a particularly vulnerable group of youth characterized by increased psychopathology and suicide risk. Finally, we tested the psychometric properties of the first non-verbal screening tool of family aggression (Chapter 5). We found initial support for the reliability, validity and diagnostic accuracy of this measure in detecting multiple forms of family aggression, including direct victimization and exposure to intimate partner violence. Overall, findings from the current thesis significantly advance knowledge of the processes by which interrelated forms of developmental adversity combine to affect mental health, as well as elucidating factors associated with individual heterogeneity to maltreatment responses

Characterising youth with callous-unemotional traits and concurrent anxiety: evidence for a high-risk clinical group

Growing evidence supports the existence of two variants of youth with high callous-unemotional (CU) traits who present with markedly different risk profiles and outcomes, with potential implications for risk assessment and treatment formulation. So far, studies have identified variants of CU youth mainly using data-driven cluster approaches based on levels of CU traits and co-occurring anxiety. Yet, the extent to which this knowledge may be translated into clinical practice is unclear. To this end, the present study employed a severity-based, cut-off approach to systematically characterise CU groups across a range of clinically informative domains, including trauma history, psychiatric symptomatology, affective functioning, attachment style and behavioural risk. Analyses were based on multi-rated data from a community sample of high-risk youths (n = 155, M = 18 years). Consistent with previous studies, we found that, whereas variants show comparable levels of antisocial behaviour, those who present with both high CU and high anxiety report more severe childhood maltreatment, psychological distress, ADHD symptomatology and behavioural risk-including substance use, suicidal ideation and unsafe sex. In addition, these youth show greater attachment insecurity and affective dysregulation, as indexed by levels of irritability and alexithymia. Together, findings indicate that (1) trauma history is a key factor that differentiates variants of CU youth high vs. low on anxiety, and (2) differences in individual functioning across variants point to the need for tailored clinical assessment tools and intervention strategies. Importantly, the present findings indicate that variants of CU youth can be meaningfully differentiated using cut-off based approaches that parallel methods used in clinical assessments

Quasi-experimental evidence on short and long-term consequences of bullying victimization: A meta-analysis

Exposure to bullying victimization is associated with a wide-range of short and long-term adverse outcomes. However, the extent to which these associations reflect a causal influence of bullying victimization remains disputed. Here, we aimed to provide the most stringent evidence regarding the consequences of bullying victimization by meta-analysing all relevant Quasi-Experimental (QE) studies. Multilevel random effects models and meta-regression were employed to (i) estimate the pooled QE-adjusted effect size (Cohen d) for bullying victimization on outcomes and to (ii) evaluate potential sources of heterogeneity. A total of 16 studies were included. We derived 101 QE-estimates from three different methods (twin design, fixed effects analysis, and propensity score matching) for three pools of outcomes (internalizing symptoms, externalizing symptoms, academic difficulties). QE-adjusted effects were small for internalizing symptoms (dadjusted=0.27, 95%CI 0.05;0.49), and smaller for externalizing symptoms (dadjusted=0.15, 95%CI 0.10;0.21) and academic difficulties (dadjusted=0.10, 95%CI 0.06; 0.13). Accounting for a shared rater effect between the exposure and the outcome further reduced the effect for internalizing (dnon-shared rater=0.14, 95%CI 0.05;0.23) and externalizing symptoms (dnon-shared rater=0.06, 95%CI 0.01;0.11). Finally, the adverse effects declined in the long-term, most markedly for internalizing symptoms (dlong-term=0.06, 95%CI -0.01;0.13). Based on the most stringent evidence available to date, findings indicate that bullying victimization may causally impact children’s wellbeing in the short-term, especially anxiety and depression levels. The reduction of adverse effects over time highlights the potential for resilience in individuals who have experienced bullying. Secondary preventive interventions in bullied children should therefore focus on resilience and address children's pre-existing vulnerabilities

Neural Profile of Callous Traits in Children: A Population-Based Neuroimaging Study

BACKGROUND: Callous traits during childhood, e.g., lack of remorse and shallow affect, are a key risk marker for antisocial behavior. Although callous traits have been found to be associated with structural and functional brain alterations, evidence to date has been almost exclusively limited to small, high-risk samples of boys. We characterized gray and white matter brain correlates of callous traits in over 2000 children from the general population. METHODS: Data on mother-reported callous traits and brain imaging were collected at age 10 years from participants of the Generation R Study. Structural magnetic resonance imaging was used to investigate brain morphology using volumetric indices and whole-brain analyses (n = 2146); diffusion tensor imaging was used to assess global and specific white matter microstructure (n = 2059). RESULTS: Callous traits were associated with lower global brain (e.g., total brain) volumes as well as decreased cortical surface area in frontal and temporal regions. Global mean diffusivity was negatively associated with callous traits, suggesting higher white matter microstructural integrity in children with elevated callous traits. Multiple individual tracts, including the uncinate and cingulum, contributed to this global association. Whereas no gender differences were observed for global volumetric indices, white matter associations were present only in girls. CONCLUSIONS: This is the first study to provide a systematic characterization of the structural neural profile of callous traits in the general pediatric population. These findings extend previous work based on selected samples by demonstrating that childhood callous traits in the general population are characterized by widespread macrostructural and microstructural differences across the brain

Gene-environment correlations and causal effects of childhood maltreatment on physical and mental health: a genetically informed approach.

BACKGROUND: Childhood maltreatment is associated with poor mental and physical health. However, the mechanisms of gene-environment correlations and the potential causal effects of childhood maltreatment on health are unknown. Using genetics, we aimed to delineate the sources of gene-environment correlation for childhood maltreatment and the causal relationship between childhood maltreatment and health. METHODS: We did a genome-wide association study meta-analysis of childhood maltreatment using data from the UK Biobank (n=143 473), Psychiatric Genomics Consortium (n=26 290), Avon Longitudinal Study of Parents and Children (n=8346), Adolescent Brain Cognitive Development Study (n=5400), and Generation R (n=1905). We included individuals who had phenotypic and genetic data available. We investigated single nucleotide polymorphism heritability and genetic correlations among different subtypes, operationalisations, and reports of childhood maltreatment. Family-based and population-based polygenic score analyses were done to elucidate gene-environment correlation mechanisms. We used genetic correlation and Mendelian randomisation analyses to identify shared genetics and test causal relationships between childhood maltreatment and mental and physical health conditions. FINDINGS: Our meta-analysis of genome-wide association studies (N=185 414) identified 14 independent loci associated with childhood maltreatment (13 novel). We identified high genetic overlap (genetic correlations 0·24-1·00) among different maltreatment operationalisations, subtypes, and reporting methods. Within-family analyses provided some support for active and reactive gene-environment correlation but did not show the absence of passive gene-environment correlation. Robust Mendelian randomisation suggested a potential causal role of childhood maltreatment in depression (unidirectional), as well as both schizophrenia and ADHD (bidirectional), but not in physical health conditions (coronary artery disease, type 2 diabetes) or inflammation (C-reactive protein concentration). INTERPRETATION: Childhood maltreatment has a heritable component, with substantial genetic correlations among different operationalisations, subtypes, and retrospective and prospective reports of childhood maltreatment. Family-based analyses point to a role of active and reactive gene-environment correlation, with equivocal support for passive correlation. Mendelian randomisation supports a (primarily bidirectional) causal role of childhood maltreatment on mental health, but not on physical health conditions. Our study identifies research avenues to inform the prevention of childhood maltreatment and its long-term effects. FUNDING: Wellcome Trust, UK Medical Research Council, Horizon 2020, National Institute of Mental Health, and National Institute for Health Research Biomedical Research Centre

Prophylactic and Therapeutic Efficacy of Avian Antibodies against Influenza Virus H5N1 and H1N1 in Mice

Background: Pandemic influenza poses a serious threat to global health and the world economy. While vaccines are currently under development, passive immunization could offer an alternative strategy to prevent and treat influenza virus infection. Attempts to develop monoclonal antibodies (mAbs) have been made. However, passive immunization based on mAbs may require a cocktail of mAbs with broader specificity in order to provide full protection since mAbs are generally specific for single epitopes. Chicken immunoglobulins (IgY) found in egg yolk have been used mainly for treatment of infectious diseases of the gastrointestinal tract. Because the recent epidemic of highly pathogenic avian influenza virus (HPAIV) strain H5N1 has resulted in serious economic losses to the poultry industry, many countries including Vietnam have introduced mass vaccination of poultry with H5N1 virus vaccines. We reasoned that IgY from consumable eggs available in supermarkets in Vietnam could provide protection against infections with HPAIV H5N1. Methods and Findings: We found that H5N1-specific IgY that are prepared from eggs available in supermarkets in Vietnam by a rapid and simple water dilution method cross-protect against infections with HPAIV H5N1 and related H5N2 strains in mice. When administered intranasally before or after lethal infection, the IgY prevent the infection or significantly reduce viral replication resulting in complete recovery from the disease, respectively. We further generated H1N1 virus-specific IgY by immunization of hens with inactivated H1N1 A/PR/8/34 as a model virus for the current pandemic H1N1/09 and found that such H1N1-specific IgY protect mice from lethal influenza virus infection. Conclusions: The findings suggest that readily available H5N1-specific IgY offer an enormous source of valuable biological material to combat a potential H5N1 pandemic. In addition, our study provides a proof-of-concept for the approach using virus-specific IgY as affordable, safe, and effective alternative for the control of influenza outbreaks, including the current H1N1 pandemic

Epigenome-wide meta-analysis of prenatal maternal stressful life events and newborn DNA methylation.

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this recordCode availability: The code used for this EWAS meta-analysis is available from the corresponding authors upon reasonable request.Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biological mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. This meta-analysis included twelve non-overlapping cohorts from ten independent longitudinal studies (N = 5,496) within the international Pregnancy and Childhood Epigenetics consortium to examine maternal stressful life events during pregnancy and DNA methylation in cord blood. Children whose mothers reported higher levels of cumulative maternal stressful life events during pregnancy exhibited differential methylation of cg26579032 in ALKBH3. Stressor-specific domains of conflict with family/friends, abuse (physical, sexual, and emotional), and death of a close friend/relative were also associated with differential methylation of CpGs in APTX, MyD88, and both UHRF1 and SDCCAG8, respectively; these genes are implicated in neurodegeneration, immune and cellular functions, regulation of global methylation levels, metabolism, and schizophrenia risk. Thus, differences in DNA methylation at these loci may provide novel insights into potential mechanisms of neurodevelopment in offspring.Medical Research Council and Wellcome Trus

Meta-analysis of epigenome-wide associations between DNA methylation at birth and childhood cognitive skills

This is the final version. Available on open access from Springer Nature via the DOI in this recordData availability: Meta-analysis results files will be deposited in the EWAS Catalog data repository (http://ewascatalog.org/) upon publication. Individual-level data are available upon request to the cohorts involved and according to their procedures.Cognitive skills are a strong predictor of a wide range of later life outcomes. Genetic and epigenetic associations across the genome explain some of the variation in general cognitive abilities in the general population and it is plausible that epigenetic associations might arise from prenatal environmental exposures and/or genetic variation early in life. We investigated the association between cord blood DNA methylation at birth and cognitive skills assessed in children from eight pregnancy cohorts within the Pregnancy And Childhood Epigenetics (PACE) Consortium across overall (total N = 2196), verbal (total N = 2206) and non-verbal cognitive scores (total N = 3300). The associations at single CpG sites were weak for all of the cognitive domains investigated. One region near DUSP22 on chromosome 6 was associated with non-verbal cognition in a model adjusted for maternal IQ. We conclude that there is little evidence to support the idea that variation in cord blood DNA methylation at single CpG sites is associated with cognitive skills and further studies are needed to confirm the association at DUSP22