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Abstract A range of rare mutations involving micro-deletion or -duplication of genetic material (copy number variants (CNVs)) have been associated with high neurodevelopmental and psychiatric risk (ND-CNVs). Irritability is frequently observed in childhood neurodevelopmental conditions, yet its aetiology is largely unknown. Genetic variation may play a role, but there is a sparsity of studies investigating the presentation of irritability in young people with ND-CNVs. This study aimed to investigate whether there is a difference in irritability in young people with rare ND-CNVs compared to those without ND-CNVs, and to what extent irritability is associated with psychiatric diagnoses and cognitive ability (IQ). Irritability and broader psychopathology were assessed in 485 young people with ND-CNVs and 164 sibling controls, using the child and adolescent psychiatric assessment. Autism was assessed using the social communication questionnaire, and intelligence quotient (IQ) by the Wechsler abbreviated scale of intelligence. Fifty four percent of young people with ND-CNVs met the threshold for irritability; significantly more than controls (OR = 3.77, CI = 3.07–7.90, p = 5.31 × 10−11). When controlling for the presence of other psychiatric comorbidities, ND-CNV status was still associated with irritability. There was no evidence for a relationship between irritability and IQ. Irritability is an important aspect of the clinical picture in young people with ND-CNVs. This work shows that genetic variation is associated with irritability in young people with ND-CNVs, independent of psychiatric comorbidities or IQ impairment. Clinicians should be aware of this increased risk to inform management and interventions.

Abstract Impaired behavioural flexibility is a core feature of neuropsychiatric disorders and is associated with underlying dysfunction of fronto-striatal circuitry. Reduced dosage of Cyfip1 is a risk factor for neuropsychiatric disorder, as evidenced by its involvement in the 15q11.2 (BP1–BP2) copy number variant: deletion carriers are haploinsufficient for CYFIP1 and exhibit a two- to four-fold increased risk of schizophrenia, autism and/or intellectual disability. Here, we model the contributions of Cyfip1 to behavioural flexibility and related fronto-striatal neural network function using a recently developed haploinsufficient, heterozygous knockout rat line. Using multi-site local field potential (LFP) recordings during resting state, we show that Cyfip1 heterozygous rats (Cyfip1 +/−) harbor disrupted network activity spanning medial prefrontal cortex, hippocampal CA1 and ventral striatum. In particular, Cyfip1 +/− rats showed reduced influence of nucleus accumbens and increased dominance of prefrontal and hippocampal inputs, compared to wildtype controls. Adult Cyfip1 +/− rats were able to learn a single cue-response association, yet unable to learn a conditional discrimination task that engages fronto-striatal interactions during flexible pairing of different levers and cue combinations. Together, these results implicate Cyfip1 in development or maintenance of cortico-limbic-striatal network integrity, further supporting the hypothesis that alterations in this circuitry contribute to behavioural inflexibility observed in neuropsychiatric diseases including schizophrenia and autism.

Background Physical health conditions are more common in individuals with autism. Some, like epilepsy, have considerable evidence supporting their increased prevalence, but many diseases lack literature to make strong conclusions. Aims To investigate the prevalence of physical health comorbidities in autism. Method We undertook a nested cross-sectional study, using a sample from the National Centre for Mental Health database. It included participants from England and Wales who reported a clinician-made diagnosis of autism (n = 813), and a control sample without autism or mental illness (n = 2781). Participants had provided a medical history at enrolment. Analysis was carried out by binomial logistic regressions controlling for age, gender, smoking status, and antipsychotic and mood stabiliser use. A subanalysis of individuals with concurrent intellectual disability (n = 86) used binomial logistic regression with the same control variables. Results Many physical health conditions were significantly more common in autism. Sixteen out of 28 conditions showed increased odds, with the highest odds ratios observed for liver disease, chronic obstructive pulmonary disease, kidney disease, osteoporosis and rheumatoid arthritis. A subanalysis demonstrated a similar pattern of physical health in individuals with autism with and without concurrent intellectual disability. Some conditions, including osteoporosis, hyperthyroidism, head injury and liver disease, had larger odds ratios in individuals with concurrent intellectual disability. Conclusions Physical health conditions occur more commonly in individuals with autism, and certain conditions are further increased in those with concurrent intellectual disability. Our findings contribute to prior evidence, including novel associations, and suggest that people with autism are at greater risk of physical health problems throughout adulthood.

Abstract Asymmetry between the left and right hemisphere is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variants, which typically exert small effects on brain-related phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We designed a pattern-learning approach to dissect the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior data fusion highlights the consequences of genetically controlled brain lateralization on uniquely human cognitive capacities.

Decoy oligodeoxynucleotides (ODNs) allow targeting undruggable transcription factors, such as STAT3, but their limited potency and lack of delivery methods hampered translation. To overcome these challenges, we conjugated a STAT3-specific decoy to thalidomide, a ligand to cereblon in E3 ubiquitin ligase complex, to generate a proteolysis-targeting chimera (STAT3DPROTAC). STAT3DPROTAC downregulated STAT3 in target cells, but not STAT1 or STAT5. Computational modeling of the STAT3DPROTAC ternary complex predicted two surface lysines, K601 and K626, in STAT3 as potential ubiquitination sites. Accordingly, K601/K626 point mutations in STAT3, as well as proteasome inhibition or cereblon deletion, alleviated STAT3DPROTAC effect. Next, we conjugated STAT3DPROTAC to a CpG oligonucleotide targeting Toll-like receptor 9 (TLR9) to generate myeloid/B cell-selective C-STAT3DPROTAC. Naked C-STAT3DPROTAC was spontaneously internalized by TLR9+ myeloid cells, B cells, and human and mouse lymphoma cells but not by T cells. C-STAT3DPROTAC effectively decreased STAT3 protein levels and also STAT3-regulated target genes critical for lymphoma cell proliferation and/or survival (BCL2L1, CCND2, and MYC). Finally, local C-STAT3DPROTAC administration to human Ly3 lymphoma-bearing mice triggered tumor regression, while control C-STAT3D and C-SCR treatments had limited effects. Our results underscore the feasibility of using a PROTAC strategy for cell-selective, decoy oligonucleotide-based STAT3 targeting of and potentially other tumorigenic transcription factors for cancer therapy.

Abstract Cell signaling is central to neuronal activity and its dysregulation may lead to neurodegeneration and cognitive decline. Here, we show that selective genetic potentiation of neuronal ERK signaling prevents cell death in vitro and in vivo in the mouse brain, while attenuation of ERK signaling does the opposite. This neuroprotective effect mediated by an enhanced nuclear ERK activity can also be induced by the novel cell penetrating peptide RB5. In vitro administration of RB5 disrupts the preferential interaction of ERK1 MAP kinase with importinα1/KPNA2 over ERK2, facilitates ERK1/2 nuclear translocation, and enhances global ERK activity. Importantly, RB5 treatment in vivo promotes neuroprotection in mouse models of Huntington's (HD), Alzheimer's (AD), and Parkinson's (PD) disease, and enhances ERK signaling in a human cellular model of HD. Additionally, RB5‐mediated potentiation of ERK nuclear signaling facilitates synaptic plasticity, enhances cognition in healthy rodents, and rescues cognitive impairments in AD and HD models. The reported molecular mechanism shared across multiple neurodegenerative disorders reveals a potential new therapeutic target approach based on the modulation of KPNA2‐ERK1/2 interactions.

IntroductionImmune checkpoint blockade (ICB) improved clinical outcomes in renal and bladder cancer patients, but the response rates remain limited especially in metastatic disease. While STAT3 transcription factor is well-known master regulator of tumor immune evasion, little is known about the role of STAT3 in the resistance of renal or bladder cancers to immunotherapy.MethodsTo better understand immune alterations associated with ICB resistance, we assessed blood biomarkers in renal cancer patients classified as responders or non-responders to first line nivolumab/ipilimumab immunotherapy.ResultsWe observed that non-responders showed elevated levels of proinflammatory mediators, such as IL-1RA, IL-6, IL-8 and to lesser extent IL-10, which are associated with STAT3 activation and tumor immunosuppression. In addition, we found STAT3 activation primarily in circulating myeloid immune cells such as tolerogenic MDSCs. To assess whether STAT3 inhibition within these cell subsets can promote antitumor immune responses and/or enhance sensitivity to ICB in vivo, we used an original antisense oligonucleotide (ASO) strategy for myeloid-cell selective STAT3 knockdown (CpG-STAT3ASO). Our results in syngeneic models of renal and bladder cancers in mice demonstrated potent antitumor activity of CpG-STAT3ASO alone in contrast to PD1 blockade alone in both models. The CpG-STAT3ASO/anti-PD1 combination improved therapeutic efficacy especially against bladder tumors. Therapeutic efficacy correlated with activation of dendritic cells (DCs) and M1 macrophages in the tumor microenvironment, reduced percentages of regulatory T cells (Tregs) and the expansion of CD8 T cells in both tumor models.Discussion/ConclusionOur study underscores the potential of using myeloid-cell targeted CpG-STAT3 inhibitors for genitourinary cancer therapy to disrupt tolerogenic signaling, restore immune cell activity and sensitivity to immune checkpoint inhibitors and/or T cell-based immunotherapies.

Abstract Children with rare neurodevelopmental genetic conditions (ND-GCs) are at high risk for a range of neuropsychiatric conditions. Sleep symptomatology may represent a transdiagnostic risk indicator within this patient group. Here we present data from 629 children with ND-GCs, recruited via the United Kingdom’s National Health Service medical genetic clinics. Sibling controls (183) were also invited to take part. Detailed assessments were conducted to characterise the sleep phenotype of children with ND-GCs in comparison to controls. Latent class analysis was conducted to derive subgroups of children with an ND-GC based on sleep symptomatology. Assessment of cognition and psychopathology allowed investigation of whether the sleep phenotypic subgroup was associated with neuropsychiatric outcomes. We found that children with an ND-GC, when compared to control siblings, were at elevated risk of insomnia (ND-GC = 41% vs Controls = 17%, p

Abstract Early-life adversity is associated with an increased risk of psychopathology, including mood disorders, later in life. Early-life stress affects several physiological systems, however, the exact mechanisms underlying pathological risk are not fully understood. This knowledge is crucial in developing appropriate therapeutic interventions. The prepubertal period is documented as a key developmental period for the maturation of the prefrontal cortex (PFC), a brain region involved in higher cognitive functions, including social function. In this study, we performed RNA sequencing on the PFC of adult rats who had experienced prepubertal stress (PPS) and controls to investigate the genome-wide consequences of this stress. PPS alters social behaviour in adulthood, therefore we also performed RNA sequencing on PPS and control rats following a social interaction test to determine social activity-dependent gene changes. At a baseline state (1 week following a social interaction test), no genes were differentially expressed in the PPS group. However, 1603 genes were differentially expressed in PPS rats compared to controls following a social interaction. These genes were enriched in biological pathways associated with cell signalling and axon myelination dynamics. Cell enrichment analysis showed these genes were associated with oligodendrocytes, and a comparison with an existing early-life stress sequencing dataset showed that pathways linked to oligodendrocyte morphology are impacted in a range of models of early-life stress in rodents. In conclusion, we identify pathways, including those involved in axon myelination, that are differentially activated in the adult in response to social stimulation following PPS. These differential responses may contribute to vulnerability to psychiatric pathology.

Abstract Genetic evidence indicates disrupted epigenetic regulation as a major risk factor for psychiatric disorders, but the molecular mechanisms that drive this association remain to be determined. EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a genetic disorder linked with neurodevelopmental disorders and associated with schizophrenia. Here, we show that reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC. We further show that EHMT1 regulates NRSF/REST indirectly via repression of miRNA and leads to aberrant neuronal gene regulation and neurodevelopment timing. Expression of a NRSF/REST mRNA that lacks the miRNA-binding sites restores neuronal gene regulation to EHMT1 deficient cells. Significantly, the EHMT1-regulated miRNA gene set not only controls NRSF/REST but is enriched for association for Intellectual Disability (ID) and schizophrenia. This reveals a broad molecular interaction between H3K9 demethylation, NSRF/REST regulation and risk for ID and Schizophrenia.

Abstract Background Individuals with 22q11.2 deletion are at considerably increased risk of neurodevelopmental and psychiatric conditions. There have been very few studies investigating how this risk manifests in early childhood and what factors may underlie developmental variability. Insights into this can elucidate transdiagnostic markers of risk that may underlie later development of neuropsychiatric outcomes. Methods Thirty two children with 22q11.2 Deletion Syndrome (22q11.2DS) (mean age = 4.1 [SD = 1.2] years) and 12 sibling controls (mean age = 4.1 [SD = 1.5] years) underwent in‐depth dimensional phenotyping across several developmental domains selected as being potential early indicators of neurodevelopmental and psychiatric liability. Comparisons were conducted of the dimensional developmental phenotype of 22q11.2DS and sibling controls. For autistic traits, both parents and children were phenotyped using the Social Responsiveness Scale. Results Young children with 22q11.2DS exhibited large impairments (Hedge's g ≥ 0.8) across a range of developmental domains relative to sibling controls, as well as high rates of transdiagnostic neurodevelopmental and psychiatric traits. Cluster analysis revealed a subgroup of children with 22q11.2DS (n = 16; 53%) in whom neurodevelopmental and psychiatric liability was particularly increased and who differed from other children with 22q11.2DS and non‐carrier siblings. Exploratory analyses revealed that early motor and sleep impairments indexed liability for neurodevelopmental and psychiatric outcomes. Maternal autism trait scores were predictive of autism traits in children with 22q11.2DS (intraclass correlation coefficients = 0.47, p = 0.046, n = 31). Conclusions Although psychiatric conditions typically emerge later in adolescence and adulthood in 22q11.2DS, our exploratory study was able to identify a range of early risk indicators. Furthermore, findings indicate the presence of a subgroup who appeared to have increased neurodevelopmental and psychiatric liability. Our findings highlight the scope for future studies of early risk mechanisms and early intervention within this high genetic risk patient group.

Genomic studies focusing on the contribution of common and rare genetic variants of schizophrenia and bipolar disorder support the view that substantial risk is conferred through molecular pathways involved in synaptic plasticity in the neurons of cortical and subcortical brain regions, including the hippocampus. Synaptic long-term potentiation (LTP) is central to associative learning and memory and depends on a pattern of gene expression in response to neuronal stimulation. Genes related to the induction of LTP have been associated with psychiatric genetic risk, but the specific cell types and timepoints responsible for the association are unknown. Using published genomic and transcriptomic datasets, we studied the relationship between temporally defined gene expression in hippocampal pyramidal neurons following LTP and enrichment for common genetic risk for schizophrenia and bipolar disorder, and for copy number variants (CNVs) and de novo coding variants associated with schizophrenia. We observed that upregulated genes in hippocampal pyramidal neurons at 60 and 120 min following LTP induction were enriched for common variant association with schizophrenia and bipolar disorder subtype I. At 60 min, LTP-induced genes were enriched in duplications from patients with schizophrenia, but this association was not specific to pyramidal neurons, perhaps reflecting the combined effects of CNVs in excitatory and inhibitory neuron subtypes. Gene expression following LTP was not related to enrichment for de novo coding variants from schizophrenia cases. Our findings refine our understanding of the role LTP-related gene sets play in conferring risk to conditions causing psychosis and provide a focus for future studies looking to dissect the molecular mechanisms associated with this risk.

Introduction: There is a growing interest in the possibility of dietary supplementation with polyunsaturated fatty acids (PUFAs) for treatment and prevention of neurodevelopmental and neuropsychiatric disorders. Studies have suggested that of the two important classes of polyunsaturated fatty acids, omega-6 (n-6) and omega-3 (n-3), n-3 polyunsaturated fatty acids support brain development and function, and when used as a dietary supplement may have beneficial effects for maintenance of a healthy brain. However, to date epidemiological studies and clinical trials on children and adults have been inconclusive regarding treatment length, dosage and use of specific n-3 polyunsaturated fatty acids. The aim of this study is to generate a simplified in vitro cell-based model system to test how different n-6 to n-3 polyunsaturated fatty acids ratios affect human-derived neurons activity as a cellular correlate for brain function and to probe the mechanism of their action.Methods: All experiments were performed by use of human induced pluripotent stem cells (iPSCs). In this study, we examined the effect of different ratios of linoleic acid (n-6) to alpha-linolenic acid in cell growth medium on induced pluripotent stem cell proliferation, generation of neuronal precursors and electrophysiology of cortical glutamatergic neurons by multielectrode array (MEA) analysis.Results: This study shows that at a n-6:n-3 ratio of 5:1 polyunsaturated fatty acids induce stem cell proliferation, generating a large increase in number of cells after 72 h treatment; suppress generation of neuronal progenitor cells, as measured by decreased expression of FOXG1 and Nestin in neuronal precursor cells (NPC) after 20 days of development; and disrupt neuronal activity in vitro, increasing spontaneous neuronal firing, reducing synchronized bursting receptor subunits. We observed no significant differences for neuronal precursor cells treated with ratios 1:3 and 3:1, in comparison to 1:1 control ratio, but higher ratios of n-6 to n-3 polyunsaturated fatty acids adversely affect early stages of neuronal differentiation. Moreover, a 5:1 ratio in cortical glutamatergic neurons induce expression of GABA receptors which may explain the observed abnormal electrophysiological activity.

Abstract Background Many children with an intellectual or developmental disability (IDD) have associated autism spectrum disorders (ASD), as well as an increased risk of mental health difficulties. In a cohort with IDD of genetic aetiology, we tested the hypothesis that excess risk attached to those with ASD + IDD, in terms of both children's mental health and parental psychological distress. Methods Participants with a copy number variant or single nucleotide variant (5–19 years) were recruited via UK National Health Service. 1904 caregivers competed an online assessment of child mental health and reported on their own psychological wellbeing. We used regression to examine the association between IDD with and without co‐occurring ASD, and co‐occurring mental health difficulties, as well as with parental psychological distress. We adjusted for children's sex, developmental level, physical health, and socio‐economic deprivation. Results Of the 1904 participants with IDD, 701 (36.8%) had co‐occurring ASD. Children with both IDD and ASD were at higher risk of associated disorders than those with IDD alone (ADHD: OR = 1.84, 95% confidence interval [CI] 1.46–2.32, p

Background Current psychiatric diagnoses, although heritable, have not been clearly mapped onto distinct underlying pathogenic processes. The same symptoms often occur in multiple disorders, and a substantial proportion of both genetic and environmental risk factors are shared across disorders. However, the relationship between shared symptoms and shared genetic liability is still poorly understood. Aims Well-characterised, cross-disorder samples are needed to investigate this matter, but few currently exist. Our aim is to develop procedures to purposely curate and aggregate genotypic and phenotypic data in psychiatric research. Method As part of the Cardiff MRC Mental Health Data Pathfinder initiative, we have curated and harmonised phenotypic and genetic information from 15 studies to create a new data repository, DRAGON-Data. To date, DRAGON-Data includes over 45 000 individuals: adults and children with neurodevelopmental or psychiatric diagnoses, affected probands within collected families and individuals who carry a known neurodevelopmental risk copy number variant. Results We have processed the available phenotype information to derive core variables that can be reliably analysed across groups. In addition, all data-sets with genotype information have undergone rigorous quality control, imputation, copy number variant calling and polygenic score generation. Conclusions DRAGON-Data combines genetic and non-genetic information, and is available as a resource for research across traditional psychiatric diagnostic categories. Algorithms and pipelines used for data harmonisation are currently publicly available for the scientific community, and an appropriate data-sharing protocol will be developed as part of ongoing projects (DATAMIND) in partnership with Health Data Research UK.

Abstract Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions.

Background: Young people living with 22q11.2 Deletion Syndrome (22q11.2DS) are at increased risk of schizophrenia, intellectual disability, attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In common with these conditions, 22q11.2DS is also associated with sleep problems. We investigated whether abnormal sleep or sleep-dependent network activity in 22q11.2DS reflects convergent, early signatures of neural circuit disruption also evident in associated neurodevelopmental conditions. Methods: In a cross-sectional design, we recorded high-density sleep EEG in young people (6–20 years) with 22q11.2DS (n=28) and their unaffected siblings (n=17), quantifying associations between sleep architecture, EEG oscillations (spindles and slow waves) and psychiatric symptoms. We also measured performance on a memory task before and after sleep. Results: 22q11.2DS was associated with significant alterations in sleep architecture, including a greater proportion of N3 sleep and lower proportions of N1 and REM sleep than in siblings. During sleep, deletion carriers showed broadband increases in EEG power with increased slow-wave and spindle amplitudes, increased spindle frequency and density, and stronger coupling between spindles and slow-waves. Spindle and slow-wave amplitudes correlated positively with overnight memory in controls, but negatively in 22q11.2DS. Mediation analyses indicated that genotype effects on anxiety, ADHD and ASD were partially mediated by sleep EEG measures. Conclusions: This study provides a detailed description of sleep neurophysiology in 22q11.2DS, highlighting alterations in EEG signatures of sleep which have been previously linked to neurodevelopment, some of which were associated with psychiatric symptoms. Sleep EEG features may therefore reflect delayed or compromised neurodevelopmental processes in 22q11.2DS, which could inform our understanding of the neurobiology of this condition and be biomarkers for neuropsychiatric disorders. Funding: This research was funded by a Lilly Innovation Fellowship Award (UB), the National Institute of Mental Health (NIMH 5UO1MH101724; MvdB), a Wellcome Trust Institutional Strategic Support Fund (ISSF) award (MvdB), the Waterloo Foundation (918-1234; MvdB), the Baily Thomas Charitable Fund (2315/1; MvdB), MRC grant Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment (IMAGINE) (MR/L011166/1; JH, MvdB and MO), MRC grant Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment 2 (IMAGINE-2) (MR/T033045/1; MvdB, JH and MO); Wellcome Trust Strategic Award ‘Defining Endophenotypes From Integrated Neurosciences’ Wellcome Trust (100202/Z/12/Z MO, JH). NAD was supported by a National Institute for Health Research Academic Clinical Fellowship in Mental Health and MWJ by a Wellcome Trust Senior Research Fellowship in Basic Biomedical Science (202810/Z/16/Z). CE and HAM were supported by Medical Research Council Doctoral Training Grants (C.B.E. 1644194, H.A.M MR/K501347/1). HMM and UB were employed by Eli Lilly & Co during the study; HMM is currently an employee of Boehringer Ingelheim Pharma GmbH & Co KG. The views and opinions expressed are those of the author(s), and not necessarily those of the NHS, the NIHR or the Department of Health funders.

Abstract Genetic risk factors can significantly increase chances of developing psychiatric disorders, but the underlying biological processes through which this risk is effected remain largely unknown. Here we show that haploinsufficiency of Cyfip1, a candidate risk gene present in the pathogenic 15q11.2(BP1–BP2) deletion may impact on psychopathology via abnormalities in cell survival and migration of newborn neurons during postnatal hippocampal neurogenesis. We demonstrate that haploinsufficiency of Cyfip1 leads to increased numbers of adult-born hippocampal neurons due to reduced apoptosis, without altering proliferation. We show this is due to a cell autonomous failure of microglia to induce apoptosis through the secretion of the appropriate factors, a previously undescribed mechanism. Furthermore, we show an abnormal migration of adult-born neurons due to altered Arp2/3 mediated actin dynamics. Together, our findings throw new light on how the genetic risk candidate Cyfip1 may influence the hippocampus, a brain region with strong evidence for involvement in psychopathology.

Abstract Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Abstract Copy number variants are amongst the most highly penetrant risk factors for psychopathology and neurodevelopmental deficits, but little information about the detailed clinical phenotype associated with particular variants is available. We present the largest study of the microdeletion and -duplication at the distal 1q21 locus, which has been associated with schizophrenia and intellectual disability, in order to investigate the range of psychiatric phenotypes. Clinical and cognitive data from 68 deletion and 55 duplication carriers were analysed with logistic regression analysis to compare frequencies of mental disorders between carrier groups and controls, and linear mixed models to compare quantitative phenotypes. Both children and adults with copy number variants at 1q21 had high frequencies of psychopathology. In the children, neurodevelopmental disorders were most prominent (56% for deletion, 68% for duplication carriers). Adults had increased prevalence of mood (35% for deletion [OR = 6.6 (95% CI: 1.4–40.1)], 55% for duplication carriers [8.3 (1.4–55.5)]) and anxiety disorders (24% [1.8 (0.4–8.4)] and 55% [10.0 (1.9–71.2)]). The adult group, which included mainly genetically affected parents of probands, had an IQ in the normal range. These results confirm high prevalence of neurodevelopmental disorders associated with CNVs at 1q21 but also reveal high prevalence of mood and anxiety disorders in a high-functioning adult group with these CNVs. Because carriers of neurodevelopmental CNVs who show relevant psychopathology but no major cognitive impairment are not currently routinely receiving clinical genetic services widening of genetic testing in psychiatry may be considered.

Objectives This study aimed to explore the experiences of parents caring for children with intellectual and developmental disabilities (IDD) during the UK national lockdown in spring 2020, resulting from the COVID-19 pandemic.Design Participants were identified using opportunity sampling from the IMAGINE-ID national (UK) cohort and completed an online survey followed by a semistructured interview. Interviews were analysed using thematic analysis.Setting Interviews were conducted over the telephone in July 2020 as the first UK lockdown was ending.Participants 23 mothers of children with intellectual and developmental disabilities aged 5–15 years were recruited.Results Themes reported by parents included: managing pre-existing challenges during a time of extreme change, having mixed emotions about the benefits and difficulties that arose during the lockdown and the need for appropriate, individualised support.Conclusions Our findings confirm observations previously found in UK parents of children with IDD and provide new insights on the use of technology during the pandemic for schooling and healthcare, as well as the need for regular check-ins.

People with a genetic deletion of the 15q11.2 locus are at increased risk for psychiatric disorders and white matter disturbances, but the gene(s) responsible are unclear. Here, the authors show that low dosage of CYFIP1, present in the human 15q11.2 region, alters white matter structure and cognition in rats.

Abstract Purpose The study of mental wellbeing requires reliable, valid, and practical measurement tools. One of the most widely used measures of mental wellbeing is the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS). Our aim was to examine the psychometric properties of SWEMWBS (a brief seven-item version) in a ‘real-world’ population sample of young people. Methods We used data from the 2017 School Health Research Network Student Health and Wellbeing Survey, completed by 103,971 students in years 7 to 11 from 193 secondary schools in Wales. We first estimated polychoric correlation matrices for the whole sample and by school year, and undertook a principal components analysis to check for configural invariance. Subsequently, we used a multiple-groups structural equation model with successively greater constraints to test measurement invariance. To examine external construct validity, we calculated correlations between the SWEMWBS score and four covariates: life satisfaction, somatisation, school pressure and bullying victimisation. Results Parallel analysis suggested that extraction of one factor was appropriate both overall and in each year group. Inspection of standardised loadings suggested that four items had progressively stronger correlations with the factor as students are older, but change in fit indices between models suggested that loadings and thresholds, but not residual variances, were invariant by age group. SWEMWBS scores were moderately correlated with measures of life satisfaction and somatisation, and weakly to moderately correlated with school pressure and bullying victimisation. Conclusions This study adds to the growing evidence that SWEMWBS is appropriate for measuring mental wellbeing in young people and suggests that SWEMWBS is appropriate for tracking the development of wellbeing across adolescence.

Abstract Background The 22q11.2 deletion is associated with psychiatric and behavioural disorders, intellectual disability and multiple physical abnormalities. Recent research also indicates impaired coordination skills may be part of the clinical phenotype. This study aimed to characterise sensorimotor control abilities in children with 22q11.2 deletion syndrome (22q11.2DS) and investigate their relationships with co-occurring IQ impairments and psychopathology. Methods Fifty-four children with 22q11.2DS and 24 unaffected sibling controls, comparable in age and gender, underwent kinematic analysis of their hand movements, whilst performing a battery of three visuo-manual coordination tasks that measured their tracking, aiming and steering abilities. Additionally, standardised assessments of full-scale IQ (FSIQ), attention deficit hyperactivity disorder, indicative autism spectrum disorder (ASD) and anxiety disorder symptomatology were conducted. Results Children with 22q11.2DS showed deficits on seven of eight kinematic descriptors of movement quality across the three coordination tasks, compared to controls. Within 22q11.2DS cases, the extent of impairment on only three kinematic descriptors was significantly related to FSIQ after correction for multiple testing. Moreover, only error whilst visuo-manually tracking was nominally associated with ADHD symptom counts. Conclusions Impairments in sensorimotor control are seen on a range of visuo-manual tasks in children with 22q11.2DS but the extent of these impairments are largely unrelated to the severity of other psychopathological and intellectual impairments commonly found in children with 22q11.2DS.

Abstract Objective Occurrences of early‐life stress (ELS) are associated with the severity of psychotic symptoms and working memory (WM) deficits in patients with psychosis (PSY). This study investigated potential mediation roles of WM behavioral performance and glutamate concentrations in prefrontal brain regions on the association between ELS and psychotic symptom severity in PSY. Method Forty‐seven patients with PSY (established schizophrenia, n = 30; bipolar disorder, n = 17) completed measures of psychotic symptom severity. In addition, data on ELS and WM performance were collected in both patients with PSY and healthy controls (HC; n = 41). Resting‐state glutamate concentrations in the bilateral dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) were also assessed with proton magnetic resonance spectroscopy for both PSY and HC groups. t tests, analyses of variance, and regression analyses were utilized. Results Participants with PSY reported significantly more ELS occurrences and showed poorer WM performance than HC. Furthermore, individuals with PSY displayed lower glutamate concentrations in the left DLPFC than HC. Neither ELS nor WM performance were predictive of severity of psychotic symptoms in participants with PSY. However, we found a significant negative correlation between glutamate concentrations in the left DLPFC and ELS occurrence in HC only. Conclusion In individuals with PSY, the current study found no evidence that the association between ELS and psychotic symptoms is mediated by WM performance or prefrontal glutamate concentrations. In HC, the association between ELS experience and glutamate concentrations may indicate a neurometabolite effect of ELS that is independent of an illness effect in psychosis.

Background: Borderline personality disorder (BPD) is a severe psychiatric disorder involving a range of symptoms including marked affective instability and disturbances in interpersonal interactions. Neuroimaging studies are beginning to provide evidence of altered processing in fronto-limbic network deficits in the disorder, however, few studies directly examine structural connections within this circuitry together with their relation to proposed causative processes and clinical features. Methods: In the current study, we investigated whether individuals with BPD (n = 20) have deficits in white matter integrity compared to a matched group of healthy controls (n = 18) using diffusion tensor MRI (DTI). We hypothesized that the BPD group would have decreased fractional anisotropy (FA), a measure of white matter integrity, compared to the controls in white matter tracts connecting frontal and limbic regions, primarily the cingulum, fornix and uncinate fasciculus. We also investigated the extent to which any such deficits related to childhood adversity, as measured by the childhood trauma questionnaire, and symptom severity as measured by the Zanarini rating scale for BPD. Results: We report decreased white matter integrity in BPD versus controls in the cingulum and fornix. There were no significant relationships between FA and measures of childhood trauma. There were, however, significant associations between FA in the cingulum and clinical symptoms of anger, and in the fornix with affective instability, and measures of avoidance of abandonment from the Zanarini rating scale. Conclusions: We report deficits within fronto-limbic connections in individuals with BPD. Abnormalities within the fornix and cingulum were related to severity of symptoms and highlight the importance of these tracts in the pathogenesis of the disorder.

Genes involved in synaptic plasticity, particularly genes encoding postsynaptic density proteins, have been recurrently linked to psychiatric disorders including schizophrenia and autism. Postsynaptic density Homer1 proteins contribute to synaptic plasticity through the competing actions of short and long isoforms. The activity-induced expression of short Homer1 isoforms, Homer1a and Ania-3, is thought to be related to processes of learning and memory. However, the precise regulation of Homer1a and Ania-3 with different components of learning has not been investigated. Here, we used in situ hybridization to quantify short and long Homer1 expression in the hippocampus following consolidation, retrieval, and extinction of associative fear memory, using contextual fear conditioning in rats. Homer1a and Ania-3, but not long Homer1, were regulated by contextual fear learning or novelty detection, although their precise patterns of expression in hippocampal subregions were dependent on the isoform. We also show for the first time that the two short Homer1 isoforms are regulated after the retrieval and extinction of contextual fear memory, albeit with distinct temporal and spatial profiles. These findings support a role of activity-induced Homer1 isoforms in learning and memory processes in discrete hippocampal subregions and suggest that Homer1a and Ania-3 may play separable roles in synaptic plasticity.

Grain oriented electrical steels (GOES) are coated with aluminium orthophosphate on top of a forsterite (Mg2SiO4) layer to provide stress and insulation resistance to reduce the power loss and magnetostriction. In this work Chromium Aluminium Nitride (CrAlN) was coated on GOES samples with electron beam physical vapour deposition and was tested in the single strip and magnetostriction tester to measure the power loss and magnetostriction before and after coating. Power loss was reduced by 2% after coating and 6 % post annealing at 800 °C. For applied compressive stress of 6 MPa, the magnetostrictive strain was zero with the CrAlN coating as compared to 22 and 24 μϵ for fully finished GOES and GOES without phosphate coating. The thickness of the coating was found to be 1.9 ± 0.2 μm estimated with Glow Discharge Optical Emission Spectroscopy (GDOES). The magnetic domain imaging showed domain narrowing after coating. The reduction in power loss and magnetostriction was due to the large residual compressive stress and Young’s modulus (270 GPa) of the coating.

We investigated the distinctiveness of gene regulatory networks in CA1 associated with the extinction of contextual fear memory (CFM) after recall using Affymetrix GeneChip Rat Genome 230 2.0 Arrays. These data were compared to previously published retrieval and reconsolidation-attributed, and consolidation datasets. A stringent dual normalization and pareto-scaled orthogonal partial least-square discriminant multivariate analysis together with a jack-knifing-based cross-validation approach was used on all datasets to reduce false positives. Consolidation, retrieval and extinction were correlated with distinct patterns of gene expression 2 hours later. Extinction-related gene expression was most distinct from the profile accompanying consolidation. A highly specific feature was the discrete regulation of neuroimmunological gene expression associated with retrieval and extinction. Immunity-associated genes of the tyrosine kinase receptor TGFβ and PDGF, and TNF families' characterized extinction. Cytokines and proinflammatory interleukins of the IL-1 and IL-6 families were enriched with the no-extinction retrieval condition. We used comparative genomics to predict transcription factor binding sites in proximal promoter regions of the retrieval-regulated genes. Retrieval that does not lead to extinction was associated with NF-κB-mediated gene expression. We confirmed differential NF-κBp65 expression, and activity in all of a representative sample of our candidate genes in the no-extinction condition. The differential regulation of cytokine networks after the acquisition and retrieval of CFM identifies the important contribution that neuroimmune signalling plays in normal hippocampal function. Further, targeting cytokine signalling upon retrieval offers a therapeutic strategy to promote extinction mechanisms in human disorders characterised by dysregulation of associative memory.

Este trabalho analisa a evolução de cinco distribuidoras de energia elétrica, localizadas no Nordeste do Brasil, por meio deindicadores técnicos e financeiros. Três empresas privatizadas e duas públicas foram analisadas entre 1997 e 2008. Os indicadoresfinanceiros mostram a lucratividade e capacidade de as firmas gerarem valor para os acionistas, enquanto os técnicosa qualidade do serviço prestado aos consumidores. Duas proposições foram estabelecidas sugerindo que as empresasprivatizadas tiveram seus indicadores financeiros e técnicos melhorados, comparativamente às empresas públicas, depoisda privatização. Observou-se que os indicadores financeiros das distribuidoras privatizadas melhoraram em relação aos daspúblicas, gerando mais valor para seus acionistas. No entanto, não há evidência de que a privatização impactou na melhoriados indicadores técnicos e qualidade do serviço.

Individuals carrying rare, but biologically informative genetic variants provide a unique opportunity to model major mental illness and inform understanding of disease mechanisms. The rarity of such variations means that their study involves small group numbers, however they are amongst the strongest known genetic risk factors for major mental illness and are likely to have large neural effects. DISC1 (Disrupted in Schizophrenia 1) is a gene containing one such risk variant, identified in a single Scottish family through its disruption by a balanced translocation of chromosomes 1 and 11; t(1;11) (q42.1;q14.3).Within the original pedigree, we examined the effects of the t(1;11) translocation on white matter integrity, measured by fractional anisotropy (FA). This included family members with (n = 7) and without (n = 13) the translocation, along with a clinical control sample of patients with psychosis (n = 34), and a group of healthy controls (n = 33).We report decreased white matter integrity in five clusters in the genu of the corpus callosum, the right inferior fronto-occipital fasciculus, acoustic radiation and fornix. Analysis of the mixed psychosis group also demonstrated decreased white matter integrity in the above regions. FA values within the corpus callosum correlated significantly with positive psychotic symptom severity.We demonstrate that the t(1;11) translocation is associated with reduced white matter integrity in frontal commissural and association fibre tracts. These findings overlap with those shown in affected patients with psychosis and in DISC1 animal models and highlight the value of rare but biologically informative mutations in modeling psychosis.

Abstract Introduction The objective structured clinical examination (OSCE) with standardized patients is commonly accepted as a reliable assessment of clinical skills. Simulation allows learners the opportunity to experience conditions and perform procedures in a safe, standardized environment. This OSCE case incorporates both the standardized patient and the high-fidelity simulator to depict a common acute clinical condition that requires emergent attention. Methods Students are presented with an asthmatic patient with shortness of breath. The patient is accompanied by a family member. The student must do a timely assessment of the situation and take corrective action. A patient care assistant/nurse is present to carry out treatment orders. The students must demonstrate competence in communication with the patient, family member, and patient care assistant. The student must recognize the acuity of the clinical presentation and apply appropriate treatment as the case evolves. Results The case was one of six cases in the multistation high-stakes OSCE given to students at the end of the third year of medical school. Students performed well on the case achieving an average score of 83% on the combined examiner and standardized patient checklists. Students rated the case difficulty as above average. Discussion Cases are typically written for standardized patients (SP) or for simulation. This case incorporates both SP and simulator in a more realistic way. The student is challenged to elicit history from the patient and the family member when the patient is incapable of speaking for himself. The student must recognize abnormal physical findings and aberrations of vital signs in order to make clinical decisions which will evolve and change with treatment; culminating in communicating a final disposition.

ObjectiveBipolar disorder is a highly heritable condition. First-degree relatives of affected individuals have a more than a ten-fold increased risk of developing bipolar disorder (BD), and a three-fold risk of developing major depressive disorder (MDD) than the general population. It is unclear however whether differences in brain activation reported in BD and MDD are present before the onset of illness.MethodsWe studied 98 young unaffected individuals at high familial risk of BD and 58 healthy controls using functional Magnetic Resonance Imaging (fMRI) scans and a task involving executive and language processing. Twenty of the high-risk subjects subsequently developed MDD after the baseline fMRI scan.ResultsAt baseline the high-risk subjects who later developed MDD demonstrated relatively increased activation in the insula cortex, compared to controls and high risk subjects who remained well. In the healthy controls and high-risk group who remained well, this region demonstrated reduced engagement with increasing task difficulty. The high risk subjects who subsequently developed MDD did not demonstrate this normal disengagement. Activation in this region correlated positively with measures of cyclothymia and neuroticism at baseline, but not with measures of depression.ConclusionsThese results suggest that increased activation of the insula can differentiate individuals at high-risk of bipolar disorder who later develop MDD from healthy controls and those at familial risk who remain well. These findings offer the potential of future risk stratification in individuals at risk of mood disorder for familial reasons.

Borderline personality disorder (BPD) is a common and serious mental illness, associated with a high risk of suicide and self harm. Those with a diagnosis of BPD often display difficulties with social interaction and struggle to form and maintain interpersonal relationships. Here we investigated the ability of participants with BPD to make social inferences from faces.20 participants with BPD and 21 healthy controls were shown a series of faces and asked to judge these according to one of six characteristics (age, distinctiveness, attractiveness, intelligence, approachability, trustworthiness). The number and direction of errors made (compared to population norms) were recorded for analysis.Participants with a diagnosis of BPD displayed significant impairments in making judgements from faces. In particular, the BPD Group judged faces as less approachable and less trustworthy than controls. Furthermore, within the BPD Group there was a correlation between scores on the Childhood Trauma Questionnaire (CTQ) and bias towards judging faces as unapproachable.Individuals with a diagnosis of BPD have difficulty making appropriate social judgements about others from their faces. Judging more faces as unapproachable and untrustworthy indicates that this group may have a heightened sensitivity to perceiving potential threat, and this should be considered in clinical management and treatment.

Functional magnetic resonance imaging (fMRI) is a powerful method for exploring emotional and cognitive brain responses in humans. However rodent fMRI has not previously been applied to the analysis of learned behaviour in awake animals, limiting its use as a translational tool. Here we have developed a novel paradigm for studying brain activation in awake rats responding to conditioned stimuli using fMRI. Using this method we show activation of the amygdala and related fear circuitry in response to a fear-conditioned stimulus and demonstrate that the magnitude of fear circuitry activation is increased following early life stress, a rodent model of affective disorders. This technique provides a new translatable method for testing environmental, genetic and pharmacological manipulations on emotional and cognitive processes in awake rodent models.

Social exclusion is an influential concept in politics, mental health and social psychology. Studies on healthy subjects have implicated the medial prefrontal cortex (mPFC), a region involved in emotional and social information processing, in neural responses to social exclusion. Impairments in social interactions are common in schizophrenia and are associated with reduced quality of life. Core symptoms such as delusions usually have a social content. However little is known about the neural underpinnings of social abnormalities. The aim of this study was to investigate the neural substrates of social exclusion in schizophrenia. Patients with schizophrenia and healthy controls underwent fMRI while participating in a popular social exclusion paradigm. This task involves passing a 'ball' between the participant and two cartoon representations of other subjects. The extent of social exclusion (ball not being passed to the participant) was parametrically varied throughout the task. Replicating previous findings, increasing social exclusion activated the mPFC in controls. In contrast, patients with schizophrenia failed to modulate mPFC responses with increasing exclusion. Furthermore, the blunted response to exclusion correlated with increased severity of positive symptoms. These data support the hypothesis that the neural response to social exclusion differs in schizophrenia, highlighting the mPFC as a potential substrate of impaired social interactions.

Behavioral studies have shown that, at a population level, women perform better on tests of social cognition and empathy than men. Furthermore Autism Spectrum Disorders (ASDs), which are characterized by impairments in social functioning and empathy, occur more commonly in males than females. These findings have led to the hypothesis that differences in the functioning of the social brain between males and females contribute to the greater vulnerability of males to ASD and the suggestion that ASD may represent an extreme form of the male brain. Here we sought to investigate this hypothesis by determining: (i) whether males and females differ in social brain function, and (ii) whether any sex differences in social brain function are exaggerated in individuals with ASD. Using fMRI we show that males and females differ markedly in social brain function when making social decisions from faces (compared to simple sex judgements) especially when making decisions of an affective nature, with the greatest sex differences in social brain activation being in the inferior frontal cortex (IFC). We also demonstrate that this difference is exaggerated in individuals with ASD, who show an extreme male pattern of IFC function. These results show that males and females differ significantly in social brain function and support the view that sex differences in the social brain contribute to the greater vulnerability of males to ASDs.

Stress experienced in childhood is associated with an increased risk of developing psychiatric disorders in adulthood. These disorders are particularly characterized by disturbances to emotional and cognitive processes, which are not currently fully modeled in animals. Assays of cognitive bias have recently been used with animals to give an indication of their emotional/cognitive state. We used a cognitive bias test, alongside a traditional measure of anxiety (elevated plus maze), to investigate the effects of juvenile stress (JS) on adulthood behaviour using a rodent model. During the cognitive bias test, animals were trained to discriminate between two reward bowls based on a stimulus (rough/smooth sandpaper) encountered before they reached the bowls. One stimulus (e.g. rough) was associated with a lower value reward than the other (e.g. smooth). Once rats were trained, their cognitive bias was explored through the presentation of an ambiguous stimulus (intermediate grade sandpaper): a rat was classed as optimistic if it chose the bowl ordinarily associated with the high value reward. JS animals were lighter than controls, exhibited increased anxiety-like behaviour in the elevated plus maze and were more optimistic in the cognitive bias test. This increased optimism may represent an optimal foraging strategy for these underweight animals. JS animals were also faster than controls to make a decision when presented with an ambiguous stimulus, suggesting altered decision making. These results demonstrate that stress in the juvenile phase can increase anxiety-like behaviour and alter cognitive bias and decision making in adulthood in a rat model.

UNLABELLED: There have been concerns that individuals with autism spectrum disorders (ASDs) are over-represented but not recognised in prison populations. A screening tool for ASDs in prisons has therefore been developed. AIMS: We aimed to evaluate this tool in Scottish prisoners by comparing scores with standard measures of autistic traits (Autism Quotient (AQ)), neurodevelopmental history (Asperger Syndrome (and High-Functioning Autism) Diagnostic Interview (ASDI)), and social cognition (Ekman 60 Faces test). METHODS: Prison officers across all 12 publicly-run closed prisons in Scotland assessed convicted prisoners using the screening tool. This sample included male and female prisoners and both adult and young offenders. Prisoners with high scores, along with an equal number of age and sex-matched controls, were invited to take part in interviews. Prisoners' relatives were contacted to complete a neurodevelopmental assessment. RESULTS: 2458 prisoners were screened using the tool, and 4% scored above the cut-off. 126 prisoners were further assessed using standardised measures. 7 of those 126 assessed scored 32 or above (cut-off) on the AQ. 44 interviews were completed with prisoners' relatives, no prisoner reached the cut-off score on the ASDI. Scores on the screening tool correlated significantly with AQ and ASDI scores, and not with the Ekman 60 Faces Test or IQ. Sensitivity was 28.6% and specificity 75.6%; AUC was 59.6%. CONCLUSIONS: Although this screening tool measures autistic traits in this population, sensitivity for scores of 32 or above on the AQ is poor. We consider that this limits its usefulness and do not recommend that the tool is routinely used to screen for ASDs in prisons.

Este trabalho analisa a evolução de cinco distribuidoras de energia elétrica, localizadas no Nordeste do Brasil, por meio de indicadores técnicos e financeiros. Três empresas privatizadas e duas públicas foram analisadas entre 1997 e 2008. Os indicadores financeiros mostram a lucratividade e capacidade de as firmas gerarem valor para os acionistas, enquanto os técnicos a qualidade do serviço prestado aos consumidores. Duas proposições foram estabelecidas sugerindo que as empresas privatizadas tiveram seus indicadores financeiros e técnicos melhorados, comparativamente às empresas públicas, depois da privatização. Observou-se que os indicadores financeiros das distribuidoras privatizadas melhoraram em relação aos das públicas, gerando mais valor para seus acionistas. No entanto, não há evidência de que a privatização impactou na melhoria dos indicadores técnicos e qualidade do serviço.