COVID-19 pandemic impact on adolescent mental health: a reassessment accounting for development.

Current prospective reports suggest a pandemic-related increase in adolescent mental health problems. We examine whether age-related change over 11-14 years accounts for this increase. Mothers and adolescents in a UK-based birth cohort (Wirral Child Health and Development Study; WCHADS; N = 737) reported on adolescent depression and behavioural problems pre-pandemic (December 2019-March 2020), mid-pandemic (June 2020-March 2021) and late pandemic (July 2021-March 2022). Analysis used repeated measures models for over-dispersed Poisson counts with an adolescent-specific intercept with age as a time-varying covariate. Maturational curves for girls, but not for boys, showed a significant increase in self-reported depression symptoms over ages 11-14 years. Behavioural problems decreased for both. After adjusting for age-related change, girls' depression increased by only 13% at mid-pandemic and returned to near pre-pandemic level at late pandemic (mid versus late - 12%), whereas boys' depression increased by 31% and remained elevated (mid versus late 1%). Age-adjusted behavioural problems increased for both (girls 40%, boys 41%) and worsened from mid- to late pandemic (girls 33%, boys 18%). Initial reports of a pandemic-related increase in depression in young adolescent girls could be explained by a natural maturational rise. In contrast, maturational decreases in boys' depression and both boys' and girls' behavioural problems may mask an effect of the pandemic.

A longitudinal comparison of emotional, behavioral and attention problems in autistic and typically developing children.

BACKGROUND: Mental health problems are elevated in autistic individuals but there is limited evidence on the developmental course of problems across childhood. We compare the level and growth of anxious-depressed, behavioral and attention problems in an autistic and typically developing (TD) cohort. METHODS: Latent growth curve models were applied to repeated parent-report Child Behavior Checklist data from age 2-10 years in an inception cohort of autistic children (Pathways, N = 397; 84% boys) and a general population TD cohort (Wirral Child Health and Development Study; WCHADS; N = 884, 49% boys). Percentile plots were generated to quantify the differences between autistic and TD children. RESULTS: Autistic children showed elevated levels of mental health problems, but this was substantially reduced by accounting for IQ and sex differences between the autistic and TD samples. There was small differences in growth patterns; anxious-depressed problems were particularly elevated at preschool and attention problems at late childhood. Higher family income predicted lower base-level on all three dimensions, but steeper increase of anxious-depressed problems. Higher IQ predicted lower level of attention problems and faster decline over childhood. Female sex predicted higher level of anxious-depressed and faster decline in behavioral problems. Social-affect autism symptom severity predicted elevated level of attention problems. Autistic girls' problems were particularly elevated relative to their same-sex non-autistic peers. CONCLUSIONS: Autistic children, and especially girls, show elevated mental health problems compared to TD children and there are some differences in predictors. Assessment of mental health should be integrated into clinical practice for autistic children.

The subcortical correlates of autistic traits in school-age children: a population-based neuroimaging study.

BACKGROUND: There is emerging evidence that the neuroanatomy of autism forms a spectrum which extends into the general population. However, whilst several studies have identified cortical morphology correlates of autistic traits, it is not established whether morphological differences are present in the subcortical structures of the brain. Additionally, it is not clear to what extent previously reported structural associations may be confounded by co-occurring psychopathology. To address these questions, we utilised neuroimaging data from the Adolescent Brain Cognitive Development Study to assess whether a measure of autistic traits was associated with differences in child subcortical morphology, and if any observed differences persisted after adjustment for child internalising and externalising symptoms. METHODS: Our analyses included data from 7005 children aged 9-10 years (female: 47.19%) participating in the Adolescent Brain Cognitive Development Study. Autistic traits were assessed using scores from the Social Responsiveness Scale (SRS). Volumes of subcortical regions of interest were derived from structural magnetic resonance imaging data. RESULTS: Overall, we did not find strong evidence for an association of autistic traits with differences in subcortical morphology in this sample of school-aged children. Whilst lower absolute volumes of the nucleus accumbens and putamen were associated with higher scores of autistic traits, these differences did not persist once a global measure of brain size was accounted for. LIMITATIONS: It is important to note that autistic traits were assessed using the SRS, of which higher scores are associated with general behavioural problems, and therefore may not be wholly indicative of autism-specific symptoms. In addition, individuals with a moderate or severe autism diagnosis were excluded from the ABCD study, and thus, the average level of autistic traits will be lower than in the general population which may bias findings towards the null. CONCLUSIONS: These findings from our well-powered study suggest that other metrics of brain morphology, such as cortical morphology or shape-based phenotypes, may be stronger candidates to prioritise when attempting to identify robust neuromarkers of autistic traits.

Synergy between callous-unemotional traits and aggression in preschool children: Cross-informant and cross-cultural replication in the UK Wirral Child Health and Development Study, and the Colombian La Sabana Parent-Child Study.

Incremental prediction of aggression from callous-unemotional (CU) traits is well established, but cross-cultural replication and studies of young children are needed. Little is understood about the contribution of CU traits in children who are already aggressive. We addressed these issues in prospective studies in the United Kingdom and Colombia. In a UK epidemiological cohort, CU traits and aggression were assessed at age 3.5 years, and aggression at 5.0 years by mothers (N = 687) and partners (N = 397). In a Colombian general population sample, CU traits were assessed at age 3.5 years and aggression at 3.5 and 5.0 years by mother report (N = 220). Analyses consistently showed prediction of age-5.0 aggression by age-3.5 CU traits controlling for age-3.5 aggression. Associations between age-3.5 CU traits and age-5.0 aggression were moderated by aggression at 3.5 years, with UK interaction terms, same informant, ß = .07 p = .014 cross-informant, ß = .14 p = .002, and in Colombia, ß = .09 p = .128. The interactions arose from stronger associations between CU traits and later aggression in those already aggressive. Our findings with preschoolers replicated across culturally diverse settings imply a major role for CU traits in the maintenance and amplification of already established aggression, and cast doubt on their contribution to its origins.

Non-verbal IQ and change in restricted and repetitive behavior throughout childhood in autism: a longitudinal study using the Autism Diagnostic Interview-Revised.

BACKGROUND: Restricted and repetitive behavior (RRB) is one of the characteristic features of Autism Spectrum Disorder. This domain of symptoms includes a broad range of behaviors. There is a need to study each behavior individually to better understand the role of each in the development of autistic children. Moreover, there are currently no longitudinal studies investigating change in these behaviors over development. METHODS: The goal of the present study was to explore the association between age and non-verbal IQ (NVIQ) on 15 RRB symptoms included in the Autism Diagnostic Interview-Revised (ADI-R) over time. A total of 205 children with ASD were assessed using the ADI-R at time of diagnosis, at age 6 years, and at age 11 years, and with the Wechsler Intelligence Scales for Children-Fourth Edition (WISC-IV) at age 8 years. RESULTS: The proportion of children showing each RRB tended to diminish with increasing age, except for sensitivity to noise and circumscribed interests, where the proportion increased over time. Although there was no significant main effect of NVIQ, there was a significant interaction between age and NVIQ. This was mainly driven by Difficulties with change in routine, for which higher NVIQ was associated with the behavior remaining relatively stable with age, while lower NVIQ was associated with the behavior becoming more prevalent with age. LIMITATIONS: The study focused on the presence/absence of each RRB but did not account for potential changes in frequency or severity of the behaviors over development. Furthermore, some limitations are inherent to the measures used. The ADI-R relies on parent report and hence has some level of subjectivity, while the Wechsler intelligence scales can underestimate the intellectual abilities of some autistic children. CONCLUSIONS: These results confirm that specific RRB are differentially linked to age and NVIQ. Studying RRB individually is a promising approach to better understanding how RRB change over the development of autistic children and are linked to other developmental domains.

An exploratory parallel-group randomised controlled trial of antenatal Guided Self-Help (plus usual care) versus usual care alone for pregnant women with depression: DAWN trial.

BACKGROUND: Depression is a common antenatal mental disorder associated with significant maternal morbidity and adverse fetal outcomes. However, there is a lack of research on the effectiveness or cost-effectiveness of psychological interventions for antenatal depression. METHODS: A parallel-group, exploratory randomised controlled trial across five hospitals. The trial compared Guided Self-Help, modified for pregnancy, plus usual care with usual care alone for pregnant women meeting DSM-IV criteria for mild-moderate depression. The trial objectives were to establish recruitment/follow-up rates, compliance and acceptability, and to provide preliminary evidence of intervention efficacy and cost-effectiveness. The primary outcome of depressive symptoms was assessed by blinded researchers using the Edinburgh Postnatal Depression Scale at 14-weeks post-randomisation. RESULTS: 620 women were screened, 114 women were eligible and 53 (46.5%) were randomised. 26 women received Guided Self-Help - 18 (69%) attending ≥4 sessions - and 27 usual care; n = 3 women were lost to follow-up (follow-up rate for primary outcome 92%). Women receiving Guided Self-Help reported fewer depressive symptoms at follow-up than women receiving usual care (adjusted effect size -0.64 (95%CI: -1.30, 0.06) p = 0.07). There were no trial-related adverse events. The cost-effectiveness acceptability curve showed the probability of Guided Self-Help being cost-effective compared with usual care ranged from 10 to 50% with a willingness-to-pay range from £0 to £50,000. CONCLUSIONS AND LIMITATIONS: Despite intense efforts we did not meet our anticipated recruitment target. However, high levels of acceptability, a lack of adverse events and a trend towards improvements in symptoms of depression post-treatment indicates this intervention is suitable for talking therapy services.

Managing uncertain recovery for patients nearing the end of life in hospital: a mixed-methods feasibility cluster randomised controlled trial of the AMBER care bundle.

BACKGROUND: The AMBER (Assessment, Management, Best Practice, Engagement, Recovery Uncertain) care bundle is a complex intervention used in UK hospitals to support patients with uncertain recovery. However, it has yet to be evaluated in a randomised controlled trial (RCT) to identify potential benefits or harms. The aim of this trial was to investigate the feasibility of a cluster RCT of the AMBER care bundle. METHODS: This is a prospective mixed-methods feasibility cluster RCT. Quantitative data collected from patients (or proxies if patients lack capacity) were used (i) to examine recruitment, retention and follow-up rates; (ii) to test data collection tools for the trial and determine their optimum timing; (iii) to test methods to identify the use of financial resources; and (iv) to explore the acceptability of study procedures for health professionals and patients. Descriptive statistical analyses and thematic analysis used the framework approach. RESULTS: In total, 894 patients were screened, of whom 220 were eligible and 19 of those eligible (8.6%) declined to participate. Recruitment to the control arm was challenging. Of the 728 patients screened for that arm, 647 (88.9%) were excluded. Overall, 65 patients were recruited (81.3% of the recruitment target of 80). Overall, many were elderly (≥80 years, 46.2%, n = 30, mean = 77.8 years, standard deviation [SD] = 12.3 years). Over half (53.8%) had a non-cancer diagnosis, with a mean of 2.3 co-morbidities; 24.6% patients (n = 16) died during their hospital stay and 35.4% (n = 23) within 100 days of discharge. In both trial arms, baseline IPOS subscale scores identified moderate patient anxiety (control: mean 13.3, SD 4.8; intervention: mean 13.3, SD 5.1), and howRwe identified a good care experience (control: mean 13.1, SD 2.5; intervention: mean 11.5, SD 2.1). Collecting quantitative service use and quality of life data was feasible. No patient participants regarded study involvement negatively. Focus groups with health professionals identified concerns regarding (i) the subjectivity of the intervention's eligibility criteria, (ii) the need to prognosticate to identify potential patients and (iii) consent procedures and the length of the questionnaire. CONCLUSIONS: A full trial of the AMBER care bundle is technically feasible but impractical due to fundamental issues in operationalising the intervention's eligibility criteria, which prevents optimal recruitment. Since this complex intervention continues to be used in clinical care and advocated in policy, alternative research approaches must be considered and tested. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) Register, ISRCTN36040085 .

Distinct chromatin structures at the monoamine oxidase-A promoter correlate with allele-specific expression in SH-SY5Y cells.

Monoamine oxidase-A (MAOA) metabolises monoamines and is implicated in the pathophysiology of psychiatric disorders. A polymorphic repetitive DNA domain, termed the uVNTR (upstream variable number tandem repeat), located at the promoter of the MAOA gene is a risk factor for many of these disorders. MAOA is on the X chromosome suggesting gender could play a role in regulation. We analysed MAOA regulation in the human female cell line, SH-SY5Y, which is polymorphic for the uVNTR. This heterozygosity allowed us to correlate allele-specific gene expression with allele-specific transcription factor binding and epigenetic marks for MAOA. Gene regulation was analysed under basal conditions and in response to the mood stabiliser sodium valproate. Both alleles were transcriptionally active under basal growth conditions; however, the alleles showed distinct transcription factor binding and epigenetic marks at their respective promoters. Exposure of the cells to sodium valproate resulted in differential allelic expression which correlated with allele-specific changes in distinct transcription factor binding and epigenetic marks at the region encompassing the uVNTR. Biochemically our model for MAOA promoter function has implications for gender differences in gene × environment responses in which the uVNTR has been implicated as a genetic risk.

Associations between maternal prenatal cortisol and fetal growth are specific to infant sex: findings from the Wirral Child Health and Development Study.

Recent findings highlight that there are prenatal risks for affective disorders that are mediated by glucocorticoid mechanisms, and may be specific to females. There is also evidence of sex differences in prenatal programming mechanisms and developmental psychopathology, whereby effects are in opposite directions in males and females. As birth weight is a risk for affective disorders, we sought to investigate whether maternal prenatal cortisol may have sex-specific effects on fetal growth. Participants were 241 mothers selected from the Wirral Child Health and Development Study (WCHADS) cohort (n=1233) using a psychosocial risk stratifier, so that responses could be weighted back to the general population. Mothers provided saliva samples, which were assayed for cortisol, at home over 2 days at 32 weeks gestation (on waking, 30-min post-waking and during the evening). Measures of infant birth weight (corrected for gestational age) were taken from hospital records. General population estimates of associations between variables were obtained using inverse probability weights. Maternal log of the area under the curve cortisol predicted infant birth weight in a sex-dependent manner (interaction term P=0.029). There was a positive and statistically significant association between prenatal cortisol in males, and a negative association in females that was not statistically significant. A sex interaction in the same direction was evident when using the waking (P=0.015), and 30-min post-waking (P=0.013) cortisol, but not the evening measure. There was no interaction between prenatal cortisol and sex to predict gestational age. Our findings add to an emerging literature that suggests that there may be sex-specific mechanisms that underpin fetal programming.

Fact or fiction: reducing the proportion and impact of false positives.

False positive findings in science are inevitable, but are they particularly common in psychology and psychiatry? The evidence that we review suggests that while not restricted to our field, the problem is acute. We describe the concept of researcher 'degrees-of-freedom' to explain how many false-positive findings arise, and how the various strategies of registration, pre-specification, and reporting standards that are being adopted both reduce and make these visible. We review possible benefits and harms of proposed statistical solutions, from tougher requirements for significance, to Bayesian and machine learning approaches to analysis. Finally we consider the organisation and methods for replication and systematic review in psychology and psychiatry.

Measurement error, time lag, unmeasured confounding: Considerations for longitudinal estimation of the effect of a mediator in randomised clinical trials.

Clinical trials are expensive and time-consuming and so should also be used to study how treatments work, allowing for the evaluation of theoretical treatment models and refinement and improvement of treatments. These treatment processes can be studied using mediation analysis. Randomised treatment makes some of the assumptions of mediation models plausible, but the mediator-outcome relationship could remain subject to bias. In addition, mediation is assumed to be a temporally ordered longitudinal process, but estimation in most mediation studies to date has been cross-sectional and unable to explore this assumption. This study used longitudinal structural equation modelling of mediator and outcome measurements from the PACE trial of rehabilitative treatments for chronic fatigue syndrome (ISRCTN 54285094) to address these issues. In particular, autoregressive and simplex models were used to study measurement error in the mediator, different time lags in the mediator-outcome relationship, unmeasured confounding of the mediator and outcome, and the assumption of a constant mediator-outcome relationship over time. Results showed that allowing for measurement error and unmeasured confounding were important. Contemporaneous rather than lagged mediator-outcome effects were more consistent with the data, possibly due to the wide spacing of measurements. Assuming a constant mediator-outcome relationship over time increased precision.

Study protocol for a randomised pragmatic trial comparing the clinical and cost effectiveness of lithium and quetiapine augmentation in treatment resistant depression (the LQD study).

BACKGROUND: Approximately 30-50% of patients with major depressive disorder can be classed as treatment resistant, widely defined as a failure to respond to two or more adequate trials of antidepressants in the current episode. Treatment resistant depression is associated with a poorer prognosis and higher mortality rates. One treatment option is to augment an existing antidepressant with a second agent. Lithium and the atypical antipsychotic quetiapine are two such add-on therapies and are currently recommended as first line options for treatment resistant depression. However, whilst neither treatment has been established as superior to the other in short-term studies, they have yet to be compared head-to-head in longer term studies, or with a superiority design in this patient group. METHODS: The Lithium versus Quetiapine in Depression (LQD) study is a parallel group, multi-centre, pragmatic, open-label, patient randomised clinical trial designed to address this gap in knowledge. The study will compare the clinical and cost effectiveness of the decision to prescribe lithium or quetiapine add-on therapy to antidepressant medication for patients with treatment resistant depression. Patients will be randomised 1:1 and followed up over 12 months, with the hypothesis being that quetiapine will be superior to lithium. The primary outcomes will be: (1) time to all-cause treatment discontinuation over one year, and (2) self-rated depression symptoms rated weekly for one year via the Quick Inventory of Depressive Symptomatology. Other outcomes will include between group differences in response and remission rates, quality of life, social functioning, cost-effectiveness and the frequency of serious adverse events and side effects. DISCUSSION: The trial aims to help shape the treatment pathway for patients with treatment resistant depression, by determining whether the decision to prescribe quetiapine is superior to lithium. Strengths of the study include its pragmatic superiority design, broad inclusion criteria (external validity) and longer follow up than previous studies. TRIAL REGISTRATION: ISRCTN registry: ISRCTN16387615 , registered 28 February 2016. ClinicalTrials.gov: NCT03004521 , registered 17 November 2016.

Effects of prenatal and postnatal depression, and maternal stroking, at the glucocorticoid receptor gene.

In animal models, prenatal and postnatal stress is associated with elevated hypothalamic-pituitary axis (HPA) reactivity mediated via altered glucocorticoid receptor (GR) gene expression. Postnatal tactile stimulation is associated with reduced HPA reactivity mediated via increased GR gene expression. In this first study in humans to examine the joint effects of prenatal and postnatal environmental exposures, we report that GR gene (NR3C1) 1-F promoter methylation in infants is elevated in the presence of increased maternal postnatal depression following low prenatal depression, and that this effect is reversed by self-reported stroking of the infants by their mothers over the first weeks of life.

Protocol for a multicentre randomiSed controlled TRial of IntraVEnous immunoglobulin versus standard therapy for the treatment of transverse myelitis in adults and children (STRIVE).

INTRODUCTION: Transverse myelitis (TM) is an immune-mediated disorder of the spinal cord which causes motor and sensory disturbance and limited recovery in 50% of patients. Standard treatment is steroids, and patients with more severe disease appear to respond to plasma exchange (PLEX). Intravenous immunoglobulin (IVIG) has also been used as an adjunct to steroids, but evidence is lacking. We propose the first randomised control trial in adults and children, to determine the benefit of additional treatment with IVIG. METHODS AND ANALYSIS: 170 adults and children aged over 1 year with acute first episode TM or neuromyelitis optica (with myelitis) will be recruited over a 2.5-year period and followed up for 12 months. Participants randomised to the control arm will receive standard therapy of intravenous methylprednisolone (IVMP). The intervention arm will receive the above standard therapy, plus additional IVIG. Primary outcome will be a 2-point improvement on the American Spinal Injury Association (ASIA) Impairment scale at 6 months postrandomisation by blinded assessors. Additional secondary and tertiary outcome measures will be collected: ASIA motor and sensory scales, Kurtzke expanded disability status scale, International Spinal Cord Injury (SCI) Bladder/Bowel Data Set, Client Services Receipt Index, Pediatric Quality of Life Inventory, EQ-5D, SCI Pain and SCI Quality of Life Data Sets. Biological samples will be biobanked for future studies. After 6-months' follow-up of the first 52 recruited patients futility analysis will be carried out. Health economics analysis will be performed to calculate cost-effectiveness. After 6 months' recruitment futility analysis will be performed. ETHICS AND DISSEMINATION: Research Ethics Committee Approval was obtained: 14/SC/1329. Current protocol: v3.0 (15/01/2015). Study findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: This study is registered with EudraCT (REF: 2014-002335-34), Clinicaltrials.gov (REF: NCT02398994) and ISRCTN (REF: 12127581).

Maternal antenatal anxiety, postnatal stroking and emotional problems in children: outcomes predicted from pre- and postnatal programming hypotheses.

BACKGROUND: Mothers' self-reported stroking of their infants over the first weeks of life modifies the association between prenatal depression and physiological and emotional reactivity at 7 months, consistent with animal studies of the effects of tactile stimulation. We now investigate whether the effects of maternal stroking persist to 2.5 years. Given animal and human evidence for sex differences in the effects of prenatal stress we compare associations in boys and girls. METHOD: From a general population sample of 1233 first-time mothers recruited at 20 weeks gestation we drew a random sample of 316 for assessment at 32 weeks, stratified by reported inter-partner psychological abuse, a risk indicator for child development. Of these mothers, 243 reported at 5 and 9 weeks how often they stroked their infants, and completed the Child Behavior Checklist (CBCL) at 2.5 years post-delivery. RESULTS: There was a significant interaction between prenatal anxiety and maternal stroking in the prediction of CBCL internalizing (p = 0.001) and anxious/depressed scores (p < 0.001). The effects were stronger in females than males, and the three-way interaction prenatal anxiety × maternal stroking × sex of infant was significant for internalizing symptoms (p = 0.003). The interactions arose from an association between prenatal anxiety and internalizing symptoms only in the presence of low maternal stroking. CONCLUSIONS: The findings are consistent with stable epigenetic effects, many sex specific, reported in animal studies. While epigenetic mechanisms may be underlying the associations, it remains to be established whether stroking affects gene expression in humans.

A molecular and ecological analysis of the trematode Plagiorchis elegans in the wood mouse Apodemus sylvaticus from a periaquatic ecosystem in the UK.

The prevalence of the digenean Plagiorchis sp. was investigated in a natural wood mouse population (Apodemus sylvaticus) in a periaquatic environment. Classical identification was complemented with the use of molecular differentiation to determine prevalence and verify species identity. Use of the complete ITS1-5.8S rDNA-ITS2 and partial 28S rDNA gene sequences have confirmed that the species reported at this location was Plagiorchis elegans and not Plagiorchis muris as reported previously. This underlines the difficulties in identification of these morphologically similar parasites. Plagiorchis elegans is typically a gastrointestinal parasite of avian species but has also been reported from small mammal populations. Although the occurrence of this digenean in A. sylvaticus in the UK is rare, in the area immediately surrounding Malham Tarn, Yorkshire, it had a high prevalence (23%) and a mean worm burden of 26.6 ± 61.5. The distribution of P. elegans followed a typically overdispersed pattern and both mouse age-group and sex were determined to be two main factors associated with prevalence. Male mice harboured the majority of worms, carrying 688 of 717 recovered during the study, and had a higher prevalence of 32.4% in comparison to only 8.7% in the small intestine of female mice. A higher prevalence of 43% was also observed in adult mice compared to 14% for young adults. No infection was observed in juvenile mice. These significant differences are likely to be due to differences in the foraging behaviour between the sexes and age cohorts of wood mice.

A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing.

Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP--rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)--had a genome-wide significant association with cognitive ageing (P=2.5 × 10(-8)). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10(-6)). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10(-8); females, P=1.66 × 10(-11); males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10(-11)) and TOMM40 (rs11556505; P=2.45 × 10(-8)) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.

Anxiolytic-induced attenuation of thigmotaxis in the Elevated Minus Maze.

Findings using exploration models of anxiety such as the Elevated Plus Maze (EPM) and Elevated Zero Maze (EZM) are remarkably consistent given the differences in layout and number of walls used to describe their closed areas. These factors therefore do not appear to be critical. The present studies were conducted to determine if anxiolytic activity could be detected using an apparatus that presented animals with only one wall. Mice were pre-treated with either vehicle, diazepam (2-4 mg/kg) or 5-10 mg/kg chlordiazepoxide (CDP) and placed for 5 min onto a square platform containing a 12 cm × 14 cm wall. Measures were taken of frequency/duration of contacts with the wall and of general activity. Time spent in contact with the wall was selectively reduced by 4 mg/kg diazepam. 10 mg/kg CDP also decreased this measure but increased measures of general activity, indicating a possible mild stimulant effect. The closed areas of the EPM are described by 3 walls. The EZM uses 2. Current findings show that anxiolytic effects can also be detected in a model with just one wall. It could and these data provide further evidence that variations in the layout of these mazes are not critical for detecting anxiolytic action. Thigmotactic cues remain present regardless of the physical characteristics of these mazes or the local conditions they are employed under. Hence, it is suggested that thigmotactic cues may be the common source of motivation to behave in these models and that this may explain their robustness.

New interview and observation measures of the broader autism phenotype: impressions of interviewee measure.

A 20 item observational measure of social functioning, the Impression of Interviewee rating scale, is one of three measures devised to assess the broader autism phenotype. The sample studied included families containing at least two individuals with autism spectrum disorder; observations were undertaken by the researcher who interviewed the subject. An exploratory factor analysis suggested a single factor was most appropriate (Cronbach's α of 0.78). There was a modest but significant retest correlation of 0.42. Correlations between live ratings and blind consensus ratings of vignettes were high (0.93). Correlations with the interview measures were moderate but statistically significant. In conclusion, the observational scale provides a promising start but further work is required before general use can be recommended.

Evidence for interplay between genes and maternal stress in utero: monoamine oxidase A polymorphism moderates effects of life events during pregnancy on infant negative emotionality at 5 weeks.

The low activity variant of the monoamine oxidase A (MAOA) functional promoter polymorphism, MAOA-LPR, in interaction with adverse environments (G × E) is associated with child and adult antisocial behaviour disorders. MAOA is expressed during foetal development so in utero G × E may influence early neurodevelopment. We tested the hypothesis that MAOA G × E during pregnancy predicts infant negative emotionality soon after birth. In an epidemiological longitudinal study starting in pregnancy, using a two stage stratified design, we ascertained MAOA-LPR status (low vs. high activity variants) from the saliva of 209 infants (104 boys and 105 girls), and examined predictions to observed infant negative emotionality at 5 weeks post-partum from life events during pregnancy. In analyses weighted to provide estimates for the general population, and including possible confounders for life events, there was an MAOA status by life events interaction (P = 0.017). There was also an interaction between MAOA status and neighbourhood deprivation (P = 0.028). Both interactions arose from a greater effect of increasing life events on negative emotionality in the MAOA-LPR low activity, compared with MAOA-LPR high activity infants. The study provides the first evidence of moderation by MAOA-LPR of the effect of the social environment in pregnancy on negative emotionality in infancy, an early risk for the development of child and adult antisocial behaviour disorders.