Developmental Aspects of Schizotypy and Suspiciousness: a Review.

PURPOSE OF THE REVIEW: This review identifies the early developmental processes that contribute to schizotypy and suspiciousness in adolescence and adulthood. It includes the most recent literature on these phenomena in childhood. RECENT FINDINGS: The early developmental processes that affect schizotypy and paranoia in later life are complex. In contrast to existing studies of psychiatric patients and clinical/nonclinical adult populations, the study of schizotypy and suspiciousness in young children and adolescents is possible due to new child-appropriate dimensional assessments. New assessments and the advancement of technology (e.g., virtual reality in mental health) as well as statistical modeling (e.g., mediation and latent-class analyses) in large data have helped identified the developmental aspects (e.g., psychosocial, neurocognitive and brain factors, nutrition, and childhood correlates) that predict schizotypy and suspiciousness in later life. SUMMARY: Prospective longitudinal designs in community youths can enhance our understanding of the etiology of schizophrenia-spectrum disorders and, in the future, the development of preventive interventions by extending adult theories and interventions to younger populations.Betty Behrens Research Fellowship, Clare Hall, University of Cambridg

Structure-based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1

The treatment of Human African Trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important and pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp. has been identified as a candidate target and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from T. brucei (J. Med. Chem. 2010, 53, 221-229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. 8 compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development

Variation in the Large-Scale Organization of Gene Expression Levels in the Hippocampus Relates to Stable Epigenetic Variability in Behavior

Despite sharing the same genes, identical twins demonstrate substantial variability in behavioral traits and in their risk for disease. Epigenetic factors-DNA and chromatin modifications that affect levels of gene expression without affecting the DNA sequence-are thought to be important in establishing this variability. Epigenetically-mediated differences in the levels of gene expression that are associated with individual variability traditionally are thought to occur only in a gene-specific manner. We challenge this idea by exploring the large-scale organizational patterns of gene expression in an epigenetic model of behavioral variability.To study the effects of epigenetic influences on behavioral variability, we examine gene expression in genetically identical mice. Using a novel approach to microarray analysis, we show that variability in the large-scale organization of gene expression levels, rather than differences in the expression levels of specific genes, is associated with individual differences in behavior. Specifically, increased activity in the open field is associated with increased variance of log-transformed measures of gene expression in the hippocampus, a brain region involved in open field activity. Early life experience that increases adult activity in the open field also similarly modifies the variance of gene expression levels. The same association of the variance of gene expression levels with behavioral variability is found with levels of gene expression in the hippocampus of genetically heterogeneous outbred populations of mice, suggesting that variation in the large-scale organization of gene expression levels may also be relevant to phenotypic differences in outbred populations such as humans. We find that the increased variance in gene expression levels is attributable to an increasing separation of several large, log-normally distributed families of gene expression levels. We also show that the presence of these multiple log-normal distributions of gene expression levels is a universal characteristic of gene expression in eurkaryotes. We use data from the MicroArray Quality Control Project (MAQC) to demonstrate that our method is robust and that it reliably detects biological differences in the large-scale organization of gene expression levels.Our results contrast with the traditional belief that epigenetic effects on gene expression occur only at the level of specific genes and suggest instead that the large-scale organization of gene expression levels provides important insights into the relationship of gene expression with behavioral variability. Understanding the epigenetic, genetic, and environmental factors that regulate the large-scale organization of gene expression levels, and how changes in this large-scale organization influences brain development and behavior will be a major future challenge in the field of behavioral genomics

PLoS Med

BACKGROUND: The effect of antiretroviral treatment (ART) eligibility expansions on patient outcomes, including rates of timely ART initiation among those enrolling in care, has not been assessed on a large scale. In addition, it is not known whether ART eligibility expansions may lead to "crowding out" of sicker patients. METHODS AND FINDINGS: We examined changes in timely ART initiation (within 6 months) at the original site of HIV care enrollment after ART eligibility expansions among 284,740 adult ART-naive patients at 171 International Epidemiology Databases to Evaluate AIDS (IeDEA) network sites in 22 countries where national policies expanding ART eligibility were introduced between 2007 and 2015. Half of the sites included in this analysis were from Southern Africa, one-third were from East Africa, and the remainder were from the Asia-Pacific, Central Africa, North America, and South and Central America regions. The median age of patients enrolling in care at contributing sites was 33.5 years, and the median percentage of female patients at these clinics was 62.5%. We assessed the 6-month cumulative incidence of timely ART initiation (CI-ART) before and after major expansions of ART eligibility (i.e., expansion to treat persons with CD4 </= 350 cells/muL [145 sites in 22 countries] and CD4 </= 500 cells/muL [152 sites in 15 countries]). Random effects metaregression models were used to estimate absolute changes in CI-ART at each site before and after guideline expansion. The crude pooled estimate of change in CI-ART was 4.3 percentage points (95% confidence interval [CI] 2.6 to 6.1) after ART eligibility expansion to CD4 </= 350, from a baseline median CI-ART of 53%; and 15.9 percentage points (pp) (95% CI 14.3 to 17.4) after ART eligibility expansion to CD4 </= 500, from a baseline median CI-ART of 57%. The largest increases in CI-ART were observed among those newly eligible for treatment (18.2 pp after expansion to CD4 </= 350 and 47.4 pp after expansion to CD4 </= 500), with no change or small increases among those eligible under prior guidelines (CD4 </= 350: -0.6 pp, 95% CI -2.0 to 0.7 pp; CD4 </= 500: 4.9 pp, 95% CI 3.3 to 6.5 pp). For ART eligibility expansion to CD4 </= 500, changes in CI-ART were largest among younger patients (16-24 years: 21.5 pp, 95% CI 18.9 to 24.2 pp). Key limitations include the lack of a counterfactual and difficulty accounting for secular outcome trends, due to universal exposure to guideline changes in each country. CONCLUSIONS: These findings underscore the potential of ART eligibility expansion to improve the timeliness of ART initiation globally, particularly for young adults

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.Peer reviewe

Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

Peer reviewe

Theory of mind and executive function during middle childhood across cultures

This is the final version of the article. It was first available from Elsevier via http://dx.doi.org/10.1016/j.jecp.2015.09.028Previous studies with preschoolers have reported ?East-West? contrasts in children?s executive function (East > West) and theory of mind (East < West). This cross-cultural study with two samples of older children from the UK and Hong Kong aimed to test competing accounts of these contrasts that focus on either global effects of culture or more specific effects of pedagogical experience. Both groups of children in Hong Kong outperformed the British children on executive function tasks. That is, with respect to executive function, general cultural influences appear salient. In contrast, compared with their UK counterparts, children attending local schools in Hong Kong (but not those attending British-based international schools in Hong Kong) performed poorly on age-appropriate tests of theory of mind. With respect to theory of mind, pedagogical experiences therefore appear more salient than factors related to the broad contrast between individualist and collectivist cultures. Our findings also contribute to the debate surrounding the relationship between theory of mind and executive function: while scores on these two sets of tasks were robustly correlated within each country, the double dissociation between delayed theory of mind but superior executive function for children in local schools in Hong Kong compared with their UK peers suggests that variation in executive functions may be necessary but is not sufficient to explain variation in theory of mind

Effects of diurnal variation and caffeine consumption on Test of Variables of Attention (TOVA) performance in healthy young adults.

The Test of Variables of Attention (TOVA) is a continuous performance test (CPT) that assesses attention, impulsivity, and processing speed. CPTs are used in the assessment of attention-deficit/hyperactivity disorder (ADHD) in children, but more young adults are being assessed for ADHD as well. The TOVA norms are based on a standardization sample that was tested early in the day, and any TOVA administered after 1:00 p.m. will be flagged as potentially invalid. Whereas the testing time recommendations make sense for pediatric samples, it is unclear whether they are appropriate for young adults in college, who typically show significant phase delay in their diurnal rhythms. In addition, many college students consume large amounts of caffeine, and it is unclear how caffeine consumption affects TOVA performance. The current study examined the impact of time of day, self-reported diurnal preference, and caffeine consumption on TOVA performance in a double-blind, placebo-controlled experiment with healthy college students. There was evidence of diurnal variation on average response time and impulsivity but not on overall ADHD score, with participants tested in the afternoon responding faster but making more commission errors than did participants tested in the morning. Caffeine consumption led to significantly faster response times, but only for participants who typically consumed relatively little caffeine. We conclude that the TOVA can be administered to young adults outside the recommended time constraints without compromising the validity of test score interpretation but that the caffeine consumption of participants should be closely monitored