Dissecting the genetic basis of comorbid epilepsy phenotypes in neurodevelopmental disorders.

BACKGROUND:Neurodevelopmental disorders (NDDs) such as autism spectrum disorder, intellectual disability, developmental disability, and epilepsy are characterized by abnormal brain development that may affect cognition, learning, behavior, and motor skills. High co-occurrence (comorbidity) of NDDs indicates a shared, underlying biological mechanism. The genetic heterogeneity and overlap observed in NDDs make it difficult to identify the genetic causes of specific clinical symptoms, such as seizures. METHODS:We present a computational method, MAGI-S, to discover modules or groups of highly connected genes that together potentially perform a similar biological function. MAGI-S integrates protein-protein interaction and co-expression networks to form modules centered around the selection of a single "seed" gene, yielding modules consisting of genes that are highly co-expressed with the seed gene. We aim to dissect the epilepsy phenotype from a general NDD phenotype by providing MAGI-S with high confidence NDD seed genes with varying degrees of association with epilepsy, and we assess the enrichment of de novo mutation, NDD-associated genes, and relevant biological function of constructed modules. RESULTS:The newly identified modules account for the increased rate of de novo non-synonymous mutations in autism, intellectual disability, developmental disability, and epilepsy, and enrichment of copy number variations (CNVs) in developmental disability. We also observed that modules seeded with genes strongly associated with epilepsy tend to have a higher association with epilepsy phenotypes than modules seeded at other neurodevelopmental disorder genes. Modules seeded with genes strongly associated with epilepsy (e.g., SCN1A, GABRA1, and KCNB1) are significantly associated with synaptic transmission, long-term potentiation, and calcium signaling pathways. On the other hand, modules found with seed genes that are not associated or weakly associated with epilepsy are mostly involved with RNA regulation and chromatin remodeling. CONCLUSIONS:In summary, our method identifies modules enriched with de novo non-synonymous mutations and can capture specific networks that underlie the epilepsy phenotype and display distinct enrichment in relevant biological processes. MAGI-S is available at https://github.com/jchow32/magi-s

Inhibitory Learning with Bidirectional Outcomes: Prevention Learning or Causal Learning in the Opposite Direction?

Influential models of causal learning assume that learning about generative and preventive relationships are symmetrical to each other. That is, a preventive cue directly prevents an outcome from occurring (i.e., “direct” prevention) in the same way a generative cue directly causes an outcome to occur. However, previous studies from our lab have shown that many participants do not infer a direct prevention causal structure after feature-negative discrimination (A+/AB–) with a unidirectional outcome (Lee & Lovibond, 2021). Melchers et al. (2006) suggested that the use of a bidirectional outcome that can either increase or decrease from baseline, encourages direct prevention learning. Here we test an alternative possibility that a bidirectional outcome encourages encoding of a 'generative' relationship in the 'opposite' direction, where B directly causes a decrease in the outcome. Thus, previous evidence of direct prevention learning using bidirectional outcomes may instead be explained by some participants inferring an “Opposite Causal” structure. In two experiments, participants did indeed report an opposite causal structure. In Experiment 1, these participants showed the lowest outcome predictions when B was combined with a novel cause in a summation test, and lowest outcome predictions when B was presented alone. In Experiment 2, B successfully blocked learning to a novel cue that was directly paired with a reduction in the outcome, and this effect was strongest among participants who endorsed an Opposite Causal structure. We conclude that previous evidence of direct prevention learning using bidirectional outcomes may be a product of excitatory rather than inhibitory learning

Birth characteristics and childhood carcinomas

BACKGROUND: Carcinomas in children are rare and have not been well studied. METHODS: We conducted a population-based case–control study and examined associations between birth characteristics and childhood carcinomas diagnosed from 28 days to 14 years during 1980–2004 using pooled data from five states (NY, WA, MN, TX, and CA) that linked their birth and cancer registries. The pooled data set contained 57 966 controls and 475 carcinoma cases, including 159 thyroid and 126 malignant melanoma cases. We used unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: White compared with ‘other' race was positively associated with melanoma (OR=3.22, 95% CI 1.33–8.33). Older maternal age increased the risk for melanoma (OR(per 5-year age increase)=1.20, 95% CI 1.00–1.44), whereas paternal age increased the risk for any carcinoma (OR=1.10(per 5-year age increase), 95% CI 1.01–1.20) and thyroid carcinoma (OR(per 5-year age increase)=1.16, 95% CI 1.01–1.33). Gestational age <37 vs 37–42 weeks increased the risk for thyroid carcinoma (OR=1.87, 95% CI 1.07–3.27). Plurality, birth weight, and birth order were not significantly associated with childhood carcinomas. CONCLUSION: This exploratory study indicates that some birth characteristics including older parental age and low gestational age may be related to childhood carcinoma aetiology

Secretion of an Argonaute protein by a parasitic nematode and the evolution of its siRNA guides

Extracellular RNA has been proposed to mediate communication between cells and organisms however relatively little is understood regarding how specific sequences are selected for export. Here, we describe a specific Argonaute protein (exWAGO) that is secreted in extracellular vesicles (EVs) released by the gastrointestinal nematode Heligmosomoides bakeri, at multiple copies per EV. Phylogenetic and gene expression analyses demonstrate exWAGO orthologues are highly conserved and abundantly expressed in related parasites but highly diverged in free-living genus Caenorhabditis. We show that the most abundant small RNAs released from the nematode parasite are not microRNAs as previously thought, but rather secondary small interfering RNAs (siRNAs) that are produced by RNA-dependent RNA Polymerases. The siRNAs that are released in EVs have distinct evolutionary properties compared to those resident in free-living or parasitic nematodes. Immunoprecipitation of exWAGO demonstrates that it specifically associates with siRNAs from transposons and newly evolved repetitive elements that are packaged in EVs and released into the host environment. Together this work demonstrates molecular and evolutionary selectivity in the small RNA sequences that are released in EVs into the host environment and identifies a novel Argonaute protein as the mediator of this

Effect of text messaging on depression in patients with coronary heart disease: A sub study analysis from the TEXT ME randomised controlled trial

Objective: We aimed to evaluate the effects on depression scores of a lifestyle-focused cardiac support program delivered via mobile-phone text messaging among patients with coronary heart disease (CHD). Design: Sub-study and secondary analysis of a parallel group, single-blind randomized controlled trial of patients with CHD Setting: A tertiary hospital in Sydney, Australia Intervention: The TEXT ME comprised 4 text messages per week for 6 months that provided education, motivation and support on diet, physical activity, general cardiac education and smoking, if relevant. The program did not have any specific mental health component. Outcomes: Depression scores at 6 months measured using the Patient Health Questionnaire-9 (PHQ-9). Treatment effect across sub-groups was measured using log-binomial regression model for the binary outcome (depressed/not depressed, where depressed is any score of PHQ-9 ≥5) with treatment, subgroup and treatment by subgroup interaction as fixed effects. Results: Depression scores at 6 months were lower in the intervention group compared to the control group, mean difference 1.9 (95% CI 1.5-2.4, p-value <0.0001). The frequency of mild or greater depressive symptoms (PHQ-9 scores ≥5) at 6 months was 21/333 (6.3%) in the intervention group and 86/350 (24.6%) in the control group (relative risk 0.26, 95% CI 0.16-0.40, p <0.001). This proportional reduction in depressive symptoms was similar across groups defined by age, sex, education, BMI, physical activity, current smoking, current drinking, and history of depression, diabetes, and hypertension. In particular, the rates of PHQ-9 ≥5 among people with a history of depression were 4/44 (9.1%) vs 29/62 (46.8%) in intervention vs control (RR 0.19, 95% CI 0.07 to 0.51, p<0.001), and were 17/289 (5.9%) vs 57/288 (19.8%) among others (RR 0.30, 95% CI 0.18 to 0.50, p<0.001). Conclusions: Among people with CHD a cardiac support program delivered via mobile-phone text messaging was associated with less symptoms of mild-to-moderate depression at 6 months in the treatment group compared to controls. Trial Registration: Australian New Zealand Clinical Trials Registry Number (ANZCTRN): anzctr.org.au Identifier: ACTRN1261100016192

Text2PreventCVD: protocol for a systematic review and individual participant data meta-analysis of text message-based interventions for the prevention of cardiovascular diseases

Introduction: Text message interventions have been shown to be effective in prevention and management of several non-communicable disease risk factors. However, the extent to which their effects might vary in different participants and settings is uncertain. We aim to conduct a systematic review and individual participant data (IPD) meta-analysis of randomised clinical trials examining text message interventions aimed to prevent cardiovascular diseases (CVD) through modification of cardiovascular risk factors (CVRFs). Methods and analysis: Systematic review and IPD meta-analysis will be conducted according to Preferred Reporting Items for Systematic review and Meta-Analysis of IPD (PRISMA-IPD) guidelines. Electronic database of published studies (MEDLINE, EMBASE, PsycINFO and Cochrane Library) and international trial registries will be searched to identify relevant randomised clinical trials. Authors of studies meeting the inclusion criteria will be invited to join the IPD meta-analysis group and contribute study data to the common database. The primary outcome will be the difference between intervention and control groups in blood pressure at 6-month follow-up. Key secondary outcomes include effects on lipid parameters, body mass index, smoking levels and self-reported quality of life. If sufficient data is available, we will also analyse blood pressure and other secondary outcomes at 12 months. IPD meta-analysis will be performed using a one-step approach and modelling data simultaneously while accounting for the clustering of the participants within studies. This study will use the existing data to assess the effectiveness of text message-based interventions on CVRFs, the consistency of any effects by participant subgroups and across different healthcare settings. Ethics and dissemination: Ethical approval was obtained for the individual studies by the trial investigators from relevant local ethics committees. This study will include anonymised data for secondary analysis and investigators will be asked to check that this is consistent with their existing approvals. Results will be disseminated via scientific forums including peer-reviewed publications and presentations at international conferences

Personal goals of women recently diagnosed with breast cancer: Protocol for a cohort study

Objectives: This study aims to identify the personal goals of women with breast cancer, to describe the characteristics of partici- pants’ personal goals over four months, and to identify barriers and facilitators to their pursuit. Methods: This protocol outlines plans to conduct a prospective cohort study. We will recruit women participating in the Ottawa In- tegrative Cancer Centre’s Head Start program (an integrative oncology psychoeducational program in Ottawa, Canada), and those on the program’s waiting list if possible. We anticipate a sample size of approximately 18 to 36 women. Prior to the beginning of Head Start, participants will identify their current personal goals and rate them on various dimensions on a questionnaire. At one and three months, participants will re-assess their goals and their goal pursuit. In a one-on-one interview at three months, they will identify barriers and facilitators to the pursuit of their goals. We will analyze quantitative data using descriptive and inferential statistics, and qualitative data using thematic content analysis. Conclusion: Findings from this study will identify important information about the personal goals of women recently diagnosed with breast cancer that can help to support the process of positive goal adjustment and enhance support to these women.  Résumé Objectifs : Cette étude vise à identifier les objectifs personnels des femmes atteintes d’un cancer du sein, à décrire les caractéristiques des objectifs personnels des participantes sur une période de quatre mois, et à identifier les obstacles et les facilitateurs à leur poursuite. Méthodes : Ce protocole décrit les plans pour mener une étude de cohorte prospective. Nous recruterons des femmes qui participeront au programme Head Start du Centre de cancérologie intégrative d’Ottawa (un programme psychopédagogique intégratif en oncologie à Ottawa, au Canada) et celles qui sont sur la liste d’attente du programme, si possible. Nous prévoyons un échantillon d’environ 18 à 36 femmes. Avant le début de Head Start, les participantes identifieront leurs objectifs personnels actuels et les noteront sur différentes dimensions dans un questionnaire. À un et trois mois, les participantes réévalueront leurs objectifs et la poursuite de leur objectif. Dans une entrevue individuelle à trois mois, elles identifieront les obstacles et les facilitateurs à la poursuite de leurs objectifs. Nous analyserons les données quantitatives à l’aide de statistiques descriptives et inférentielles, et les données qualitatives à l’aide d’analyses de contenu thématiques. Conclusion : Les résultats de cette étude permettront d’identifier des informations importantes sur les objectifs personnels des femmes récemment diagnostiquées avec un cancer du sein qui peuvent aider à soutenir le processus d’ajustement positif des objectifs et améliorer le soutien à ces femmes.