Background: With the now routine use of next-generation sequencing it is important to know the baseline outcomes as they relate to clinical care for pediatric epilepsy in Ontario. We sought to assess the diagnostic yield of genetic epilepsy panel testing and characterize the impact on patient care. Methods: We conducted a retrospective chart review of patients with epilepsy seen at CHEO between 2012-2020 with genetic testing. 227 patients met our inclusion criteria. Patient charts were reviewed for clinical details, co-morbidities, genetic testing results, and changes to management. Results: Diagnostic yield was 19% for multi-gene epilepsy panel testing. A further 10% received a diagnosis from additional genetic testing. The diagnostic yield was significantly higher in patients with a younger age of onset of seizures. A direct change in clinical management as a result of the molecular diagnosis was evident for 9% of patients; however, all diagnoses impacted prognosis and family counselling. Conclusions: The diagnostic yield of genetic epilepsy panel testing conducted at CHEO is comparable to other reported rates. Genetic testing resulted in clinical benefits of recurrence risk counselling, prognostic information and though a direct change in management was advised in a minority of individuals, targeted treatment recommendations will continue to increase with ongoing testing.

Cross-species evidence suggests that the ability to exert control over a stressor is a key dimension of stress exposure that may sensitize frontostriatal-amygdala circuitry to promote more adaptive responses to subsequent stressors. The present study examined neural correlates of stressor controllability in young adults. Participants (N = 56; M age = 23.74, range = 18–30 years) completed either the controllable or uncontrollable stress condition of the first of two novel stressor controllability tasks during functional magnetic resonance imaging (fMRI) acquisition. Participants in the uncontrollable stress condition were yoked to age- and sex-matched participants in the controllable stress condition. All participants were subsequently exposed to uncontrollable stress in the second task, which is the focus of fMRI analyses reported here. A whole-brain searchlight classification analysis revealed that patterns of activity in the right dorsal anterior insula (dAI) during subsequent exposure to uncontrollable stress could be used to classify participants' initial exposure to either controllable or uncontrollable stress with a peak of 73% accuracy. Previous experience of exerting control over a stressor may change the computations performed within the right dAI during subsequent stress exposure, shedding further light on the neural underpinnings of stressor controllability.

Background: Cerebellar atrophy is characterized by loss of cerebellar tissue, with evidence on brain imaging of enlarged interfolial spaces compared to the foliae. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of disorders. We investigated the prevalence in Canada and the diagnostic yield of whole exome sequencing (WES) for this group of conditions. Methods: Between 2011 and 2017, WES was performed in 91 participants with cerebellar atrophy as part of one of two national research programs, Finding of Rare Genetic Disease Genes (FORGE) or Enhanced Care for Rare Genetic Diseases in Canada (Care4Rare). Results: A genetic diagnosis was established in 58% of cases (53/91). Pathogenic variants were found in 24 known genes, providing a diagnosis for 46/53 participants (87%), and in four novel genes, accounting for 7/53 cases (13%). 38/91 cases (42%) remained unsolved. The most common diagnoses were channelopathies in 12/53 patients (23%) and mitochondrial disorders in 9/53 (17%). Inheritance was autosomal recessive in the majority of cases. Additional clinical findings provided useful clues to some of the diagnoses. Conclusions: This is the first report on the prevalence of genetic ataxias associated with cerebellar atrophy in Canada, and the utility of WES for this group of conditions.

Background: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB) is a member of the PI3K complex. This complex has two p110 members; PIK3CA (p110a) and PIK3CB (p110b) which are both ubiquitously expressed. PI3K complex functions to phosphorylate PIP2 to PIP3 which activates AKT and subsequently mTOR. PIK3CA mutations have been previously linked with macrocephaly and developmental delay. Methods: An 18 month old girl was investigated for severe hypotonia, developmental delay and macrocephaly. Head circumference was >97%ile at birth and 53.0 cm (>99%ile, +5.4 SD) at 13 months old. She had no hydrocephalus or epilepsy. MRI brain (18 months old) re-identified megalencephaly and diffuse polymicrogyria. Symmetric signal abnormality was noted in the periventricular white matter, unchanged between 8 and 18 month images. MR spectroscopy was unrevealing. At 18 months she remains unable to sit independently. Exome sequencing was performed and functional studies to further support variant pathogenicity. Results: Exome sequencing identified de novo variant in PIK3CB: c.1735G>T; p.Asp579Tyr. No mutations were noted in other genes known to cause developmental delay, macrocephaly or overgrowth syndromes. Functional studies in patient cells showed dysregulation of PIK3CB and downstream signalling, providing support for causality of this novel disease gene. Conclusions: We believe that our patient’s macrocephaly (+5.4 SD) and diffuse polymicrogyria results from altered PIK3CB function.

A number of laser facilities coming online all over the world promise the capability of high-power laser experiments with shot repetition rates between 1 and 10 Hz. Target availability and technical issues related to the interaction environment could become a bottleneck for the exploitation of such facilities. In this paper, we report on target needs for three different classes of experiments: dynamic compression physics, electron transport and isochoric heating, and laser-driven particle and radiation sources. We also review some of the most challenging issues in target fabrication and high repetition rate operation. Finally, we discuss current target supply strategies and future perspectives to establish a sustainable target provision infrastructure for advanced laser facilities.

Background: Recent research has highlighted the importance of psychological interventions such as cognitive behavioural therapy (CBT) in improving outcomes and promoting recovery for people with experience of psychosis, although a lack of trained therapists means that availability of face-to-face CBT is low. Alternative modes of delivering CBT are being explored, such as telephone and self-help methods, although research to date on whether they can be implemented effectively is limited. Aims: The aims of the present study were to describe and evaluate a new therapy fidelity scale (ROSTA; Recovery Oriented Self-help and Telephone therapy Adherence). This scale was developed to assess fidelity to cognitive behaviour therapy for psychosis (CBTp) focused on improving recovery, with optional subscales for delivery over the telephone and alongside a self-help guide. Method: Experienced CBT therapists rated recorded therapy sessions using the ROSTA scale. The scores were used to assess internal consistency and inter-rater reliability, before being compared to scores from an independent expert rater using an alternative fidelity scale for cognitive therapy in psychosis (the CTS-Psy), to investigate concurrent validity. Results: The ROSTA scale demonstrated excellent internal consistency, inter-rater reliability and validity when evaluated as a whole, although findings were mixed in terms of the individual subscales and items. Conclusions: The ROSTA scale is, on the whole, a reliable and valid tool, which may be useful in training and supervision, a utility that would be further emphasized if the therapeutic intervention it assesses is deemed to be efficacious based on future work.