Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Online Demand Forecasting with Spatial-Temporal Graph Attention Networks: A Proof of Concept

Predicting future demand from the current state of the network is an unsolved challenge in dynamic traffic management systems which show the current state of traffic as well as demand and supply forecasts for simulations of response plans. In the context of the TANGENT H2020 project, data-driven methodologies are developed focusing on the real-time demand prediction problem. This paper presents a spatial-temporal graph attention network (ST-GAT) to model: 1) the geometry of the network including centroids as demand generation points; 2) the temporal resolution of traffic counts. Preliminary experiments show promising outcomes when quasi-perfect synthetic data is used for training. Yet more research is needed to fully cater for the challenging requirements of the demand prediction task in real-time settings

Assessing risk of self-harm in acute paediatric settings: a multicentre exploratory evaluation of the CYP-MH SAPhE instrument

Objective To psychometrically assess the Children and Young People-Mental Health Self-harm Assessment in Paediatric healthcare Environments (CYP-MH SAPhE) instrument for the identification of immediate risk of self-harm in CYP, aged 10–19 years, in acute paediatric wards or emergency departments.Design The CYP-MH SAPhE Instrument was developed through a robust scoping review and Delphi consensus with 30 clinicians/topic experts. To evaluate the psychometric properties, a multicentre exploratory study was conducted.Setting Three acute hospitals in the UK.Participants 163 CYP presenting at acute hospital settings with primary mental health (cases) or physical health (non-cases) conditions.Primary and secondary outcome measures Psychometric properties of the CYP-MH SAPhE instrument were evaluated through Principle Axis Factoring (PAF) with Oblimin (Kaiser normalisation) alongside measures of internal consistency (Cronbach’s α), convergent, discriminant and face validity.Results PAF of the dichotomous items (n=9) loaded onto three factors (1) behaviours and intentions; (2) suicidality and (3) self-harm. Factors 1 (Cronbach’s α=0.960) and 3 (Cronbach’s α=1) had high internal consistency. There was: good level of agreement between raters (kappa=0.65); a moderately positive correlation between the CYP-MH SAPhE instrument and the Columbia-Suicide Severity Rating Scale; and discrimination between cases and non-cases across the three factors (factor 1: m=88 vs 70; factor 2: m=102 vs 70; factor 3: m=104 vs 68). Assessment of face validity resulted in six items being removed, culminating in an eight question, rapid assessment instrument.Conclusions The results support the CYP-MH SAPhE Tool as a potentially reliable and valid instrument to identify immediate risk of self-harm in CYP presenting to acute paediatric healthcare environments, which is a burgeoning and significant global health issue