Evaluating fenfluramine hydrochloride as an oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome

IntroductionLennox-Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterised by treatment-refractory seizures, including tonic/atonic "drop" seizures, and intellectual impairment and slow spike-wave discharges on the electroencephalogram. Fenfluramine, previously prescribed as a weight-loss drug but then withdrawn, has recently been approved in the US, EU and UK for the adjunct treatment of seizures associated with LGS.Areas coveredEfficacy and safety findings from clinical trials of fenfluramine in LGS are reviewed. The evidence for adverse effects that may be of particular concern with fenfluramine, namely cardiac abnormalities and weight loss, are discussed in the context of the use of fenfluramine for the treatment of the refractory seizures in LGS.Expert opinionFenfluramine has demonstrated efficacy in reducing the frequency of seizures in LGS, notably drop seizures, in short-term and long-term clinical trials. Valvular heart disease and pulmonary hypertension have not been reported at the low doses (≤ 26 mg/day) used in these studies, however, data are limited. Due to its novel mechanism of action, fenfluramine may be of benefit in LGS which has not responded adequately to other antiseizure medications. However, none of these medications, including fenfluramine, achieves the ultimate goal of seizure freedom in most cases.<br/

Critical phenomena in exponential random graphs

The exponential family of random graphs is one of the most promising class of network models. Dependence between the random edges is defined through certain finite subgraphs, analogous to the use of potential energy to provide dependence between particle states in a grand canonical ensemble of statistical physics. By adjusting the specific values of these subgraph densities, one can analyze the influence of various local features on the global structure of the network. Loosely put, a phase transition occurs when a singularity arises in the limiting free energy density, as it is the generating function for the limiting expectations of all thermodynamic observables. We derive the full phase diagram for a large family of 3-parameter exponential random graph models with attraction and show that they all consist of a first order surface phase transition bordered by a second order critical curve.Comment: 14 pages, 8 figure

Bayesian Parameter Estimation for Latent Markov Random Fields and Social Networks

Undirected graphical models are widely used in statistics, physics and machine vision. However Bayesian parameter estimation for undirected models is extremely challenging, since evaluation of the posterior typically involves the calculation of an intractable normalising constant. This problem has received much attention, but very little of this has focussed on the important practical case where the data consists of noisy or incomplete observations of the underlying hidden structure. This paper specifically addresses this problem, comparing two alternative methodologies. In the first of these approaches particle Markov chain Monte Carlo (Andrieu et al., 2010) is used to efficiently explore the parameter space, combined with the exchange algorithm (Murray et al., 2006) for avoiding the calculation of the intractable normalising constant (a proof showing that this combination targets the correct distribution in found in a supplementary appendix online). This approach is compared with approximate Bayesian computation (Pritchard et al., 1999). Applications to estimating the parameters of Ising models and exponential random graphs from noisy data are presented. Each algorithm used in the paper targets an approximation to the true posterior due to the use of MCMC to simulate from the latent graphical model, in lieu of being able to do this exactly in general. The supplementary appendix also describes the nature of the resulting approximation.Comment: 26 pages, 2 figures, accepted in Journal of Computational and Graphical Statistics (http://www.amstat.org/publications/jcgs.cfm

Epilepsy, Antiepileptic Drugs, and Aggression: An Evidence-Based Review.

Antiepileptic drugs (AEDs) have many benefits but also many side effects, including aggression, agitation, and irritability, in some patients with epilepsy. This article offers a comprehensive summary of current understanding of aggressive behaviors in patients with epilepsy, including an evidence-based review of aggression during AED treatment. Aggression is seen in a minority of people with epilepsy. It is rarely seizure related but is interictal, sometimes occurring as part of complex psychiatric and behavioral comorbidities, and it is sometimes associated with AED treatment. We review the common neurotransmitter systems and brain regions implicated in both epilepsy and aggression, including the GABA, glutamate, serotonin, dopamine, and noradrenaline systems and the hippocampus, amygdala, prefrontal cortex, anterior cingulate cortex, and temporal lobes. Few controlled clinical studies have used behavioral measures to specifically examine aggression with AEDs, and most evidence comes from adverse event reporting from clinical and observational studies. A systematic approach was used to identify relevant publications, and we present a comprehensive, evidence-based summary of available data surrounding aggression-related behaviors with each of the currently available AEDs in both adults and in children/adolescents with epilepsy. A psychiatric history and history of a propensity toward aggression/anger should routinely be sought from patients, family members, and carers; its presence does not preclude the use of any specific AEDs, but those most likely to be implicated in these behaviors should be used with caution in such cases

Psychotropic Medication Prescribing for Neuropsychiatric Comorbidities in Individuals Diagnosed with Autism Spectrum Disorder (ASD) in the UK

Autism spectrum disorder (ASD) is a lifelong disorder. In the UK, risperidone is the only psychotropic medication approved for the management of the behavioural symptoms that may accompany autism. This is a population-based study aimed to provide an evaluation of the changing trend in the incidence and prevalence of ASD and to analyse the pattern of psychotropic medication prescribing in the UK. 20,194 patients with ASD were identified. The prevalence increased 3.3-fold from 0.109 per 100 persons in 2009 to 0.355 per 100 persons in 2016. Approximately one-third of the identified cohort was prescribed at least one psychotropic medication. Although the medications approved to manage the symptoms of ASD are limited, the prescribing of such medications is increasing

Using Affiliation Networks to Study the Determinants of Multilateral Research Cooperation Some empirical evidence from EU Framework Programs in biotechnology

This paper studies multilateral cooperation networks among organizations and work on a two-mode representation to study the decision to participate in a consortium. Our objective is to explain the underlying processes that give rise to multilateral collaboration networks. Particularly, we are interested in how heterogeneity in organizations' attributes plays a part and in the geographical dimension of this formation process. We use the data on project proposals submitted to the 7th Framework Program (FP) in the area of Life sciences, Biotechnology and Biochemistry for Sustainable Non-Food. We employ exponential random graph models (p* models) (Frank and Strauss, 1986 ; Wasserman and Pattison, 1996) with node attributes (Agneessens et al., 2004), and we make use of extensions for affiliation networks (Wang et al., 2009). These models do not only enable handling variability in consortium sizes but also relax the assumption on tie/triad independence. We obtained some preliminary results indicating institutional types as a source of heterogeneity affecting participation decisions. Also, these initial results point out that organizations take their potential partners' participations in other projects into account in giving their decision ; organizations located in the core European countries tend to participate in the same project ; the tendency to preserve the composition of a consortium across projects and the tendency of organizations with the same institutional type to co-participate are not significant