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BACKGROUND: Palpitations and pre-syncope are together responsible for 300,000 annual Emergency Department (ED) attendances in the United Kingdom (UK). Diagnosis of the underlying rhythm is difficult as many patients are fully recovered on ED arrival; and examination and presenting electrocardiogram (ECG) are commonly normal. The only way to establish the underlying heart rhythm is to capture an ECG during symptoms. Recent technology advances have led to several novel ECG monitoring devices appearing on the market. This trial aims to compare the symptomatic rhythm detection rate at 90 days of one such smart phone-based event recorder (AliveCor Heart Monitor and AliveECG) with standard care for participants presenting to the ED with palpitations and pre-syncope and no obvious cause in the ED.METHODS/DESIGN: This is a multi-centre hospital ED / Acute Medical Unit (AMU) open label, randomised controlled trial. Participants will be recruited in 10 tertiary and district general hospitals in the UK. Participants aged ≥ 16 years presenting with an episode of palpitations or pre-syncope with no obvious cause and whose underlying ECG rhythm during these episodes remains undiagnosed after clinical assessment will be included. Participants will be randomised to either: (1) the intervention arm, standard care plus the use of a smart phone-based event recorder; or (2) the control arm, standard care. Primary endpoint will be symptomatic rhythm detection rate at 90 days. A number of secondary clinical, process and cost-effectiveness endpoints will be collected and analysed. Analysis will be on an intention-to-treat basis.DISCUSSION: The Investigation of Palpitations in the ED (IPED) study aims to recruit 242 participants across 10 hospital sites. It will be the first study to investigate the ability of a smart phone-based event recorder to detect symptomatic cardiac rhythms compared to standard care for ED patients with palpitations and pre-syncope with no obvious cause in the ED. This smart phone event recorder will allow ED patients who have presented with palpitations or pre-syncope to record their ECG tracing if they have a further episode and may increase the rate of underlying rhythm diagnosis.TRIAL REGISTRATION: ClinicalTrials.gov, NCT02783898 . Registered on 26 May 2016.

Human Artificial Chromosomes (HACs) have been confirmed as viable gene expression vectors and a potential tool for gene therapy. However, standard lipid-based delivery methods pose a developmental barrier. The work presented in this thesis includes the development of a novel and efficient HAC vector system for gene delivery into human cells using Herpes Simplex Virus-1 (HSV-1) amplicon technology. The development of HSV-1 amplicons for HAC delivery is a major step forward in the HAC field. In this study, utilising the technology allowed the generation of HACs at a high efficiency in a range of human cell types, which is a significant step in the development for HAC gene expression systems. Further work also showed a significant difference in HAC stability between cell lines. Real-time PCR analysis determined that Aurora B was over expressed in cell lines in which the HACs were unstable. This correlated with high levels of chromosomal instability and was confirmed by western blot analysis. Since Aurora B is a kinase involved in at least two cell cycle checkpoints, cellular phosphorylation levels were perturbed to mimic that observed in the unstable cells, using okadaic acid, which is both a protein phosphatase inhibitor and activates Aurora B. Treatment of cells showed an increase in both HAC and overall chromosomal instability and an increase in histone H3 Serine 10 and Serine 28 phosphorylation. The project also focussed on the development of a gene expression system using HSV-1 amplicons. Two different strategies were explored. Firstly, one approach involved engineering the HPRT genomic locus into an HSV-HAC vector, by Red mediated recombination for complementing the HPRT deficiency in HPRT- HT1080 cells. As an alternative approach, co-infection of two different HSV-1 HAC amplicons for generating a single HAC gene vector was investigated. Initial experiments utilising the latter approach were the most successful and show promise for generating HAC containing genes via this strategy.