Directional Next-Generation RNA Sequencing and Examination of Premature Termination Codon Mutations in Endoglin/Hereditary Haemorrhagic Telangiectasia

Hereditary haemorrhagic telangiectasia (HHT) is a disease characterised by abnormal vascular structures, and most commonly caused by mutations in ENG, ACVRL1 or SMAD4 encoding endothelial cell-expressed proteins involved in TGF-β superfamily signalling. The majority of mutations reported on the HHT mutation database are predicted to lead to stop codons, either due to frameshifts or direct nonsense substitutions. The proportion is higher for ENG (67%) and SMAD4 (65%) than for ACVRL1 (42%), p < 0.0001. Here, by focussing on ENG, we report why conventional views of these mutations may need to be revised. Of the 111 stop codon-generating ENG mutations, on ExPASy translation, all except one were premature termination codons (PTCs), sited at least 50-55 bp upstream of the final exon-exon boundary of the main endoglin isoform, L-endoglin. This strongly suggests that the mutated RNA species will undergo nonsense-mediated decay. We provide new in vitro expression data to support dominant negative activity of stable truncated endoglin proteins but suggest these will not generate HHT: the single natural stop codon mutation in L-endoglin (sited within 50-55 nucleotides of the final exon-exon boundary) is unlikely to generate functional protein since it replaces the entire transmembrane domain, as would 8 further natural stop codon mutations, if the minor S-endoglin isoform were implicated in HHT pathogenesis. Finally, next-generation RNA sequencing data of 7 different RNA libraries from primary human endothelial cells demonstrate that multiple intronic regions of ENG are transcribed. The potential consequences of heterozygous deletions or duplications of such regions are discussed. These data support the haploinsufficiency model for HHT pathogenesis, explain why final exon mutations have not been detected to date in HHT, emphasise the potential need for functional examination of non-PTC-generating mutations, and lead to proposals for an alternate stratification system of mutational types for HHT genotype-phenotype correlations

VICTour 1.1: Introducing virtual learning environments and gamification

Game engines are one of the few solutions to providing a true virtual campus tour experience. In this paper, we explore the evolution of the virtual campus tour and thereby the current and future work of game technology within virtual touring. An investigation is conducted into the application of objective-based gamification and its ability to encourage exploration of a virtual world. We also examine virtual campus tours as an alternate form of taught content via virtual learning environments (VLEs). An investigation into the use of head mounted displays to improve immersion is also explored

'The ICECAP-SCM tells you more about what I'm going through: a think-aloud study measuring quality of life among patients receiving supportive and palliative care

Background: The ICECAP-Supportive Care Measure is a self-complete questionnaire developed to aid economic evaluation of supportive care interventions.Aim: To determine the feasibility of completing ICECAP–Supportive Care Measure alongside EQ-5D-5L and ICECAP-A (generic measures used in economic evaluation) among patients receiving hospice care, close persons and healthcare professionals.Design: Participants were asked to ‘think aloud’ while completing ICECAP-Supportive Care Measure and two other generic measures used in economic evaluation, EQ-5D-5L and ICECAP-A, and then participate in a semi-structured interview. From verbatim transcripts, five raters identified the frequency of errors in comprehension, retrieval, judgement and response. Qualitative data were analysed using constant comparison.Setting/participants: Eligible patients were identified from one UK hospice by a research nurse. Close persons and healthcare professionals were identified by the patient. In all, 72 semi-structured interviews were conducted with patients (n?=?33), close persons (n?=?22) and healthcare professionals (n?=?17).Results: Patients and close persons reported that the ICECAP-Supportive Care Measure was most appropriate for measuring their quality of life. It appeared more meaningful, easier to complete and had fewest errors (3.9% among patients, 4.5% among close persons) compared to EQ-5D-5L (9.7% among patients, 5.5% among close persons). Healthcare professionals acknowledged the value of the ICECAP-Supportive Care Measure but had fewer errors in completing the EQ-5D-5L (3.5% versus 6.7%). They found it easier to complete because it focuses on observable health states.Conclusions: The ICECAP-Supportive Care Measure is feasible to use and perceived as appropriate for evaluating palliative care interventions. Healthcare professionals with limited knowledge of the patient who act as proxy completers may find the measure difficult to complete

Cost-Effectiveness Findings from the Agewell Pilot Study of Behaviour Change to Promote Health and Wellbeing in Later Life.

Background: Participation in cognitive and physical activities may help to maintain health and wellbeing in older people. The Agewell study explored the feasibility of increasing cognitive and physical activity in older people through a goal-setting approach. This paper describes the findings of the cost-effectiveness analysis. Method: Individuals over the age of 50 and attending an Agewell centre in North Wales were randomised to one of three conditions: control (IC), goal-setting (GS), or goal-setting with mentoring (GM). We undertook a cost-effectiveness analysis comparing GS vs. IC, GM vs. IC and GM vs. GS. The primary outcome measure for this analysis was the QALY, calculated using the EQ-5D. Participants’ health and social care contacts were recorded and costed using national unit costs. Results: Seventy participants were followed-up at 12 months. Intervention set up and delivery costs were £252 per participant in the GS arm and £269 per participant in the GM arm. Mean health and social care costs over 12 months were £1,240 (s.d. £3,496) per participant in the IC arm, £1,259 (s.d. £3,826) per participant in the GS arm and £1,164 (s.d. £2,312) per participant in the GM arm. At a willingness to pay threshold of £20,000 per QALY there was a 65% probability that GS was cost-effective compared to IC (ICER of £1,070). However, there was only a 41% probability that GM was cost-effective compared to IC (ICER of £2,830) at a threshold of £20,000 per QALY. Conclusion: Setting up and running the community based intervention was feasible. Due to the small sample size it is not possible to draw a firm conclusion about cost-effectiveness; however, our preliminary results suggest that goal- setting is likely to be cost-effective compared to the control condition of no goal-setting, the addition of mentoring was effective but not cost-effective.Lifelong Health and Well-being Programme through the Medical Research Counci