Prioritising Informed Health Choices Key Concepts for those impacted by cancer: a protocol [version 1; peer review: 2 approved]

Background: Few areas of health have been as insidiously influenced by misinformation as cancer. Thus, interventions that can help people impacted by cancer reduce the extent to which they are victims of misinformation are necessary. The Informed Health Choices (IHC) initiative has developed Key Concepts that can be used in the development of interventions for evaluating the trustworthiness of claims about the effects of health treatments. We are developing an online education programme called Informed Health Choices-Cancer (IHC-C) based on the IHC Key Concepts. We will provide those impacted by cancer with the knowledge and skills necessary to think critically about the reliability of health information and claims and make informed choices. Methods: We will establish a steering group (SG) of 12 key stakeholders, including oncology specialists and academics. In addition, we will establish a patient and public involvement (PPI) panel of 20 people impacted by cancer. After training the members on the Key Concepts and the prioritisation process, we will conduct a two-round prioritisation process. In the first round, 12 SG members and four PPI panel members will prioritise Key Concepts for inclusion. In the second round, the remaining 16 PPI members will undertake the prioritisation based on the prioritised Key Concepts from the first round. Participants in both rounds will use a structured judgement form to rate the importance of the Key Concepts for inclusion in the online IHC-C programme. A consensus meeting will be held, where members will reach a consensus on the Key Concepts to be included and rank the order in which the prioritised Key Concepts will be addressed in the IHC-C programme. Conclusions: At the end of this process, we will identify which Key Concepts should be included and the order in which they should be addressed in the IHC-C programme

A design-led framework for engaged research: Using a design approach to understand and place the public at the core of health and social care

This paper offers a multi-perspective approach on the role of engaged research in health and social care. Each of the authors focuses on their individual experiences of this domain, from the perspective of an academic partner of the Health Research Board’s PPI Ignite programme, a CEO of an umbrella organisation for health research charities and a researcher in design innovation, focusing on health research. The paper outlines the values which underpin public and patient involvement, as well as examples of its application as engaged research. It details how organisations like Health Research Charities Ireland support and enable engaged research within health and social research and policy. This paper offers a framework for facilitating dialogue and response across all stakeholders in the engaged research process, illustrating the importance of engaged research and how we can further our understanding and application of it within health and social care policy by adopting a design-led approach. We argue that a design-led approach can both facilitate engaged research as well as support policymakers in the design of new policies and practices

Aberrant retinal tight junction and adherens junction protein expression in an animal model of autosomal recessive Retinitis pigmentosa : the Rho(-/-) mouse

Retinitis pigmentosa (RP) comprises a heterogenous group of inherited diseases that are characterised by primary degeneration of rod photoreceptors and secondary degeneration of cone photoreceptors in the retina. Additional pathological changes include vascular changes and invasion of the inner retina by retinal pigment epithelial (RPE) cells. RP represents a major cause of progressive retinal disease worldwide. Using a mouse model of autosomal dominant Retinitis pigmentosa (adRP) with retinopathy induced by targeted disruption of the rhodopsin gene Rho(−/−), we have analysed the levels of expression of a range of tight and adherens junction associated proteins, in order to further elucidate the pathogenic mechanisms occurring at an early stage of this condition. Using western blot analysis and indirect immunostaining of retinal cryosections from 6-week-old mice from a C-129 background we have determined changes, if any, in the levels of expression and localisation of a series of tight and adherens junction associated proteins, including Zonula Occludens-1 (ZO-1), occludin, N-Cadherin, p120-Catenin, α-Catenin, γ-Catenin, β-Catenin, and E-Cadherin. We have found an up-regulation of the tight junction and adherens junction associated protein Zonula Occludens-1 (ZO-1) in the neural retina of 6-week-old Rho(−/−) knockout mice compared with 6-week-old Wild-Type (WT) mice. Following immunohistochemistry, however, it appears, that ZO-1, β-Catenin and p120-Catenin expression at the Outer Limiting Membrane (OLM) of the Rho(−/−) retina is compromised, in part, compared to WT animals of the same age. We hypothesise that these retinal changes following photoreceptor cell death may contribute to the pathogenesis of adRP. Our findings of changes in the levels of expression of ZO-1 and associated adherens junction proteins β-Catenin and p120-Catenin at the OLM in 6-week-old Rho(−/−) mice provide evidence for tight junction and adherens junction associated protein modifications in an animal model of autosomal dominant RP (adRP).9 page(s

Direct costs of epidermolysis bullosa by disease severity

Direct costs of epidermolysis bullosa by disease severit

On the molecular pathology of neurodegeneration in IMPDH1-based retinitis pigmentosa

Retinitis pigmentosa (RP), the hereditary degenerative disease of the photoreceptor neurons of the retina, probably represents the most prevalent cause of registered blindness amongst those of working age in developed countries. Mutations within the gene encoding inosine monophosphate dehydrogenase 1 (IMPDH1), the widely expressed rate-limiting enzyme of the de novo pathway of guanine nucleotide biosynthesis, have recently been shown to cause the RP10 form of autosomal dominant RP. We examined the expression of IMPDH1, IMPDH2 and HPRT transcripts, encoding enzymes of the de novo and salvage pathways of guanine nucleotide biosynthesis, respectively, in retinal sections of mice, the data indicating that the bulk of GTP within photoreceptors is generated by IMPDH1. Impdh1(-/-) null mice are shown here to display a slowly progressive form of retinal degeneration in which visual transduction, analysed by electroretinographic wave functions, becomes gradually compromised, although at 12 months of age most photoreceptors remain structurally intact. In contrast, the human form of RP caused by mutations within the IMPDH1 gene is a severe autosomal dominant degenerative retinopathy in those families that have been examined to date. Expression of mutant IMPDH1 proteins in bacterial and mammalian cells, together with computational simulations, indicate that protein misfolding and aggregation, rather than reduced IMPDH1 enzyme activity, is the likely cause of the severe phenotype experienced by human subjects. Taken together, these findings suggest that RP10 may represent an attractive target for therapeutic intervention, based upon a strategy combining simultaneous suppression of transcripts from normal and mutant IMPDH1 alleles with supplementation of GTP within retinal tissues.

Characterization of RP1L1, a highly polymorphic paralog of the retinitis pigmentosa 1 (RP1) gene

Retinitis pigmentosa (RP) is a genetically heterogeneous inherited retinal degeneration which affects approximately 1 of 3,500 people worldwide. Individuals affected with retinitis pigmentosa exhibit night blindness, followed by a progressive reduction of visual field, which usually culminates in legal or complete blindness. Reduced or absent electroretinogram (ERG) and bone spicule-like pigmentary deposits accompany these symptoms Despite the large number of recent disease gene discoveries, much work still remains to completely understand the genetics of retinitis pigmentosa. Mutation analysis of the known disease-associated genes fails to identify mutations in at least 50% of cases and prevelences determined by linkage mapping are often inflated. For instance, despite the relatively large number of families originally mapped to the RP10 locus, mutations in the RP10 gene, IMPDH1, appear to account for less than 5% of adRP cases (unpublished data). The RP11 locus, estimated to be responsible for approximately 20% of adRP cases, also shows less than predicted mutation frequencies One strategy that can be used to find new adRP genes is to identify candidates that have sequence similarity to known adRP genes or that share functional pathways. For instance, three of the recently identified adRP disease-associated genes, HPRP3, PRPF8, and PRPF31, encode pre-mRNA splicing factors that participate in a common pathway. Using this strategy, we decided to characterize the nearest relative of RP1, and to determine if mutations in this newly characterized gene cause adRP. Purpose: To determine the full-length sequence of a gene with similarity to RP1 and to screen for mutations in this newly characterized gene, named retinitis pigmentosa 1-like 1(RP1L1). Since mutations in the RP1 gene cause autosomal dominant retinitis pigmentosa, it is possible that mutations in RP1's most sequence similar relative, RP1L1, may also be a cause of inherited retinal degeneration. Methods: A combination of cDNA clone sequencing, RACE, and database analysis were used to determine the RP1L1 mRNA sequence and its genomic organization. PCR analysis, semi-quantitative RT PCR, and in situ hybridization were used to determine the expression pattern of RP1L1. Single-strand conformational analysis and automated sequencing were used to screen probands from 60 adRP families for potential disease-causing mutations in RP1L1. Results: The human RP1L1 gene is encoded in 4 exons, which span 50 kb on chromosome 8p. The length of the RP1L1 mRNA is large, over 7 kb, but its exact length is variable between individuals due to the presence of several length polymorphisms, including a 48 bp repeat. RP1L1 encodes a protein with a minimal length of 2,400 amino acids and a predicted weight of 252 kDa. Expression of RP1L1 is limited to the retina and appears to be specific to photoreceptors. Mutational analysis of 60 autosomal dominant retinitis pigmentosa probands revealed the presence of 38 sequence substitutions in RP1L1. Over half of these substitutions result in alteration of the RP1L1 protein, but none of these substitutions appear to be pathogenic. Conclusions: The RP1L1 gene encodes a large, highly polymorphic, retinal-specific protein. No RP1L1 disease-causing mutations were identified in any of the samples tested, making it unlikely that mutations in RP1L1 are a frequent cause of autosomal dominant retinitis pigmentosa. Additional experiments will be needed to determine if mutations in RP1L1 cause other forms of inherited retinal degeneration