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People with an intellectual disability face inequality accessing healthcare that extends to end-of-life care. Furthermore, end-of-life care for people with an intellectual disability is more complex than that for the general population. This protocol sets out how our review will explore the available evidence and identify the key characteristics of care that are required for people with an intellectual disability to have a good end-of-life experience. A critical interpretive synthesis approach will be adopted, combining some elements of a systematic review with interpretive synthesis. This approach has been selected as it allows a diverse body of literature to be considered. Furthermore, it is compatible with theory generation allowing new insights to emerge in an iterative process. Electronic databases and grey literature sources will be searched using pre-defined search terms. Following initial title and abstract screening, eligible papers will undergo full text screening. Papers that are deemed to be 'fatally flawed' will be excluded and remaining papers appraised for relevance. Resultant papers will be included in the sampling frame from which data extraction will occur. An existing framework outlining key factors in the provision of excellent end-of-life care to people with an intellectual disability will be used to support data extraction and synthesis. Data extracted will be integrated into a synthesising argument in the form of a theoretical framework. This will identify the key characteristics in the provision of care that are required for people with an intellectual disability to have a good end-of-life experience. The developing theoretical framework will guide further selection of relevant literature to fill any conceptual gaps until saturation is reached. Our review will add to the existing body of evidence, shedding light on the key factors necessary in the provision of care to ensure that people with an intellectual disability have a good end-of-life experience.

BackgroundExercise is the cornerstone of cardiac rehabilitation (CR). Hospital-based CR exercise programmes are a routine part of clinical care and are typically 6-12 weeks in duration. Following completion, physical activity levels of patients decline. Multi-disease, community-based exercise programmes (MCEP) are an efficient model that could play an important role in the long-term maintenance of positive health behaviours in individuals with cardiovascular disease (CVD) following their medically supervised programme.AimTo explore patients experiences of the initiation and early participation in a MCEP programme and the dimensions that facilitate and hinder physical activity engagement.MethodsIndividuals with established CVD who had completed hospital-based CR were referred to a MCEP. The programme consisted of twice weekly group exercise classes supervised by clinical exercise professionals. Those that completed (n = 31) an initial 10 weeks of the programme were invited to attend a focus group to discuss their experience. Focus groups were transcribed and analysed using reflexive thematic analysis.ResultsTwenty-four (63% male, 65.5±6.12yrs) patients attended one of four focus groups. The main themes identified were 'Moving from fear to confidence', 'Drivers of engagement,' and 'Challenges to keeping it (exercise) up'.ConclusionParticipation in a MCEP by individuals with CVD could be viewed as a double-edged sword. Whilst the programme clearly provided an important transition from the clinical to the community setting, there were signs it may breed dependency and not effectively promote independent exercise. Another novel finding was the use of social comparison that provided favourable valuations of performance and increased exercise confidence.

People with an intellectual disability face inequality accessing healthcare that extends to end-of-life care. Furthermore, end-of-life care for people with an intellectual disability is more complex than that for the general population. This protocol sets out how our review will explore the available evidence and identify the key characteristics of care that are required for people with an intellectual disability to have a good end-of-life experience. A critical interpretive synthesis approach will be adopted, combining some elements of a systematic review with interpretive synthesis. This approach has been selected as it allows a diverse body of literature to be considered. Furthermore, it is compatible with theory generation allowing new insights to emerge in an iterative process. Electronic databases and grey literature sources will be searched using pre-defined search terms. Following initial title and abstract screening, eligible papers will undergo full text screening. Papers that are deemed to be 'fatally flawed' will be excluded and remaining papers appraised for relevance. Resultant papers will be included in the sampling frame from which data extraction will occur. An existing framework outlining key factors in the provision of excellent end-of-life care to people with an intellectual disability will be used to support data extraction and synthesis. Data extracted will be integrated into a synthesising argument in the form of a theoretical framework. This will identify the key characteristics in the provision of care that are required for people with an intellectual disability to have a good end-of-life experience. The developing theoretical framework will guide further selection of relevant literature to fill any conceptual gaps until saturation is reached. Our review will add to the existing body of evidence, shedding light on the key factors necessary in the provision of care to ensure that people with an intellectual disability have a good end-of-life experience. [ABSTRACT FROM AUTHOR]

Understanding the medication and supplement use of aging people is critical to ensuring that health service providers in primary care can optimise use of these agents. An increasing number of people with different levels of intellectual disability (ID) are living in the community and becoming for the first time substantial users of primary health care services. This, however, brings new challenges that need to be addressed at the primary health care level. We quantified the use of medicines and food supplements and described the associated patterns of morbidity in the two comparable cohorts of aging population with and without intellectual disability.This research aligned participants of 50 years and over who lived in the community from two nationally representative cohorts of older people; those with ID from the Intellectual Disability Supplement (n = 238) and those without ID (n = 8,081) from the Irish Longitudinal Study on Ageing.Data showed that both medication and supplement use in the two groups was prevalent but that those with ID received more of both medications and supplements (e.g. polypharmacy was 39.0% in ID vs. 18.1% in non-ID cohort). Moreover, based on an analysis of the therapeutic groups and medications used that treatment was more intense in the ID cohort (95.8 vs. 7.0 International Non-proprietary Names per 100 participants). Supplement use was almost twice as prevalent in the ID group but substantially less diverse with only 10 types of supplements reported. Morbidity was higher in the ID group and showed a higher prevalence of neurological and mental health disorders.The results highlight that the burden of therapy management and the potential risks in those ageing with ID differs substantially from those ageing without ID. Understanding the medication and supplement use of people aging with intellectual disability (ID) is critical to ensuring that health service providers in primary/ambulatory care can optimise use of these agents.

Calcium channel subunits, including CACNA1C, have been associated with multiple psychiatric disorders. Specifically, genome wide association studies (GWAS) have repeatedly identified the single nucleotide polymorphism (SNP) rs1006737 in intron 3 of CACNA1C to be strongly associated with schizophrenia and bipolar disorder. Here, we show that rs1006737 marks a quantitative trait locus for CACNA1C transcript levels. We test 16 SNPs in high linkage disequilibrium with rs1007637 and find one, rs4765905, consistently showing allele-dependent regulatory function in reporter assays. We find allele-specific protein binding for 13 SNPs including rs4765905. Using protein microarrays, we identify several proteins binding ≥3 SNPs, but not control sequences, suggesting possible functional interactions and combinatorial haplotype effects. Finally, using circular chromatin conformation capture, we show interaction of the disease-associated region including the 16 SNPs with the CACNA1C promoter and other potential regulatory regions. Our results elucidate the pathogenic relevance of one of the best-supported risk loci for schizophrenia and bipolar disorder.

We recently demonstrated that the gene encoding the RNA binding motif protein 24 (RBM24) is expressed during mouse cardiogenesis, and determined the developmental requirement for its zebrafish homologs Rbm24a and Rbm24b during cardiac development. We demonstrate here that both Rbm24a and Rbm24b are also required for normal somite and craniofacial development. Diminution of rbm24a or rbm24b gene products by morpholino knockdown resulted in significant disruption of somite formation. Detailed in situ hybridization-based analyses of a spectrum of somitogenesis-associated transcripts revealed reduced expression of the cyclic muscle pattering genes dlc and dld encoding Notch ligands, as well as their respective target genes her7, her1. By contrast expression of the Notch receptors notch1a and notch3 appears unchanged. Some RBM-family members have been implicated in pre-mRNA processing. Analysis of affected Notch-pathway mRNAs in rbm24a and rbm24b morpholino-injected embryos revealed aberrant transcript fragments of dlc and dld, but not her1 or her7, suggesting the reduction in transcription levels of Notch pathway components may result from aberrant processing of its ligands. These data imply a previously unknown requirement for Rbm24a and Rbm24b in somite and craniofacial development. Although we anticipate the influence of disrupting RBM24 homologs likely extends beyond the Notch pathway, our results suggest their perturbation may directly, or indirectly, compromise post-transcriptional processing, exemplified by imprecise processing of dlc and dld.

Myelin protein zero (MPZ) is a critical structural component of myelin in the peripheral nervous system. The MPZ gene is regulated, in part, by the transcription factors SOX10 and EGR2. Mutations in MPZ, SOX10, and EGR2 have been implicated in demyelinating peripheral neuropathies, suggesting that components of this transcriptional network are candidates for harboring disease-causing mutations (or otherwise functional variants) that affect MPZ expression.We utilized a combination of multi-species sequence comparisons, transcription factor-binding site predictions, targeted human DNA re-sequencing, and in vitro and in vivo enhancer assays to study human non-coding MPZ variants.Our efforts revealed a variant within the first intron of MPZ that resides within a previously described SOX10 binding site is associated with decreased enhancer activity, and alters binding of nuclear proteins. Additionally, the genomic segment harboring this variant directs tissue-relevant reporter gene expression in zebrafish.This is the first reported MPZ variant within a cis-acting transcriptional regulatory element. While we were unable to implicate this variant in disease onset, our data suggests that similar non-coding sequences should be screened for mutations in patients with neurological disease. Furthermore, our multi-faceted approach for examining the functional significance of non-coding variants can be readily generalized to study other loci important for myelin structure and function.

Remarkably, although cardiac disease accounts for the largest proportion of adult mortality and morbidity in the industrialized world, the genetic programs controlling early cardiogenesis are largely incompletely understood. To better understand this process, we set out to identify genes whose expression is enriched within early cardiac fated populations, obtaining the transcriptional signatures of mouse embryonic stem cells (mESCs) at defined intervals during their differentiation along a cardiac path. We compared the RNA profiles of cardiac precursors cells (CPCs) with time-matched non-CPCs and undifferentiated mESCs, using a transgenic mESC line harboring an Nkx2-5 cardiac-specific regulatory sequence driving green fluorescent protein (GFP) to facilitate selection of CPCs. We identify 176 transcripts that are significantly elevated in their abundance within CPCs compared with other assayed populations, predicting that they will likely play a role in cardiogenesis. Of note, approximately 24% (43/176) of the cardiogenic candidate transcripts have known roles in cardiac function or development. Importantly, we evaluated the biological relevance of a significant subset 31/133 (23%) of the remaining candidate genes by in situ hybridization at multiple time points during development (embryonic day, E7.5-9.5) and report that all were expressed in key cardiac structures during cardiogenesis. Furthermore 9/31, of which many were previously uncharacterized, were detected as early as the formation of the cardiac crescent. These data demonstrate the potential power of integrating genomic approaches with mESC differentiation to illuminate developmental processes, and provides a valuable resource that may be mined to further elucidate the genetic programs underlying cardiogenesis.

Background: Myelin protein zero (MPZ) is a critical structural component of myelin in the peripheral nervous system. The MPZ gene is regulated, in part, by the transcription factors SOX10 and EGR2. Mutations in MPZ, SOX10, and EGR2 have been implicated in demyelinating peripheral neuropathies, suggesting that components of this transcriptional network are candidates for harboring disease-causing mutations (or otherwise functional variants) that affect MPZ expression. Methodology: We utilized a combination of multi-species sequence comparisons, transcription factor-binding site predictions, targeted human DNA re-sequencing, and in vitro and in vivo enhancer assays to study human non-coding MPZ variants. Principal Findings: Our efforts revealed a variant within the first intron of MPZ that resides within a previously described SOX10 binding site is associated with decreased enhancer activity, and alters binding of nuclear proteins. Additionally, the genomic segment harboring this variant directs tissue-relevant reporter gene expression in zebrafish. Conclusions: This is the first reported MPZ variant within a cis-acting transcriptional regulatory element. While we were unable to implicate this variant in disease onset, our data suggests that similar non-coding sequences should be screened for mutations in patients with neurological disease. Furthermore, our multi-faceted approach for examining the functional significance of non-coding variants can be readily generalized to study other loci important for myelin structure and function. [ABSTRACT FROM AUTHOR]