Plays That Won't Go Away

A public reading of work by playwrights Jimmy McAleavey and Owen McCafferty as part of the Seamus Heaney Centre programme of readings.

FLT1 Genetic Variation Predisposes to Neovascular AMD in Ethnically Diverse Populations and Alters Systemic FLT1 Expression

Purpose: Current understanding of the genetic risk factors for age-related macular degeneration (AMD) is not sufficiently predictive of the clinical course. The VEGF pathway is a key therapeutic target for treatment of neovascular AMD; however, risk attributable to genetic variation within pathway genes is unclear. We sought to identify single nucleotide polymorphisms (SNPs) associated with AMD within the VEGF pathway.
Methods: Using a tagSNP, direct sequencing and meta-analysis approach within four ethnically diverse cohorts, we identified genetic risk present in FLT1, though not within other VEGF pathway genes KDR, VEGFA, or VASH1. We used ChIP and ELISA in functional analysis.
Results: The FLT1 SNPs rs9943922, rs9508034, rs2281827, rs7324510, and rs9513115 were significantly associated with increased risk of neovascular AMD. Each association was more significant after meta-analysis than in any one of the four cohorts. All associations were novel, within noncoding regions of FLT1 that do not tag for coding variants in linkage disequilibrium. Analysis of soluble FLT1 demonstrated higher expression in unaffected individuals homozygous for the FLT1 risk alleles rs9943922 (P = 0.0086) and rs7324510 (P = 0.0057). In silico analysis suggests that these variants change predicted splice sites and RNA secondary structure, and have been identified in other neovascular pathologies. These data were supported further by murine chromatin immunoprecipitation demonstrating that FLT1 is a target of Nr2e3, a nuclear receptor gene implicated in regulating an AMD pathway.
Conclusions: Although exact variant functions are not known, these data demonstrate relevancy across ethnically diverse genetic backgrounds within our study and, therefore, hold potential for global efficacy.

Natural variation of rice strigolactone biosynthesis is associated with the deletion of two MAX1 orthologs

Rice (Oryza sativa) cultivar Azucena--belonging to the Japonica subspecies--exudes high strigolactone (SL) levels and induces high germination of the root parasitic plant Striga hermonthica. Consistent with the fact that SLs also inhibit shoot branching, Azucena is a low-tillering variety. In contrast, Bala, an Indica cultivar, is a low-SL producer, stimulates less Striga germination, and is highly tillered. Using a Bala × Azucena F6 population, a major quantitative trait loci--qSLB1.1--for the exudation of SL, tillering, and induction of Striga germination was detected on chromosome 1. Sequence analysis of the corresponding locus revealed a rearrangement of a 51- to 59-kbp stretch between 28.9 and 29 Mbp in the Bala genome, resulting in the deletion of two cytochrome P450 genes--SLB1 and SLB2--with high homology to the Arabidopsis SL biosynthesis gene, MAX1. Both rice genes rescue the Arabidopsis max1-1 highly branched mutant phenotype and increase the production of the SL, ent-2'-epi-5-deoxystrigol, when overexpressed in Bala. Furthermore, analysis of this region in 367 cultivars of the publicly available Rice Diversity Panel population shows that the rearrangement at this locus is a recurrent natural trait associated with the Indica/Japonica divide in rice.

Behavioural outcomes at 3 years of age among late preterm infants admitted to neonatal intensive care: a cohort study

Objective: Examine the behavioural outcomes at age 3 years of late preterm infants (LPIs) who were admitted to neonatal intensive care (NIC) in comparison with LPIs who were not admitted.
Method: This cohort study prospectively recruited 225 children born late preterm (34–36+6 weeks gestation) in 2006 in Northern Ireland, now aged 3 years. Two groups were compared: LPIs who received NIC (study; n=103) and LPIs who did not receive NIC (control; n=122). Parents/guardians completed the Child Behaviour Checklist/1½-5. Descriptive maternal and infant data were also collected.
Results: As expected LPI children admitted to NIC had higher medical risk than the non-admitted comparison group (increased caesarean section, born at earlier gestation, lower birth weight and an episode of resuscitation at birth). LPIs admitted to NIC scored higher on the Child Behaviour Checklist/1½-5 compared with those who were not admitted indicating more behavioural problems; this was statistically significant for the Aggressive Behaviour Subscale (z=−2.36) and the Externalising Problems Scale (z=−2.42). The group difference on the Externalising Problems Scale was no longer significant after controlling for gender, gestational age and deprivation score.
Conclusions: This study provides valuable data on the behaviour at age 3 years of LPIs admitted to NIC compared with LPIs not admitted to NIC. Further research would be beneficial to explore medical and psychosocial explanations for observed differences between groups using large prospective cohort studies.

Detectability of bovine TB using the tuberculin skin test does not vary significantly according to pathogen genotype within Northern Ireland

Strains of many infectious diseases differ in parameters that influence epidemic spread, for example virulence, transmissibility, detectability and host specificity. Knowledge of inter-strain variation can be exploited to improve management and decrease disease incidence. Bovine tuberculosis (bTB) is increasingly prevalent among farmed cattle in the UK, exerting a heavy economic burden on the farming industry and government. We aimed to determine whether strains of Mycobacterium bovis (the causative agent of bTB) identified and classified using genetic markers (spoligotyping and multi-locus VNTR analysis) varied in response to the tuberculin skin test; this being the primary method of bTB detection used in the UK. Inter-strain variation in detectability of M. bovis could have important implications for disease control. The skin test is based on a differential delayed type hypersensitivity (DTH) response to intradermal injections of purified protein derivative (PPD) from M. bovis (PPD-B) and Mycobacterium avium (PPD-A). We searched for an association between skin test response (PPD-B skin rise minus PPD-A skin rise) and M. bovis genotype at the disclosing test in culture-confirmed cases using a field dataset consisting of 21,000 isolates belonging to 63 genotypes of M. bovis from cattle in Northern Ireland. We found no substantial variation among genotypes (estimated responses clustered tightly around the mean) controlling for animal sex, breed and test effects. We also estimated the ratio of skin test detected to undetected cases (i.e. cases only detected at abattoir). The skin test detection ratio varied among abattoirs with some detecting a greater proportion of cases than others but this variation was unrelated to the community composition of genotypes within each abattoir catchment. These two lines of evidence indicate that M. bovis genotypes in Northern Ireland have similar detectability using the skin test.

Polemic and apocalyptic in the Cromwellian invasion of Scotland

This article describes the culture of print and polemic associated with the Cromwellian invasion of Scotland and the resistance of the Church of Scotland. It argues that print solidified Parliamentary ideas during the invasion but that it did not continue to do so after English dominance had been established. These texts illustrate the divisions between the mentalité of the Cromwellian rank-and-file and that of the rather small and probably unrepresentative body of opinion formers who sought to control and represent it.

Predictors and dynamics of postpartum relapses in women with multiple sclerosis

Several studies have shown that pregnancy reduces multiple sclerosis (MS) relapses, which increase in the early postpartum period. Postpartum relapse risk has been predicted by pre-pregnancy disease activity in some studies.

Large-scale association analysis identifies new risk loci for coronary artery disease

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2)

Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC

The Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC) highlighted 81 single-nucleotide polymorphisms (SNPs) with moderate evidence for association to schizophrenia. After follow-up in independent samples, seven loci attained genome-wide significance (GWS), but multi-locus tests suggested some SNPs that did not do so represented true associations. We tested 78 of the 81 SNPs in 2640 individuals with a clinical diagnosis of schizophrenia attending a clozapine clinic (CLOZUK), 2504 cases with a research diagnosis of bipolar disorder, and 2878 controls. In CLOZUK, we obtained significant replication to the PGC-associated allele for no fewer than 37 (47%) of the SNPs, including many prior GWS major histocompatibility complex (MHC) SNPs as well as 3/6 non-MHC SNPs for which we had data that were reported as GWS by the PGC. After combining the new schizophrenia data with those of the PGC, variants at three loci (ITIH3/4, CACNA1C and SDCCAG8) that had not previously been GWS in schizophrenia attained that level of support. In bipolar disorder, we also obtained significant evidence for association for 21% of the alleles that had been associated with schizophrenia in the PGC. Our study independently confirms association to three loci previously reported to be GWS in schizophrenia, and identifies the first GWS evidence in schizophrenia for a further three loci. Given the number of independent replications and the power of our sample, we estimate 98% (confidence interval (CI) 78-100%) of the original set of 78 SNPs represent true associations. We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder.

Service user perspectives on palliative care education for health and social care professionals supporting people with learning disabilities

Background and objectives
Evidence from European and American studies indicates limited referrals of people with learning (intellectual) disabilities to palliative care services. Although professionals’ perceptions of their training needs in this area have been studied, the perceptions of people with learning disabilities and family carers are not known. This study aimed to elicit the views of people with learning disabilities, and their family carers concerning palliative care, to inform healthcare professional education and training.

Methods
A qualitative, exploratory design was used. A total of 17 people with learning disabilities were recruited to two focus groups which took place within an advocacy network. Additionally, three family carers of someone with a learning disability, requiring palliative care, and two family carers who had been bereaved recently were also interviewed.

Results
Combined data identified the perceived learning needs for healthcare professionals. Three subthemes emerged: ‘information and preparation’, ‘provision of care’ and ‘family-centred care’.

Conclusions
This study shows that people with learning disabilities can have conversations about death and dying, and their preferred end-of-life care, but require information that they can understand. They also need to have people around familiar to them and with them. Healthcare professionals require skills and knowledge to effectively provide palliative care for people with learning disabilities and should also work in partnership with their family carers who have expertise from their long-term caring role. These findings have implications for educators and clinicians.

Developing a best practice model for partnership practice between specialist palliative care and intellectual disability services: a mixed methods study

Background: The lack of access to good quality palliative care for people with intellectual disabilities is highlighted in the international literature. In response, more partnership practice in end-of-life care is proposed. 
Aim: This study aimed to develop a best practice model to guide and promote partnership practice between specialist palliative care and intellectual disability services. 
Design: A mixed methods research design involving two phases was used, underpinned by a conceptual model for partnership practice. 
Setting/participants: Phase 1 involved scoping end-of-life care to people with intellectual disability, based on self-completed questionnaires. In all, 47 of 66 (71.2%) services responded. In Phase 2, semi-structured interviews were undertaken with a purposive sample recruited of 30 health and social care professionals working in intellectual disability and palliative care services, who had provided palliative care to someone with intellectual disability. For both phases, data were collected from primary and secondary care in one region of the United Kingdom. 
Results: In Phase 1, examples of good practice were apparent. However, partnership practice was infrequent and unmet educational needs were identified. Four themes emerged from the interviews in Phase 2: challenges and issues in end-of-life care, sharing and learning, supporting and empowering and partnership in practice. 
Conclusion: Joint working and learning between intellectual disability and specialist palliative care were seen as key and fundamental. A framework for partnership practice between both services has been developed which could have international applicability and should be explored with other services in end-of-life care.