Pharmacological evaluation of selective α2c-adrenergic agonists in experimental animal models of nasal congestion

Nasal congestion is one of the most troublesome symptoms of many upper airways diseases. We characterized the effect of selective α2c-adrenergic agonists in animal models of nasal congestion. In porcine mucosa tissue, compound A and compound B contracted nasal veins with only modest effects on arteries. In in vivo experiments, we examined the nasal decongestant dose-response characteristics, pharmacokinetic/pharmacodynamic relationship, duration of action, potential development of tolerance, and topical efficacy of α2c-adrenergic agonists. Acoustic rhinometry was used to determine nasal cavity dimensions following intranasal compound 48/80 (1%, 75 µl). In feline experiments, compound 48/80 decreased nasal cavity volume and minimum cross-sectional areas by 77% and 40%, respectively. Oral administration of compound A (0.1-3.0 mg/kg), compound B (0.3-5.0 mg/kg), and d-pseudoephedrine (0.3 and 1.0 mg/kg) produced dose-dependent decongestion. Unlike d-pseudoephedrine, compounds A and B did not alter systolic blood pressure. The plasma exposure of compound A to produce a robust decongestion (EC(80)) was 500 nM, which related well to the duration of action of approximately 4.0 hours. No tolerance to the decongestant effect of compound A (1.0 mg/kg p.o.) was observed. To study the topical efficacies of compounds A and B, the drugs were given topically 30 minutes after compound 48/80 (a therapeutic paradigm) where both agents reversed nasal congestion. Finally, nasal-decongestive activity was confirmed in the dog. We demonstrate that α2c-adrenergic agonists behave as nasal decongestants without cardiovascular actions in animal models of upper airway congestion.

Identifying solutions to increase participation in physical activity interventions within a socio-economically disadvantaged community: a qualitative study

Background: There is an urgent need to increase population levels of physical activity, particularly amongst those who are socio-economically disadvantaged. Multiple factors influence physical activity behaviour but the generalisability of current evidence to such ‘hard-to-reach’ population subgroups is limited by difficulties in recruiting them into studies. Also, rigorous qualitative studies of lay perceptions and perceptions of community leaders about public health efforts to increase physical activity are sparse. We sought to explore, within a socio-economically disadvantaged community, residents’ and community leaders’ perceptions of physical activity (PA) interventions and issues regarding their implementation, in order to improve understanding of needs, expectations, and social/environmental factors relevant to future interventions.

Methods: Within an ongoing regeneration project (Connswater Community Greenway), in a socio-economically disadvantaged community in Belfast, we collaborated with a Community Development Agency to purposively sample leaders from public- and voluntary-sector community groups and residents. Individual semi-structured interviews were conducted with 12 leaders. Residents (n=113), of both genders and a range of ages (14 to 86 years) participated in focus groups (n=14) in local facilities. Interviews and focus groups were recorded, transcribed verbatim and analysed using a thematic framework.

Results: Three main themes were identified: awareness of PA interventions; factors contributing to intervention effectiveness; and barriers to participation in PA interventions. Participants reported awareness only of interventions in which they were involved directly, highlighting a need for better communications, both inter- and intra-sectoral, and with residents. Meaningful engagement of residents in planning/organisation, tailoring to local context, supporting volunteers, providing relevant resources and an ‘exit strategy’ were perceived as important factors related to intervention effectiveness. Negative attitudes such as apathy, disappointing experiences, information with no perceived personal relevance and limited access to facilities were barriers to people participating in interventions.

Conclusions: These findings illustrate the complexity of influences on a community’s participation in PA interventions and support a social-ecological approach to promoting PA. They highlight the need for cross-sector working, effective information exchange, involving residents in bottom-up planning and providing adequate financial and social support. An in-depth understanding of a target population’s perspectives is of key importance in translating PA behaviour change theories into practice.

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

Defining the role of common variation in the genomic and biological architecture of adult human height

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/I 2-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

AGWAN: A Generative Model for Labelled, Weighted Graphs

Real-world graphs or networks tend to exhibit a well-known set of properties, such as heavy-tailed degree distributions, clustering and community formation. Much effort has been directed into creating realistic and tractable models for unlabelled graphs, which has yielded insights into graph structure and evolution. Recently, attention has moved to creating models for labelled graphs: many real-world graphs are labelled with both discrete and numeric attributes. In this paper, we presentAgwan (Attribute Graphs: Weighted and Numeric), a generative model for random graphs with discrete labels and weighted edges. The model is easily generalised to edges labelled with an arbitrary number of numeric attributes. We include algorithms for fitting the parameters of the Agwanmodel to real-world graphs and for generating random graphs from the model. Using real-world directed and undirected graphs as input, we compare our approach to state-of-the-art random labelled graph generators and draw conclusions about the contribution of discrete vertex labels and edge weights to graph structure.

Connectivity and Physical Activity: Using Footpath Networks to Measure the Walkability of Built Environments

There is now a strong body of research that suggests that the form of the built environment can influence levels of physical activity, leading to an increasing interest in incorporating health objectives into spatial planning and regeneration policies and projects. There have been a number of strands to this research, one of which has sought to develop “objective” measurements of the built environment using Geographic Information Science (GIS) involving measures of connectivity and proximity to compare the relative “walkability” of different neighbourhoods. The development of the “walkability index” (e.g. Leslie et al 2007, Frank et al 2010) has become a popular indicator of spatial distribution of those features of the built environment that are considered to have the greatest positive influence on levels of physical activity. The success of this measure is built on its ability to succinctly capture built environment correlates of physical activity using routinely available spatial data, which includes using road centre lines as a basis of a proxy for connectivity.

This paper discusses two key aspects of the walkability index. First, it follows the suggestion of Chin et al (2008) that the use of a footpath network (where available), rather than road centre lines, may be far more effective in evaluating walkability. This may be particularly important for assessing changes in walkability arising from pedestrian-focused infrastructure projects, such as greenways. Second, the paper explores the implication of this for how connectivity can be measured. The paper takes six different measures of connectivity and first analyses the relationships between them and then tests their correlation with actual levels of physical activity of local residents in Belfast, Northern Ireland. The analysis finds that the best measurements appear to be intersection density and metric reach and uses this finding to discuss the implications of this for developing tools that may better support decision-making in spatial planning.

"Hidden" Social Networks in Behavior Change Interventions

We investigated whether “hidden” (or unobserved) social networks were evident in a 2011 physical activity behavior change intervention in Belfast, Northern Ireland. Results showed evidence of unobserved social networks in the intervention and illustrated how the network evolved over short periods and affected behavior. Behavior change interventions should account for the interaction among participants (i.e., social networks) and how such interactions affect intervention outcome.

New genetic loci link adipose and insulin biology to body fat distribution

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

The Prenatal Distress Questionnaire:An investigation of factor structure in a high risk population

Background: The Prenatal Distress Questionnaire (PDQ) is a short measure designed to assess specific worries and concerns related to pregnancy. The aim of this study was to confirm the factor structure of the PDQ in a group of pregnant women with a small for gestational age infant (< 10th centile). Methods: The first PDQ assessment for each of 337 pregnant women participating in the Prospective Observational Trial to Optimise paediatric health (PORTO) study was analysed. All women enrolled in the study were identified as having a small for gestational age foetus (< 10th centile), thus representing an 'elevated risk' group. Data were analysed using confirmatory factor analysis (CFA). Three models of the PDQ were evaluated and compared in the current study: a theoretical uni-dimensional measurement model, a bi-dimensional model, and a three-factor model solution. Results: The three-factor model offered the best fit to the data while maintaining sound theoretical grounds(χ² (51df) = 128.52; CFI = 0.97; TLI = 0.96; RMSEA = 0.07). Factor 1 contained items reflecting concerns about birth and the baby, factor 2 concerns about physical symptoms and body image and factor 3 concerns about emotions and relationships. Conclusions: CFA confirmed that the three-factor model provided the best fit, with the items in each factor reflecting the findings of an earlier exploratory data analysis. © 2013 Society for Reproductive and Infant Psychology.

Michael Allen: Close Readings: Essays on Irish Poetry

The late Michael Allen was a member of the famous Belfast Group, and one of the most authoritative critical voices on poetry from Northern Ireland, intimately part of the North’s poetic movement since the early 1960s. He taught at Queen’s University, where he was a colleague of Seamus Heaney and tutor to poets such as Paul Muldoon and Medbh McGuckian. Seamus Heaney called him ‘the reader over my shoulder’. Close Readings brings together interlinked critical writings which have crucially influenced approaches to Irish poetry during the last forty years. The book ends with an extended essay, hitherto unpublished: ‘Doubles, Twins and the Feminine: Development in the Poetry of Michael Longley’.

Close Readings contains a Foreword by Fran Brearton, which relates Michael Allen’s essays to continuing critical and cultural debates. Edna Longley’s Afterword offers a personal view of Allen’s involvement with poetry in Belfast.