Systems-level analysis of age-related macular degeneration reveals global biomarkers and phenotype-specific functional networks

Abstract Background Age-related macular degeneration (AMD) is a leading cause of blindness that affects the central region of the retinal pigmented epithelium (RPE), choroid, and neural retina. Initially characterized by an accumulation of sub-RPE deposits, AMD leads to progressive retinal degeneration, and in advanced cases, irreversible vision loss. Although genetic analysis, animal models, and cell culture systems have yielded important insights into AMD, the molecular pathways underlying AMD's onset and progression remain poorly delineated. We sought to better understand the molecular underpinnings of this devastating disease by performing the first comparative transcriptome analysis of AMD and normal human donor eyes. Methods RPE-choroid and retina tissue samples were obtained from a common cohort of 31 normal, 26 AMD, and 11 potential pre-AMD human donor eyes. Transcriptome profiles were generated for macular and extramacular regions, and statistical and bioinformatic methods were employed to identify disease-associated gene signatures and functionally enriched protein association networks. Selected genes of high significance were validated using an independent donor cohort. Results We identified over 50 annotated genes enriched in cell-mediated immune responses that are globally over-expressed in RPE-choroid AMD phenotypes. Using a machine learning model and a second donor cohort, we show that the top 20 global genes are predictive of AMD clinical diagnosis. We also discovered functionally enriched gene sets in the RPE-choroid that delineate the advanced AMD phenotypes, neovascular AMD and geographic atrophy. Moreover, we identified a graded increase of transcript levels in the retina related to wound response, complement cascade, and neurogenesis that strongly correlates with decreased levels of phototransduction transcripts and increased AMD severity. Based on our findings, we assembled protein-protein interactomes that highlight functional networks likely to be involved in AMD pathogenesis. Conclusions We discovered new global biomarkers and gene expression signatures of AMD. These results are consistent with a model whereby cell-based inflammatory responses represent a central feature of AMD etiology, and depending on genetics, environment, or stochastic factors, may give rise to the advanced AMD phenotypes characterized by angiogenesis and/or cell death. Genes regulating these immunological activities, along with numerous other genes identified here, represent promising new targets for AMD-directed therapeutics and diagnostics. Please see related commentary: http://www.biomedcentral.com/1741-7015/10/21/abstrac

A pairwise randomised controlled trial of a peer-mediated play-based intervention to improve the social play skills of children with ADHD: Outcomes of the typically-developing playmates

To examine the effectiveness of a play-based intervention for improving social play skills of typically-developing playmates of children with ADHD. Children (5–11 years) were randomised to an intervention (n = 15) or waitlisted control group (n = 14). The Test of Playfulness was scored by a blinded rater. Between-group statistics compared the change of the intervention (10-week intervention) and waitlisted control (10-week wait) groups. Change in the intervention group following intervention was significantly greater than the change in the waitlisted control group. When combining data from the groups, playmates’ (n = 29) mean ToP scores improved significantly following intervention, with a large effect pre- to post-intervention and pre-intervention to follow-up. Typically-developing playmates of children with ADHD benefited from participation in a peer-mediated intervention

‘Trying to pin down jelly’ - exploring intuitive processes in quality assessment for meta-ethnography

Background: Studies that systematically search for and synthesise qualitative research are becoming more evident in health care, and they can make an important contribution to patient care. However, there is still no agreement as to whether, or how we should appraise studies for inclusion. We aimed to explore the intuitive processes that determined the ‘quality’ of qualitative research for inclusion in qualitative research syntheses. We were particularly interested to explore the way that knowledge was constructed. Methods: We used qualitative methods to explore the process of quality appraisal within a team of seven qualitative researchers funded to undertake a meta-ethnography of chronic non-malignant musculoskeletal pain. Team discussions took place monthly between October 2010 and June 2012 and were recorded and transcribed. Data was coded and organised using constant comparative method. The development of our conceptual analysis was both iterative and collaborative. The strength of this team approach to quality came from open and honest discussion, where team members felt free to agree, disagree, or change their position within the safety of the group. Results: We suggest two core facets of quality for inclusion in meta-ethnography - (1) Conceptual clarity; how clearly has the author articulated a concept that facilitates theoretical insight. (2) Interpretive rigour; fundamentally, can the interpretation ‘be trusted?’ Our findings showed that three important categories help the reader to judge interpretive rigour: (ii) What is the context of the interpretation? (ii) How inductive is the interpretation? (iii) Has the researcher challenged their interpretation? Conclusions: We highlight that methods alone do not determine the quality of research for inclusion into a meta-ethnography. The strength of a concept and its capacity to facilitate theoretical insight is integral to meta-ethnography, and arguably to the quality of research. However, we suggest that to be judged ‘good enough’ there also needs to be some assurance that qualitative findings are more than simply anecdotal. Although our conceptual model was developed specifically for meta-ethnography, it may be transferable to other research methodologies

Active restoration accelerates the carbon recovery of human modified-tropical forests

More than half of all tropical forests are degraded by human impacts, leaving them threatened with conversion to agricultural plantations and risking substantial biodiversity and carbon losses. Restoration could accelerate recovery of aboveground carbon density (ACD), but adoption of restoration is constrained by cost and uncertainties over effectiveness. We report a long-term comparison of ACD recovery rates between naturally regenerating and actively restored logged tropical forests. Restoration enhanced decadal ACD recovery by more than 50%, from 2.9 to 4.4 megagrams per hectare per year. This magnitude of response, coupled with modal values of restoration costs globally, would require higher carbon prices to justify investment in restoration. However, carbon prices required to fulfill the 2016 Paris climate agreement [$40 to$80 (USD) per tonne carbon dioxide equivalent] would provide an economic justification for tropical forest restoration

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

If you build it, they still may not come: outcomes and process of implementing a community-based integrated knowledge translation mapping innovation

<p>Abstract</p> <p>Background</p> <p>Maps and mapping tools through geographic information systems (GIS) are highly valuable for turning data into useful information that can help inform decision-making and knowledge translation (KT) activities. However, there are several challenges involved in incorporating GIS applications into the decision-making process. We highlight the challenges and opportunities encountered in implementing a mapping innovation as a KT strategy within the non-profit (public) health sector, reflecting on the processes and outcomes related to our KT innovations.</p> <p>Methods</p> <p>A case study design, whereby the case is defined as the data analyst and manager dyad (a two-person team) in selected Ontario Early Year Centres (OEYCs), was used. Working with these paired individuals, we provided a series of interventions followed by one-on-one visits to ensure that our interventions were individually tailored to personal and local decision-making needs. Data analysis was conducted through a variety of qualitative assessments, including field notes, interview data, and maps created by participants. Data collection and data analysis have been guided by the Ottawa Model of Research Use (OMRU) conceptual framework.</p> <p>Results</p> <p>Despite our efforts to remove all barriers associated with our KT innovation (maps), our results demonstrate that both individual level and systemic barriers pose significant challenges for participants. While we cannot claim a causal association between our project and increased mapping by participants, participants did report a moderate increase in the use of maps in their organization. Specifically, maps were being used in decision-making forums as a way to allocate resources, confirm tacit knowledge about community needs, make financially-sensitive decisions more transparent, evaluate programs, and work with community partners.</p> <p>Conclusions</p> <p>This project highlights the role that maps can play and the importance of communicating the importance of maps as a decision support tool. Further, it represents an integrated knowledge project in the community setting, calling to question the applicability of traditional KT approaches when community values, minimal resources, and partners play a large role in decision making. The study also takes a unique perspective--where research producers and users work as dyad-pairs in the same organization--that has been under-explored to date in KT studies.</p

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Expression of the Multiple Sclerosis-Associated MHC Class II Allele HLA-DRB1*1501 Is Regulated by Vitamin D

Multiple sclerosis (MS) is a complex trait in which allelic variation in the MHC class II region exerts the single strongest effect on genetic risk. Epidemiological data in MS provide strong evidence that environmental factors act at a population level to influence the unusual geographical distribution of this disease. Growing evidence implicates sunlight or vitamin D as a key environmental factor in aetiology. We hypothesised that this environmental candidate might interact with inherited factors and sought responsive regulatory elements in the MHC class II region. Sequence analysis localised a single MHC vitamin D response element (VDRE) to the promoter region of HLA-DRB1. Sequencing of this promoter in greater than 1,000 chromosomes from HLA-DRB1 homozygotes showed absolute conservation of this putative VDRE on HLA-DRB1*15 haplotypes. In contrast, there was striking variation among non–MS-associated haplotypes. Electrophoretic mobility shift assays showed specific recruitment of vitamin D receptor to the VDRE in the HLA-DRB1*15 promoter, confirmed by chromatin immunoprecipitation experiments using lymphoblastoid cells homozygous for HLA-DRB1*15. Transient transfection using a luciferase reporter assay showed a functional role for this VDRE. B cells transiently transfected with the HLA-DRB1*15 gene promoter showed increased expression on stimulation with 1,25-dihydroxyvitamin D3 (P = 0.002) that was lost both on deletion of the VDRE or with the homologous “VDRE” sequence found in non–MS-associated HLA-DRB1 haplotypes. Flow cytometric analysis showed a specific increase in the cell surface expression of HLA-DRB1 upon addition of vitamin D only in HLA-DRB1*15 bearing lymphoblastoid cells. This study further implicates vitamin D as a strong environmental candidate in MS by demonstrating direct functional interaction with the major locus determining genetic susceptibility. These findings support a connection between the main epidemiological and genetic features of this disease with major practical implications for studies of disease mechanism and prevention

Integrating evidence into policy and sustainable disability services delivery in western New South Wales, Australia: the 'wobbly hub and double spokes' project

<p>Abstract</p> <p>Background</p> <p>Policy that supports rural allied health service delivery is important given the shortage of services outside of Australian metropolitan centres. The shortage of allied health professionals means that rural clinicians work long hours and have little peer or service support. Service delivery to rural and remote communities is further complicated because relatively small numbers of clients are dispersed over large geographic areas. The aim of this five-year multi-stage project is to generate evidence to confirm and develop evidence-based policies and to evaluate their implementation in procedures that allow a regional allied health workforce to more expeditiously respond to disability service need in regional New South Wales, Australia.</p> <p>Methods/Design</p> <p>The project consists of four inter-related stages that together constitute a full policy cycle. It uses mixed quantitative and qualitative methods, guided by key policy concerns such as: access, complexity, cost, distribution of benefits, timeliness, effectiveness, equity, policy consistency, and community and political acceptability.</p> <p>Stage 1 adopts a policy analysis approach in which existing relevant policies and related documentation will be collected and reviewed. Policy-makers and senior managers within the region and in central offices will be interviewed about issues that influence policy development and implementation.</p> <p>Stage 2 uses a mixed methods approach to collecting information from allied health professionals, clients, and carers. Focus groups and interviews will explore issues related to providing and receiving allied health services. Discrete Choice Experiments will elicit staff and client/carer preferences.</p> <p>Stage 3 synthesises Stage 1 and 2 findings with reference to the key policy issues to develop and implement policies and procedures to establish several innovative regional workforce and service provision projects.</p> <p>Stage 4 uses mixed methods to monitor and evaluate the implementation and impact of new or adapted policies that arise from the preceding stages.</p> <p>Discussion</p> <p>The project will provide policy makers with research evidence to support consideration of the complex balance between: (i) the equitable allocation of scarce resources; (ii) the intent of current eligibility and prioritisation policies; (iii) workforce constraints (and strengths); and (iv) the most effective, evidence-based clinical practice.</p

A Randomised Controlled Trial of a Play-Based Intervention to Improve the Social Play Skills of Children with Attention Deficit Hyperactivity Disorder (ADHD).

There is a need for effective interventions to address the social difficulties of children with ADHD. This randomised controlled trial examined the effectiveness of a play-based intervention for improving the social play skills of children with ADHD in peer-to-peer interactions. Children with ADHD (5 to 11 years) were randomised to an intervention-first (n = 15) or waitlist control-first group (n = 14). Participants allocated to the control-first group received the intervention after a 10-week wait period. Children invited a typically-developing playmate and parents of children with ADHD participated. The intervention involved: six clinic play-sessions, weekly home-modules and a one-month home follow up. The Test of Playfulness (ToP) was scored by a blinded rater. Parent reported treatment adherence was used to assess treatment fidelity. Between group statistics were used to compare the change of the intervention-first (10-week intervention period) and control-first (10-week wait period) groups. Once all children had received the intervention, repeated measures ANOVA, post hoc Least Significance Difference tests and Cohen's-d were used to measure effect. Changes in ToP social items were analysed using Friedman's ANOVA. Linear regression analyses were used to identify variables that predicted change. The control-first group did not change during the wait period. The change in the intervention-first group was significantly greater than the change in the control-first group (during the wait period). When the data from the two groups were combined, the mean ToP scores of the children with ADHD (n = 29) improved significantly following the intervention, with a large effect from pre to post intervention and from pre intervention to follow up. Children maintained treatment gains at follow up. All ToP social items improved significantly following the intervention. The findings support the use of play involving parent and peer mediated components to enhance the social play skills of children with ADHD. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12614000973617