Biomedical subjects

Ryan O'Connell

Publications and source records attributed to Ryan O'Connell.

5 recordsLinked to original sources

PubMed2005

The GuideLine Implementability Appraisal (GLIA): development of an instrument to identify obstacles to guideline implementation.

BACKGROUND: Clinical practice guidelines are not uniformly successful in influencing clinicians' behaviour toward best practices. Implementability refers to a set of characteristics that predict ease of (and obstacles to) guideline implementation. Our objective is to develop and validate a tool for appraisal of implementability of clinical guidelines. METHODS: Indicators of implementability were identified from the literature and used to create items and dimensions of the GuideLine Implementability Appraisal (GLIA). GLIA consists of 31 items, arranged into 10 dimensions. Questions from 9 of the 10 dimensions are applied individually to each recommendation of the guideline. Decidability and Executability are critical dimensions. Other dimensions are Global, Presentation and Formatting, Measurable Outcomes, Apparent Validity, Flexibility, Effect on Process of Care, Novelty/Innovation, and Computability. We conducted a series of validation activities, including validation of the construct of implementability, expert review of content for clarity, relevance, and comprehensiveness, and assessment of construct validity of the instrument. Finally, GLIA was applied to a draft guideline under development by national professional societies. RESULTS: Evidence of content validity and preliminary support for construct validity were obtained. The GLIA proved to be useful in identifying barriers to implementation in the draft guideline and the guideline was revised accordingly. CONCLUSION: GLIA may be useful to guideline developers who can apply the results to remedy defects in their guidelines. Likewise, guideline implementers may use GLIA to select implementable recommendations and to devise implementation strategies that address identified barriers. By aiding the design and operationalization of highly implementable guidelines, our goal is that application of GLIA may help to improve health outcomes, but further evaluation will be required to support this potential benefit.

Benchmarking↗

PubMed2004

Cutting edge: TLR4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway.

The triggering molecular mechanism of ischemia-reperfusion injury (IRI), which in clinical settings results in excessive and detrimental inflammatory responses, remains unclear. This study analyzes the role of the TLR system in an established murine model of liver warm ischemia followed by reperfusion. By contrasting in parallel TLR knockout mice with their wild-type counterparts, we found that TLR4, but not TLR2, was specifically required in initiating the IRI cascade, as manifested by liver function (serum alanine aminotransferase levels), pathology, and local induction of proinflammatory cytokines/chemokines (TNF-alpha, IL-6, IFN-inducible protein 10). We then investigated the downstream signaling pathway of TLR4 activation. Our results show that IFN regulatory factor 3, but not MyD88, mediated IRI-induced TLR4 activation leading to liver inflammation and hepatocellular damage. This study documents the selective usage of TLR in a clinically relevant noninfectious disease model, and identifies a triggering molecular mechanism in the pathophysiology of liver IRI.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Toll-like receptor 3 mediates a more potent antiviral response than Toll-like receptor 4.

We have recently described an IFN regulatory factor 3-mediated antiviral gene program that is induced by both Toll-like receptor (TLR)3 and TLR4 ligands. In our current study, we show that activation of IFN/viral response gene expression in primary macrophage cells is stronger and prolonged with TLR3 stimulation compared with that of TLR4. Our data also reveal that the cytoplasmic tails of both TLR3 and TLR4 can directly interact with myeloid differentiation factor 88 (MyD88). However, although Toll/IL-1 receptor homology domain-containing adaptor protein/MyD88 adaptor-like is able to associate with TLR4, we were unable to detect any interaction between Toll/IL-1 receptor homology domain-containing adaptor protein/MyD88 adaptor-like and TLR3. By using quantitative real-time PCR assays, we found that TLR3 expression is inducible by both TLR3 and TLR4 ligands, while TLR4 expression is not inducible by these same stimuli. Furthermore, using cells derived from mice deficient in the IFN-alphabetaR, we show that both TLR3 and TLR4 require IFN-beta autocrine/paracrine feedback to induce TLR3 expression and activate/enhance genes required for antiviral activity. More specifically, a subset of antiviral genes is initially induced independent of IFN-beta, yet the cytokine further enhances expression at later time points. This was in contrast to a second set of genes (including TLR3) that is induced only after IFN-beta production. Taken together, our data argue that, despite both TLR3 and TLR4 being able to use IFN-beta to activate/enhance antiviral gene expression, TLR3 uses multiple mechanisms to enhance and sustain the antiviral response more strongly than TLR4.

Adaptor Proteins, Signal Transducing↗

PubMed2002

IRF3 mediates a TLR3/TLR4-specific antiviral gene program.

We have identified a subset of genes that is specifically induced by stimulation of TLR3 or TLR4 but not by TLR2 or TLR9. Further gene expression analyses established that upregulation of several primary response genes was dependent on NF-kappaB, commonly activated by several TLRs, and interferon regulatory factor 3 (IRF3), which was found to confer TLR3/TLR4 specificity. Also identified was a group of secondary response genes which are part of an autocrine/paracrine loop activated by the primary response gene product, interferon beta (IFNbeta). Selective activation of the TLR3/TLR4-IRF3 pathway potently inhibited viral replication. These results suggest that TLR3 and TLR4 have evolutionarily diverged from other TLRs to activate IRF3, which mediates a specific gene program responsible for innate antiviral responses.

3T3 Cells↗

PubMed2002

An approach to object-relational mapping in bioscience domains.

Object-relational mapping (mapping object-oriented software systems to relational databases) remains a challenging undertaking because of the inherent differences between these two technologies. Effective application of this technique in biomedical informatics applications can provide robust, adaptive solutions but requires careful attention to specific issues in the bioscience domain. Mapping from a single, fixed, stably defined object to a table is straightforward, and several standard patterns have been described for mapping inheritance trees to tables. However, mapping becomes more problematic when it involves complex, evolving inheritance trees, sparse, dynamic attributes, or associations and aggregations whose requirements and definitions change frequently during development. All of these seem to be inherent, inescapable facts in the development of biological information systems. Here we describe modifications of the basic patterns of object-relational mapping that are being applied to two systems in ongoing collaborations between biomedical investigators and informaticians. In this approach a small set of objects for each entity collaborates to provide the usual required services of an object-relational implementation including query capacity, transaction management, object relationships (associations, aggregation, composition, many-many relations) and persistence functions. This set of objects also allows dynamic attributes for a selected set of entities by merging an entity-attribute-value approach for data storage with the object-relational approach to managing relationships among objects. Templates are used for class generation to allow flexibility and synchronization of schema/object during design evolution, facilitating changing persistence strategies across the whole system for testing and development. The entity-attribute-value details as well as all database access are encapsulated in a persistence layer which would allow change of this layer to a conventional storage model, if the design evolution is stabilized or for performance requirements, with no change to the domain or presentation layers.

Biology↗