Browsing Royal College of Surgeons in Ireland (RCSI) by Title
Now showing items 1-20 of 141
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Activation of complement component 3 is associated with airways disease and pulmonary emphysema in alpha-1 antitrypsin deficiency.Direct binding of complement C3 to AAT was identified in vivo and in vitro. Compared with healthy controls, a breakdown product of C3, C3d, was increased in AATD (0.04 µg/mL vs 1.96 µg/mL, p=0.0002), with a significant correlation between radiographic pulmonary emphysema and plasma levels of C3d (R2=0.37, p=0.001). In vivo, AAT augmentation therapy significantly reduced plasma levels of C3d in comparison to patients not receiving AAT therapy (0.15 µg/mL vs 2.18 µg/mL, respectively, p=0.001).
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Alpha-1 Antitrypsin-A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis.Cystic fibrosis (CF) is an autosomal recessive genetic disorder arising from mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Disruption to normal ion homeostasis in the airway results in impaired mucociliary clearance, leaving the lung more vulnerable to recurrent and chronic bacterial infections. The CF lung endures an excess of neutrophilic inflammation, and whilst neutrophil serine proteases are a crucial part of the innate host defence to infection, a surplus of neutrophil elastase (NE) is understood to create a net destructive effect. Alpha-1 antitrypsin (A1AT) is a key antiprotease in the control of NE protease activity but is ineffective in the CF lung due to the huge imbalance of NE levels. Therapeutic strategies to boost levels of protective antiproteases such as A1AT in the lung remain an attractive research strategy to limit the damage from excess protease activity. microRNAs are small non-coding RNA molecules that bind specific cognate sequences to inhibit expression of target mRNAs. The inhibition of miRNAs which target the SERPINA1 (A1AT-encoding gene) mRNA represents a novel therapeutic approach for CF inflammation. This could involve the delivery of antagomirs that bind and sequester the target miRNA, or target site blockers that bind miRNA recognition elements within the target mRNA to prevent miRNA interaction. Therefore, miRNA targeted therapies offer an alternative strategy to drive endogenous A1AT production and thus supplement the antiprotease shield of the CF lung.
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Application of the intervention Complexity Assessment Tool for Systematic Reviews within a Cochrane review: an illustrative case study.Background: The intervention Complexity Assessment Tool for Systematic Reviews (iCAT_SR) has been developed to facilitate detailed assessments of intervention complexity in systematic reviews. Worked examples of the tool's application are needed to promote its use and refinement. The aim of this case study was to apply the iCAT_SR to a subset of 20 studies included in a Cochrane review of interventions aimed at improving appropriate polypharmacy in older people. Methods: Interventions were assessed independently by two authors using the six core iCAT_SR dimensions: (1) 'Target organisational levels/categories'; (2) 'Target behaviour/actions'; (3) 'Active intervention components'; (4) 'Degree of tailoring'; (5) 'Level of skill required by intervention deliverers'; (6) 'Level of skill required by intervention recipients'. Attempts were made to apply four optional dimensions: 'Interaction between intervention components'; 'Context/setting'; 'Recipient/provider factors'; 'Nature of causal pathway'. Inter-rater reliability was assessed using Cohen's Kappa coefficient. Disagreements were resolved by consensus discussion. The findings are presented narratively. Results: Assessments involving the core iCAT_SR dimensions showed limited consistency in intervention complexity across included studies, even when categorised according to clinical setting. Interventions were delivered across various organisational levels and categories (i.e. healthcare professionals and patients) and typically comprised multiple components. Intermediate skill levels were required by those delivering and receiving the interventions across all studies. A lack of detail in study reports precluded application of the iCAT_SR's optional dimensions. The inter-rater reliability was substantial (Cohen's Kappa = 0.75) Conclusions: This study describes the application of the iCAT_SR to studies included in a Cochrane systematic review. Future intervention studies need to ensure more detailed reporting of interventions, context and the causal pathways underlying intervention effects to allow a more holistic understanding of intervention complexity and facilitate replication in other settings. The experience gained has helped to refine the original guidance document relating to the application of iCAT_SR.
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Cognitive impairment and cardiovascular medication use: Results from wave 1 of The Irish Longitudinal Study on Ageing.To explore the association between cardiovascular medication use and cognitive impairment in adults aged 50 years and over.
