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).

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.

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.

Background: Professionalism is the basis of trust in patient-physician relationships; however, there is very limited evidence focusing on attitudes towards professionalism among medical students. Hence, the main aim of our study was to investigate Malaysian medical students' attitudes towards professionalism with specific emphasis on the comparison between pre-clinical and clinical students. Our secondary aim was to compare the differences in perception of medical students in Malaysia (pre-clinical and clinical) with Asian medical students studying in Dublin, IrelandMethods: This study utilized the Professionalism Mini-Evaluation Exercise (P-MEX) instrument which consists of 25 items that represent four skill categories: Doctor-Patient Relationship skills, Reflective skills, Time Management and Inter-Professional Relationship skills. Descriptive statistics were used to describe the demographic information of students and given the ordinal nature of the data, Mann-Whitney U-tests were used.Results: Overall, students have positive attitudes to all the professionalism items with more than 80% of the students agreeing that each of the professionalism attributes is important or very important. There was evidence of a significant difference between Malaysian pre-clinical and clinical students in relation to 'avoiding derogatory language' only (p = 0.015). When comparing between Malaysian and Dublin Asian students, there was a statistically significant difference in relation to 'show interest in patient as a person' (p < 0.003) for clinical students.Conclusion: Our results point to several curriculum implications such as 1) assessing students' attitudes towards professional attributes is essential when developing the professionalism curriculum, 2) integrating more effective clinical modules early in the curriculum and 3) considering geographical and cultural factors when assessing perception towards professional attributes.