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Objectives: Following the Medical Research Council (MRC, 2008) guidelines relating to feasibility studies of complex interventions, stage 1 of this study was an uncontrolled trial investigating recruitment, acceptability of intervention and potential outcome measures for a novel phase 3 Complex Trauma intervention based on Acceptance and Commitment Therapy. Stage 2 investigated barriers to participation in ‘stage 1’ by conducting interviews with the GG&C Psychological Trauma Service clinicians. Methods: Stage 1 – Participants: Eleven participants were recruited from the NHS Greater Glasgow & Clyde Psychological Trauma Service. Nine participants completed baseline assessments. The following measures were used to assess outcome: General Health Questionnaire (12 item version; GHQ-12) and Sense of Coherence – Orientation to Life Questionnaire (13 item version; SoC-13); Acceptance and Action Questionnaire-2nd edition (AAQ-II), Cognitive Fusion Questionnaire (CFQ), and Valuing Questionnaire (8 item version; VQ). The Working Alliance Inventory (short-form revised; WAI-SR) was used to measure therapeutic alliance. Procedure: Participants took part in a novel ACT intervention comprising 4 group sessions and 2 individual sessions. Measures were completed pre-intervention, post-group and on completion of the full intervention. Data Analysis: Clinically significant cut-offs and Reliable Change Indexes (RCIs) were used to investigate clinically significant change. Stage 2 – Participants: Seven of the 14 (50%) GG&C Psychological Trauma Service clinicians were recruited to the study. Procedure: Interviews were conducted with the clinicians to address the recruitment difficulties that emerged in stage 1. Data Analysis: Framework Analysis was used to analyse data from the interviews. Results: Stage 1 – Five (45.5%) of the 11 recruited participants completed the final assessment. One of the 5 (20%) participants showed clinically significant improvement in general mental health. One of 5 (20%) who completed final assessment exhibited clinically significant improvement on levels of cognitive fusion and sense of coherence. Stage 2 – Analysis of the interviews produced 14 ‘robust’ themes, which have provided insight into the recruitment difficulties. Conclusion: Investigating recruitment was one of the key objectives of this feasibility study. It emerged as a substantial barrier and impacted on the extent to which conclusions can be drawn about the acceptability of the ACT intervention or the assessment measures. It is proposed that a more refined feasibility study is developed that addresses such barriers and that will be better equipped to inform larger-scale pilot trials.

In wound healing and tissue repair, the presence of α-smooth muscle actin (α-SMA) containing myofibroblasts leads to wound closure and collagen-rich scar formation. This thesis investigated mechanisms of transforming growth factor-β1 (TGF-β1)-mediated differentiation and the dysfunctions involved in age-associated loss of differentiation. The loss of epidermal growth factor receptor (EGFR) and hyaluronan (HA) production, and diminished interaction of HA with its receptor CD44 (compromising its function) were the principal contributors to aged fibroblast resistance to differentiation. In response to TGF-β1, CD44 relocated to EGFR held in cholesterol-rich membrane-bound lipid rafts. This was HA-dependent, as hyaluronidase or 4-methylumbelliferone treatments restricted CD44 motility and prevented CD44-EGFR co-localisation. Additionally the intracellular signalling cascade was found to be a sequential phosphorylation of extracellular signal regulated kinase 1 & 2 followed by Ca2+/calmodulin kinase II. The activation of both proteins was required for differentiation. Elevated microRNA-7 (miR-7) expression was found in aged fibroblasts. Overexpressing miR-7 in young fibroblasts attenuated the expression of EGFR and inhibited differentiation. When miR-7 was inhibited, EGFR and hyaluronan synthase 2 expression, CD44 membrane motility, and TGF-β1-mediated differentiation in aged fibroblasts were restored. Activation of EGFR drove miR-7 promoter activity and expression in a JAK/STAT1 dependent manner. Treatments of aged fibroblasts with 17β-estradiol (E2) resulted in decreased miR-7 expression and, when TGF-β1 was added, restored the α-SMA-positive phenotype. E2 treatments had no impact on STAT1 phosphorylation; leading to the hypothesis that E2 regulation of inflammatory mediators may be involved. The data demonstrated different points of intervention for the promotion or prevention of TGF-β1-regulated myofibroblast differentiation. The interactions between HA-CD44 and EGFR were crucial elements in the differentiation process and the importance of miR-7 was apparent. The mechanisms shown here may have direct implications for modifying the wound healing response, particularly for developing therapeutic strategies to improve healing in the elderly.

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