Psychosocial outcomes of enhanced external counterpulsation treatment : illness perceptions and psychological wellbeing

The portfolio has three parts: Part 1 is a systematic literature review, in which the theoretical, conceptual and empirical literature relating to the relationship between illness perceptions, mood and quality of life in coronary heart disease populations is reviewed. The results of this study provide support that illness perceptions are related to outcomes across CHD populations and disease progression, however the results do not selectively support one particular model. Recommendations are consistent with cardiac rehabilitation guidelines. Further research should focus on the systemic impact of illness perceptions.Part 2 is divided into two empirical papers:Paper 1 utilises a qualitative methodology to explore refractory angina patients' experiences of undergoing EECP, and their lives before and after the treatment. The study adds to existing literature by proposing that the process of undergoing EECP treatment not only leads to physiological improvement, but also effects psychological pathways, through providing hope, establishing a therapeutic relationship and increasing confidence and self-efficacy to confront positive and challenging health-behaviour changes.Paper 2 utilises a quantitative methodology to explore the relationship between illness perceptions, mood and quality of life in chronic refractory angina patients that have undergone EECP treatment. The current study supports constructs from relevant models; the self-regulatory model, theory of planned behaviour and an adapted version of the fear-avoidance model. A possible model demonstrating the process between illness perceptions and outcomes specific for chronic refractory angina patients is proposed. Future research could focus on concomitant interventions to improve physical and psychological outcomes, for example the Angina Plan could be delivered in conjunction with EECP to establish an integrated, multidisciplinary model of care and service delivery.Part 3 comprises the appendices. This includes a reflective statement and supplementary information relevant to all three papers

Activation of Epidermal Growth Factor Receptor Is Required for NTHi-Induced NF-κB-Dependent Inflammation

Inflammation is a hallmark of many serious human diseases. Nontypeable Haemophilus influenzae (NTHi) is an important human pathogen causing respiratory tract infections in both adults and children. NTHi infections are characterized by inflammation, which is mainly mediated by nuclear transcription factor-kappa B (NF-κB)-dependent production of proinflammatory mediators. Epidermal growth factor receptor (EGFR) has been shown to play important roles in regulating diverse biological processes, including cell growth, differentiation, apoptosis, adhesion, and migration. Its role in regulating NF-κB activation and inflammation, however, remains largely unknown.In the present study, we demonstrate that EGFR plays a vital role in NTHi-induced NF-κB activation and the subsequent induction of proinflammatory mediators in human middle ear epithelial cells and other cell types. Importantly, we found that AG1478, a specific tyrosine kinase inhibitor of EGFR potently inhibited NTHi-induced inflammatory responses in the middle ears and lungs of mice in vivo. Moreover, we found that MKK3/6-p38 and PI3K/Akt signaling pathways are required for mediating EGFR-dependent NF-κB activation and inflammatory responses by NTHi.Here, we provide direct evidence that EGFR plays a critical role in mediating NTHi-induced NF-κB activation and inflammation in vitro and in vivo. Given that EGFR inhibitors have been approved in clinical use for the treatment of cancers, current studies will not only provide novel insights into the molecular mechanisms underlying the regulation of inflammation, but may also lead to the development of novel therapeutic strategies for the treatment of respiratory inflammatory diseases and other inflammatory diseases

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Psychosocial outcomes of enhanced external counterpulsation treatment : illness perceptions and psychological wellbeing

The portfolio has three parts: Part 1 is a systematic literature review, in which the theoretical, conceptual and empirical literature relating to the relationship between illness perceptions, mood and quality of life in coronary heart disease populations is reviewed. The results of this study provide support that illness perceptions are related to outcomes across CHD populations and disease progression, however the results do not selectively support one particular model. Recommendations are consistent with cardiac rehabilitation guidelines. Further research should focus on the systemic impact of illness perceptions. Part 2 is divided into two empirical papers: Paper 1 utilises a qualitative methodology to explore refractory angina patients' experiences of undergoing EECP, and their lives before and after the treatment. The study adds to existing literature by proposing that the process of undergoing EECP treatment not only leads to physiological improvement, but also effects psychological pathways, through providing hope, establishing a therapeutic relationship and increasing confidence and self-efficacy to confront positive and challenging health-behaviour changes. Paper 2 utilises a quantitative methodology to explore the relationship between illness perceptions, mood and quality of life in chronic refractory angina patients that have undergone EECP treatment. The current study supports constructs from relevant models; the self-regulatory model, theory of planned behaviour and an adapted version of the fear-avoidance model. A possible model demonstrating the process between illness perceptions and outcomes specific for chronic refractory angina patients is proposed. Future research could focus on concomitant interventions to improve physical and psychological outcomes, for example the Angina Plan could be delivered in conjunction with EECP to establish an integrated, multidisciplinary model of care and service delivery. Part 3 comprises the appendices. This includes a reflective statement and supplementary information relevant to all three papers

Psychosocial outcomes of enhanced external counterpulsation treatment : illness perceptions and psychological wellbeing

The portfolio has three parts: Part 1 is a systematic literature review, in which the theoretical, conceptual and empirical literature relating to the relationship between illness perceptions, mood and quality of life in coronary heart disease populations is reviewed. The results of this study provide support that illness perceptions are related to outcomes across CHD populations and disease progression, however the results do not selectively support one particular model. Recommendations are consistent with cardiac rehabilitation guidelines. Further research should focus on the systemic impact of illness perceptions. Part 2 is divided into two empirical papers: Paper 1 utilises a qualitative methodology to explore refractory angina patients' experiences of undergoing EECP, and their lives before and after the treatment. The study adds to existing literature by proposing that the process of undergoing EECP treatment not only leads to physiological improvement, but also effects psychological pathways, through providing hope, establishing a therapeutic relationship and increasing confidence and self-efficacy to confront positive and challenging health-behaviour changes. Paper 2 utilises a quantitative methodology to explore the relationship between illness perceptions, mood and quality of life in chronic refractory angina patients that have undergone EECP treatment. The current study supports constructs from relevant models; the self-regulatory model, theory of planned behaviour and an adapted version of the fear-avoidance model. A possible model demonstrating the process between illness perceptions and outcomes specific for chronic refractory angina patients is proposed. Future research could focus on concomitant interventions to improve physical and psychological outcomes, for example the Angina Plan could be delivered in conjunction with EECP to establish an integrated, multidisciplinary model of care and service delivery. Part 3 comprises the appendices. This includes a reflective statement and supplementary information relevant to all three papers.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Inhibitors of TLR8 reduce TNF production from human rheumatoid synovial membrane cultures

The advent of anti-TNF biologicals has been a seminal advance in the treatment of rheumatoid arthritis (RA) and has confirmed the important role of TNF in disease pathogenesis. However, it is unknown what sustains the chronic production of TNF. In this study, we have investigated the anti-inflammatory properties of mianserin, a serotonin receptor antagonist. We discovered mianserin was able to inhibit the endosomal TLRs 3, 7, 8, and 9 in primary human cells and inhibited the spontaneous release of TNF and IL-6 from RA synovial membrane cultures. This suggested a role for these TLRs in production of TNF and IL-6 from RA which was supported by data from chloroquine, an inhibitor of endosomal acidification (a prerequisite for TLRs 3, 7, 8, and 9 activation) which also inhibited production of these cytokines from RA synovial cultures. Only stimulation of TLR 3 or 8 induced TNF from these cultures, indicating that TLR7 and TLR9 were of less consequence in this model. The key observation that indicated the importance of TLR8 was the inhibition of spontaneous TNF production by imiquimod, which we discovered to be an inhibitor of TLR8. Together, these data suggest that TLR8 may play a role in driving TNF production in RA. Because this receptor can be inhibited by small m.w. molecules, it may prove to be an important therapeutic target