Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are common partners with common problems. Both are chronic systemic disorders incurring significant morbidity and mortality. Although around one third of patients with HF have concurrent COPD,1 remarkably few reports have addressed this often ignored combination. The systematic review presented within this thesis defines the diagnostic challenges, prevalence and prognostic implications of HF with coexistent COPD. I then critically appraise the twin controversies of β-blockade in COPD and β-agonists in HF. The two are inextricably linked, each therapy exerting the reverse pharmacologic activity of the other. The evidence for symptomatic or prognostic benefit from either therapy is limited, and in the case of β-agonists adverse consequences appear more likely. A Cochrane meta-analysis concluded that long term cardioselective β-blockade is safe and well tolerated in patients with moderate to severe or reversible COPD.2 Although often cited,3 these conclusions are simply not true. Of the 20 randomised controlled trials included in the meta-analysis, 11 involved single doses and only one lasted longer than a month. The 9 ‘long term’ studies (defined as more than a single treatment dose) involved 147 young, predominantly male patients with moderate airways obstruction (mean forced expiratory volume in 1 second (FEV1) 1.8 litres). The effect on health status has never been assessed in any cohort with COPD. The long term impact of β-blockade on pulmonary function, symptoms and quality of life is therefore largely unknown. Most importantly, no study has included patients with HF. I randomised 27 patients with HF and coexistent moderate or severe COPD to receive bisoprolol or placebo, titrated to maximum tolerated dose over 4 months. Patients were elderly and predominantly male. Cardiovascular comorbidity, smoking history and pulmonary function were similar in each group (mean FEV1 1.37L vs 1.26L). There were several key findings. A reduction in FEV1 occurred after 4 months following treatment with bisoprolol compared with placebo (–70 ml vs +120 ml, p=0.01). Reversibility following inhaled β2-agonist and static lung volumes were not impaired by bisoprolol. All measures of health status exhibited a consistent non-significant improvement, including the Short Form 36 physical and mental component scores, Minnesota Living with Heart Failure Questionnaire, and Chronic Respiratory Questionnaire. The mean number of COPD exacerbations was similar in the bisoprolol and placebo groups. Although recruitment was limited, the results pose crucial questions and provide direction for larger randomised controlled trials. I analysed cross-sectional data from 61 primary care practices (377,439 patients) participating in the Scottish Continuous Morbidity Recording scheme. The prevalence of COPD in patients with HF increased year on year from 19.8% in 1999 to 23.8% in 2004. These changes may previously have been attributed to an ageing population or increasing age of presentation. However, the trend remained significant after age standardisation. A clear socioeconomic gradient was observed, with prevalence greatest in the most deprived. Consultation rates for HF or COPD in those with both conditions were greater than disease specific contact rates in patients with either condition alone. Cardiovascular comorbidity was similar in HF patients with and without COPD, despite differences in smoking history (respectively 76% vs 47%, p<0.001). This is concerning and suggests that common cardiovascular conditions are being under diagnosed (and likely under treated) in patients with HF and COPD. Although overall β-blocker prescribing increased over time, the adjusted odds of β-blocker prescription in patients with COPD was low (odds ratio 0.30 [95% CI 0.28–0.32], p<0.001). Whether the gap between patients with and without COPD is improving was previously unknown. Despite the overall improvement in beta-blocker prescribing, the relative difference in prescribing between those with and without COPD remained unchanged. By 2004, only 18% of individuals with HF and COPD were prescribed β-blockers. COPD is consistently an independent predictor of death and HF hospitalisation in patients with HF. However, the causes of increased mortality were unclear. I examined the relationship between COPD and cardiovascular outcomes in patients with myocardial infarction (MI) complicated by heart failure, left ventricular systolic dysfunction (LVSD), or both enrolled in the Valsartan in Acute Myocardial Infarction (VALIANT) trial. COPD was an independent predictor of mortality, largely due to increased non-cardiovascular (HR 1.86 [1.43–2.42]) and sudden death (HR 1.26 [1.03–1.53]). However, after multivariate adjustment COPD was not an independent predictor of atherosclerotic events (MI or stroke: HR 0.98 [0.77–1.23]). This is an important finding, as atherosclerotic consequences of chronic systemic inflammation in COPD have been postulated. These appear of limited clinical significance, at least during intermediate follow-up. Part of the adverse risk associated with COPD may be attributable to bronchodilators. The prognosis of patients with HF prescribed bronchodilators is however ill defined. I examined the prognostic implications of bronchodilator use in patients with HF enrolled in the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme. The diversity and magnitude of adverse outcomes associated with bronchodilator therapy was surprising. Bronchodilator use was associated with increased all cause mortality (HR 1.26 [1.09–1.45]), cardiovascular death (HR 1.21 [1.03-1.42]), death due to HF progression (HR 1.40 [1.07-1.82]) and HF hospitalisation (HR 1.49 [1.29-1.72]). Although association is not causation, it is possible that bronchodilators compound maladaptive remodeling and further depress myocardial function. Finally, β-blockers were independently associated with better survival in both VALIANT and CHARM. No significant interaction was observed between either COPD or bronchodilators and β-blockade with respect to mortality. Furthermore, β-blocker use was not associated adversely with any pre-specified outcome in patients with COPD or those prescribed bronchodilators, including non-cardiovascular mortality. Although recruitment bias and the absence of spirometry limit inference to patients with severe or reversible airflow obstruction, the results should encourage β-blockade in patients with COPD. In summary, the studies presented in this thesis extend our understanding of HF with concurrent COPD. Only large randomised controlled trials will solve the quandary of β-blockers and β-agonists. Justification for these trials evolves from observational data and smaller prospective studies such as my own. In the meantime, I hope the evidence presented will stimulate physicians to re-evaluate the management of patients with HF and COPD.

Background: The RSVP (Risk of Sexual Violence Protocol; Hart et al, 2003) is a structured professional judgement tool for assessing risk of sexual violence. Despite being widely used in forensic mental health settings, the reliability and validity of the RSVP has not been adequately established. There is an urgent need to investigate the inter-rater reliability of the tool in a multi-disciplinary clinical context. Method: Clinicians (n=28) with varying professions, levels of experience and training, used the RSVP to evaluate six case vignettes with varying offence characteristics, clinical-complexity and risk. ICC (Intra-class Correlation Coefficient) and percentage agreement statistics were used to evaluate inter-rater reliability of RSVP items, domains and steps. Items included additional forced-choice judgements relating to Scenario Planning and Case Management steps. Clinician responses were also compared to ‘gold-standard’ judgements developed by experts in the field of forensic risk assessment. Results: Inter-rater reliability was ‘fair’ overall with individual items ranging from ‘poor’ to ‘excellent’. Importantly, there was a ‘good’ level of inter-rater reliability on Summary Judgements and Supervision Recommendations. Inter-rater reliability was highest when used by professionals who were highly trained in forensic risk-assessment. On average, professionals with lower levels of specialist training agreed less with their colleagues and experts, and provided higher estimations of sexual violence risk. Lower levels of agreement were found in cases with moderate levels of complexity and risk. Conclusions: The RSVP can be used to attain adequate levels of inter-rater reliability. However this is dependant on the training and expertise of professionals who use the tool. Methodological strengths and limitations are considered, followed by a discussion of implications for training, practice and future research.

Hypertension is a common, highly heritable trait of complex aetiology. Multiple environmental and lifestyle factors contribute to blood pressure variation. Hence the study of hypertension causality is not straightforward. Genetic linkage studies have implicated a number of loci involved in blood pressure regulation and the development of hypertension. Candidate gene association studies, however, have not reported any reproducible associations. Early genome-wide association studies (GWAS) showed remarkable success in identifying validated common variants associated with common diseases such as coronary artery disease and type 1 diabetes. However, the first GWAS of hypertension showed little success. This was largely because of a lack of statistical power and insufficient genomic coverage. Furthermore, it is widely believed that the failure of one GWAS of hypertension was partly due to misclassification of controls that were not phenotyped for blood pressure. Subsequently, two large international consortia-run GWAS of blood pressure as a quantitative trait produced tangible results. The current study is a GWAS of hypertension using an extreme case-control design. It employed intensive phenotyping and extreme case-control definitions to select a sample of individuals from a restricted geographical area of relative homogeneity. The aim was to reduce misclassification bias and increase the likelihood of detecting any genetic effects. Cases were sampled from the Nordic Diltiazem study, and defined as individuals younger than 60 years with at least two consecutive measurements of systolic blood pressure (SBP) ≥ 160 mmHg or diastolic blood pressure (DBP) ≥ 100 mmHg. Controls were sampled from the prospective Malmö Diet and Cancer Study, and defined as individuals aged at least 50 years with SBP ≤ 120 mmHg and DBP ≤ 80 mmHg with no evidence of cardiovascular disease during ten years of follow-up. The groups represent, respectively, the upper 1.7% and lower 9.2% of the Swedish blood pressure distribution. Comparison of groups from the extreme tails of distribution increased statistical power by inflating observed effect sizes. With genome-wide SNP coverage we were able to adjust for population stratification using principal components analysis. Following quality control exclusions, a final set of 521,220 single nucleotide polymorphisms was available for analysis in 1,621 cases and 1,699 controls. Seventeen SNPs were associated with hypertension at a P < 1 × 10-5 threshold of significance, of which three attained genome-wide significance, defined as P < 5 × 10-7. The top hit, rs13333226, underwent a two stage validation process in a total of 14 independent cohorts. The combined odds ratio for the discovery cohort and all replication cohorts meta-analysed was 0.87 (95% CI 0.84 – 0.91, P = 3.67 × 10-11) with the minor G allele associated with a lower risk of hypertension. In total 21,466 cases and 18,240 controls were included. After adjustment for age, age2, sex, and BMI, and when the discovery cohort was excluded from analysis, the association remained significant. Estimated glomerular filtration rate (eGFR), a measure of kidney function, was available in seven of the cohorts. When the analysis was repeated with adjustment for eGFR the effect was marginally strengthened. rs13333226 is located in close proximity, at -1617 base pairs, to the uromodulin (UMOD) transcription start site. UMOD encodes uromodulin, also known as the Tamm-Horsfall protein. Uromodulin is produced predominantly in the thick ascending limb of the loop of Henle and is the most abundant protein in urine. Its function is unclear; however, variants in UMOD have been associated with chronic kidney disease. Clinical functional studies were conducted in three separate populations. The minor G allele of rs13333226 (associated with a lower risk of hypertension) was associated with lower urinary uromodulin excretion. Furthermore, in one sample following a low salt diet urinary uromodulin excretion was significantly lower in the presence of the G allele, whereas after a high salt diet genotype was no longer associated with urinary uromodulin. If this were verified, this would entail a gene-environment interaction. Our combined results suggest that UMOD may have a role in regulating blood pressure, possibly through an effect on sodium homeostasis. There is ample evidence of a strong, graded relationship between blood pressure and subsequent renal disease. Hence the current finding is biologically plausible. Information on kidney disease was not available for the discovery samples so this could not be explored. However, the association between rs13333226 and hypertension was not substantively altered by adjustment for eGFR in the seven validation cohorts in which it was recorded, suggesting that it is independent of renal function. In conclusion, we have performed a GWAS of hypertension using an extreme case-control design. The most significant hit was validated in a meta-analysis of the discovery sample and 14 additional cohorts. Moreover, functional studies showed a relationship between genotype and urinary protein excretion. Overall, we demonstrate that with careful methodological planning and phenotyping it is possible to generate replicable hypertension GWAS results in a relatively small sample size.

The present thesis describes the impact of glycaemic index of high carbohydrate diets consumed for 5 days on exercise energy metabolism and capacity and fasting plasma lipids in healthy physically active individuals. The thesis consists of a literature review (Chapter 1), general methods (Chapter 2), four experimental chapters (Chapter 3-Chapter 6) and general discussion and conclusion (Chapter 7). Chapter 3 presents a pilot study aimed to investigate whether high carbohydrate meals with high and low glycaemic index of foods present within meals developed by using the glycaemic index values from the published glycaemic index tables, produce significant differences in postprandial glucose response. Eight healthy active women consumed prescribed high carbohydrate diets with either high or low glycaemic index in a randomised counterbalanced order. The experimental meals which consisted of breakfast, morning snack and lunch were consumed after an overnight fast. Plasma glucose responses were measured at baseline and every 30 minutes for 300 minutes after baseline. We concluded that high carbohydrate meals with high and low glycaemic index prescribed using the glycaemic index values from the existing glycaemic index tables in the literature produced a significant difference in postprandial plasma glucose responses. Thus, for further studies high carbohydrate diets with high and low glycaemic index were developed using glycaemic index values from available glycaemic index tables. The aim of Chapter 4 and Chapter 5 was to investigate the extent to which the glycaemic index of high carbohydrate diets consumed for 5 days reduces the rate of fat oxidation during endurance exercise and exercise capacity during running conducted in the fasted state in men and women. To determine this, 9 healthy physically active men (Chapter 4) and 9 healthy physically active women (Chapter 5) performed three treadmill runs to exhaustion at 65% max after their habitual diet, after 5 days on a high carbohydrate high glycaemic index diet, and after 5 days on high carbohydrate low glycaemic index diet, in a randomised counterbalanced order. Blood samples for the measurements of glucose, insulin, glycerol and non-esterified fatty acids, and expired air samples for the measurements of the rates of fat and carbohydrate oxidation were obtained at 15, 30, 45, 60, 75, 90 minutes and at the point of exhaustion. Running capacity was measured as time to exhaustion and distance covered. It was found that in both men and women, the extent to which high carbohydrate diets consumed for 5 days reduced the rate of fat oxidation during running in the fasted state was not influenced by the glycaemic index of the diet, and that glycaemic index of high carbohydrate diets consumed for 5 days had no impact on running capacity. Chapter 6 aimed to investigate the impact of the consumption of high carbohydrate diets with high and low glycaemic index for 5 days on fasting plasma concentration of lipids, insulin sensitivity and biomarkers for endothelial function (i.e. intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) in physically active individuals. Fasting blood was collected from 17 healthy individuals on three occasions in a randomised counterbalanced order: after consuming habitual diet, after 5 days on high carbohydrate high glycaemic index diet and after 5 days on high carbohydrate low glycaemic index diet. It was found that the extent to which high carbohydrate diets consumed for 5 days increases fasting plasma concentration of triglyceride and reduces the concentration of high density lipoprotein cholesterol was not influenced by the glycaemic index of the diets. It was also found that glycaemic index of high carbohydrate diets consumed for 5 days had no impact on insulin sensitivity or on biomarkers of endothelial activation. In conclusion, consideration of the glycaemic index of high carbohydrate diets consumed by physically active healthy men and women for 5 days has no impact on insulin sensitivity and fasting concentration of plasma lipids, it does not influence the rate of fat oxidation induced by high carbohydrate diets during running conducted in the fasted state and has no influence on running capacity. Thus, when physically active individuals increase carbohydrate intake for the purposes of muscle glycogen accumulation, consideration of the glycaemic index is not important. Future studies are needed to determine whether the glycaemic index of high carbohydrate diets modify exercise energy metabolisms in top grade athletes.

Introduction: While many studies on rheumatoid arthritis have focused on the active phase of the disease, the events that lead to the development of autoimmunity remain poorly defined. We have developed a model of breach of self tolerance, where a Th1 response to irrelevant antigen (OVA) results in arthropathy associated with spontaneous induction of autoreactive T and B cell responses, which allows the investigation of the immnologival events that lead to the development of autoreactivity. Employing this model the role of Th17 cells, a a subset of IL-17 producing CD4+ T important in autoimmunity, was investigated in the development of autoimmunity. In addition, the relative ability of Th1 and Th17 polarised populations in supporting B cell responses was analysed. Finally, in this thesis the role of sterile damage regulation in the development of autoimmunity was assesed, by investigating the role of Siglec-G, a molecule involved in DAMP-signalling regulation, in this process. Results: Transfer of OVA specific Th17 cells induced similar levels of inflammation as Th1 cells, and could induce a breach of self tolerance as demonstrated by CII specific T and B cell responses. While the CII specific T cells in the Th1 recipients produced IFNγ and not IL-17, surprisingly the CII T cell responses in the Th17 recipients were predominantly IFNγ producers. Whereas the transferred OVA specific Th1 population retained its phenotype, the transferred Th17 population displayed significantly reduced IL-17 production. However, cells polarised under Th17 conditions expanded in a higher degree and persisted for longer time in response to immunisation. This resulted in a higher ability of Th17 polarised population in supporting B cell responses. Finally in this thesis, preliminaty data for a role of Siglec-G in the development of autoimmunity were presented, as Siglec-G deficient mice were protected from the development of autoreactive B cell responses. Conclusion: The results of this thesis suggest that the developing autoimmuniy in both Th1 and Th17 models is mediated by Th1 cells. These studies highlight the plasticity of transferred cell populations in vivo, and support the use of blocking and fate-mapping studies to definitively address how auto-reactive responses develop.

The principal aim of this research was the development of a technique (based upon the effects of nanoscale topography) that facilitates the in vitro expansion of bone graft for subsequent implantation. Nanoscale topography increases the bioactivity of a material and stimulates specific responses at the molecular level (third generation biomaterial properties). Nanoscale topography thus confers these third generation properties upon biomaterials that are otherwise first generation (bioinert) or second generation (bioresorbable or bioactive) in nature. Two topographies (nanopits and nanoislands) were embossed into the clinically licensed bioresorbable polymer Polycaprolactone (PCL). A protocol was developed which enabled three dimensional cell culture using double-sided embossing of substrates, seeding of both sides, and vertical positioning of the substrates during cell culture. Human bone marrow was harvested and the mononuclear cell fraction culture expanded. These human bone marrow cells (HBMCs) were used for cellular analysis of substrate bioactivity. In addition, acellular analysis of substrate patterning and degradation was also performed. The osteogenic behaviour (and cell line specificity) was demonstrated using alizarin red staining, immunohistochemistry, real-time polymerase chain reaction (rtPCR), and quantitative PCR (qPCR). The osteogenicity of PCL was increased by the presence of nanotopography, and by the incorporation of hydroxyapatite (HA) into the PCL forming a hydroxyapatite-PCL composite (HAPCL). The performance of these substrates was compared to exposure to bone morphogenic protein 2 (BMP2), and the use of osteogenic media. The protocol from shim production to bone marrow harvesting and vertical cell culture on nanoembossed PCL has been shown to be reproducible and potentially applicable to economical larger scale production.

Background: Diabetes mellitus type 1 (DM1) is the most common form of diabetes in children. Strict glycaemic control can increase the risk of hypoglycaemia, which is characterised by a number of unpleasant and often frightening symptoms. Fear of Hypoglycaemia (FOH) is thought to contribute to psychological distress and diabetes management, however little is known about parents’ experiences of FOH. The aim of this study was to explore parents’ experience of FOH and its impact on their engagement with intensive insulin therapy. Methods: This qualitative study was conducted and analysed utilising an Interpretative Phenomenological Analysis (IPA) approach. Purposive, volunteer sampling was used. Semi-structured interviews were conducted with 4 parents in the hospital setting. These were transcribed and analysed. Results: The results of this study suggest that FOH is a very salient topic for parents of children with DM1. Four super-ordinate themes emerged: parents’ internal experience, coping, family unit and school. FOH appears to be characterised by a range of emotional and psychological symptoms. Parents attempt to manage the condition and their experiences through a combination of emotion-focused and problem-focused coping strategies. The systemic challenges of diabetes and FOH were highlighted by parents’ worries about their child’s safety when under the care of others and the burden that this places on them.

Milner and Goodale (1995, 2006) propose a model of vision that makes a distinction between ‘vision for perception’ and ‘vision for action’. Regarding hemispatial neglect, they, somewhat contentiously, hypothesize that this disorder is better explained by damage to a high-level representational structure that receives input from the ventral visual stream, but not from the dorsal-stream. Consequently, they postulate that neglect patients should code spatial parameters for action veridically. Another strong claim of the model is that the dorsal stream’s control of action is designed for dealing with target stimuli in the ‘here and now’, yet when time is allowed to pass and a reaction has to be made on the basis of a visual memory, the ventral stream is required for successful performance. One prediction from this is that neglect patients should be able to perform immediate actions, but should present specific impairments when the action is delayed. In Part I of this thesis the pattern of spared and impaired visuomotor abilities in patients with neglect, as specifically predicted by the perception and action model (Milner & Goodale, 1995, 2006), was investigated. In Chapter 1, the performance of patients with and without neglect after right hemisphere stroke was compared with that of age-matched controls. Participants were asked to point either directly towards targets or halfway between two stimuli (gap bisection), both with and without visual feedback during movement. No neglect-specific impairment was found in timing, accuracy or reach trajectory measures in either pointing or gap bisection. In Chapter 2, I tested whether neglect patients would be unimpaired in immediate pointing, yet show inaccurate pointing in a condition where a delay is interposed between the presentation of the stimulus and the response signal. Similarly to Chapter 1, it was found that neglect patients showed no accuracy impairments when asked to perform an immediate action. Conversely, when pointing towards remembered leftward locations they presented specific accuracy deficits that correlated with neglect severity. Moreover, an initial voxel-based lesion-symptom analysis further revealed that these deficits were associated with damage to occipito-temporal areas which were also mostly damaged in the neglect group. Furthermore, training of grasping the centre of rods (visuomotor feedback training) has been shown to improve neglect (Robertson, Nico & Hood, 1997; Harvey et al., 2003). It is postulated that by using the spared visuomotor abilities in these patients it is possible to ‘bootstrap’ their perceptual deficits through some ‘dorsal-to-ventral recalibration’. Hence, in Part II the immediate and long-term effects of visuomotor feedback training were explored on neglect conventional measures, as well as in daily life tasks. I found that this technique improves neglect symptoms and crucially that these improvements were long lasting, as they were present even after 4-months post-training. Importantly, I also show that the training effects generalize to the patient’s daily lives at follow-up. These findings are very encouraging for the rehabilitation of neglect as this condition has been shown to be the best single predictor of poor recovery after stroke and very difficult to treat.

Abstract The detection of pathogen-associated molecules by Toll-like receptors (TLRs) is instrumental to the induction and regulation of an inflammatory response. However, prolonged or inappropriate stimulation of TLRs is associated with disease. A family of molecules coded for by the ST2 gene have been implicated as negative regulators of TLR4-signalling in murine cells. Here, the existence and potential role of these ST2 molecules in human macrophages has been investigated. Following the discovery of IL-33 as a ligand for ST2, the effect of this ligand on human macrophages was explored. We found elevated levels of the soluble form of ST2 (sST2) in the synovial fluid (SF) of patients with inflammatory forms of arthritis compared to amount in SF from people diagnosed with a less inflammatory form of arthritis. First confirming that human macrophages express the trans-membrane version of ST2 known as ST2L, we showed these cells respond to a recombinant form of the IL-33 ligand by inducing the release of inflammatory chemokines but not cytokines. The migration of inflammatory cells into inflamed tissue is influenced by their recognition of chemokines. The expression of receptors for these chemokines, the so called chemokine receptors (CCRs) is therefore pivotal in the recruitment of leukocytes into inflamed tissues. The regulation of the CCRs by TLR agonists has recently emerged as a fundamental axis in regulating inflammation. Whilst the local administration of TLR-ligands paradoxically increases leukocyte recruitment to sites of inflammation (thereby exacerbating it), in contrast, low, systemic doses of TLR-ligand have been found to be anti-inflammatory. The work of the second part of this thesis has reinforced the concept that the attenuation of inflammation by systemically-delivered TLR-agonists is due to a reduced migration of leukocytes into sites of inflammation. By adoptively transferring an equal number of discretely labelled cells from WT- and TLR2-KO- mice into WT mice with an existing inflammation, we were able to show that systemic administration of a TLR2 agonist caused a reduction in the number of transferred WT- but not TLR2-KO- cells migrating into the site inflammation. Consistent with this, more WT- than TLR2-KO-cells were detected in the lymph nodes of TLR2 agonist-, but not control- treated mice. For the first time the anti-inflammatory effect of TLR ligands has been shown to work in a cell autonomous manner, i.e. the migratory cells need to detect the TLR ligand directly for their migratory capacity to be diminished.

This study explored the experience of patients with generalized anxiety disorder (GAD) undertaking a six week intervention of a Zen meditation programme in Taiwan. Mix-methods were used including the Revised State and Trait Anxiety Inventory (RSTAI), repeated focus groups, individual interviews, diaries and field notes. Heidegger’s interpretative phenomenology was adopted as a theoretical framework. Two groups of 9 and 12 patients (n=21) participated in the study. Three themes emerged from repeated focus groups: First ‘Expectation of Zen meditation regarding GAD symptoms included sub themes of ‘ambivalence towards meditation’, ‘crave a good sleep’, ‘stop thinking’ and ‘regain memory and concentration’. The second theme, ‘The process of Zen meditation’ included the sub themes of ‘struggling to reach a state of calm’, ‘signs of improvement’ and ‘an individual process’. The last theme, ‘The cultural beliefs regarding Zen meditation in Taiwan’ involved the ‘spiritual influence’ of Zen meditation practice. Four themes emerged from individual interviews. Firstly, ‘Separation’ referred to the issues that participants faced in dealing with the termination of the programme, including ‘concern about other participants’ and ‘examining the relationship between Zen meditation and self’. The second theme ‘Body experience of Zen meditation practice’ incorporated ‘body awareness’ and ‘preparing to practise Zen meditation’. The third theme, ‘States of mind while meditating’ consisted of ‘the state of engagement with real life’, ‘the state of detachment from real life’ and ‘the state of calm’. Lastly, ‘Benefits of Zen meditation practice’ incorporated the categories ‘less pressure with daily life’ and ‘more acceptance of being a GAD patient’. The RSTAI was administrated at baseline and post intervention and also at the two week follow-up of the Zen meditation programme. Neither the Trait Anxiety Score nor the State Anxiety Score showed significant differences between Groups 1 and 2 at baseline. This allowed the RSTAI data from the 2 groups to be merged.The results of 95% confidence interval for differences of both groups showed a significant improvement in the Trait Anxiety Score over time but not the State Anxiety Score. This study contributes to the existing body of knowledge and associated literature regarding Zen meditation and GAD in three ways. Firstly, the findings confirmed that the essential or authentic traditional qualities of meditation should be addressed in meditation study. Secondly, the meaning of Zen meditation for the groups of GAD patients was revealed in the context of Taiwan society. How their lived experience of GAD shaped their understanding of Zen meditation was interpreted. Thirdly, a comprehensive understanding of Zen meditation is reported. The findings (including themes, i.e. diverse Zen meditation processes, body experiences, concepts of obstacles and spiritual influence) add to the current knowledge by providing insight derived from participants’ lived experiences.