Antisense oligonucleotide therapy is one of the most promising strategies for treatment of myotonic dystrophy type 1 (DM1), type 2 (DM2) and Duchene muscular dystrophy (DMD). These three diseases have nuclear retained mRNA, suitable for antisense therapy targeting. The delivery of oligonucleotides to their desired target has long been an obstacle in antisense therapy with a large number of delivery reagents or methods having adverse side effects. Promising work published detailing the successful delivery of various chemically modified oligonucleotides (CMOs) naked, via gymnosis, led to us investigating a number of these CMOs: deoxyribonucleic acids (DNA), Peptide nucleic acids (PNAs), 2’OMethyl (2’OMe), and Phosphorodiamidate morpholino (PMO) oligonucleotides. In DM1 expanded CUG repeat (CUGexp) mRNAs aggregate in the nucleus forming “foci”. Testing the CMOs effectiveness at disrupting nuclear foci in a cell based assay, using high content imaging to visualise the number, size and intensity of foci we initially discovered that PNA and 2’OMe, were seemingly taken up via gymnosis by DM1 cells, and removed nuclear foci at nanomolar concentrations. However further experimentation using live cell imaging indicated that although all CMOs could enter the cell, in all disease models tested, via gymnosis, the CMOs could not penetrate the nuclear membrane. In depth analysis led us to identify an artefact of the in-situ process used to identify these foci, explaining earlier positive results. As the target mRNA is trapped within the nuclear compartment we investigated several transfection reagents for their ability to deliver 2’OMe oligonucleotides to the nucleus using live cell fluorescent imaging and a modified northern blot based method. It was established that polyethylenimine could successfully deliver 2’OMe oligonucleotides to the cell, with a high abundance of the oligonucleotide residing within the nuclear compartment. It was observed that PEI degrades the expanded nuclear retained repeat in the DMPK transcript of a DM1 patient cell line alone, without the addition of an antisense agent, in a concentration dependent manner.

The ability to accurately perceive and respond to our visual environment is critical for optimising primate behaviour. A number of related cognitive functions, such as visual learning and longer-term memory, also depend upon an accurate percept of objects and their location within the visual environment. Understanding how the healthy brain supports higher-order visual perception is, therefore, a key goal for cognitive neuroscientist. A substantial body of research involving both humans and animals highlights a role for regions within the extrastriate cortex in visual perception, with many of these regions apparently exhibiting a high degree of functional specialisation for the processing of particular categories of complex stimuli (e.g. faces versus scenes). More recently, studies have found that patients with damage to structures within the medial temporal lobe, such as the hippocampus and perirhinal cortex, can also present with impairments in higher-level perception. More specifically, damage to perirhinal cortex has been linked to impairments in perception for complex objects and faces, whereas hippocampal damage has been linked to impairments in scene perception. Multiple regions distributed across the extrastriate cortex and medial temporal lobe may make individual category-sensitive contributions to visual perception, but it remains unclear how these regions interact with one another, and to what extent their ability to interact underpins successful visual perception. These issues are addressed here via a series of novel experiments involving a combination of behavioural paradigms and magnetic resonance imaging techniques in healthy human participants. These experiments aim to: a) investigate the functional and structural connections that support the category-sensitive contributions of the perirhinal cortex and hippocampus to higher-level visual perception; b) demonstrate that inter-individual variation in the structural properties of white matter pathways providing inputs/outputs to the perirhinal cortex or hippocampus is an important factor underpinning the contributions of these regions to successful higher-level perceptions.

Aims: Peer support has been incorporated into clinical and national stroke guidelines as an important component of community rehabilitation, yet there is a paucity of research in this area. This study aimed to evaluate the efficacy of a community-based stroke peer support intervention for survivors and carers. Design: Stroke survivors and carers (n=47) were randomly assigned to either a five-week peer support group intervention or a waiting-list comparison condition. Mixed multivariate (MANCOVA) and univariate (ANCOVA / ANOVA) analyses were used to compare mean scores over time on a range of self-report measures. Additionally, mediation analysis was used to explore the processes underlying peer support. Method: All participants completed measures of psychological distress (GHQ-30), perceived social support (Multidimensional Scale of Perceived Social Support), quality of life (EQ-5D-3L) and activities of daily living (Barthel Index). Intervention group participants completed a group process questionnaire (TFI-19). Assessments were completed at baseline, post-intervention (five-weeks) and at follow-up (four-weeks). Due to significant differences between the two groups on the Barthel Index at baseline, these scores were added as a covariate in the MANCOVA and follow-up ANCOVAs used in analysis with the outcome variables (i.e. GHQ-30 and EQ-5D-3L). Results: Participants in the peer support intervention group reported decreased psychological distress and increased perceived social support and quality of life over time. These changes were significantly greater when compared to the control group, over the same time period. Perceived social support was found to mediate the relationship between group condition and psychological distress. Conclusions: Peer support can facilitate improvements in psychosocial wellbeing for stroke survivors and carers. Social support was found to be an important mechanism underlying peer support. Theoretical and clinical implications of peer support in stroke are discussed and recommendations for future research are outlined.

This thesis broadly explores evidence-based practice (EBP) in mental health, with a particular focus on dissemination and implementation of research evidence regarding family intervention in psychosis. Chapter one comprises a review of evidence-based practice in mental health, including the uptake of evidence-based practice, the effects of training, research dissemination and implementation strategies. A brief narrative review is presented followed by a systematic review examining uptake of evidence-based therapies by mental health practitioners. Eleven papers were selected for review and were measured against the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines (von Elm, Altman, Egger, Pocock, Gøtzsche & Vandenbroucke, 2007). Following this, conclusions regarding the current evidence and areas which need to be developed are discussed, primarily the need for standardised measures, an indication of clinical change and provision of follow-up studies. Chapter Two comprises an empirical paper intended to be submitted to the journal ‘Implementation Science’. The aim was to address some of the issues identified in Chapter One, namely the use of standardised measures and the measure of a change in clinical practice. Mixed methods were used to assess attitudes to EBP in Trainee Clinical Psychologists and the effect that different dissemination methods had on their attitudes to a specific facet of EBP, family interventions in psychosis. A total of 104 trainee clinical psychologists from 23 UK training programmes participated in the online study, and were randomly allocated to one of four conditions. i. ‘Minimal information’: Participants viewed a brief summary of a fictitious service-user with psychosis, this served as the baseline condition. ii. ‘Case study’: Participants viewed a detailed case study describing the use of family interventions with a fictitious service-user with psychosis iii. ‘Research summary’: Participants viewed a detailed research summary showing research into the effectiveness of family interventions in psychosis iv. ‘Combined’, participants viewed both the case study and research summary Following this, participants completed a survey of their experience with different therapies and demographic information and a standardised measure of attitudes to EBP. Participants then viewed the minimal information about the fictitious client, followed by the summary specified in the condition they were allocated to. Participants then completed a questionnaire designed to assess their attitudes to family intervention in psychosis and their willingness to engage in further training. Responses to these served as the dependent variables. Participants were also given the opportunity to give their own views on the use of family interventions in clinical practice. Data were analysed using MANOVA and multiple regression, with thematic analysis (Braun & Clarke, 2006) employed for the qualitative data. Participants who viewed both case and research information showed a greater willingness to train than those who viewed research information alone. Chapter Three, the concluding section, consists of a general discussion of the research, focusing on the findings and their relation to previous findings in the area, the implications of the findings for research and clinical training and practice, as well as strengths and limitations of the research. The main limitations identified were the lack of a follow-up and the suitability of willingness to train as a measure in trainee clinical psychologists. Recommendations for future research in this area are made. Following the general discussion section a proposal for a follow-on study, extending the current study and improving the methodology is presented. Lastly, the research is presented in the form of a report intended for submission to ‘Clinical Psychology Forum’.

Introduction: Glucose-regulated protein 78-kDa (GRP78) is an endoplasmic reticulum (ER)-resident molecular chaperone that is essential for correct protein folding and assembly in the ER lumen. Micro-environmental stress and a requirement for increased protein synthesis, typical of solid tumours, leads to a disruption of ER homeostasis, and accumulation of misfolded proteins. The ability of GRP78 to dissociate from several important ER-resident transmembrane proteins under conditions of ER stress leads to a cascade of signal transduction pathways, known as the unfolded protein response (UPR), that modulate cell survival or, if the stress is significantly severe, apoptosis. GRP78 has been found to be overexpressed in a variety of cancers compared with benign tissue and has been associated with poor outcome. In-vitro data indicate that GRP78 expression is often associated with aggressive phenotype and drug resistance. Thus, GRP78 has potential as a biomarker for tumour behaviour and treatment response. For stage III colorectal cancer, there is overwhelming evidence to recommend the use of fluoropyrimidine-based adjuvant chemotherapy. Unfortunately, a large proportion of patients do not benefit from adjuvant chemotherapy, and biomarkers that can determine the likelihood of response to chemotherapy remain elusive. The benefit of chemotherapy in stage II disease is less certain and markers that could reliably predict benefit would be particularly useful in this population. This study explores a potential mechanistic relationship between GRP78 and 5-FU sensitivity using both siRNA transfection and treatment with an engineered fusion protein, epidermal growth factor (EGF)-SubA, which has been demonstrated to cause highly selective cleavage of GRP78 at a single amino acid point. It was then examined whether GRP78 may have prognostic or predictive value in the context of colorectal cancer patients treated with fluoropyrimidine-based chemotherapy. The potential therapeutic value of targeting GRP78 in vitro using EGF-SubA is also examined. Methods: Colon cancer cell lines were used to examine response to 5-FU upon modulation of endogenous GRP78 using siRNA technology and EGF-SubA. Apoptosis and cell cycle progression were assessed using flow cytometry. Immunohistochemistry was used to characterise GRP78 expression in a large cohort of colorectal cancers on tissue microarrays and the results were correlated with clinicopathological parameters and with 5-year survival for the whole cohort and those treated with fluoropyrimidine-based (5-FU) adjuvant chemotherapy. The action of EGF-SubA upon colon cancer cells was examined using western blotting, MTT assay and flow cytometry. Results: GRP78 promotes apoptosis in response to 5-FU. Better overall 5-year survival was associated with high GRP78 expression (P=0.036). Stage III patients with high GRP78 showed significant benefit from adjuvant chemotherapy (P=0.026), whereas patients with low GRP78 failed to benefit (P=0.805). Low GRP78 was an independent poor prognostic indicator of overall 5-year survival (P=0.005; HR=1.536; 95%CI 1.139-2.122). Colon cancer cells expressing EGFR were highly sensitive to EGF-SubA, demonstrating reduced proliferation and cell cycle arrest. However, EGF-SubA did not induce significant apoptosis and reduced the effectiveness of 5-FU in vitro. Conclusion: This study demonstrates a mechanistic relationship between GRP78 expression and response to 5-FU. GRP78 expression may provide a useful additional risk stratification to inform the adjuvant treatment of colorectal cancer. EGF-SubA does not have therapeutic value in colorectal cancer but is a useful tool for studying GRP78 and the UPR.

Objective: To develop a current understanding of the differences in how physicians communicate with Black and Minority Ethnic (BME) patients in comparison to non-BME patients. Methods: Systematic searches of electronic databases and references lists were performed. Data from the included studies were extracted in line with the review’s aims, and the studies’ quality was assessed using a standardised criteria. Results: Sixteen studies were included. The results indicated that physicians communicated differently with BME patients compared to non-BME patients as a consequence of patients’ race. Physicians were found to show less participative and affective behaviours towards BME patients and black patients received more information giving behaviours than other ethnicities. Additionally, BME patients displayed less conversational behaviours in comparison to non-BME patients. Studies have also begun to relate other culture related variables to communication but their relationship was less established. Conclusion: While physicians’ communication behaviours varied across patients’ race, there still continues to remain a gap in relation to the literature base being able to sufficiently explain, (a) how race exerts its effect on physician communication and (b) what other variables can account for the differences in physicians’ communication. This gap may reflect the complexity of communication and the measures used. The review firstly reinforces the need for a diverse workforce and the necessity to incorporate affective dimensions of communication in physicians’ cultural communication training, and secondly, calls for future research to expand explanations beyond patients’ race.

Epilepsy is a chronic neurological disorder which can arise following an initial insult that over time, progresses into a condition characterised by recurrent spontaneous seizures. During a latent period between the initial insult and the epilepsy condition proper, major changes occur within the brain at both a cellular and molecular level, in a process known as epileptogenesis. It is postulated that during epileptogenesis, signal transduction pathways are perturbed following the initial insult, which may bring about long term changes in gene expression profiles. For example, the expression of a host of neuropeptides is known to be modulated in response to an initial insult, including the up-regulation of the pro-convulsant tachykinins Substance P and Neurokinin B, encoded by the TAC1 and TAC3 genes, respectively. In this thesis I have explored the regulation of both of these genes by two distinct transcription factor (TF) families; the Neuron Restrictive Silencing Factor (NRSF) isoforms, and the Upstream Stimulatory Factor (USF) proteins. I demonstrate that both NRSF and USF variants regulate TAC3 promoter activity, and that NRSF isoforms can modulate endogenous NKB expression in a human neuroblastoma cell line. Furthermore, these distinct TF families are shown to work in cooperation to regulate the activity of the rat TAC1 promoter. Thus, both NRSF and USF variants are shown to be important in the regulation of pro-convulsant neuropeptides and as both NRSF and USF proteins have been shown to be induced by pro-convulsant stresses here, they are potential key TFs in epileptogenesis, responding to an initial insult, and orchestrating downstream gene expression changes. Consistent with such a model, I have also revealed that both NRSF and USF variants are modulated by anti-convulsant drug treatment. Here, three distinct anti-convulsant drugs, were found to differentially modulate the expression of both the full-length NRSF, and its truncated isoform, as well as the USF proteins USF1 and USF2. Furthermore, whilst the drugs had limited impact upon the localisation of these TFs in human neuroblastoma cells, they did affect the binding of these TFs to target DNA sequences, particularly NRSF binding to its recognition DNA sequence, the NRSE, in a number of genes. In addition, due to an increasingly appreciation of the role of cocaine and the dopaminergic pathways in seizure progression, I explored the impact of cocaine treatment on the expression of these TFs. Cocaine was found to modulate both NRSF and USF variant expression, and NRSF binding to target DNA sequences. These findings suggest that both NRSF and USF variants are important in epileptogenesis and are targets for modulation by the anti-convulsant drugs investigated here. To further explore the significance of NRSF expression in seizure progression, I explored the impact of over-expression of NRSF isoforms, modelling that which occurs in response to seizure in animal models, on global gene expression pathways. I reveal that NRSF isoform over-expression significantly modulates the expression of a host of genes with known associations with epilepsy, supporting a model that NRSF isoforms are key TFs which respond to the initial insult and coordinate long-term changes in gene expression. These findings may help our understanding of the molecular mechanisms at work during epileptogenesis, and may better our understanding of the progression of epilepsy.

Theory and research in the field of persecutory beliefs have identified a number of important psychological processes involved in clinical and non-clinical paranoia. This dissertation set out to investigate some of these processes. Firstly, the empirical evidence for the distinction of 'Poor Me' and 'Bad Me' paranoia (Trower & Chadwick, 1995) was reviewed systematically. Secondly, an empirical study with two phases aimed to investigate the contribution of key processes to paranoia in clinical and non-clinical samples. Investigated factors were: anxiety, depression, anger, attachment anxiety, attachment avoidance, deservedness, submissiveness, self-attacking, self-compassion and experiential avoidance. The review found the distinction of 'Poor Me' and 'Bad Me' paranoia to have some validity and clinical usefulness; however, as yet not all of the theoretical predictions have been borne out in the empirical literature. The importance of the role of deservedness and its measurement was discussed. A series of one-way ANCOVAs found levels of a number of processes to distinguish clinical and non-clinical paranoid groups. Hierarchical regression revealed experiential avoidance to be a significant predictor of paranoia in the final model. A concluding section synthesised these findings and consideration was given to future directions.

Reports of posttraumatic growth can sometimes be illusory. Several researchers have argued that reports of posttraumatic growth may incorporate two separate phenomena, namely real posttraumatic growth and illusory posttraumatic growth. However, it is not often made explicit which kinds of illusions indicate illusory posttraumatic growth. An explicit conceptualisation of illusory posttraumatic growth is, however, necessary in order to investigate the research questions within this thesis, namely (a) whether reports of posttraumatic growth are correlated with illusions and (b) whether real posttraumatic growth and illusory posttraumatic growth differ in their correlation with well-being. Within the thesis, it was, therefore, primarily suggested that defensiveness could be responsible for illusory posttraumatic growth. The assumption was that high levels of maladaptive defensiveness may be used when distress cannot be endured. Internal and external experiences could then be pushed away. This case could potentially indicate illusory posttraumatic growth. In contrast, people who use low levels of maladaptive defences or high levels of mature defences may be able to endure the distress following a trauma or adversity. Internal and external experiences may be processed and accommodated. This case could potentially indicate real posttraumatic growth. The assumptions about illusions were tested within the thesis. It was investigated which kind of illusions could be adaptive psychological operations and which illusions could be maladaptive psychological operations. The results supported the assumptions within this thesis concerning adaptive versus maladaptive illusions. Within three studies, self-reported posttraumatic growth was significantly correlated with a neurotic defence style. It was concluded that this correlation could indicate that sometimes reports of posttraumatic growth are not real. However, other interpretations were also discussed. Four studies investigated whether real posttraumatic growth and illusory posttraumatic growth differ in their correlation with well-being. Within chapter 5, real posttraumatic growth, indicated by low levels of a neurotic or an immature defence style, was correlated positively with negative change following adversity (non significant). In contrast, illusory posttraumatic growth, indicated by high levels of a neurotic or an immature defence style, was not correlated with negative change following adversity. Although the difference between illusory posttraumatic growth and real posttraumatic growth concerning negative change following adversity had a meaningful effect size, it was not significant. Within chapter 7.3, real posttraumatic growth, indicated by extremely low levels of neurotic defensiveness, was correlated significantly with posttraumatic stress. In contrast, illusory posttraumatic growth, indicated by extremely high levels of neurotic defensiveness, was not correlated with posttraumatic stress. The difference between real posttraumatic growth and illusory posttraumatic growth was significant. Within chapter 8, real posttraumatic growth (high levels of mature defensiveness) was correlated with decreases in hedonic well-being measured by positive and negative affect. In contrast, illusory posttraumatic growth (low levels of mature defensiveness) was correlated with increased levels of hedonic well-being. The difference between real posttraumatic growth and illusory posttraumatic growth was significant. In total, reports of posttraumatic growth may, in fact, sometimes be correlated with defensiveness. However, real posttraumatic growth and illusory posttraumatic growth do only slightly differ concerning their correlation with well-being.

Background: In April 2009, the NHS Institute for Innovation and Improvement released four Better Care Better Value (BCBV) prescribing indicators. One indicator targeted renin–angiotensin–aldosterone system (RAAS) drugs, i.e., angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), to improve their prescribing efficiency. The indicator affects the proportion of items written for ACEIs as a percentage of the total number of prescriptions for RAAS drugs. A proportion of 80% ACEIs has been proposed and considered as an achievable target based on the small proportion (2–10%) of patients who cannot tolerate the ACEIs-related side effects, mostly dry cough. However, neither the impact of the BCBV indicator on the utilisation of ACEIs/ARBs nor its cost-saving implication is yet known. The BCBV indicator involves switching established ARBs users to ACEIs, where appropriate. However, no previous studies have specifically investigated the clinical and economic impact of the switch of ARBs and hence it is unclear whether the switch from ARBs to ACEIs, promoted by the BCBV indicator, would be associated with any clinical or economic issues. Without any financial incentives or legislation enforcement, uptake of the BCBV policy is predicted to be low, especially as evidence suggests that single measures are ineffective in altering GPs’ prescribing behaviour. However, the uptake and implementation of the BCBV indicator has not yet been explored. Aims: This thesis aimed to evaluate the impact of the BCBV indicator for ACEIs/ARBs on the utilisation of ACEIs/ARBs in treating hypertension (HT) and any associated cost savings. The effects of switching patients from ARBs to ACEIs on clinical outcomes (adherence, blood pressure [BP] level and HT-related complications), healthcare resources and costs were also investigated. Prior to this, patients’ adherence and persistence patterns (discontinuation and switching), and potential associated factors were studied. Finally, the uptake and implementation of the BCBV indicator in real practice was explored. Methods:This research used an explanatory sequential mixed-method approach. Firstly, an interrupted time series analysis was used on data extracted from the Clinical Practice Research Datalink (CPRD), from April 2006 to March 2012, to examine the impact of the BCBV indicator on the repeated cross-sectional monthly ACEIs/ARBs prescriptions and costs in patients with primary hypertension, which was validated using national dispensing datasets. Secondly, a retrospective cohort study was conducted using prescription records extracted from CPRD for patients with primary hypertension who were prescribed antihypertensive drugs from April 2006 to March 2013. Patients’ adherence and persistence patterns (including switching) to antihypertensive drug classes were quantified and their association with patients’ characteristics tested, using Generalised Linear Models and survival analysis. Thirdly, a retrospective cohort study was conducted on patients who switched their index drug class from ARBs to ACEIs to evaluate the clinical outcomes and resources used associated with ARBs switching, using data from CPRD in linkage with Hospital Episode Statistics, and applying multilevel regression for data analysis. Finally, semi-structured interviews were conducted with 16 general practitioners, to explore their views about ACEIs/ARBs prescribing and the BCBV policy to understand the reasons underpinning the effectiveness/ineffectiveness of the BCBV indicator. The interviews were recorded, transcribed verbatim and analysed using a thematic approach. Results: Impact of the BCBV indicator on ACEIs/ARBs utilisation and cost saving. The ACEIs prescription proportion declined from 71.2% in April 2006 to 70.7% in March 2012. The policy initially resulted in a sudden reduction of 0.3% (95%CI: –0.44, –0.16) in the level of ACEIs prescription proportion; however, it was thereafter associated with a sustained, significant increase of 0.013% (95%CI: 0.0007, 0.02). The failure to achieve the 80% target by the end of the study period resulted in missing a potential cost saving of 23.9% of the total ACEIs/ARBs cost. In June 2014, a potential cost saving of ~£1 million was predicted, had the 80% target been achieved; this substantial saving was several years after the availability of several low-cost generic ARBs. Adherence and persistence to antihypertensive drug classes: Among the 176,835 patients with primary hypertension included in this analysis, 38.4% and 20% were non-adherent (proportion of days covered [PDC]<80%) to their antihypertensive drug class and therapy, respectively. The discontinuation rate of antihypertensive drug class (56.1%) and therapy (35.5%) was relatively high by the end of six-year follow-up period. Using ARBs as the index drug class, prevalent hypertensive patients, prevalent antihypertensive drug users and increasing age were associated with higher PDC to antihypertensive drug class and therapy but a lower risk of drug discontinuation; whereas a higher deprivation level, comorbidity score and switching of antihypertensive drug class were associated with lower PDC to antihypertensive drug therapy but a higher risk of discontinuation. Overall, 26% of the included patients switched their antihypertensive drug class. Using ARBs, higher deprivation, higher comorbidity and prevalent antihypertensive drug users were protective factors against switching; whereas female gender, prevalent hypertensive patients, higher BP level and increasing age were associated with a higher risk of switching. Clinical and economic implications of switching patients from ARBs to ACEIs: Of the 46,193 patients who switched their antihypertensive drug therapy, only 470 patients switched from ARBs to ACEIs – they were included in this study. Based on whether the patient combined ACEIs with other antihypertensive drug classes in the post-switching period, 369 patients were classified into ACEIs-combined group and 101 patients into ACEIs-monotherapy group. Compared with the pre-switching period, the proportion of non-adherent patients (PDC<80%) in the post-switching period increased significantly (17% vs. 27%); however, this significant increase was observed only in the ACEIs-combined group (17.3% vs. 29%). The switching of ARBs was associated with a significant reduction in both systolic and diastolic BP (144.2 vs. 141.9 mmHg, p<0.001) and (84.6 vs. 82.6 mmHg, p<0.001), respectively; however, this effect was found only in the ACEIs-combined group. The incidence of all HT-related complications was comparable in both pre- and post-switching periods, except for the incidence of MI, which reduced significantly only in the ACEIs-combined group (OR=0.1, 95%CI: 0.04, 0.6). Importantly, the switching of ARBs to ACEIs was associated with a significant reduction in the total medical costs (mean cost difference: –£329.2, 95%CI: –534.6, –205.7). Uptake and implementation of the BCBV indicator: Potential barriers suggested for the poor uptake of the BCBV policy, included a lack of GP awareness of the policy, GPs’ negative attitudes toward the policy and a lack of financial incentives. Among other reasons, the current high proportion of ARBs users appeared to be related to an over-switching of ACEIs to ARBs in anticipation of an ACEIs-related dry cough. Suggested measures for increasing the policy uptake included effective dissemination strategies, linking the policy to financial incentives and providing guidance on performing the switching. Furthermore, strategies to address the over-switching of ACEIs to ARBs were considered essential for the BCBV policy to achieve its 80% ACEIs target. Conclusions:The BCBV indicator was ineffective and failed to achieve the 80% ACEIs target. The association of achieving the 80% target with a remarkable cost-saving opportunity and the lack of any negative clinical consequences following the switching of ARBs to ACEIs indicate the ongoing necessity to reconsider and reinforce this policy through multiple initiatives to increase its future effectiveness, building on the study’s identified barriers and suggested solutions. This thesis represents a case study of a failed and an ineffective prescribing policy, attributed primarily to inappropriate policy implementation. It provides key lessons for policy makers and healthcare authorities on the importance of effective implementation strategies as an integral component to any successful policy.