Non-human primate experimentation provokes passionate and opposing exchanges, particularly in the UK. This disagreement contributes to an impasse which in turn has prevented the exploration of the important question, if and how primate research could be ended. This project aims to support the examination of this question of impasse presenting data on how it might be overcome by providing a novel and challenging perspective using a multi-method approach, and insights from science and technology studies, to better understand the animal research controversy. The project primarily draws on data from face-to-face semi-structured interviews with primate users and with scientists who do not use primates across two areas of research, namely schistosomiasis and Parkinson’s disease. This multiple-case study method was combined with a documentary analysis of primate reports produced by key stakeholders. The dataset was then analysed using a semi-inductive, thematic approach to identify how aspects of the social dynamics of science can help to explain the different viewpoints provided by participants. The analysis showed that issues of (i) competition and reputation, (ii) expectations, core sets and publications, (iii) entrenchment and policy, and (iv) ethics and speciesism are centrally relevant to a better understanding of the apparent stalemate in replacing primate experiments. The key finding is therefore that the social dynamics of science play a critical role in explaining why the primate impasse persists, and can also help to understand how to overcome it. Constructive recommendations to achieve progress are made, focussing on improved collaboration and communication, increasing flexibility and explicit examination of the ethical considerations. The thesis also draws conclusions on how best to ensure the necessary involvement of key stakeholders. Recommendations from this project also have wider implications for scientific practice particularly for those involved in alternatives to animal research, and for the field of science communication.

Introduction: Renal Ischaemia-Reperfusion injury (IRI) is a complex mechanism involving the interplay between endothelium, leukocytes and the complement system. To evaluate the role of these three key mediators, a rat model was used to evaluate changes seen in renal IRI. Two interventional agents: Anti-Thymocyte Globulin (ATG) and Soluble Complement Receptor-1 (sCR1) were used to modulate leukocyte and complement response in this IRI model with a view to assess, and define IRI mechanism. Methods: The Ischaemia-Reperfusion (IR) model involved unilateral left renal ischemia (n=10) for 40 minutes, followed by 48 hours of reperfusion. ATG (n=8), ATG Isotype (n=8) and sCR1(n=8) were given IV prior to the laparotomy followed by IR model. The sham group (n=6) served as controls. Blood CD3 lymphocyte counts and CH50 complement assay were used to check efficacy of ATG and sCR1 respectively. The kidneys retrieved at 48 hours were analysed for histology, immunohistochemistry and RT-qPCR studies. Results: The IR group showed significant injury compared to the sham group. ATG treatment offered significant histological protection mainly via decreased leukocyte infiltrate and endothelial protection compared to the IR and Isotype controls. CH50 assay showed complete ablation of complement activity at the time of reperfusion, with return to normality at 24 hours. sCR1 treatment conferred protection from IRI predominantly via suppression of the complement cascade (C3, C9), reduced leukocyte infiltrates and V endothelial protection. RT-qPCR showed down-regulation of injury molecules – KIM-1 and NGAL in both the intervention groups. Conclusion: Modulation of leukocytes and complement system using single dose ATG and sCR1 led to significant endothelial protection, resulting in amelioration of renal ischaemia-reperfusion injury. The complement system was ablated at the time of reperfusion and was reconstituted by 24 hours, thus indicating that suppression of complement system during the phase of IR provides an avenue for mitigating IRI.

The peak incidence of Inflammatory Bowel Disease is between 15 – 25 years. A significant number of young people whose disease is not controlled by medication undergo surgery. However, the experiences of young adults with Inflammatory Bowel Disease have not been well researched. The aim of this two phase exploratory mixed methods sequential study was to investigate the process of transition in young adults aged 18 – 25 years with Inflammatory Bowel Disease who faced the prospect of, or had undergone, surgery. Schlossberg’s Transition Theory (Goodman et al, 2006) was used to identify the important factors that influenced their experience. Phase1 was qualitative and exploratory and obtained narratives from semi structured interviews with 24 young adults. Phase 2 was a survey. In order to establish whether findings from Phase 1 could be generalised a questionnaire developed from the Phase 1 findings was developed and sent to 158 young adults randomly sampled from seven NHS centres in England,. One hundred and twenty people responded (76%). Key findings from Phase 1 were that preoperatively most young people knew that their disease was out of control. Afterwards they perceived that surgery had improved their physical health and positively changed their lives. The key findings from Phase 2 were that 72 (60%) young people had a positive perception of their surgery. Participants also experienced an improvement in physical health and made a good psychological recovery. The majority of participants (n=106, 84%) received appropriate support and used positive coping strategies such as acceptance and positive reframing. Fear, worry, uncertainty, negative experiences of surgery and body image concerns hindered the process of transition. The specialist Inflammatory Bowel Disease or stoma nurse had a key role in facilitating a positive transition. The study findings will enable health care practitioners to provide appropriate information, care and support for young adult patients with Inflammatory Bowel Disease facing surgery.

Antibiotic resistance is an increasing global public health problem. Resistance is increasing sharply in gram-negative organisms, including Escherichia coli (E. coli), the main causative organism for community-acquired urinary tract infection (UTI). Antimicrobial stewardship strategies in primary care to help contain antibiotic resistance include supporting general practitioners (GPs) in deciding whether to prescribe an antibiotic for UTI and selecting the most appropriate antibiotic. In this thesis, I aim to describe the management of uncomplicated UTI in primary care and evaluate potential point of care tests (POCT) to assist the diagnosis and/or appropriate prescribing of antibiotics for uncomplicated UTI. The program of work includes: 1. Laboratory evaluation of a culture-based test that allows the quantification, identification and susceptibility profile of infecting bacteria from urine (FlexicultTM). 2. Evaluation of a novel chromatic sensing technique to identify bacterially infected urine compared to visual assessment of urine turbidity and urinalysis dipsticks. 3. Systematic review and analysis of data (descriptive and multi-level modelling) from an international primary care based observational study to describe UTI management. I identified unwarranted variation in clinical management of UTI between countries and between general practices within countries. Empirical antibiotic prescribing for UTI in Europe is high and treatment is generally prescribed for longer than guidelines recommend. FlexicultTM identifying bacterial UTI. The use of FlexicultTM in practice may support GPs in screening out negative samples reducing the proportion of patients that are prescribed antibiotics empirically. Chromatic sensing and visually assessing turbidity were equally useful at identifying negative urine samples and both improved the analytic performance of urinalysis dipsticks. The chromatic sensing system requires development prior to further evaluation.

The aerodynamic characteristics of the dose emitted from dry powder inhalers (DPIs) varies from patient to patient depending on their peak inhalation flow (PIF) and may also be affected by other factors such as the inhaled volume (Vin) and the initial acceleration of the inhalation manoeuvre (ACIM). Compendial methods for the in-vitro determination of the dose emitted from inhalers recommend using a vacuum pump to simulate an inhalation but this is not representative of that made by a patient. In this study a new in-vitro methodology has been developed by adapting a mixing inlet with the Andersen Cascade Impactor (ACI) to use COPD patient inhalation profiles in place of a vacuum pump. The aim was to investigate the effect of inhalation manoeuvre parameters (PIF, Vin and ACIM) on the dose emission performance of both Symbicort® Turbuhaler® and DuoResp® Spiromax®. The medium (200 μg/6 μg budesonide[BUD]/formoterol[FORM]) and high strength (400 μg/12 μg BUD/FORM) products have been used. In the first part of this thesis a comparison has been made between the Alberta Idealised Throat (AIT) and the traditional USP Induction Port (IP) using standard in-vitro compendial methodology. The medium strength version of the Symbicort® Turbuhaler® was used. The results show that the AIT captured more drug compared to the USP IP throat (p<0.05). Regardless of the inhalation volume, no significant change was observed for the FPD at 28.3 L/min between the two throats, although there was a significant difference in the FPD when the flow was increased to 60 L/min (p<0.05). In contrast to an inhalation flow of 28.3 L/min, at 60 L/min the MMAD reduced significantly (p<0.05). No significant change was observed for TED at both inhalation flows while changing the size of the throats regardless of the inhalation volume. In the second and the last but major part, the performance of the Symbicort® Turbuhaler® and DuoResp® Spiromax® was evaluated using the medium and high strength products. The results of both inhalers indicate the importance of PIF on the dose emission characteristics as it increased from <30 to >60 L/min. As a result, both FPD and TED increased and MMAD decreased significantly (p<0.05). The Vin and ACIM showed different effects on the medium and high strength of both inhalers. Generally, Vin had a small effect on both FPD and TED which increased and no change was observed with MMAD. The ACIM also had a small impact on FPD, TED and MMAD for Symbicort® Turbuhaler® and only FPD and MMAD for DuoResp® Spiromax®. The results highlights the potential of this methodology to characterise the dose a patient receive during real life use by using these inhalation profiles in place of the inhalation provided by a vacuum pump. Overall, PIF was the dominant inhalation manoeuver parameter for the dose emission from the Symbicort® Turbuhaler® and DuoResp® Spiromax®.

Stroke is currently one of the leading causes of death and disability worldwide. Despite recent advances in the treatment of stroke there is a major unmet clinical need for novel therapeutics for intervention. miRNAs are small coding RNAs which act to post-transcriptionally inhibit expression of genes. Emerging evidence has supported the view that miRNAs play an important role in the development and progression of ischaemic stroke, although understanding remains relatively poor. This research uses several models to investigate the effects of miRNAs in the context of stroke in vivo and in vitro, as well as assessment of patient serum samples in order to identify biomarkers for stroke. miR-29b was found to be significantly upregulated in SHRSP rat brain peri-infarct at 72h following stroke, and downregulated in ischaemic core at 24h and 72h following stroke, whilst miR-29c was significantly downregulated in remainder tissue at 24h following stroke and in infarct at 72h following stroke. The upreglation of miR-29b at 72h corresponded to a significant downregulation of miR-29 target genes MMP2, MMP9 and TGF-β1 in peri-infarct tissue at 72h following stroke. Modulation of miR-29b and miR-29c was achieved in a rat neuronal cell line but suppression of genes of interest was not observed following oxygen glucose deprivation. Several candidate miRNAs were then identified by microRNA Openarray analysis in stroke patient serum samples. Validation of these miRNAs was not demonstrated in the population studied, but assessment of these miRNAs in rat serum and isolated exosomes demonstrated that several of these miRNAs were significantly altered in SHRSP rats following stroke. Finally miR-21 was demonstrated to be significantly upregulated in SHRSP rat peri-infarct following stroke. This was associated with a change in miR-21 localization as determined by in situ hybridization. Modulation of miR-21 via the use of CAG-miR-21 mice demonstrated no difference in infarct size as measured by T2 -weighted MRI scan nor was any difference present in behavioural tests versus wild type. KO of miR-21 resulted in a reduction of survival rate compared with wild type. This thesis demonstrates that miR-29 and miR-21 are modulated following stroke in animal models, and these are potential candidates for therapeutic intervention in the future. Analysis of clinical samples has illustrated difficulties in the identification of serum miRNA profiles and suggests that looking at the exosomal component of serum may provide better information regarding miRNA profiles after stroke.

South Asians migrating to the Western world have a 3 to 5-fold higher risk of developing type 2 diabetes and double the risk of cardiovascular disease (CVD) than the background population of White European descent, without exhibiting a proportional higher prevalence of conventional cardiometabolic risk factors. Notably, women of South Asian descent are more likely to be diagnosed with type 2 diabetes as they grow older compared with South Asian men and, in addition, they have lost the cardio-protective effects of being females. Despite South Asian women in Western countries being a high risk group for developing future type 2 diabetes and CVD, they have been largely overlooked. The aims of this thesis were to compare lifestyle factors, body composition and cardiometabolic risk factors in healthy South Asian and European women who reside in Scotland, to examine whether ethnicity modifies the associations between modifiable environmental factors and cardiometabolic risks and to assess whether vascular reactivity is altered by ethnicity or other conventional and novel CVD risks. I conducted a cross-sectional study and recruited 92 women of South Asian and 87 women of White European descent without diagnosed diabetes or CVD. Women on hormone replacement therapy or hormonal contraceptives were excluded too. Age and body mass index (BMI) did not differ between the two ethnic groups. Physical activity was assessed and with self-reported questionnaires and objectively with the use of accelerometers. Cardiorespiratory fitness was quantified with the predicted maximal oxygen uptake (VO2 max) during a submaximal test (Chester step test). Body composition was assessed with skinfolds measured at seven body sites, five body circumferences, measurement of abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) with the use of magnetic resonance imaging (MRI) and liver fat with the use MR spectroscopy. Dietary density was assessed with food frequency questionnaires. Vascular response was assessed by measuring the response to acetylcholine and sodium nitroprusside with the use of Laser Doppler Imaging with Iontophoresis (LDI-ION) and the response to shear stress with the use of Peripheral Arterial Tonometry (EndoPAT). The South Asian women exhibited a metabolic profile consistent with the insulin resistant phenotype, characterised by greater levels of fasting insulin, lower levels of high density lipoprotein (HDL) and higher levels of triglycerides (TG) compared with their European counterparts. In addition, the South Asians had greater levels of glycated haemoglobin (HbA1c) for any given level of fasting glucose. The South Asian women engaged less time weekly with moderate to vigorous physical activity (MVPA) and had lower levels of cardiorespiratory fitness for any given level of physical activity than the women of White descent. In addition, they accumulated more fat centrally for any given BMI. Notably, the South Asians had equivalent SAT with the European women but greater VAT and hepatic fat for any given BMI. Dietary density did not differ among the groups. Increasing central adiposity had the largest effect on insulin resistance in both ethic groups compared with physical inactivity or decreased cardiorespiratory fitness. Interestingly, ethnicity modified the association between central adiposity and insulin resistance index with a similar increase in central adiposity having a substantially larger effect on insulin resistance index in the South Asian women than in the Europeans. I subsequently examined whether ethnic specific thresholds are required for lifestyle modifications and demonstrated that South Asian women need to engage with MVPA for around 195 min.week-1 in order to equate their cardiometabolic risk with that of the Europeans exercising 150 min.week-1. In addition, lower thresholds of abdominal adiposity and BMI should apply for the South Asians compared with the conventional thresholds. Although the South Asians displayed an adverse metabolic profile, vascular reactivity measured with both methods did not differ among the two groups. An additional finding was that menopausal women with hot flushing of both ethnic groups showed a paradoxical vascular profile with enhanced skin perfusion (measured with LDI-ION) but decreased reactive hyperaemia index (measured with EndoPAT) compared with asymptomatic menopausal women. The latter association was independent of conventional CVD risk factors. To conclude, South Asian women without overt disease who live in Scotland display an adverse metabolic profile with steeper associations between lifestyle risk factors and adverse cardiometabolic outcomes compared with their White counterparts. Further work in exploring ethnic specific thresholds in lifestyle interventions or in disease diagnosis is warranted.

No description available.

Background: Attitudes and beliefs that healthcare practitioners (HCPs) hold about musculoskeletal (MSK) pain influence their clinical behaviour. The Pain Attitudes and Beliefs Scale (PABS), originally developed for low back pain (LBP), is the most widely used and tested measure of HCPs’ attitudes and beliefs, however further development and testing is indicated. Poor performance of its biopsychosocial orientation scale is attributed to inadequate conceptualisation of the orientation. Aims: To develop a new biopsychosocial orientation scale for the PABS and adapt the original LBP specific version as a measure of HCPs' attitudes and beliefs about common MSK pain. Methods: The research was conducted in six stages. Firstly, a scoping review identified constructs used to quantify HCPs’ attitudes towards common MSK pain. Stage two used a concept mapping methodology to develop a new conceptual framework for biopsychosocial clinical orientation to common MSK pain. This framework was used to generate candidate items for redevelopment of the biopsychosocial scale (stage three) and then included in a national survey of physiotherapists, GPs and chiropractors (stage four) to collect data for initial development and testing (stage five and six). Methods: The research was conducted in six stages. Firstly, a scoping review identified constructs used to quantify HCPs’ attitudes towards common MSK pain. Stage two used a concept mapping methodology to develop a new conceptual framework for biopsychosocial clinical orientation to common MSK pain. This framework was used to generate candidate items for redevelopment of the biopsychosocial scale (stage three) and then included in a national survey of physiotherapists, GPs and chiropractors (stage four) to collect data for initial development and testing (stage five and six). Conclusion: The new version of the PABS (the PABS-MSK) is the most comprehensively developed measure of HCPs’ attitudes and beliefs concerning MSK pain to date. The biomedical scale is robust and while both scales require further validation, the research provides a solid conceptual grounding for further amendments of the measure. The conceptual framework provides a contemporary comprehensive understanding of the biopsychosocial clinical approach to MSK pain.

Background: Ankle sprain is common and can lead to chronic ankle instability (CAI), characterised by decreased functional performance. However, there is still a limitation regarding the optimal approach used to assess functional recovery. This thesis aimed to explore the functional performance of those subjects and to investigate their progress plus to identify recovery predicator. Methods: 60 subjects (Acute Sprain (AS)=20, CAI=20, Healthy=20) were recruited. Parameters investigated: decision-making (DMT) and task time (TT) under unanticipated and planned conditions, Time to Peak muscle activity (TTP), jump height, muscle strength, and dorsiflexion ROM. These were also used to investigate the progress of the AS=10 over a six-month period and to identify recovery predicator. Results: The healthy subjects demonstrated faster DMT only during unanticipated conditions comparing with AS (p=0.003) and CAI (p=0.001). DMT was also longer in CAI compared with AS by 51.8ms (p=0.03). A significant difference was found in jump height between injured and non-injured ankles for the AS and CAI subjects and better dfROM in the healthy subjects. Measuring TTP revealed that the TTP occurred in a different order in each group. In the longitudinal study the AS subjects performed better DMT by 74.2ms and jump higher by 1.68cm when compared with the 1st visit. Additionally, Jump height found predictor of functional outcome score at 1-month using FADI-ADL% and also muscle strength (Eversion Con-PT, Eversion Con-PT/BW and Eversion Ecc-PT/BW) can predict the functional outcome at 12-month using FADI-Sport %. Conclusion: This thesis suggest that using unanticipated conditions in functional tests could provide important performance outcomes such as DMT in assessing the ability to return to previous sporting activity. A combination between jump height and fast contact time is also useful. Overall the result provides a foundation for further investigations. Larger and more detailed studies are also needed to investigate muscle activity in response to an unanticipated condition.