Continued pressure to reduce costs and manage healthcare delivery in risk-based reimbursement environments, has, internationally, resulted in hospitals adopting different methods to manage pharmaceutical and surgical consumable products. An initial review of systems of management of these products showed that the trend is to manage them separately. Pharmaceutical products are managed using dedicated resources and structures in each hospital, which may be difficult to establish and sustain in smaller, non-academic hospitals. Amongst other factors, the absence of a classification system and a lack of utilisation information hindered the development of management systems for surgical consumable products. In addition, traditional materials management processes applied to these products, often do not adequately address the impact that these products have on clinical care. In this study, the decision was made to develop an integrated system for both pharmaceutical and surgical consumable products and to adopt a systems approach in which all hospitals in the group were included as a single system. The study was multi-methodological with the design being contextual and qualitative and the research strategy, exploratory and descriptive. A multi-phased, action research approach was used, comprising of three (3) cycles, two (2) in which the integrated system was developed and enhanced and a third in which it was independently tested in 19 newly acquired hospitals. The result of the three (3) cycles was an implemented integrated system across 43 acute-care hospitals in the group comprising six (6) processes namely: a product selection process, information technology (IT) support system, a hospital implementation process, measurement and management tools, pharmacy capability and a supplier strategy and interface process. These processes included several key unique features, such as one (1) product selection team for all hospitals, a surgical classification system based on functional therapeutic uses, a single IT system and utilisation review capability for all products, extending the role of pharmacy departments in hospitals to include the management of surgical consumable products and an integrated quality assessment process for both types of products. By the end of the three (3) cycles (September 1999), the product selection process covered 66,5% of value of product spend, the percentage reduction in the number of products used was 68% and the value of products purchased that complied with specified products and suppliers was 90%. Ongoing and further application showed that the integrated system could be sustained in existing hospitals, applied to a further four (4) newly acquired hospitals and expanded to include specialised pharmaceutical and surgical consumable products in cardiac catheterisation laboratories. By September 2003, the total spend on pharmaceutical and surgical consumable products had reached R1,7 billion. The product selection process covered 67,6% of total spend, the compliance value reached 95% and there were additional financial improvements realised. Following a further literature review, limitations and improvements to the approach were identified and further adaptations were added as concepts in the graphic representation of system. One (1) of these was to show the integrated system as an open system. The second adaptation highlighted the systems-based input-process-outcomes feedback concept that is critical to continuous improvement of the system. In the final progression, a systems approach to strategic planning and management was incorporated in order to provide a structured approach for adapting to the rapid and ongoing changes in healthcare and aligning the system of management of pharmaceutical and surgical consumables to the overall business strategy. Overall, this research study succeeded in bringing new perspectives and an innovative approach to the management of pharmaceutical and surgical consumable products by developing and implementing an integrated system for both products, establishing essential processes with key unique features and tools, and the application of a systems thinking approach. Four (4) areas of further research are suggested, namely testing the integrated system in other contexts, improved methods of measurement of quality of care, extension to other areas of healthcare and use of the systems approach in other areas of the business.

Background and Aims: To explore outcomes following gastrointestinal endoscopy using a clinical dataset and then routinely collected administrative data linked to death registry data. Predictors of outcome were studied and variations in crude mortality were analysed. Methods: Endoscopy cases from a single tertiary centre were identified retrospectively using a clinical endoscopy database. Sedation levels, type of procedure and demographic data were analysed. Adverse events following the procedures, including mortality were assessed before and after changes in sedation practice were introduced. For subsequent chapters national administrative data in the form of Hospital Episode Statistics (HES) were linked to the Office of National Statistics Death Registry. Data from 2006 – 2008 were analysed. Episodes of care containing codes for therapeutic endoscopic procedures were extracted (Endoscopic retrograde cholangio-pancreatography (ERCP) and percutaneous endoscopic gastrostomy (PEG)). Finally, episodes of care containing new stroke diagnoses were extracted to analyse the use of percutaneous gastrostomies in the stroke population in England. Factors associated with death following endoscopy were identified. Crude and case-mix adjusted mortality were analysed at institutional level. Results: 7,234 endoscopy cases were identified from the endoscopy clinical database. Following changes in sedation practice 7,071 cases were assessed. Significant reductions in sedation doses were achieved but mortality rates did not fall (0.7% in 2004 and 0.8% in 2006 (p=0.5)). 40,938 episodes of care containing ERCP procedures were identified within the HES data. Logistic regression analysis confirmed age, sex, cancer, emergency admission, and non-cancer co-morbidity as independent predictors of 30-day death after ERCP. Adjusted odds ratios for age were 6.2 for ≥85 yrs vs. <55 yrs; male sex 1.2 vs. female; emergency admission 2.0 vs. elective; cancer 8.6 vs. no cancer and non-cancer co-morbidity 1.5 vs. none. Trust volume of ERCP was not found to be a significant factor in post procedure mortality. Funnel plots of trust level mortality rates, both unadjusted and adjusted, showed all trusts lying within 3 standard deviations of the national mean. 10,952 PEG cases were identified. All-cause mortality was 4.2% at 7 days and 14.6% at 30 days. Logistic regression identified age over 85 years, male sex, emergency admission, motor neurone disease and dementia as predictors of death within 30 days of PEG procedure (p<0.03 for all). No correlation for 30-day death versus PEG volume was identified at NHS Trust level (Pearson r=0.04). 1560 emergency stroke admissions that had a new PEG procedure were identified. Admission to Trusts with a high PEG procedure volume was associated with lower 7-day mortality after PEG procedure of 4.3%, compared to 7.8% and 6.8% in low and medium volume Trusts respectively (p=0.045). Although suggestive of a lower threshold for PEG insertion, the 5 Trusts with the highest rate of PEG insertions in stroke patients had a higher mortality at 30 days (3% compared to 0.9% in the other Trusts). Conclusions: Patient factors are the main determinants of outcome following endoscopy. Analyses of clinical and administrative datasets both require significant man-hours to produce results. Assessing disease severity within HES data is unsatisfactory, limiting case-mix adjustment. However, the data have the advantage of allowing consistent methods of analysis across institutions at a national level providing a more real world analysis than smaller or single centre studies.

Antivenom is the only effective treatment against the systemic effects of snakebite and is currently developed by a century-old immunisation protocol that aims to generate IgGs capable of binding and neutralizing most (if not all) of the venom toxins. However, snake venoms comprise more than a hundred proteins and peptides that exhibit a significant diversity in terms of isoform complexity, toxicity and immunogenicity. Therefore, antivenom doesn’t take into account the representation of venom toxins and contains therapeutically redundant IgGs to non-toxic venom components, and a lack of high titre IgGs to highly toxic, but weakly immunogenic components. The usual consequence of the century old immunisation protocol is the need to administer large volumes to achieve venom-neutralisation in an envenomed patient, which greatly increases the risk of antivenom-induced adverse effects and reduces its affordability. The Alistair Reid Venom Research Unit has pioneered a new approach using the rationale of generating venom toxin‐specific antibodies on the basis that an antivenom that only targets the most pathogenic toxin groups would be predicted to overcome these issues by improving the clinical efficacy of the treatment. Based upon preliminary work illustrating extensive cross‐specific and cross‐generic reactivity of a toxin‐specific antibodies generated against some of the most pathogenic toxin groups of venoms from medically-important species, the overarching aim of the work described in this thesis was to extended this toxin-specific antivenom approach with a view to ultimately generating a therapy against all the African species of the Echis genus. In order to overcome the high isoform diversity known for most of the pathologically-important venom toxin groups, we conducted a bioinformatic interrogation of the venom gland transcriptomes of Echis ocellatus, Echis pyramidum leakeyi and Echis coloratus for five major target toxin groups: Phospholipases A2 (PLA2), Serine proteases (SP) C-type lectins (CTLs), Metalloproteinases (SVMPs) and Disintegrins that identified epitopes on the basis of i) sequence conservation, ii) antigenicity, (iii) surface exposure and (iv) coverage across the EST data. Resultant sequences were synthesised as epitope-strings and subsequently delivered as DNA and recombinant proteins immunogens that in a proteic form successfully generated antibodies capable of binding to a number of reduced venom proteins in a cross-reactive manner, suggesting the presence of specific and generic shared epitopes of importance. The results obtained in this study helped identifying key elements of the toxin-specific approach for the design of antivenoms and highlighted the need to elucidate several aspects of the molecular interaction of the raised antibodies against the target venom proteins, in order to have an accurate approach to their binding in a native state. In addition, the study successfully approached venom glycosylation, and aspect that hasn’t been studied in detail and came apparent during the progress of the toxin specific antivenom gave light in the future stages of its development.

Background and introduction: Maternal deaths are highest in low resource countries. Skilled attendance at birth (SBA) and the availability of emergency obstetric care (EmOC) are key strategies to improve maternal health and achieve the millennium development goal number 5. In-service emergency obstetric and newborn care (EmONC) training has been used for many years to improve the quality of skilled attendance at birth and availability of EmOC, however few packages have been properly described and evaluated. There is no published comprehensive evaluation of EmONC in-service training packages in low resourced countries. An evaluation of the effectiveness of an EmONC training intervention in 10 comprehensive EmOC Kenya hospitals was carried out from 2010-2011. Methods: A systematic review was performed based on grading of recommendations assessments development and evaluation (GRADE) guidelines to identify the various EmONC training packages in low and middle income countries, identify literature on the effectiveness of these packages or effectiveness of various components of EmONC training globally. The components of the intervention were training in EmONC, provision of EmOC equipment and supportive supervision. The objective of the intervention was to improve the recognition and treatment of emergency obstetric and newborn complications at all study sites by trained maternity care providers (MCP). A before/after study design and an adapted four level Kirkpatrick framework (level 1: reaction to training, level 2: learning, level 3: behaviour/practice, level 4: EmOC availability, health outcomes and ‘up-skilling’) was used to evaluate the effectiveness of the training package. Mixed research methods (quantitative and qualitative approaches) were used to collect data 3 months before the intervention and at 3 monthly intervals after up to 12 months after the intervention. Quantitative data were analysed using SPSS version 20 and qualitative data was analysed using Nvivo 9. Descriptive statistics and analysis using t-tests were performed for quantitative data (significance in mean difference at 95% confidence) while framework analysis was used for qualitative data. Results: 20 EmONC in-service training programmes implemented in low and middle-income countries were identified. The content of 85% (17) of the programmes identified included EmOC signal functions and 7 programmes were 7 days or more in duration. 50% (10) of the EmONC training packages identified had training reports of which only two studies were evaluated at Kirkpatrick level 3 (behaviour) and there was no evaluation at level 4 (health outcomes) identified. Over 70% of all identified maternity care providers from all 10 hospitals were trained. 83% (328) of the 400 health care workers trained were midwives, 6% (26) were medical doctors, 2% (8) were clinical officers and 3% (11) were obstetricians. At 12 months post training the proportion of MCP trained in each hospital was at least 83% except for Nakuru PGH (23%) and Mbagathi GH (50%). Kirkpatrick level 1: About 95% (380) participants responded to level 1 assessment questionnaire. Trainees reacted positively to all lectures (n=11, mean score was 9.38/100, SD: 0.12) and breakout sessions (n=25, mean score was 9.33/10, SD: 0.14). Kirkpatrick level 2: There was a statistically significant difference between the pre and post training knowledge scores in all modules except preventing obstructed labour 0.10 CI (0.06-0.26) p=0.201. The mean difference between pre and post-test skill scores was statistically significant 3.5 CI (3.3-3.8) P<0.001, n=284. Kirkpatrick level 3: 153 data sources (FGDs, paired interviews, KIIs) were collected over 12 months and analysed. 49% (184) and 129 (34.5%) of health care workers and managers participated. They reported a positive impact of the intervention on communication and teamwork, pre-service midwifery education, reduced treatment time, improved knowledge, skills, improved confidence to perform EmOC, organisation of care and supportive supervision. Availability of EmOC equipment post training and supportive supervisors were factors that facilitated change in practice post training. Barriers to availability of EmOC identified were poor staff deployment and retention policy post training, lack of equipment to perform EmONC, lack of support from obstetricians, senior midwives and nurse/midwifery administrators, lack of training for all MCP (including medical interns, medical officers and staff from lower level health care facilities) and lack of clarity on the scope of practice for nurses/midwives. Kirkpatrick level 4: 16, 764 and 17, 404 deliveries were conducted at baseline and at 12 months post intervention respectively. There was 66.8% increase in obstetric complications recorded and managed at 12 months post training compared to baseline. Health outcome indicators: There was an expected increasing trend for number of complications recorded and treated, availability of SBA and EmOC. There was also an expected decreasing trend in the proportion of newborns admitted to NBU for birth asphyxia, direct obstetric case fatality rate (DOCFR) and stillbirth rate (SBR). There was no change in caesarean section (C/S) rate or Fresh stillbirth rate (FSBR). For the health outcome indicators (DOCFR, SBR, FSBR), when PGH Nakuru was excluded from the analysis, a non-statistically significant reduction but greater effect at 12 months compared to baseline was observed for complications recorded and treated (87.9% vs. 66.8%), DOCFR (47% vs. 35%), SBR (66% vs. 34%) and FSBR (14 vs. 10%). There was 34%, 48%, and 35% mean reduction in the SBR, proportion of newborns admitted to newborn care unit and DOCFR at 12 months post intervention compared to baseline respectively. “Up-skilling” indicators: There was a 53.8%, 80%, 100% mean increase in the proportion of all breech vaginal deliveries, proportion of all vacuum extractions performed and proportion of vacuum extractions performed by non-physician clinicians, at 12 months post intervention compared to baseline. Assisted vaginal delivery by vacuum extraction was the least available EmOC signal function (SF) and medical doctors only performed this SF at baseline. At 12 months post intervention, non-physician clinicians performed this as well, in all study sites. Overall the EmONC training intervention resulted in improved ‘up-skilling’ of maternity care providers, a trend towards improved availability of SBA and EmOC and improved health outcomes. Implications for policy and practice The results of this study are important for designing and implementing evidence based EmONC programmes in resource poor countries. None medical doctors can be ‘up-skilled’, the recognition and management of obstetric and newborn emergencies and the availability of quality EmOC can be improved using similar packages and implementation methods in other resource poor settings. Future research: Evaluation designs that include control groups are needed. Studies to assess the relative importance of supportive supervision for behaviour change after training, the knowledge and skills retention with time post training in resource limited settings should be undertaken.

During rehabilitation from Stroke, patients require assessment of their upper-limb motor control. Outcome measures can often be subjective and objective data is required to supplement therapist/patient opinion on progress. This can be performed through goniometry; however, goniometry can be time-consuming, have inaccuracies of ±23º, and is therefore, often not used. Motion tracking technology is a possible answer to this problem, but can also be costly, time-consuming and not suitable for the clinical environment. This thesis aims to provide an objective, digital intervention method for assessing range of motion to supplement current outcome measures which is suitable for the clinical environment. This was performed by creating a low-cost technology through a user-centred design approach. Requirements elicitation demonstrated that a motivational, portable, cost-effective, non-invasive, time saving system for assessing functional activities was needed. Therefore, a system which utilised a Microsoft Kinect and EZ430 chronos wrist watch to track patient’s movements during and/or outside of therapy sessions was created. Measurements can be taken in a matter of minutes and provide a high quantity of objective data regarding patient movement. The system was verified, using healthy volunteers, by showing similar error rates in the system across 3 weeks in 10 able-bodied individuals, with error rates produced by a physiotherapist using goniometry. The system was also validated in the clinical setting with 6 stroke patients, over 15 weeks, as selected by 6 occupational therapists and 3 physiotherapists in 2 NHS stroke wards. The approach which has been created in this thesis is objective, repeatable, low-cost, portable, and non-invasive; allowing it to be the first tool for the objective assessment of upper-limb ROM which is efficiently designed and suitable for everyday use in stroke rehabilitation.

Increasing applications of nano materials in medicine, construction, textiles, computers, and other consumer goods have lead to increasing concerns of their effect on human health and ecology during synthesis, manufacturing, use, and disposal of nano-materials. Though much scientific progress has been made in nano material synthesis, manufacturing, and application in consumer goods and other sectors such as medicine, textiles and more, not much progress has been made in understanding the adverse effects of nano materials on human health and the environment. Physical, chemical, toxicological characteristics of these nano materials and their fate in the environment are important in understanding their adverse effects on the environmental and human health. This study is aimed at developing a preliminary framework for risk assessment (RA) and risk management (RM) of nano materials based on fundamental principles of chemistry, physics, toxicology, and other related disciplines.

This thesis is comprised of three chapters written as articles for publication. The theme linking the chapters is the focus on interaction between service users and professionals working in health and care settings. Chapter one reviews discursive research on health and care professional interaction with people with a learning disability. The focus is on how professionals talk with and about people with a learning disability. Citations are explored which describe professional talk in research interviews, interactions with people with a learning disability in everyday settings, questionnaire-based interviews, therapeutic interactions and meetings. Certain practices have been found to work well in particular contexts and some not so well. There is potential to use practices across contexts, however there is no guarantee that a particular practice will perform the same action in a different interactional setting. Future research in the area could look at the effects of trying to increase the use of some of the more successful practices through staff training. Chapter two details an empirical study on how questions are used by participants in care programme approach (CPA) review meetings in the NHS. Questions were found to be asked by the professionals at the meeting in a manner that followed the format of a semi-structured interview. Six question types are described in the paper that perform a range of actions; switching topic, prompting the service user, avoiding overt disagreement, bringing the meeting back on topic, offering the service user the opportunity to ask questions and ensuring a particular structure is followed. The analysis suggests that government guidance on CPA regarding service user participation is not being realised in the way that the process is conducted on an interactional level. Chapter three contains a reflective piece about my experiences conducting discursive research in an NHS setting. It describes the challenges faced in doing research using this methodology and makes suggestions on how some of these potential issues might be tackled.

Os radionuclídeos naturais das séries radioativas do 238U, 235U e 232Th são frequentemente utilizados como traçadores em estudos ambientais para a compreensão da dinâmica que ocorre no ambiente marinho e terrestre, como por exemplo, em pesquisas de processos oceânicos e gerenciamento da região costeira. No ambiente marinho, estes radionuclídeos podem ser empregados para estimar fluxos biogeoquímicos de partículas e de nutrientes que ocorrem tanto na coluna dágua, quanto nos sedimentos. Várias pesquisas aplicam a distribuição e o respectivo desequilíbrio dos radionuclídeos naturais no meio ambiente, inclusive em modelos geocronológicos para se obter informações históricas em testemunhos sedimentares. Nesse estudo, realizou-se a caracterização radioquímica das distribuições de 226Ra, 228Ra e 210Pb de uma coluna sedimentar denominada 1B (248 cm de comprimento), coletada na Baía do Almirantado, Antártica. A metodologia utilizada incluiu a lixiviação ácida de amostras de sedimentos, seguida de separação radioquímica sequencial de 226Ra e de 228Ra pela co-precipitação com Ba(Ra)SO4 e de 210Pb pela co-precipitação com PbCrO4. Todas as medidas foram realizadas pela contagem alfa e beta total dos precipitados obtidos, em um detector proporcional de fluxo gasoso de baixa radiação de fundo. As concentrações de atividade de 226Ra e 210Pb foram empregadas para se estimar a atividade de 210Pbnão-suportado presentes no perfil sedimentar 1B. Considerando-se as concentrações de atividade de 210Pbnão-suportado obtidas e a aplicação do modelo CIC(Constant Initial Concentration), foi possível determinar a taxa de sedimentação de 0,59±0,05 cm/ ano. / The natural radionuclides from radioactive series of 238U, 235U and 232Th have been applied as tracers in environmental studies for understanding the dynamics that occur in both marine and terrestrial environment, as for example, in research of oceanic processes and management of the coastal region. In the marine environment, these radionuclides can be used to estimate biogeochemical fluxes of marine particles and nutrients that occur in the water column as well as in the sediment. Several research works applied the distribution and the respective disequilibrium degree of natural radionuclides in the environment, including geochronological models for obtaining historical information on samples of certain sediment profile. In this study we performed a radiochemical characterization of the distribution of 226Ra, 228Ra and 210Pb from a sedimentary column called 1B (248 cm long) collected in the Admiralty Bay, Antarctic Peninsula region. The methodology used included the acid leaching of sediment samples followed by the radiochemical sequential separation of 226Ra and 228Ra by co-precipitation with Ba(Ra)SO4 and 210Pb by co-precipitation with PbCrO4. All measurements were carried out by counting of gross alpha and gross beta measures in a low background gas flow proportional detector. The activity concentrations of 226Ra and 210Pb were used to estimate the unsupported 210Pb activities present in sediment profile 1 B. Based on unsupported 210Pb data and the application of the CIC model (Constant Initial Concentration), it was possible to determine the sedimentation rate of 0.59 ± 0.05 cm /year.

Hepatitis C Virus (HCV) infection is a hepatotropic, enveloped virus with a positive sense RNA genome. The prevalence rate of the virus has been shown to be 2.9% of the world population, equating to around 170 million infected individuals. Due to the high level of chronic infection and progressive nature of the liver disease, HCV is a major health concern. Four host proteins have so far been indicated as viral receptors; scavenger receptor BI, CD81, Claudin1 and Occludin. The interaction of CD81 and Claudin1 has been previously demonstrated which lead us to determine whether specific interactions are essential for HCV entry. Using a combination of imaging and biochemical methods we were able to demonstrate that only receptor active Claudins specifically interacted with CD81. We also evaluated the ability of previously published Claudin1 mutants to interact with CD81 and demonstrated that receptor inactive mutants no longer form an association with CD81. A bioinformatic model predicted the association of the T149, E152 and T153 residues of CD81 EC2 with the 62-66 region of Claudin1. Mutation of these residues lead to an ablation of Claudin1 association and a reduction in on HCV entry, further indicating the requirement of the Claudin1-CD81 complex in the entry process.

AcrA is the periplasmic adaptor protein component of the major efflux system AcrB-TolC of \(Salmonella\) Typhimurium. AcrA of S. \(Typhimurium\) SL1344 was inactivated and the mutant phenotype characterised. RT-PCR and western blotting were used to confirm expression of \(acrB/AcrB\) was retained in the acrA mutant. The AcrA mutant was hyper-susceptible to a range of antimicrobials and was more susceptible to some agents than strains lacking AcrB and TolC. This is partially explained by the increase in accumulation of Hoechst H33342, a fluorescent substrate of AcrAB-TolC, indicating that the inactivation of \(acrA\) resulted in reduced efflux activity. Lack of AcrA also attenuated the ability of S. Typhimurium to infect INT-407 and RAW 264.7 cells \(in vitro\) as previously published for AcrB and TolC mutants. The virulence defect of the mutants could not be rescued by addition of supernatant from an infection of INT-407 cells with SL1344 or addition of media conditioned by uninfected INT 407 cells. However, addition of media conditioned by overnight growth of SL1344 was able to ameliorate the virulence defect of the mutants. This suggests that AcrAB-TolC of SL1344 exports a factor/s required for virulence which the mutants are unable to export and that exogenous addition of this factor can restore the virulent phenotype. Inactivation of \(acrA\) conferred a phenotype distinct to that of inactivation of \(acrB\) or \(tolC\) indicating a role for AcrA distinct to that of other protein partners in both efflux of substrates and virulence