Recent studies have shown that the proliferation of various human and murine tumour lines can be inhibited by the addition of gamma-linolenic acid (GLA) to the culture medium. These findings are consistent with the proposal put forward by Horrobin (1980) that malignant cells lack the enzyme/ A 6 desaturase; which is responsible for the conversion of linoleic acid (LA) to GLA. Since GLA is a prostaglandin (PG) precursor/ inadequate conversion of LA to GLA would result in decreased production of PGs/ particularly PGEi/ which has been shown to have an inhibitory effect on cell growth. Provision of GLA to enzyme deficient malignant cells should therefore bypass this blockade/ increase PGET synthesis and thus "normalise malignant cells". This study was performed to examine further the effects of exogenous GLA on growth of malignant cells in vitro and in vivo. Cells of the continuous murine sarcoma (M52B) line and primary cultures of non malignant fibroblasts were used to investigate effects of GLA in vitro. Cultures were exposed to either single or multiple doses of a range of concentrations of GLA. Radioimmunoassay (RIA) was performed to compare the amounts of PGE and PGF released into the medium by GLA treated and control M52B cultures and thus determine whether the addition of GLA in vitro significantly affected production of these PGs. Athymic BALB/c mice and immunocompetent BALB/c and Biozze mice as well as mice of the "Onderstepoort Strain" were used in various in vivo studies. Tumours were induced by the subcutaneous inoculation of approximately 1 x 106 cells of either the M52B line (into immunocompetent and athymic mice) or human breast carcinoma (NUB 1) line (into athymic mice). Take rates and latent periods were recorded. GLA treatment was initiated after tumours were established. In one study the fatty acid in hydrogenated coconut oil (HCO), which contains no PG precursors/ was administered parenterally (100 ug/ml/day) to Biozze mice. Control mice were either untreated or injected with HCO only. In another study, BALB/c mice and mice of the "Onderstepoort Strain" had their diet supplemented with GLA (in the form of EPO) to an extent of 3.5%. Control mice consumed either standard laboratory chow only or, chow supplemented with either 35% sunflower seed oil (SSO) or 35% HCO/ neither of which contain GLA. All diets were supplied ad libitum. Tumour sizes were measured every 48 hours and at the end of each experiment at which time tumours were excised and examined histologically. GLA was found to produce inhibitory and toxic effects on growth of both M52B cells and non malignant fibroblasts in vitro/ although the effect in the latter was observed only with high concentrations of the fatty acid. The inhibition of malignant cell growth was concentration dependant and was positively related to the duration of exposure to the fatty acid. Prior to death/ cells treated with GLA accumulated vii paranuclear granules which were shown histochemically to be lipid in nature. Electron microscopy confirmed the presence of large lipid deposits. Cultured M52B cells treated with GLA also released more PGE and PGF into the medium than did cells not exposed to the fatty acid. However, analysis of results using the Mann Whitney U test showed these differences to be statistically non significant for both PGE and PGF on two tailed tests. In contrast to the inhibition of M52B cell growth observed in vitro, growth of solid M52B sarcomas and NUB 1 carcinoma xenografts in athymic mice was apparently unaffected by administration of dietary GLA. Analysis of data using an unpaired student's t-test showed that the differences in tumour volumes between control and treated groups were not statistically significant either before or at the end of the experiment. While the inhibition of malignant cell growth caused by GLA in vitro was consistent with Horrobin's proposal that malignant cells may lack this PG precursor, whether or not these actions are mediated by the PGs remains obscure. Although an increase in PGE production by M52B cells was observed following GLA treatment, besides this increase being statistically non significant, it was not possible to determine whether this was due to PGE, (as suggested by Horrobin) or PGE2. It is possible that the effect produced in vitro was due to some factor other than raised PGE production, for example a non-specific fat-overload effect or a change in cell membrane fluidity. The lack of effect of GLA on tumour growth in vivo may have been due to inadequate delivery of the fatty acid to the tumour site. However, whatever the mechanism of action of GLA in vitro/ since oral GLA was supplemented to the maximum tolerated extent and produced no effect in immunodeficient mice inyiyo, it would seem that in a similar clinical situation oral doses which would be practical may be ineffective. / Thesis (M.Sc.)-University of Natal, Durban, 1985.

Yes / Poor medicines management places patients at risk, particularly during care transitions. For patients with heart failure (HF), optimal medicines management is crucial to control symptoms and prevent hospital readmission. This study explored the concept of resilience using HF as an example condition to understand how the system compensates for known and unknown weaknesses. We explored resilience using a mixed-methods approach in four healthcare economies in the north of England. Data from hospital site observations, healthcare staff and patient interviews, and documentary analysis were collected between June 2016 and March 2017. Data were synthesised and analysed using framework analysis. Interviews were conducted with 45 healthcare professionals, with 20 patients at three timepoints and 189 hours of observation were undertaken. We identified four primary inter-related themes concerning organisational resilience. These were named as gaps, traps, bridges and props. Gaps were discontinuities in processes that had the potential to result in poorly optimised medicines. Traps were features of the system that could produce errors or unintended adverse medication events. ‘Bridges’ were features of the medicines management system that promoted safety and continuity which ensured that, despite varying conditions, care could be delivered successfully. ‘Props’ were informal, temporary or impromptu actions taken by patients or healthcare staff to avoid potential adverse events. The numerous opportunities for HF patient safety to be compromised and sub-optimal medicines management during this common care transition are mitigated by system resilience. Cross-organisational bridges and temporary fixes or ‘props’ put in place by patients and carers, healthcare teams and organisations are critical for safe and optimal care to be delivered in the face of continued system pressures.

The first workers to use the isolated perfused rat liver for the study of gluconeogenesis were Corey and Britton (1941). Subsequently, other investigators found the modified method of Miller et al (1951) to be more suitable. This technique, with modifications introduced by Mortimore (1961) and Hems et al (1966) was used in the present study. The isolated liver is perfused through the portal vein with saline, supplemented by bovine serum albumin and washed human erythrocytes, under a pressure of about 20cm of water, maintained by a reservoir of adjustable height. The perfusate which passes through the liver enters the inferior vena cava and passes, via a cannula, to a collecting vessel from which it is pumped to the top of a multiple bulb oxygenator and then returned to the liver for re-perfusion. This technique has proved to be a satisfactory means of assessing changes in the metabolic status of hepatic cells in response to starvation and exposure to halothane. The study described here was performed to determine whether the isolated liver perfusion technique can be used to measure the effects on liver perfusion of therapeutic and supratherapeutic doses of various drugs, some of which have been reported to affect liver metabolism adversely in the intact animal. Liver function was assessed by studying gluconeogenesis and bromosulphthalein clearance. Alcohol and hexane were administered in toxic doses, rifampicin and isoniazid in high doses and paracetamol in therapeutic doses. Inbred male Wistar rats were used for these studies. Hexane was injected subcutaneously, while the other drugs were given per os on 7 consecutive days each week for a period of 90 days; with the exception of the control group in the hexane study, all the control groups were untreated. Pyruvate, a precursor for gluconeogenesis (synthesis of glucose from non-carbohydrate sources) is an excellent substrate for the formation of oxaloacetate, which is probably an obligatory intermediate in the pathway to glucose synthesis. It has been used over a number of years by different investigators who have .studied gluconeogenesis using the isolated liver perfusion technique. It was used for the same purpose in the present study. Methylene blue, a redox dye, capable of oxidising NADH to NAD+, was used to determine whether an altered NADH : NAD+ ratio would have any effect on the output of glucose in the ethanol, paracetamol and hexane studies. Fructose, a non-NAD+ dependent precursor of glucose. was also used for this purpose in the ethanol study. All the drugs studied were found to inhibit gluconeogenesis. This was shown by a decrease in glucose levels and an increase in lactate : pyruvate ratios in the perfusion medium of experimental livers. The decreased glucose production by the experimental livers, which occurred pari passu with an increased pyruvate utilization, indicates that in these animals pyruvate was used for the production of other compounds such as lactate. In contrast. glucose production and pyruvate utilization were increased in the control group indicating that pyruvate was used mainly for the production of glucose. In the ethanol group, impaired gluconeogenesis was probably due to a change in the NADH : NAD+ ratio; when methylene blue was introduced into the perfusion medium of this group the output of glucose was high. Impaired gluconeogenesis in the paracetamol and hexane-treated groups was probably related to the non-availability of oxaloacetate or impairment of the activity of key enzymes involved in gluconeogenesis; when methylene blue was added to the perfusion medium of these animals the glucose output remained low. Except for the rifampicin study. bromosulphthalein clearance was impaired in all the experimental groups. Histological examination of liver tissue obtained from the hexane-treated animals demonstrated severe fatty change. In conclusion, these studies have demonstrated that the isolated liver perfusion technique is a suitable method of evaluating the effect of therapeutic and supra-therapeutic doses of some drugs which affect hepatic function. Ethanol, isoniazid, rifampicin, paracetamol (in therapeutic doses) and hexane were found to alter liver function as evidenced by impaired gluconeogenesis and bromosulphthalein clearance. In addition, histological evidence of liver damage was noted in rats treated with hexane. / Thesis (M.Med.Sc.)-University of Natal, Durban, 1988.

Yes / Introduction: There are risks to the safety of medicines management when patient care is transferred between healthcare organisations, for example when a patient is discharged from hospital. Using the theoretical concept of resilience in healthcare, this study aimed to better understand the proactive role that patients can play in creating a safer, resilient medicines management at a common transition of care. Methods: Qualitative interviews with 60 cardiology patients six weeks after their discharge from two UK hospitals explored patients’ experiences with their discharge medicines. Data were initially subjected to an inductive thematic analysis and a subsequent theory-guided deductive analysis. Results: During interviews twenty-three patients described medicines management resilience strategies in two main themes: identifying system vulnerabilities; and establishing self-management strategies. Patients could anticipate problems in the system that supplied them with medicines and took specific actions to prevent them. They also identified when errors had occurred both before and after medicines had been supplied and took corrective action to avoid harm. Some reported how they had not foreseen problems or experienced patient safety incidents. Patients recounted how they ensured information about medicines changes was correctly communicated and acted upon, and identified their strategies to enhance their own reliability in adherence and resource management. Conclusion: Patients experience the impact of vulnerabilities in the medicines management system across the secondary-primary care transition but many are able to enhance system resilience through developing strategies to reduce the risk of medicines errors occurring. Consequently, there are opportunities – with caveats – to elicit, develop and formalise patients’ capabilities which would contribute to safer patient care and more effective medicines management.

Improving medication management at transitions of care is a national and international priority. People with dementia, who transition between hospitals and care homes, can be at an increased risk of adverse events, harm and costly re-hospitalisation. There is limited research which examines factors which may influence the quality and continuity of medication management in this context, particularly in the UK. This research uses a systems approach to explore the factors which may influence the quality and continuity of medication management when people, with dementia, move between the care home and hospital setting. This multi method, multi-phase study included interviews with hospital staff, care home staff, residents with dementia and relatives and examination of policies and documents used to support medication management at transition. Overall, policy recommendations and implementation strategies to support medication management at transition were limited. Residents, staff and relatives emphasised the importance of administration routines and preferences, but there were no strategies to support the communication of this information. Procedures, tools and training to support care homes based medication reconciliation was also limited. Residents and relatives were rarely involved in medication management due to limited resources and decision making. This sustained, rather than challenged, the power imbalance between residents and staff. Better defined roles and integrated processes which take account of the needs of this transition may help residents, relatives and care home staff to feel valued and empowered to provide information which supports person-centred medication management and boost resilience by helping to identify medication errors or adverse events. / Alzheimer’s Society

No / Avoidable harm associated with medicines is widespread – particularly at care transitions – and unintended discrepancies in patients’ medicines after discharge from hospital affect more than half of all patients. Patients with heart failure are frequent service users (including readmission to hospital), and susceptible to deficiencies in medicines management. Heart failure is responsible for approximately 5% of medical admissions and the readmission rate within 3 months of discharge may be as high as 50%.[1] The Improving Safety and Continuity of Medicines management at Transitions of care (ISCOMAT) study is an NIHR-funded programme of research in patients with heart failure. The first work package, described here, aimed to map and evaluate current medicines management pathways across care transitions, describing the core characteristics of best practice and effective systems at each stage. Mixed-methods research collecting data centred on patients’ journey out of hospital and back home exploring current practice relating on heart failure. NHS REC approval was obtained (16/NS/0018). Following a process of informed consent, data were collected from patients (n=16) in four health economies in England using semi-structured interviews conducted shortly after their discharge from hospital and again after two and six weeks and included video recording. Non-participant observation was conducted on cardiology wards in the four areas to understand predominant systems employed by the hospitals to deliver information to patients and to primary care. Interviews with staff in hospitals and primary care explored policy, practice and systems across the transition. Data were analysed using integrative ‘parallel mixed’ analysis. Several themes emerged that described the resilience of the system that manages patients’ medicines across the whole pathway. Spatial dimensions – including local working conditions – impacted on staff who managed transfers. Process efficiencies and effectiveness, including the degree of staff training and policy awareness, both enhanced and hindered communication with patients and health care professionals (HCPs) in primary care. The system did not allow staff to assess the impact of the management of medicines at discharge across the transition into primary care. Patients themselves were found to have different levels of knowledge and confidence in their medicines once back at home and, where their pathway included this, to value the care co-ordination functions of heart failure nurses. Primary care staff operated varying systems for managing discharge communication and implementing recommendations and some reported positive outcomes from integration of practice pharmacists into the system. To our knowledge this is the first UK study of medicines management along the patient’s journey from hospital into primary care for patients with heart failure. A whole pathway analysis has enabled a detailed understanding of resilience in each part of the healthcare system. These findings will be used in the co-design of an intervention to improve medicines management in the next phase of the research.

Yes / Introduction A key priority for the UK National Health Service and patients is to ensure that medicines are used safely and effectively. However, medication changes are not always optimally communicated and implemented when patients transfer from hospital into community settings. Heart failure is a common reason for admission to hospital. Patients with heart failure have a high burden of morbidity, mortality and complex pharmacotherapeutic regimens. The Improving the Safety and Continuity Of Medicines management at Transitions of care programme comprises a cluster randomised controlled trial which will test the effectiveness of a complex behavioural intervention aimed at improving medications management at the interface between hospitals discharge and community care. We will conduct a rigorous process evaluation to inform interpretation of the trial findings, inform implementation of the intervention on a wider scale and aid dissemination of the intervention. Methods and analysis The process evaluation will be conducted in six purposively selected intervention sites (ie, hospital trusts and associated community pharmacies) using a mixed-methods design. Fidelity and barriers/enablers of implementation of the Medicines at Transitions Intervention (MaTI) will be explored using observation, interviews (20 patients, 40 healthcare professionals), surveys and routine trial data collection on adherence to MaTI. A parallel mixed analysis will be applied. Qualitative data will be thematically analysed using Framework analysis and survey data will be analysed descriptively. Data will be synthesised, triangulated and mapped to the Consolidated Framework for Implementation Research where appropriate. The process evaluation commenced on June 2018 and is due to end on February 2021. Ethics and dissemination Approved by Research Ethics Committee and the UK Health Research Authority REC: 18/YH/0017/IRAS: 231 431. Findings will be disseminated via academic and policy conferences, peer-reviewed publications and social media. Trial registration number ISRCTN66212970.

Improving the safety of medicines management when people leave hospital is an international priority. There is evidence that poor co-ordination of medicines between providers can cause preventable harm to patients, yet there is insufficient evidence of the structure and function of the medicines management system that patients experience. This research used a mixed-methods social network analysis to determine the structure, content and function of that system as experienced by patients. Patients’ networks comprised a range of loosely connected healthcare professionals in different organisations and informal, personal contacts. Networks performed multiple functions, including health condition management, and orienting patients concerning their medicines. Some patients experienced safety incidents as a function of their networks. Staff discharging patients from hospital were also observed. Contributory factors that were found to risk the safety of patients’ discharge with medicines included active failures, individual factors and local working conditions. System defences involving staff and patients were also observed. The study identified how patients often co-ordinated a system that lacked personalisation and there is a need to provide more consistent support for patients’ self-management of medicines after they leave hospital. This could be achieved through interventions that include patients’ informal contacts in supporting their medicines use, enhancing their resilience to preventable harm, and developing and testing the role of a ‘medicines key worker’ in safely managing the transfer of care. The role of GP practices in co-ordinating the involvement of multiple professionals in patient polypharmacy needs to be further explored.

This thesis consists of three main parts. An introduction to diode-pumped solid-state lasers, thermal modelling of solid-state lasers and rate-equation modelling of solid-state lasers. The first part explains the basic components and operation principles of a typical diode-end-pumped solid-state laser. The stimulated emission process, solid-state laser gain media, various pump geometries and a basic end-pumped laser resonator configuration are among the topics that are explained. Since thermal effects are one of the main limiting factors in the power-scaling of diode-pumped solid-state lasers, the second part of this thesis describes numerical and analytical thermal models that determine the thermal lens and thermally induced stresses in a laser crystal. As a first step, a time-independent numerical thermal model which calculates the three-dimensional temperature distribution in the laser crystal is implemented. In order to calculate the time dependent thermally induced stresses in a laser crystal, a coupled thermal-stress finite element analysis model was implemented. Even though some steady-state analytical solutions for simple crystal geometries do exist, the finite element analysis approach was taken so that the time dependent thermally induced stresses could be calculated for birefringent crystals of various geometries. In order to validate the numerical results, they are compared to experimental data and analytical solutions where possible. In the last part, the population dynamics inside the laser gain medium are described and modelled with a quasi-three-level rate-equation model. A comprehensive spatially resolved rate-equation model is developed and discussed. In order to simplify the implementation of the rate-equation model as a computer simulation, the spatial dependence of the laser parameters is ignored so that the model reduces to a singleelement plane-wave model. The simplified rate-equation model is implemented and solved numerically. The model is applied to a four-level CW and Q-switched Nd:YLF laser as well as a quasi-three-level QCW Tm:GdV04 laser. The models' predictions are thoroughly verified with experimental results and also with analytical solutions where possible. / Thesis (M.Med.Sc.)-University of KwaZulu-Natal, Durban, 2007.

Theophylline is one of the few preparations available for the treatment of apnoea of prematurity. Currently little data is available on the pharmacokinetics and the pharmacokinetic/pharmacodynamic relationships of theophylline for premature neonates during the first few days of life, a time when neonates undergo profound physiological changes and when the drug is most often used. Furthermore, the influence of theophylline on hypoxaemic episodes has not yet been quantified. The study aimed to investigate optimal theophylline dosing in this group by establishing pharmacokinetic parameters, assessing the effectiveness of the drug in abolishing apnoea and hypoxaemic episodes and investigating the concentration/effect relationship. The project was conducted in the neonatal wards of King Edward VIII Hospital, Durban, South Africa. The study group comprised a total of 105 Black, apnoeic, premature neonates, with respiratory distress syndrome, who were receiving intravenous theophylline. Serum samples (263), collected from patients during routine care, were analysed for theophylline. Forty-six patients were monitored before and after theophylline therapy with a neonatal capnograph linked to a data acquisition. Apnoea incidents were classified into total (all apnoea <_5 seconds) and pathologic (all apnoea >_20 seconds) and a hypoxaemic episode was defined as a >_10% fall for >10 seconds in peripheral oxygen saturation. Within each of these groups patients were assessed as responders (>_50% reduction in the clinical effect from baseline to the last recording) and non-responders. Patient characteristics were identified as possible markers of non-response to theophylline therapy. The Nonlinear Mixed Effects Model (NONMEM) was used to derive population pharmacokinetic models and parameters for theophylline as well as to assess the concentration-effect relationship. The pharmacokinetic analysis estimated a low clearance and volume of distribution, with oxygen support enhancing clearance. Relatively high inter-individual and residual variability values were obtained prompting testing for inter-occasion variability. This resulted in a decrease of inter-individual variability for clearance and volume of distribution as well as in residual variability. In the theophylline doses used, a significant reduction in total and pathologic apnoea but not in hypoxaemic episodes occurred over the first three days after birth. The most positive improvement was seen on the first day of treatment after the loading dose. A statistically significant increase in the average pulse rate and a decrease in episodes of bradycardia from baseline to all three days of monitoring were recorded. Most patients responded at serum theophylline concentrations of 3 to 9 mg/L. Most serum theophylline concentration measurements were also in this range and it was not possible to clearly define a concentration-effect relationship. The cumulative percentage of non-responders was relatively high for total apnoea (48%) and hypoxaemic episodes (45%), but low for pathological apnoea (13%). Being one of a set of twins was identified as a marker of poor response for both total apnoea and hypoxaemic episodes. Other possible markers for poor response, in terms of total hypoxaemic episodes, were being born by caesarean section and having more than the 75th percentile pathologic apnoea per hour at baseline. It was interesting to note that, with regard to total apnoea, there were some features that seemed to predict a favourable response to theophylline. These were birth weight and 5 minute Apgar score below the 25th percentile, and patients with baseline total apnoea counts above the 75th percentile. The cumulative graphs of the responders and non-responders resembled the fixed effect model, which is the simplest model to explain drug-effect relationships. More sophisticated analysis of the concentration-effect relationship, using NONMEM and the count model proved difficult. None of the models tested were found to be satisfactory, but that which included the influence of a hypothetical respiratory depressant factor gave the most realistic value of EC50. It is suggested that further even more complex modelling may be required to accurately define the concentration-effect relationship (and hence the therapeutic range) for theophylline in neonatal apnoea. / Thesis (Ph.D.)-University of Natal, Durban, 2000.