Lipoprotein Metabolism in the Nephrotic Syndrome in Man

The aim of this thesis was to characterise the abnormalities of plasma lipoprotein metabolism which occur in the nephrotic syndrome in man. Both quantitative and qualitative changes in plasma lipoproteins were documented in a series of 45 consecutive patients with heavy proteinuria. Patients with proteinuria less than the nephrotic range (<3g/24 hours) did not have any significant elevations in cholesterol concentrations compared to controls but there was a relationship between urinary albumin loss and blood cholesterol. Primary hyperlipidaemia was not associated with increased urinary albumin losses. The duration and magnitude of postprandial lipaemia following an oral fat load were not significantly greater in a group of nephrotic subjects compared to controls. However, both groups showed a high degree of interindividual variation. The lipoproteins isolated in the d< 1.006g/mL fraction following an oral fat load did not differ in composition between the two groups. Post-heparin lipase activities were not significantly different. The transfer of apolipoprotein B along the delipidation cascade from very low to low density lipoproteins was investigated using radioiodinated lipoproteins. Overall, apoB synthesis in nephrotic syndrome was not greater than in controls although the range in the nephrotic group was wide (up to four times normal). There was a significant increase in the production of apoB into the smaller, triglyceride-poor VLDL2 density interval. Both VLDL1 and VLDL2 were cleared from the plasma at slower rates in the nephrotic syndrome. There was a modest increase in apoB transfer to LDL. Studies of LDL metabolism revealed a consistent defect in fractional catabolism of LDL by the receptor-mediated pathway. LDL production was closely related to proteinuria and only rose when this exceeded 10g/day. Inhibition of cholesterol synthesis with simvastatin produced dramatic falls in total and LDL-cholesterol in these subjects. Metabolic studies revealed a heterogeneous response with a majority of patients demonstrating increased catabolism of LDL but some showing reduced synthesis. Two serious and potentially worrying adverse events were witnessed during simvastatin therapy. Particles corresponding to both HDL and LDL were isolated form urine collected from nephrotic subjects. The significance of this is uncertain but justified the corrections made for urinary LDL losses in the metabolic studies and gives credence to the suggestion that filterd lipoproteins may be nephrotoxic. The results of these studies are compared with the relatively few previous reports of lipoprotein metabolism in human nephrotic syndrome and the extensive literature on animal work. In man, catabolic defects appear to be at least as important as increases in lipoprotein production in the genesis of the hyperlipidaemia. However, some of the data is difficult to reconcile. Reasons for conflicting observations are discussed and areas requiring further research are highlighted

Corpus callosotomy outcomes in paediatric patients

Corpus callosotomy is a palliative disconnective neurosurgical treatment that is typically employed for patients with medically refractory epilepsy characterised by injurious drop attacks. This thesis describes the 20 year experience with corpus callosotomy at Great Ormond Street Hospital for Children (GOSH) in London and the Children’s Hospital at Westmead (CHW) in Sydney. Between January 1995 and December 2015, 76 patients underwent corpus callosotomy at GOSH (n=47) and CHW (n=29); 55 patients met inclusion criteria. Patient records were analysed for changes in seizure type and frequency, changes in injuries, changes in use of antiepileptic drugs, and neurological and surgical complications. Rare or no drop attacks was analysed using Kaplan–Meier event-free survival curves using right-censoring of data. Multivariable regression analysis was used to assess the effect of clinical characteristics on outcome at last follow up. Median follow up was 36 months (interquartile range 34 months). Overall 26/55 patients (47.3%) had rare or no drop attacks at last follow up. Of the children who had drop attacks at last follow up, 26/29 of these patients (89.7%) had a return of drop attacks within 12 months of surgery. There were no significant predictors of developing drop attacks post-surgery. Neurological complications occurred in 11/55 operations (20.0%) and resolved within 6 weeks in all patients. Surgical complications occurred in 6/55 operations (10.9%), with only one major complication (hydrocephalus) and no deaths. Corpus callosotomy was a well-tolerated palliative procedure that was effective at reducing the severity of drop attacks in this case series. In patients for whom drop attacks return, they are likely to do so within 12 months of surgery. Several other case series and systematic reviews provide evidence to support the hypothesis that corpus callosotomy is a safe and effective palliative treatment for patients with medically refractory generalised seizures that is typically characterised by injurious drop attacks. But there is no strong evidence to demonstrate the validity of that hypothesis. A case study is presented to highlight some of the bioethical issues of corpus callosotomy in children. Parental resistance to epilepsy surgery is a well-known barrier to access for all epilepsy surgery. While earlier intervention has demonstrable benefits on quality of life, some parents find the prospect of disconnection syndrome challenging and resist corpus callosotomy. The case study is then used to frame issues relating to consent and the best interests of children undergoing corpus callosotomy, highlighting the shortcomings of the concept of autonomy

Time, timing, talking and training : findings from an exploratory action research study to improve quality of end of life care for minority ethnic kidney patients

Background. With an ageing and increasingly diverse population at risk from rising levels of obesity, diabetes and cardiovascular disease, including kidney complications, there is a need to provide quality care at all stages in the care pathway including at the end of life and to all patients. Aim. This study purposively explored South Asian patients' experiences of kidney end of life care to understand how services can be delivered in a way that meets diverse patient needs. Methods. Within an action research design 14 focus groups (45 care providers) of kidney care providers discussed the recruitment and analysis of individual interviews with 16 South Asian kidney patients (eight men, eight women). Emergent themes from the focus groups were analysed thematically. The research took place at four UK centres providing kidney care to diverse populations: West London, Luton, Leicester and Bradford. Results. Key themes related to time and the timing of discussions about end of life care and the factors that place limitations on patients and providers in talking about end of life care. Lack of time and confidence of nurses in areas of kidney care, individual attitudes and workforce composition influence whether and how patients have access to end of life care through kidney services. Conclusion. Training, team work and time to discuss overarching issues (including timing and communication about end of life) with colleagues could support service providers to facilitate access and delivery of end of life care to this group of patients.Peer reviewedFinal Published versio

The efficient use of the maternity workforce and the implications for safety and quality in maternity care : a population-based, cross-sectional study

Background: The performance of maternity services is seen as a touchstone of whether or not we are delivering high-quality NHS care. Staffing has been identified in numerous reports as being a critical component of safe, effective, user-centred care. There is little evidence regarding the impact of maternity workforce staffing and skill mix on the safety, quality and cost of maternity care in the UK. Objectives: To understand the relationship between organisational factors, maternity workforce staffing and skill mix, cost and indicators of safe and high-quality care. Design and methods: Data included Hospital Episode Statistics (HES) from 143 NHS trusts in England in 2010–11 (656,969 delivery records), NHS Workforce Statistics, England, 2010–11, Care Quality Commission Maternity Survey of women’s experiences 2010 and NHS reference costs 2010/11. Ten indicators were derived from HES data. They included healthy mother and healthy baby outcomes and mode of birth. Adjustments were made for background characteristics and clinical risk. Data were analysed to examine the influence of organisational factors, staffing and costs using multilevel logistic regression models. A production function analysis examined the relationship between staffing, skill mix and output. Results: Outcomes were largely determined by women’s level of clinical risk [based on National Institute for Health and Care Excellence (NICE) guidance], parity and age. The effects of trust size and trust university status were small. Larger trust size reduced the chance of a healthy mother outcome and also reduced the likelihood of a healthy mother/healthy baby dyad outcome, and increased the chances of other childbirth interventions. Increased investment in staff did not necessarily have an effect on the outcome and experience measures chosen, although there was a higher rate of intact perineum and also of delivery with bodily integrity in trusts with greater levels of midwifery staffing. An analysis of the multiplicative effects of parity and clinical risk with the staffing variables was more revealing. Increasing the number of doctors had the greatest impact on outcomes in higher-risk women and increasing the number of midwives had the greatest impact on outcomes in lower-risk women. Although increased numbers of support workers impacted on reducing childbirth interventions in lower-risk women, they also had a negative impact on the healthy mother/healthy baby dyad outcomes in all women. In terms of maximising the capacity of a trust to deliver babies, midwives and support workers were found to be substitutes for each other, as were consultants and other doctors. However, any substitution between staff groups could impact on the quality of care given. Economically speaking, midwives are best used in combination with consultants and other doctors. Conclusions: Staffing levels have positive and negative effects on some outcomes, and deployment of doctors and midwives where they have most beneficial impact is important. Managers may wish to exercise caution in increasing the number of support workers who care for higher-risk women. There also appear to be limited opportunities for role substitution. Future work: Wide variations in outcomes remain after adjustment for sociodemographic and clinical risk, and organisational factors. Further research is required on what may be influencing unexplained variation such as organisational climate and culture, use of NICE guidelines in practice, variation of models of care within trusts and women’s choices. Funding: The National Institute for Health Research Health Services and Delivery Research programme

Rainfall–runoff simulations to assess the potential of SuDS for mitigating flooding in highly urbanized catchments

Sustainable Urban Drainage Systems (SuDS) constitute an alternative to conventional drainage when managing stormwater in cities, reducing the impact of urbanization by decreasing the amount of runoff generated by a rainfall event. This paper shows the potential benefits of installing different types of SuDS in preventing flooding in comparison with the common urban drainage strategies consisting of sewer networks of manholes and pipes. The impact of these systems on urban water was studied using Geographic Information Systems (GIS), which are useful tools when both delineating catchments and parameterizing the elements that define a stormwater drainage system. Taking these GIS-based data as inputs, a series of rainfall–runoff simulations were run in a real catchment located in the city of Donostia (Northern Spain) using stormwater computer models, in order to compare the flow rates and depths produced by a design storm before and after installing SuDS. The proposed methodology overcomes the lack of precision found in former GIS-based stormwater approaches when dealing with the modeling of highly urbanized catchments, while the results demonstrated the usefulness of these systems in reducing the volume of water generated after a rainfall event and their ability to prevent localized flooding and surcharges along the sewer network

Janina Maria Sokołowska (1945): the first woman veterinary surgeon from the Royal (Dick) Veterinary College, Edinburgh

Internationally, almost all the students who qualified as veterinary surgeons prior lo 1900 were men. However, in the last two decades of the nineteenth century women were expressing their wishes to be similarly qualified. One of the first women to achieve that ambition was Stephania Kruszevska, from Warsaw, Poland, who acquired her veterinary degree in Zurich in 1889. ln Scotland, in 1894, William Williams of the New Veterinary College, Elm Row, Edinburgh accepted the apptication or Aleen Cust (1868-1937). She enrolled in the college under the name A.l. Custance to study veterinary medicine. Despite examination entitlement impediments placed in her way by the lawyers of the Royal College of Veterinary Surgeons, Williams gave her a testimonial in 1900 at the end of her coursework in his college, expressing his satisfaction that she was now a qualified veterinary surgeon

Exploring access to end of life care for ethnic minorities with end stage kidney disease through recruitment in action research

BACKGROUND: Variation in provision of palliative care in kidney services and practitioner concerns to provide equitable access led to the development of this study which focussed on the perspectives of South Asian patients and their care providers. As people with a South Asian background experience a higher risk of Type 2 Diabetes (T2DM) and end stage kidney failure (ESKF) compared to the majority population but wait longer for a transplant, there is a need for end of life care to be accessible for this group of patients. Furthermore because non English speakers and people at end of life are often excluded from research there is a dearth of research evidence with which to inform service improvement. This paper aims to explore issues relating to the process of recruitment of patients for a research project which contribute to our understanding of access to end of life care for ethnic minority patients in the kidney setting. METHODS: The study employed an action research methodology with interviews and focus groups to capture and reflect on the process of engaging with South Asian patients about end of life care. Researchers and kidney care clinicians on four NHS sites in the UK recruited South Asian patients with ESKF who were requiring end of life care to take part in individual interviews; and other clinicians who provided care to South Asian kidney patients at end of life to take part in focus groups exploring end of life care issues. In action research planning, action and evaluation are interlinked and data were analysed with emergent themes fed back to care providers through the research cycle. Reflections on the process of patient recruitment generated focus group discussions about access which were analysed thematically and reported here. RESULTS: Sixteen patients were recruited to interview and 45 different care providers took part in 14 focus groups across the sites. The process of recruiting patients to interview and subsequent focus group data highlighted some of the key issues concerning access to end of life care. These were: the identification of patients approaching end of life; and their awareness of end of life care; language barriers and informal carers' roles in mediating communication; and contrasting cultures in end of life kidney care. CONCLUSIONS: Reflection on the process of recruitment in this action research study provided insight into the complex scenario of end of life in kidney care. Some of the emerging issues such as the difficulty identifying patients are likely to be common across all patient groups, whilst others concerning language barriers and third party communication are more specific to ethnic minorities. A focus on South Asian ethnicity contributes to better understanding of patient perspectives and generic concepts as well as access to end of life kidney care for this group of patients in the UK. Action research was a useful methodology for achieving this and for informing future research to include informal carers and other ethnic groups.Peer reviewedFinal Published versio