Vitamin D and endothelial function in chronic kidney disease

PhDVitamin D deficiency in patients with chronic kidney disease, measured by reduced serum concentrations of 25 hydroxy vitamin D, is highly prevalent and associated with both endothelial dysfunction and an increased risk of cardiovascular disease. Observational studies in chronic kidney disease have demonstrated that vitamin D therapy reduces the risk of cardiovascular disease. In patients with chronic kidney disease and concomitant vitamin D deficiency, the effect of vitamin D therapy on endothelial function, which is associated with cardiovascular disease, is poorly understood. The mechanism by which vitamin D affects endothelial function is unclear. Methods Presented in this thesis, two studies have addressed these issues: 1. A double blind, randomized controlled trial evaluating the effect of ergocalciferol compared to placebo on microcirculatory endothelial function in patients with non-dialysis chronic kidney disease and concomitant vitamin D deficiency 2. In vitro and in vivo experiments to determine the mechanistic effect of ergocalciferol on endothelial function in an experimental model of uraemia. Results In the clinical study, ergocalciferol increased vitamin D serum concentrations and improved microcirculatory endothelial function measured by laser Doppler flowmetry after iontophoresis of acetylcholine. Oxidative stress measured by skin autofluorescence for advanced glycation end products did not change in the ergocalciferol group but increased significantly in the placebo group. Ergocalciferol increased endothelial nitric oxide synthase expression and activity in cultured human endothelial cells and improved endothelial function in an in vivo model of mild uraemia. The findings from the in vivo and clinical studies occurred independently of changes in blood pressure, conduit artery function, serum calcium, phosphate and parathyroid hormone supporting in vitro findings that ergocalciferol acts directly on the endothelium. Conclusion Ergocalciferol improved endothelial function in both rodent and human subjects with chronic kidney disease. Experimental evidence suggests this effect occurs through an endothelium dependent mechanism involving changes in the upregulation and function of endothelial nitric oxide synthase.This thesis was supported by funding from the British Renal Society (Grant number BRS 09/010) and the Barts and the London Charitable Trus

Inclusive jet spectrum for small-radius jets

Following on our earlier work on leading-logarithmic (LLR) resummations for the properties of jets with a small radius, R, we here examine the phenomenological considerations for the inclusive jet spectrum. We discuss how to match the NLO predictions with small-R resummation. As part of the study we propose a new, physically-inspired prescription for fixed-order predictions and their uncertainties. We investigate the R-dependent part of the next-to-next-to-leading order (NNLO) corrections, which is found to be substantial, and comment on the implications for scale choices in inclusive jet calculations. We also examine hadronisation corrections, identifying potential limitations of earlier analytical work with regards to their $p_t$-dependence. Finally we assemble these different elements in order to compare matched (N)NLO+LLR predictions to data from ALICE and ATLAS, finding improved consistency for the R-dependence of the results relative to NLO predictions.Comment: 42 pages, 24 figures, additional material at http://microjets.hepforge.org/, updated to match published versio

Health related quality of life in patients with end stage kidney disease treated with haemodialysis in Malawi: a cross sectional study

Kidney Disease and Quality of Life Short Form Questionnaire (KDQOL-SFTM). (PDF 168 kb

Small-radius jets to all orders in QCD

As hadron collider physics continues to push the boundaries of precision, it becomes increasingly important to have methods for predicting properties of jets across a broad range of jet radius values R, and in particular for small R. In this paper we resum all leading logarithmic terms, $\alpha_s^n \ln^n R$, in the limit of small R, for a wide variety of observables. These include the inclusive jet spectrum, jet vetoes for Higgs physics and jet substructure tools. Some of the quantities that we consider are relevant also for heavy-ion collisions. Furthermore, we examine and comment on the underlying order-by-order convergence of the perturbative series for different R values. Our results indicate that small-R effects can be substantial. Phenomenological studies will appear in a forthcoming companion paper.Comment: 34 pages, 10 figures, updated to match published versio

Framing energetic top-quark pair production at the LHC

Top-quark pair production is central to many facets of LHC physics. At leading order, the top and anti-top are produced in a back-to-back topology, however this topology accounts only for a minority of $t \bar t$ events with TeV-scale momentum transfer. The remaining events instead involve the splitting of an initial or final-state gluon to $t \bar t$. We provide simple quantitative arguments that explain why this is the case and examine the interplay between different topologies and a range of variables that characterise the event hardness. We then develop a method to classify the topologies of individual events and use it to illustrate our findings in the context of simulated events, using both top partons and suitably defined fiducial tops. For events with large $t \bar t$ invariant mass, we comment on additional features that have important experimental and theoretical implications.Comment: 23 pages + 2 appendice

Use of an electronic medical record to monitor efficacy of diabetes care in out-patients in a central hospital in Malawi: Patterns of glycaemic control and lessons learned

The Malawian health sector has a strong tradition of systematic data collection for monitoring and evaluation of large-scale services. A highly successful adapted Directly Observed Treatment, Short course “DOTS” framework, based on patient registers and paperbased mastercards was introduced to facilitate the management and monitoring of the scale up of antiretroviral therapy. Subsequently, a simple, touch-screen based electronic medical record system (EMRs) was effectively introduced at high burden ART sites. Based on this model, in 2010, a diabetes specific EMRs was introduced in the diabetes clinic at Queen Elizabeth Central Hospital. In this paper we report on the first 3 years experience with the diabetes EMRs. We highlight the strengths and weaknesses of the diabetes EMRs and present data on glycaemic control recorded in the system

Cost-Effectiveness of Automated Digital Microscopy for Diagnosis of Active Tuberculosis.

BACKGROUND: Automated digital microscopy has the potential to improve the diagnosis of tuberculosis (TB), particularly in settings where molecular testing is too expensive to perform routinely. The cost-effectiveness of TB diagnostic algorithms using automated digital microscopy remains uncertain. METHODS: Using data from a demonstration study of an automated digital microscopy system (TBDx, Applied Visual Systems, Inc.), we performed an economic evaluation of TB diagnosis in South Africa from the health system perspective. The primary outcome was the incremental cost per new TB diagnosis made. We considered costs and effectiveness of different algorithms for automated digital microscopy, including as a stand-alone test and with confirmation of positive results with Xpert MTB/RIF ('Xpert', Cepheid, Inc.). Results were compared against both manual microscopy and universal Xpert testing. RESULTS: In settings willing to pay $2000 per incremental TB diagnosis, universal Xpert was the preferred strategy. However, where resources were not sufficient to support universal Xpert, and a testing volume of at least 30 specimens per day could be ensured, automated digital microscopy with Xpert confirmation of low-positive results could facilitate the diagnosis of 79-84$1280 per incremental TB diagnosis (95% uncertainty range, UR: $340-$3440) in the base case, but improved under conditions likely reflective of many settings in sub-Saharan Africa: $677 per diagnosis (95$450-$935) when sensitivity of manual smear microscopy was lowered to 0.5, and$956 per diagnosis (95% UR: $40-$2910) when the prevalence of multidrug-resistant TB was lowered to 1%. CONCLUSIONS: Although universal Xpert testing is the preferred algorithm for TB diagnosis when resources are sufficient, automated digital microscopy can identify the majority of cases and halve the cost of diagnosis and treatment when resources are more scarce and multidrug-resistant TB is not common

Proteinuric kidney disease in children at Queen Elizabeth Central Hospital, Malawi

Background: There is a paucity of data on paediatric kidney disease in developing countries such as Malawi. Descriptive research on kidney disease is essential to improving patient outcomes. Methods: We conducted a cross-sectional study at a tertiary hospital in Malawi from 2012 to 2013. Children under 14 years with proteinuric kidney disease were enrolled from paediatric wards and outpatient clinics at Queen Elizabeth Central Hospital (QECH). Demographic, clinical and laboratory data were collected from patients at enrolment and at 3 months review at which point clinical status and disease outcome were ascertained. Results: Thirty-four (22 male) patients were studied, mean age 8.54 (SD = 3.62 years). Glomerular disease (n = 25, 68%) was the most common presumed renal lesion at presentation. Nephritic syndrome (10) was characterised by a lower baseline complement C3 than nephrotic syndrome (p = 0.0027). Seven (47%) cases of nephrotic syndrome achieved complete remission. Eight (80%) cases of nephritic syndrome improved with supportive therapy. Nineteen (56%) patients presented with clinically significant renal damage with eGFR< 60 ml/min/1.73m2 . Six patients presented in chronic kidney disease (CKD) stage 5 of unclear aetiology, five (83%) died. Three (9%) patients had impaired kidney function and obstructive uropathy demonstrated on ultrasound, two recovered after surgery and one died. Eight (24%) patients had acute kidney injury (AKI) due to primary kidney disease, three of these patients progressed to CKD stage G3a. Seven (21%) patients were lost to follow up. Conclusion: Kidney disease is a significant cause of mortality and morbidity in children at QECH. Less than half of Nephrotic syndrome cases achieved complete remission. Mortality is highest in children with CKD of unclear cause. Some patients with AKI secondary to primary renal disease progressed to CKD. Understanding the aetiology of paediatric kidney disease and improving patient outcomes by developing enhanced diagnostic and clinical services are priorities at QECH and within Malawi