Survival modelling for patients with end stage renal failure: implications for access to renal transplantation in the UK

Kidney transplantation has revolutionised the treatment of end stage renal disease (ESRD), offering a significant increase in life expectancy, quality of life and cost-effectiveness when compared with dialysis. However, the provision of transplantation is under immense pressure due to the vastly insufficient number of donor organs, the growing incidence of ESRD and the increasing age and burden of comorbidity of the ESRD population. There is evidence for considerable disparities in access to transplantation across transplant centres in the UK and in the outcomes and prognosis of individual patients. This raises complex issues regarding the assessment of patient suitability for transplantation, maximisation of transplant outcomes and equitable access to transplantation at an individual as well as a societal level. The aims of this thesis were to address the following key questions: 1) What factors may be contributing to inequity in access to transplantation in the UK? 2) How do patient factors including comorbidity affect graft and patient survival after renal transplantation, and do survival rates differ between centres in the UK? 3) Do patient reported outcome measures differ after living and deceased donor kidney transplantation? 4) What factors affect the survival of patients on dialysis, and can these risk factors be quantified in a survival prediction score aimed at reducing inequity and standardising access to the waiting list? The research was conducted as part of the national prospective cohort study Access to Transplantation and Transplant Outcome Measures (ATTOM), which is the first study to include ESRD patients from all 72 renal units in the UK. The study included a total of 6844 patients recruited into three different cohorts; incident dialysis, incident transplant and prevalent matched control waiting list cohorts. The findings showed significant variation between UK centres with regard to the level of comorbidity among patients accepted to the waiting list and to transplantation. Thus, centre differences in selection criteria, patient assessment and risk tolerance are likely to be contributing to inequity in access to transplantation across the UK. The data highlighted significant socio-demographic differences between dialysis, waiting list and transplant patients. Older, more socially deprived patients and patients with a lower level of educational attainment were significantly less likely to be listed for transplantation. These same groups of patients in addition to patients from ethnic minorities were additionally disadvantaged with regard to undergoing living donor transplantation and pre-emptive transplantation. Geographic factors also contributed to disparities in living donor transplantation. The key comorbid conditions that predict poorer two year graft and patient survival after kidney transplantation were identified. Peripheral vascular disease and obesity were associated with a higher risk of graft failure, while cerebrovascular disease, heart failure and chronic liver disease were associated with inferior patient survival after transplantation. The risks associated with these conditions have been quantified and can be used to fully inform patients of their individual risks, thereby facilitating shared decision-making and informed consent. Contrary to previous reports, there was no evidence of any inter-centre variation in survival outcomes of transplant patients in the UK. Living donor kidney transplantation was associated with better patient reported health status, wellbeing, quality of life and treatment satisfaction compared with deceased donor kidney transplantation. Patients who underwent pre-emptive transplantation reported significantly worse treatment satisfaction compared with patients who received a period of dialysis prior to transplantation. Analysis of patients on dialysis showed that older age, female gender, lower serum albumin, being underweight or having diabetes, heart failure, atrial fibrillation, chronic respiratory disease, chronic liver disease or malignancy were important predictors of mortality within two years of starting dialysis. These results were developed into a survival prediction score that was internally validated. This score could be easily implemented in the clinical setting to provide patients with individual survival prediction and could also be used as a tool to aid listing decisions. The findings of this thesis have the ability to positively impact the care of patients with ESRD by driving initiatives to reduce inequity in access to transplantation, targeting disadvantaged patient groups, providing individual survival prediction for patients, informing national guidelines for fairer transplant listing and allocation and guiding future research into improving outcomes for all patients

Real-time finite-temperature correlators from AdS/CFT

In this paper we use AdS/CFT ideas in conjunction with insights from finite temperature real-time field theory formalism to compute 3-point correlators of ${\cal N}{=}4$ super Yang-Mills operators, in real time and at finite temperature. To this end, we propose that the gravity field action is integrated only over the right and left quadrants of the Penrose diagram of the Anti de Sitter-Schwarzschild background, with a relative sign between the two terms. For concreteness we consider the case of a scalar field in the black hole background. Using the scalar field Schwinger-Keldysh bulk-to-boundary propagators, we give the general expression of a 3-point real-time Green's correlator. We then note that this particular prescription amounts to adapting the finite-temperature analog of Veltman's circling rules to tree-level Witten diagrams, and comment on the retarded and Feynman scalar bulk-to-boundary propagators. We subject our prescription to several checks: KMS identities, the largest time equation and the zero-temperature limit. When specializing to a particular retarded (causal) 3-point function, we find a very simple answer: the momentum-space correlator is given by three causal (two retarded and one advanced) bulk-to-boundary propagators, meeting at a vertex point which is integrated from spatial infinity to the horizon only. This result is expected based on analyticity, since the retarded n-point functions are obtained by analytic continuation from the imaginary time Green's function, and based on causality considerations.Comment: 43 pages, 6 figures Typos fixed, reference added, one set of plots update

Mechanisms of Hypoxic Regulation of Plasminogen Activator Inhibitor-1 Gene Expression in Keloid Fibroblasts

Keloids are an excessive accumulation of extracellular matrix. Although numerous studies have shown elevated plasminogen activator inhibitor-1 (PAI-1) levels in keloid fibroblasts compared with those of normal skin. Their specific mechanisms involved in the differential expression of PAI-1 in these cell types. In this study, the upregulation of PAI-1 expression is demonstrated in keloid tissues and their derived dermal fibroblasts, attesting to the persistence, if any, of fundamental differences between in vivo and in vitro paradigms. We further examined the mechanisms involved in hypoxia-induced regulation of PAI-1 gene in dermal fibroblast derived from keloid lesions and associated clinically normal peripheral skins from the same patient. Primary cultures were exposed to an environmental hypoxia or desferroxamine. We found that the hypoxia-induced elevation of PAI-1 gene appears to be regulated at both transcriptional and post-transcriptional levels in keloid fibroblasts. Furthermore, our results showed a consistent elevation of HIF-1α protein level in keloid tissues compared with their normal peripheral skin controls, implying a potential role as a biomarker for local skin hypoxia. Treatment with antisense oligonucleotides against hypoxia-inducible factor 1α (HIF-1α) led to the downregulation of steady-state levels of PAI-1 mRNA under both normoxic and hypoxic conditions. Conceivably, our results suggest that HIF-1α may be a novel therapeutic target to modulate the scar fibrosis process

Mechanisms of Hypoxic Regulation of Plasminogen Activator Inhibitor-1 Gene Expression in Keloid Fibroblasts

Keloids are an excessive accumulation of extracellular matrix. Although numerous studies have shown elevated plasminogen activator inhibitor-1 (PAI-1) levels in keloid fibroblasts compared with those of normal skin. Their specific mechanisms involved in the differential expression of PAI-1 in these cell types. In this study, the upregulation of PAI-1 expression is demonstrated in keloid tissues and their derived dermal fibroblasts, attesting to the persistence, if any, of fundamental differences between in vivo and in vitro paradigms. We further examined the mechanisms involved in hypoxia-induced regulation of PAI-1 gene in dermal fibroblast derived from keloid lesions and associated clinically normal peripheral skins from the same patient. Primary cultures were exposed to an environmental hypoxia or desferroxamine. We found that the hypoxia-induced elevation of PAI-1 gene appears to be regulated at both transcriptional and post-transcriptional levels in keloid fibroblasts. Furthermore, our results showed a consistent elevation of HIF-1α protein level in keloid tissues compared with their normal peripheral skin controls, implying a potential role as a biomarker for local skin hypoxia. Treatment with antisense oligonucleotides against hypoxia-inducible factor 1α (HIF-1α) led to the downregulation of steady-state levels of PAI-1 mRNA under both normoxic and hypoxic conditions. Conceivably, our results suggest that HIF-1α may be a novel therapeutic target to modulate the scar fibrosis process

Pneumomediastinum as a complication of emphysematous cholecystitis: Case report

<p>Abstract</p> <p>Background</p> <p>Emphysematous cholecystitis is a variant of acute cholecystitis which is generally caused by gas-forming organisms. Emphysematous cholecystitis may cause gas spreading within the subcutaneous tissue, peritoneal cavity and retroperitoneum.</p> <p>Case presentation</p> <p>We present a case of emphysematous cholecystitis in a middle-aged diabetic patient who, postoperatively, presented edema in both flanks and left chest crepitation on palpation, associated with hemodynamic worsening. Computed tomography scan of the chest and abdomen revealed a large pneumomediastinum, pneumoretroperitoneum, gas in subcutaneous tissue and flank abscesses. In both blood and surgical wound exudate cultures, <it>Escherichia coli </it>was found.</p> <p>Conclusion</p> <p>Emphysematous cholecystitis should be considered as a possible cause of pneumomediastinum.</p

Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).

BackgroundPatients with gastrointestinal cancers and brain metastases (BM) represent a unique and heterogeneous population. Our group previously published the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with GI cancers (GI-GPA) (1985-2007, n = 209). The purpose of this study is to update the GI-GPA based on a larger contemporary database.MethodsAn IRB-approved consortium database analysis was performed using a multi-institutional (18), multi-national (3) cohort of 792 patients with gastrointestinal (GI) cancers, with newly-diagnosed BM diagnosed between 1/1/2006 and 12/31/2017. Survival was measured from date of first treatment for BM. Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios. These factors were incorporated into the updated GI-GPA.ResultsMedian survival (MS) varied widely by primary site and other prognostic factors. Four significant factors (KPS, age, extracranial metastases and number of BM) were used to formulate the updated GI-GPA. Overall MS for this cohort remains poor; 8 months. MS by GPA was 3, 7, 11 and 17 months for GPA 0-1, 1.5-2, 2.5-3.0 and 3.5-4.0, respectively. &gt;30% present in the worst prognostic group (GI-GPA of ≤1.0).ConclusionsBrain metastases are not uncommon in GI cancer patients and MS varies widely among them. This updated GI-GPA index improves our ability to estimate survival for these patients and will be useful for therapy selection, end-of-life decision-making and stratification for future clinical trials. A user-friendly, free, on-line app to calculate the GPA score and estimate survival for an individual patient is available at brainmetgpa.com

Comparative analysis of homology models of the Ah receptor ligand binding domain: Verification of structure-function predictions by site-directed mutagenesis of a nonfunctional receptor

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates the biological and toxic effects of a wide variety of structurally diverse chemicals, including the toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). While significant interspecies differences in AHR ligand binding specificity, selectivity, and response have been observed, the structural determinants responsible for those differences have not been determined, and homology models of the AHR ligand-binding domain (LBD) are available for only a few species. Here we describe the development and comparative analysis of homology models of the LBD of 16 AHRs from 12 mammalian and nonmammalian species and identify the specific residues contained within their ligand binding cavities. The ligand-binding cavity of the fish AHR exhibits differences from those of mammalian and avian AHRs, suggesting a slightly different TCDD binding mode. Comparison of the internal cavity in the LBD model of zebrafish (zf) AHR2, which binds TCDD with high affinity, to that of zfAHR1a, which does not bind TCDD, revealed that the latter has a dramatically shortened binding cavity due to the side chains of three residues (Tyr296, Thr386, and His388) that reduce the amount of internal space available to TCDD. Mutagenesis of two of these residues in zfAHR1a to those present in zfAHR2 (Y296H and T386A) restored the ability of zfAHR1a to bind TCDD and to exhibit TCDD-dependent binding to DNA. These results demonstrate the importance of these two amino acids and highlight the predictive potential of comparative analysis of homology models from diverse species. The availability of these AHR LBD homology models will facilitate in-depth comparative studies of AHR ligand binding and ligand-dependent AHR activation and provide a novel avenue for examining species-specific differences in AHR responsiveness. © 2013 American Chemical Society

Integrating population variation and protein structural analysis to improve clinical interpretation of missense variation: application to the WD40 domain

We present a generic, multidisciplinary approach for improving our understanding of novel missense variants in recently discovered disease genes exhibiting genetic heterogeneity, by combining clinical and population genetics with protein structural analysis. Using six new de novo missense diagnoses in TBL1XR1 from the Deciphering Developmental Disorders study, together with population variation data, we show that the β-propeller structure of the ubiquitous WD40 domain provides a convincing way to discriminate between pathogenic and benign variation. Children with likely pathogenic mutations in this gene have severely delayed language development, often accompanied by intellectual disability, autism, dysmorphology and gastrointestinal problems. Amino acids affected by likely pathogenic missense mutations are either crucial for the stability of the fold, forming part of a highly conserved symmetrically repeating hydrogen-bonded tetrad, or located at the top face of the β-propeller, where ‘hotspot’ residues affect the binding of β-catenin to the TBLR1 protein. In contrast, those altered by population variation are significantly less likely to be spatially clustered towards the top face or to be at buried or highly conserved residues. This result is useful not only for interpreting benign and pathogenic missense variants in this gene, but also in other WD40 domains, many of which are associated with disease