Elevated Airway Purines in COPD

Adenosine and related purines have established roles in inflammation, and elevated airway concentrations are predicted in patients with COPD. However, accurate airway surface purine measurements can be confounded by stimulation of purine release during collection of typical respiratory samples

SB-656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation in humans

To determine the safety and tolerability of a novel selective CXCR2 antagonist and assess its pharmacodynamic effects using measures of neutrophil activation and function, including CD11b expression in whole blood and ozone-induced airway inflammation in healthy subjects

Plasma sTNFR1 and IL8 for prognostic enrichment in sepsis trials: a prospective cohort study.

BackgroundEnrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors.MethodsIn a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies.Measurements and main resultsAn admission sTNFR1 concentration > 8861 pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration > 94 pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level > 9761 pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor.ConclusionsThresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials

Mechanisms of Vascular Dysfunction in COPD and Effects of a Novel Soluble Epoxide Hydrolase Inhibitor in Smokers.

BACKGROUND: Smoking and COPD are risk factors for cardiovascular disease, and the pathogenesis may involve endothelial dysfunction. We tested the hypothesis that endothelium-derived epoxyeicosatrienoic acid (EET)-mediated endothelial function is impaired in patients with COPD and that a novel soluble epoxide hydrolase inhibitor, GSK2256294, attenuates EET-mediated endothelial dysfunction in human resistance vessels both in vitro and in vivo. METHODS: Endogenous and stimulated endothelial release of EETs was assessed in 12 patients with COPD, 11 overweight smokers, and two matched control groups, using forearm plethysmography with intraarterial infusions of fluconazole, bradykinin, and the combination. The effects of GSK2256294 on EET-mediated vasodilation in human resistance arteries were assessed in vitro and in vivo in a phase I clinical trial in healthy overweight smokers. RESULTS: Compared with control groups, there was reduced vasodilation with bradykinin (P = .005), a blunted effect of fluconazole on bradykinin-induced vasodilation (P = .03), and a trend toward reduced basal EET/dihydroxyepoxyeicosatrienoic acid ratio in patients with COPD (P = .08). A similar pattern was observed in overweight smokers. In vitro, 10 μM GSK2256294 increased 11,12-EET-mediated vasodilation compared with vehicle (90% ± 4.2% vs 72.6% ± 6.2% maximal dilatation) and shifted the bradykinin half-maximal effective concentration (EC50) (-8.33 ± 0.172 logM vs -8.10 ± 0.118 logM; P = .001 for EC50). In vivo, 18 mg GSK2256294 improved the maximum bradykinin response from 338% ± 46% before a dose to 566% ± 110% after a single dose (P = .02) and to 503% ± 123% after a chronic dose (P = .003). CONCLUSIONS: GSK2256294 attenuates smoking-related EET-mediated endothelial dysfunction, suggesting potential therapeutic benefits in patients with COPD. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01762774; URL: www.clinicaltrials.gov.This work was supported by GSK [SEH114068] and Innovate UK (ERICA Consortium 10037625), the Wellcome Trust grant numbers 100780/Z/12/Z, and WT103782AIA awarded to LY, and DEN respectively; the Raymond and Beverley Sackler fellowship awarded to LY; National Institute for Health Research funding awarded to IBW, and JC in the Cambridge Comprehensive Biomedical Research, and the British Heart Foundation grant numbers CH/0 9/002, and RG66885 RCZA/008 awarded to DEN, and IBW. JLG and ZA are funded by the Medical Research Council (Medical Research Council Lipid Profiling and Signalling, MC UP A90 1006 & Lipid Dynamics and Regulation, MC PC 130 30)

Valuation of initial margin and model risk

PhD (Business Mathematics and Informatics), North-West University, Potchefstroom CampusThe research work of the thesis focuses on two themes: the valuation of initial margin and model risk quantification. The first theme addresses matters arising from the valuation of initial margin for over-the-counter derivatives in the real market with outstanding gross notional amount smaller than two billion, but acknowledging the present work for high outstanding gross notional amount in developed financial institutions. The initial margin requirement for uncleared derivatives is well in place for developed countries and for the high risk financial institutions, but the spill-over of the financial crises from developing institutions, the gradual phasing in of initial margin and the impact thereof are yet to be known. Hence, the major interest is drawn to this work. To mitigate risk due to unforeseen financial markets turmoil, we propose a bootstrap initial margin valuation process that can be applicable during normal and stressed financial markets. The proposed parametric bootstrap method is in favour of the bootstrap initial margin (BIM) amounts for the simulated and real datasets. These BIM amounts are reasonably exceeding the traditional initial margin amounts when-ever the significance level increases. The proposed valuation of initial margin reduces spill-over effects by ensuring that collateral, such as initial margin, is available to ffset losses caused by the default of an over-the-counter derivatives. The second theme of the thesis addresses three components of model risk quantification: model risk due to inappropriate statistical distribution; model misspecification; and inappropriate parameter estimation methods. Inappropriate statistical distribution was assessed using four bootstrap confidence interval techniques. The modified hybrid percentile bootstrap method was a superior technique because it reveals that with the same sample size and very small simulation iterations the other confidence methods produces similar goodness-of-fit results but completely different and insignificant performance measures. By way of illustrating the model misspecification for some credit risk models, we carry out quantitative analysis of two specific statistical predictive response models using simulated balanced dataset and Taiwan credit card default dataset. The maximum likelihood estimation technique is employed for pa-rameter estimation and inference, precisely the goodness of fit and model performance assessments. The binary logistic regression technique for the balanced datasets reveals prominent goodness of fit and performance measures as opposed to the complemen-tary log-log technique. To deal with model risk due to parameter estimation methods, several statistical and mathematical numerical methods for determining the param-eter values are utilized for predicting probability of default through binary logistic regression model and determining optimum parameters that minimize the objective model’s cost function. The Mini-Batch Gradient Descent method is revealed to be the better parameter estimator among the chosen parameter estimation methods. The banking industry utilises models on a daily basis. This research will assist banks to manage model risk better, particularly the selection of an appropriate statistical distribution, the identification of model misspecification and the quantification of an appropriate parameter estimation method. Researchers and practitioners will be able to compare the results of model risk techniques and choose the optimum method for their current market conditions. However, this practice needs to be validated and exercised regularly as the financial markets evolves rapidly.Doctora