Carl Scarrott

Prediction of Oncotype DX and TAILORx risk categories using histopathological and immunohistochemical markers by classification and regression tree (CART) analysis.

Oncotype DX is an RT-PCR assay used to predict which patients with ER-positive node-negative (NN) disease will benefit from chemotherapy. Each patient is stratified into a risk category based on a recurrence score (RS) and the TAILORx trial is determining the benefit of chemotherapy for patients with mid-range RSs. We tested if Oncotype DX and TAILORx risk categories could be predicted by standard pathological features and protein markers corresponding to 10 genes in the assay (ER, PR, Ki67, HER2, BCL2, CD68, Aurora A kinase, survivin, cyclin B1 and BAG1) on 52 patients who enrolled on TAILORx. Immunohistochemistry for the protein markers was performed on whole tissue sections. Classification and regression tree (CART) analysis correctly classified 69% of cases into Oncotype DX risk categories based on the expression of PR, survivin and nuclear pleomorphism. All tumours with PR staining (Allred score ≥ 2) and marked nuclear pleomorphism were in the high-risk category. No case with PR <2, low survivin (≤ 15.5%) and nuclear pleomorphism <3 was high-risk. Similarly, 77% of cases were correctly classified into TAILORx categories based on nuclear pleomorphism, survivin, BAG1 and cyclin B1. Ki67 was the only variable that predicted the absolute RS with a cut-off for positivity of 15% (p = 0.003). In conclusion, CART revealed key predictors including proliferation markers, PR and nuclear pleomorphism that correctly classified over two thirds of ER-positive NN cancers into Oncotype DX and TAILORx risk categories. These variables could be used as an alternative to the RT-PCR assay to reduce the number of patients requiring Oncotype DX testing.

The effectiveness of a structured education pulmonary rehabilitation programme for improving the health status of people with moderate and severe chronic obstructive pulmonary disease in primary care: the PRINCE cluster randomised trial

Objective To evaluate the effectiveness of a structured education pulmonary rehabilitation programme on the health status of people with chronic obstructive pulmonary disease (COPD). Design Two-arm, cluster randomised controlled trial. Setting 32 general practices in the Republic of Ireland. Participants 350 participants with a diagnosis of moderate or severe COPD. Intervention Experimental group received a structured education pulmonary rehabilitation programme, delivered by the practice nurse and physiotherapist. Control group received usual care. Main outcome measure Health status as measured by the Chronic Respiratory Questionnaire (CRQ) at baseline and at 12–14 weeks postcompletion of the programme. Results Participants allocated to the intervention group had statistically significant higher mean change total CRQ scores (adjusted mean difference (MD) 1.11, 95% CI 0.35 to 1.87). However, the CI does not exclude a smaller difference than the one that was prespecified as clinically important. Participants allocated to the intervention group also had statistically significant higher mean CRQ Dyspnoea scores after intervention (adjusted MD 0.49, 95% CI 0.20 to 0.78) and CRQ Physical scores (adjusted MD 0.37, 95% CI 0.14 to 0.60). However, CIs for both the CRQ Dyspnoea and CRQ Physical subscales do not exclude smaller differences as prespecified as clinically important. No other statistically significant differences between groups were seen. Conclusions A primary care based structured education pulmonary rehabilitation programme is feasible and may increase local accessibility to people with moderate and severe COPD. Trial registration ISRCTN52403063.

Changes in acute biochemical markers of inflammatory and structural stress in rugby union

Abstract Rugby union is a sport governed by the impacts of high force and high frequency. Analysis of physiological markers following a game can provide an understanding of the physiological response of an individual and the time course changes in response to recovery. Urine and saliva were collected from 11 elite amateur rugby players 24 h before, immediately after, and at 17, 25, 38, 62 and 86 h post-game. Myoglobin, salivary immunoglobulin A and cortisol were analysed by ELISA, whereas neopterin and total neopterin were analysed by high-performance liquid chromatography. There was a significant post-game increase of all four markers. The increases were cortisol 4-fold, myoglobin 2.85-fold, neopterin 1.75-fold and total neopterin 2.3-fold when corrected with specific gravity. All significant changes occurred post-game only, with markers returning to and remaining at baseline within 17 h. The intensity of the game caused significant changes in key physiological markers of stress. They provide an understanding of the stress experienced during a single game of rugby and the time course changes associated with player recovery. Neopterin provides a new marker of detecting an acute inflammatory response in physical exercise, while specific gravity should be considered for urine volume correction post-exercise.

Effectiveness of pads and enclosures as safety interventions on consumer trampolines

Background Trampolines continue to be a major source of childhood injury. Objective To examine available data on trampoline injuries in order to determine the effectiveness of padding and enclosures. Design Trampoline injuries from the NEISS database from 2002 to 2007 were reclassified into five cause-categories, to examine evidence for injury trends. Setting The ASTM trampoline standard recommendations for safety padding were upgraded in 1999 and enclosures were introduced in 1997. This is the first study to examine the impact of these changes. Patients The sampling frame comprises patients with NEISS product code ‘consumer trampolines’ (1233). A systematic sample of 360 patients each year is taken. Interventions The prominent interventions recommended by the ASTM are netting enclosures to prevent falling off and safety padding to cover frames and springs. Main outcome measures Proportion of injuries within each cause-category and trend estimates. Results There was no evidence for a decline within the injury cause-categories that should be prevented by these interventions from 2002 to 2007. Conclusions If these interventions were effective the associated injury causes would be in decline. Instead they remain close to half of all trampoline injuries with no significant change over the period of the study. Follow-up studies are proposed to determine the reasons. Given the number of injuries involved it is recommended that steps be taken to ensure these safety interventions or their equivalents are in place, work properly and remain effective for the life of consumer trampolines.

GARCH dependence in extreme value models with Bayesian inference

Extreme value methods are widely used in financial applications such as risk analysis, forecasting and pricing models. One of the challenges with their application in finance is accounting for the temporal dependence between the observations, for example the stylised fact that financial time series exhibit volatility clustering. Various approaches have been proposed to capture the dependence. Commonly a two-stage approach is taken, where the volatility dependence is removed using a volatility model like a GARCH (or one of its many incarnations) followed by application of standard extreme value models to the assumed independent residual innovations. This study examines an alternative one stage approach, which makes parameter estimation and accounting for the associated uncertainties more straightforward than the two-stage approach. The location and scale parameters of the extreme value distribution are defined to follow a conditional autoregressive heteroscedasticity process. Essentially, the model implements GARCH volatility via the extreme value model parameters. Bayesian inference is used and implemented via Markov chain Monte Carlo, to permit all sources of uncertainty to be accounted for. The model is applied to both simulated and empirical data to demonstrate performance in extrapolating the extreme quantiles and quantifying the associated uncertainty.

Plasma Cortisol Concentrations and Perceived Anxiety in Response to On-Sight Rock Climbing

Previous research suggested plasma cortisol concentrations in response to rock climbing have a cubic relationship with state anxiety and self-confidence. This research, however, was conducted in a situation where the climbers had previously climbed the route. The purpose of our study was to examine this relationship in response to on-sight climbing. Nineteen (13 male, 6 female) intermediate climbers volunteered to attend anthropometric and baseline testing sessions, prior to an on-sight ascent (lead climb or top-rope) of the test climb (grade 19 Ewbank/6a sport/5.10b YDS). Data recorded included state anxiety, self-confidence and cortisol concentrations prior to completing the climb. Results indicated that there were no significant differences in state anxiety, self-confidence and plasma cortisol concentration regardless of the style of ascent (lead climb or top-rope) in an on-sight sport climbing context. Regression analysis indicated there was a significant linear relationship between plasma cortisol concentrations and self-confidence (r= - 0.52, R2=0.267, p=0.024), cognitive (r=0.5, R2=0.253, p=0.028), and somatic anxieties (r=0.46, R2=0.210, p=0.049). In an on-sight condition the relationships between plasma cortisol concentrations with anxiety (cognitive and somatic) and self-confidence were linear.

Forearm oxygenation and blood flow kinetics during a sustained contraction in multiple ability groups of rock climbers

Abstract Currently, the physiological mechanisms that allow elite level climbers to maintain intense isometric contractions for prolonged periods of time are unknown. Furthermore, it is unclear whether blood flow or muscle oxidative capacity best governs performance. This study aimed to determine the haemodynamic kinetics of 2 forearm flexor muscles in 3 ability groups of rock climbers. Thirty-eight male participants performed a sustained contraction at 40% of maximal voluntary contraction (MVC) until volitional fatigue. Oxygen saturation and blood flow was assessed using near infrared spectroscopy and Doppler ultrasound. Compared to control, intermediate, and advanced groups, the elite climbers had a significantly (P < 0.05) higher strength-to-weight ratio (MVC/N), de-oxygenated the flexor digitorum profundus significantly (P < 0.05) more (32, 34.3, and 42.8 vs. 63% O2, respectively), and at a greater rate (0.32, 0.27, and 0.34 vs. 0.77 O2%·s−1, respectively). Furthermore, elite climbers de-oxygenated the flexor carpi radialis significantly (P < 0.05) more and at a greater rate than the intermediate group (36.5 vs. 14.6% O2 and 0.43 vs. 0.1O2%·s−1, respectively). However, there were no significant differences in total forearm ∆ blood flow. An increased MVC/N is not associated with greater blood flow occlusion in elite climbers; therefore, oxidative capacity may be more important for governing performance.

Assessing the effectiveness of selected biomarkers in the acute and cumulative physiological stress response in professional rugby union through non-invasive assessment

Rugby union is a sport involving high force and frequency impacts making the likelihood of injury a significant risk. The aim of this study was to measure and report the individual and group acute and cumulative physiological stress response during 3 professional rugby games through non-invasive sampling. 24 professional rugby players volunteered for the study. Urine and saliva samples were collected pre and post 3 matches. Myoglobin, salivary immunoglobulin A, cortisol, neopterin and total neopterin (neopterin+7,8-dihydroneopterin) were analysed by high performance liquid chromatography or enzyme linked immunosorbent assay. Significant increases in cortisol, myoglobin, neopterin and total neopterin when urine volume was corrected with specific gravity were observed (p<0.05). Significant decreases in salivary immunoglobulin A concentration were observed for games 1 and 2 while secretion rate decreased after games 2 and 3. Significant decreases were seen with the percent of 7,8-dihydroneopterin being converted to neopterin following games 2 and 3. The intensity of 3 professional rugby games was sufficient to elicit significant changes in the physiological markers selected for our study. Furthermore, results suggest the selected markers not only provide a means for analysing the stress encountered during a single game of rugby but also highlight the unique pattern of response for each individual player.

Extreme value modelling for forecasting market crisis impacts

This article introduces a new approach for estimating Value at Risk (VaR), which is then used to show the likelihood of the impacts of the current financial crisis. A commonly used two-stage approach is taken, by combining a Generalized Autoregressive Conditional Heteroscedasticity (GARCH) volatility model with a novel extreme value mixture model for the innovations. The proposed mixture model permits any distribution function for the main mode of the innovations, with the very flexible Generalized Pareto Distribution (GPD) for the upper and lower tails. A major advance with the mixture model is that it overcomes the problems with threshold choice in traditional methods as it is treated as a parameter in the model to be estimated. The model describes the tail distribution of both the losses and gains simultaneously, which is natural for financial applications. As the threshold is treated as a parameter, the uncertainty from its estimation is accounted for, which is a challenging and often overlooked problem in traditional approaches. The model is shown to be sufficiently flexible that it can be directly applied to reliably estimate the likelihood of impact of the financial crisis on stock and index returns.

Survey of injury sources for a trampoline with equipment hazards designed out

Aim:  In Australia, trampolines contribute approximately one‐quarter of all childhood play‐equipment injuries. The purpose of this study was to gather and evaluate injury data from a nontraditional, ‘soft‐edged’, consumer trampoline in which the equipment injury sources have been designed out.