A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?

Background: Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies.

Patients and methods: Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload.

Results: A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival.

Conclusions: Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.

Enhanced proton beam collimation in the ultra-intense short pulse regime

The collimation of proton beams accelerated during ultra-intense laser irradiation of thin aluminum foils was measured experimentally whilst varying laser contrast. Increasing the laser contrast using a double plasma mirror system resulted in a marked decrease in proton beam divergence (20° to <10°), and the enhanced collimation persisted over a wide range of target thicknesses (50 nm–6 µm), with an increased flux towards thinner targets. Supported by numerical simulation, the larger beam divergence at low contrast is attributed to the presence of a significant plasma scale length on the target front surface. This alters the fast electron generation and injection into the target, affecting the resultant sheath distribution and dynamics at the rear target surface. This result demonstrates that careful control of the laser contrast will be important for future laser-driven ion applications in which control of beam divergence is crucial.

Ecological impacts of invasive alien species along temperature gradients: testing the role of environmental matching

Invasive alien species (IAS) can cause substantive ecological impacts, and the role of temperature in mediating these impacts may become increasingly significant in a changing climate. Habitat conditions and physiological optima offer predictive information for IAS impacts in novel environments. Here, using meta-analysis and laboratory experiments, we tested the hypothesis that the impacts of IAS in the field are inversely correlated with the difference in their ambient and optimal temperatures. A meta-analysis of 29 studies of consumptive impacts of IAS in inland waters revealed that the impacts of fishes and crustaceans are higher at temperatures that more closely match their thermal growth optima. In particular, the maximum impact potential was constrained by increased differences between ambient and optimal temperatures, as indicated by the steeper slope of a quantile regression on the upper 25th percentile of impact data compared to that of a weighted linear regression on all data with measured variances. We complemented this study with an experimental analysis of the functional response - the relationship between predation rate and prey supply - of two invasive predators (freshwater mysid shrimp, Hemimysis anomala and Mysis diluviana) across relevant temperature gradients; both of these species have previously been found to exert strong community-level impacts that are corroborated by their functional responses to different prey items. The functional response experiments showed that maximum feeding rates of H. anomala and M. diluviana have distinct peaks near their respective thermal optima. Although variation in impacts may be caused by numerous abiotic or biotic habitat characteristics, both our analyses point to temperature as a key mediator of IAS impact levels in inland waters and suggest that IAS management should prioritize habitats in the invaded range that more closely match the thermal optima of targeted invaders.

Testing Tidal Turbines - Part 1: Steady Towing Tests vs Tidal Moored Tests

Tidal turbines have been tested extensively at many scales in steady state flow. Testing medium- or full-scale devices in turbulent flow has been less thoroughly examined. The differences between turbine performances in these two different states are needed for testing method verification and numerical model validation. The work in this paper documents the performance of a 1/10 scale turbine in steady state pushing tests and tidal moored tests. The overall performance of the device appears to decrease with turbulent flow, though there is increased data scatter and therefore, reduced uncertainty. At maximum power performance, as velocity increases the mechanical power and electrical power reduction from steady to unsteady flow increases. The drive train conversion efficiency also decreases. This infers that the performance for this turbine design is affected by the presence of turbulent flow.

Testing Tidal Turbines Part II: Tidal Flow Characterisation Using ADV Data

The study outlined in Testing Tidal Turbines Part 1 explains the variation in performance between turbines operating in steady and turbulent flow conditions. However, the impact of turbulence on devices is generally not well understood. Furthermore, the turbulence characteristics of high velocity marine currents have not been extensively studied. Therefore, knowledge of their characteristics must be expanded and methodologies to predict the impact of the characteristics on devices developed and improved. This study examines the measurement of tidal currents at a site used for testing of medium scale tidal turbines. The data being discussed was collected with a point velocimeter (ADV). The processing procedures implemented are discussed and the resulting estimated turbulence spectra and turbulence intensities are presented. The results contribute to the improvement of knowledge regarding tidal current characteristics. This will be fundamental to the optimisation of the design and operation of tidal stream devices.

Empirical testing of genuine savings as an indicator of weak sustainability: a three-country analysis of long run trends

Genuine Savings has emerged as a widely-used indicator of sustainable development. In this paper, we use long-term data stretching back to 1870 to undertake empirical tests of the relationship between Genuine Savings (GS) and future well-being for three countries: Britain, the USA and Germany. Our tests are based on an underlying theoretical relationship between GS and changes in the present value of future consumption. Based on both single country and panel results, we find evidence supporting the existence of a cointegrating (long run equilibrium) relationship between GS and future well-being, and fail to reject the basic theoretical result on the relationship between these two macroeconomic variables. This provides some support for the GS measure of weak sustainability. We also show the effects of modelling shocks, such as World War Two and the Great Depression.

Development of dynamic structural testing to current state-of-the-art hybrid testing

Even though computational power used for structural analysis is ever increasing, there is still a fundamental need for testing in structural engineering, either for validation of complex numerical models or to assess material behaviour. In addition to analysis of structures using scale models, many structural engineers are aware to some extent of cyclic and shake-table test methods, but less so of ‘hybrid testing’. The latter is a combination of physical testing (e.g. hydraulic
actuators) and computational modelling (e.g. finite element modelling). Over the past 40 years, hybrid testing of engineering structures has developed from concept through to maturity to become a reliable and accurate dynamic testing technique. The hybrid test method provides users with some additional benefits that standard dynamic testing methods do not, and the method is more cost-effective in comparison to shake-table testing. This article aims to provide the reader with a basic understanding of the hybrid test method, including its contextual development and potential as a dynamic testing technique.

Cold-formed steel portal frames in fire: Full-scale testing and finite element analysis

A full-scale, non-uniform natural fire test on a cold-formed steel portal frame building is described. The results of the test are used to validate a non-linear, elasto-plastic, finite element shell idealisation, for the purposes of later forming the basis of a performance-based design approach for cold-formed steel portal frames at elevated temperatures.

Developments in performance-based testing of concrete

Implementation of both design for durability and performance-based standards and specifications are limited by the lack of rapid, simple, science-based test methods for characterizing the transport properties and deterioration resistance of concrete. To this end, this paper presents the background rationale and current developments in the application of electrical property measurements - conductivity in this instance - as a testing methodology to evaluate the relative performance of a range of concrete mixes. The technique can not only be used on standard specimens (e.g. cubes), but also lends itself to in-situ monitoring thereby allowing measurements to be obtained on the as-placed concrete. It is the latter which forms the focus of the current work. Conductivity measurements are presented for concretes with and without supplementary cementitious materials (SCM's) from demoulding up to 400-days. It is shown that electrical conductivity measurements display a continual decrease over the entire test period and attributed to the pore structure refinement due to hydration and pozzolanic reaction in those concretes containing blast furnace slag or fly ash. The term Formation Factor is introduced to rank concrete performance in terms of is resistance to chloride penetration.