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.

Effect of nozzle geometry on the flow characteristics of hydroentangling jets

Cone-capillary nozzles with varying cone angles from 10° to 120° and a capillary diameter of 120μ are experimentally investigated for their application in the hydroentanglement process. Cone-up and cone-down configurations in a range of water pressures of 30-120 bar are tested. The effects of the cone angle on flow parameters such as discharge and velocity coefficients and intact length are studied. Flow visualization techniques are used to recognize the flow regimes and characteristics and to inspect and compare the intact length and appearance of the jets. Cone-down nozzles with more consistent flow properties, lower discharges, and higher velocity coefficients are more suitable for the hydroentanglement process. Single-cone nozzles without capillaries and with varying cone angles are also tested. The flow properties of the jets from the single-cone nozzles are compared with the cone-capillary nozzles of the same cone angle to study the effect of the capillary section. The effect of the interaction of adjacent nozzles on the flow from multi-hole nozzles is studied, and the characteristics of the jets from the multi-hole nozzles are compared with the single-hole nozzles.

Mantle flow, volatiles, slab-surface temperatures and melting dynamics in the north Tonga arc-Lau back-arc basin

The Fonualei Spreading Center affords an excellent opportunity to evaluate geochemical changes with increasing depth to the slab in the Lau back-arc basin. We present H2O and CO2 concentrations and Sr, Nd, Pb, Hf and U-Th-Ra isotope data for selected glasses as well as new Hf isotope data from boninites and seamounts to the north of the Tonga arc. The Pb and Hf isotope data are used to show that mantle flow is oriented to the southwest and that the tear in the northern end of the slab may not extend east as far as the boninite locality. Along the Fonualei Spreading Center, key geochemical parameters change smoothly with increasing distance from the arc front and increasing slab surface temperatures. The latter may range from 720 to 866 degrees C, based on decreasing H2O/Ce ratios. Consistent with experimental data, the geochemical trends are interpreted to reflect changes in the amount and composition of wet pelite melts or super-critical fluids and aqueous fluids derived from the slab. With one exception, all of the lavas preserve both U-238 excesses and Ra-226 excesses. We suggest that lavas from the Fonualei Spreading Center and Valu Fa Ridge are dominated by fluid-fluxed melting whereas those from the East and Central Lau Spreading Centers, where slab surface temperatures exceed similar to 850-900 degrees C, are largely derived through decompression. A similar observation is found for the Manus and East Scotia back-arc basins and may reflect the expiry of a key phase such as lawsonite in the subducted basaltic crust.

Combining multi-scale geophysical techniques for robust hydro-structural characterisation in catchments underlain by hard rock in post-glacial regions

Accurate conceptual models of groundwater systems are essential for correct interpretation of monitoring data in catchment studies. In surface-water dominated hard rock regions, modern ground and surface water monitoring programmes often have very high resolution chemical, meteorological and hydrological observations but lack an equivalent emphasis on the subsurface environment, the properties of which exert a strong control on flow pathways and interactions with surface waters. The reasons for this disparity are the complexity of the system and the difficulty in accurately characterising the subsurface, except locally at outcrops or in boreholes. This is particularly the case in maritime north-western Europe, where a legacy of glacial activity, combined with large areas underlain by heterogeneous igneous and metamorphic bedrock, make the structure and weathering of bedrock difficult to map or model. Traditional approaches which seek to extrapolate information from borehole to field-scale are of limited application in these environments due to the high degree of spatial heterogeneity. Here we apply an integrative and multi-scale approach, optimising and combining standard geophysical techniques to generate a three-dimensional geological conceptual model of the subsurface in a catchment in NE Ireland. Available airborne LiDAR, electromagnetic and magnetic data sets were analysed for the region. At field-scale surface geophysical methods, including electrical resistivity tomography, seismic refraction, ground penetrating radar and magnetic surveys, were used and combined with field mapping of outcrops and borehole testing. The study demonstrates how combined interpretation of multiple methods at a range of scales produces robust three-dimensional conceptual models and a stronger basis for interpreting groundwater and surface water monitoring data.

Complex organic molecules along the accretion flow in isolated and externally irradiated protoplanetary disks

(Abridged) The birth environment of the Sun will have influenced the conditions in the pre-solar nebula, including the attainable chemical complexity, important for prebiotic chemistry. The formation and distribution of complex organic molecules (COMs) in a disk around a T Tauri star is investigated for two scenarios: (i) an isolated disk, and (ii) a disk irradiated externally by a nearby massive star. The chemistry is calculated along the accretion flow from the outer disk inwards using a comprehensive network. Two simulations are performed, one beginning with complex ices and one with simple ices only. For the isolated disk, COMs are transported without major alteration into the inner disk where they thermally desorb into the gas reaching an abundance representative of the initial assumed ice abundance. For simple ices, COMs efficiently form on grain surfaces under the conditions in the outer disk. Gas-phase COMs are released into the molecular layer via photodesorption. For the irradiated disk, complex ices are also transported inwards; however, they undergo thermal processing caused by the warmer conditions in the irradiated disk which tends to reduce their abundance along the accretion flow. For simple ices, grain-surface chemistry cannot synthesise COMs in the outer disk because the necessary grain-surface radicals, which tend to be particularly volatile, are not sufficiently abundant on the grain surfaces. Gas-phase COMs are formed in the inner region of the irradiated disk via gas-phase chemistry induced by the desorption of strongly bound molecules such as methanol; hence, the abundances are not representative of the initial molecular abundances injected into the outer disk. These results suggest that the composition of comets formed in isolated disks may differ from those formed in externally irradiated disks with the latter composed of more simple ices.

Shortening design time through multiplatform simulations with a portable OpenCL golden-model: the LDPC decoder case

Hardware designers and engineers typically need to explore a multi-parametric design space in order to find the best configuration for their designs using simulations that can take weeks to months to complete. For example, designers of special purpose chips need to explore parameters such as the optimal bitwidth and data representation. This is the case for the development of complex algorithms such as Low-Density Parity-Check (LDPC) decoders used in modern communication systems. Currently, high-performance computing offers a wide set of acceleration options, that range from multicore CPUs to graphics processing units (GPUs) and FPGAs. Depending on the simulation requirements, the ideal architecture to use can vary. In this paper we propose a new design flow based on OpenCL, a unified multiplatform programming model, which accelerates LDPC decoding simulations, thereby significantly reducing architectural exploration and design time. OpenCL-based parallel kernels are used without modifications or code tuning on multicore CPUs, GPUs and FPGAs. We use SOpenCL (Silicon to OpenCL), a tool that automatically converts OpenCL kernels to RTL for mapping the simulations into FPGAs. To the best of our knowledge, this is the first time that a single, unmodified OpenCL code is used to target those three different platforms. We show that, depending on the design parameters to be explored in the simulation, on the dimension and phase of the design, the GPU or the FPGA may suit different purposes more conveniently, providing different acceleration factors. For example, although simulations can typically execute more than 3x faster on FPGAs than on GPUs, the overhead of circuit synthesis often outweighs the benefits of FPGA-accelerated execution.

Resonantly Enhanced Multi-Photon Ionization Spectrum of the Neutral Green Fluorescent Protein Chromophore

The photophysics of the green fluorescent protein is governed by the electronic structure of the chromophore at the heart of its β-barrel protein structure. We present the first two-color, resonance-enhanced, multiphoton ionization spectrum of the isolated neutral chromophore in vacuo with supporting electronic structure calculations. We find the absorption maximum to be 3.65 ± 0.05 eV (340 ± 5 nm), which is blue-shifted by 0.5 eV (55 nm) from the absorption maximum of the protein in its neutral form. Our results show that interactions between the chromophore and the protein have a significant influence on the electronic structure of the neutral chromophore during photoabsorption and provide a benchmark for the rational design of novel chromophores as fluorescent markers or photomanipulators.

Spatial allocation of material flow analysis in residential developments: a case study of Kildare County, Ireland

Studies of urban metabolism provide important insights for environmental management of cities, but are not widely used in planning practice due to a mismatch of data scale and coverage. This paper introduces the Spatial Allocation of Material Flow Analysis (SAMFA) model as a potential decision support tool aimed as a contribution to overcome some of these difficulties and describes its pilot use at the county level in the Republic of Ireland. The results suggest that SAMFA is capable of identifying hotspots of higher material and energy use to support targeted planning initiatives, while its ability to visualise different policy scenarios supports more effective multi-stakeholder engagement. The paper evaluates this pilot use and sets out how this model can act as an analytical platform for the industrial ecology–spatial planning nexus.

The radiated energy budget of Chromospheric Plasma in a major solar flare deduced from multi-wavelength observations

This paper presents measurements of the energy radiated by the lower solar atmosphere, at optical, UV, and EUV wavelengths, during an X-class solar flare (SOL2011-02-15T01:56) in response to an injection of energy assumed to be in the form of nonthermal electrons. Hard X-ray observations from RHESSI were used to track the evolution of the parameters of the nonthermal electron distribution to reveal the total power contained in flare accelerated electrons. By integrating over the duration of the impulsive phase, the total energy contained in the nonthermal electrons was found to be >2 × 1031 erg. The response of the lower solar atmosphere was measured in the free–bound EUV continua of H i (Lyman), He i, and He ii, plus the emission lines of He ii at 304 Å and H i (Lyα) at 1216 Å by SDO/EVE, the UV continua at 1600 Å and 1700 Å by SDO/AIA, and the white light continuum at 4504 Å, 5550 Å, and 6684 Å, along with the Ca ii H line at 3968 Å using Hinode/SOT. The summed energy detected by these instruments amounted to ~3 × 1030 erg; about 15% of the total nonthermal energy. The Lyα line was found to dominate the measured radiative losses. Parameters of both the driving electron distribution and the resulting chromospheric response are presented in detail to encourage the numerical modeling of flare heating for this event, to determine the depth of the solar atmosphere at which these line and continuum processes originate, and the mechanism(s) responsible for their generation.

New multi-stage DC-DC converters for grid-connected photovoltaic systems

Renewable energy is high on international and national agendas. Currently, grid-connected photovoltaic (PV) systems are a popular technology to convert solar energy into electricity. Existing PV panels have a relatively low and varying output voltage so that the converter installed between the PVs and the grid should be equipped with high step-up and versatile control capabilities. In addition, the output current of PV systems is rich in harmonics which affect the power quality of the grid. In this paper, a new multi-stage hysteresis control of a step-up DC-DC converter is proposed for integrating PVs into a single-phase power grid. The proposed circuitry and control method is experimentally validated by testing on a 600W prototype converter. The developed technology has significant economic implications and could be applied to many distributed generation (DG) systems, especially for the developing countries which have a large number of small PVs connected to their single-phase distribution network. 

Enhancing Linear Programming with Motion Modeling for Multi-target Tracking

In this paper we extend the minimum-cost network flow approach to multi-target tracking, by incorporating a motion model, allowing the tracker to better cope with longterm occlusions and missed detections. In our new method, the tracking problem is solved iteratively: Firstly, an initial tracking solution is found without the help of motion information. Given this initial set of tracklets, the motion at each detection is estimated, and used to refine the tracking solution.
Finally, special edges are added to the tracking graph, allowing a further revised tracking solution to be found, where distant tracklets may be linked based on motion similarity. Our system has been tested on the PETS S2.L1 and Oxford town-center sequences, outperforming the baseline system, and achieving results comparable with the current state of the art.

Development of a doped titania immobilised thin film multi tubular photoreactor

This paper describes a novel doped titania immobilised thin film multi tubular photoreactor which has been developed for use with liquid, vapour or gas phase media. In designing photocatalytic reactors measuring active surface area of photocatalyst within the unit is one of the critical design parameters. This dictate greatly limits the applicability of any semi-conductor photocatalyst in industrial applications, as a large surface area equates to a powder catalyst. This demonstration of a thin film coating, doped with a rare earth element, novel photoreactor design produces a photocatalytic degradation of a model pollutant (methyl orange) which displayed a comparable degradation achieved with P25 TiO2. The use of lanthanide doping is reported here in the titania sol gel as it is thought to increase the electron hole separation therefore widening the potential useful wavelengths within the electromagnetic spectrum. Increasing doping from 0.5% to 1.0% increased photocatalytic degradation by ∼17% under visible irradiation. A linear relationship has been seen between increasing reactor volume and degradation which would not normally be observed in a typical suspended reactor system. © 2012 Elsevier B.V.

Analysis of a three-dimensional flow generated by a linear aerospike

Linear aerospike nozzles are envisaged as a possible means to improve launcher engine performance. One of the most interesting properties of these nozzles is the possibility of a good integration with the vehicle. To improve the knowledge of the flow-field and performance of aerospike nozzles, they are studied numerically, with particular attention to the differences between the basic two-dimensional nozzle, usually considered in the design phase, and the more realistic three-dimensional nozzle. The study considers also the effect of flight condition, which cannot be neglected because of the characteristic external expansion of aerospike nozzles.

Constrained Multi-Objective Aerofoil Design Using a Multi-Level Optimisation Strategy

A novel approach for the multi-objective design optimisation of aerofoil profiles is presented. The proposed method aims to exploit the relative strengths of global and local optimisation algorithms, whilst using surrogate models to limit the number of computationally expensive CFD simulations required. The local search stage utilises a re-parameterisation scheme that increases the flexibility of the geometry description by iteratively increasing the number of design variables, enabling superior designs to be generated with minimal user intervention. Capability of the algorithm is demonstrated via the conceptual design of aerofoil sections for use on a lightweight laminar flow business jet. The design case is formulated to account for take-off performance while reducing sensitivity to leading edge contamination. The algorithm successfully manipulates boundary layer transition location to provide a potential set of aerofoils that represent the trade-offs between drag at cruise and climb conditions in the presence of a challenging constraint set. Variations in the underlying flow physics between Pareto-optimal aerofoils are examined to aid understanding of the mechanisms that drive the trade-offs in objective functions.