The addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for advanced colorectal cancer: results of the MRC COIN trial.

Background: In the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in first-line treatment of advanced colorectal cancer with the aim of assessing effect on overall survival.
Methods: In this randomised controlled trial, patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fluoropyrimidine therapy (capecitabine or infused fluouroracil plus leucovorin) was decided before randomisation. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and C is described in a companion paper. Here, we present the comparison of arm A and B, for which the primary outcome was overall survival in patients with KRAS wild-type tumours. Analysis was by intention to treat. Further analyses with respect to NRAS, BRAF, and EGFR status were done. The trial is registered, ISRCTN27286448.
Findings: 1630 patients were randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab). Tumour samples from 1316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367; arm B, n=362), overall survival did not differ between treatment groups (median survival 17·9 months [IQR 10·3—29·2] in the control group vs 17·0 months [9·4—30·1] in the cetuximab group; HR 1·04, 95% CI 0·87—1·23, p=0·67). Similarly, there was no effect on progression-free survival (8·6 months [IQR 5·0—12·5] in the control group vs 8·6 months [5·1—13·8] in the cetuximab group; HR 0·96, 0·82—1·12, p=0·60). Overall response rate increased from 57% (n=209) with chemotherapy alone to 64% (n=232) with addition of cetuximab (p=0·049). Grade 3 and higher skin and gastrointestinal toxic effects were increased with cetuximab (14 vs 114 and 67 vs 97 patients in the control group vs the cetuximab group with KRAS wild-type tumours, respectively). Overall survival differs by somatic mutation status irrespective of treatment received: BRAF mutant, 8·8 months (IQR 4·5—27·4); KRAS mutant, 14·4 months (8·5—24·0); all wild-type, 20·1 months (11·5—31·7).
Interpretation: This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer. Cetuximab increases response rate, with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours. The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended.

Limitations of instantaneous water quality sampling in surface-water catchments: Comparison with near-continuous phosphorus time-series data.

The validity of load estimates from intermittent, instantaneous grab sampling is dependent on adequate spatial coverage by monitoring networks and a sampling frequency that re?ects the variability in the system under study. Catchments with a ?ashy hydrology due to surface runoff pose a particular challenge as intense short duration rainfall events may account for a signi?cant portion of the total diffuse transfer of pollution from soil to water in any hydrological year. This can also be exacerbated by the presence of strong background pollution signals from point sources during low flows. In this paper, a range of sampling methodologies and load estimation techniques are applied to phosphorus data from such a surface water dominated river system, instrumented at three sub-catchments (ranging from 3 to 5 km2 in area) with near-continuous monitoring stations. Systematic and Monte Carlo approaches were applied to simulate grab sampling using multiple strategies and to calculate an estimated load, Le based on established load estimation methods. Comparison with the actual load, Lt, revealed signi?cant average underestimation, of up to 60%, and high variability for all feasible sampling approaches. Further analysis of the time series provides an insight into these observations; revealing peak frequencies and power-law scaling in the distributions of P concentration, discharge and load associated with surface runoff and background transfers. Results indicate that only near-continuous monitoring that re?ects the rapid temporal changes in these river systems is adequate for comparative monitoring and evaluation purposes. While the implications of this analysis may be more tenable to small scale ?ashy systems, this represents an appropriate scale in terms of evaluating catchment mitigation strategies such as agri-environmental policies for managing diffuse P transfers in complex landscapes.

Methods in wind power prediction & forecasting

Globally on-shore wind power has seen considerable growth in all grid systems. In the coming decade off-shore wind power is also expected to expand rapidly. Wind power is variable and intermittent over various time scales because it is weather dependent. Therefore wind power integration into traditional grids needs additional power system and electricity market planning and management for system balancing. This extra system balancing means that there is additional system costs associated with wind power assimilation. Wind power forecasting and prediction methods are used by system operators to plan unit commitment, scheduling and dispatch and by electricity traders and wind farm owners to maximize profit. Accurate wind power forecasting and prediction has numerous challenges. This paper presents a study of the existing and possible future methods used in wind power forecasting and prediction for both on-shore and off-shore wind farms.

Rapid Fluctuations in the Lower Solar Atmosphere

The Rapid Oscillations in the Solar Atmosphere instrument reveals solar atmospheric fluctuations at high frequencies. Spectra of variations of the G-band intensity (IG ) and Ca II K-line intensity (IK ) show correlated fluctuations above white noise to frequencies beyond 300 mHz and 50 mHz, respectively. The noise-corrected G-band spectrum for f = 28-326 mHz shows a power law with exponent -1.21 ± 0.02, consistent with the presence of turbulent motions. G-band spectral power in the 25-100 mHz ("UHF") range is concentrated at the locations of magnetic bright points in the intergranular lanes and is highly intermittent in time. The intermittence of the UHF G-band fluctuations, shown by a positive kurtosis ?, also suggests turbulence. Combining values of IG , IK , UHF power, and ? reveals two distinct states of the solar atmosphere. State 1, including almost all the data, is characterized by low IG , IK , and UHF power and ? ˜ 6. State 2, including only a very small fraction of the data, is characterized by high IG , IK , and UHF power and ? ˜ 3. Superposed epoch analysis shows that the UHF power peaks simultaneously with spatio-temporal IG maxima in either state. For State 1, IK shows 3.5 minute chromospheric oscillations with maxima occurring 21 s after IG maxima implying a 150-210 km effective height difference. However, for State 2 the IK and IG maxima are simultaneous; in this highly magnetized environment sites of G-band and K-line emission may be spatially close together.

Cycle Ergometer Tests in Children With Cystic Fibrosis:Reliability and Feasibility

The aim of this study was to assess the reliability and feasibility of cycle ergometer tests in young children with cystic fibrosis (CF). Children with CF aged 6-11 years and with stable lung disease performed two cycle ergometry tests (intermittent sprint and continuous incremental) on two occasions 1 week apart. Reliability was assessed using repeated-measures ANOVA. Bias was considered to be significant at P?

Micro-Environmental monitoring of temperature and moisture changes in building stone

The monitoring of temperature and moisture changes in response to different micro-environment of building stones is essential to understand the material behaviour and the degradation mechanisms. From a practical point of view, having a continuous and detailed understanding of micro-environmental changes in building stones helps to assist in their maintenance and repair strategies. Temperature within the stone is usually monitored by means of thermistors, whereas wide ranges of techniques are available for monitoring the moisture. In the case of concrete an electrical resistance method has previously been used as an inexpensive tool for monitoring moisture changes. This paper describes the adaptation of this technique and describes its further development for monitoring moisture movement in building stones.
In this study a block of limestone was subjected to intermittent infrared radiation with programmed cycles of ambient temperature, rainfall and wind conditions in an automated climatic chamber. The temperature and moisture changes at different depths within the stone were monitored by means of bead thermistors and electrical resistance sensors. This experiment has helped to understand the thermal conductivity and moisture transport from surface into deeper parts of the stone at different simulated extreme climatic conditions. Results indicated that variations in external ambient conditions could substantially affect the moisture transport and temperature profile within the micro-environment of building stones and hence they could have a significant impact on stone decay.

Field observation of sequestration of uranium in iron-rich sediments under sequential reduction-oxidation conditions at the DOE Oak Ridge IFRC

At the U.S. DOE Oak Ridge Integrated Field Research Challenge (ORIFRC) site, the iron content of shallow subsurface materials (i.e. weathered saprolite) is relatively high (up to 5-6% as w/w), and therefore, the forms of the iron species present plays a critical role in the long-term sequestration of uranium. A long term pilot-scale study of the bioreduction and reoxidation of uranium conducted at the ORIFRC area 3 site, adjacent to the former S-3 disposal ponds (source zone), has provided us with the opportunity to study the impact of iron species on the sequestration of U(VI). The aqueous U(VI) concentrations at the site were decreased to below the EPA MCL through the intermittent injection of ethanol as the electron donor. Previous field tests indicated that both oxygen and nitrate could oxidize the bioreduced U(IV) and cause a short-term rebound of aqueous phase uranium concentration after the oxidative agents were delivered directly to the bioreduced zone.

A field test has been conducted to examine the long-term effect of exposure of bioreduced sediments to nitrate in contaminated groundwater for more than 1,380 days at the Area 3 site. Contaminated groundwater was allowed to invade the previously bioreduced zone via the natural groundwater gradient after an extended period in which reducing conditions were maintained and the bioreduced zone was protected from the influx of upgradient contaminated groundwater. The geochemical response to the invasion of contaminated groundwater was dependent on whether the monitoring location is in the middle or the fringe of the previously bioreduced zone. In general, the nitrate concentrations in the previously bioreduced area, increased gradually from near zero to ~50-300 mM within 200 days and then stabilized. The pH declined from bioreduced levels of 6.2-6.7 to below 5.0. Uranium concentrations rebounded in all monitoring wells but at different rates. At most locations U concentrations rebounded, declined and then rebounded again. Methane gas disappeared while a significant level (20,000 to 44,000 ppmv) N2O was found in the groundwater of monitoring wells after three years of reoxidization.

The U(IV) in sediments was mainly reoxidized to U(VI) species. Based on XANES analysis, the predominate uranium in all samples after re-oxidation was similar to a uranyl nitrate form. But the U content in the sediment remained as high as that determined after bioreduction activates were completed, indicating that much of the U is still sequestrated in situ. SEM observations of surged fine sediments revealed that clusters of colloidal-sized (200-500nm) U-containing precipitates appeared to have formed in situ, regardless from sample of FW106 in non-bioactivity control area or of pre-bioreduced FW101-2 and FW102-3. Additionally, SEM-EDS and microprobe analysis, showed that the U-containing precipitates (~1% U) in FW106 are notably higher in Fe, compared to the precipitates (~1-2.5% U) from FW101-2 and FW102-3. However, XRF analysis indicated that the U content was remained as high as 2180 and 1810 mg/kg with U/Fe ratio at 0.077 and 0.055 vs 0.037 g/g, respectively in pre-bioreduced FW101-2 and FW102-3, suggesting more U sequestrated by Fe in pre-bioreduced sediments.

Effect of the surface water layer on the optical signal in apertureless scanning near field optical microscopy

Optical signals measured in apertureless scanning near field optical microscopy (ASNOM) under ambient conditions are found to be affected significantly by the thin water layer absorbed on the surface under investigation, the presence of which is detected through measurements of the shear force experienced by the tip. This water layer also results in a large hysteresis between optical signals measured during approach and withdrawal of the tip to the sample surface. The role of this effect in ASNOM is anticipated to be significant, with the possibility of resultant topographically induced artefacts for ASNOM involving intermittent contact of tip and sample, but also providing a potential mechanism for nanoscale optical resolution.

A theoretical assessment of surface defect machining and hot machining of nanocrystalline silicon carbide

In this paper, a newly proposed machining method named “surface defect machining” (SDM) [Wear, 302, 2013 (1124-1135)] was explored for machining of nanocrystalline beta silicon carbide (3C-SiC) at 300K using MD simulation. The results were compared with isothermal high temperature machining at 1200K under the same machining parameters, emulating ductile mode micro laser assisted machining (µ-LAM) and with conventional cutting at 300 K. In the MD simulation, surface defects were generated on the top of the (010) surface of the 3C-SiC work piece prior to cutting, and the workpiece was then cut along the <100> direction using a single point diamond tool at a cutting speed of 10 m/sec. Cutting forces, sub-surface deformation layer depth, temperature in the shear zone, shear plane angle and friction coefficient were used to characterize the response of the workpiece. Simulation results showed that SDM provides a unique advantage of decreased shear plane angle which eases the shearing action. This in turn causes an increased value of average coefficient of friction in contrast to the isothermal cutting (carried at 1200 K) and normal cutting (carried at 300K). The increase of friction coefficient however was found to aid the cutting action of the tool due to an intermittent dropping in the cutting forces, lowering stresses on the cutting tool and reducing operational temperature. Analysis shows that the introduction of surface defects prior to conventional machining can be a viable choice for machining a wide range of ceramics, hard steels and composites compared to hot machining.

Geophysical and hydrogeological characterisation of the impacts of on-site wastewater treatment discharge to groundwater in a poorly productive bedrock acquifer

Contaminants discharging from on-site wastewater treatment systems (OSWTSs) can impact groundwater quality, threatening human health and surface water ecosystems. Risk of negative impacts becomes elevated in areas of extreme vulnerability with high water tables, where thin unsaturated intervals limit vadose zone attenuation. A combined geophysical/hydrogeological investigation into the effects of an OSWTS, located over a poorly productive aquifer (PPA) with thin subsoil cover, aimed to characterise effluent impacts on groundwater. Groundwater, sampled from piezometers down-gradient of the OSWTS percolation area displayed spatially erratic, yet temporally consistent, contaminant distributions. Electrical resistivity tomography identified an area of gross groundwater contamination close to the percolation area and, when combined with seismic refraction and water quality data, indicated that infiltrating effluent reaching the water table discharged to a deeper more permeable zone of weathered shale resting on more competent bedrock. Subsurface structure, defined by geophysics, indicated that elevated chemical and microbiological contaminant levels encountered in groundwater samples collected from piezometers, down-gradient of sampling points with lower contaminant levels, corresponded to those locations where piezometers were screened close to the weathered shale/competent rock interface; those immediately up-gradient were too shallow to intercept this interval, and thus the more impacted zone of the contaminant plume. Intermittent occurrence of faecal indicator bacteria more than 100 m down gradient of the percolation area suggested relatively short travel times. Study findings highlight the utility of geophysics as part of multidisciplinary investigations for OSWTS contaminant plume characterisation, while also demonstrating the capacity of effluent discharging to PPAs to impact groundwater quality at distance. Comparable geophysical responses observed in similar settings across Ireland suggest the phenomena observed in this study are more widespread than previously suspected.

Geochemical records of palaeoenvironmental controls on peat forming processes in the Mfabeni peatland, Kwazulu Natal, South Africa since the Late Pleistocene

The Mfabeni peatland is the only known sub-tropical coastal fen that transcends the Last Glacial Maximum (LGM). This ca. 10m thick peat sequence provides a continuous sedimentation record spanning from the late Pleistocene to present (basal age c. 47kcalyr BP). We investigated the paleaeoenvironmental controls on peat formation and organic matter source input at the Mfabeni fen by: 1) exploring geochemical records (mass accumulation rate, total organic carbon, carbon accumulation rate, δC, δN and C/N ratio) to delineate primary production, organic matter source input, preservation and diagenetic processes, and 2) employ these geochemical signatures to reconstruct the palaeoenvironmental conditions and prevailing climate that drove carbon accumulation in the peatland. We established that the Mfabeni peat sediments have undergone minimal diagenetic alteration. The peat sequence was divided into 5 linear sedimentation rate (LSR) stages indicating distinct changes in climate and hydrological conditions: LSR stage 1 (c. 47 to c. 32.2kcalyr BP): predominantly cool and wet climate with C4 plant assemblages, interrupted by two short warming events. LSR stage 2 (c. 32.2 to c. 27.6kcalyr BP): dry and windy climate followed by a brief warm and wet period with increased C4 sedge swamp vegetation. LSR stage 3 (c. 27.6 to c. 20.3kcalyr BP): initial cool and wet period with prevailing C4 sedge plant assemblage until c. 23kcalyr BP; then an abrupt change to dry and cool glacial conditions and steady increases in C3 grasses. LSR stage 4 (c. 20.3 to c. 10.4kcalyr BP): continuation of cool and dry conditions and strong C3 grassland signature until c. 15kcalyr BP, after which precipitation increases. LSR stage 5 (c. 10.4kcalyr BP to present): characterised by extreme fluctuations between pervasive wet and warm to cool interglacial conditions with intermittent abrupt millennial-scale cooling/drying events and oscillations between C3 and C4 plant assemblages. In this study we reconstructed a high-resolution record of local hydrology, bulk plant assemblage and inferred climate since the Late Pleistocene, which suggest an anti-phase link between Southern African and the Northern Hemisphere, most notably during Heinrich (5 to 2) and Younger Dryas events. © 2013 Elsevier B.V.

Our Construct or Theirs?

Identity is relational and a construct, and is expressed in a myriad of ways. For example, material culture and its pluralist meanings have been readily manipulated by humans in a prehistoric context in order to construct personal and group identities. Artefacts were often from or reminiscent of far-flung places and were used to demonstrate membership of an (imagined) regional, or European community. Earthworks frequently archive maximum visual impact through elaborate ramparts and entrances with the minimum amount of effort, indicating that the construction of identities were as much in the eye of the perceivor, as of the perceived. Variations in domestic architectural style also demonstrate the malleability of identity, and the prolonged, intermittent use of particular places for specific functions indicates that the identity of place is just as important in our archaeological understanding as the identity of people. By using a wide range of case studies, both temporally and spatially, these thought processes may be explored further and diachronic and geographic patterns in expressions of identity investigated.

A Smart Grid Information System for Demand Side Participation: Remote Control of Domestic Appliances to Balance Demand

Due to the intermittent nature of renewable generation it is desirable to consider the potential of controlling the demand-side load to smooth overall system demand. The architecture and control methodologies of such a system on a large scale would require careful consideration. Some of these considerations are discussed in this paper; such as communications infrastructure, systems architecture, control methodologies and security. A domestic fridge is used in this paper as an example of a controllable appliance. A layered approach to smart-grid is introduced and it can be observed how each smart-grid component from physical cables, to the end-devices (or smart-applications) can be mapped to these set layers. It is clear how security plays an integral part in each component of the smart-grid so this is also an integral part of each layer. The controllable fridge is described in detail and as one potential smart-grid application which maps to the layered approach. A demonstration system is presented which involves a Raspberry Pi (a low-power, low-cost device representing the appliance controller).

Biogas reforming using renewable wind energy and induction heating

While the benefits of renewable energy are well known and used to influence government policy there are a number of problems which arise from having significant quantities of renewable energies on an electricity grid. The most notable problem stems from their intermittent nature which is often out of phase with the demands of the end users. This requires the development of either efficient energy storage systems, e.g. battery technology, compressed air storage etc. or through the creation of demand side management units which can utilise power quickly for manufacturing operations. Herein a system performing the conversion of synthetic biogas to synthesis gas using wind power and an induction heating system is shown. This approach demonstrates the feasibility of such techniques for stabilising the electricity grid while also providing a robust means of energy storage. This exemplar is also applicable to the production of hydrogen from the steam reforming of natural gas.

At Home in Care: Children living with birth parents on a Care Order

This study explored the processes, background information, and perceived reasons why children and young people returned home while remaining in care, in the five HSC Trusts in Northern Ireland. The research also focused on understanding the functions the Care Order had for social services, the birth parents, and young people involved.
It was found that on 31st March 2009, there were 193 children/young people living with their birth parents on a Care Order in Northern Ireland. This is eight per cent of the total population of Looked After children, and is lower than had been anticipated from governmental statistics. In total, the case files of 47 of these young people (24% of them) were reviewed, and interviews were conducted with ten of them and their birth parent/s.
The analysis revealed that the majority of them had in common a parental background history of alcohol abuse and domestic violence, and most return breakdowns in the study were related to continuing parental alcohol and/or drugs misuse. While some children had a planned return home after parents had engaged in supports and completed assessments, many young people had returns that were not planned, as they initiated the move themselves, or previous foster placements had broken down and there were no alternative placements identified for them. Many of these young people essentially ‘voted with their feet’, and social services were required to ensure that they remained safe in often less than optimal circumstances.
After returning home, for many, Care Orders remained for initially unintended lengthy periods because of the risks posed by parents’ intermittent alcohol abuse and their lifestyle, contact issues, and parents’ desire to ensure that their children were able to access the supports that they needed. Thus, Care Orders at home tended to serve two main functions: to either monitor and/or support the placement.