The double triangular test in practice

The double triangular test was introduced twenty years ago, and the purpose of this paper is to review applications that have been made since then. In fact, take-up of the method was rather slow until the late 1990s, but in recent years several clinical trial reports have been published describing its use in a wide range of therapeutic areas. The core of this paper is a detailed account of five trials that have been published since 2000 in which the method was applied to studies of pancreatic cancer, breast cancer, myocardial infarction, epilepsy and bedsores. Before those accounts are given, the method is described and the history behind its evolution is presented. The future potential of the method for sequential case-control and equivalence trials is also discussed. Copyright © 2004 John Wiley & Sons, Ltd.

The role of satellite image-processing for national-scale estimates of gene flow from genetically modified crops: rapeseed in the UK as a model

1.There is concern over the possibility of unwanted environmental change following transgene movement from genetically modified (GM) rapeseed Brassica napus to its wild and weedy relatives. 2. The aim of this research was to develop a remote sensing-assisted methodology to help quantify gene flow from crops to their wild relatives over wide areas. Emphasis was placed on locating sites of sympatry, where the frequency of gene flow is likely to be highest, and on measuring the size of rapeseed fields to allow spatially explicit modelling of wind-mediated pollen-dispersal patterns. 3. Remote sensing was used as a tool to locate rapeseed fields, and a variety of image-processing techniques was adopted to facilitate the compilation of a spatially explicit profile of sympatry between the crop and Brassica rapa. 4. Classified satellite images containing rapeseed fields were first used to infer the spatial relationship between donor rapeseed fields and recipient riverside B. rapa populations. Such images also have utility for improving the efficiency of ground surveys by identifying probable sites of sympatry. The same data were then also used for the calculation of mean field size. 5. This paper forms a companion paper to Wilkinson et al. (2003), in which these elements were combined to produce a spatially explicit profile of hybrid formation over the UK. The current paper demonstrates the value of remote sensing and image processing for large-scale studies of gene flow, and describes a generic method that could be applied to a variety of crops in many countries. 6.Synthesis and applications. The decision to approve or prevent the release of a GM cultivar is made at a national rather than regional level. It is highly desirable that data relating to the decision-making process are collected at the same scale, rather than relying on extrapolation from smaller experiments designed at the plot, field or even regional scale. It would be extremely difficult and labour intensive to attempt to carry out such large-scale investigations without the use of remote-sensing technology. This study used rapeseed in the UK as a model to demonstrate the value of remote sensing in assembling empirical information at a national level.

The effect of test meal monounsaturated fatty acid: saturated fatty acid ratio on postprandial lipid metabolism

Epidemiological evidence shows that a diet high in monounsaturated fatty acids (MUFA) but low in saturated fatty acids (SFA) is associated with reduced risk of CHD. The hypocholesterolaemic effect of MUFA is known but there has been little research on the effect of test meal MUFA and SFA composition on postprandial lipid metabolism. The present study investigated the effect of meals containing different proportions of MUFA and SFA on postprandial triacylglycerol and non-esterified fatty acid (NEFA) metabolism. Thirty healthy male volunteers consumed three meals containing equal amounts of fat (40 g), but different proportions of MUFA (12, 17 and 24% energy) in random order. Postprandial plasma triacylglycerol, apolipoprotein B-48, cholesterol, HDL-cholesterol, glucose and insulin concentrations and lipoprotein lipase (EC 3.1.1.34) activity were not significantly different following the three meals which varied in their levels of SFA and MUFA. There was a significant difference in the postprandial NEFA response between meals. The incremental area under the curve of postprandial plasma NEFA concentrations was significantly (P = 0.03) lower following the high-MUFA meal. Regression analysis showed that the non-significant difference in fasting NEFA concentrations was the most important factor determining difference between meals, and that the test meal MUFA content had only a minor effect. In conclusion, varying the levels of MUFA and SFA in test meals has little or no effect on postprandial lipid metabolism.

Influence of end-capping on the self-assembly of model amyloid peptide fragments

The influence of charge and aromatic stacking interactions on the self-assembly of a series of four model amyloid peptides has been examined. The four model peptides are based on the KLVFF motif from the amyloid Beta peptide, ABeta(16-20) extended at the N terminus with two Beta-alanine residues. We have studied NH2-BetaABetaAKLVFF-COOH (FF), NH2-BetaABetaAKLVFCOOH (F), CH3CONH-BetaABetaAKLVFF-CONH2 (CapF), and CH3CONH-BetaABetaAKLVFFCONH2 (CapFF). The former two are uncapped (net charge plus 2) and differ by one hydrophobic phenylalanine residue; the latter two are the analogous capped peptides (net charge plus 1). The self-assembly characteristics of these peptides are remarkably different and strongly dependent on concentration. NMR shows a shift from carboxylate to carboxylic acid forms upon increasing concentration. Saturation transfer measurements of solvent molecules indicate selective involvement of phenylalanine residues in driving the self-assembly process of CapFF due presumably to the effect of aromatic stacking interactions. FTIR spectroscopy reveals beta-sheet features for the two peptides containing two phenylalanine residues but not the single phenylalanine residue, pointing again to the driving force for self-assembly. Circular dichroism (CD) in dilute solution reveals the polyproline II conformation, except for F which is disordered. We discuss the relationship of this observation to the significant pH shift observed for this peptide when compared the calculated value. Atomic force microscopy and cryogenic-TEM reveals the formation of twisted fibrils for CapFF, as previously also observed for FF. The influence of salt on the self-assembly of the model beta-sheet forming capped peptide CapFF was investigated by FTIR. Cryo-TEM reveals that the extent of twisting decreases with increased salt concentration, leading to the formation of flat ribbon structures. These results highlight the important role of aggregation-induced pKa shifts in the self-assembly of model beta-sheet peptides.

Dependence of Indian monsoon rainfall on moisture fluxes across the Arabian Sea and the impact of coupled model sea surface temperature biases

The Arabian Sea is an important moisture source for Indian monsoon rainfall. The skill of climate models in simulating the monsoon and its variability varies widely, while Arabian Sea cold sea surface temperature (SST) biases are common in coupled models and may therefore influence the monsoon and its sensitivity to climate change. We examine the relationship between monsoon rainfall, moisture fluxes and Arabian Sea SST in observations and climate model simulations. Observational analysis shows strong monsoons depend on moisture fluxes across the Arabian Sea, however detecting consistent signals with contemporaneous summer SST anomalies is complicated in the observed system by air/sea coupling and large-scale induced variability such as the El Niño-Southern Oscillation feeding back onto the monsoon through development of the Somali Jet. Comparison of HadGEM3 coupled and atmosphere-only configurations suggests coupled model cold SST biases significantly reduce monsoon rainfall. Idealised atmosphere-only experiments show that the weakened monsoon can be mainly attributed to systematic Arabian Sea cold SST biases during summer and their impact on the monsoon-moisture relationship. The impact of large cold SST biases on atmospheric moisture content over the Arabian Sea, and also the subsequent reduced latent heat release over India, dominates over any enhancement in the land-sea temperature gradient and results in changes to the mean state. We hypothesize that a cold base state will result in underestimation of the impact of larger projected Arabian Sea SST changes in future climate, suggesting that Arabian Sea biases should be a clear target for model development.

Validation of the FALL3D ash dispersion model using observations of the 2010 Eyjafjallajökull volcanic ash clouds

During April-May 2010 volcanic ash clouds from the Icelandic Eyjafjallajökull volcano reached Europe causing an unprecedented disruption of the EUR/NAT region airspace. Civil aviation authorities banned all flight operations because of the threat posed by volcanic ash to modern turbine aircraft. New quantitative airborne ash mass concentration thresholds, still under discussion, were adopted for discerning regions contaminated by ash. This has implications for ash dispersal models routinely used to forecast the evolution of ash clouds. In this new context, quantitative model validation and assessment of the accuracies of current state-of-the-art models is of paramount importance. The passage of volcanic ash clouds over central Europe, a territory hosting a dense network of meteorological and air quality observatories, generated a quantity of observations unusual for volcanic clouds. From the ground, the cloud was observed by aerosol lidars, lidar ceilometers, sun photometers, other remote-sensing instru- ments and in-situ collectors. From the air, sondes and multiple aircraft measurements also took extremely valuable in-situ and remote-sensing measurements. These measurements constitute an excellent database for model validation. Here we validate the FALL3D ash dispersal model by comparing model results with ground and airplane-based measurements obtained during the initial 14e23 April 2010 Eyjafjallajökull explosive phase. We run the model at high spatial resolution using as input hourly- averaged observed heights of the eruption column and the total grain size distribution reconstructed from field observations. Model results are then compared against remote ground-based and in-situ aircraft-based measurements, including lidar ceilometers from the German Meteorological Service, aerosol lidars and sun photometers from EARLINET and AERONET networks, and flight missions of the German DLR Falcon aircraft. We find good quantitative agreement, with an error similar to the spread in the observations (however depending on the method used to estimate mass eruption rate) for both airborne and ground mass concentration. Such verification results help us understand and constrain the accuracy and reliability of ash transport models and it is of enormous relevance for designing future operational mitigation strategies at Volcanic Ash Advisory Centers.

Breakdown of hydrostatic balance at convective scales in the forecast errors in the Met Office Unified Model

For data assimilation in numerical weather prediction, the initial forecast-error covariance matrix Pf is required. For variational assimilation it is particularly important to prescribe an accurate initial matrix Pf, since Pf is either static (in the 3D-Var case) or constant at the beginning of each assimilation window (in the 4D-Var case). At large scales the atmospheric flow is well approximated by hydrostatic balance and this balance is strongly enforced in the initial matrix Pf used in operational variational assimilation systems such as that of the Met Office. However, at convective scales this balance does not necessarily hold any more. Here we examine the extent to which hydrostatic balance is valid in the vertical forecast-error covariances for high-resolution models in order to determine whether there is a need to relax this balance constraint in convective-scale data assimilation. We use the Met Office Global and Regional Ensemble Prediction System (MOGREPS) and a 1.5 km resolution version of the Unified Model for a case study characterized by the presence of convective activity. An ensemble of high-resolution forecasts valid up to three hours after the onset of convection is produced. We show that at 1.5 km resolution hydrostatic balance does not hold for forecast errors in regions of convection. This indicates that in the presence of convection hydrostatic balance should not be enforced in the covariance matrix used for variational data assimilation at this scale. The results show the need to investigate covariance models that may be better suited for convective-scale data assimilation. Finally, we give a measure of the balance present in the forecast perturbations as a function of the horizontal scale (from 3–90 km) using a set of diagnostics. Copyright © 2012 Royal Meteorological Society and British Crown Copyright, the Met Office

Incorporation of water vapour transfer in the JULES Land Surface Model: implications for key soil variables and land surface fluxes

This study focuses on the mechanisms underlying water and heat transfer in upper soil layers, and their effects on soil physical prognostic variables and the individual components of the energy balance. The skill of the JULES (Joint UK Land Environment Simulator) land surface model (LSM) to simulate key soil variables, such as soil moisture content and surface temperature, and fluxes such as evaporation, is investigated. The Richards equation for soil water transfer, as used in most LSMs, was updated by incorporating isothermal and thermal water vapour transfer. The model was tested for three sites representative of semi-arid and temperate arid climates: the Jornada site (New Mexico, USA), Griffith site (Australia) and Audubon site (Arizona, USA). Water vapour flux was found to contribute significantly to the water and heat transfer in the upper soil layers. This was mainly due to isothermal vapour diffusion; thermal vapour flux also played a role at the Jornada site just after rainfall events. Inclusion of water vapour flux had an effect on the diurnal evolution of evaporation, soil moisture content and surface temperature. The incorporation of additional processes, such as water vapour flux among others, into LSMs may improve the coupling between the upper soil layers and the atmosphere, which in turn could increase the reliability of weather and climate predictions.