The risks to human populations in coastal areas are changing due to climate and socio-economic changes, and these trends are predicted to accelerate during the twenty-first century. To understand ...these changing risks, and the resulting choices and pathways to successful management and adaptation, broad-scale integrated assessment is essential. Due to their complexity the two risks of flooding and erosion are usually managed independently, yet frequently they are interconnected by longshore exchange of sediments and the resulting broad scale morphological system behaviour. In order to generate new insights into the effects of climate change and coastal management practises on coastal erosion and flood risk, we present an integrated assessment of 72 km of shoreline over the twenty-first century on the East Anglian coast of England which is a site of significant controversy about how to manage coastal flood and erosion risks over the twenty-first century. A coupled system of hydrodynamic, morphological, reliability and socio-economic models has been developed for the analysis, implemented under scenarios of coastal management, climate and socio-economic change. The study is unique in coastal management terms because of the large spatial scale and extended temporal scale over which the analysis is quantified. This study for the first time quantifies what has for some years been argued qualitatively: the role of sediments released from cliff erosion in protecting neighbouring low-lying land from flooding. The losses and benefits are expressed using the common currency of economic risk. The analysis demonstrates that over the twenty-first century, flood risk in the study area is expected to be an order of magnitude greater than erosion risk. Climate and socio-economic change and coastal management policy have a significant influence on flood risk. This study demonstrates that the choices concerning coastal management are profound, and there are clear tradeoffs between erosion and flood impacts.
The pharmaceutical industry continues to face significant challenges. Very few compounds that enter development reach the marketplace, and the investment required for each success can surpass $1.8 ...billion. Despite attempts to improve efficiency and increase productivity, total investment continues to rise whereas the output of new medicines declines. With costs increasing exponentially through each development phase, it is failure in phase II and phase III that is most wasteful. In today's development paradigm, late‐stage failure is principally a result of insufficient efficacy. This is manifested as either a failure to differentiate sufficiently from placebo (shown for both novel and precedented mechanisms) or a failure to demonstrate sufficient differentiation from existing compounds. Set in this context, this article will discuss the role model‐based drug development (MBDD) approaches can and do play in accelerating and optimizing compound development strategies through a series of illustrative examples.
Clinical Pharmacology & Therapeutics (2013); 93 6, 502–514. doi:10.1038/clpt.2013.54
Gallium-nitride power transistor (GaN HEMT) and integrated circuit technologies have matured dramatically over the last few years, and many hundreds of thousands of devices have been manufactured and ...fielded in applications ranging from pulsed radars and counter-IED jammers to CATV modules and fourth-generation infrastructure base-stations. GaN HEMT devices, exhibiting high power densities coupled with high breakdown voltages, have opened up the possibilities for highly efficient power amplifiers (PAs) exploiting the principles of waveform engineered designs. This paper summarizes the unique advantages of GaN HEMTs compared to other power transistor technologies, with examples of where such features have been exploited. Since RF power densities of GaN HEMTs are many times higher than other technologies, much attention has also been given to thermal management-examples of both commercial "off-the-shelf" packaging as well as custom heat-sinks are described. The very desirable feature of having accurate large-signal models for both discrete transistors and monolithic microwave integrated circuit foundry are emphasized with a number of circuit design examples. GaN HEMT technology has been a major enabler for both very broadband high-PAs and very high-efficiency designs. This paper describes examples of broadband amplifiers, as well as several of the main areas of high-efficiency amplifier design-notably Class-D, Class-E, Class-F, and Class-J approaches, Doherty PAs, envelope-tracking techniques, and Chireix outphasing.
The treatment of older patients with acute myeloid leukaemia, who are not considered suitable for conventional intensive therapy, is unsatisfactory. Low-dose Ara-C(LDAC) has been established as ...superior to best supportive care, but only benefits the few patients who enter complete remission. Alternative or additional treatments are required to improve the situation. This randomised trial compared the addition of the immunoconjugate, gemtuzumab ozogamicin (GO), at a dose of 5 mg on day 1 of each course of LDAC, with the intention of improving the remission rate and consequently survival. Between June 2004 and June 2010, 495 patients entered the randomisation. The addition of GO significantly improved the remission rate (30% vs 17%; odds ratio(OR) 0.48 (0.32-0.73); P=0.006), but not the 12 month overall survival (25% vs 27%). The reason for the induction benefit failing to improve OS was two-fold: survival of patients in the LDAC arm who did not enter remission and survival after relapse were both superior in the LDAC arm. Although the addition of GO to LDAC doubled the remission rate it did not improve overall survival. Maintaining remission in older patients remains elusive.
SABRE (Sodium iodide with Active Background REjection) is a direct detection dark matter experiment based on arrays of radio-pure NaI(Tl) crystals. The experiment aims at achieving an ultra-low ...background rate and its primary goal is to confirm or refute the results from the DAMA/LIBRA experiment. The SABRE Proof-of-Principle phase was carried out in 2020-2021 at the Gran Sasso National Laboratory (LNGS), in Italy. The next phase consists of two full-scale experiments: SABRE South at the Stawell Underground Physics Laboratory, in Australia, and SABRE North at LNGS. This paper focuses on SABRE South and presents a detailed simulation of the detector, which is used to characterise the background for dark matter searches including DAMA/LIBRA-like modulation. We estimate an overall background of 0.72 cpd/kg/ Formula omitted in the energy range 1-6 Formula omitted primarily due to radioactive contamination in the crystals. Given this level of background and considering that the SABRE South has a target mass of 50 kg, we expect to exclude (confirm) DAMA/LIBRA modulation at Formula omitted within 2.5 years of data taking.
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► Twenty two participants have analysed four precisely defined tensile membrane structures. ► Results show high levels of variability of stresses, displacements and reactions. ► ...Stress factors utilised to determine material strength vary widely. ► Harmonisation and benchmarking are required to improve consistency in analysis.
Tensile fabric structures are used for large-scale iconic structures worldwide, yet analysis and design methodologies are not codified in most countries and there is limited design guidance available. Non-linear material behaviour, large strains and displacements and the use of membrane action to resist loads require a fundamentally different approach to structural analysis and design compared to conventional roof structures.
The aim of the round robin analysis exercise presented here is to understand the current state of analysis practice for tensile fabric structures, and to assess the level of consistency and harmony in current practice. The exercise consists of four precisely defined tensile fabric structures, with participants required to carry out the form finding and load analysis of each structure and report key values of stress, deflection and reactions.
The results show very high levels of variability in terms of stresses, displacements, reactions and material design strengths, and highlight the need for future work to harmonise analysis methods and provide validation and benchmarking for membrane analysis software. Greater consistency is required to give confidence in the analysis and design process, to enable third party checking to be carried out in a meaningful and efficient manner, to provide a harmonious approach for Eurocode development, and to enable the full potential of tensile structures to be realised.
The feasibility of combining gemtuzumab ozogamicin (GO) with intensive chemotherapy as first-line treatment of acute myeloid leukemia (AML) was assessed in 72 patients, aged 17 to 59 years, as a ...prelude to the United Kingdom Medical Research Council (MRC) AML15 trial. Sixty-four patients received induction chemotherapy (DAT daunorubicin, ara-C, thioguanine, DA daunorubicin, ara-C, or FLAG-Ida fludarabine, ara-C, G-CSF, idarubicin) with GO on day 1. It was possible to give GO 3 mg/m2with course 1, but 6 mg/m2with course 1 or GO in a dose of 3 mg/m2with consecutive courses was not feasible because of hepatotoxicity and delayed hematopoietic recovery. Thirty-one patients who were treated in consolidation with MACE (amsacrine, ara-C, etoposide) or HidAC (HidAC) and GO (3 mg/m2), and 23 in induction and consolidation, tolerated GO (3 mg/m2) well. Grade 4 liver toxicity and sinusoidal obstructive syndrome was more common in thioguanine-containing schedules (P= .007). Remission with course 1 was seen in 86% of patients. DA or FLAG-Ida with GO in induction achieved complete remission in 91% of patients and 78% of these patients are in continuous complete remission at 8 months. GO given with induction (DA or FLAG-Ida) and consolidation (MACE or HidAC) was well tolerated. These schedules are now being compared in the MRC AML15 trial in patients younger than 60 years. (Blood. 2003; 102:4277-4283)
Augmented Reality (AR) in industrial applications connects users across digital and physical worlds and coupled with rapid return of investment, easy adoption, and as a meaningful way to stand out ...from the competition, AR is quickly becoming increasingly common in the industrial world. This paper first provides the reader with a description on what exactly is augmented reality and the difference between augmented reality and virtual reality, before moving onto describing the scope of this new application for an organisation like Howden. A brief analysis of how augmented reality is quickly finding a footing within this sphere is offered alongside an overview of the main players and actors. The paper then focuses on how the 3D CAD modelling already completed by the research and development, bare-shaft engineering and package engineering teams can be utilised in the rapid development of augmented reality applications. Examples of how Howden are developing and using these AR applications are then given with specific reference to the Screw sales teams using them to show prospective clients the model of their package / machine; the Screw package build teams sharing knowledge using AR during package fit-out and hazard and operability studies; the bare-shaft test team using AR within their acoustic enclosure and finally the impact of AR in the service teams. The paper concludes with how, as this technology becomes more mainstream, manufacturers adopting AR can significantly add value to their customers experience both in terms of service and satisfaction but also differentiate themselves from their competitors.
RTS,S/AS02 is a pre-erythrocytic malaria vaccine based on the circumsporozoite surface protein of Plasmodium falciparum fused to HBsAg, incorporating a new adjuvant (AS02). We did a randomised trial ...of the efficacy of RTS,S/AS02 against natural P falciparum infection in semi-immune adult men in The Gambia.
306 men aged 18–45 years were randomly assigned three doses of either RTS,S/AS02 or rabies vaccine (control). Volunteers were given sulfadoxine/pyrimethamine 2 weeks before dose 3, and kept under surveillance throughout the malaria transmission season. Blood smears were collected once a week and whenever a volunteer developed symptoms compatible with malaria. The primary endpoint was time to first infection with P falciparum. Analysis was per protocol.
250 men (131 in the RTS,S/AS02 group and 119 in the control group) received three doses of vaccine and were followed up for 15 weeks. RTS,S/AS02 was safe and well tolerated. P falciparum infections occurred significantly earlier in the control group than the RTS,S/AS02 group (Wilcoxon's test p=0–018). Vaccine efficacy, adjusted for confounders, was 34% (95% CI 8–0–53, p=0–014). Protection seemed to wane: estimated efficacy during the first 9 weeks of follow-up was 71% (46–85), but decreased to 0% (−52 to 34) in the last 6 weeks. Vaccination induced strong antibody responses to circumsporozoite protein and strong T-cell responses. Protection was not limited to the NF54 parasite genotype from which the vaccine was derived. 158 men received a fourth dose the next year and were followed up for 9 weeks; during this time, vaccine efficacy was 47% (4–71, p=0–037).
RTS,S/AS02 is safe, immunogenic, and is the first pre-erythrocytic vaccine to show significant protection against natural P falciparum infection.
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