Insulin analog preparations and their use in children and adolescents with type 1 diabetes mellitus.

Standard or 'traditional' human insulin preparations such as regular soluble insulin and neutral protamine Hagedorn (NPH) insulin have shortcomings in terms of their pharmacokinetic and pharmacodynamic properties that limit their clinical efficacy. Structurally modified insulin molecules or insulin 'analogs' have been developed with the aim of delivering insulin replacement therapy in a more physiological manner. In the last 10 years, five insulin analog preparations have become commercially available for clinical use in patients with type 1 diabetes mellitus: three 'rapid' or fast-acting analogs (insulin lispro, aspart, and glulisine) and two long-acting analogs (insulin glargine and detemir). This review highlights the specific pharmacokinetic properties of these new insulin analog preparations and focuses on their potential clinical advantages and disadvantages when used in children and adolescents with type 1 diabetes mellitus. The fast-acting analogs specifically facilitate more flexible insulin injection timing with regard to meals and activities, whereas the long-acting analogs have a more predictable profile of action and lack a peak effect. To date, clinical trials in children and adolescents have been few in number, but the evidence available from these and from other studies carried out in adults with type 1 diabetes suggest that they offer significant benefits in terms of reduced frequency of nocturnal hypoglycemia, better postprandial blood glucose control, and improved quality of life when compared with traditional insulins. In addition, insulin detemir therapy is unique in that patients may benefit from reduced risk of excessive weight, particularly during adolescence. Evidence for sustained long-term improvements in glycosylated hemoglobin, on the other hand, is modest. Furthermore, alterations to insulin/insulin-like growth factor I receptor binding characteristics have also raised theoretical concerns that insulin analogs may have an increased mitogenic potential and risk of tumor development, although evidence from both in vitro and in vivo animal studies do not support this assertion. Long-term surveillance has been recommended and further carefully designed prospective studies are needed to evaluate the overall benefits and clinical efficacy of insulin analog therapy in children and adolescents with type 1 diabetes.

Using internal fibre geometry to improve the performance of pin-loaded holes in composite materials

The anisotropic nature of fibre reinforced composites leads to large stress concentrations around pin-loaded holes through standard weave cloths. Proper understanding of how this anisotropic nature affects the load distribution around holes can be utilised to reduce these con-centrations if sufficient thought is given to the internal fibre geometry near to the hole. Such local reinforcements need not be highly complex and can be readily produced without excessive effort, producing significant improvements in performance. © 1996 Kluwer Academic Publishers.

Centrifuge modelling of pile-soil interaction in liquefiable slopes

Piles passing through sloping liquefiable deposits are prone to lateral loading if these deposits liquefy and flow during earthquakes. These lateral loads caused by the relative soil-pile movement will induce bending in the piles and may result in failure of the piles or excessive pile-head displacement. Whilst the weak nature of the flowing liquefied soil would suggest that only small loads would be exerted on the piles, it is known from case histories that piles do fail owing to the influence of laterally spreading soils. It will be shown, based on dynamic centrifuge test data, that dilatant behaviour of soil close to the pile is the major cause of these considerable transient lateral loads which are transferred to the pile. This paper reports the results of geotechnical centrifuge tests in which models of gently sloping liquefiable sand with pile foundations passing through them were subjected to earthquake excitation. The soil close to the pile was instrumented with pore-pressure transducers and contact stress cells in order to monitor the interaction between soil and pile and to track the soil stress state both upslope and downslope of the pile. The presence of instrumentation measuring pore-pressure and lateral stress close to the pile in the research described in this paper gives the opportunity to better study the soil stress state close to the pile and to compare the loads measured as being applied to the piles by the laterally spreading soils with those suggested by the JRA design code. This test data shows that lateral stresses much greater than one might expect from calculations based on the residual strength of liquefied soil may be applied to piles in flowing liquefied slopes owing to the dilative behaviour of the liquefied soil. It is shown at least for the particular geometry studied that the current JRA design code can be un-conservative by a factor of three for these dilation-affected transient lateral loads.

Regulation: A Burden in Biopharmaceutical Industry? The Case of EU-Risk Management Plans

The generation of new medicinal products is both a contributor to global economic growth and a source of valuable benefits to human health. Given their direct responsibility for public health, regulatory authorities monitor closely both the development and exploitation of the underlying technologies and the products derived from them. The manner in which such regulation is implemented can result in regulators constraining or facilitating the generation of new products. This paper will study as an example the impact of EU Risk Management Plans (EU-RMPs), which have been mandatory for the approval of new medicines since 2005, on both the industry and regulatory authorities. In interviews, the responses of those who had experience of the implementation of EU-RMPs were mixed. Although the benefits of a more structured and predictable approach to the evaluation of risk were appreciated, some respondents perceived the regulation as an excessive burden on their organisations. The exploration of factors that influence how EU-RMP regulation affects individual firms provides new insights for both regulators and managers, and demonstrates one aspect of the complexity of the process by which new medicinal products are brought to market.

Regulation: A burden in biopharmaceutical industry? The case of EU-risk management plans

The generation of new medicinal products is both a contributor to global economic growth and a source of valuable benefits to human health. Given their direct responsibility for public health, regulatory authorities monitor closely both the development and exploitation of the underlying technologies and the products derived from them. The manner in which such regulation is implemented can result in regulators constraining or facilitating the generation of new products. This paper will study as an example the impact of EU Risk Management Plans (EU-RMPs), which have been mandatory for the approval of new medicines since 2005, on both the industry and regulatory authorities. In interviews, the responses of those who had experience of the implementation of EU-RMPs were mixed. Although the benefits of a more structured and predictable approach to the evaluation of risk were appreciated, some respondents perceived the regulation as an excessive burden on their organisations. The exploration of factors that influence how EU-RMP regulation affects individual firms provides new insights for both regulators and managers, and demonstrates one aspect of the complexity of the process by which new medicinal products are brought to market. © 2010 IEEE.

Improving model quality through computer controlled saturation

In dynamic centrifuge modelling, fluids with enhanced viscosity are often used to correct for the discrepancy in time scaling. However, great care must be taken when using a high viscosity fluid that hydraulic gradients during saturation do not become high enough to cause excessive model disturbance. This paper introduces the CAM-Sat system which aims to improve the saturation process by continually controlling the fluid flow into the model, limiting it to rates low enough to avoid model disturbance. A new method for measuring the fluid flow rate is then described, and its implementation & improvement to the system is discussed. © 2010 Taylor & Francis Group, London.

Effect of previous cyclic axial loads on pile groups

Numerous piles are often subjected to the combination of cyclic axial and cyclic lateral loads in service, such as piled foundations for offshore platforms which may suffer swaying and rocking motions owing to wind and wave actions. In this research, centrifuge tests were conducted to investigate the effect of previous cyclic axial loads on the performance of pile groups subjected to subsequent cyclic lateral loads. Different pile installation methods were also applied to study the different behaviour of bored and jacked pile groups subjected to cyclic loads. During lateral load cycling, it is seen that cyclic axial loads to which pile groups were previously subjected could reduce the pile cap permanent lateral displacement in the first lateral load cycle but do not influence the incremental rate of permanent displacement in the following lateral load cycles. Moreover, it is found that previous cyclic axial loads could improve the pile cap cyclic lateral secant stiffness, especially for the pre-jacked pile group. When rocking motions were induced by cyclic lateral loads, pile groups subjected to cyclic axial loads before have smaller permanent settlement than those without the cyclic axial loading effect. The designers of piles that are intended to resist significant lateral loads without excessive deformations in service may wish to deploy cyclic axial preloading, accordingly.

Effect of superstructure stiffness on liquefaction-induced failure Mechanisms

Soil liquefaction following strong earthquakes causes extensive damage to civil engineering structures. Foundations of buildings, bridges etc can suffer excessive rotation/settlement due to liquefaction. Many of the recent earthquakes bear testimony for such damage. In this article a hypothesis that "Superstructure stiffness can determine the type of liquefaction-induced failure mechanism suffered by the foundations" is proposed. As a rider to this hypothesis, it will be argued that liquefaction will cause failure of a foundation system in a mode of failure that offers least resistance. Evidence will be offered in terms of field observations during the 921 Ji-Ji earthquake in 1999 in Taiwan and Bhuj earthquake of 2001 in India. Dynamic centrifuge test data and finite element analyses results are presented to illustrate the traditional failure mechanisms. Copyright © 2010, IGI Global. Copying or distributing in print or electronic forms without written permission of IGI Global is prohibited.

Plasma stabilisation of metallic nanoparticles on silicon for the growth of carbon nanotubes

Ammonia (NH 3) plasma pretreatment is used to form and temporarily reduce the mobility of Ni, Co, or Fe nanoparticles on boron-doped mono- and poly-crystalline silicon. X-ray photoemission spectroscopy proves that NH 3 plasma nitrides the Si supports during nanoparticle formation which prevents excessive nanoparticle sintering/diffusion into the bulk of Si during carbon nanotube growth by chemical vapour deposition. The nitridation of Si thus leads to nanotube vertical alignment and the growth of nanotube forests by root growth mechanism. © 2012 American Institute of Physics.

Understanding ground deformation mechanisms during multi-propped excavation in soft clay

To maximize the utility of high land cost in urban development, underground space is commonly exploited, both to reduce the load acting on the ground and to increase the space available. The execution of underground constructions requires the use of appropriate retaining wall and bracing systems. Inadequate support systems have always been a major concern, as any excessive ground movement induced during excavation could cause damage to neighboring structures, resulting in delays, disputes and cost overruns. Experimental findings on the effect of wall stiffness, depth of the stiff stratum away from the wall toe and wall toe fixity condition are presented and discussed. © 2012 Taylor & Francis Group.

High-order DES and zonal LES of a labyrinth seal

Hybrid numerical large eddy simulation (NLES) and detached eddy simulation (DES) methods are assessed on a labyrinth seal geometry. A high sixth order discretization scheme is used and is validated using a test case of a two dimensional vortex. The hybrid approach adopts a new blending function and along with DES is initially validated using a simple cavity flow. The NLES method is also validated outside of RANS zones. It is found that there is very little resolved turbulence in the cavity for the DES simulation. For the labyrinth seal calculations the DES approach is problematic giving virtually no resolved turbulence content. It is seen that over the tooth tips the extent of the LES region is small and is likely to be a strong contributor to excessive flow damping in these regions. On the other hand the zonal Hamilton-Jacobi approach did not suffer from this trait. In both cases the meshes used are considered to be hybrid RANS-LES adequate. Fortunately (or perhaps unfortunately) the DES profiles are in agreement with the time mean experimental measurements. It is concluded that for an inexperienced CFD practitioner this could have wider implications particularly if transient results such as unsteady loading are desired. Copyright © 2012 by the American Institute of Aeronautics and Astronautics, Inc.

Optimization of burnable poison design for Pu incineration in fully fertile free PWR core

The design challenges of the fertile-free based fuel (FFF) can be addressed by careful and elaborate use of burnable poisons (BP). Practical fully FFF core design for PWR reactor has been reported in the past [1]. However, the burnable poison option used in the design resulted in significant end of cycle reactivity penalty due to incomplete BP depletion. Consequently, excessive Pu loading were required to maintain the target fuel cycle length, which in turn decreased the Pu burning efficiency. A systematic evaluation of commercially available BP materials in all configurations currently used in PWRs is the main objective of this work. The BP materials considered are Boron, Gd, Er, and Hf. The BP geometries were based on Wet Annular Burnable Absorber (WABA), Integral Fuel Burnable Absorber (IFBA), and Homogeneous poison/fuel mixtures. Several most promising combinations of BP designs were selected for the full core 3D simulation. All major core performance parameters for the analyzed cases are very close to those of a standard PWR with conventional UO2 fuel including possibility of reactivity control, power peaking factors, and cycle length. The MTC of all FFF cores was found at the full power conditions at all times and very close to that of the UO2 core. The Doppler coefficient of the FFF cores is also negative but somewhat lower in magnitude compared to UO2 core. The soluble boron worth of the FFF cores was calculated to be lower than that of the UO2 core by about a factor of two, which still allows the core reactivity control with acceptable soluble boron concentrations. The main conclusion of this work is that judicial application of burnable poisons for fertile free fuel has a potential to produce a core design with performance characteristics close to those of the reference PWR core with conventional UO2 fuel.

Bayesian parameter identification for vibro-acoustic models with nonparametric uncertainty

Vibration and acoustic analysis at higher frequencies faces two challenges: computing the response without using an excessive number of degrees of freedom, and quantifying its uncertainty due to small spatial variations in geometry, material properties and boundary conditions. Efficient models make use of the observation that when the response of a decoupled vibro-acoustic subsystem is sufficiently sensitive to uncertainty in such spatial variations, the local statistics of its natural frequencies and mode shapes saturate to universal probability distributions. This holds irrespective of the causes that underly these spatial variations and thus leads to a nonparametric description of uncertainty. This work deals with the identification of uncertain parameters in such models by using experimental data. One of the difficulties is that both experimental errors and modeling errors, due to the nonparametric uncertainty that is inherent to the model type, are present. This is tackled by employing a Bayesian inference strategy. The prior probability distribution of the uncertain parameters is constructed using the maximum entropy principle. The likelihood function that is subsequently computed takes the experimental information, the experimental errors and the modeling errors into account. The posterior probability distribution, which is computed with the Markov Chain Monte Carlo method, provides a full uncertainty quantification of the identified parameters, and indicates how well their uncertainty is reduced, with respect to the prior information, by the experimental data. © 2013 Taylor & Francis Group, London.