Detection and Prediction of Factor VIII Antibody Formation in Congenital and Acquired Haemophilia A

Factor VIII (FVIII) is a co-factor in the haemostatic system required for fibrin-rich clot formation. Inherited F8 gene defects result in haemophilia A (HA), one of the commonest inherited bleeding disorders. Acquired FVIII defects (acquired haemophilia A, AHA) occur through auto-antibody formation. FVIII antibodies (allo and auto-antibodies) are the greatest challenges facing the haemophilia treating physician. Prediction of risk of antibody formation is based on genetic and environmental factors. There is incomplete understanding of the total immune response to FVIII due to limitations in current laboratory methodology used for FVIII antibody testing. The aim of this this work was to assess clinical practices, laboratory methodology and high-throughput approaches to further characterise the immune response to FVIII. The key findings are as follows: 1) Sub-optimal compliance with targeted inhibitor screening following FVIII treatment was seen in non-severe HA in London haemophilia centres. 2) A national survey of AHA demonstrated heterogeneity in the management of immunosuppression and testing. 3) A FVIII ELISA was specific with a high negative predictive values for FVIII antibody detection in routine practice. 4) Pre-analytical heat treatment prior to antibody testing, improved sensitivity for auto-antibody detection and a systematic evaluation optimised incubation conditions for this modification. 5) A novel re-usable high-throughput peptide microarray, characterised B-cell epitopes of monoclonal and polyclonal FVIII antibodies, demonstrating immunodominant epitopes in regions of functional or structural importance. 6) A modified low volume RNA sample tube demonstrated feasibility for transcriptome analysis in patients with severe haemophilia A, providing a repository of transcriptome data for developing understanding of the allo-immune response to FVIII. Heterogeneity in clinical and laboratory practices limits interpretation of data from observational studies of FVIII antibodies. Improvements in detection and characterisation of FVIII antibodies, may further advance understanding of the total immune response to FVIIIOctapharm

A flawed construct? Understanding and unpicking the concept of resilience in the context of economic hardship

Increasingly, the construct of resilience has been used by social scientists and (social) policy makers in relation to individual resilience to economic hardship. There are a number of issues within the literature on the subject that are unresolved including: whether it is an attribute or a process; the extent to which resilience is a positive phenomenon; the extent to which individuals living in economic hardship have agency; and, whether it is finite. The article unpacks these issues, drawing on qualitative data from a longitudinal study in Northern Ireland. It found resilience to be a negative experience for study participants, although they did exhibit a number of attributes that may be described as being positive. They were often unable to exercise 'positive', transformative agency, because the choices available were limited and pernicious in nature. The paper concludes that as an analytical tool for exploring the experiences of people living in economic hardship the construct of resilience is not helpful

Is telomere length a biomarker for aging: cross-sectional evidence from the west of Scotland?

Background <p> The search for biomarkers of aging (BoAs) has been largely unsuccessful to-date and there is widespread skepticism about the prospects of finding any that satisfy the criteria developed by the American Federation of Aging Research. This may be because the criteria are too strict or because a composite measure might be more appropriate. Telomere length has attracted a great deal of attention as a candidate BoA. We investigate whether it meets the criteria to be considered as a single biomarker of aging, and whether it makes a useful contribution to a composite measure. </p> Methodology/Principal Findings <p> Using data from a large population based study, we show that telomere length is associated with age, with several measures of physical and cognitive functioning that are related to normal aging, and with three measures of overall health. In the majority of cases, telomere length adds predictive power to that of age, although it was not nearly as good a predictor overall. We used principal components analysis to form two composites from the measures of functioning, one including telomere length and the other not including it. These composite BoAs were better predictors of the health outcomes than chronological age. There was little difference between the two composites. </p> Conclusions <p> Telomere length does not satisfy the strict criteria for a BoA, but does add predictive power to that of chronological age. Equivocal results from previous studies might be due to lack of power or the choice of measures examined together with a focus on single biomarkers. Composite biomarkers of aging have the potential to outperform age and should be considered for future research in this area.</p&gt

An Energy Accounting Evaluation of Several Alternatives for Hydropower and Geothermal Development

Alternative management strategies for hydropower and geothermal development are myriad. This study does not attempt to evaluate or even summarize the many schemes which are possible. In an era of plentiful natural resources, economic analysis procedures for selecting a particular alternative have been developed which traditionally have tended to optimize on the basis of capital and labor. The approach taken in this study is based on the notion of optimum deployment of finite resources. A legitimate question which this study has attempted to address is: Does the construction of large water management facilities, such as hydropower dams, which involve huge amounts of energy, concrete, and steel, constitute an efficient use of basic resources? An energy accounting analysis technique is proposed, and using this procedure energy resource inputs are examined and compared for specific hydropower dams and geothermal power plants. The technique, though promising, still contains certain problems, and further development is needed in order to establish a consistent and uniform methodology. The energy accounting technique indicates that construction of hydropower facilities is a relatively efficient use of basic energy resources. However, because of large evaporation losses from storage reservoirs, water consumption per unit of power produced tends to be high. An analysis subsequent to the energy accounting approach suggests that combining once-through cooling of thermal power plants with pumped storage hydropower facilities could produce large water savings per unit of generated power. Further study of this configuration is recommended. The energy accounting technique also clearly identifies the high efficiency of geothermal power plants in terms of resource deployment. However, warm water geothermal resources of the type generally available in the intermountain region present formidable problems in utilization. The report proposes a he at exchange r system design which is capable of utilizing warm and highly mineralized waters, and recommends that the design be constructed and tested on a demonstration basis

Energy Impacts of Water Based Recreation

The overall objective of the study reported here was to determine to what extent energy accounting could supplement and/or complement economic benfit/cost analyses of water management projects and to specifically examine the energy impacts of water based recreation. The energy accounting literature was carefully reviewed and an energy accounting methodology applicable to water management was devised. Data pertaining to receation at five reservoirs in Utah were assembled from visitation recoreds and on-site surveys. Energy requirements for site construction, travel to and from the recreation site, and recreation at the site were estimated. It was determined that energy devoted to water based recreation is not inconsequential. As much energy is devoted to recreation at Lake Powell alone as is required for all of production agriculture in Utah. It is suggested that while the models developed in this study could be used with confidence in the preparation of energy impact statements the authors are not persuaded energy accounting provides additional information to water use planners beyong that obtainable from traditional economic analysis

Probing Matter Radii of Neutron-Rich Nuclei by Antiproton Scattering

We propose to use antiprotons to investigate the sizes of stable and neutron-rich exotic nuclei by measurements of the \pbar A absorption cross section along isotopic chains in inverse kinematics. The expected effects are studied theoretically in a microscopic model. The \pbar U optical potentials are obtained by folding free space \pbar N scattering amplitudes with HFB ground state densities and solving the scattering equations by direct integration. The mass dependence of absorption cross sections is found to follow closely the nuclear root-mean-square radii. The total absorption cross section is shown to be a superposition of cross sections describing partial absorption on neutrons and protons, respectively. Thus measuring the differential cross sections for absorption on neutrons and protons will give information on their respective distributions. In neutron-rich nuclei the outer neutron layer shields the absorption on the protons giving access to investigations of antiproton-neutron interactions in matter.Comment: 8 pages, 4 figure

Event-Related Potentials and Emotion Processing in Child Psychopathology

In recent years there has been increasing interest in the neural mechanisms underlying altered emotional processes in children and adolescents with psychopathology. This review provides a brief overview of the most up-to-date findings in the field of Event-Related Potentials (ERPs) to facial and vocal emotional expressions in the most common child psychopathological conditions. In regards to externalising behaviour (i.e. ADHD, CD), ERP studies show enhanced early components to anger, reflecting enhanced sensory processing, followed by reductions in later components to anger, reflecting reduced cognitive-evaluative processing. In regards to internalising behaviour, research supports models of increased processing of threat stimuli especially at later more elaborate and effortful stages. Finally, in autism spectrum disorders abnormalities have been observed at early visual-perceptual stages of processing. An affective neuroscience framework for understanding child psychopathology can be valuable in elucidating underlying mechanisms and inform preventive intervention