Recruiting patients to medical research: double blind randomised trial of "opt-in" versus "opt-out" strategies

Objective To evaluate the effect of opt-in compared with opt-out recruitment strategies on response rate and selection bias. Design Double blind randomised controlled trial. Setting Two general practices in England. Participants 510 patients with angina. Intervention Patients were randomly allocated to an opt-in (asked to actively signal willingness to participate in research) or opt-out (contacted repeatedly unless they signalled unwillingness to participate) approach for recruitment to an observational prognostic study of patients with angina. Main outcome measures Recruitment rate and clinical characteristics of patients. Results The recruitment rate, defined by clinic attendance, was 38% (96/252) in the opt-in arm and 50% (128/258) in the opt-out arm (P = 0.014). Once an appointment had been made, non-attendance at the clinic was similar (20% opt-in arm v 17% opt-out arm; P = 0.86). Patients in the opt-in arm had fewer risk factors (44% v 60%; P = 0.053), less treatment for angina (69% v 82%; P = 0.010), and less functional impairment (9% v 20%; P = 0.023) than patients in the opt-out arm. Conclusions The opt-in approach to participant recruitment, increasingly required by ethics committees, resulted in lower response rates and a biased sample. We propose that the opt-out approach should be the default recruitment strategy for studies with low risk to participants

The impact of volcanic eruptions in the period 2000-2013 on global mean temperature trends evaluated in the HadGEM2-ES climate model

This is the final version of the article. Available from Wiley via the DOI in this record.The slow-down in global warming over the last decade has lead to significant debate about whether the causes are of natural or anthropogenic origin. Using an ensemble of HadGEM2-ES coupled climate model simulations we investigate the impact of overlooked modest volcanic eruptions. We deduce a global mean cooling of around -0.02 to -0.03K over the period 2008-2012. Thus while these eruptions do cause a cooling of the Earth and may therefore contribute to the slow-down in global warming, they do not appear to be the sole or primary cause. © 2014 Royal Meteorological Society.JMH, AJ, and GSJ were supported by the Joint DECC/Defra Met Office Hadley Centre Climate Programme (GA01101). We acknowledge the World Climate Research Programme's Working Group on Coupled Modelling, which is responsible for CMIP, and we thank the climate modelling groups for producing and making available their model output

Uncertainties in the attribution of greenhouse gas warming and implications for climate prediction

This is the final version. Available from the American Geophysical Union via the DOI in this record. Using optimal detection techniques with climate model simulations, most of the observed increase of near-surface temperatures over the second half of the twentieth century is attributed to anthropogenic influences. However, the partitioning of the anthropogenic influence to individual factors, such as greenhouse gases and aerosols, is much less robust. Differences in how forcing factors are applied, in their radiative influence and in models’ climate sensitivities, substantially influence the response patterns. We find that standard optimal detection methodologies cannot fully reconcile this response diversity. By selecting a set of experiments to enable the diagnosing of greenhouse gases and the combined influence of other anthropogenic and natural factors, we find robust detections of well-mixed greenhouse gases across a large ensemble of models. Of the observed warming over the twentieth century of 0.65 K/century we find, using a multimodel mean not incorporating pattern uncertainty, a well-mixed greenhouse gas warming of 0.87 to 1.22 K/century. This is partially offset by cooling from other anthropogenic and natural influences of-0.54 to-0.22 K/century. Although better constrained than recent studies, the attributable trends across climate models are still wide, with implications for observational constrained estimates of transient climate response. Some of the uncertainties could be reduced in future by having more model data to better quantify the simulated estimates of the signals and natural variability, by designing model experiments more effectively and better quantification of the climate model radiative influences. Most importantly, how model pattern uncertainties are incorporated into the optimal detection methodology should be improved.Joint UK DECC/Defra Met Office Hadley Centre Climate Programm

Transient nuclear criticality excursion analysis of highly dispersed particulate three-phase fluidised systems

The aim of this study was to perform sensitivity analysis, investigating how different fluidisation and sedimentation characteristics of three-phase wetted UO2 powder beds, may affect a transient nuclear criticality excursion initiated through the addition of water into a fissile powder bed. This type of postulated nuclear criticality accident scenario may occur in nuclear fuel fabrication facilities when a fire is fought through the use of water, supplied via an automatic or manual fire-suppression system. A similar scenario may also develop as a result of water leaks or flooding of the process area housing UO2 powder. The article introduces a model for gas-bubble induced fluidisation of a UO2 powder bed and examines how this phenomenon may affect the neutron kinetic response of a three-phase fluidised fissile powder system. Empirical analysis has shown that fissile suspensions form agglomerated structures when suspended in water, at agglomerate sizes that range from 18 to 40 . Simulation results indicate that both the critical gas velocity and rate of fluidisation may significantly affect transient nuclear criticality excursion dynamics. The re-distribution of fissile mass into a highly dispersed suspension generally reduces the reactivity of the system, however, depending on the H/U ratio, a positive reactivity may be added to the system. Low Péclet numbers in the suspension suggest that gas-bubble induced motion of the suspension causes a highly dispersive flow field. An oscillatory power response is predicted for low critical gas velocities where the reactivity of the system is predominantly governed by the re-distribution of fissile mass within the system. The frequency of these oscillations is greater for a higher hindered settling rate of powder particles. At a higher critical gas velocity, the transient nuclear criticality excursion is governed by the voidage reactivity feedback, making the response quite independent of fluidisation. In all cases, large volumes of UO2 powder may leave the domain due to overflowing of the suspension. Transient nuclear criticality excursions in UO2 powder beds with a low critical gas velocity are terminated once the bed becomes fully saturated

Oligoclonal expansions of CD8(+) T cells in chronic HIV infection are antigen specific

Acute HIV infection is associated with a vigorous immune response characterized by the proliferation of selected T cell receptor V beta (BV)-expressing CD8(+) T cells. These 'expansions', which are commonly detected in the peripheral blood, can persist during chronic HIV infection and may result in the dominance of particular clones. Such clonal populations are most consistent with antigen-driven expansions of CD8(+) T cells. However, due to the difficulties in studying antigen-specific T cells in vivo, it has been hard to prove that oligoclonal BV expansions are actually HIV specific. The use of tetrameric major histocompatibility complex-peptide complexes has recently enabled direct visualization of antigen-specific T cells ex vivo but has not provided information on their clonal composition. We have now made use of these tetrameric complexes in conjunction with anti-BV chain-specific monoclonal antibodies and analysis of cytotoxic T lymphocyte lines/clones to show that chronically clonally expanded CD8(+) T cells are HIV specific in vivo

Diagnosing Sporadic Creutzfeldt-Jakob Disease by the Detection of Abnormal Prion Protein in Patient Urine

IMPORTANCE: Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder associated with the accumulation of infectious abnormal prion protein through a mechanism of templated misfolding. A recent report has described the detection of abnormal prion protein in the urine of patients with variant CJD (vCJD) using protein misfolding by cyclic amplification, which was apparently absent in the more common sporadic form of CJD (sCJD). A noninvasive diagnostic test could improve early diagnosis of sCJD and, by screening donations, mitigate the potential risks of prion transmission through human urine–derived pharmaceuticals. Here, we describe the adaptation of the direct detection assay, developed originally as a blood test for vCJD, for the detection of disease-associated prion protein in urine samples from patients with sCJD. OBJECTIVE: To determine the feasibility of sCJD diagnosis by adaptation of an established vCJD diagnostic blood test to urine. DESIGN, SETTINGS AND PARTICIPANTS: This retrospective, cross-sectional study included anonymized urine samples from healthy nonneurological control individuals (n = 91), patients with non-prion neurodegenerative diseases (n = 34), and patients with prion disease (n = 37) of which 20 had sCJD. Urine samples obtained during the Medical Research Council PRION-1 Trial, the National Prion Monitoring Cohort Study, and/or referred to the National Prion Clinic or Dementia Research Centre at the National Hospital for Neurology and Neurosurgery in the United Kingdom. MAIN OUTCOMES AND MEASURES: Presence of sCJD infection determined by an assay that captures, enriches, and detects disease-associated prion protein isoforms. RESULTS: A total of 162 samples were analyzed, composed of 91 normal control individuals (51 male, 33 female, and 7 not recorded), 34 neurological disease control individuals (19 male and 15 female), and 37 with prion disease (22 male and 15 female). The assay’s specificity for prion disease was 100% (95% CI, 97%-100%), with no false-positive reactions from 125 control individuals, including 34 from a range of neurodegenerative diseases. In contrast to a previous study, which used a different method, sensitivity to vCJD infection was low (7.7%; 95% CI, 0.2%-36%), with only 1 of 13 patients with positive test results, while sensitivity to sCJD was unexpectedly high at 40% (95% CI, 19%-64%). CONCLUSIONS AND RELEVANCE: We determined 40% of sCJD urine sample results as positive. To our knowledge, this is the first demonstration of an assay that can detect sCJD infection in urine or any target analyte outside of the central nervous system. Urine detection could allow the development of rapid, molecular diagnostics for sCJD and has implications for other neurodegenerative diseases where disease-related assemblies of misfolded proteins might also be present in urine

Scoping the strengths and weaknesses of different auction and PES mechanisms for Countryside Stewardship

This is the final version. Available from Defra (Department for Environment, Food and Rural Affairs) via the link in this recordThe majority of farmers in England currently receive a fixed fee for managing their land under an agrienvironment scheme (Environmental Stewardship), which is based on an estimate of the typical income forgone by participating. The aim of this research is to explore alternative mechanisms for allocating agri-environment contracts with a view to achieving a more cost-efficient and effective use of funds. The focus is on reverse auctions, whereby farmers opt into a bidding process, offering to manage their land under prescribed management options at a price that more closely reflects their cost of doing so. The researchers have used a combination of laboratory experiments, simulation modelling and farmer workshops to consider the opportunity for efficiency gains, aspects of auction design and farmer responses to auctions. A secondary objective of the work is to explore opportunities for the private sector to engage in agrienvironment actions by leveraging match-funding where there are common goals and mutual benefits for private firms and society. This has entailed a review of the payment for ecosystem services (PES) literature and consultations with a number of relevant private firms. A particular focus for the latter has been the water companies, as they have already established some initiatives on PES around improving water quality

On misunderstanding Heraclitus: The justice of organisation structure

Writers on organisational change often refer to the cosmology of Heraclitus in their work. Some use these references to support arguments for the constancy and universality of organisational change and the consignment to history of organisational continuity and stability. These writers misunderstand the scope of what Heraclitus said. Other writers focus exclusively on the idea that originated with Heraclitus that the universe is composed of processes and not of things. This idea, which has been particularly associated with Heraclitus’s thought from the time of Plato, does indeed provide a rich source of insights into organisational analysis, not least the current trends towards giving proper attention to processual studies of organisational change. Yet there is some uncertainty as to whether Heraclitus actually said that the universe was composed exclusively of processes rather than things, and even if that was what he thought, he intended his ideas on flux to be understood not in isolation but in the context of other aspects of his cosmology. Writers on organisational change seldom make reference to this wider context. Heraclitus was a rational but also a religious thinker. A central element in his thought was the notion of divine Justice, which to a Greek of his era meant the order of the universe. Remote as his Olympian theology may seem today, it sets a crucial and entirely rational context for understanding his ideas about flux. It means that ideas about continuity and stability were quite as important in Heraclitus’s cosmology as his more commonly quoted ideas about change. This paper sets out an overview of Heraclitus’s philosophy, insofar as it appears to have potential relevance to organisational analysis, and discusses how far it supports or contradicts the ideas that organisational change scholars have drawn from it

Multinational tagging efforts illustrate regional scale of distribution and threats for east pacific green turtles (Chelonia mydas agassizii).

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tThis is the final version of the article. Available from Public Library of Science via the DOI in this record.To further describe movement patterns and distribution of East Pacific green turtles (Chelonia mydas agassizii) and to determine threat levels for this species within the Eastern Pacific. In order to do this we combined published data from existing flipper tagging and early satellite tracking studies with data from an additional 12 satellite tracked green turtles (1996-2006). Three of these were tracked from their foraging grounds in the Gulf of California along the east coast of the Baja California peninsula to their breeding grounds in Michoacán (1337-2928 km). In addition, three post-nesting females were satellite tracked from Colola beach, Michoacán to their foraging grounds in southern Mexico and Central America (941.3-3020 km). A further six turtles were tracked in the Gulf of California within their foraging grounds giving insights into the scale of ranging behaviour. Turtles undertaking long-distance migrations showed a tendency to follow the coastline. Turtles tracked within foraging grounds showed that foraging individuals typically ranged up to 691.6 km (maximum) from release site location. Additionally, we carried out threat analysis (using the cumulative global human impact in the Eastern Pacific) clustering pre-existing satellite tracking studies from Galapagos, Costa Rica, and data obtained from this study; this indicated that turtles foraging and nesting in Central American waters are subject to the highest anthropogenic impact. Considering that turtles from all three rookeries were found to migrate towards Central America, it is highly important to implement conservation plans in Central American coastal areas to ensure the survival of the remaining green turtles in the Eastern Pacific. Finally, by combining satellite tracking data from this and previous studies, and data of tag returns we created the best available distributional patterns for this particular sea turtle species, which emphasized that conservation measures in key areas may have positive consequences on a regional scale.The work was supported by Earthwatch Institute, David and Lucile Packard Foundation, Wallace Research Foundation, PADI Foundation and the Arizona-Sonora Desert Museum. C. E. H. received a Masters degree bursary from the University of Exeter and the European Social Fund and would like to thank Consejo Nacional de Ciencia y Tecnología (Mexico) for support through a PhD scholarship. W. J. N. was supported by a Fulbright Fellowship and a Marshall Fellowship during the period field research in Baja California was conducted. B. J. G. is supported by the Darwin Initiative, European Social Fund and The Natural Environment Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript