Performance of point-of-care HbA1c test devices: implications for use in clinical practice – a systematic review and meta-analysis

Regular monitoring of glycated hemoglobin subfraction A1c (HbA1c) in people with diabetes and treatment with glucose-lowering medications to improve glycaemic control can reduce the risk of developing complications [1]. In 2011, a World Health Organization consultation concluded that HbA1cat a threshold of 6.5% (48 mmol/mol) can be used as a diagnostic test for diabetes [2]. HbA1c monitoring often requires the patient to attend the health center twice: once to have blood taken and then returning to get test results and receive adjustments to medication. Point-of-care (POC) analysers are bench-top instruments that use a finger-prick blood sample and are designed for use in a treatment room or at the bed-side. They provide a test result within a few minutes allowing clinical decisions and medication changes to take place immediately. The suitability of many of these devices for the accurate measurement of HbA1c has been questioned, with some POC HbA1c test devices reported not to meet accepted accuracy and precision criteria [3]. Ideal imprecision goals for HbA1c should be coefficient of variation (CV) of <2% for HbA1c reported in % units (or <3% in SI units, mmol/mol) [4], [5], [6]. Most evaluations of POC HbA1c devices have taken place in laboratory settings [7], [8]; fewer studies have assessed device performance in a POC setting or with clinicians performing the tests [9], [10]. The only published review that has attempted to combine data from accuracy studies identified five studies covering three devices and compared correlation coefficients [11]. Systematically reporting and pooling data estimates of bias and precision between POC HbA1c devices and laboratory measurements would enable end users to assess which analysers best meet their analytical performance needs. This may be of particular importance for clinicians in primary care settings where much of the management of diabetes patients takes place. The comparison of accuracy between devices over the entire therapeutic range would need to be carried out by combining data on measurement error (bias) between POC and laboratory tests [12]. The aim of this study was to compare accuracy and precision of POC HbA1c devices with the local laboratory method based on data from published studies and discuss the clinical implications of the findings

New insights into the role of androgen and oestrogen receptors in molecular apocrine breast tumours

Two recent studies on a rare androgen-dependent form of breast cancer have shed light on the biology of luminal tumours and reinforced the view that interfering with androgen signalling may have a place in the therapy of some forms of breast cancer

Impact of Fatty-Acid Labeling of Bacillus subtilis Membranes on the Cellular Lipidome and Proteome

Developing cultivation methods that yield chemically and isotopically defined fatty acid (FA) compositions within bacterial cytoplasmic membranes establishes an in vivo experimental platform to study membrane biophysics and cell membrane regulation using novel approaches. Yet before fully realizing the potential of this method, it is prudent to understand the systemic changes in cells induced by the labeling procedure itself. In this work, analysis of cellular membrane compositions was paired with proteomics to assess how the proteome changes in response to the directed incorporation of exogenous FAs into the membrane of Bacillus subtilis. Key findings from this analysis include an alteration in lipid headgroup distribution, with an increase in phosphatidylglycerol lipids and decrease in phosphatidylethanolamine lipids, possibly providing a fluidizing effect on the cell membrane in response to the induced change in membrane composition. Changes in the abundance of enzymes involved in FA biosynthesis and degradation are observed; along with changes in abundance of cell wall enzymes and isoprenoid lipid production. The observed changes may influence membrane organization, and indeed the well-known lipid raft-associated protein flotillin was found to be substantially down-regulated in the labeled cells – as was the actin-like protein MreB. Taken as a whole, this study provides a greater depth of understanding for this important cell membrane experimental platform and presents a number of new connections to be explored in regard to modulating cell membrane FA composition and its effects on lipid headgroup and raft/cytoskeletal associated proteins

EURO-WABB: an EU rare diseases registry for Wolfram syndrome, Alström syndrome and Bardet-Biedl syndrome

Background: Wolfram, Alström and Bardet-Biedl (WABB) syndromes are rare diseases with overlapping features of multiple sensory and metabolic impairments, including diabetes mellitus, which have caused diagnostic confusion. There are as yet no specific treatments available, little or no access to well characterized cohorts of patients, and limited information on the natural history of the diseases. We aim to establish a Europe-wide registry for these diseases to inform patient care and research. Methods: EURO-WABB is an international multicenter large-scale observational study capturing longitudinal clinical and outcome data for patients with WABB diagnoses. Three hundred participants will be recruited over 3 years from different sites throughout Europe. Comprehensive clinical, genetic and patient experience data will be collated into an anonymized disease registry. Data collection will be web-based, and forms part of the project's Virtual Research and Information Environment (VRIE). Participants who haven't undergone genetic diagnostic testing for their condition will be able to do so via the project. Conclusions: the registry data will be used to increase the understanding of the natural history of WABB diseases, to serve as an evidence base for clinical management, and to aid the identification of opportunities for intervention to stop or delay the progress of the disease. The detailed clinical characterisation will allow inclusion of patients into studies of novel treatment interventions, including targeted interventions in small scale open label studies; and enrolment into multi-national clinical trials. The registry will also support wider access to genetic testing, and encourage international collaborations for patient benefit

Petrogenesis and rare earth element mineralization of the Elk Creek carbonatite, Nebraska, USA

Although carbonatites are the primary source of the world&rsquo;s rare earth elements (REEs), the processes responsible for ore-grade REE enrichment in carbonatites are still poorly understood. In this study, we present a petrologic, geochemical, and isotopic evaluation of the Elk Creek carbonatite in southeast Nebraska to constrain the origin of REE mineralization. The Elk Creek carbonatite is a multilithologic carbonatite comprised of an early apatite-dolomite carbonatite, a middle/heavy REE-enriched magnetite-dolomite carbonatite, and a late-stage light REE-enriched, barite-dolomite carbonatite, as well as a suite of breccias. Neodymium, strontium, and carbon isotopic data from the early apatite-dolomite carbonatite, &epsilon;Nd(T)&nbsp;=&nbsp;2.3 to 3.4, 87Sr/86Sr(i)&nbsp;=&nbsp;0.702704 to 0.702857, and &delta;13C&nbsp;=&nbsp;&minus;3.3 to &minus;3.4, indicate that the parental magma and REEs were derived from the mantle, and textural and chemical data suggest that hydrothermal processes played an important role in reaching ore-grade enrichment. Higher initial 87Sr/86Sr values (&sim;0.7041) of REE-mineralized lithologies are evidence that these fluids were derived, in part, from meteoric water that interacted with the country rock. Modeling of the C-O isotopic data reveals that some of the isotopic variation results from closed-system Rayleigh fractionation of an evolving carbonatitic magma between 300 and 500&nbsp;&deg;C, but an excursion to heavier &delta;18O is likely the result of interaction with H2O-CO2-fluids at temperatures from 400 to 100&nbsp;&deg;C. Hydrothermal dolomite has higher 87Sr/86Sr values than early-formed magmatic dolomite, consistent with metasomatism by fluids derived, in part, from a more radiogenic source such as the Precambrian-age wall rock. Rare earth element mineralization occurs primarily in fine-grained, cavity filling minerals including monazite, bastn&auml;site, parisite, and synchysite along with barite, dolomite, quartz, and iron oxides. We interpret the LREE enrichment at Elk Creek to be the product of hydrothermal fluids derived from the evolving carbonatite magma and fluids from the wall rock. The REEs likely became enriched in late-stage fluids from the evolving magma as well as being remobilization by the dissolution of earlier formed minerals. Middle/heavy REE-enrichment in the magnetite-dolomite carbonatite is hosted in hydrothermal dolomite and is attributed to variations in the composition of hydrothermal fluids. &nbsp;</p

‘An almost continuous picture of sordid vice’: The Keeler Affair, the Profumo Scandal and ‘Political’ Film Censorship in the 1960s

In 1963, the Profumo affair brought Christine Keeler to public attention and transformed her, briefly, into one of the most talked about women in the world. Seeking to exploit her notoriety, Topaz Films entered into an agreement with Keeler to make a cinematic version of her life story, The Keeler Affair. This article explores some of the controversies surrounding The Keeler Affair, especially in terms of the way in which the British Board of Film Censors dealt with the film. The Keeler Affair was submitted to the BBFC on two occasions – once when it was completed and then again in 1969 when Keeler's memoirs were serialised in the News of the World – and was rejected both times. On the second occasion, The Keeler Affair was also submitted to, and rejected by, the Greater London Council. The article seeks to establish some of the political factors that shaped the BBFC's and the GLC's attitudes towards politically contentious films, and demonstrates that the decisions made by the censors were guided not simply by the content of The Keeler Affair, but also by personal relationships, shared Establishment attitudes, concerns about public perceptions of the film industry and a desire not to be drawn into political controversies. Consequently, the article serves to reinforce the idea that censorship is best understood as a dynamic process shaped by a host of determining factors, many of which might best be described as extra- or para-cinematic

Linkage between solid-phase apportionment and bioaccessible arsenic, chromium and lead in soil from Glasgow, Scotland, UK

The chemical composition of soil from the Glasgow (UK) urban area was used to identify the controls on the availability of potentially harmful elements (PHEs) in soil to humans. Total and bioaccessible concentrations of arsenic (As), chromium (Cr) and lead (Pb) in 27 soil samples, collected from different land uses, were coupled to information on their solid-phase partitioning derived from sequential extraction data. The total element concentrations in the soils were in the range <0.1–135mgkg–1 for As; 65–3680mgkg–1 for Cr and 126–2160mgkg–1 for Pb, with bioaccessible concentrations averaging 27, 5 and 27% of the total values, respectively. Land use does not appear to be a predictor of contamination; however, the history of the contamination is critically important. The Chemometric Identification of Substrates and Element Distribution (CISED) sequential chemical extraction and associated self-modelling mixture resolution analysis identified three sample groupings and 16 geochemically distinct phases (substrates). These were related to iron (n=3), aluminium–silicon (Al–Si; n=2), calcium (n=3), phosphorus (n=1), magnesium (Mg; n=3), manganese (n=1) and easily extractable (n=3), which was predominantly made up of sodium and sulphur. As, Cr and Pb were respectively found in 9, 10 and 12 of the identified phases, with bioaccessible As predominantly associated with easily extractable phases, bioaccessible Cr with the Mg-dominated phases and bioaccessible Pb with both the Mg-dominated and Al–Si phases. Using a combination of the Unified Barge Method to measure the bioaccessibility of PHEs and CISED to identify the geochemical sources has allowed a much better understanding of the complexity of PHE mobility in the Glasgow urban environment. This approach can be applied to other urban environments and cases of soil contamination, and made part of land-use planning

Evolutionary connectionism: algorithmic principles underlying the evolution of biological organisation in evo-devo, evo-eco and evolutionary transitions

The mechanisms of variation, selection and inheritance, on which evolution by natural selection depends, are not fixed over evolutionary time. Current evolutionary biology is increasingly focussed on understanding how the evolution of developmental organisations modifies the distribution of phenotypic variation, the evolution of ecological relationships modifies the selective environment, and the evolution of reproductive relationships modifies the heritability of the evolutionary unit. The major transitions in evolution, in particular, involve radical changes in developmental, ecological and reproductive organisations that instantiate variation, selection and inheritance at a higher level of biological organisation. However, current evolutionary theory is poorly equipped to describe how these organisations change over evolutionary time and especially how that results in adaptive complexes at successive scales of organisation (the key problem is that evolution is self-referential, i.e. the products of evolution change the parameters of the evolutionary process). Here we first reinterpret the central open questions in these domains from a perspective that emphasises the common underlying themes. We then synthesise the findings from a developing body of work that is building a new theoretical approach to these questions by converting well-understood theory and results from models of cognitive learning. Specifically, connectionist models of memory and learning demonstrate how simple incremental mechanisms, adjusting the relationships between individually-simple components, can produce organisations that exhibit complex system-level behaviours and improve the adaptive capabilities of the system. We use the term “evolutionary connectionism” to recognise that, by functionally equivalent processes, natural selection acting on the relationships within and between evolutionary entities can result in organisations that produce complex system-level behaviours in evolutionary systems and modify the adaptive capabilities of natural selection over time. We review the evidence supporting the functional equivalences between the domains of learning and of evolution, and discuss the potential for this to resolve conceptual problems in our understanding of the evolution of developmental, ecological and reproductive organisations and, in particular, the major evolutionary transitions

Understanding perceptions on 'Buruli' in northwestern Uganda: A biosocial investigation.

BACKGROUND: An understudied disease, little research thus far has explored responses to Buruli ulcer and quests for therapy from biosocial perspective, despite reports that people seek biomedical treatment too late. METHODS AND FINDINGS: Taking an inductive approach and drawing on long-term ethnographic fieldwork in 2013-14, this article presents perspectives on this affliction of people living and working along the River Nile in northwest Uganda. Little is known biomedically about its presence, yet 'Buruli', as it is known locally, was and is a significant affliction in this region. Establishing a biosocial history of 'Buruli', largely obscured from biomedical perspectives, offers explanations for contemporary understandings, perceptions and practices. CONCLUSIONS/SIGNIFICANCE: We must move beyond over-simplifying and problematising 'late presentation for treatment' in public health, rather, develop biosocial approaches to understanding quests for therapy that take into account historical and contemporary contexts of health, healing and illness. Seeking to understand the context in which healthcare decisions are made, a biosocial approach enables greater depth and breadth of insight into the complexities of global and local public health priorities such as Buruli ulcer

Key Concepts for Estimating the Burden of Surgical Conditions and the Unmet Need for Surgical Care

Background: Surgical care is emerging as a crucial issue in global public health. Methodology is needed to assess the impact of surgical care from a public health perspective. Methods: A consensus opinion of a group of surgeons, anesthesiologists, and public health experts was established regarding the methodology for estimating the burden of surgical conditions and the unmet need for surgical care. Results: For purposes of analysis, we define surgical conditions as any disease state requiring the expertise of a surgically trained provider. Abnormalities resulting from a surgical condition or its treatment are termed surgical sequelae. Surgical care is defined as any measure that reduces the rates of physical disability or premature death associated with a surgical condition. To measure the burden of surgical conditions and unmet need for surgical care we propose using cumulative disability-adjusted life-year (DALY) curves generated from age-specific population-based data. This conceptual framework is based on the premise that surgically associated disability and death is determined by the incidence of surgical conditions and the quantity and quality of surgical care. The burden of surgical conditions is defined as the total disability and premature deaths that would occur in a population should there be no surgical care; the unmet need for surgical care is defined as the potentially treatable disability and premature deaths due to surgical conditions. Burden of surgical conditions should be expressed as DALYs and unmet need as potential DALYs avertable. Conclusions: Methodology is described for estimating the burden of surgical conditions and unmet need for surgical care. Using this approach it will be feasible to estimate the global burden of surgical conditions and help clarify where surgery fits among other global health priorities. These methods need to be validated using population-based data