Financial interests of patient organisations contributing to technology appraisal at England's National Institute for Health and Care Excellence (NICE): a policy review

Objectives: To investigate the prevalence of financial interests among patient organisations contributing to health technology assessment at the National Institute for Health and Care Excellence (NICE) in England, and the extent to which current disclosure policy ensures decision-making committees are aware of these interests. Design: Policy review using annual accounts, reports and websites of patient organisations, a database of payments declared by pharmaceutical manufacturers (Disclosure UK), other manufacturer declarations, responses from patient organisations, and declarations of interests by nominated representatives of patient organisations. Setting: Appraisals of medicines and treatments for use in the English and Welsh National Health Service. Participants: 53 patient organisations contributing to 41 NICE technology appraisals published in 2015 and 2016, with 117 separate occasions that a patient organisation contributed to the appraisal of a technology. Main outcome measures: (i) Prevalence of specific interests, i.e. funding from manufacturer(s) of a technology under appraisal or competitor products; (ii) Proportion of specific interests of which NICE decision-making committees were aware; (iii) Proportion of specific interests for which disclosure was not required by current NICE policy. Results: 38/53 (71.7%) patient organisations had accepted funding from the manufacturer(s) of a technology or a competitor product in the same or previous year that they had contributed to the appraisal of that technology. Specific interests were 46 present on 92 out of 117 (78.6%) occasions that patient organisations contributed to appraisals in 2015 and 2016. NICE decision-making committees were aware of less than a third of specific interests (36/115, 31.3%). For over half of the specific interests of which committees were unaware (42/79, 53.2%), disclosure by patient organisations was not required by current NICE policy. Conclusions: Specific interests are highly prevalent among patient organisations contributing to health technology assessment. NICE is reviewing its disclosure policy to ensure that decision-making committees are aware of all relevant interests

Merging enzymes with chemocatalysis for amide bond synthesis

Amides are one of the most fundamental chemical bonds in nature. In addition to proteins and other metabolites, many valuable synthetic products comprise amide bonds. Despite this, there is a need for more sustainable amide synthesis. Herein, we report an integrated next generation multi-catalytic system, merging nitrile hydratase enzymes with a Cu-catalysed N-arylation reaction in a single reaction vessel, for the construction of ubiquitous amide bonds. This synergistic one-pot combination of chemo- and biocatalysis provides an amide bond disconnection to precursors, that are orthogonal to those in classical amide synthesis, obviating the need for protecting groups and delivering amides in a manner unachievable using existing catalytic regimes. Our integrated approach also affords broad scope, very high (molar) substrate loading, and has excellent functional group tolerance, telescoping routes to natural product derivatives, drug molecules, and challenging chiral amides under environmentally friendly conditions at scale

Fast Neutron And Gamma-ray Detectors For The Csiro Air Cargo Scanner

oS(FNDA2006)074 © Copyright owned by the author(s) under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike Licence

Survey of Pasture Species and Management, Manure Management, Milk Production and Reproduction on Pasture-Based Dairy Farms in Florida and Georgia, USA

Traditionally, most dairy farms in the south-eastern United States confine cows to barns or on pasture lots year-round and feed stored forages and concentrated feeds (Fontaneli et al. 2005). Often, much of the feed is purchased, however, the cost of purchased feed and fuel has risen rapidly in the last 5 years (NASS 2009). In addition, a significant amount of capital is tied up in buildings, machinery and manure management systems on the farms. For these reasons, many dairy farmers have shown an interest in or started transitioning to pasture-based dairy systems (Ricks and Hardee 2012). The management practices and production results of pasture-based dairy farms in the south-east appear to vary widely (Macoon et al. 2011), but have not been described. The objective of this study was to document pasture and crop management, manure management and milk production on pasture-based dairy farms in Florida and Georgia

Synthesizing greenhouse gas fluxes across nine European peatlands and shrublands: responses to climatic and environmental changes

In this study, we compare annual fluxes of methane (CH4), nitrous oxide (N2O) and soil respiratory carbon dioxide (CO2) measured at nine European peatlands (n = 4) and shrublands (n = 5). The sites range from northern Sweden to Spain, covering a span in mean annual air temperature from 0 to 16 �C, and in annual precipitation from 300 to 1300mmyr−1. The effects of climate change, including temperature increase and prolonged drought, were tested at five shrubland sites. At one peatland site, the long-term (>30 yr) effect of drainage was assessed, while increased nitrogen deposition was investigated at three peatland sites. The shrublands were generally sinks for atmospheric CH4, whereas the peatlands were CH4 sources, with fluxes ranging from −519 to +6890 mgCH4-Cm−2 yr−1 across the studied ecosystems. At the peatland sites, annual CH4 emission increased with mean annual air temperature, while a negative relationship was found between net CH4 uptake and the soil carbon stock at the shrubland sites. Annual N2O fluxes were generally small ranging from −14 to 42 mgN2O-Nm−2 yr−1. Highest N2O emission occurred at the sites that had highest nitrate (NO− 3 ) concentration in the soil water. Furthermore, experimentally increased NO− 3 deposition led to increased N2O efflux, whereas prolonged drought and long-term drainage reduced the N2O efflux. Soil CO2 emissions in control plots ranged from 310 to 732 gCO2-Cm−2 yr−1. Drought and long-term drainage generally reduced the soil CO2 efflux, except at a hydric shrubland where drought tended to increase soil respiration. In terms of fractional importance of each greenhouse gas to the total numerical global warming response, the change in CO2 efflux dominated the response in all treatments (ranging 71–96 %), except for NO− 3 addition where 89% was due to change in CH4 emissions. Thus, in European peatlands and shrublands the effect on global warming induced by the investigated anthropogenic disturbances will be dominated by variations in soil CO2 fluxes

Freshwater umbrella - the effects of nitrogen deposition & climate change on freshwaters in the UK

In upland areas of the UK located away from direct human disturbance through agriculture, industrial activities and urban pollution, atmospheric pollution poses one of the major threats to the chemical and biological quality of lakes and streams. One of the most important groups of pollutants is nitrogen (N) compounds, including oxidised forms of N called NOx, generated mainly by fossil fuel combustion especially in motor vehicles, and reduced forms of N (ammonia gas or dissolved ammonium compounds) generated mainly from agricultural activities and livestock. These nitrogen compounds may dissolve in rain or soilwater to form acids, or may be taken up as nutrients by plants and soil microbes in upland catchments, and then subsequently released in acid form associated with nitrate leaching at a later date. It is well established that nitrate leaching contributes to acidification of upland waters, with damage to aquatic ecosystems including plants, invertebrates and fish. However it has recently been suggested that nitrate leaching may also be associated with nutrient enrichment of upland waters that contain biological communities adapted to very low nutrient levels

Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis.

Crohn disease (CD) and ulcerative colitis (UC) are increasingly common, chronic forms of inflammatory bowel disease. The behavior of these diseases varies unpredictably among patients. Identification of reliable prognostic biomarkers would enable treatment to be personalized so that patients destined to experience aggressive disease could receive appropriately potent therapies from diagnosis, while those who will experience more indolent disease are not exposed to the risks and side effects of unnecessary immunosuppression. Using transcriptional profiling of circulating T cells isolated from patients with CD and UC, we identified analogous CD8+ T cell transcriptional signatures that divided patients into 2 otherwise indistinguishable subgroups. In both UC and CD, patients in these subgroups subsequently experienced very different disease courses. A substantially higher incidence of frequently relapsing disease was experienced by those patients in the subgroup defined by elevated expression of genes involved in antigen-dependent T cell responses, including signaling initiated by both IL-7 and TCR ligation - pathways previously associated with prognosis in unrelated autoimmune diseases. No equivalent correlation was observed with CD4+ T cell gene expression. This suggests that the course of otherwise distinct autoimmune and inflammatory conditions may be influenced by common pathways and identifies what we believe to be the first biomarker that can predict prognosis in both UC and CD from diagnosis, a major step toward personalized therapy

Nitrous oxide emissions from European agriculture - An analysis of variability and drivers of emissions from field experiments

Nitrous oxide emissions from a network of agricultural experiments in Europe were used to explore the relative importance of site and management controls of emissions. At each site, a selection of management interventions were compared within replicated experimental designs in plot-based experiments. Arable experiments were conducted at Beano in Italy, El Encin in Spain, Foulum in Denmark, Logården in Sweden, Maulde in Belgium, Paulinenaue in Germany, and Tulloch in the UK. Grassland experiments were conducted at Crichton, Nafferton and Peaknaze in the UK, Gödöllö in Hungary, Rzecin in Poland, Zarnekow in Germany and Theix in France. Nitrous oxide emissions were measured at each site over a period of at least two years using static chambers. Emissions varied widely between sites and as a result of manipulation treatments. Average site emissions (throughout the study period) varied between 0.04 and 21.21 kg N₂O-N ha⁻¹ yr⁻¹, with the largest fluxes and variability associated with the grassland sites. Total nitrogen addition was found to be the single most important determinant of emissions, accounting for 15% of the variance (using linear regression) in the data from the arable sites (<i>p</i> < 0.0001), and 77% in the grassland sites. The annual emissions from arable sites were significantly greater than those that would be predicted by IPCC default emission factors. Variability of N₂O emissions within sites that occurred as a result of manipulation treatments was greater than that resulting from site-to-site and year-to-year variation, highlighting the importance of management interventions in contributing to greenhouse gas mitigation

EROS is a selective chaperone regulating the phagocyte NADPH oxidase and purinergic signalling

EROS (essential for reactive oxygen species) protein is indispensable for expression of gp91phox, the catalytic core of the phagocyte NADPH oxidase. EROS deficiency in humans is a novel cause of the severe immunodeficiency, chronic granulomatous disease, but its mechanism of action was unknown until now. We elucidate the role of EROS, showing it acts at the earliest stages of gp91phox maturation. It binds the immature 58 kDa gp91phox directly, preventing gp91phox degradation and allowing glycosylation via the oligosaccharyltransferase machinery and the incorporation of the heme prosthetic groups essential for catalysis. EROS also regulates the purine receptors P2X7 and P2X1 through direct interactions, and P2X7 is almost absent in EROS-deficient mouse and human primary cells. Accordingly, lack of murine EROS results in markedly abnormal P2X7 signalling, inflammasome activation, and T cell responses. The loss of both ROS and P2X7 signalling leads to resistance to influenza infection in mice. Our work identifies EROS as a highly selective chaperone for key proteins in innate and adaptive immunity and a rheostat for immunity to infection. It has profound implications for our understanding of immune physiology, ROS dysregulation, and possibly gene therapy.</jats:p