2,388 research outputs found

    Infliximab, adalimumab and golimumab for treating moderately to severely active ulcerative colitis after the failure of conventional therapy (including a review of TA140 and TA262): clinical effectiveness systematic review and economic model.

    Get PDF
    BACKGROUND: Ulcerative colitis (UC) is the most common form of inflammatory bowel disease in the UK. UC can have a considerable impact on patients' quality of life. The burden for the NHS is substantial. OBJECTIVES: To evaluate the clinical effectiveness and safety of interventions, to evaluate the incremental cost-effectiveness of all interventions and comparators (including medical and surgical options), to estimate the expected net budget impact of each intervention, and to identify key research priorities. DATA SOURCES: Peer-reviewed publications, European Public Assessment Reports and manufacturers' submissions. The following databases were searched from inception to December 2013 for clinical effectiveness searches and from inception to January 2014 for cost-effectiveness searches for published and unpublished research evidence: MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, The Cochrane Library including the Cochrane Systematic Reviews Database, Cochrane Controlled Trials Register, Database of Abstracts of Reviews of Effects, the Health Technology Assessment database and NHS Economic Evaluation Database; ISI Web of Science, including Science Citation Index, and the Conference Proceedings Citation Index-Science and Bioscience Information Service Previews. The US Food and Drug Administration website and the European Medicines Agency website were also searched, as were research registers, conference proceedings and key journals. REVIEW METHODS: A systematic review [including network meta-analysis (NMA)] was conducted to evaluate the clinical effectiveness and safety of named interventions. The health economic analysis included a review of published economic evaluations and the development of a de novo model. RESULTS: Ten randomised controlled trials were included in the systematic review. The trials suggest that adult patients receiving infliximab (IFX) [Remicade(®), Merck Sharp & Dohme Ltd (MSD)], adalimumab (ADA) (Humira(®), AbbVie) or golimumab (GOL) (Simponi(®), MSD) were more likely to achieve clinical response and remission than those receiving placebo (PBO). Hospitalisation data were limited, but suggested more favourable outcomes for ADA- and IFX-treated patients. Data on the use of surgical intervention were sparse, with a potential benefit for intervention-treated patients. Data were available from one trial to support the use of IFX in paediatric patients. Safety issues identified included serious infections, malignancies and administration site reactions. Based on the NMA, in the induction phase, all biological treatments were associated with statistically significant beneficial effects relative to PBO, with the greatest effect associated with IFX. For patients in response following induction, all treatments except ADA and GOL 100 mg at 32-52 weeks were associated with beneficial effects when compared with PBO, although these were not significant. The greatest effects at 8-32 and 32-52 weeks were associated with 100 mg of GOL and 5 mg/kg of IFX, respectively. For patients in remission following induction, all treatments except ADA at 8-32 weeks and GOL 50 mg at 32-52 weeks were associated with beneficial effects when compared with PBO, although only the effect of ADA at 32-52 weeks was significant. The greatest effects were associated with GOL (at 8-32 weeks) and ADA (at 32-52 weeks). The economic analysis suggests that colectomy is expected to dominate drug therapies, but for some patients, colectomy may not be considered acceptable. In circumstances in which only drug options are considered, IFX and GOL are expected to be ruled out because of dominance, while the incremental cost-effectiveness ratio for ADA versus conventional treatment is approximately £50,300 per QALY gained. LIMITATIONS: The health economic model is subject to several limitations: uncertainty associated with extrapolating trial data over a lifetime horizon, the model does not consider explicit sequential pathways of non-biological treatments, and evidence relating to complications of colectomy was identified through consideration of approaches used within previous models rather than a full systematic review. CONCLUSIONS: Adult patients receiving IFX, ADA or GOL were more likely to achieve clinical response and remission than those receiving PBO. Further data are required to conclusively demonstrate the effect of interventions on hospitalisation and surgical outcomes. The economic analysis indicates that colectomy is expected to dominate medical treatments for moderate to severe UC. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013006883. FUNDING: The National Institute for Health Research Health Technology Assessment programme

    Steam reforming on transition-metal carbides from density-functional theory

    Full text link
    A screening study of the steam reforming reaction (CH_4 + H_2O -> CO + 3H_2) on early transition-metal carbides (TMC's) is performed by means of density-functional theory calculations. The set of considered surfaces includes the alpha-Mo_2C(100) surfaces, the low-index (111) and (100) surfaces of TiC, VC, and delta-MoC, and the oxygenated alpha-Mo_2C(100) and TMC(111) surfaces. It is found that carbides provide a wide spectrum of reactivities towards the steam reforming reaction, from too reactive via suitable to too inert. The reactivity is discussed in terms of the electronic structure of the clean surfaces. Two surfaces, the delta-MoC(100) and the oxygen passivated alpha-Mo_2C(100) surfaces, are identified as promising steam reforming catalysts. These findings suggest that carbides provide a playground for reactivity tuning, comparable to the one for pure metals.Comment: 6 pages, 4 figure

    An analysis of fast photochemistry over high northern latitudes during spring and summer using in-situ observations from ARCTAS and TOPSE

    Get PDF
    Observations of chemical constituents and meteorological quantities obtained during the two Arctic phases of the airborne campaign ARCTAS (Arctic Research of the Composition of the Troposphere from Aircraft and Satellites) are analyzed using an observationally constrained steady state box model. Measurements of OH and HO2 from the Penn State ATHOS instrument are compared to model predictions. Forty percent of OH measurements below 2 km are at the limit of detection during the spring phase (ARCTAS-A). While the median observed-to-calculated ratio is near one, both the scatter of observations and the model uncertainty for OH are at the magnitude of ambient values. During the summer phase (ARCTAS-B), model predictions of OH are biased low relative to observations and demonstrate a high sensitivity to the level of uncertainty in NO observations. Predictions of HO2 using observed CH2O and H2O2 as model constraints are up to a factor of two larger than observed. A temperature-dependent terminal loss rate of HO2 to aerosol recently proposed in the literature is shown to be insufficient to reconcile these differences. A comparison of ARCTAS-A to the high latitude springtime portion of the 2000 TOPSE campaign (Tropospheric Ozone Production about the Spring Equinox) shows similar meteorological and chemical environments with the exception of peroxides; observations of H2O2 during ARCTAS-A were 2.5 to 3 times larger than those during TOPSE. The cause of this difference in peroxides remains unresolved and has important implications for the Arctic HOx budget. Unconstrained model predictions for both phases indicate photochemistry alone is unable to simultaneously sustain observed levels of CH2O and H2O2; however when the model is constrained with observed CH2O, H2O2 predictions from a range of rainout parameterizations bracket its observations. A mechanism suitable to explain observed concentrations of CH2O is uncertain. Free tropospheric observations of acetaldehyde (CH3CHO) are 2–3 times larger than its predictions, though constraint of the model to those observations is sufficient to account for less than half of the deficit in predicted CH2O. The box model calculates gross O3 formation during spring to maximize from 1–4 km at 0.8 ppbv d−1, in agreement with estimates from TOPSE, and a gross production of 2–4 ppbv d−1 in the boundary layer and upper troposphere during summer. Use of the lower observed levels of HO2 in place of model predictions decreases the gross production by 25–50%. Net O3 production is near zero throughout the ARCTAS-A troposphere, and is 1–2 ppbv in the boundary layer and upper altitudes during ARCTAS-B

    Measurement of event shapes in deep inelastic scattering at HERA

    Get PDF
    Inclusive event-shape variables have been measured in the current region of the Breit frame for neutral current deep inelastic ep scattering using an integrated luminosity of 45.0 pb^-1 collected with the ZEUS detector at HERA. The variables studied included thrust, jet broadening and invariant jet mass. The kinematic range covered was 10 < Q^2 < 20,480 GeV^2 and 6.10^-4 < x < 0.6, where Q^2 is the virtuality of the exchanged boson and x is the Bjorken variable. The Q dependence of the shape variables has been used in conjunction with NLO perturbative calculations and the Dokshitzer-Webber non-perturbative corrections (`power corrections') to investigate the validity of this approach.Comment: 7+25 pages, 6 figure

    On the temperature dependence of organic reactivity, nitrogen oxides, ozone production, and the impact of emission controls in San Joaquin Valley, California

    Get PDF
    The San Joaquin Valley (SJV) experiences some of the worst ozone air quality in the US, frequently exceeding the California 8 h standard of 70.4 ppb. To improve our understanding of trends in the number of ozone violations in the SJV, we analyze observed relationships between organic reactivity, nitrogen oxides (NO[subscript x]), and daily maximum temperature in the southern SJV using measurements made as part of California at the Nexus of Air Quality and Climate Change in 2010 (CalNex-SJV). We find the daytime speciated organic reactivity with respect to OH during CalNex-SJV has a temperature-independent portion with molecules typically associated with motor vehicles being the major component. At high temperatures, characteristic of days with high ozone, the largest portion of the total organic reactivity increases exponentially with temperature and is dominated by small, oxygenated organics and molecules that are unidentified. We use this simple temperature classification to consider changes in organic emissions over the last and next decade. With the CalNex-SJV observations as constraints, we examine the sensitivity of ozone production (PO[subscript 3]) to future NO[subscript x] and organic reactivity controls. We find that PO[subscript 3] is NO[subscript x]-limited at all temperatures on weekends and on weekdays when daily maximum temperatures are greater than 29 °C. As a consequence, NO[subscript x] reductions are the most effective control option for reducing the frequency of future ozone violations in the southern SJV.California Environmental Protection Agency. Air Resources Board (Contract CARB 08-316)United States. National Aeronautics and Space Administration (Grant NNX10AR36G

    An analysis of fast photochemistry over high northern latitudes during spring and summer using in-situ observations from ARCTAS and TOPSE

    Get PDF
    Observations of chemical constituents and meteorological quantities obtained during the two Arctic phases of the airborne campaign ARCTAS (Arctic Research of the Composition of the Troposphere from Aircraft and Satellites) are analyzed using an observationally constrained steady state box model. Measurements of OH and HO&lt;sub&gt;2&lt;/sub&gt; from the Penn State ATHOS instrument are compared to model predictions. Forty percent of OH measurements below 2 km are at the limit of detection during the spring phase (ARCTAS-A). While the median observed-to-calculated ratio is near one, both the scatter of observations and the model uncertainty for OH are at the magnitude of ambient values. During the summer phase (ARCTAS-B), model predictions of OH are biased low relative to observations and demonstrate a high sensitivity to the level of uncertainty in NO observations. Predictions of HO&lt;sub&gt;2&lt;/sub&gt; using observed CH&lt;sub&gt;2&lt;/sub&gt;O and H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; as model constraints are up to a factor of two larger than observed. A temperature-dependent terminal loss rate of HO&lt;sub&gt;2&lt;/sub&gt; to aerosol recently proposed in the literature is shown to be insufficient to reconcile these differences. A comparison of ARCTAS-A to the high latitude springtime portion of the 2000 TOPSE campaign (Tropospheric Ozone Production about the Spring Equinox) shows similar meteorological and chemical environments with the exception of peroxides; observations of H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; during ARCTAS-A were 2.5 to 3 times larger than those during TOPSE. The cause of this difference in peroxides remains unresolved and has important implications for the Arctic HO&lt;sub&gt;x&lt;/sub&gt; budget. Unconstrained model predictions for both phases indicate photochemistry alone is unable to simultaneously sustain observed levels of CH&lt;sub&gt;2&lt;/sub&gt;O and H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt;; however when the model is constrained with observed CH&lt;sub&gt;2&lt;/sub&gt;O, H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; predictions from a range of rainout parameterizations bracket its observations. A mechanism suitable to explain observed concentrations of CH&lt;sub&gt;2&lt;/sub&gt;O is uncertain. Free tropospheric observations of acetaldehyde (CH&lt;sub&gt;3&lt;/sub&gt;CHO) are 2–3 times larger than its predictions, though constraint of the model to those observations is sufficient to account for less than half of the deficit in predicted CH&lt;sub&gt;2&lt;/sub&gt;O. The box model calculates gross O&lt;sub&gt;3&lt;/sub&gt; formation during spring to maximize from 1–4 km at 0.8 ppbv d&lt;sup&gt;−1&lt;/sup&gt;, in agreement with estimates from TOPSE, and a gross production of 2–4 ppbv d&lt;sup&gt;−1&lt;/sup&gt; in the boundary layer and upper troposphere during summer. Use of the lower observed levels of HO&lt;sub&gt;2&lt;/sub&gt; in place of model predictions decreases the gross production by 25–50%. Net O&lt;sub&gt;3&lt;/sub&gt; production is near zero throughout the ARCTAS-A troposphere, and is 1–2 ppbv in the boundary layer and upper altitudes during ARCTAS-B

    Future therapeutic targets in rheumatoid arthritis?

    Get PDF
    Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches

    Measurements of fiducial and differential cross sections for Higgs boson production in the diphoton decay channel at s√=8 TeV with ATLAS

    Get PDF
    Measurements of fiducial and differential cross sections are presented for Higgs boson production in proton-proton collisions at a centre-of-mass energy of s√=8 TeV. The analysis is performed in the H → γγ decay channel using 20.3 fb−1 of data recorded by the ATLAS experiment at the CERN Large Hadron Collider. The signal is extracted using a fit to the diphoton invariant mass spectrum assuming that the width of the resonance is much smaller than the experimental resolution. The signal yields are corrected for the effects of detector inefficiency and resolution. The pp → H → γγ fiducial cross section is measured to be 43.2 ±9.4(stat.) − 2.9 + 3.2 (syst.) ±1.2(lumi)fb for a Higgs boson of mass 125.4GeV decaying to two isolated photons that have transverse momentum greater than 35% and 25% of the diphoton invariant mass and each with absolute pseudorapidity less than 2.37. Four additional fiducial cross sections and two cross-section limits are presented in phase space regions that test the theoretical modelling of different Higgs boson production mechanisms, or are sensitive to physics beyond the Standard Model. Differential cross sections are also presented, as a function of variables related to the diphoton kinematics and the jet activity produced in the Higgs boson events. The observed spectra are statistically limited but broadly in line with the theoretical expectations
    corecore