186 research outputs found
PNP16: THE COMPARISON OF DIFFERENT METHODS FOR DETERMINING THE IMPACT OF MIGRAINE PROPHYLAXIS ON COSTS
Rationale and design of the Novel Uses of adaptive Designs to Guide provider Engagement in Electronic Health Records (NUDGE-EHR) pragmatic adaptive randomized trial: a trial protocol
Background: The prescribing of high-risk medications to older adults remains extremely common and results in potentially avoidable health consequences. Efforts to reduce prescribing have had limited success, in part because they have been sub-optimally timed, poorly designed, or not provided actionable information. Electronic health record (EHR)-based tools are commonly used but have had limited application in facilitating deprescribing in older adults. The objective is to determine whether designing EHR tools using behavioral science principles reduces inappropriate prescribing and clinical outcomes in older adults. Methods: The Novel Uses of Designs to Guide provider Engagement in Electronic Health Records (NUDGE-EHR) project uses a two-stage, 16-arm adaptive randomized pragmatic trial with a βpick-the-winnerβ design to identify the most effective of many potential EHR tools among primary care providers and their patients β₯ 65 years chronically using benzodiazepines, sedative hypnotic (βZ-drugsβ), or anticholinergics in a large integrated delivery system. In stage 1, we randomized providers and their patients to usual care (n = 81 providers) or one of 15 EHR tools (n = 8 providers per arm) designed using behavioral principles including salience, choice architecture, or defaulting. After 6 months of follow-up, we will rank order the arms based upon their impact on the trialβs primary outcome (for both stages): reduction in inappropriate prescribing (via discontinuation or tapering). In stage 2, we will randomize (a) stage 1 usual care providers in a 1:1 ratio to one of the up to 5 most promising stage 1 interventions or continue usual care and (b) stage 1 providers in the unselected arms in a 1:1 ratio to one of the 5 most promising interventions or usual care. Secondary and tertiary outcomes include quantities of medication prescribed and utilized and clinically significant adverse outcomes. Discussion: Stage 1 launched in October 2020. We plan to complete stage 2 follow-up in December 2021. These results will advance understanding about how behavioral science can optimize EHR decision support to improve prescribing and health outcomes. Adaptive trials have rarely been used in implementation science, so these findings also provide insight into how trials in this field could be more efficiently conducted. Trial registration: Clinicaltrials.gov (NCT04284553, registered: February 26, 2020
Compactifications and algebraic completions of Limit groups
In this paper we consider the existence of dense embeddings of Limit groups
in locally compact groups generalizing earlier work of Breuillard, Gelander,
Souto and Storm [GBSS] where surface groups were considered. Our main results
are proved in the context of compact groups and algebraic groups over local
fields. In addition we prove a generalization of the classical Baumslag lemma
which is a useful tool for generating eventually faithful sequences of
homomorphisms. The last section is dedicated to correct a mistake from [BGSS]
and to get rid of the even genus assumption.Comment: v2: Substantial changes to sections 7 and 8.2. Typos corrected.
References added. v3: Acknowledgement correcte
How is Democracy Applied within the EU: Combining Elements of Traditional and Innovative Democratic Practice
The EU represents a new and complex political system which, according to
numerous social scholars, suffers from the so-called democratic deficit. The basic
argument behind this claim is that citizens lack control of the EU because,
within its political system, national parliaments of member states possess only
limited powers which have not been adequately compensated through steady
empowerment of the European parliament (EP). Starting from this notion, the
paper will explore the application of various concepts of democracy within the
political system of the EU. First and foremost, it will analyse representative democracy
in the EU, which stands as a foundation of all contemporary democratic
systems. However, the paper will not stop at representative democracy, but
it will also look at participatory, direct and deliberative democracy as applied
within the political system of the EU. These concepts of democracy can only be
viewed in relation and as an addition to representative democracy, but their application
is very important for the EU due to limited possibilities for developing
representative democracy at the supranational level. The paper will argue that,
with regard to participatory and deliberative democracy, the EU can be viewed
in many respects as a showcase for the national level, because it successfully
developed various mechanisms related to implementation of these concepts.
Particular attention will be paid to the Lisbon Treaty, which clarified many uncertainties
that previously burdened the application of democracy within the
EU. It will be argued that with the Lisbon Treaty the classic argument about the
EUβs democratic deficit lost some of its appeal, because this treaty transformed
the EP from secondary to equal participant in the EUβs legislative process
Income-Related Minimum Taxation Concepts and Their Impact on Corporate Investment Decisions
Cross-Border Group-Taxation and Loss-Offset in the EU - An Analysis for CCCTB (Common Consolidated Corporate Tax Base) and Etas (European Tax Allocation System)
Results of a survey by the European Society of Radiology (ESR): undergraduate radiology education in Europeβinfluences of a modern teaching approach
Beta-HPV 5 and 8 E6 Promote p300 Degradation by Blocking AKT/p300 Association
The E6 oncoprotein from high-risk genus alpha human papillomaviruses (Ξ±-HPVs), such as HPV 16, has been well characterized with respect to the host-cell proteins it interacts with and corresponding signaling pathways that are disrupted due to these interactions. Less is known regarding the interacting partners of E6 from the genus beta papillomaviruses (Ξ²-HPVs); however, it is generally thought that Ξ²-HPV E6 proteins do not interact with many of the proteins known to bind to Ξ±-HPV E6. Here we identify p300 as a protein that interacts directly with E6 from both Ξ±- and Ξ²-HPV types. Importantly, this association appears much stronger with Ξ²-HPV types 5 and 8-E6 than with Ξ±-HPV type 16-E6 or Ξ²-HPV type 38-E6. We demonstrate that the enhanced association between 5/8-E6 and p300 leads to p300 degradation in a proteasomal-dependent but E6AP-independent manner. Rather, 5/8-E6 inhibit the association of AKT with p300, an event necessary to ensure p300 stability within the cell. Finally, we demonstrate that the decreased p300 protein levels concomitantly affect downstream signaling events, such as the expression of differentiation markers K1, K10 and Involucrin. Together, these results demonstrate a unique way in which Ξ²-HPV E6 proteins are able to affect host-cell signaling in a manner distinct from that of the Ξ±-HPVs
Population preference values for health states in relapsed or refractory B-precursor acute lymphoblastic leukemia in the United Kingdom
Lysine120 Interactions with p53 Response Elements can Allosterically Direct p53 Organization
p53 can serve as a paradigm in studies aiming to figure out how allosteric perturbations in transcription factors (TFs) triggered by small changes in DNA response element (RE) sequences, can spell selectivity in co-factor recruitment. p53-REs are 20-base pair (bp) DNA segments specifying diverse functions. They may be located near the transcription start sites or thousands of bps away in the genome. Their number has been estimated to be in the thousands, and they all share a common motif. A key question is then how does the p53 protein recognize a particular p53-RE sequence among all the similar ones? Here, representative p53-REs regulating diverse functions including cell cycle arrest, DNA repair, and apoptosis were simulated in explicit solvent. Among the major interactions between p53 and its REs involving Lys120, Arg280 and Arg248, the bps interacting with Lys120 vary while the interacting partners of other residues are less so. We observe that each p53-RE quarter site sequence has a unique pattern of interactions with p53 Lys120. The allosteric, DNA sequence-induced conformational and dynamic changes of the altered Lys120 interactions are amplified by the perturbation of other p53-DNA interactions. The combined subtle RE sequence-specific allosteric effects propagate in the p53 and in the DNA. The resulting amplified allosteric effects far away are reflected in changes in the overall p53 organization and in the p53 surface topology and residue fluctuations which play key roles in selective co-factor recruitment. As such, these observations suggest how similar p53-RE sequences can spell the preferred co-factor binding, which is the key to the selective gene transactivation and consequently different functional effects
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