The Effect of Question Order on Outcomes in the Core Outcome Set for Brief Alcohol Interventions Among Online Help-Seekers: Protocol for a Factorial Randomized Trial

Background: A core outcome set (COS) for trials and evaluations of the effectiveness and efficacy of alcohol brief interventions (ABIs) has recently been established through international consensus to address the variability of outcomes evaluated. / Objective: This is a protocol for studies to assess if there are order effects among the questions included in the COS. / Methods: The 10 items of the COS are organized into 4 clusters. A factorial design will be used with 24 arms, where each arm represents 1 order of the 4 clusters. Individuals searching online for help will be asked to complete a questionnaire, and consenting participants will be randomized to 1 of the 24 arms (double-blind with equal allocation). Participants will be included if they are 18 years or older. The primary analyses will (1) estimate how the order of the clusters of outcomes affects how participants respond and (2) investigate patterns of abandonment of the questionnaire. / Results: Data collection is expected to commence in November 2020. A Bayesian group sequential design will be used with interim analyses planned for every 50 participants completing the questionnaire. Data collection will end no more than 24 months after commencement, and the results are expected to be published no later than December 2023. / Conclusions: Homogenizing the outcomes evaluated in studies of ABIs is important to support synthesis, and the COS is an important step toward this goal. Determining whether there may be issues with the COS question order may improve confidence in using it and speed up its dissemination in the research community. We encourage others to adopt the protocol as a study within their trial as they adopt the ORBITAL (Outcome Reporting in Brief Intervention Trials: Alcohol) COS to build a worldwide repository and provide materials to support such analysis. / Trial Registration: ISRCTN Registry ISRCTN17954645; http://www.isrctn.com/ISRCTN17954645 / International Registered Report Identifier (IRRID): PRR1-10.2196/2417

The Effect of Question Order on Outcomes in the Core Outcome Set for Brief Alcohol Interventions Among Online Help-Seekers: Protocol for a Factorial Randomized Trial

Background: A core outcome set (COS) for trials and evaluations of the effectiveness and efficacy of alcohol brief interventions (ABIs) has recently been established through international consensus to address the variability of outcomes evaluated. / Objective: This is a protocol for studies to assess if there are order effects among the questions included in the COS. / Methods: The 10 items of the COS are organized into 4 clusters. A factorial design will be used with 24 arms, where each arm represents 1 order of the 4 clusters. Individuals searching online for help will be asked to complete a questionnaire, and consenting participants will be randomized to 1 of the 24 arms (double-blind with equal allocation). Participants will be included if they are 18 years or older. The primary analyses will (1) estimate how the order of the clusters of outcomes affects how participants respond and (2) investigate patterns of abandonment of the questionnaire. / Results: Data collection is expected to commence in November 2020. A Bayesian group sequential design will be used with interim analyses planned for every 50 participants completing the questionnaire. Data collection will end no more than 24 months after commencement, and the results are expected to be published no later than December 2023. / Conclusions: Homogenizing the outcomes evaluated in studies of ABIs is important to support synthesis, and the COS is an important step toward this goal. Determining whether there may be issues with the COS question order may improve confidence in using it and speed up its dissemination in the research community. We encourage others to adopt the protocol as a study within their trial as they adopt the ORBITAL (Outcome Reporting in Brief Intervention Trials: Alcohol) COS to build a worldwide repository and provide materials to support such analysis. / Trial Registration: ISRCTN Registry ISRCTN17954645; http://www.isrctn.com/ISRCTN17954645 / International Registered Report Identifier (IRRID): PRR1-10.2196/2417

Kornets og Rodfrugternes Dyrkning i Skotland.

Kornets og Rodfrugternes Dyrkning i Skotland

Kinase inhibition leads to hormesis in a dual phosphorylation-dephosphorylation cycle

This is the final version of the article. Available from the publisher via the DOI in this record.Many antimicrobial and anti-tumour drugs elicit hormetic responses characterised by low-dose stimulation and high-dose inhibition. While this can have profound consequences for human health, with low drug concentrations actually stimulating pathogen or tumour growth, the mechanistic understanding behind such responses is still lacking. We propose a novel, simple but general mechanism that could give rise to hormesis in systems where an inhibitor acts on an enzyme. At its core is one of the basic building blocks in intracellular signalling, the dual phosphorylation-dephosphorylation motif, found in diverse regulatory processes including control of cell proliferation and programmed cell death. Our analytically-derived conditions for observing hormesis provide clues as to why this mechanism has not been previously identified. Current mathematical models regularly make simplifying assumptions that lack empirical support but inadvertently preclude the observation of hormesis. In addition, due to the inherent population heterogeneities, the presence of hormesis is likely to be masked in empirical population-level studies. Therefore, examining hormetic responses at single-cell level coupled with improved mathematical models could substantially enhance detection and mechanistic understanding of hormesis.Funding bodies: BBSRC (BB/J010340/1); EPSRC (EP/I00503X/1); Wellcome Trust (ISSF to University of Exeter)

Fuel Optimization in Multiple Diesel Driven Generator Power Plants

This paper presents two fuel optimization approaches for independent power producer (IPP) power plants consisting of multiple diesel driven generator sets (DGs). The optimization approaches utilize assumed information about the fuel consumption characteristics of each DG in an effort to demonstrate the potential benefits of acquiring such information. Reasonable variations in fuel consumption characteristics are based on measurements of a DG during restricted air filter flow operation. The two approaches are: (i) a gradient search approach capable of finding the optimal power generation for each DG in a fixed selection of DGs accommodating a given plant power reference and (ii) a genetic algorithm approach further capable of determining the optimal selection of DGs to operate in an IPP power plant. Both approaches show notable potential benefits, in terms of fuel savings, compared to current market-leading solutions

Fuel Optimization in Multiple Diesel Driven Generator Power Plants

This paper presents two fuel optimization approaches for independent power producer (IPP) power plants consisting of multiple diesel driven generator sets (DGs). The optimization approaches utilize assumed information about the fuel consumption characteristics of each DG in an effort to demonstrate the potential benefits of acquiring such information. Reasonable variations in fuel consumption characteristics are based on measurements of a DG during restricted air filter flow operation. The two approaches are: (i) a gradient search approach capable of finding the optimal power generation for each DG in a fixed selection of DGs accommodating a given plant power reference and (ii) a genetic algorithm approach further capable of determining the optimal selection of DGs to operate in an IPP power plant. Both approaches show notable potential benefits, in terms of fuel savings, compared to current market-leading solutions

X-Ray Computed Tomography: Semiautomated Volumetric Analysis of Late-Stage Lung Tumors as a Basis for Response Assessments

Background. This study presents a semiautomated approach for volumetric analysis of lung tumors and evaluates the feasibility of using volumes as an alternative to line lengths as a basis for response evaluation criteria in solid tumors (RECIST). The overall goal for the implementation was to accurately, precisely, and efficiently enable the analyses of lesions in the lung under the guidance of an operator. Methods. An anthropomorphic phantom with embedded model masses and 71 time points in 10 clinical cases with advanced lung cancer was analyzed using a semi-automated workflow. The implementation was done using the Cognition Network Technology. Results. Analysis of the phantom showed an average accuracy of 97%. The analyses of the clinical cases showed both intra- and interreader variabilities of approximately 5% on average with an upper 95% confidence interval of 14% and 19%, respectively. Compared to line lengths, the use of volumes clearly shows enhanced sensitivity with respect to determining response to therapy. Conclusions. It is feasible to perform volumetric analysis efficiently with high accuracy and low variability, even in patients with late-stage cancer who have complex lesions

What do the patients with medication overuse headache expect from treatment and what are the preferred sources of information?

This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution and reproduction in any medium, provided the original author(s) and source are credited

Quantifying the phosphorylation timescales of receptor–ligand complexes: a Markovian matrix-analytic approach

Cells interact with the extracellular environment by means of receptor molecules on their surface. Receptors can bind different ligands, leading to the formation of receptor–ligand complexes. For a subset of receptors, called receptor tyrosine kinases, binding to ligand enables sequential phosphorylation of intra-cellular residues, which initiates a signalling cascade that regulates cellular function and fate. Most mathematical modelling approaches employed to analyse receptor signalling are deterministic, especially when studying scenarios of high ligand concentration or large receptor numbers. There exist, however, biological scenarios where low copy numbers of ligands and/or receptors need to be considered, or where signalling by a few bound receptor–ligand complexes is enough to initiate a cellular response. Under these conditions stochastic approaches are appropriate, and in fact, different attempts have been made in the literature to measure the timescales of receptor signalling initiation in receptor–ligand systems. However, these approaches have made use of numerical simulations or approximations, such as moment-closure techniques. In this paper, we study, from an analytical perspective, the stochastic times to reach a given signalling threshold for two receptor–ligand models. We identify this time as an extinction time for a conveniently defined auxiliary absorbing continuous time Markov process, since receptor–ligand association/dissociation events can be analysed in terms of quasi-birth-and-death processes. We implement algorithmic techniques to compute the different order moments of this time, as well as the steady-state probability distribution of the system. A novel feature of the approach introduced here is that it allows one to quantify the role played by each kinetic rate in the timescales of signal initiation, and in the steady-state probability distribution of the system. Finally, we illustrate our approach by carrying out numerical studies for the vascular endothelial growth factor and one of its receptors, the vascular endothelial growth factor receptor of human endothelial cells