Identification of atropine-and P2X1 receptor antagonist-reistant, neurogenic contractions of the urinary bladder

Acetylcholine and ATP are excitatory cotransmitters in parasympathetic nerves. We used P2X1 receptor antagonists to further characterize the purinergic component of neurotransmission in isolated detrusor muscle of guinea pig urinary bladder. In the presence of atropine (1 μm) and prazosin (100 nm), pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS) (0.1–100 μm) and suramin (1–300 μm) inhibited contractions evoked by 4 Hz nerve stimulation in a concentration-dependent manner (IC50 of 6.9 and 13.4 μm, respectively). Maximum inhibition was 50–60%, which was unaffected by coadministration of the ectonucleotidase inhibitor ARL67156 (6-N,N-diethyl-d-β,γ-dibromomethyleneATP) (100 μm). The remaining responses were abolished by tetrodotoxin (1 μm). PPADS and suramin also reduced contractions to exogenous ATP (300 μm) by 40–50%, but abolished those to the P2X1 agonist α,β-methyleneATP (α,β-meATP) (1 μm). The P2X1 antagonists reactive blue 2, NF279 (8,8′-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)] bis-1,3,5-naphthalenetrisulfonic acid), MRS2159 (pyridoxal-α5-phosphate-6-phenylazo-4′-carboxylic acid) (100 μm), and NF449 [4,4′,4,4-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis-benzene-1,3-disulfonic acid] (3 μm) abolished contractions to α,β-meATP (1 μm; n = 4–5), but only reduced contractions evoked by 4 Hz nerve stimulation by ∼40–60% (n = 4–6) and ATP by 30–60% (n = 4–7). However, prolonged exposure to α,β-meATP (50 μm) abolished contractions evoked by all three stimuli (n = 5–12). PPADS (100 μm) and suramin (300 μm) reduced the peak neurogenic contraction of the mouse urinary bladder to 30–40% of control. At the same concentrations, the P2X1 antagonists abolished the nonadrenergic, purinergic component of neurogenic contractions in the guinea pig vas deferens (n = 4–5). Thus, P2X1 receptor antagonists inhibit, but do not abolish, the noncholinergic component of neurogenic contractions of guinea pig and mouse urinary bladder, indicating a second mode of action of neuronally released ATP. This has important implications for treatment of dysfunctional urinary bladder, for which this atropine- and P2X1 antagonist-resistant site represents a novel therapeutic target

Correction: Intra- and inter-task reliability of spatial attention measures in pseudoneglect

No abstract available

Device-measured Desk-based Occupational Sitting Patterns and Stress (hair cortisol and perceived stress)

Background: Stress and poor mental health are significant issues in the workplace and are a major cause of absenteeism and reduce productivity. Understanding what might contribute towards employee stress is important for managing mental health in this setting. Physical activity has been shown to be beneficial to stress but less research has addressed the potential negative impact of sedentary behaviour such as sitting. Therefore, the aim of this study was to assess the relationship between device-measured occupational desk-based sitting patterns and stress (hair cortisol levels (HCL), as a marker of chronic stress and self-reported perceived stress (PS)). Methods: Employees were recruited from four workplaces located in Central Scotland with large numbers of desk-based occupations. Seventy-seven participants provided desk-based sitting pattern data (desk-based sitting time/day and desk-based sit-to-stand transitions/day), a hair sample and self-reported perceived stress. HCL were measured using enzyme-linked immunosorbent assay and PS using the Cohen Self-Perceived Stress Scale. Linear regression models were used to test associations between desk-based sitting time/day, desk-based sit-to-stand transitions/day, HCL and PS. Results: There were no associations between any of the desk-based sitting measures and either HCL or PS. Conclusion. Desk-based sitting patterns in the workplace may not be related to stress when using HCL as a biomarker or PS. The relationship between sitting patterns and stress therefore requires further investigation

Physiochemical and nutritional characteristics, bioaccessibility and sensory acceptance of baked crackers containing broccoli co‐products

The effects of the inclusion of broccoli co‐products into crackers on the bioaccessibility as well as their overall physical and nutritional quality were evaluated. Crackers were formulated using a 12.5 or 15.0% flour substitution level. Broccoli‐containing crackers presented higher specific volume and spread ratio and lower weight and specific volume than control crackers (P < 0.05). Crackers containing broccoli co‐products showed an increased green hue and a higher colour intensity (P < 0.05). Incorporation of broccoli co‐products into crackers significantly increased the total phenolic content and antioxidant capacity (P < 0.05). A simulated gastrointestinal digestion suggested that the amount of phenolic and antioxidant compounds released during digestion might be higher than what could be expected from common water‐organic extracts. The incorporation of broccoli co‐products into baked crackers would not only reduce the amount of food discarded as waste but also promote health and open novel commercial opportunities to food processors.This work was supported by the CERCA Programme of Generalitat de Catalunya. T. Lafarga is in receipt of Juan de la Cierva contract awarded by the Spanish Ministry of Economy and Competitiveness (FJCI‐2016‐29541). I. Aguiló‐Aguayo thanks the Spanish Ministry of Economy and Competitiveness and to the European Social Fund for the Postdoctoral Senior Grant Ramon y Cajal (RYC‐2016‐19949). Authors thank Congelados de Navarra S.A.U (Navarra, Spain) for providing broccoli processing co‐products and Silvia Villaró for her technical assistance

Geomagnetically Induced Currents in the Irish Power Network during Geomagnetic Storms

Geomagnetically induced currents (GICs) are a well-known terrestrial space weather hazard. They occur in power transmission networks and are known to have adverse effects in both high and mid-latitude countries. Here, we study GICs in the Irish power transmission network (geomagnetic latitude 54.7--58.5$^{\circ}$ N) during five geomagnetic storms (06-07 March 2016, 20-21 December 2015, 17-18 March 2015, 29-31 October 2003 and 13-14 March 1989). We simulate electric fields using a plane wave method together with two ground resistivity models, one of which is derived from magnetotelluric measurements (MT model). We then calculate GICs in the 220, 275 and 400~kV transmission network. During the largest of the storm periods studied, the peak electric field was calculated to be as large as 3.8~V~km\textsuperscript{-1}, with associated GICs of up to 23~A using our MT model. Using our homogenous resistivity model, those peak values were 1.46~V~km\textsuperscript{-1} and 25.8~A. We find that three 400 and 275~kV substations are the most likely locations for the Irish transformers to experience large GICs.Comment: 14 pages, 11 Figures, 4 Table

Geomagnetic conditions in Ireland During the St. Patrick's Day 2015 Storm

<p>Poster at UK National Astronomy Meeting in Llandudno, Wales on July 5-9, 2015 (www.nam2015.org)</p> <p>Abstract:</p> <p>Two coronal mass ejections were launched in quick succession from the Sun on March 15, 2015. They impacted the Earth's magnetosphere two days later on St. Patrick's Day (March 17), resulting in a geomagnetic storm with a planetary K-Index of 8.</p> <p>Magnetic variations were measured across a recently deployed magnetometer network in Ireland and geoelectric fields were measured at a site in Co. Leitrim (magnetic latitude 57.08°). A local K-index maximum of 7 was calculated at Birr, Co. Offaly (magnetic latitude 55.97), while the aurora</p> <p>borealis accompanying the geomagnetic storm was visible as far south as Co. Waterford (magnetic latitude 55.13°).</p> <p>The British Geological Survey thin-sheet surface electric field model was used together with our magnetometer measurements to calculate electric fields and geomagnetically induced currents (GICs) in the Irish power grid.</p> <p>Although it was one of the most magnetically disturbed days in a decade, with dB/dt reaching ~50 nT/min, the peak GIC level estimated in the Irish power grid was ~10 Amps. Note, no adverse effects were reported in the Irish power grid demonstrating its resilience to geomagnetic storms of this magnitude.</p

Personalizing Actions in Context for Risk Management using Semantic Web Technologies

International audienceThe process of managing risks of client contracts is manual and resource-consuming, particularly so for Fortune 500 companies. As an example, Accenture assesses the risk of eighty thousand contracts every year. For each contract, different types of data will be consolidated from many sources and used to compute its risk tier. For high-risk tier contracts, a Quality Assurance Director (QAD) is assigned to mitigate or even prevent the risk. The QAD gathers and selects the recommended actions during regular portfolio review meetings to enable leadership to take the appropriate actions. In this paper, we propose to automatically personalize and contextualize actions to improve the efficacy. Our approach integrates enterprise and external data into a knowledge graph and interprets actions based on QADs' profiles through semantic reasoning over this knowledge graph. User studies showed that QADs could efficiently select actions that better mitigate the risk than the existing approach

A detailed model of the Irish High Voltage Power Network for simulating GICs

Constructing a power network model for geomagnetically induced current (GIC) calculations requires information on the DC resistances of elements within a network. This information is often not known, and power network models are simplified as a result, with assumptions used for network element resistances. Ireland's relatively small, isolated network presents an opportunity to model a complete power network in detail, using as much real‐world information as possible. A complete model of the Irish 400, 275, 220, and 110 kV network was made for GIC calculations, with detailed information on the number, type, and DC resistances of transformers. The measured grounding resistances at a number of substations were also included in the model, which represents a considerable improvement on previous models of the Irish power network for GIC calculations. Sensitivity tests were performed to show how calculated GIC amplitudes are affected by different aspects of the model. These tests investigated: (1) How the orientation of a uniform electric field affects GICs. (2) The effect of including/omitting lower voltage elements of the power network. (3) How the substation grounding resistances assumptions affected GIC values. It was found that changing the grounding resistance value had a considerable effect on calculated GICs at some substations and no discernible effect at others. Finally, five recent geomagnetic storm events were simulated in the network. It was found that heavy rainfall prior to the 26–28 August 2015 geomagnetic storm event may have had a measurable impact on measured GIC amplitudes at a 400/220 kV transformer ground

Design and rationale of the MyHeartMate study: a randomised controlled trial of a game-based app to promote behaviour change in patients with cardiovascular disease

Introduction: Recurrence of cardiac events is common after a first event, leading to hospitalisations and increased health burden. Patients have difficulties achieving the lifestyle changes required for secondary prevention and access to secondary prevention programs is limited. This study aims to evaluate the impact of a game-based mobile app, MyHeartMate, which is designed to motivate engagement in secondary prevention behaviours for cardiovascular risk factors.Methods and analysis: The MyHeartMate study is a randomised controlled trial with 6-month follow-up and blinded assessment of the primary outcome. Participants (n=394) with coronary heart disease will be recruited from hospitals in metropolitan Sydney and randomly allocated to standard care or the MyHeartMate app intervention. The intervention group will receive the app, which uses game techniques to promote engagement and lifestyle behaviour change for secondary prevention. The primary outcome is difference between the groups in physical activity (metabolic equivalent of task minutes/week) at 6 months. Secondary outcomes include change in low-density lipoprotein cholesterol, systolic blood pressure, medication adherence, body mass index, waist circumference, mood and dietary changes at 6 months. Data on app engagement, and patient perspectives of usability and acceptability, will also be analysed.Ethics and dissemination: The study has received ethics approval from Northern Sydney Local Health District Human Research Ethics Committee. The study findings will be disseminated via peer-reviewed publications and presentation at international scientific meetings/conferences.Trial registration number: ACTRN12617000869370; Pre-results

The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer - a study protocol.

BACKGROUND: Window-of-opportunity trials, evaluating the engagement of drugs with their biological target in the time period between diagnosis and standard-of-care treatment, can help prioritise promising new systemic treatments for later-phase clinical trials. Renal cell carcinoma (RCC), the 7th commonest solid cancer in the UK, exhibits targets for multiple new systemic anti-cancer agents including DNA damage response inhibitors, agents targeting vascular pathways and immune checkpoint inhibitors. Here we present the trial protocol for the WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer (WIRE). METHODS: WIRE is a Phase II, multi-arm, multi-centre, non-randomised, proof-of-mechanism (single and combination investigational medicinal product [IMP]), platform trial using a Bayesian adaptive design. The Bayesian adaptive design leverages outcome information from initial participants during pre-specified interim analyses to determine and minimise the number of participants required to demonstrate efficacy or futility. Patients with biopsy-proven, surgically resectable, cT1b+, cN0-1, cM0-1 clear cell RCC and no contraindications to the IMPs are eligible to participate. Participants undergo diagnostic staging CT and renal mass biopsy followed by treatment in one of the treatment arms for at least 14 days. Initially, the trial includes five treatment arms with cediranib, cediranib + olaparib, olaparib, durvalumab and durvalumab + olaparib. Participants undergo a multiparametric MRI before and after treatment. Vascularised and de-vascularised tissue is collected at surgery. A ≥ 30% increase in CD8+ T-cells on immunohistochemistry between the screening and nephrectomy is the primary endpoint for durvalumab-containing arms. Meanwhile, a reduction in tumour vascular permeability measured by Ktrans on dynamic contrast-enhanced MRI by ≥30% is the primary endpoint for other arms. Secondary outcomes include adverse events and tumour size change. Exploratory outcomes include biomarkers of drug mechanism and treatment effects in blood, urine, tissue and imaging. DISCUSSION: WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritising promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03741426 / EudraCT: 2018-003056-21