Inhaled methoxyflurane (Penthrox®) versus placebo for injury-associated analgesia in children - The MAGPIE trial (MEOF-002): Study protocol for a randomised controlled trial

BackgroundPain from injuries is one of the commonest symptoms in children attending emergency departments (EDs), and this is often inadequately treated in both the pre-hospital and ED settings, in part due to challenges of continual assessment and availability of easily administered analgesic options. Pain practices are therefore a key research priority, including within the field of paediatric emergency medicine. Methoxyflurane, delivered via a self-administered Penthrox® inhaler, belongs to the fluorinated hydrocarbon group of volatile anaesthetics and is unique among the group in having analgesic properties at low doses. Despite over 30 years of clinical acute analgesia use, and a large volume of evidence supporting its safety and efficacy, there is a paucity of randomised controlled trial data for Penthrox®.MethodsThis is an international multi-centre randomised, double-blind, placebo-controlled phase III trial assessing the efficacy and safety of methoxyflurane delivered via the Penthrox® inhaler for the management of moderate to severe acute traumatic pain in children and young people aged 6–17 years. Following written informed consent, eligible participants are randomised to self-administer either inhaled methoxyflurane (maximum dose of 2 × 3 ml) or normal saline placebo (maximum dose 2 × 5 ml). Patients, treating clinicians and research nurses are blinded to the treatment. The primary outcome is the change in pain intensity at 15 min after the commencement of treatment, as measured by the Visual Analogue Scale (VAS) or the Wong-Baker FACES® Pain Rating scale, with the latter converted to VAS values. Secondary outcome measures include the number and proportion of responders who achieve a 30% reduction in VAS score compared to baseline, rescue medication requested, time and number of inhalations to first pain relief, global medication performance assessment by the patient, clinician and research nurse, and evaluation of adverse events experienced during treatment and during the subsequent 14 ± 2 days. The primary analysis will be by intention to treat. The total sample size is 110 randomised and treated patients per treatment arm.DiscussionThe Methoxyflurane AnalGesia for Paediatric InjuriEs (MAGPIE) trial will provide efficacy and safety data for methoxyflurane administered via the Penthrox® inhaler, in children and adolescents who present to EDs with moderate to severe injury-related pain.Trial registrationEudraCT, 2016–004290-41. Registered on 11 April 2017.ClinicalTrials.gov, NCT03215056. Registered on 12 July 2017

Gaps present a trade-off between dispersal and establishment that nourishes species diversity

We took advantage of two natural experiments to investigate processes that regulate tree recruitment in gaps. In the first, we examined the recruitment of small and large saplings and trees into 31 gaps resulting from treefalls occurring between 1984 and 2015 in the 2.25-ha core area of a 4-ha tree plot at Cocha Cashu in Peru. In the second, we identified the tallest saplings recruiting into 69 gaps created during a violent wind storm in February 2000. In the established tree plot, we were able to compare the composition of saplings in the disturbance zones of gaps prior to, during, and subsequent to the period of gap formation. Recruitment in gaps was compared with that in "nofall" zones, areas within the plot that had not experienced a treefall at least since the early 1980s. Our results confirmed earlier findings that a consistently high proportion (~60%) of established saplings survived gap formation. Light demanding species, as proxied by mortality rates, recruited under all conditions, but preferentially during periods of gap formation, a pattern that was especially strong among gap pioneers. Similar results were noted, separately, for small and large saplings and trees recruiting at >= 10 cm dbh. One hundred percent of previously untagged trees recruiting into gaps in the first post-disturbance census were gap pioneers, suggesting rapid development. This conclusion was strongly supported in a follow-up survey taken of 69 gaps 19 months after they had been synchronously created in a wind storm. Ten species of gap pioneers, eight of which are not normally present in the advance regeneration, had attained heights of 6-10 m in 19 months. The 10 gap pioneers were dispersed, variously, by primates, bats, birds, and wind and reached maximum frequency in different-sized gaps (range 1,000 m(2)). Both gap size and limited dispersal of zoochorous species into gaps serve as filters for establishment, creating a complex mosaic of conditions that enhances species diversity

Assessment of the Antiviral Properties of Recombinant Porcine SP-D against Various Influenza A Viruses In Vitro

The emergence of influenza viruses resistant to existing classes of antiviral drugs raises concern and there is a need for novel antiviral agents that could be used therapeutically or prophylacticaly. Surfactant protein D (SP-D) belongs to the family of C-type lectins which are important effector molecules of the innate immune system with activity against bacteria and viruses, including influenza viruses. In the present study we evaluated the potential of recombinant porcine SP-D as an antiviral agent against influenza A viruses (IAVs) in vitro. To determine the range of antiviral activity, thirty IAVs of the subtypes H1N1, H3N2 and H5N1 that originated from birds, pigs and humans were selected and tested for their sensitivity to recombinant SP-D. Using these viruses it was shown by hemagglutination inhibition assay, that recombinant porcine SP-D was more potent than recombinant human SP-D and that especially higher order oligomeric forms of SP-D had the strongest antiviral activity. Porcine SP-D was active against a broad range of IAV strains and neutralized a variety of H1N1 and H3N2 IAVs, including 2009 pandemic H1N1 viruses. Using tissue sections of ferret and human trachea, we demonstrated that recombinant porcine SP-D prevented attachment of human seasonal H1N1 and H3N2 virus to receptors on epithelial cells of the upper respiratory tract. It was concluded that recombinant porcine SP-D holds promise as a novel antiviral agent against influenza and further development and evaluation in vivo seems warranted

Collaboration between Science and Religious Education teachers in Scottish Secondary schools

The article reports on quantitative research that examines: (1) the current practice in collaboration; and (2) potential for collaboration between Science and Religious Education teachers in a large sample of Scottish secondary schools. The authors adopt and adapt three models (conflict; concordat and consonance) to interrogate the relationship between science and religion (and the perceived relation between these two subjects in schools) (Astley and Francis 2010). The findings indicate that there is evidence of limited collaboration and, in a few cases, a dismissive attitude towards collaboration (conflict and concordat and very weak consonance). There is, however, evidence of a genuine aspiration for greater collaboration among many teachers (moving towards a more robust consonance model). The article concludes by discussing a number of key factors that must be realised for this greater collaboration to be enacted

Affine modifications and affine hypersurfaces with a very transitive automorphism group

We study a kind of modification of an affine domain which produces another affine domain. First appeared in passing in the basic paper of O. Zariski (1942), it was further considered by E.D. Davis (1967). The first named author applied its geometric counterpart to construct contractible smooth affine varieties non-isomorphic to Euclidean spaces. Here we provide certain conditions which guarantee preservation of the topology under a modification. As an application, we show that the group of biregular automorphisms of the affine hypersurface $X \subset C^{k+2}$ given by the equation $uv=p(x_1,...,x_k)$ where $p \in C[x_1,...,x_k],$ acts $m-$transitively on the smooth part reg$X$ of $X$ for any $m \in N.$ We present examples of such hypersurfaces diffeomorphic to Euclidean spaces.Comment: 39 Pages, LaTeX; a revised version with minor changes and correction

Human surfactant protein D alters oxidative stress and HMGA1 expression to induce p53 apoptotic pathway in eosinophil leukemic cell line

This article is made available through the Brunel Open Access Publishing Fund. Copyright: © 2013 Mahajan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Surfactant protein D (SP-D), an innate immune molecule, has an indispensable role in host defense and regulation of inflammation. Immune related functions regulated by SP-D include agglutination of pathogens, phagocytosis, oxidative burst, antigen presentation, T lymphocyte proliferation, cytokine secretion, induction of apoptosis and clearance of apoptotic cells. The present study unravels a novel ability of SP-D to reduce the viability of leukemic cells (eosinophilic leukemic cell line, AML14.3D10; acute myeloid leukemia cell line, THP-1; acute lymphoid leukemia cell lines, Jurkat, Raji; and human breast epithelial cell line, MCF-7), and explains the underlying mechanisms. SP-D and a recombinant fragment of human SP-D (rhSP-D) induced G2/M phase cell cycle arrest, and dose and timedependent apoptosis in the AML14.3D10 eosinophilic leukemia cell line. Levels of various apoptotic markers viz. activated p53, cleaved caspase-9 and PARP, along with G2/M checkpoints (p21 and Tyr15 phosphorylation of cdc2) showed significant increase in these cells. We further attempted to elucidate the underlying mechanisms of rhSP-D induced apoptosis using proteomic analysis. This approach identified large scale molecular changes initiated by SPD in a human cell for the first time. Among others, the proteomics analysis highlighted a decreased expression of survival related proteins such as HMGA1, overexpression of proteins to protect the cells from oxidative burst, while a drastic decrease in mitochondrial antioxidant defense system. rhSP-D mediated enhanced oxidative burst in AML14.3D10 cells was confirmed, while antioxidant, N-acetyl-L-cysteine, abrogated the rhSP-D induced apoptosis. The rhSP-D mediated reduced viability was specific to the cancer cell lines and viability of human PBMCs from healthy controls was not affected. The study suggests involvement of SP-D in host’s immunosurveillance and therapeutic potential of rhSP-D in the eosinophilic leukemia and cancers of other origins.Department of Biotechnology, Indi

Variation in treatment of acute childhood wheeze in emergency departments of the United Kingdom and Ireland: An international survey of clinician practice

© 2015, BMJ Publishing Group. All rights reserved. Objective: National clinical guidelines for childhood wheeze exist, yet despite being one of the most common reasons for childhood emergency department (ED) attendance, signi ficant variation in practice occurs in other settings. We, therefore, evaluated practice variations of ED clinicians in the UK and Ireland. Design: Two-stage survey undertaken in March 2013. Stage one examined department practice and stage two assessed ED consultant practice in acute childhood wheeze. Questions interrogated pharmacological and other management strategies, including inhaled and intravenous therapies. Setting and participants: Member departments of Paediatric Emergency Research in the United Kingdom and Ireland and ED consultants treating children with acute wheeze. Results: 30 EDs and 183 (81%) clinicians responded. 29 (97%) EDs had wheeze guidelines and 12 (40%) had care pathways. Variation existed between clinicians in dose, timing and frequency of inhaled bronchodilators across severities. When escalating to intravenous bronchodilators, 99 (54%) preferred salbutamol first line, 52 (28%) magnesium sulfate (MgSO4) and 27 (15%) aminophylline. 87 (48%) administered intravenous bronchodilators sequentially and 30 (16%) concurrently, with others basing approach on case severity. 146 (80%) continued inhaled therapy after commencing intravenous bronchodilators. Of 170 who used intravenous salbutamol, 146 (86%) gave rapid boluses, 21 (12%) a longer loading dose and 164 (97%) an ongoing infusion, each with a range of doses and durations. Of 173 who used intravenous MgSO4, all used a bolus only. 41 (24%) used non-invasive ventilation. Conclusions: Signi ficant variation in ED consultant management of childhood wheeze exists despite the presence of national guidance. This reflects the lack of evidence in key areas of childhood wheeze and emphasises the need for further robust multicentre research studies