Azithromycin treatment modifies airway and blood gene expression networks in neutrophilic COPD.

Long-term, low-dose azithromycin reduces exacerbation frequency in chronic obstructive pulmonary disease (COPD), yet the mechanism remains unclear. This study characterised genome-wide gene expression changes in patients with neutrophilic COPD following long-term, low-dose azithromycin treatment. Patients with neutrophilic COPD (>61% or >162×104 cells per mL sputum neutrophils) were randomised to receive either azithromycin or placebo for 12 weeks. Sputum and blood were obtained before and after 12 weeks of treatment. Gene expression was defined using microarrays. Networks were analysed using the Search Tool for the Retrieval of Interacting Gene database. In sputum, 403 genes were differentially expressed following azithromycin treatment (171 downregulated and 232 upregulated), and three following placebo treatment (one downregulated and two upregulated) compared to baseline (adjusted p1.5). In blood, 138 genes were differentially expressed with azithromycin (121 downregulated and 17 upregulated), and zero with placebo compared to baseline (adjusted p1.3). Network analysis revealed one key network in both sputum (14 genes) and blood (46 genes), involving interferon-stimulated genes, human leukocyte antigens and genes regulating T-cell responses. Long-term, low-dose azithromycin is associated with downregulation of genes regulating antigen presentation, interferon and T-cell responses, and numerous inflammatory pathways in the airways and blood of neutrophilic COPD patients

The effect of azithromycin in adults with stable neutrophilic COPD: A double blind randomised, placebo controlled trial

Background: Chronic Obstructive Pulmonary Disease (COPD) is a progressive airway disease characterised by neutrophilic airway inflammation or bronchitis. Neutrophilic bronchitis is associated with both bacterial colonisation and lung function decline and is common in exacerbations of COPD. Despite current available therapies to control inflammation, neutrophilic bronchitis remains common. This study tested the hypothesis that azithromycin treatment, as an add-on to standard medication, would significantly reduce airway neutrophil and neutrophils chemokine (CXCL8) levels, as well as bacterial load. We conducted a randomised, double-blind, placebo-controlled study in COPD participants with stable neutrophilic bronchitis. Methods: Eligible participants (n = 30) were randomised to azithromycin 250 mg daily or placebo for 12 weeks in addition to their standard respiratory medications. Sputum was induced at screening, randomisation and monthly for a 12 week treatment period and processed for differential cell counts, CXCL8 and neutrophil elastase assessment. Quantitative bacteriology was assessed in sputum samples at randomisation and the end of treatment visit. Severe exacerbations where symptoms increased requiring unscheduled treatment were recorded during the 12 week treatment period and for 14 weeks following treatment. A sub-group of participants underwent chest computed tomography scans (n = 15). Results: Nine participants with neutrophilic bronchitis had a potentially pathogenic bacteria isolated and the median total bacterial load of all participants was 5.22×107 cfu/mL. Azithromycin treatment resulted in a non-significant reduction in sputum neutrophil proportion, CXCL8 levels and bacterial load. The mean severe exacerbation rate was 0.33 per person per 26 weeks in the azithromycin group compared to 0.93 exacerbations per person in the placebo group (incidence rate ratio (95%CI): 0.37 (0.11,1.21), p = 0.062). For participants who underwent chest CT scans, no alterations were observed. Conclusions: In stable COPD with neutrophilic bronchitis, add-on azithromycin therapy showed a trend to reduced severe exacerbations sputum neutrophils, CXCL8 levels and bacterial load. Future studies with a larger sample size are warranted. Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12609000259246. © 2014 Simpson et al

Treatment of spontaneous preterm labour with retosiban: a phase 2 proof-of-concept study

This is the peer reviewed version of the article which has been published in final form at doi: 10.1111/bcp.12646. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.AIM: To investigate the efficacy and safety of intravenous retosiban in women with spontaneous preterm labour. METHODS: Randomised, double-blind, placebo-controlled, phase 2 trial. Retosiban was administered intravenously for 48 hours to women in spontaneous preterm labour between 30(0/7) and 35(6/7)  weeks' gestation with an uncomplicated singleton pregnancy in an in-patient obstetric unit. Outcome measures were uterine quiescence (primary endpoint), days to delivery, preterm delivery, and safety. RESULTS: Uterine quiescence was achieved in 62% of women who received retosiban (n = 30) compared with 41% who received placebo (n = 34). The relative risk (RR) was 1.53 (95% credible interval [CrI]: 0.98, 2.48; NS). Retosiban resulted in a significant increase in time to delivery compared with placebo (mean difference, 8.2 days; 95% CrI: 2.7, 13.74); this difference was consistent across all gestational ages. The proportion of preterm births in the retosiban and placebo groups was 18.7% (95% CrI: 7.4%, 33.7%) and 47.2% (95% CrI: 31.4%, 63.4%), respectively. The RR of preterm birth in women treated with retosiban was 0.38 (95% CrI: 0.15, 0.81). There were no deliveries within 7 days in the retosiban group, but there were six (17.6%) births in the placebo group. Maternal, fetal, and neonatal adverse events were similar in the retosiban and placebo groups. CONCLUSIONS: Intravenous administration of retosiban in women with spontaneous preterm labour was associated with a greater than 1-week increase in time to delivery compared with placebo, a significant reduction in preterm deliveries, a non-significant increase in uterine quiescence, and a favourable safety profile.GlaxoSmithKlin

Process evaluation of the Bristol girls dance project

Background: The Bristol Girls Dance Project was a cluster randomised controlled trial that aimed to increase objectively measured moderate-to-vigorous physical activity (MVPA) levels of Year 7 (age 11–12) girls through a dance-based after-school intervention. The intervention was delivered in nine schools and consisted of up to forty after-school dance sessions. This paper reports on the main findings from the detailed process evaluation that was conducted. / Methods: Quantitative and qualitative data were collected from intervention schools. Dose and fidelity were reported by dance instructors at every session. Intervention dose was defined as attending two thirds of sessions and was measured by attendance registers. Fidelity to the intervention manual was reported by dance instructors. On four randomly-selected occasions, participants reported their perceived level of exertion and enjoyment. Reasons for non-attendance were self-reported at the end of the intervention. Semi-structured interviews were conducted with all dance instructors who delivered the intervention (n = 10) and school contacts (n = 9) in intervention schools. A focus group was conducted with girls who participated in each intervention school (n = 9). / Results: The study did not affect girls’ MVPA. An average of 31.7 girls participated in each school, with 9.1 per school receiving the intervention dose. Mean attendance and instructors’ fidelity to the intervention manual decreased over time. The decline in attendance was largely attributed to extraneous factors common to after-school activities. Qualitative data suggest that the training and intervention manual were helpful to most instructors. Participant ratings of session enjoyment were high but perceived exertion was low, however, girls found parts of the intervention challenging. / Conclusions: The intervention was enjoyed by participants. Attendance at the intervention sessions was low but typical of after-school activities. Participants reported that the intervention brought about numerous health and social benefits and improved their dance-based knowledge and skills. The intervention could be improved by reducing the number of girls allowed to participate in each school and providing longer and more in-depth training to those delivering the intervention. / Trial registration: ISRCTN52882523 Registered 25th April 2013

ARIADNE - A novel optical LArTPC: technical design report and initial characterisation using a secondary beam from the CERN PS and cosmic muons

ARIADNE is a 1-ton (330 kg fiducial mass) dual-phase liquid argon (LAr) time projection chamber (TPC) featuring a novel optical readout. Four electron-multiplying charge-coupled device (EMCCD) cameras are mounted externally, and these capture the secondary scintillation light produced in the holes of a thick electron gas multiplier (THGEM). Track reconstruction using this novel readout approach is demonstrated. Optical readout has the potential to be a cost effective alternative to charge readout in future LArTPCs. In this paper, the technical design of the detector is detailed. Results of mixed particle detection using a secondary beam from the CERN PS (representing the first ever optical images of argon interactions in a dual-phase LArTPC at a beamline) and cosmic muon detection at the University of Liverpool are also presented.Comment: 58 pages, 40 figures. Changes from previous version based on pre-publication review: improved quality of various figures, improved clarity of some definitions and reduced longer sentences for better readability, fixed typos and formatting error

Randomized Trials of Retosiban Versus Placebo or Atosiban in Spontaneous Preterm Labor.

OBJECTIVE:  The aim of this study is to assess the efficacy and safety of retosiban in spontaneous preterm labor (sPTL). STUDY DESIGN:  Two multicenter, randomized, and double-blind trials compared retosiban with placebo and retosiban with atosiban in women with a singleton pregnancy and intact membranes in sPTL at 24 to 336/7 weeks' gestation. Coprimary endpoints in the placebo-controlled trial were time to delivery (TTD) or treatment failure (whichever occurred first) and neonatal composite morbidity and mortality. The primary endpoint of the atosiban comparator trial was TTD. RESULTS:  The trials were terminated early because of slow recruitment. The placebo-controlled trial enrolled 23 participants (February 2016-July 2017; 2.6% of target);the atosiban-comparator trial enrolled 97 (March 2015-August 2017; 29% of target). Baseline participant characteristics were similar between treatments. In the placebo-controlled trial, mean gestational ages at randomization were 30.8 (retosiban, n = 10) and 30.5 weeks (placebo, n = 13), and mean times to delivery/treatment failure were 18.9 days (retosiban) and 11.1 days (placebo). Two and four neonates in the retosiban and placebo groups, respectively, had ≥1 component of the neonatal composite endpoint. In the atosiban-comparator trial, mean gestational age at randomization was 31.5 weeks (for both retosiban, n = 47, and atosiban, n = 50), and adjusted mean TTDs were 32.51 days (retosiban) and 33.71 days (atosiban; p > 0.05). Adverse events were no more common with retosiban than placebo or atosiban. CONCLUSION:  Despite considerable efforts to conduct two adequate and well-controlled studies in patients with sPTL, both studies were unable to recruit effectively and consequently terminated prematurely. Key factors negatively affecting participation were patient and physician resistance to use of a placebo comparator, lack of investigator consensus on diagnostic criteria and acceptance of protocol procedures, and ethics committee decisions. Meaningful cooperation between pharmaceutical companies, regulatory authorities, and the obstetric community is essential for future development of drugs to treat sPTL

Omacetaxine may have a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 and induction of apoptosis in stem/progenitor cells

Chronic myeloid leukaemia (CML) is maintained by a rare population of tyrosine kinase inhibitor (TKI)-insensitive malignant stem cells. Our long-term aim is to find a BcrAbl-independent drug that can be combined with a TKI to improve overall disease response in chronic-phase CML. Omacetaxine mepesuccinate, a first in class cetaxine, has been evaluated by clinical trials in TKI-insensitive/resistant CML. Omacetaxine inhibits synthesis of anti-apoptotic proteins of the Bcl-2 family, including (myeloid cell leukaemia) Mcl-1, leading to cell death. Omacetaxine effectively induced apoptosis in primary CML stem cells (CD34<sup>+</sup>38<sup>lo</sup>) by downregulation of Mcl-1 protein. In contrast to our previous findings with TKIs, omacetaxine did not accumulate undivided cells <i>in vitro</i>. Furthermore, the functionality of surviving stem cells following omacetaxine exposure was significantly reduced in a dose-dependant manner, as determined by colony forming cell and the more stringent long-term culture initiating cell colony assays. This stem cell-directed activity was not limited to CML stem cells as both normal and non-CML CD34<sup>+</sup> cells were sensitive to inhibition. Thus, although omacetaxine is not leukaemia stem cell specific, its ability to induce apoptosis of leukaemic stem cells distinguishes it from TKIs and creates the potential for a curative strategy for persistent disease

A taxonomic, genetic and ecological data resource for the vascular plants of Britain and Ireland

The vascular flora of Britain and Ireland is among the most extensively studied in the world, but the current knowledge base is fragmentary, with taxonomic, ecological and genetic information scattered across different resources. Here we present the first comprehensive data repository of native and alien species optimized for fast and easy online access for ecological, evolutionary and conservation analyses. The inventory is based on the most recent reference flora of Britain and Ireland, with taxon names linked to unique Kew taxon identifiers and DNA barcode data. Our data resource for 3,227 species and 26 traits includes existing and unpublished genome sizes, chromosome numbers and life strategy and life-form assessments, along with existing data on functional traits, species distribution metrics, hybrid propensity, associated biomes, realized niche description, native status and geographic origin of alien species. This resource will facilitate both fundamental and applied research and enhance our understanding of the flora’s composition and temporal changes to inform conservation efforts in the face of ongoing climate change and biodiversity loss

A hysteretic multiscale formulation for nonlinear dynamic analysis of composite materials

This article has been made available through the Brunel Open Access Publishing Fund.A new multiscale finite element formulation is presented for nonlinear dynamic analysis of heterogeneous structures. The proposed multiscale approach utilizes the hysteretic finite element method to model the microstructure. Using the proposed computational scheme, the micro-basis functions, that are used to map the microdisplacement components to the coarse mesh, are only evaluated once and remain constant throughout the analysis procedure. This is accomplished by treating inelasticity at the micro-elemental level through properly defined hysteretic evolution equations. Two types of imposed boundary conditions are considered for the derivation of the multiscale basis functions, namely the linear and periodic boundary conditions. The validity of the proposed formulation as well as its computational efficiency are verified through illustrative numerical experiments

Small RNA analysis in Sindbis virus infected human HEK293 cells

In contrast to the defence mechanism of RNA interference (RNAi) in plants and invertebrates, its role in the innate response to virus infection of mammals is a matter of debate. Since RNAi has a well-established role in controlling infection of the alphavirus Sindbis virus (SINV) in insects, we have used this virus to investigate the role of RNAi in SINV infection of human cells