Publications by authors named "Lucy Ellis"

25 Publications

  • Page 1 of 1

A randomized controlled trial comparing controlled reoxygenation and standard cardiopulmonary bypass in paediatric cardiac surgery.

Eur J Cardiothorac Surg 2021 Jan;59(2):349-358

Department of Cardiac Surgery, Clinical Trials and Evaluation Unit, Bristol Trials Centre, University of Bristol, Bristol, UK.

Objectives: Controlled reoxygenation on starting cardiopulmonary bypass (CPB) rather than hyperoxic CPB may confer clinical advantages during surgery for congenital cyanotic heart disease.

Methods: A single-centre, randomized controlled trial was carried out to compare the effectiveness of controlled reoxygenation (normoxia) versus hyperoxic CPB in children with congenital cyanotic heart disease undergoing open-heart surgery (Oxic-2). The co-primary clinical outcomes were duration of inotropic support, intubation time and postoperative intensive care unit (ICU) and hospital stay. Analysis of the primary outcomes included data from a previous trial (Oxic-1) conducted to the same protocol.

Results: Ninety participants were recruited to Oxic-2 and 79 were recruited to the previous Oxic-1 trial. There were no significant differences between the groups for any of the co-primary outcomes: inotrope duration geometric mean ratio (normoxia/hyperoxic) 0.97, 95% confidence interval (CI) (0.69-1.37), P-value = 0.87; intubation time hazard ratio (HR) 1.03, 95% CI (0.74-1.42), P-value = 0.87; postoperative ICU stay HR 1.14 95% CI (0.77-1.67), P-value = 0.52, hospital stay HR 0.90, 95% CI (0.65-1.25), P-value = 0.53. Lower oxygen levels were successfully achieved during the operative period in the normoxic group. Serum creatinine levels were lower in the normoxic group at day 2, but not on days 1, 3-5. Childhood developmental outcomes were similar. In the year following surgery, 85 serious adverse events were reported (51 normoxic group and 34 hyperoxic group).

Conclusions: Controlled reoxygenation (normoxic) CPB is safe but with no evidence of a clinical advantage over hyperoxic CPB.

Clinical Trial Registration Number: Current Controlled Trials-ISRCTN81773762.
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http://dx.doi.org/10.1093/ejcts/ezaa318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850030PMC
January 2021

Eplerenone for chronic central serous chorioretinopathy in patients with active, previously untreated disease for more than 4 months (VICI): a randomised, double-blind, placebo-controlled trial.

Lancet 2020 01;395(10220):294-303

Bristol Trials Centre, Clinical Trials and Evaluation Unit, University of Bristol, Bristol Royal Infirmary, Bristol, UK.

Background: In chronic central serous chorioretinopathy (CSCR), fluid accumulates in the subretinal space. CSCR is a common visually disabling condition that develops in individuals up to 60 years of age, and there is no definitive treatment. Previous research suggests the mineralocorticoid receptor antagonist, eplerenone, is effective for treating CSCR; however, this drug is not licensed for the treatment of patients with CSCR. We aimed to evaluate whether eplerenone was superior to placebo in terms of improving visual acuity in patients with chronic CSCR.

Methods: This randomised, double-blind, parallel-group, multicentre placebo-controlled trial was done at 22 hospitals in the UK. Participants were eligible if they were aged 18-60 years and had had treatment-naive CSCR for 4 months or more. Patients were randomly assigned (1:1) to either the eplerenone or the placebo group by a trial statistician through a password-protected system online. Allocation was stratified by best-corrected visual acuity (BCVA) and hospital. Patients were given either oral eplerenone (25 mg/day for 1 week, increasing to 50 mg/day for up to 12 months) plus usual care or placebo plus usual care for up to 12 months. All participants, care teams, outcome assessors, pharmacists, and members of the trial management group were masked to the treatment allocation. The primary outcome was BCVA, measured as letters read, at 12 months. All outcomes apart from safety were analysed on a modified intention-to-treat basis (participants who withdrew consent without contributing a post-randomisation BCVA measurement were excluded from the primary analysis population and from most secondary analysis populations). The trial is registered with ISRCTN, ISRCTN92746680, and is completed.

Findings: Between Jan 11, 2017, and Feb 22, 2018, we enrolled and randomly assigned 114 patients to receive either eplerenone (n=57) or placebo (n=57). Three participants in the placebo group withdrew consent without contributing a post-randomisation BCVA measurement and were excluded from the primary outcome analysis population. All patients from the eplerenone group and 54 patients from the placebo group were included in the primary outcome. Modelled mean BCVA at 12 months was 79·5 letters (SD 4·5) in the placebo group and 80·4 letters (4·6) in the eplerenone group, with an adjusted estimated mean difference of 1·73 letters (95% CI -1·12 to 4·57; p=0·24) at 12 months. Hyperkalaemia occurred in eight (14%) patients in each group. No serious adverse events were reported in the eplerenone group and three unrelated serious adverse events were reported in the placebo group (myocardial infarction [anticipated], diverticulitis [unanticipated], and metabolic surgery [unanticipated]).

Interpretation: Eplerenone was not superior to placebo for improving BCVA in people with chronic CSCR after 12 months of treatment. Ophthalmologists who currently prescribe eplerenone for CSCR should discontinue this practice.

Funding: Efficacy and Mechanism Evaluation Programme, and National Institute for Health Research and Social Care.
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http://dx.doi.org/10.1016/S0140-6736(19)32981-2DOI Listing
January 2020

Three wound-dressing strategies to reduce surgical site infection after abdominal surgery: the Bluebelle feasibility study and pilot RCT.

Health Technol Assess 2019 08;23(39):1-166

Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Background: Surgical site infection (SSI) affects up to 20% of people with a primary closed wound after surgery. Wound dressings may reduce SSI.

Objective: To assess the feasibility of a multicentre randomised controlled trial (RCT) to evaluate the effectiveness and cost-effectiveness of dressing types or no dressing to reduce SSI in primary surgical wounds.

Design: Phase A - semistructured interviews, outcome measure development, practice survey, literature reviews and value-of-information analysis. Phase B - pilot RCT with qualitative research and questionnaire validation. Patients and the public were involved.

Setting: Usual NHS care.

Participants: Patients undergoing elective/non-elective abdominal surgery, including caesarean section.

Interventions: Phase A - none. Phase B - simple dressing, glue-as-a-dressing (tissue adhesive) or 'no dressing'.

Main Outcome Measures: Phase A - pilot RCT design; SSI, patient experience and wound management questionnaires; dressing practices; and value-of-information of a RCT. Phase B - participants screened, proportions consented/randomised; acceptability of interventions; adherence; retention; validity and reliability of SSI measure; and cost drivers.

Data Sources: Phase A - interviews with patients and health-care professionals (HCPs), narrative data from published RCTs and data about dressing practices. Phase B - participants and HCPs in five hospitals.

Results: Phase A - we interviewed 102 participants. HCPs interpreted 'dressing' variably and reported using available products. HCPs suggested practical/clinical reasons for dressing use, acknowledged the weak evidence base and felt that a RCT including a 'no dressing' group was acceptable. A survey showed that 68% of 1769 wounds (727 participants) had simple dressings and 27% had glue-as-a-dressing. Dressings were used similarly in elective and non-elective surgery. The SSI questionnaire was developed from a content analysis of existing SSI tools and interviews, yielding 19 domains and 16 items. A main RCT would be valuable to the NHS at a willingness to pay of £20,000 per quality-adjusted life-year. Phase B - from 4 March 2016 to 30 November 2016, we approached 862 patients for the pilot RCT; 81.1% were eligible, 59.4% consented and 394 were randomised (simple,  = 133; glue,  = 129; no dressing,  = 132); non-adherence was 3 out of 133, 8 out of 129 and 20 out of 132, respectively. SSI occurred in 51 out of 281 participants. We interviewed 55 participants. All dressing strategies were acceptable to stakeholders, with no indication that adherence was problematic. Adherence aids and patients' understanding of their allocated dressing appeared to be key. The SSI questionnaire response rate overall was 67.2%. Items in the SSI questionnaire fitted a single scale, which had good reliability (test-retest and Cronbach's alpha of > 0.7) and diagnostic accuracy (-statistic = 0.906). The key cost drivers were hospital appointments, dressings and redressings, use of new medicines and primary care appointments.

Limitations: Multiple activities, often in parallel, were challenging to co-ordinate. An amendment took 4 months, restricting recruitment to the pilot RCT. Only 67% of participants completed the SSI questionnaire. We could not implement photography in theatres.

Conclusions: A main RCT of dressing strategies is feasible and would be valuable to the NHS. The SSI questionnaire is sufficiently accurate to be used as the primary outcome. A main trial with three groups (as in the pilot) would be valuable to the NHS, using a primary outcome of SSI at discharge and patient-reported SSI symptoms at 4-8 weeks.

Trial Registration: Phase A - Current Controlled Trials ISRCTN06792113; Phase B - Current Controlled Trials ISRCTN49328913.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 23, No. 39. See the NIHR Journals Library website for further project information. Funding was also provided by the Medical Research Council ConDuCT-II Hub (reference number MR/K025643/1).
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http://dx.doi.org/10.3310/hta23390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698727PMC
August 2019

Discovery of Soft-Drug Topical Tool Modulators of Sphingosine-1-phosphate Receptor 1 (S1PR1).

ACS Med Chem Lett 2019 Mar 14;10(3):341-347. Epub 2019 Feb 14.

Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee, Dow Street, Dundee DDI 5EH, U.K.

In order to study the role of S1PRs in inflammatory skin disease, S1PR modulators are dosed orally and topically in animal models of disease. The topical application of S1PR modulators in these models may, however, lead to systemic drug concentrations, which can complicate interpretation of the observed effects. We set out to design soft drug S1PR modulators as topical tool compounds to overcome this limitation. A fast follower approach starting from the drug ponesimod allowed the rapid development of an active phenolic series of soft drugs. The phenols were, however, chemically unstable. Protecting the phenol as an ester removed the instability and provided a compound that is converted by enzymatic hydrolysis in the skin to the phenolic soft drug species. In simple formulations, topical dosing of these S1PR modulators to mice led to micromolar skin concentrations but no detectable blood concentrations. These topical tools will allow researchers to investigate the role of S1PR in skin, without involvement of systemic S1PR biology.
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http://dx.doi.org/10.1021/acsmedchemlett.8b00616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421539PMC
March 2019

Normothermic versus hypothermic cardiopulmonary bypass in low-risk paediatric heart surgery: a randomised controlled trial.

Heart 2019 03 15;105(6):455-464. Epub 2018 Oct 15.

Clinical Trials and Evaluation Unit, Bristol Trials Centre, University of Bristol, Bristol, UK.

Objective: To compare normothermic (35°C-36°C) versus hypothermic (28°C) cardiopulmonary bypass (CPB) in paediatric patients undergoing open heart surgery to test the hypothesis that normothermic CPB perfusion maintains the functional integrity of major organ systems leading to faster recovery.

Methods: Two single-centre, randomised controlled trials (known as and , respectively) were carried out to compare the effectiveness and acceptability of normothermic versus hypothermic CPB in children with congenital heart disease undergoing open heart surgery. In both studies, the co-primary clinical outcomes were duration of inotropic support, intubation time and postoperative hospital stay.

Results: In total, 200 participants were recruited; 59 to the study and 141 to the study. 98 patients received normothermic CPB and 102 patients received hypothermic CPB. There were no significant differences between the treatment groups for any of the co-primary outcomes: inotrope duration HR=1.01, 95% CI (0.72 to 1.41); intubation time HR=1.14, 95% CI (0.86 to 1.51); postoperative hospital stay HR=1.06, 95% CI (0.80 to 1.40). Differences favouring normothermia were found in urea nitrogen at 2 days geometric mean ratio (GMR)=0.86 95% CI (0.77 to 0.97); serum creatinine at 3 days GMR=0.89, 95% CI (0.81 to 0.98); urinary albumin at 48 hours GMR=0.32, 95% CI (0.14 to 0.74) and neutrophil gelatinase-associated lipocalin at 4 hours GMR=0.47, 95% CI (0.22 to 1.02), but not at other postoperative time points.

Conclusions: Normothermic CPB is as safe and effective as hypothermic CPB and can be routinely adopted as a perfusion strategy in low-risk infants and children undergoing open heart surgery.

Trial Registration Number: ISRCTN93129502.
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http://dx.doi.org/10.1136/heartjnl-2018-313567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580777PMC
March 2019

Clinical efficacy of eplerenone versus placebo for central serous chorioretinopathy: study protocol for the VICI randomised controlled trial.

Eye (Lond) 2019 02 7;33(2):295-303. Epub 2018 Sep 7.

Department of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.

Aims: Chronic central serous chorioretinopathy (CSCR) is poorly understood. Fluid accumulates in the subretinal space and retinal pigment epitheliopathy and neurosensory atrophy may develop. Permanent vision loss occurs in approximately one third of cases. There are no effective treatments for CSCR. Recent studies have shown the mineralocorticoid receptor antagonist, eplerenone, to be effective in resolving subretinal fluid and improving visual acuity. This trial aims to compare the safety and efficacy of eplerenone in patients with CSCR in a double-masked randomised placebo-controlled trial.

Methods: Patients are randomised 1:1 to receive eplerenone with usual care or placebo with usual care for 12 months; 25 mg per day for 1 week, then 50 mg per day up to 12 months (unless discontinued for safety or resolution of CSCR). Key eligibility criteria are: age 18-60 years, one eye with CSCR for ≥4 months duration, best-corrected visual acuity (BCVA) >53 and <86 letters and no previous treatment. The primary outcome is BCVA at 12 months. Secondary outcomes include resolution of subretinal fluid, development of macular atrophy, subfoveal choroidal thickness, changes in low luminance visual acuity, health-related quality of life and safety.

Conclusions: Recruitment is complete but was slower than expected. We maintained the eligibility criteria to ensure participants had 'true' CSCR and recruited additional centres. Effective distribution of the investigational medicinal product (IMP) was achieved by implementing a database to manage ordering and accountability of IMP packs. The results will provide adequately powered evidence to inform clinical decisions about using eplerenone to treat patients with CSCR.
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http://dx.doi.org/10.1038/s41433-018-0212-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367466PMC
February 2019

2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and Mycobacterium tuberculosis: Structure-Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization.

ACS Infect Dis 2018 06 26;4(6):954-969. Epub 2018 Mar 26.

Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease , National Institutes of Health , 9000 Rockville Pike , Bethesda , Maryland 20892 , United States.

Mycobacterium tuberculosis ( MTb) possesses two nonproton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing for the structure-based design of small-molecule inhibitors. Herein, we disclose MTb whole-cell structure-activity relationships (SARs) for a series of 2-mercapto-quinazolinones which target the ndh encoded NDH-2 with nanomolar potencies. The compounds were inactivated by glutathione-dependent adduct formation as well as quinazolinone oxidation in microsomes. Pharmacokinetic studies demonstrated modest bioavailability and compound exposures. Resistance to the compounds in MTb was conferred by promoter mutations in the alternative nonessential NDH-2 encoded by ndhA in MTb. Bioenergetic analyses revealed a decrease in oxygen consumption rates in response to inhibitor in cells in which membrane potential was uncoupled from ATP production, while inverted membrane vesicles showed mercapto-quinazolinone-dependent inhibition of ATP production when NADH was the electron donor to the respiratory chain. Enzyme kinetic studies further demonstrated noncompetitive inhibition, suggesting binding of this scaffold to an allosteric site. In summary, while the initial MTb SAR showed limited improvement in potency, these results, combined with structural information on the bacterial protein, will aid in the future discovery of new and improved NDH-2 inhibitors.
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http://dx.doi.org/10.1021/acsinfecdis.7b00275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996347PMC
June 2018

Effectiveness of terrestrial protected areas for conservation of lake fish communities.

Conserv Biol 2018 06 25;32(3):607-618. Epub 2018 Jan 25.

Aquatic Research and Monitoring Section, Ontario Ministry of Natural Resources and Forestry, 2140 East Bank Drive, Peterborough, ON K9L 0G2, Canada.

Freshwater protected areas are rare even though freshwater ecosystems are among the most imperiled in the world. Conservation actions within terrestrial protected areas (TPAs) such as development or resource extraction regulations may spill over to benefit freshwater ecosystems within their boundaries. Using data from 175 lakes across Ontario, Canada, we compared common indicators of fish-assemblage status (i.e., species richness, Shannon diversity index, catch per unit effort, and normalized-length size spectrum slopes) to evaluate whether TPAs benefit lake fish assemblages. Nearest neighbor cluster analysis was used to generate pairs of lakes: inside versus outside, inside versus bordering, and bordering versus outside TPAs based on lake characteristics. The diversity and abundance indicators did not differ significantly across comparisons, but normalized-length size spectrum slopes (NLSS) were significantly steeper in lakes outside parks. The latter indicated assemblage differences (greater abundances of small-bodied species) and less-efficient energy transfer through the trophic levels of assemblages outside parks. Although not significantly different, pollution- and turbidity-tolerant species were more abundant outside parks, whereas 3 of the 4 pollution-intolerant species were more abundant within parks. Twenty-one percent of the difference in slopes was related to higher total dissolved solids concentrations and angling pressure. Our results support the hypothesis that TPAs benefit lake fish assemblages and suggest that NLSS slopes are informative indicators for aquatic protected area evaluations because they represent compositional and functional aspects of communities.
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http://dx.doi.org/10.1111/cobi.13034DOI Listing
June 2018

Chemical Validation of Methionyl-tRNA Synthetase as a Druggable Target in Leishmania donovani.

ACS Infect Dis 2017 10 2;3(10):718-727. Epub 2017 Oct 2.

Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, United Kingdom.

Methionyl-tRNA synthetase (MetRS) has been chemically validated as a drug target in the kinetoplastid parasite Trypanosoma brucei. In the present study, we investigate the validity of this target in the related trypanosomatid Leishmania donovani. Following development of a robust high-throughput compatible biochemical assay, a compound screen identified DDD806905 as a highly potent inhibitor of LdMetRS (K of 18 nM). Crystallography revealed this compound binds to the methionine pocket of MetRS with enzymatic studies confirming DDD806905 displays competitive inhibition with respect to methionine and mixed inhibition with respect to ATP binding. DDD806905 showed activity, albeit with different levels of potency, in various Leishmania cell-based viability assays, with on-target activity observed in both Leishmania promastigote cell assays and a Leishmania tarentolae in vitro translation assay. Unfortunately, this compound failed to show efficacy in an animal model of leishmaniasis. We investigated the potential causes for the discrepancies in activity observed in different Leishmania cell assays and the lack of efficacy in the animal model and found that high protein binding as well as sequestration of this dibasic compound into acidic compartments may play a role. Despite medicinal chemistry efforts to address the dibasic nature of DDD806905 and analogues, no progress could be achieved with the current chemical series. Although DDD806905 is not a developable antileishmanial compound, MetRS remains an attractive antileishmanial drug target.
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http://dx.doi.org/10.1021/acsinfecdis.7b00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663395PMC
October 2017

Group-Based Optimization of Potent and Cell-Active Inhibitors of the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase: Structure-Activity Relationships Leading to the Chemical Probe (2S,4R)-1-((S)-2-(1-Cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298).

J Med Chem 2018 01 18;61(2):599-618. Epub 2017 Sep 18.

Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, Scotland, U.K.

The von Hippel-Lindau tumor suppressor protein is the substrate binding subunit of the VHL E3 ubiquitin ligase, which targets hydroxylated α subunit of hypoxia inducible factors (HIFs) for ubiquitination and subsequent proteasomal degradation. VHL is a potential target for treating anemia and ischemic diseases, motivating the development of inhibitors of the VHL:HIF-α protein-protein interaction. Additionally, bifunctional proteolysis targeting chimeras (PROTACs) containing a VHL ligand can hijack the E3 ligase activity to induce degradation of target proteins. We report the structure-guided design and group-based optimization of a series of VHL inhibitors with low nanomolar potencies and improved cellular permeability. Structure-activity relationships led to the discovery of potent inhibitors 10 and chemical probe VH298, with dissociation constants <100 nM, which induced marked HIF-1α intracellular stabilization. Our study provides new chemical tools to probe the VHL-HIF pathways and new VHL ligands for next-generation PROTACs.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788404PMC
January 2018

A mixed-methods feasibility and external pilot study to inform a large pragmatic randomised controlled trial of the effects of surgical wound dressing strategies on surgical site infections (Bluebelle Phase B): study protocol for a randomised controlled trial.

Trials 2017 08 29;18(1):401. Epub 2017 Aug 29.

University Hospitals Bristol NHS Foundation Trust, Bristol, UK.

Background: Surgical site infections (SSIs) are common, occurring in up to 25% of > 4 million operations performed in England each year. Previous trials of the effect of wound dressings on the risk of developing a SSI are of poor quality and underpowered.

Methods/design: This study is a feasibility and pilot trial to examine the feasibility of a full trial that will compare simple dressings, no dressing and tissue-glue as a dressing. It is examining the overall acceptability of trial participation, identifying opportunities for refinement, testing the feasibility of and validating new outcome tools to assess SSI, wound management issues and patients' wound symptom experiences. It is also exploring methods for avoiding performance bias and blinding outcome assessors by testing the feasibility of collecting wound photographs taken in theatre immediately after wound closure and, at 4-8 weeks after surgery, taken by participants themselves or their carers. Finally, it is identifying the main cost drivers for an economic evaluation of dressing types. Integrated qualitative research is exploring acceptability and reasons for non-adherence to allocation. Adults undergoing primary elective or unplanned abdominal general surgery or Caesarean section are eligible. The main exclusion criteria are abdominal or other major surgery less than three months before the index operation or contraindication to dressing allocation. The trial is scheduled to recruit for nine months. The findings will be used to inform the design of a main trial.

Discussion: This pilot trial is the first pragmatic study to randomise participants to no dressing or tissue-glue as a dressing versus a simple dressing. Early evidence from the ongoing pilot shows that recruitment is proceeding well and that the interventions are acceptable to participants. Combined with the qualitative findings, the findings will inform whether a main, large trial is feasible and, if so, how it should be designed.

Trial Registration: ISRCTN49328913 . Registered on 20 October 2015.
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http://dx.doi.org/10.1186/s13063-017-2102-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576037PMC
August 2017

Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition.

Nat Commun 2016 11 4;7:13312. Epub 2016 Nov 4.

Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK.

Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes. We show that VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-α in a concentration- and time-dependent fashion in different cell lines, with subsequent upregulation of HIF-target genes at both mRNA and protein levels. VH298 represents a high-quality chemical probe of the HIF signalling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signalling.
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http://dx.doi.org/10.1038/ncomms13312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097156PMC
November 2016

Essential but Not Vulnerable: Indazole Sulfonamides Targeting Inosine Monophosphate Dehydrogenase as Potential Leads against Mycobacterium tuberculosis.

ACS Infect Dis 2017 01 17;3(1):18-33. Epub 2016 Oct 17.

Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health , Bethesda, Maryland 20892-3206, United States.

A potent, noncytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This noncytotoxic compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning from Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH). Subsequent biochemical validation confirmed direct inhibition of IMPDH by an uncompetitive mode of inhibition, and growth inhibition could be rescued by supplementation with guanine, a bypass mechanism for the IMPDH pathway. Beads containing immobilized indazole sulfonamides specifically interacted with IMPDH in cell lysates. X-ray crystallography of the IMPDH-IMP-inhibitor complex revealed that the primary interactions of these compounds with IMPDH were direct pi-pi interactions with the IMP substrate. Advanced lead compounds in this series with acceptable pharmacokinetic properties failed to show efficacy in acute or chronic murine models of tuberculosis (TB). Time-kill experiments in vitro suggest that sustained exposure to drug concentrations above the minimum inhibitory concentration (MIC) for 24 h were required for a cidal effect, levels that have been difficult to achieve in vivo. Direct measurement of guanine levels in resected lung tissue from tuberculosis-infected animals and patients revealed 0.5-2 mM concentrations in caseum and normal lung tissue. The high lesional levels of guanine and the slow lytic, growth-rate-dependent effect of IMPDH inhibition pose challenges to developing drugs against this target for use in treating TB.
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http://dx.doi.org/10.1021/acsinfecdis.6b00103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972394PMC
January 2017

The Effect of Patient-Specific Cerebral Oxygenation Monitoring on Postoperative Cognitive Function: A Multicenter Randomized Controlled Trial.

JMIR Res Protoc 2015 Dec 18;4(4):e137. Epub 2015 Dec 18.

Clinical Trials & Evaluation Unit, University of Bristol, Bristol, United Kingdom.

Background: Indices of global tissue oxygen delivery and utilization such as mixed venous oxygen saturation, serum lactate concentration, and arterial hematocrit are commonly used to determine the adequacy of tissue oxygenation during cardiopulmonary bypass (CPB). However, these global measures may not accurately reflect regional tissue oxygenation and ischemic organ injury remains a common and serious complication of CPB. Near-infrared spectroscopy (NIRS) is a noninvasive technology that measures regional tissue oxygenation. NIRS may be used alongside global measures to optimize regional perfusion and reduce organ injury. It may also be used as an indicator of the need for red blood cell transfusion in the presence of anemia and tissue hypoxia. However, the clinical benefits of using NIRS remain unclear and there is a lack of high-quality evidence demonstrating its efficacy and cost effectiveness.

Objective: The aim of the patient-specific cerebral oxygenation monitoring as part of an algorithm to reduce transfusion during heart valve surgery (PASPORT) trial is to determine whether the addition of NIRS to CPB management algorithms can prevent cognitive decline, postoperative organ injury, unnecessary transfusion, and reduce health care costs.

Methods: Adults aged 16 years or older undergoing valve or combined coronary artery bypass graft and valve surgery at one of three UK cardiac centers (Bristol, Hull, or Leicester) are randomly allocated in a 1:1 ratio to either a standard algorithm for optimizing tissue oxygenation during CPB that includes a fixed transfusion threshold, or a patient-specific algorithm that incorporates cerebral NIRS monitoring and a restrictive red blood cell transfusion threshold. Allocation concealment, Internet-based randomization stratified by operation type and recruiting center, and blinding of patients, ICU and ward care staff, and outcome assessors reduce the risk of bias. The primary outcomes are cognitive function 3 months after surgery and infectious complications during the first 3 months after surgery. Secondary outcomes include measures of inflammation, organ injury, and volumes of blood transfused. The cost effectiveness of the NIRS-based algorithm is described in terms of a cost-effectiveness acceptability curve. The trial tests the superiority of the patient-specific algorithm versus standard care. A sample size of 200 patients was chosen to detect a small to moderate target difference with 80% power and 5% significance (two tailed).

Results: Over 4 years, 208 patients have been successfully randomized and have been followed up for a 3-month period. Results are to be reported in 2015.

Conclusions: This study provides high-quality evidence, both valid and widely applicable, to determine whether the use of NIRS monitoring as part of a patient-specific management algorithm improves clinical outcomes and is cost effective.

Trial Registration: International Standard Randomized Controlled Trial Number (ISRCTN): 23557269; http://www.isrctn.com/ISRCTN23557269 (Archived by Webcite at http://www.webcitation.org/6buyrbj64).
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http://dx.doi.org/10.2196/resprot.4562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704972PMC
December 2015

Normothermic versus hypothermic cardiopulmonary bypass in children undergoing open heart surgery (thermic-2): study protocol for a randomized controlled trial.

JMIR Res Protoc 2015 May 25;4(2):e59. Epub 2015 May 25.

Clinical Trials and Evaluation Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.

Background: During open heart surgery, patients are connected to a heart-lung bypass machine that pumps blood around the body ("perfusion") while the heart is stopped. Typically the blood is cooled during this procedure ("hypothermia") and warmed to normal body temperature once the operation has been completed. The main rationale for "whole body cooling" is to protect organs such as the brain, kidneys, lungs, and heart from injury during bypass by reducing the body's metabolic rate and decreasing oxygen consumption. However, hypothermic perfusion also has disadvantages that can contribute toward an extended postoperative hospital stay. Research in adults and small randomized controlled trials in children suggest some benefits to keeping the blood at normal body temperature throughout surgery ("normothermia"). However, the two techniques have not been extensively compared in children.

Objective: The Thermic-2 study will test the hypothesis that the whole body inflammatory response to the nonphysiological bypass and its detrimental effects on different organ functions may be attenuated by maintaining the body at 35°C-37°C (normothermic) rather than 28°C (hypothermic) during pediatric complex open heart surgery.

Methods: This is a single-center, randomized controlled trial comparing the effectiveness and acceptability of normothermic versus hypothermic bypass in 141 children with congenital heart disease undergoing open heart surgery. Children having scheduled surgery to repair a heart defect not requiring deep hypothermic circulatory arrest represent the target study population. The co-primary clinical outcomes are duration of inotropic support, intubation time, and postoperative hospital stay. Secondary outcomes are in-hospital mortality and morbidity, blood loss and transfusion requirements, pre- and post-operative echocardiographic findings, routine blood gas and blood test results, renal function, cerebral function, regional oxygen saturation of blood in the cerebral cortex, assessment of genomic expression changes in cardiac tissue biopsies, and neuropsychological development.

Results: A total of 141 patients have been successfully randomized over 2 years and 10 months and are now being followed-up for 1 year. Results will be published in 2015.

Conclusions: We believe this to be the first large pragmatic study comparing clinical outcomes during normothermic versus hypothermic bypass in complex open heart surgery in children. It is expected that this work will provide important information to improve strategies of cardiopulmonary bypass perfusion and therefore decrease the inevitable organ damage that occurs during nonphysiological body perfusion.

Trial Registration: ISRCTN Registry: ISRCTN93129502, http://www.isrctn.com/ISRCTN93129502 (Archived by WebCitation at http://www.webcitation.org/6Yf5VSyyG).
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http://dx.doi.org/10.2196/resprot.4338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460263PMC
May 2015

ATP-dependent transport of statins by human and rat MRP2/Mrp2.

Toxicol Appl Pharmacol 2013 Jun 2;269(2):187-94. Epub 2013 Apr 2.

Section of Translational Medicine, Division of Applied Biology, Polwarth Building, Foresterhill, Aberdeen, UK.

Multidrug resistance associated protein-2, MRP2 (human), Mrp2 (rat) are an efflux transporter, responsible for the transport of numerous endogenous and xenobiotic compounds including taurocholate, methotrexate and carboxydichlorofluorescein (CDF). The present study aims to characterise transport of statins by human and rat MRP2/Mrp2 using membrane and vesicle preparations. All statins tested (simvastatin, pravastatin, pitavastatin, fluvastatin, atorvastatin, lovastatin and rosuvastatin) stimulated vanadate-sensitive ATPase activity in membranes expressing human or rat MRP2/Mrp2, suggesting that all statins are substrates of human and rat MRP2/Mrp2. The substrate affinity (Km) of all statins for MRP2/Mrp2 was comparable and no correlation between lipophilicity (logD7.0) and Km was seen. All statins also inhibited uptake of the fluorescent Mrp2 substrate, CDF (1μM) into vesicles expressing human or rat MRP2/Mrp2 with similar IC50 values. Fitting of the inhibitory data to the hill slope equation, gave hill coefficients (h) of greater than one, suggesting that transport involved more than one binding site for inhibitors of MPR2 and Mrp2. We conclude that statins were transported by both human and rat MRP2/Mrp2 with similar affinity. Statins were also shown to compete with other substrates for transport by MRP2/Mrp2 and that this transport involved more than one binding site on the Mrp2/MRP2 protein.
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http://dx.doi.org/10.1016/j.taap.2013.03.019DOI Listing
June 2013

Context-gated statistical learning and its role in visual-saccadic decisions.

J Exp Psychol Gen 2012 Feb 15;141(1):150-69. Epub 2011 Aug 15.

Department of Experimental Psychology, University of Bristol, England.

Adaptive behavior in a nonstationary world requires humans to learn and track the statistics of the environment. We examined the mechanisms of adaptation in a nonstationary environment in the context of visual-saccadic inhibition of return (IOR). IOR is adapted to the likelihood that return locations will be refixated in the near future. We examined 2 potential learning mechanisms underlying adaptation: (a) a local tracking or priming mechanism that facilitates behavior that is consistent with recent experience and (b) a mechanism that supports retrieval of knowledge of the environmental statistics based on the contextual features of the environment. Participants generated sequences of 2 saccadic eye movements in conditions where the probability that the 2nd saccade was directed back to the previously fixated location varied from low (.17) to high (.50). In some conditions, the contingency was signaled by a contextual cue (the shape of the movement cue). Adaptation occurred in the absence of contextual signals but was more pronounced in the presence of contextual cues. Adaptation even occurred when different contingencies were randomly intermixed, showing the parallel formation of multiple associations between context and statistics. These findings are accounted for by an evidence accumulation framework in which the resting baseline of decision alternatives is adjusted on a trial-by-trial basis. This baseline tracks the subjective prior beliefs about the behavioral relevance of the different alternatives and is updated on the basis of the history of recent events and the contextual features of the current environment.
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http://dx.doi.org/10.1037/a0024916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268529PMC
February 2012

Influence of environmental statistics on inhibition of saccadic return.

Proc Natl Acad Sci U S A 2010 Jan 22;107(2):929-34. Epub 2009 Dec 22.

Department of Experimental Psychology, University of Bristol, Bristol BS8 1TU, United Kingdom.

Initiating an eye movement is slowed if the saccade is directed to a location that has been fixated in the recent past. We show that this inhibitory effect is modulated by the temporal statistics of the environment: If a return location is likely to become behaviorally relevant, inhibition of return is absent. By fitting an accumulator model of saccadic decision-making, we show that the inhibitory effect and the sensitivity to local statistics can be dissociated in their effects on the rate of accumulation of evidence, and the threshold controlling the amount of evidence needed to generate a saccade.
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http://dx.doi.org/10.1073/pnas.0906845107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818969PMC
January 2010

The mechanism underlying inhibition of saccadic return.

Cogn Psychol 2009 Sep 10;59(2):180-202. Epub 2009 Jun 10.

University of Bristol, Department of Experimental Psychology, Bristol BS8 1TU, UK.

Human observers take longer to re-direct gaze to a previously fixated location. Although there has been some exploration of the characteristics of inhibition of saccadic return (ISR), the exact mechanisms by which ISR operates are currently unknown. In the framework of accumulation models of response times, in which evidence is integrated over time to a response threshold, ISR could reflect a reduction in the rate of accumulation for saccades to return locations or an increase in the effective criterion for response. In two experiments, participants generated sequences of three saccades, in response to a peripheral or a central cue. ISR occurred across these manipulations: saccade latency was consistently increased for movements to the immediately previously fixated location. Latency distributions from individual observers were fit with a Linear Ballistic Accumulator model. ISR was best accounted for as a change in the accumulation rate. We suggest this parameter represents the overall desirability of a particular course of action, the evidence for which may be derived from a variety of sensory and non-sensory sources.
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http://dx.doi.org/10.1016/j.cogpsych.2009.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734060PMC
September 2009

Regional and foreign accent processing in English: can listeners adapt?

J Psycholinguist Res 2009 Aug 1;38(4):379-412. Epub 2009 Jan 1.

School of Psychology, University of Plymouth, Plymouth, UK.

Recent data suggest that the first presentation of a foreign accent triggers a delay in word identification, followed by a subsequent adaptation. This study examines under what conditions the delay resumes to baseline level. The delay will be experimentally induced by the presentation of sentences spoken to listeners in a foreign or a regional accent as part of a lexical decision task for words placed at the end of sentences. Using a blocked design of accents presentation, Experiment 1 shows that accent changes cause a temporary perturbation in reaction times, followed by a smaller but long-lasting delay. Experiment 2 shows that the initial perturbation is dependent on participants' expectations about the task. Experiment 3 confirms that the subsequent long-lasting delay in word identification does not habituate after repeated exposure to the same accent. Results suggest that comprehensibility of accented speech, as measured by reaction times, does not benefit from accent exposure, contrary to intelligibility.
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http://dx.doi.org/10.1007/s10936-008-9097-8DOI Listing
August 2009

Formation of micronuclei in erythrocytes of the fathead minnow (Pimephales promelas) after acute treatment with mitomycin C or cyclophosphamide.

Mutat Res 2007 May 1;629(2):89-99. Epub 2007 Mar 1.

AstraZeneca Global Safety, Health and Environment, United Kingdom.

Despite the widespread use of the fathead minnow in ecotoxicology, there have been relatively few studies on genotoxicity biomarkers in this small, warm-water fish species. Consequently, we investigated the effect of two known genotoxins, mitomycin C and cyclophosphamide, on micronucleus induction in spleen and peripheral blood erythrocytes of this species. Initially, 96-h experiments after intra-peritoneal (i.p.) injections of mitomycin C and cyclophosphamide were undertaken to determine the maximum tolerated dose (MTD). From these studies, MTDs of 10 and 400 mg/kg, respectively, were obtained: doses that were higher than those reported for other fish species. Next, an assessment of micronucleus induction at 1, 2, 4, 8 and 14 days after injection was undertaken for each compound at the MTD. Mitomycin C at 10 mg/kg significantly induced micronuclei in erythrocytes from the spleen, but not from the peripheral blood, at 8 and 14 days. In addition, the overall levels of micronuclei observed were lower than most previously published data from other fish species. In contrast to mitomycin C, treatment with 400 mg/kg cyclophosphamide failed to significantly induce micronuclei in erythrocytes from any of the tissues employed, in contrast to previous reports of significant induction in other species. The reasons for the apparent relative insensitivity of the fathead minnow to these clastogens, with respect to both MTDs and micronucleus induction, are not clear. The fathead minnow, however, has previously been described as relatively insensitive compared to other fish species with respect to selected carcinogens and cytochrome P450 inducers; the latter suggesting that the lack of a significant induction following cyclophosphamide exposure may be due to low metabolic activation in vivo. Consequently, further clarifying work is required to delineate the response shown, considering the extensive use of this species in ecotoxicology research and regulatory testing.
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http://dx.doi.org/10.1016/j.mrgentox.2007.01.010DOI Listing
May 2007

Articulatory placement for /t/, /d/, /k/ and /g/ targets in school age children with speech disorders associated with cleft palate.

Clin Linguist Phon 2004 Sep-Dec;18(6-8):391-404

Queen Margaret University College, Edinburgh, UK.

This study used electropalatography (EPG) to identify place of articulation for lingual plosive targets /t/, /d/, /k/ and /g/ in the speech of 15 school age children with repaired cleft palate. Perceptual judgements indicated that all children had correct velar placement for /k/, /g/ targets, but /t/, /d/ targets were produced as errors involving palatalization or velar placement. An EPG classification scheme identified alveolar, palatal and velar placement. Articulations involving contact in alveolar and velar regions simultaneously were identified as alveolar velar double articulations (AVDAs). The classification revealed that AVDAs were relatively frequent, with 28% of alveolar and 12% of velar targets affected, and ten out of the 15 children produced one or more of these abnormal articulations. The majority of children had variable placements, with alveolar more variable than velar targets. The positive finding from the EPG data revealed that most children with perceptual errors for /t/, /d/ were able to make closure in the alveolar region during at least some of their attempts to articulate these targets. It is argued that appropriate analysis and interpretation of EPG data provide clinically relevant information about tongue placement in cleft palate speech.
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http://dx.doi.org/10.1080/02699200410001703691DOI Listing
April 2005

Cystic fibrosis presenting as acute pancreatitis and obstructive azoospermia in a young adult male with a novel mutation in the CFTR gene.

Pediatr Pulmonol 2002 Dec;34(6):491-5

Regional Cystic Fibrosis Unit, Seacroft Hospital, Leeds, UK.

Cystic fibrosis is rare in the Asian population, and is often associated with consanguinity and rare genotypes. We report on a 23-year-old Asian man from a consanguineous pedigree referred to the regional cystic fibrosis unit after a diagnosis of congenital bilateral absence of the vas deferens during investigations for infertility. A detailed history revealed several previous episodes of acute pancreatitis. Full diagnostic appraisal showed homozygosity for a novel cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation, but normal sweat test and nasal potential difference studies. An endoscopic retrograde cholangiopancreatogram (ERCP) showed chronic pancreatitis with bulky side branches. The vas deferens and the pancreas appeared exquisitely sensitive to mild CFTR dysfunction. Patients with cystic fibrosis and unexplained upper abdominal pain should be screened for pancreatitis, and consideration should be given to screening patients with idiopathic pancreatitis for mutations in the CFTR gene.
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http://dx.doi.org/10.1002/ppul.10190DOI Listing
December 2002