Publications
288 results found
Chambers ES, Viardot A, Psichas A, et al., 2014, Targeted delivery of propionate to the human colon prevents body weight and intra-abdominal adipose tissue gain in overweight adults, PROCEEDINGS OF THE NUTRITION SOCIETY, Vol: 73, Pages: E22-E22, ISSN: 0029-6651
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- Citations: 1
Hughes D, Waddingham EAJ, Mt-Isa S, et al., 2013, Recommendations for the methodology and visualisation techniques to be used in the assessment of benefit and risk of medicines
Horsley AR, Davies JC, Gray RD, et al., 2013, Changes in physiological, functional and structural markers of cystic fibrosis lung disease with treatment of a pulmonary exacerbation, Thorax, Vol: 68, Pages: 532-539, ISSN: 1468-3296
Background Clinical trials in cystic fibrosis (CF) have been hindered by the paucity of well characterised and clinically relevant outcome measures.Aim To evaluate a range of conventional and novel biomarkers of CF lung disease in a multicentre setting as a contributing study in selecting outcome assays for a clinical trial of CFTR gene therapy.Methods A multicentre observational study of adult and paediatric patients with CF (>10 years) treated for a physician-defined exacerbation of CF pulmonary symptoms. Measurements were performed at commencement and immediately after a course of intravenous antibiotics. Disease activity was assessed using 46 assays across five key domains: symptoms, lung physiology, structural changes on CT, pulmonary and systemic inflammatory markers.Results Statistically significant improvements were seen in forced expiratory volume in 1 s (p<0.001, n=32), lung clearance index (p<0.01, n=32), symptoms (p<0.0001, n=37), CT scores for airway wall thickness (p<0.01, n=31), air trapping (p<0.01, n=30) and large mucus plugs (p=0.0001, n=31), serum C-reactive protein (p<0.0001, n=34), serum interleukin-6 (p<0.0001, n=33) and serum calprotectin (p<0.0001, n=31).Discussion We identify the key biomarkers of inflammation, imaging and physiology that alter alongside symptomatic improvement following treatment of an acute CF exacerbation. These data, in parallel with our study of biomarkers in patients with stable CF, provide important guidance in choosing optimal biomarkers for novel therapies. Further, they highlight that such acute therapy predominantly improves large airway parameters and systemic inflammation, but has less effect on airway inflammation.
Lamb SE, Gates S, Williams MA, et al., 2013, Emergency department treatments and physiotherapy for acute whiplash: a pragmatic, two-step, randomised controlled trial, LANCET, Vol: 381, Pages: 546-556, ISSN: 0140-6736
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- Citations: 86
Mt-Isa S, Hallgreen CE, Asiimwe A, et al., 2013, Review of visualisation methods for the representation of benefit-risk assessment of medication: Stage 2 of 2
Mt-Isa S, Peters R, Phillips LD, et al., 2013, Review of visualisation methods for the representation of benefit-risk assessment of medication: Stage 1 of 2
Howard LSGE, Watson GMJ, Wharton J, et al., 2013, Supplementation of iron in pulmonary hypertension: Rationale and design of a phase II clinical trial in idiopathic pulmonary arterial hypertension, Pulmonary Circulation, Vol: 3, Pages: 100-107, ISSN: 2045-8940
Our aim is to assess the safety and potential clinical benefit of intravenous iron (Ferinject) infusion in iron deficient patients with idiopathic pulmonary arterial hypertension (IPAH). Iron deficiency in the absence of anemia (1) is common in patients with IPAH; (2) is associated with inappropriately raised levels of hepcidin, the key regulator of iron homeostasis; and (3) correlates with disease severity and worse clinical outcomes. Oral iron absorption may be impeded by reduced absorption due to elevated hepcidin levels. The safety and benefits of parenteral iron replacement in IPAH are unknown. Supplementation of Iron in Pulmonary Hypertension (SIPHON) is a Phase II, multicenter, double-blind, randomized, placebo-controlled, crossover clinical trial of iron in IPAH. At least 60 patients will be randomized to intravenous ferric carboxymaltose (Ferinject) or saline placebo with a crossover point after 12 weeks of treatment. The primary outcome will be the change in resting pulmonary vascular resistance from baseline at 12 weeks, measured by cardiac catheterization. Secondary measures include resting and exercise hemodynamics and exercise performance from serial bicycle incremental and endurance cardiopulmonary exercise tests. Other secondary measurements include serum iron indices, 6-Minute Walk Distance, WHO functional class, quality of life score, N-terminal pro-brain natriuretic peptide (NT-proBNP), and cardiac anatomy and function from cardiac magnetic resonance. We propose that intravenous iron replacement will improve hemodynamics and clinical outcomes in IPAH. If the data supports a potentially useful therapeutic effect and suggest this drug is safe, the study will be used to power a Phase III study to address efficacy.
Priebe S, Yeeles K, Bremner S, et al., 2013, Effectiveness of financial incentives to improve adherence to maintenance treatment with antipsychotics: cluster randomised controlled trial., BMJ, Vol: 347, ISSN: 0959-535X
To test whether offering financial incentives to patients with psychotic disorders is effective in improving adherence to maintenance treatment with antipsychotics.
Cheng K, Ashby D, Smyth RL, 2013, Oral steroids for long-term use in cystic fibrosis, COCHRANE DATABASE OF SYSTEMATIC REVIEWS, ISSN: 1469-493X
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- Citations: 30
Alton EWFW, Ashby D, Boyd C, et al., 2012, UPDATE ON THE UK CF GENE THERAPY CONSORTIUM MULTIDOSE, NON-VIRAL, GENE THERAPY TRIAL, Winter Meeting of the British-Thoracic-Society 2012, Publisher: BMJ PUBLISHING GROUP, Pages: A58-A58, ISSN: 0040-6376
Lamb SE, Williams MA, Williamson EM, et al., 2012, Managing Injuries of the Neck Trial (MINT): a randomised controlled trial of treatments for whiplash injuries, HEALTH TECHNOLOGY ASSESSMENT, Vol: 16, Pages: 1-+, ISSN: 1366-5278
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- Citations: 23
Alton EW, Ashby D, Boyd C, et al., 2012, UPDATE ON THE UK CF GENE THERAPY CONSORTIUM MULTIDOSE, NON-VIRAL, GENE THERAPY TRIAL, PEDIATRIC PULMONOLOGY, Vol: 47, Pages: 309-310, ISSN: 8755-6863
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- Citations: 2
Foster V, Young A, 2012, The use of routinely collected patient data for research: A critical review, HEALTH, Vol: 16, Pages: 448-463, ISSN: 1363-4593
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- Citations: 7
Everitt AR, Clare S, Pertel T, et al., 2012, IFITM3 restricts the morbidity and mortality associated with influenza., Nature, Vol: 484, Pages: 519-523
The 2009 H1N1 influenza pandemic showed the speed with which a novel respiratory virus can spread and the ability of a generally mild infection to induce severe morbidity and mortality in a subset of the population. Recent in vitro studies show that the interferon-inducible transmembrane (IFITM) protein family members potently restrict the replication of multiple pathogenic viruses1, 2, 3, 4, 5, 6, 7. Both the magnitude and breadth of the IFITM proteins’ in vitro effects suggest that they are critical for intrinsic resistance to such viruses, including influenza viruses. Using a knockout mouse model8, we now test this hypothesis directly and find that IFITM3 is essential for defending the host against influenza A virus in vivo. Mice lacking Ifitm3 display fulminant viral pneumonia when challenged with a normally low-pathogenicity influenza virus, mirroring the destruction inflicted by the highly pathogenic 1918 ‘Spanish’ influenza9, 10. Similar increased viral replication is seen in vitro, with protection rescued by the re-introduction of Ifitm3. To test the role of IFITM3 in human influenza virus infection, we assessed the IFITM3 alleles of individuals hospitalized with seasonal or pandemic influenza H1N1/09 viruses. We find that a statistically significant number of hospitalized subjects show enrichment for a minor IFITM3 allele (SNP rs12252-C) that alters a splice acceptor site, and functional assays show the minor CC genotype IFITM3 has reduced influenza virus restriction in vitro. Together these data reveal that the action of a single intrinsic immune effector, IFITM3, profoundly alters the course of influenza virus infection in mouse and humans.
Gordon AC, Wang N, Walley KR, et al., 2012, The cardio-pulmonary effects of vasopressin compared to norepinephrine in septic shock., Chest, Vol: 142, Pages: 593-605
Abstract BACKGROUND:Vasopressin is known to be an effective vasopressor in the treatment of septic shock but uncertainty remains about its effect on other hemodynamic parameters. METHODS:We examined the cardio-pulmonary effects of vasopressin compared to norepinephrine in 779 adult patients who had septic shock recruited to the Vasopressin and Septic Shock Trial (VASST). More detailed cardiac output data was analyzed for the subset of 241 patients managed with a pulmonary artery catheter and data was collected for the first 96 hours after randomization. We compared the effects of vasopressin versus norepinephrine in all patients and also according to severity of shock (< or ≥ 15μg/min of norepinephrine) and cardiac output at baseline. RESULTS:Equal blood pressures were maintained in both treatment groups with a significant reduction in norepinephrine requirements in the vasopressin treated patients. The major haemodynamic difference between the two groups was a significant reduction in heart rate in the vasopressin treated patients (p < 0.0001) and this was most pronounced in the less severe shock stratum (treatment x shock stratum interaction, p = 0.03). There were no other major cardio-pulmonary differences between treatment groups, including no difference in cardiac index or stroke volume index between vasopressin and norepinephrine treated patients. There was significantly greater use of inotropic drugs in the vasopressin group compared to the norepinephrine group. CONCLUSIONS:Vasopressin treatment in septic shock is associated with a significant reduction in heart rate but no change in cardiac output or other measures of perfusion. (Controlled Trials number, ISRCTN94845869.).
Mt-Isa S, Wang N, Hallgreen CE, et al., 2012, Review of methodologies for benefit and risk assessment of medication
Ashby D, Bird SM, Hunt I, et al., 2012, Discussion on the paper by Spiegelhalter, Sherlaw-Johnson, Bardsley, Blunt, Wood and Grigg, JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES A-STATISTICS IN SOCIETY, Vol: 175, Pages: 25-47, ISSN: 0964-1998
Tan TM, Field BCT, Minnion JS, et al., 2012, Pharmacokinetics, adverse effects and tolerability of a novel analogue of human pancreatic polypeptide, PP 1420., British Journal of Clinical Pharmacology, Vol: 73, Pages: 232-239
AIMS: The objectives of this phase 1 study were to confirm the tolerability ofsingle ascending subcutaneous doses of PP 1420 in healthy subjects, to assess itsadverse effects and to investigate the drug's pharmacokinetics and doseproportionality.METHODS: This was a double-blind, placebo-controlled, randomized study. Therewere three dosing periods. Each subject (n= 12) was randomized to receive onedose of placebo and two ascending doses of PP 1420, given as a subcutaneousinjection. Blood samples were taken over 24 h to assess pharmacokinetics.Standard safety and laboratory data were collected. The primary endpoint was the tolerability of PP 1420. The secondary endpoint was exposure to PP 1420 asassessed by C(max) and AUC(0,∞).RESULTS: PP 1420 was well tolerated by all subjects with no serious adverseeffects. Following single subcutaneous doses of PP 1420 at 2, 4 and 8 mg to male subjects, C(max) was reached at a median t(max) of approximately 1 h post dose(range 0.32-2.00 h). Thereafter, plasma concentrations of PP 1420 declined withgeometric mean apparent terminal elimination t(1/2) ranging from 2.42-2.61 h(range 1.64-3.95 h) across all dose levels.CONCLUSIONS: Subcutaneous PP 1420 was well tolerated in healthy human subjects atsingle doses between 2-8 mg, with no tolerability issues arising. Where observed,adverse events were not serious, and there was no evidence of a dose-relationshipto frequency of adverse events. The results therefore support the conduct ofclinical trials to investigate efficacy, tolerability and pharmacokinetics duringrepeated dosing.
MacCallum PK, Ashby D, Hennessy EM, et al., 2011, Cumulative flying time and risk of venous thromboembolism, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 155, Pages: 613-619, ISSN: 0007-1048
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- Citations: 9
Pitcher A, Ashby D, Elliott P, et al., 2011, Cardiac MRI as end point in clinical trials reply, HEART, Vol: 97, Pages: 1991-1991, ISSN: 1355-6037
Pitcher A, Ashby D, Elliott P, et al., 2011, Cardiovascular MRI in clinical trials: expanded applications through novel surrogate endpoints, Heart, Vol: 97, Pages: 1286-1292, ISSN: 1468-201X
Recent advances in cardiovascular magnetic resonance (CMR) now allow the accurate and reproducible measurement of many aspects of cardiac and vascular structure and function, with prognostic data emerging for several key imaging biomarkers. These biomarkers are increasingly used in the evaluation of new drugs, devices and lifestyle modifications for the prevention and treatment of cardiovascular disease. This review outlines a conceptual framework for the application of imaging biomarkers to clinical trials, highlights several important CMR techniques which are in use in randomised studies, and reviews certain aspects of trial design, conduct and interpretation in relation to the use of CMR.
Bhui KS, Dinos S, Ashby D, et al., 2011, Chronic fatigue syndrome in an ethnically diverse population: the influence of psychosocial adversity and physical inactivity, BMC MEDICINE, Vol: 9, ISSN: 1741-7015
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- Citations: 31
Cheng K, Ashby D, Smyth RL, 2011, Oral steroids for long-term use in cystic fibrosis, COCHRANE DATABASE OF SYSTEMATIC REVIEWS, ISSN: 1469-493X
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- Citations: 12
Mt-Isa S, Tzoulaki I, Callreus T, et al., 2011, Weighing benefit-risk of medicines: concepts and approaches, Drug Discovery Today: Technologies, Vol: In Press, Corrected Proof, Pages: ---, ISSN: 1740-6749
McDowell SE, Mt-Isa S, Ashby D, et al., 2010, Republished paper: Where errors occur in the preparation and administration of intravenous medicines: a systematic review and Bayesian analysis, POSTGRADUATE MEDICAL JOURNAL, Vol: 86, Pages: 734-738, ISSN: 0032-5473
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- Citations: 10
McDowell SE, Mt-Isa S, Ashby D, et al., 2010, Where errors occur in the preparation and administration of intravenous medicines: a systematic review and Bayesian analysis, QUALITY & SAFETY IN HEALTH CARE, Vol: 19, Pages: 341-345, ISSN: 1475-3898
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- Citations: 60
Mt-Isa S, Croft NM, Shafe A, et al., 2010, Gastro-Oesophageal Reflux Medicines - Evidence for Trials (GORMET), London, Publisher: Medicines and Healthcare Regulatory Agency, London, UK, SDS011
Dinos S, Khoshaba B, Ashby D, et al., 2009, A systematic review of chronic fatigue, its syndromes and ethnicity: prevalence, severity, co-morbidity and coping, INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, Vol: 38, Pages: 1554-1570, ISSN: 0300-5771
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- Citations: 76
Priebe S, Burton A, Ashby D, et al., 2009, Financial incentives to improve adherence to anti-psychotic maintenance medication in non-adherent patients - a cluster randomised controlled trial (FIAT), BMC PSYCHIATRY, Vol: 9
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- Citations: 25
McCulloch P, Altman DG, Campbell WB, et al., 2009, No surgical innovation without evaluation: the IDEAL recommendations., Lancet, Vol: 374, Pages: 1105-1112
Surgery and other invasive therapies are complex interventions, the assessment of which is challenged by factors that depend on operator, team, and setting, such as learning curves, quality variations, and perception of equipoise. We propose recommendations for the assessment of surgery based on a five-stage description of the surgical development process. We also encourage the widespread use of prospective databases and registries. Reports of new techniques should be registered as a professional duty, anonymously if necessary when outcomes are adverse. Case series studies should be replaced by prospective development studies for early technical modifications and by prospective research databases for later pre-trial evaluation. Protocols for these studies should be registered publicly. Statistical process control techniques can be useful in both early and late assessment. Randomised trials should be used whenever possible to investigate efficacy, but adequate pre-trial data are essential to allow power calculations, clarify the definition and indications of the intervention, and develop quality measures. Difficulties in doing randomised clinical trials should be addressed by measures to evaluate learning curves and alleviate equipoise problems. Alternative prospective designs, such as interrupted time series studies, should be used when randomised trials are not feasible. Established procedures should be monitored with prospective databases to analyse outcome variations and to identify late and rare events. Achievement of improved design, conduct, and reporting of surgical research will need concerted action by editors, funders of health care and research, regulatory bodies, and professional societies.
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