Deborah Ashby

Imperial College London, Londinium, England, United Kingdom

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Publications (59)514.35 Total impact

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    ABSTRACT: The colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults. To investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults. Propionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group. These data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans. NCT00750438. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Gut 12/2014; · 13.32 Impact Factor
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    ABSTRACT: BACKGROUND. Patients with mutations that inactivate kisspeptin signaling are infertile. Kisspeptin-54, the major circulating isoform of kisspeptin in humans, potently stimulates reproductive hormone secretion in humans. Animal studies suggest that kisspeptin is involved in generation of the luteinizing hormone surge, which is required for ovulation; therefore, we hypothesized that kisspeptin-54 could be used to trigger egg maturation in women undergoing in vitro fertilization therapy. METHODS. Following superovulation with recombinant follicle-stimulating hormone and administration of gonadotropin-releasing hormone antagonist to prevent premature ovulation, 53 women were administered a single subcutaneous injection of kisspeptin-54 (1.6 nmol/kg, n = 2; 3.2 nmol/kg, n = 3; 6.4 nmol/kg, n = 24; 12.8 nmol/kg, n = 24) to induce a luteinizing hormone surge and egg maturation. Eggs were retrieved transvaginally 36 hours after kisspeptin injection, assessed for maturation (primary outcome), and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos. RESULTS. Egg maturation was observed in response to each tested dose of kisspeptin-54, and the mean number of mature eggs per patient generally increased in a dose-dependent manner. Fertilization of eggs and transfer of embryos to the uterus occurred in 92% (49/53) of kisspeptin-54-treated patients. Biochemical and clinical pregnancy rates were 40% (21/53) and 23% (12/53), respectively. CONCLUSION. This study demonstrates that a single injection of kisspeptin-54 can induce egg maturation in women with subfertility undergoing in vitro fertilization therapy. Subsequent fertilization of eggs matured following kisspeptin-54 administration and transfer of resulting embryos can lead to successful human pregnancy. TRIAL REGISTRATION. ClinicalTrials.gov NCT01667406 FUNDING. Medical Research Council, Wellcome Trust, and National Institute for Health Research.
    The Journal of clinical investigation. 07/2014;
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    ABSTRACT: Vasopressin is an alternative vasopressor in the management of septic shock. It spares catecholamine use but whether it improves outcome remains uncertain. Current evidence suggests that it may be most effective if used early and possibly in conjunction with corticosteroids. This trial will compare vasopressin to noradrenaline as initial vasopressor in the management of adult septic shock and investigate whether there is an interaction of vasopressin with corticosteroids.
    BMJ Open 07/2014; 4(7):e005866. · 2.06 Impact Factor
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    ABSTRACT: PurposeDifficulties may be encountered when undertaking a benefit–risk assessment for an older product with well-established use but with a benefit–risk balance that may have changed over time. This case study investigates this specific situation by applying a formal benefit–risk framework to assess the benefit–risk balance of warfarin for primary prevention of patients with atrial fibrillation.Methods We used the qualitative framework BRAT as the starting point of the benefit–risk analysis, bringing together the relevant available evidence. We explored the use of a quantitative method (stochastic multi-criteria acceptability analysis) to demonstrate how uncertainties and preferences on multiple criteria can be integrated into a single measure to reduce cognitive burden and increase transparency in decision making.ResultsOur benefit–risk model found that warfarin is favourable compared with placebo for the primary prevention of stroke in patients with atrial fibrillation. This favourable benefit–risk balance is fairly robust to differences in preferences. The probability of a favourable benefit–risk for warfarin against placebo is high (0.99) in our model despite the high uncertainty of randomised clinical trial data.In this case study, we identified major challenges related to the identification of relevant benefit–risk criteria and taking into account the diversity and quality of evidence available to inform the benefit–risk assessment.Conclusion The main challenges in applying formal methods for medical benefit–risk assessment for a marketed drug are related to outcome definitions and data availability. Data exist from many different sources (both randomised clinical trials and observational studies), and the variability in the studies is large. Copyright © 2014 John Wiley & Sons, Ltd.
    Pharmacoepidemiology and Drug Safety 07/2014; · 2.90 Impact Factor
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    ABSTRACT: Meta-analyses of epidemiologic studies have suggested that metformin may reduce cancer incidence, but randomized controlled trials did not support this hypothesis.RESEARCH DESIGN AND METHODS: A retrospective cohort study, Clinical Practice Research Datalink, was designed to investigate the association between use of metformin compared with other antidiabetes medications and cancer risk by emulating an intention-to-treat analysis as in a trial. A total of 95,820 participants with type 2 diabetes who started taking metformin and other oral antidiabetes medications within 12 months of their diagnosis (initiators) were followed up for first-incident cancer diagnosis without regard to any subsequent changes in pharmacotherapy. Cox proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HR) and 95% CI.RESULTS: A total of 51,484 individuals (54%) were metformin initiators and 18,264 (19%) were sulfonylurea initiators, and 3,805 first-incident cancers were diagnosed during a median follow-up time of 5.1 years. Compared with initiators of sulfonylurea, initiators of metformin had a similar incidence of total cancer (HR 0.96; 95% CI 0.89-1.04) and colorectal (HR 0.92; 95% CI 0.76-1.13), prostate (HR 1.02; 95% CI 0.83-1.25), lung (HR 0.85; 95% CI 0.68-1.07), or postmenopausal breast (HR 1.03; 95% CI 0.82-1.31) cancer, or any other cancer.CONCLUSIONS: In this large study, individuals with diabetes who used metformin had a similar risk of developing cancer compared with those who used sulfonylureas.
    Diabetes care. 06/2014;
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    ABSTRACT: Organ dysfunction consequent to infection ('severe sepsis') is the leading cause of admission to an intensive care unit (ICU). In both animal models and early clinical studies the calcium channel sensitizer levosimendan has been demonstrated to have potentially beneficial effects on organ function. The aims of the Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS) trial are to identify whether a 24-hour infusion of levosimendan will improve organ dysfunction in adults who have septic shock and to establish the safety profile of levosimendan in this group of patients.
    Trials. 06/2014; 15(1):199.
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    ABSTRACT: Background The need for formal and structured approaches for benefit–risk assessment of medicines is increasing, as is the complexity of the scientific questions addressed before making decisions on the benefit–risk balance of medicines. We systematically collected, appraised and classified available benefit–risk methodologies to facilitate and inform their future use.MethodsA systematic review of publications identified benefit–risk assessment methodologies. Methodologies were appraised on their fundamental principles, features, graphical representations, assessability and accessibility. We created a taxonomy of methodologies to facilitate understanding and choice.ResultsWe identified 49 methodologies, critically appraised and classified them into four categories: frameworks, metrics, estimation techniques and utility survey techniques. Eight frameworks describe qualitative steps in benefit–risk assessment and eight quantify benefit–risk balance. Nine metric indices include threshold indices to measure either benefit or risk; health indices measure quality-of-life over time; and trade-off indices integrate benefits and risks. Six estimation techniques support benefit–risk modelling and evidence synthesis. Four utility survey techniques elicit robust value preferences from relevant stakeholders to the benefit–risk decisions.Conclusions Methodologies to help benefit–risk assessments of medicines are diverse and each is associated with different limitations and strengths. There is not a ‘one-size-fits-all’ method, and a combination of methods may be needed for each benefit–risk assessment. The taxonomy introduced herein may guide choice of adequate methodologies. Finally, we recommend 13 of 49 methodologies for further appraisal for use in the real-life benefit–risk assessment of medicines. Copyright © 2014 John Wiley & Sons, Ltd.
    Pharmacoepidemiology and Drug Safety 05/2014; · 2.90 Impact Factor
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    ABSTRACT: Vasopressin and corticosteroids are both commonly used adjunctive therapies in septic shock. Retrospective analyses have suggested that there may be an interaction between these drugs, with higher circulating vasopressin levels and improved outcomes in patients treated with both vasopressin and corticosteroids. We aimed to test for an interaction between vasopressin and corticosteroids in septic shock. Prospective open-label randomized controlled pilot trial. Four adult ICUs in London teaching hospitals. Sixty-one adult patients who had septic shock. Initial vasopressin IV infusion titrated up to 0.06 U/min and then IV hydrocortisone (50 mg 6 hourly) or placebo. Plasma vasopressin levels were measured at 6-12 and 24-36 hours after hydrocortisone/placebo administration. Thirty-one patients were allocated to vasopressin + hydrocortisone and 30 patients to vasopressin + placebo. The hydrocortisone group required a shorter duration of vasopressin therapy (3.1 d; 95% CI, 1.1-5.1; shorter in hydrocortisone group) and required a lower total dose of vasopressin (ratio, 0.47; 95% CI, 0.32-0.71) compared with the placebo group. Plasma vasopressin levels were not higher in the hydrocortisone group compared with the placebo group (64 pmol/L difference at 6- to 12-hour time point; 95% CI, -32 to 160 pmol/L). Early vasopressin use was well tolerated with only one serious adverse event possibly related to study drug administration reported. There were no differences in mortality rates (23% 28-day mortality in both groups) or organ failure assessments between the two treatment groups. Hydrocortisone spared vasopressin requirements, reduced duration, and reduced dose, when used together in the treatment of septic shock, but it did not alter plasma vasopressin levels. Further trials are needed to assess the clinical effectiveness of vasopressin as the initial vasopressor therapy with or without corticosteroids.
    Critical care medicine 02/2014; 42(6):1325-1333. · 6.15 Impact Factor
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    ABSTRACT: Background Although in-vitro fertilisation (IVF) treatment allows infertile couples to conceive, it can result in a potentially life-threatening condition termed the ovarian hyperstimulation syndrome (OHSS). The major cause of OHSS is use of human chorionic gonadotropin (hCG) in current IVF protocols for initiating oocyte maturation. The development of a more physiological stimulus for oocyte maturation would avoid this dangerous side-effect and thus improve safety of IVF treatment. Kisspeptin is a recently identified hypothalamic hormone that acutely and potently increases endogenous secretion of luteinising hormone in a gonadotropin-releasing hormone (GnRH)-dependent manner. We aimed to investigate whether kisspeptin can induce oocyte maturation in IVF treatment. Methods In this single-centre prospective clinical trial at Hammersmith Hospital, London, women were recruited with the following inclusion criteria: age 18–35 years, body mass index less than 30 kg/m2, serum anti-Mullerian hormone 10–40 pmol/L, and no more than one previous IVF cycle. They underwent a recombinant follicle stimulating hormone plus GnRH antagonist IVF protocol with a single subcutaneous injection of kisspeptin. A control group was not recruited for ethical reasons. Primary outcome was production of mature oocytes (metaphase II oocytes) after egg collection. Participants and doctors giving IVF treatment were masked to the dose of kisspeptin administered. Women were independently randomised by the study statistician, initially to the lowest tier of kisspeptin doses (1·6 or 3·2 nmol/kg, n=2–3 per dose) and then as per protocol to a higher tier of doses (6·4 or 12·8 nmol/kg, n=21 per dose). Oocyte retrieval was done 36 h after kisspeptin injection. After intracytoplasmic sperm injection (ICSI) one or two embryos were transferred to the woman and pregnancy testing done 12 days later. Clinical pregnancy was confirmed on ultrasound scan at 6 weeks of gestation. Multiple means were compared by use of one-way ANOVA with post-hoc Bonferroni correction. Proportions were compared by χ2 test. All data were analysed on an intention-to-treat basis. Women gave written informed consent. The study received approval from the Hammersmith and Queen Charlottes Research Ethics Committee (application number 10/H0707/2) and the Medicines and Healthcare Products Regulatory Agency. The trial is registered with ClinicalTrials.gov, number NCT01667406. Findings Up to Sept 1, 2013, 47 women completed the study protocol. All doses of kisspeptin resulted in a mean 9·0-fold (SD 7·5) increase in luteinising hormone release 12 h after injection. Oocyte maturation was observed at all doses of kisspeptin. 45 women (96%) had oocyte maturation (mean number of metaphase II oocytes 7·9, SD 4·1). Embryogenesis occurred in 43 women (91%) after treatment with kisspeptin (mean number of zygotes 5·7, SD 3·5). Complete pregnancy data are awaited, but up to Sept 1, 2013, 16 (36%) of 44 women had a positive pregnancy test at 12 days post embryo transfer and ten (23%) had clinical pregnancy confirmed on ultrasound examination at 6 weeks of gestation. Clinical follow-up during pregnancy is continuing, but already the first participant to have received kisspeptin to induce oocyte maturation gave birth to a healthy baby boy in May, 2013. No adverse events were noted at any time during the study. Interpretation The results of this study suggest, for the first time, to our knowledge, that kisspeptin induces oocyte maturation in women undergoing IVF treatment. Kisspeptin might therefore offer a novel therapeutic option for fertility treatment. This small pilot study provides proof of concept that kisspeptin can stimulate oocyte maturation in women undergoing IVF treatment. Further work is now underway in a larger number of patients to determine the optimum protocol for kisspeptin administration to induce oocyte maturation in a population at high risk of OHSS. Funding UK Medical Research Council, National Institute for Health Research.
    The Lancet 02/2014; 383:S17. · 39.21 Impact Factor
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    ABSTRACT: To test whether offering financial incentives to patients with psychotic disorders is effective in improving adherence to maintenance treatment with antipsychotics. Cluster randomised controlled trial. Community mental health teams in secondary psychiatric care in the United Kingdom. Patients with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder, who were prescribed long acting antipsychotic (depot) injections but had received 75% or less of the prescribed injections. We randomly allocated 73 teams with a total of 141 patients. Primary outcome data were available for 35 intervention teams with 75 patients (96% of randomised) and for 31 control teams with 56 patients (89% of randomised). Participants in the intervention group were offered £15 (€17; $22) for each depot injection over a 12 month period. Participants in the control condition received treatment as usual. The primary outcome was the percentage of prescribed depot injections given during the 12 month intervention period. 73 teams with 141 consenting patients were randomised, and outcomes were assessed for 131 patients (93%). Average baseline adherence was 69% in the intervention group and 67% in the control group. During the 12 month trial period adherence was 85% in the intervention group and 71% in the control group. The adjusted effect estimate was 11.5% (95% confidence interval 3.9% to 19.0%, P=0.003). A secondary outcome was an adherence of ≥95%, which was achieved in 28% of the intervention group and 5% of the control group (adjusted odds ratio 8.21, 95% confidence interval 2.00 to 33.67, P=0.003). Although differences in clinician rated clinical improvement between the groups failed to reach statistical significance, patients in the intervention group had more favourable subjective quality of life ratings (β=0.71, 95% confidence interval 0.26 to 1.15, P=0.002). The number of admissions to hospital and adverse events were low in both groups and did not show substantial differences. Offering modest financial incentives to patients with psychotic disorders is an effective method for improving adherence to maintenance treatment with antipsychotics. Current Controlled Trials ISRCTN77769281.
    BMJ (online) 10/2013; 347:f5847. · 16.38 Impact Factor
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    ABSTRACT: 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.
    Thorax 02/2013; · 8.56 Impact Factor
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    ABSTRACT: BACKGROUND: Little is known about the effectiveness of treatments for acute whiplash injury. We aimed to estimate whether training of staff in emergency departments to provide active management consultations was more effective than usual consultations (Step 1) and to estimate whether a physiotherapy package was more effective than one additional physiotherapy advice session in patients with persisting symptoms (Step 2). METHODS: Step 1 was a pragmatic, cluster randomised trial of 12 NHS Trust hospitals including 15 emergency departments who treated patients with acute whiplash associated disorder of grades I-III. The hospitals were randomised by clusters to either active management or usual care consultations. In Step 2, we used a nested individually randomised trial. Patients were randomly assigned to receive either a package of up to six physiotherapy sessions or a single advice session. Randomisation in Step 2 was stratified by centre. Investigator-masked outcomes were obtained at 4, 8, and 12 months. Masking of clinicians and patients was not possible in all steps of the trial. The primary outcome was the Neck Disability Index (NDI). Analysis was intention to treat, and included an economic evaluation. The study is registered ISRCTN33302125. FINDINGS: Recruitment ran from Dec 5, 2005 to Nov 30, 2007. Follow-up was completed on Dec 19, 2008. In Step 1, 12 NHS Trusts were randomised, and 3851 of 6952 eligible patients agreed to participate (1598 patients were assigned to usual care and 2253 patients were assigned to active management). 2704 (70%) of 3851 patients provided data at 12 months. NDI score did not differ between active management and usual care consultations (difference at 12 months 0·5, 95% CI -1·5 to 2·5). In Step 2, 599 patients were randomly assigned to receive either advice (299 patients) or a physiotherapy package (300 patients). 479 (80%) patients provided data at 12 months. The physiotherapy package at 4 months showed a modest benefit compared to advice (NDI difference -3·7, -6·1 to -1·3), but not at 8 or 12 months. Active management consultations and the physiotherapy package were more expensive than usual care and single advice session. No treatment-related serious adverse events or deaths were noted. INTERPRETATION: Provision of active management consultation did not show additional benefit. A package of physiotherapy gave a modest acceleration to early recovery of persisting symptoms but was not cost effective from a UK NHS perspective. Usual consultations in emergency departments and a single physiotherapy advice session for persistent symptoms are recommended. FUNDING: NIHR Health Technology Assessment programme.
    The Lancet 12/2012; · 39.21 Impact Factor
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    ABSTRACT: OBJECTIVES: To examine the clinical effectiveness of a stepped care approach over a 12-month period after an acute whiplash injury; to estimate the costs and cost-effectiveness of each strategy including treatments and subsequent health-care costs; and to gain participants' perspective on experiencing whiplash injury, NHS treatment, and recovery within the context of the Managing Injuries of the Neck Trial (MINT). DESIGN: Two linked, pragmatic, randomised controlled trials. In Step 1, emergency departments (EDs) were cluster randomised to usual care advice (UCA) or The Whiplash Book advice (WBA)/active management advice. In Step 2, participants were individually randomised to either a single session of advice from a physiotherapist or a physiotherapy package of up to six sessions. An economic evaluation and qualitative study were run in parallel with the trial. SETTING: Twelve NHS trusts in England comprising 15 EDs. PARTICIPANTS: People who attended EDs with an acute whiplash injury of whiplash-associated disorder grades I-III were eligible for Step 1. People who had attended EDs with whiplash injuries and had persistent symptoms 3 weeks after ED attendance were eligible for Step 2. INTERVENTIONS: In Step 1, the control intervention was UCA and the experimental intervention was a psycho-educational intervention (WBA/active management advice). In Step 2 the control treatment was reinforcement of the advice provided in Step 1 and the experimental intervention was a package of up to six physiotherapy treatments. MAIN OUTCOME: The primary outcome was the Neck Disability Index (NDI), which measures severity and frequency of pain and symptoms, and a range of activities including self-care, driving, reading, sleeping and recreation. Secondary outcomes included the mental and physical health-related quality-of-life (HRQoL) subscales of the Short Form questionnaire-12 items (SF-12) and the number of work days lost. RESULTS: A total of 3851 patients were recruited to Step 1 of the trial. 1598 patients attending EDs were randomised to UCA, and 2253 were randomised to WBA/active management. Outcome data were obtained at 12 months for 70% and 80% of participants at Step 1 and Step 2, respectively. The majority of people recovered from the injury. Eighteen per cent of the Step 1 cohort had late whiplash syndrome. There was no statistically or clinically significant difference observed in any of the outcomes for participants attending EDs randomised to UCA or active management advice [difference in NDI 0.5, 95% confidence interval (CI) -1.8 to 2.8]. In Step 2 the physiotherapy package resulted in improvements in neck disability at 4 months compared with a single advice session, but these effects were small at the population level (difference in NDI -3.2, 95% CI -5.8 to -0.7). The physiotherapy package was accompanied by a significant reduction in the number of work days lost at 4-month follow-up (difference -40.2, 95% CI -44.3 to -35.8). CONCLUSIONS: MINT suggests that enhanced psycho-educational interventions in EDs are no more effective than UCA in reducing the burden of acute whiplash injuries. A physiotherapy package provided to people who have persisting symptoms within the first 6 weeks of injury produced additional short-term benefits in neck disability compared with a single physiotherapy advice session. However, from a health-care perspective, the physiotherapy package was not cost-effective at current levels of willingness to pay. Both experimental treatments were associated with increased cost with no discernible gain in health-related quality of life. However, an important benefit of the physiotherapy package was a reduction in work days lost; consequently, the intervention may prove cost-effective at the societal level. TRIAL REGISTRATION: Current Controlled Trials ISRCTN33302125. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 49. See the HTA programme website for further project information.
    Health technology assessment (Winchester, England). 12/2012; 16(49):1-141.
  • Thorax 11/2012; 67(Suppl 2):A58-A58. · 8.56 Impact Factor
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    ABSTRACT: 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.).
    Chest 04/2012; · 7.13 Impact Factor
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    ABSTRACT: The risk of venous thromboembolism (VTE) associated with cumulative flying time remains uncertain. In a case-control study in general practices throughout the UK, participants comprised 550 VTE cases identified from practice records and 1971 age- and gender-matched controls. Participants returned identical questionnaires asking for information including air travel details. Compared to not flying, cumulative flying time >12 h within the previous 4 weeks was associated with a threefold increase in the risk of VTE [odds ratio (OR) 2·75, 95% confidence interval (CI), 1·44-5·28]. Those who had flown >4 h in a single leg in the previous 4 weeks had twice the risk of VTE (OR 2·20, 95% CI, 1·29-3·73). These risks were no longer evident by 12 weeks and were similar to those of day-case or minor surgery (OR 5·35, 95% CI, 2·15-13·33). Equivalent risks for moderate and high-risk surgery were over 30-fold (OR 36·57, 95% CI, 13·05-102·52) and 140-fold (OR 141·71, 95% CI, 19·38-1036·01) respectively. The temporary nature of the association of cumulative and long-haul air travel with VTE suggests a causal relationship. The risks of VTE in those with a higher baseline risk due to surgery, previous VTE or obesity are further increased by air travel.
    British Journal of Haematology 12/2011; 155(5):613-9. · 4.94 Impact Factor
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    ABSTRACT: Over recent years in the UK there has been growing interest in the potential for routinely collected NHS (National Health Service) patient data to be used for secondary purposes, facilitated by the potential of increasingly sophisticated electronic databases. This article is based on a critically reflective literature review which analyses the key debates pertaining to this issue. The work arose in the context of a programme of research concerning routine patient data use in neonatal care. The article includes analysis of commentary (opinion and ethical inquiry) as well as empirically derived claims. It aims to deconstruct the knowledge assumptions on which relevant research studies have been based or are proposed and it also incorporates ontological position and moral argument. Results are presented according to three predominant debates: the prevailing claim that all health research benefits civic society; the varieties of informed consent and choices open to patients regarding secondary uses of their data; and the 'rights and responsibilities' of patients when it comes to their data being used for research purposes. It examines the relevance of these themes specifically to the neonatal context and the implications for our own research, concluding that employing an alternative ethical model to the traditional professional one might be useful in order to provide a further perspective on the issue.
    Health 11/2011; 16(4):448-63. · 2.10 Impact Factor
  • Heart (British Cardiac Society) 10/2011; · 6.02 Impact Factor
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    ABSTRACT: The objectives of this phase 1 study were to confirm the tolerability of single ascending subcutaneous doses of PP 1420 in healthy subjects, to assess its adverse effects and to investigate the drug's pharmacokinetics and dose proportionality. This was a double-blind, placebo-controlled, randomized study. There were three dosing periods. Each subject (n= 12) was randomized to receive one dose of placebo and two ascending doses of PP 1420, given as a subcutaneous injection. 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 as assessed by C(max) and AUC(0,∞). PP 1420 was well tolerated by all subjects with no serious adverse effects. 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 with geometric mean apparent terminal elimination t(1/2) ranging from 2.42-2.61 h (range 1.64-3.95 h) across all dose levels. Subcutaneous PP 1420 was well tolerated in healthy human subjects at single 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-relationship to frequency of adverse events. The results therefore support the conduct of clinical trials to investigate efficacy, tolerability and pharmacokinetics during repeated dosing.
    British Journal of Clinical Pharmacology 08/2011; 73(2):232-9. · 3.69 Impact Factor
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    ABSTRACT: 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.
    Heart (British Cardiac Society) 06/2011; 97(16):1286-92. · 6.02 Impact Factor

Publication Stats

2k Citations
514.35 Total Impact Points

Institutions

  • 2014
    • Imperial College London
      Londinium, England, United Kingdom
  • 2009
    • McGill University Health Centre
      Montréal, Quebec, Canada
    • University of Oxford
      Oxford, England, United Kingdom
    • McGill University
      • Department of Surgery
      Montréal, Quebec, Canada
  • 2008
    • University of Melbourne
      • Department of Psychiatry
      Melbourne, Victoria, Australia
  • 2006–2007
    • University of London
      Londinium, England, United Kingdom
  • 2004–2005
    • University of Bristol
      Bristol, England, United Kingdom
  • 2001
    • Queen Mary, University of London
      Londinium, England, United Kingdom