Wellcome Trust Clinical Research Facility

Edinburgh, United Kingdom

Wellcome Trust Clinical Research Facility

Edinburgh, United Kingdom
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Rahman I.A.,University of Birmingham | Mascaro J.G.,University of Birmingham | Steeds R.P.,University of Birmingham | Frenneaux M.P.,University of Birmingham | And 5 more authors.
Circulation | Year: 2010

Background-: We assessed whether remote ischemic preconditioning (RIPC) improves myocardial, renal, and lung protection after on-pump coronary surgery. Methods and results-: This was a single-center, prospective, randomized (1:1), placebo-controlled trial. Patients, investigators, anesthetists, surgeons, and critical care teams were blinded to group allocation. Subjects received RIPC (or placebo) stimuli (×3 upper limb (or dummy arm), 5-minute cycles of 200 mm Hg cuff inflation/deflation) before aortic clamping. Anesthesia, perfusion, cardioplegia, and surgical techniques were standardized. The primary end point was 48-hour area under the curve (AUC) troponin T (cTnT) release. Secondary end points were 6-hour and peak cTnT, ECG changes, cardiac index, inotrope and vasoconstrictor use, renal dysfunction, and lung injury. Hospital survival was 99.4%. Comparing placebo and RIPC, median (interquartile range) AUC 48-hour cTnT (ng/mL-1/48 h-1); 28 (19, 39) versus 30 (22, 38), 6-hour cTnT (ng/mL-1); 0.93(0.59, 1.35) versus 1.01(0.72, 1.43), peak cTnT (ng/mL-1); 1.02 (0.74, 1.44) versus 1.04 (0.78, 1.51), de novo left bundle-branch block (4% versus 0%) and Q waves (5.3% versus 5.5%), serial cardiac indices, intraaortic balloon pump usage (8.5% versus 7.5%), inotrope (39% versus 50%) and vasoconstrictor usage (66% versus 64%) were not different. Dialysis requirement (1.2% versus 3.8%), peak creatinine (median [interquartile range], 1.2 mg/dL-1 (1.1, 1.4) versus 1.2 (1.0, 1.4)), and AUC urinary albumin-creatinine ratios 69 (40, 112) versus 58 (32, 85) were not different. Intubation times; median (interquartile range), 937 minutes(766, 1402) versus 895(675, 1180), 6-hour; 278 (210, 338) versus 270 (218, 323) and 12-hour pO2:FiO2 ratios 255 (195, 323) versus 263 (210, 308) were similar. Conclusions-: In contrast to prior smaller studies, RIPC did not reduce troponin release, improve hemodynamics, or enhance renal or lung protection. © 2010 American Heart Association, Inc.

Mills N.L.,University of Edinburgh | Churchhouse A.M.D.,University of Edinburgh | Lee K.K.,University of Edinburgh | Anand A.,University of Edinburgh | And 9 more authors.
JAMA - Journal of the American Medical Association | Year: 2011

Context: Although troponin assays have become increasingly more sensitive, it is unclear whether further reductions in the threshold of detection for plasma troponin concentrations will improve clinical outcomes in patients with suspected acute coronary syndrome (ACS). Objective: To determine whether lowering the diagnostic threshold for myocardial infarction (MI) with a sensitive troponin assay could improve clinical outcomes. Design, Setting, and Patients: All consecutive patients admitted with suspected ACS to the Royal Infirmary of Edinburgh, Edinburgh, Scotland, before (n = 1038; February 1-July 31, 2008, during the validation phase) and after (n = 1054; February 1-July 31, 2009, during the implementation phase) lowering the threshold of detection for myocardial necrosis from 0.20 to 0.05 ng/mL with a sensitive troponin I assay were stratified into 3 groups (<0.05 ng/mL, 0.05-0.19 ng/mL, and ≥0.20 ng/mL). During the validation phase, only concentrations above the original diagnostic threshold of 0.20 ng/mL were reported to clinicians. Main Outcome Measure: Event-free survival (recurrent MI and death) at 1 year in patients grouped by plasma troponin concentrations. Results: Plasma troponin concentrations were less than 0.05 ng/mL in 1340 patients (64%), 0.05 to 0.19 ng/mL in 170 patients (8%), and 0.20 ng/mL or more in 582 patients (28%). During the validation phase, 39% of patients with plasma troponin concentrations of 0.05 to 0.19 ng/mL were dead or had recurrent MI at 1 year compared with 7% and 24% of those patients with troponin concentrations of less than 0.05 ng/mL (P < .001) or 0.20 ng/mL or more (P = .007), respectively. During the implementation phase, lowering the diagnostic threshold to 0.05 ng/mL was associated with a lower risk of death and recurrent MI (from 39% to 21%) in patients with troponin concentrations of 0.05 to 0.19 ng/mL (odds ratio, 0.42; 95% confidence interval, 0.24-0.84; P = .01). Conclusions: In patients with suspected ACS, implementation of a sensitive troponin assay increased the diagnosis of MI and identified patients at high risk of recurrent MI and death. Lowering the diagnostic threshold of plasma troponin was associated with major reductions in morbidity and mortality. ©2011 American Medical Association. All rights reserved.

Lewis T.,University of Birmingham | Chaudhry R.,University of Birmingham | Nightingale P.,Wellcome Trust Clinical Research Facility | Lambert P.,Aston University | Das I.,University of Birmingham
International Journal of Infectious Diseases | Year: 2011

Objective: To analyze the recent epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia in a UK tertiary referral center. Methods: We collected epidemiological and laboratory data on all cases of MRSA bacteremia from September 1, 2005 to December 31, 2007. Results: There were 195 clinically significant episodes. Most were hospital-acquired. Only one episode occurred in patients without a history of hospital admission in the previous 12 months. An intravascular device was the most common focus of infection (37%), with no identifiable source found in 35% of episodes. Twenty-eight percent of patients died within 30 days of bacteremia. Mortality was significantly higher in the absence of an identifiable focus. Failure to include an antibiotic active against MRSA in the empirical treatment was only significantly associated with death in patients showing signs of hemodynamic instability (p < 0.001). No isolates had a minimum inhibitory concentration to vancomycin above 1.5. mg/l and no heteroresistance to glycopeptide antibiotics (heteroresistant vancomycin-intermediate Staphylococcus aureus; hVISA) was detected. All isolates were sensitive to daptomycin, tigecycline, and linezolid. Conclusions: Despite improvement in infection control measures, medical devices remain the most common source of infection. Inappropriate empirical antibiotic usage is associated with a poor outcome in patients with signs of severe sepsis. Susceptibility to glycopeptides and newer antibiotics remains good. © 2010 International Society for Infectious Diseases.

Mackenzie I.M.J.,Foundation Medicine | Mackenzie I.M.J.,University of Birmingham | Whitehouse T.,Foundation Medicine | Whitehouse T.,University of Birmingham | Nightingale P.G.,Wellcome Trust Clinical Research Facility
Intensive Care Medicine | Year: 2011

Introduction: Trials of tight glucose control have compared measures of central tendency, such as average blood glucose, and yielded conflicting results. Other metrics, such as standard deviation, reflect different properties of glucose control and are also associated with changes in outcome. It is possible, therefore, that the conflicting results from interventional studies arise from effects on glycaemic control that have not been reported. Methods: Using glucose measurements from patients admitted to four adult intensive care units in one UK hospital, we sought to identify metrics of glycaemic control, examine the relationship between them and identify the metrics that are both independently and most strongly associated with outcome. Results: We examined nine previously described metrics and identified a further four. Cluster analysis classified these metrics into two families, namely, those reflecting measures of central tendency and those reflecting measures of dispersion. A measure of minimum glucose was also identified but related to neither family. Plots of the quintiles of these metrics against hospital mortality revealed population-specific relationships. Areas under receiver-operating characteristic curves could not identify an optimum metric of central tendency or dispersion. Using odds ratios, we were able to show that the effect of these metrics is independent of one another. Conclusion: Our results suggest that glycaemic control is associated with outcome on the basis of three independent metrics, reflecting measures of central tendency, measures of dispersion and a measure of minimum glucose. © 2010 Copyright jointly held by Springer and ESICM.

Das I.,University of Birmingham | Nightingale P.,Wellcome Trust Clinical Research Facility | Patel M.,University of Birmingham | Jumaa P.,University of Birmingham
International Journal of Infectious Diseases | Year: 2011

Objectives: To review the epidemiology of candidemia in a UK tertiary referral center. Methods: Clinical and laboratory data from patients with candidemia were collected prospectively from October 1, 2005 to June 30, 2008 (a 33-month period). Results: A total of 107 episodes were identified. The incidence was 10.9 episodes/100 000 bed-days. The most common predisposing factors were the use of broad-spectrum antibiotics (92%), the presence of an intravascular device (IVD) (82%), admission to an intensive care unit (ICU) (51%), and recent surgery (50%). Non-Candida albicans species accounted for 58% of the episodes, which is higher than the percentage reported from other UK centers. C. albicans was the most common species, accounting for 43% of episodes, followed by C. glabrata (31%) and C. parapsilosis (20%). Overall C. tropicalis, C. krusei, C. norvegensis, and C. lusitaniae caused 7% of episodes. The crude 30-day mortality rate was 37%. Advanced age (p = 0.003) and the presence of septic shock (p = 0.038) were associated with mortality. Conclusions: Candidemia continues to be associated with a high mortality. Preventative measures should be targeted against high-risk hospitalized patients, especially those in ICUs, the elderly, and those undergoing major surgery. Local surveillance of candidemia is important to optimize management. © 2011 International Society for Infectious Diseases.

Oldham J.,University of Manchester | Herbert J.,Westminster Business Center | McBride K.,Wellcome Trust Clinical Research Facility
Neurourology and Urodynamics | Year: 2013

Aims To test the null hypothesis that a novel disposable "tampon like" electrostimulation device (Pelviva®) is no better than unsupervised pelvic floor muscle exercise for treatment of urinary incontinence in women. Methods Pre/post-intervention assessor blinded, single center RCT. A total of 123 community dwelling self referred women with symptoms of stress, urge, or mixed incontinence were randomly assigned to one of two 12-week duration treatments: Pelviva® used for 30 min a day plus unsupervised pelvic floor muscle exercise or unsupervised exercises alone. Outcome measures included ICIQ-UI (primary), ICIQ FLUTSex and global impression of severity and improvement (secondary) completed at recruitment, after 4 weeks of unsupervised exercise and immediately post-treatment. Diary of exercise frequency/type, overall impression, and usage of device was completed mid- and post-treatment. Results Pelviva® plus exercise produced significantly better outcome than unsupervised exercise alone: 5 points (45%) versus 1 point (10%) for ICIQ-UI (P = 0.014); 67% versus 33% for leak frequency (P = 0.005); 40% versus 20% for leak interference with life (P = 0.018). Incontinence was less bothersome during sex to a greater extent in the Pelviva® group (P = 0.026). Women were enthusiastic about the device, found it comfortable/easy to use and experienced no adverse events. Conclusions The Pelviva® device plus unsupervised exercise is more successful than unsupervised pelvic floor muscle exercise alone in treating urinary incontinence. The device is easy/comfortable to use, there are no apparent adverse incidents, and women can manage their incontinence in the privacy of their own home. The product will be launched 2013. Copyright © 2012 Wiley Periodicals, Inc.

Rezai M.-R.,University of Manchester | Cowan B.R.,University of Auckland | Sherratt N.,Wellcome Trust Clinical Research Facility | Finn J.D.,University of Manchester | And 2 more authors.
Blood Pressure Monitoring | Year: 2013

BACKGROUND: Simple reproducible methods of measuring arterial stiffness, a powerful index of prognosis, are becoming available. AIM: To compare the pulse wave transit time (TT) and pulse wave velocity (PWV) between MRI and an arm cuff-based oscillometric method, the Arteriograph. MATERIALS AND METHODS: MRI phase-contrast data were acquired at the aortic arch and just above the aortic bifurcation in 49 men (age 53±6 years). Supine left-arm Arteriograph measurements were made after MRI using the surface sternal notch to symphysis pubis pathway length. RESULTS: MRI TT and PWV covered 86% of aortic root-bifurcation length omitting a mean 4.7 cm of proximal ascending aorta. Arteriograph TT (71±9 ms) was 6.6 ms [95% confidence interval (CI) 3.9-9.4] or 10% higher than MRI (64±10 ms). Arteriograph PWV (7.9±1.3 m/s) was 1.33 m/s (95% CI 0.95-1.70) higher than MRI (6.6±1.2 m/s), primarily because the surface aortic length was 70 mm (95% CI 59-81) longer than MRI. Arteriograph-MRI PWV difference decreased to 0.31 m/s (95% CI 0.01-0.61) when Arteriograph PWV was calculated using the MRI aortic path length and to 0.25 m/s (95% CI -0.05 to 0.55) after correcting for the aortic segments omitted in the MRI method. After similar TT corrections for MRI, the Arteriograph-MRI difference in TT reduced to 3.2 ms (95% CI 0.2-6). CONCLUSION: TT estimations by Arteriograph and MRI are close. More accurate length estimation from MRI-derived models improves Arteriograph PWV measurement. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Grainge C.L.,University of Southampton | Grainge C.L.,Wellcome Trust Clinical Research Facility | Lau L.C.K.,University of Southampton | Ward J.A.,University of Southampton | And 9 more authors.
New England Journal of Medicine | Year: 2011

BACKGROUND: Asthma is characterized pathologically by structural changes in the airway, termed airway remodeling. These changes are associated with worse long-term clinical outcomes and have been attributed to eosinophilic inflammation. In vitro studies indicate, however, that the compressive mechanical forces that arise during bronchoconstriction may induce remodeling independently of inflammation. We evaluated the influence of repeated experimentally induced bronchoconstriction on airway structural changes in patients with asthma. METHODS: We randomly assigned 48 subjects with asthma to one of four inhalation challenge protocols involving a series of three challenges with one type of inhaled agent presented at 48-hour intervals. The two active challenges were with either a dust-mite allergen (which causes bronchoconstriction and eosinophilic inflammation) or methacholine (which causes bronchoconstriction without eosinophilic inflammation); the two control challenges (neither of which causes bronchoconstriction) were either saline alone or albuterol followed by methacholine (to control for nonbronchoconstrictor effects of methacholine). Bronchial-biopsy specimens were obtained before and 4 days after completion of the challenges. RESULTS: Allergen and methacholine immediately induced similar levels of bronchoconstriction. Eosinophilic inflammation of the airways increased only in the allergen group, whereas both the allergen and the methacholine groups had significant airway remodeling not seen in the two control groups. Subepithelial collagen-band thickness increased by a median of 2.17 μm in the allergen group (interquartile range [IQR], 0.70 to 3.67) and 1.94 μm in the methacholine group (IQR, 0.37 to 3.24) (P<0.001 for the comparison of the two challenge groups with the two control groups); periodic acid - Schiff staining of epithelium (mucus glands) also increased, by a median of 2.17 percentage points in the allergen group (IQR, 1.03 to 4.77) and 2.13 percentage points in the methacholine group (IQR, 1.14 to 7.96) (P = 0.003 for the comparison with controls). There were no significant differences between the allergen and methacholine groups. CONCLUSIONS: Bronchoconstriction without additional inflammation induces airway remodeling in patients with asthma. These findings have potential implications for management. Copyright © 2011 Massachusetts Medical Society.

Kerrigan S.,University of Edinburgh | Erridge S.,University of Edinburgh | Liaquat I.,Western General Hospital | Graham C.,Wellcome Trust Clinical Research Facility | Grant R.,University of Edinburgh
Neurology | Year: 2014

Objective: To evaluate the prevalence of mental incapacity to make neuro-oncologic treatment decisions and to identify patients likely to experience difficulty with medical decision-making to enable a more rigorous and focused assessment. Methods: The preoperative mental capacity to give valid consent to neurosurgery of 100 patients with radiologically suspected intracranial tumors was assessed. Mental capacity was formally assessed using the MacArthur Competence Assessment Tool for Treatment (MACCAT-T) conducted by a dual-qualified physician and lawyer. To assess the relationship between cognition and mental capacity, cognitive function was assessed after the MACCAT-T interview using the Addenbrooke's Cognitive Examination-revised (ACE-R). Decisions about capacity made by the assessor were compared with the informal assessment of capacity of the neurosurgical team. Results: Of 100 patients, 25 were identified by the assessor as lacking the necessarymental capacity to give valid consent to neurosurgery. Mental incapacity wasmost common among patients with World Health Organization grade IV tumors (38%) and was more common in men than women (36% of men lacked capacity vs 14% of women). Patients lacking mental capacity were significantly more cognitively impaired than those with capacity (median [interquartile range (IQR)] total ACE-R of 44 [0, 65.5] for incapable patients compared with a median [IQR] total ACE-R score of 88 [82, 95] for patients with capacity). Of 25 patients found to lack capacity by the assessor, 13 (52%) were identified as lacking capacity by the neurosurgical teamand were treated under the provisions of the Adults with Incapacity (Scotland) Act 2000. A score of <4/7 in the semantic verbal fluency subset of the ACE-R (naming up to 10 animals in 1 minute) was predictive of incapacity (96% sensitivity, 63% specificity). Conclusions: Mental incapacity in patients with intracranial tumors is common and is underestimated by clinicians seeking consent for neuro-oncologic treatment. Cognitive impairment is associated with incapacity. We propose a simple, brief cognitive screening test to identify patients who warrant a more rigorous interrogation of their mental capacity as part of the process of seeking consent for neuro-oncologic treatment. © 2014 American Academy of Neurology.

Brady R.R.,Queen Margaret Hospital | Ventham N.T.,Queen Margaret Hospital | Roberts D.M.,Queen Margaret Hospital | Graham C.,Wellcome Trust Clinical Research Facility | Daniel T.,Queen Margaret Hospital
Annals of the Royal College of Surgeons of England | Year: 2012

INTRODUCTION: Reducing exogenously administered opioids in the post-operative period is associated with early return of bowel function and decreased post-operative complication rates. We evaluated the effectiveness of a surgeon-delivered open transversus abdominis plane (TAP) block as a method to reduce post-operative opioid requirements, sedation and inpatient stay. METHODS: The patient cohort was identified from those who had undergone a right hemicolectomy for colonic cancer. Patients received either an open TAP block and post-operative patient controlled anaesthesia (PCA) (n=20) or were part of a control group who received subcutaneous local anaesthetic infiltration and PCA (n=16). RESULTS: PCA morphine use was reduced within the first 24 hours post-operatively in the TAP block group compared with controls (42.1mg vs 72.3mg, p=0.002). Sedation was also reduced significantly in the early post-operative period (p<0.04). There was a non-significant trend towards reduced length of stay in the intervention group (8.2 vs 8.73 days). There were no recorded complications attributable to the open TAP block. CONCLUSIONS: Open TAP blocks are safe and reduce post-operative opioid requirements and sedation after right hemicolectomies. They should be considered as part of a multimodal enhanced recovery approach to patients undergoing abdominal surgery via a transverse incision.

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