Publications by authors named "Ellen Murray"

32 Publications

The Advantages and Challenges of Using Endolysins in a Clinical Setting.

Viruses 2021 04 15;13(4). Epub 2021 Apr 15.

School of Microbiology, University College Cork, T12 YT20 Cork, Ireland.

Antibiotic-resistant pathogens are increasingly more prevalent and problematic. Traditional antibiotics are no longer a viable option for dealing with these multidrug-resistant microbes and so new approaches are needed. Bacteriophage-derived proteins such as endolysins could offer one effective solution. Endolysins are bacteriophage-encoded peptidoglycan hydrolases that act to lyse bacterial cells by targeting their cell's wall, particularly in Gram-positive bacteria due to their naturally exposed peptidoglycan layer. These lytic enzymes have received much interest from the scientific community in recent years for their specificity, mode of action, potential for engineering, and lack of resistance mechanisms. Over the past decade, a renewed interest in endolysin therapy has led to a number of successful applications. Recombinant endolysins have been shown to be effective against prominent pathogens such as MRSA, strains in biofilm formation, and . Endolysins have also been studied in combination with other antimicrobials, giving a synergistic effect. Although endolysin therapy comes with some regulatory and logistical hurdles, the future looks promising, with the emergence of engineered "next-generation" lysins. This review will focus on the likelihood that endolysins will become a viable new antimicrobial therapy and the challenges that may have to be overcome along the way.
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http://dx.doi.org/10.3390/v13040680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071259PMC
April 2021

Tuberculosis Screening, Testing, and Treatment of US Health Care Personnel: ACOEM and NTCA Joint Task Force on Implementation of the 2019 MMWR Recommendations.

J Occup Environ Med 2020 07;62(7):e355-e369

American College of Occupational and Environmental Medicine, Elk Grove, Illinois.

: On May 17, 2019, the US Centers for Disease Control and Prevention and National Tuberculosis Controllers Association issued new Recommendations for Tuberculosis Screening, Testing, and Treatment of Health Care Personnel, United States, 2019, updating the health care personnel-related sections of the Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health-Care Settings, 2005. This companion document offers the collective effort and experience of occupational health, infectious disease, and public health experts from major academic and public health institutions across the United States and expands on each section of the 2019 recommendations to provide clarifications, explanations, and considerations that go beyond the 2019 recommendations to answer questions that may arise and to offer strategies for implementation.
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http://dx.doi.org/10.1097/JOM.0000000000001904DOI Listing
July 2020

Anisotropic Synthesis of Armchair Graphene Nanoribbon Arrays from Sub-5 nm Seeds at Variable Pitches on Germanium.

J Phys Chem Lett 2019 Aug 17;10(15):4266-4272. Epub 2019 Jul 17.

Department of Materials Science & Engineering , University of Wisconsin-Madison , Madison , Wisconsin 53706 , United States.

At widths below 10 nm, armchair graphene nanoribbons become semiconductors. One promising route to synthesize nanoribbons is chemical vapor deposition (CVD) of hydrocarbons on Ge(001), and synthesis from seeds reduces nanoribbon polydispersity. In this contribution, we advance the seed-initiated synthesis of nanoribbons and explore the impact of seed size and nanoribbon spacing on growth kinetics. Periodic arrays of graphene seeds are lithographically patterned and etched to reduce their diameter. The viability of initiating synthesis from sub-5 nm seeds is demonstrated, and the pitch between nanoribbons is reduced from 500 to 50 nm to show that crowding effects do not perturb nanoribbon growth kinetics. The invariance of kinetics with pitch in combination with density functional theory (DFT) calculations indicate that (1) the growth species for synthesis has a diffusion length of ≪50 nm and/or (2) the kinetics are strongly attachment-limited. These results demonstrate that seed-initiated synthesis on Ge(001) is a promising route for creating dense arrays of armchair graphene nanoribbons for semiconductor electronics applications.
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http://dx.doi.org/10.1021/acs.jpclett.9b01079DOI Listing
August 2019

Alignment of semiconducting graphene nanoribbons on vicinal Ge(001).

Nanoscale 2019 Mar;11(11):4864-4875

Department of Materials Science and Engineering, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.

Chemical vapor deposition of CH4 on Ge(001) can enable anisotropic growth of narrow, semiconducting graphene nanoribbons with predominately smooth armchair edges and high-performance charge transport properties. However, such nanoribbons are not aligned in one direction but instead grow perpendicularly, which is not optimal for integration into high-performance electronics. Here, it is demonstrated that vicinal Ge(001) substrates can be used to synthesize armchair nanoribbons, of which ∼90% are aligned within ±1.5° perpendicular to the miscut. When the growth rate is slow, graphene crystals evolve as nanoribbons. However, as the growth rate increases, the uphill and downhill crystal edges evolve asymmetrically. This asymmetry is consistent with stronger binding between the downhill edge and the Ge surface, for example due to different edge termination as shown by density functional theory calculations. By tailoring growth rate and time, nanoribbons with sub-10 nm widths that exhibit excellent charge transport characteristics, including simultaneous high on-state conductance of 8.0 μS and a high on/off conductance ratio of 570 in field-effect transistors, are achieved. Large-area alignment of semiconducting ribbons with promising charge transport properties is an important step towards understanding the anisotropic nanoribbon growth and integrating these materials into scalable, future semiconductor technologies.
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http://dx.doi.org/10.1039/c9nr00713jDOI Listing
March 2019

Genomic Investigation of a Outbreak Involving Prison and Community Cases in Florida, United States.

Am J Trop Med Hyg 2018 10;99(4):867-874

Division of Infectious Diseases and Global Medicine, College of Medicine, University of Florida, Gainesville, Florida.

We used whole-genome sequencing to investigate a tuberculosis outbreak involving U.S.-born persons in the prison system and both U.S.- and foreign-born persons in the community in Florida over a 7-year period (2009-2015). Genotyping by spacer oligonucleotide typing and 24-locus mycobacterial interspersed repetitive unit-variable number tandem repeat suggested that the outbreak might be clonal in origin. However, contact tracing could not link the two populations. Through a multidisciplinary approach, we showed that the cluster involved distinct bacterial transmission networks segregated by country of birth. The source strain is of foreign origin and circulated in the local Florida community for more than 20 years before introduction into the prison system. We also identified novel transmission links involving foreign and U.S.-born cases not discovered during contact investigation. Our data highlight the potential for spread of strains originating from outside the United States into U.S. "high-risk" populations, such as prisoners, with subsequent movement back to the general community.
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http://dx.doi.org/10.4269/ajtmh.17-0700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159577PMC
October 2018

Monocyte Function and Clinical Outcomes in Febrile and Afebrile Patients With Severe Sepsis.

Shock 2018 10;50(4):381-387

Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri.

Introduction: Absence of fever is associated with higher mortality in septic patients, but the reason for this is unknown. Immune dysfunction may be a potential link between failure to mount a fever and poor outcomes. The purpose of this study was to evaluate monocyte function and clinical surrogates of immunity (i.e., mortality and acquisition of secondary infections) in febrile and afebrile septic patients.

Methods: Single-center, prospective cohort study of 92 critically ill septic patients. Patients were categorized into febrile (≥38.0°C) and afebrile (<38.0°C) groups based on temperature measurements within 24 hours of sepsis diagnosis. HLA-DR expression and LPS-induced TNF-α production were quantified on days 1-2, days 3-4, and days 6-8 after sepsis diagnosis. A repeated measures mixed models analysis was used to compare these markers between the two groups.

Results: Forty-four patients (47.8%) developed a fever within 24 h of sepsis diagnosis. There were no significant differences in HLA-DR expression or LPS-induced TNF-α production between febrile and afebrile patients at any individual time point. However, HLA-DR expression significantly increased between days 1-2 and days 6-8 (median difference 8118 [IQR 1,662, 9,878] antibodies/cell, P = 0.002) in febrile patients, but not in afebrile patients (median difference 403 [-3,382, 3,507] antibodies/cell, P = 0.25). Afebrile patients demonstrated higher 28-day mortality (37.5% vs 18.2%) and increased acquisition of secondary infections (35.4% vs. 15.9%).

Conclusions: Absence of fever is associated with suppressed HLA-DR expression over time, a finding suggestive of monocyte dysfunction in sepsis, as well as worse clinical outcomes.
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http://dx.doi.org/10.1097/SHK.0000000000001083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999533PMC
October 2018

Antipyretic Therapy in Critically Ill Septic Patients: A Systematic Review and Meta-Analysis.

Crit Care Med 2017 May;45(5):806-813

1Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO. 2Departments of Emergency Medicine and Anesthesiology, Washington University School of Medicine, St. Louis, MO. 3University of Missouri-Columbia School of Medicine, Columbia, MO. 4Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO. 5Bernard Becker Medical Library, Washington University School of Medicine, St. Louis, MO.

Objective: This meta-analysis aimed to examine the impact of antipyretic therapy on mortality in critically ill septic adults.

Data Sources: Literature searches were implemented in Ovid Medline, Embase, Scopus, Cumulative Index of Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, and ClinicalTrials.gov through February 2016.

Study Selection: Inclusion criteria were observational or randomized studies of septic patients, evaluation of antipyretic treatment, mortality reported, and English-language version available. Studies were excluded if they enrolled pediatric patients, patients with neurologic injury, or healthy volunteers. Criteria were applied by two independent reviewers.

Data Extraction: Two reviewers independently extracted data and evaluated methodologic quality. Outcomes included mortality, frequency of shock reversal, acquisition of nosocomial infections, and changes in body temperature, heart rate, and minute ventilation. Randomized and observational studies were analyzed separately.

Data Synthesis: Eight randomized studies (1,507 patients) and eight observational studies (17,432 patients) were analyzed. Antipyretic therapy did not reduce 28-day/hospital mortality in the randomized studies (relative risk, 0.93; 95% CI, 0.77-1.13; I = 0.0%) or observational studies (odds ratio, 0.90; 95% CI, 0.54-1.51; I = 76.1%). Shock reversal (relative risk, 1.13; 95% CI, 0.68-1.90; I = 51.6%) and acquisition of nosocomial infections (relative risk, 1.13; 95% CI, 0.61-2.09; I = 61.0%) were also unchanged. Antipyretic therapy decreased body temperature (mean difference, -0.38°C; 95% CI, -0.63 to -0.13; I = 84.0%), but not heart rate or minute ventilation.

Conclusions: Antipyretic treatment does not significantly improve 28-day/hospital mortality in adult patients with sepsis.
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http://dx.doi.org/10.1097/CCM.0000000000002285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389594PMC
May 2017

Comparison of monocyte human leukocyte antigen-DR expression and stimulated tumor necrosis factor alpha production as outcome predictors in severe sepsis: a prospective observational study.

Crit Care 2016 10 20;20(1):334. Epub 2016 Oct 20.

Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid, St. Louis, MO, USA.

Background: Identifying patients in the immunosuppressive phase of sepsis is essential for development of immunomodulatory therapies. Little data exists comparing the ability of the two most well-studied markers of sepsis-induced immunosuppression, human leukocyte antigen (HLA)-DR expression and lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-ɑ) production, to predict mortality and morbidity. The purpose of this study was to compare HLA-DR expression and LPS-induced TNF-ɑ production as predictors of 28-day mortality and acquisition of secondary infections in adult septic patients.

Methods: A single-center, prospective observational study of 83 adult septic patients admitted to a medical or surgical intensive care unit. Blood samples were collected at three time points during the septic course (days 1-2, days 3-4, and days 6-8 after sepsis diagnosis) and assayed for HLA-DR expression and LPS-induced TNF-ɑ production. A repeated measures mixed model analysis was used to compare values of these immunological markers among survivors and non-survivors and among those who did and did not develop a secondary infection.

Results: Twenty-five patients (30.1 %) died within 28 days of sepsis diagnosis. HLA-DR expression was significantly lower in non-survivors as compared to survivors on days 3-4 (p = 0.04) and days 6-8 (p = 0.002). The change in HLA-DR from days 1-2 to days 6-8 was also lower in non-survivors (p = 0.04). Median HLA-DR expression decreased from days 1-2 to days 3-4 in patients who developed secondary infections while it increased in those without secondary infections (p = 0.054). TNF-ɑ production did not differ between survivors and non-survivors or between patients who did and did not develop a secondary infection.

Conclusions: Monocyte HLA-DR expression may be a more accurate predictor of mortality and acquisition of secondary infections than LPS-stimulated TNF-ɑ production in adult medical and surgical critically ill patients.
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http://dx.doi.org/10.1186/s13054-016-1505-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5072304PMC
October 2016

Controlled delivery of antibodies from injectable hydrogels.

Mater Sci Eng C Mater Biol Appl 2016 Feb 30;59:801-806. Epub 2015 Oct 30.

Department of Chemical & Biological Engineering, Colorado School of Mines, 1613 Illinois Street, Golden, CO 80401, United States. Electronic address:

Therapeutic antibodies are currently used for the treatment of various diseases, but large doses delivered systemically are typically required. Localized controlled delivery techniques would afford major benefits such as decreasing side effects and required doses. Injectable biopolymer systems are an attractive solution due to their minimally invasive potential for controlled release in a localized area. Here, alginate-chitosan hydrogels are demonstrated to provide controlled delivery of IgG model antibodies and also of Fab antibody fragments. Also, an alternate delivery system comprised of poly(lactic-co-glycolic acid) (PLGA) microspheres loaded with antibodies and encapsulated in alginate was shown to successfully provide another level of control over release. These biopolymer systems that offer controlled delivery for antibodies and antibody fragments will be promising for many applications in drug delivery and regenerative medicine.
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http://dx.doi.org/10.1016/j.msec.2015.10.096DOI Listing
February 2016

Assessing the utility of an online registry for patients monitoring their own warfarin therapy.

J Clin Pathol 2016 Apr 30;69(4):331-6. Epub 2015 Oct 30.

Department of Primary Care Clinical Sciences, University of Birmingham, Birmingham, UK.

Aims: To evaluate the utility of an online self-report registry for patient self-monitoring and self-management (PSM) of warfarin therapy.

Methods: A prospective observational study of UK-based patients undertaking PSM and recording their international normalised ratio (INR) data via an online registry. Consenting participants recorded INR test dates, results and warfarin dosages using the online registry for a period of 12 months. Participants reported demographic data, disease characteristics and treatment-related adverse events and provided feedback via a survey. Data accuracy was assessed through comparison of INR results recorded online with results stored on 19 INR testing devices. Percentage time spent within therapeutic time in range (TTR) was also examined.

Results: Eighty-seven per cent (39/45) completed the study period. Age ranged from 26 to 83 years, 44% had undertaken PSM for >5 years. Sixty-six per cent (25/38) reported that the registry was easy to navigate and use. Forty-two participants contributed a total of 1669 INR results. Agreement between self-reported INR results and source INR data was high (99%). Mean TTR was 76% (SD 18.58) with 83% having >60% TTR.

Conclusions: Findings suggest that an online PSM registry is feasible, accurate and acceptable to patients. These findings require confirmation in a larger cohort of PSM patients. An online self-report registry could provide a valuable resource for gathering real world evidence of clinical effectiveness and safety of these developing models of care.
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http://dx.doi.org/10.1136/jclinpath-2015-203168DOI Listing
April 2016

Possible role of the microbiome in the development of acute malnutrition and implications for food-based strategies to prevent and treat acute malnutrition.

Food Nutr Bull 2015 Mar;36(1 Suppl):S72-5

A pattern of changes in the microbiome composition have been observed in the normal maturation of the human gut. Perturbations from this pattern have been described in malnourished humans and reproduced in animal models of severe malnutrition. Treatment and prevention of malnutrition in the future may be more effective if the interventions not only restore body composition, but the composition of the microbiome as well.
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http://dx.doi.org/10.1177/15648265150361S112DOI Listing
March 2015

Extending supplementary feeding for children younger than 5 years with moderate acute malnutrition leads to lower relapse rates.

J Pediatr Gastroenterol Nutr 2015 Apr;60(4):544-9

*Department of Pediatrics, Washington University, St Louis, MO †Department of Community Health, University of Malawi, Blantyre, Malawi.

Objectives: Children with moderate acute malnutrition (MAM) have a high rate of relapse and death in the year following recovery. In this pilot study, we evaluate the long-term benefits of an extended course of nutritional therapy for children with MAM.

Methods: Rural Malawian children 6 to 59 months old with MAM, defined as a weight-for-height z score (WHZ) between -2 and -3, were provided supplementary feeding for a fixed duration of 12 weeks. The children were then studied for 12 months to assess long-term nutritional status, and compared with children initially treated only until they first reached WHZ > -2.

Results: Compared with children treated until they reached WHZ > -2, children treated for 12 weeks were more likely to remain well nourished (71% vs 63%, P = 0.0015) and maintain more normal anthropometric indices during 12 months of follow-up; there was also a trend towards lower rates of severe acute malnutrition (7% vs 10%, P = 0.067) and death (2% vs 4%, P = 0.082). Regression modeling showed that mid-upper arm circumference and WHZ at the end of supplementary feeding were the most important factors in predicting which children remained well nourished (P < 0.001 for each).

Conclusions: The duration of supplementary feeding for children with MAM may not be as important as their anthropometry in terms of remaining well nourished after initial recovery. The presently accepted recovery criteria of WHZ of -2 may be insufficient for ensuring long-term nutritional health; consideration should be given to setting higher recovery criteria.
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http://dx.doi.org/10.1097/MPG.0000000000000639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380557PMC
April 2015

Home-based therapy for severe acute malnutrition with ready-to-use food.

Paediatr Int Child Health 2014 Nov 28;34(4):266-70. Epub 2014 Jul 28.

Severe acute malnutrition is a devastating condition afflicting under-5 children in many developing countries, but concentrated in sub-Saharan Africa. This paper examines the development of home-based lipid-nutrient therapeutic foods for the treatment of acute malnutrition in sub-Saharan Africa and the adoption of these therapies as a standard of care for non-complicated cases of acute malnutrition. Several of the early key clinical and operational effectiveness trials are discussed as well as the adoption of home-based treatment as a standard operating procedure in regions where malnutrition is present.
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http://dx.doi.org/10.1179/2046905514Y.0000000135DOI Listing
November 2014

Zinc or albendazole attenuates the progression of environmental enteropathy: a randomized controlled trial.

Clin Gastroenterol Hepatol 2014 Sep 22;12(9):1507-13.e1. Epub 2014 Jan 22.

Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri; Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas; Department of Community Health, University of Malawi College of Medicine, Blantyre, Malawi. Electronic address:

Background & Aims: Environmental enteropathy (EE) is a subclinical condition among children in the developing world, characterized by T-cell infiltration of the small-bowel mucosa and diffuse villous atrophy. EE leads to macronutrient and micronutrient malabsorption and stunting, with a resultant increased risk for infection and reduced cognitive development. We tested the hypothesis that zinc and albendazole treatments would reduce the severity of EE in rural African children.

Methods: In a randomized, double-blind, placebo-controlled trial in rural southern Malawi, asymptomatic children, 1 to 3 years old and at high risk for EE, received either a single dose of albendazole, a 14-day course of 20 mg zinc sulfate, or a placebo. Subjects were given the dual-sugar absorption test, and the ratio of lactulose to mannitol (L:M) in urine was used to determine the severity of EE at baseline and 34 days after completion of the assigned regimen. The primary outcome was the change in the L:M.

Results: A complete set of urine samples was obtained from 222 of 234 children enrolled and analyzed. The mean baseline L:M was 0.32 ± 0.18 among all children and did not differ among groups (normal L:M range, <0.12). At the end of the study, the L:M ratio had increased more in the placebo group (0.12 ± 0.31) than in the zinc group (0.03 ± 0.20; P < .03) or the albendazole group (0.04 ± 0.22; P < .04).

Conclusions: Treatment with zinc or albendazole protects against a significant increase in the L:M ratio, a biomarker for EE, in asymptomatic rural Malawian children. These findings could provide insight into the etiology and pathogenesis of EE. Clinicaltrials.gov Number: NCT01440608.
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http://dx.doi.org/10.1016/j.cgh.2014.01.024DOI Listing
September 2014

An international longitudinal registry of patients with atrial fibrillation at risk of stroke (GARFIELD): the UK protocol.

BMC Cardiovasc Disord 2013 Apr 23;13:31. Epub 2013 Apr 23.

Primary Care Clinical Sciences, School of Health and Population Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.

Background: Atrial fibrillation (AF) is an independent risk factor for stroke and a significant predictor of mortality. Evidence-based guidelines for stroke prevention in AF recommend antithrombotic therapy corresponding to the risk of stroke. In practice, many patients with AF do not receive the appropriate antithrombotic therapy and are left either unprotected or inadequately protected against stroke. The purpose of the Global Anticoagulant Registry in the FIELD (GARFIELD) is to determine the real-life management and outcomes of patients newly diagnosed with non-valvular AF.

Methods/design: GARFIELD is an observational, international registry of newly diagnosed AF patients with at least one additional investigator-defined risk factor for stroke. The aim is to enrol 55,000 patients at more than 1000 centres in 50 countries worldwide. Enrolment will take place in five independent, sequential, prospective cohorts; the first cohort includes a retrospective validation cohort. Each cohort will be followed up for 2 years. The UK stands to be a significant contributor to GARFIELD, aiming to enrol 4,582 patients, and reflecting the care environment in which patients with AF are managed. The UK protocol will also focus on better understanding the validity of the two main stroke risk scores (CHADS2 and CHA2DS2VASC) and the HAS-BLED bleeding risk score, in the context of a diverse patient population.

Discussion: The GARFIELD registry will describe how therapeutic strategies, patient care, and clinical outcomes evolve over time. This study will provide UK-specific comprehensive data that will allow a range of evaluations both at a national level and in relation to global data and contribute to a better understanding of AF management in the UK.

Trial Registration: ClinicalTrial.gov: NCT01090362.
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http://dx.doi.org/10.1186/1471-2261-13-31DOI Listing
April 2013

ExPeKT--Exploring prevention and knowledge of venous thromboembolism: a two-stage, mixed-method study protocol.

BMJ Open 2013 2;3(4). Epub 2013 Apr 2.

Primary Care Clinical Sciences, University of Birmingham, Birmingham, UK.

Introduction: There is little awareness of venous thromboembolism (VTE) in the public arena. Most commonly known causes are-travellers' thrombosis and thrombosis associated with oral contraception, both frequently referred to in the media. However, VTE is a substantial healthcare problem, resulting in mortality, morbidity and economic cost. Most hospitalised patients have one or more risk factors for VTE. Around 60% of people undergoing hip or knee replacement will suffer a deep vein thrombosis without preventative intervention. Studies demonstrate a risk reduction for VTE of up to 70% with preventative medicine for medical and surgical conditions: cancer, orthopaedic surgery, general surgery and acutely ill medical admissions. Results will be used to identify methods of increasing knowledge of VTE prevention and for the development of educational and patient information materials.

Methods And Analysis: A two-stage, mixed-method study using surveys with primary healthcare professionals and patients followed by interviews with primary healthcare professionals, patients, acute trusts and other relevant organisations. Survey and qualitative interview data will examine the current practice of thromboprophylaxis, and the knowledge and experience of VTE prevention for the development of education initiatives for primary healthcare professionals and patients to adopt thromboprophylaxis outside the hospital setting. As this is a scientific exploratory study for the generation, rather than testing, of new hypotheses a sample-size analysis is not called for. Survey data will be analysed using SPSS version 20. Open-ended responses will be analysed using qualitative thematic methods. The recorded and transcribed semistructured interview data will be analysed using constant comparative methods.

Ethics And Dissemination: Ethics approval has been provided by the National Research Ethics Committee (reference: 11/H0605/5) and site-specific R&D approval granted by the relevant R&D National Health Service trusts. Findings will be disseminated at healthcare and academic conferences and written for peer-reviewed publication.

Trial Grant Number: NIHR RP-PG-0608-10073.
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http://dx.doi.org/10.1136/bmjopen-2013-002766DOI Listing
April 2013

Trial Protocol: a randomised controlled trial of extended anticoagulation treatment versus routine anticoagulation treatment for the prevention of recurrent VTE and post thrombotic syndrome in patients being treated for a first episode of unprovoked VTE (The ExACT Study).

BMC Cardiovasc Disord 2013 Mar 9;13:16. Epub 2013 Mar 9.

Primary Care Clinical Sciences, School of Health and Population Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

Background: Venous thromboembolism comprising pulmonary embolism and deep vein thrombosis is a common condition with an incidence of approximately 1 per 1,000 per annum causing both mortality and serious morbidity. The principal aim of treatment of a venous thromboembolism with heparin and warfarin is to prevent extension or recurrence of clot. However, the recurrence rate following a deep vein thrombosis remains approximately 10% per annum following treatment cessation irrespective of the duration of anticoagulation therapy. Patients with raised D-dimer levels after discontinuing oral anticoagulation treatment have also been shown to be at high risk of recurrence.Post thrombotic syndrome is a complication of a deep vein thrombosis which can lead to chronic venous insufficiency and ulceration. It has a cumulative incidence after 2 years of around 25% and it has been suggested that extended oral anticoagulation should be investigated as a possible preventative measure.

Methods/design: Patients with a first idiopathic venous thromboembolism will be recruited through anticoagulation clinics and randomly allocated to either continuing or discontinuing warfarin treatment for a further 2 years and followed up on a six monthly basis. At each visit D-dimer levels will be measured using a Roche Cobas h 232 POC device. In addition a venous sample will be taken for laboratory D-dimer analysis at the end of the study. Patients will be examined for signs and symptoms of PTS using the Villalta scale and complete VEINES and EQ5D quality of life questionnaires.

Discussion: The primary aim of the study is to investigate whether extending oral anticoagulation treatment (prior to discontinuing treatment) beyond 3-6 months for patients with a first unprovoked proximal deep vein thrombosis or pulmonary embolism prevents recurrence. The study will also determine the role of extending anticoagulation for patients with elevated D-dimer levels prior to discontinuing treatment and identify the potential of D-dimer point of care testing for identification of high risk patients within a primary care setting.

Trial Registration: ISRCTN73819751.
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http://dx.doi.org/10.1186/1471-2261-13-16DOI Listing
March 2013

The representation of health professionals on governing boards of health care organizations in New York City.

J Urban Health 2013 Oct;90(5):888-901

Center for Health Media and Policy, Hunter College, City University of New York, 425 E. 25th Street, Box 837, New York, NY, 10010, USA,

The Representation of Health Professionals on Governing Boards of Health Care Organizations in New York City. The heightened importance of processes and outcomes of care-including their impact on health care organizations' (HCOs) financial health-translate into greater accountability for clinical performance on the part of HCO leaders, including their boards, during an era of health care reform. Quality and safety of care are now fiduciary responsibilities of HCO board members. The participation of health professionals on HCO governing bodies may be an asset to HCO governing boards because of their deep knowledge of clinical problems, best practices, quality indicators, and other issues related to the safety and quality of care. And yet, the sparse data that exist indicate that physicians comprise more than 20 % of the governing board members of hospitals while less than 5 % are nurses and no data exist on other health professionals. The purpose of this two-phased study is to examine health professionals' representations on HCOs-specifically hospitals, home care agencies, nursing homes, and federally qualified health centers-in New York City. Through a survey of these organizations, phase 1 of the study found that 93 % of hospitals had physicians on their governing boards, compared with 26 % with nurses, 7 % with dentists, and 4 % with social workers or psychologists. The overrepresentation of physicians declined with the other HCOs. Only 38 % of home care agencies had physicians on their governing boards, 29 % had nurses, and 24 % had social workers. Phase 2 focused on the barriers to the appointment of health professionals to governing boards of HCOs and the strategies to address these barriers. Sixteen health care leaders in the region were interviewed in this qualitative study. Barriers included invisibility of health professionals other than physicians; concerns about "special interests"; lack of financial resources for donations to the organization; and lack of knowledge and skills with regard to board governance, especially financial matters. Strategies included developing an infrastructure for preparing and getting appointed various health professionals, mentoring, and developing a personal plan of action for appointments.
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http://dx.doi.org/10.1007/s11524-012-9772-9DOI Listing
October 2013

Point of Care INR testing devices: performance of the Roche CoaguChek XS and XS Plus in the UK NEQAS BC external quality assessment programme for healthcare professionals: four years' experience.

J Clin Pathol 2012 Dec 4;65(12):1119-23. Epub 2012 Oct 4.

Point of Care, UK National External Quality Assessment Scheme for Blood Coagulation, Sheffield, UK.

Background: Vitamin K antagonists have been used for many decades and have been traditionally monitored by the measurement of the International Normalised Ratio (INR) in the laboratory. Introduction of Point of Care (POC) testing devices to measure INR has resulted in many tests being undertaken in primary care. External Quality Assessment (EQA) of these POC devices is recommended to ensure accuracy and reliability of INR results outside a laboratory setting.

Aim: To assess the quality of INR results for users of two POC devices (CoaguChek XS and CoaguChek XS Plus) over a four-year period.

Methods: Four surveys (two samples) were sent in each 12-month period. The median INR value of each sample was calculated and the percentage deviation from this median determined. Any results greater than 15% from the median were considered to be outside consensus which indicated a possible problem within the testing system.

Results: Variability of INR results in this UK National External Quality Assessment Scheme (NEQAS) programme was comparable to that in the UK NEQAS EQA programme for laboratory INR testing. Occurrence of persistent problems was lower in the POC programme than the laboratory programme.

Conclusions: Utilisation of an EQA programme for POC devices in primary care is feasible and necessary. Our data suggest for those health professionals using EQA, the reliability and accuracy of INR testing matches the quality of laboratory testing.
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http://dx.doi.org/10.1136/jclinpath-2012-201049DOI Listing
December 2012

Thromboembolism.

Am Fam Physician 2012 Jan;85(2):188-90

University of Birmingham, Birmingham, United Kingdom.

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January 2012

Thromboembolism.

BMJ Clin Evid 2011 Mar 8;2011. Epub 2011 Mar 8.

Primary Care Clinical Sciences, University of Birmingham, Birmingham, UK.

Introduction: Deep venous thrombosis (DVT) or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. Around 5% to 15% of people with untreated DVT may die from pulmonary embolism. Risk factors for DVT include immobility, surgery (particularly orthopaedic), malignancy, pregnancy, older age, and inherited or acquired prothrombotic clotting disorders.

Methods And Outcomes: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for proximal DVT? What are the effects of treatments for isolated calf DVT? What are the effects of treatments for pulmonary embolism? What are the effects of interventions on oral anticoagulation management in people with thromboembolism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results: We found 45 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions: In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticoagulation; compression stockings; low molecular weight heparin (short and long term, once or twice daily, and home treatment); oral anticoagulants (short and long term, high intensity, abrupt discontinuation, and computerised decision support); prolonged duration of anticoagulation; thrombolysis; vena cava filters; and warfarin.
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March 2011

Does self-management of oral anticoagulation therapy improve quality of life and anxiety?

Fam Pract 2011 Apr 10;28(2):134-40. Epub 2010 Nov 10.

Primary Care Clinical Sciences, School of Health and Population Sciences, Primary Care Clinical Sciences Building, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

Background: Research related to service requirements for anticoagulation management has focussed on clinical and health economic outcomes and paid little attention to the impact of treatment and service delivery on patients' quality of life. This was the first large UK study to evaluate the effect of patient self-management (PSM) of oral anticoagulation on treatment-related quality of life (TRQoL) and anxiety in comparison with routine care (RC) and to explore the effect of level of therapeutic control on TRQoL and anxiety across and within each model of care.

Methods: A quantitative survey, set in primary care in the West Midlands. The subjects were 517 randomized controlled trial participants, 242 receiving PSM and 275 RC. Postal questionnaires at baseline and 12 months comprised the State Trait Anxiety Inventory and a treatment-specific measure of positive (satisfaction and self-efficacy) and negative aspects (daily hassles, strained social network and psychological distress) of TRQoL. Change in anxiety and TRQoL scores were compared between PSM and RC. Subgroup analysis was based upon level of therapeutic control (high, medium and low).

Results: Overall, 83% (n = 202) PSM and 55% (n = 161) RC patients contributed data. Anxiety scores were similar in both groups. PSM demonstrated greater improvement in self-efficacy than RC across the study period. A statistically significant between-group difference (PSM versus RC) in the self-efficacy also existed in subgroups with medium and high levels of therapeutic control.

Conclusions: PSM is not associated with increased anxiety and has a positive effect upon some aspects of TRQoL compared to RC.
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http://dx.doi.org/10.1093/fampra/cmq089DOI Listing
April 2011

Thromboembolism.

BMJ Clin Evid 2009 Mar 9;2009. Epub 2009 Mar 9.

Department of Primary Care and General Practice, The Medical School, University of Birmingham, Birmingham, UK.

Introduction: DVT or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. Around 5-15% of people with untreated DVT may die from pulmonary embolism. Risk factors for deep vein thrombosis include immobility, surgery (particularly orthopaedic), malignancy, pregnancy, older age, and inherited or acquired prothrombotic clotting disorders.

Methods And Outcomes: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for: proximal deep vein thrombosis; isolated calf deep vein thrombosis; and pulmonary embolism? What are the effects of computerised decision support on oral anticoagulation management? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results: We found 40 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions: In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticoagulation, compression stockings, low molecular weight heparin (short and long term, once or twice daily, home treatment), oral anticoagulants (short and long term, high intensity, abrupt discontinuation, computerised decision support), prolonged duration of anticoagulation, thrombolysis, vena cava filters, and warfarin.
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March 2009

Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial.

Lancet 2007 Aug;370(9586):493-503

Primary Care Clinical Sciences, University of Birmingham, Birmingham, UK.

Background: Anticoagulants are more effective than antiplatelet agents at reducing stroke risk in patients with atrial fibrillation, but whether this benefit outweighs the increased risk of bleeding in elderly patients is unknown. We assessed whether warfarin reduced risk of major stroke, arterial embolism, or other intracranial haemorrhage compared with aspirin in elderly patients.

Methods: 973 patients aged 75 years or over (mean age 81.5 years, SD 4.2) with atrial fibrillation were recruited from primary care and randomly assigned to warfarin (target international normalised ratio 2-3) or aspirin (75 mg per day). Follow-up was for a mean of 2.7 years (SD 1.2). The primary endpoint was fatal or disabling stroke (ischaemic or haemorrhagic), intracranial haemorrhage, or clinically significant arterial embolism. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN89345269.

Findings: There were 24 primary events (21 strokes, two other intracranial haemorrhages, and one systemic embolus) in people assigned to warfarin and 48 primary events (44 strokes, one other intracranial haemorrhage, and three systemic emboli) in people assigned to aspirin (yearly risk 1.8%vs 3.8%, relative risk 0.48, 95% CI 0.28-0.80, p=0.003; absolute yearly risk reduction 2%, 95% CI 0.7-3.2). Yearly risk of extracranial haemorrhage was 1.4% (warfarin) versus 1.6% (aspirin) (relative risk 0.87, 0.43-1.73; absolute risk reduction 0.2%, -0.7 to 1.2).

Interpretation: These data support the use of anticoagulation therapy for people aged over 75 who have atrial fibrillation, unless there are contraindications or the patient decides that the benefits are not worth the inconvenience.
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http://dx.doi.org/10.1016/S0140-6736(07)61233-1DOI Listing
August 2007

Screening versus routine practice in detection of atrial fibrillation in patients aged 65 or over: cluster randomised controlled trial.

BMJ 2007 Aug 2;335(7616):383. Epub 2007 Aug 2.

Department of Primary Care and General Practice, University of Birmingham, Birmingham B15 2TT.

Objectives: To assess whether screening improves the detection of atrial fibrillation (cluster randomisation) and to compare systematic and opportunistic screening.

Design: Multicentred cluster randomised controlled trial, with subsidiary trial embedded within the intervention arm.

Setting: 50 primary care centres in England, with further individual randomisation of patients in the intervention practices.

Participants: 14,802 patients aged 65 or over in 25 intervention and 25 control practices.

Interventions: Patients in intervention practices were randomly allocated to systematic screening (invitation for electrocardiography) or opportunistic screening (pulse taking and invitation for electrocardiography if the pulse was irregular). Screening took place over 12 months in each practice from October 2001 to February 2003. No active screening took place in control practices.

Main Outcome Measure: Newly identified atrial fibrillation.

Results: The detection rate of new cases of atrial fibrillation was 1.63% a year in the intervention practices and 1.04% in control practices (difference 0.59%, 95% confidence interval 0.20% to 0.98%). Systematic and opportunistic screening detected similar numbers of new cases (1.62% v 1.64%, difference 0.02%, -0.5% to 0.5%).

Conclusion: Active screening for atrial fibrillation detects additional cases over current practice. The preferred method of screening in patients aged 65 or over in primary care is opportunistic pulse taking with follow-up electrocardiography.

Trial Registration: Current Controlled Trials ISRCTN19633732 [controlled-trials.com].
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http://dx.doi.org/10.1136/bmj.39280.660567.55DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1952508PMC
August 2007

Accuracy of diagnosing atrial fibrillation on electrocardiogram by primary care practitioners and interpretative diagnostic software: analysis of data from screening for atrial fibrillation in the elderly (SAFE) trial.

BMJ 2007 Aug 29;335(7616):380. Epub 2007 Jun 29.

Department of Primary Care and General Practice, University of Birmingham, Birmingham B15 2TT.

Objective: To assess the accuracy of general practitioners, practice nurses, and interpretative software in the use of different types of electrocardiogram to diagnose atrial fibrillation.

Design: Prospective comparison with reference standard of assessment of electrocardiograms by two independent specialists.

Setting: 49 general practices in central England.

Participants: 2595 patients aged 65 or over screened for atrial fibrillation as part of the screening for atrial fibrillation in the elderly (SAFE) study; 49 general practitioners and 49 practice nurses.

Interventions: All electrocardiograms were read with the Biolog interpretative software, and a random sample of 12 lead, limb lead, and single lead thoracic placement electrocardiograms were assessed by general practitioners and practice nurses independently of each other and of the Biolog assessment.

Main Outcome Measures: Sensitivity, specificity, and positive and negative predictive values.

Results: General practitioners detected 79 out of 99 cases of atrial fibrillation on a 12 lead electrocardiogram (sensitivity 80%, 95% confidence interval 71% to 87%) and misinterpreted 114 out of 1355 cases of sinus rhythm as atrial fibrillation (specificity 92%, 90% to 93%). Practice nurses detected a similar proportion of cases of atrial fibrillation (sensitivity 77%, 67% to 85%), but had a lower specificity (85%, 83% to 87%). The interpretative software was significantly more accurate, with a specificity of 99%, but missed 36 of 215 cases of atrial fibrillation (sensitivity 83%). Combining general practitioners' interpretation with the interpretative software led to a sensitivity of 92% and a specificity of 91%. Use of limb lead or single lead thoracic placement electrocardiograms resulted in some loss of specificity.

Conclusions: Many primary care professionals cannot accurately detect atrial fibrillation on an electrocardiogram, and interpretative software is not sufficiently accurate to circumvent this problem, even when combined with interpretation by a general practitioner. Diagnosis of atrial fibrillation in the community needs to factor in the reading of electrocardiograms by appropriately trained people.
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http://dx.doi.org/10.1136/bmj.39227.551713.AEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1952490PMC
August 2007

Patient self-management of anticoagulation therapy: a trial-based cost-effectiveness analysis.

Br J Haematol 2006 Sep;134(6):632-9

Health Economics Facility, Health Services Management Centre, University of Birmingham, Birmingham, UK.

Demand for anticoagulation management is increasing due to an expansion of clinical indications for therapy. One possible model of care to meet demand is patient self-management (PSM), beneficial to patients who need control over their condition. This study aimed to determine the cost and cost-effectiveness of PSM of anticoagulation compared with routine clinic-based care for patients receiving long-term anticoagulation. A cost-utility analysis was conducted alongside a randomised controlled trial; 617 patients were recruited and followed up for 12 months. There was no significant difference in mean quality-adjusted life years (QALYs) between groups - after adjusting for baseline, the mean difference in QALYs was 0.009 (95% CI, -0.012 to 0.030). Overall mean healthcare costs in the PSM arm were significantly higher at pounds sterling 417 (CI pounds sterling 394- pounds sterling 442) compared with pounds sterling 122 (CI pounds sterling 103- pounds sterling 144) in the control arm. Therefore, using a formal cost-effectiveness analysis, PSM of anticoagulation does not appear to be cost-effective. However, PSM may have other benefits in relieving pressure on traditional clinic-based care, and the cost-effectiveness of this model of care for some subgroups of anticoagulation patients needs to be explored further.
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http://dx.doi.org/10.1111/j.1365-2141.2006.06243.xDOI Listing
September 2006

A randomised controlled trial and cost effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in the over 65s: (SAFE) [ISRCTN19633732].

BMC Cardiovasc Disord 2004 Jul 29;4:12. Epub 2004 Jul 29.

Department of Primary Care and General Practice, The University of Birmingham, UK.

Background: Atrial fibrillation (AF) has been recognised as an important independent risk factor for thromboembolic disease, particularly stroke for which it provides a five-fold increase in risk. This study aimed to determine the baseline prevalence and the incidence of AF based on a variety of screening strategies and in doing so to evaluate the incremental cost-effectiveness of different screening strategies, including targeted or whole population screening, compared with routine clinical practice, for detection of AF in people aged 65 and over. The value of clinical assessment and echocardiography as additional methods of risk stratification for thromboembolic disease in patients with AF were also evaluated.

Methods: The study design was a multi-centre randomised controlled trial with a study population of patients aged 65 and over from 50 General Practices in the West Midlands. These purposefully selected general practices were randomly allocated to 25 intervention practices and 25 control practices. GPs and practice nurses within the intervention practices received education on the importance of AF detection and ECG interpretation. Patients in the intervention practices were randomly allocated to systematic (n = 5000) or opportunistic screening (n = 5000). Prospective identification of pre-existing risk factors for AF within the screened population enabled comparison between high risk targeted screening and total population screening. AF detection rates in systematically screened and opportunistically screened populations in the intervention practices were compared to AF detection rate in 5,000 patients in the control practices.
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http://dx.doi.org/10.1186/1471-2261-4-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC509245PMC
July 2004

Training for patients in a randomised controlled trial of self management of warfarin treatment.

BMJ 2004 Feb;328(7437):437-8

Department of Primary Care and General Practice, Medical School, University of Birmingham, Birmingham B15 2TT.

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http://dx.doi.org/10.1136/bmj.328.7437.437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC344261PMC
February 2004
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