Publications by authors named "Donall Forde"

11 Publications

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An informatics consult approach for generating clinical evidence for treatment decisions.

BMC Med Inform Decis Mak 2021 10 12;21(1):281. Epub 2021 Oct 12.

Institute of Health Informatics, University College London, London, UK.

Background: An Informatics Consult has been proposed in which clinicians request novel evidence from large scale health data resources, tailored to the treatment of a specific patient. However, the availability of such consultations is lacking. We seek to provide an Informatics Consult for a situation where a treatment indication and contraindication coexist in the same patient, i.e., anti-coagulation use for stroke prevention in a patient with both atrial fibrillation (AF) and liver cirrhosis.

Methods: We examined four sources of evidence for the effect of warfarin on stroke risk or all-cause mortality from: (1) randomised controlled trials (RCTs), (2) meta-analysis of prior observational studies, (3) trial emulation (using population electronic health records (N = 3,854,710) and (4) genetic evidence (Mendelian randomisation). We developed prototype forms to request an Informatics Consult and return of results in electronic health record systems.

Results: We found 0 RCT reports and 0 trials recruiting for patients with AF and cirrhosis. We found broad concordance across the three new sources of evidence we generated. Meta-analysis of prior observational studies showed that warfarin use was associated with lower stroke risk (hazard ratio [HR] = 0.71, CI 0.39-1.29). In a target trial emulation, warfarin was associated with lower all-cause mortality (HR = 0.61, CI 0.49-0.76) and ischaemic stroke (HR = 0.27, CI 0.08-0.91). Mendelian randomisation served as a drug target validation where we found that lower levels of vitamin K1 (warfarin is a vitamin K1 antagonist) are associated with lower stroke risk. A pilot survey with an independent sample of 34 clinicians revealed that 85% of clinicians found information on prognosis useful and that 79% thought that they should have access to the Informatics Consult as a service within their healthcare systems. We identified candidate steps for automation to scale evidence generation and to accelerate the return of results.

Conclusion: We performed a proof-of-concept Informatics Consult for evidence generation, which may inform treatment decisions in situations where there is dearth of randomised trials. Patients are surprised to know that their clinicians are currently not able to learn in clinic from data on 'patients like me'. We identify the key challenges in offering such an Informatics Consult as a service.
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http://dx.doi.org/10.1186/s12911-021-01638-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506488PMC
October 2021

Circadian control of hepatitis B virus replication.

Nat Commun 2021 03 12;12(1):1658. Epub 2021 Mar 12.

Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Chronic hepatitis B virus (HBV) infection is a major cause of liver disease and cancer worldwide for which there are no curative therapies. The major challenge in curing infection is eradicating or silencing the covalent closed circular DNA (cccDNA) form of the viral genome. The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the liver transcriptome and yet their role in HBV replication is unknown. We establish a circadian cycling liver cell-model and demonstrate that REV-ERB directly regulates NTCP-dependent hepatitis B and delta virus particle entry. Importantly, we show that pharmacological activation of REV-ERB inhibits HBV infection in vitro and in human liver chimeric mice. We uncover a role for BMAL1 to bind HBV genomes and increase viral promoter activity. Pharmacological inhibition of BMAL1 through REV-ERB ligands reduces pre-genomic RNA and de novo particle secretion. The presence of conserved E-box motifs among members of the Hepadnaviridae family highlight an evolutionarily conserved role for BMAL1 in regulating this family of small DNA viruses.
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http://dx.doi.org/10.1038/s41467-021-21821-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955118PMC
March 2021

Temporal development and neutralising potential of antibodies against SARS-CoV-2 in hospitalised COVID-19 patients: An observational cohort study.

PLoS One 2021 26;16(1):e0245382. Epub 2021 Jan 26.

Wales Specialist Virology Centre, Public Health Wales Microbiology, University Hospital of Wales, Cardiff, Wales, United Kingdom.

Antibody responses are important in the control of viral respiratory infection in the human host. What is not clear for SARS-CoV-2 is how rapidly this response occurs, or when antibodies with protective capability evolve. Hence, defining the events of SARS-CoV-2 seroconversion and the time frame for the development of antibodies with protective potential may help to explain the different clinical presentations of COVID-19. Furthermore, accurate descriptions of seroconversion are needed to inform the best use of serological assays for diagnostic testing and serosurveillance studies. Here, we describe the humoral responses in a cohort of hospitalised COVID-19 patients (n = 19) shortly following the onset of symptoms. Commercial and 'in-house' serological assays were used to measure IgG antibodies against different SARS-CoV-2 structural antigens-Spike (S) S1 sub-unit and Nucleocapsid protein (NP)-and to assess the potential for virus neutralisation mediated specifically by inhibition of binding between the viral attachment protein (S protein) and cognate receptor (ACE-2). Antibody response kinetics varied amongst the cohort, with patients seroconverting within 1 week, between 1-2 weeks, or after 2 weeks, following symptom onset. Anti-NP IgG responses were generally detected earlier, but reached maximum levels slower, than anti-S1 IgG responses. The earliest IgG antibodies produced by all patients included those that recognised the S protein receptor-binding domain (RBD) and were capable of inhibiting binding to ACE-2. These data revealed events and patterns of SARS-CoV-2 seroconversion that may be important predictors of the outcome of infection and guide the delivery of clinical services in the COVID-19 response.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245382PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837461PMC
January 2021

Hepatitis B virus seroepidemiology data for Africa: Modelling intervention strategies based on a systematic review and meta-analysis.

PLoS Med 2020 04 21;17(4):e1003068. Epub 2020 Apr 21.

Nuffield Department of Medicine, University of Oxford, Medawar Building for Pathogen Research, Oxford, United Kingdom.

Background: International Sustainable Development Goals (SDGs) for elimination of hepatitis B virus (HBV) infection set ambitious targets for 2030. In African populations, infant immunisation has been fundamental to reducing incident infections in children, but overall population prevalence of chronic hepatitis B (CHB) infection remains high. In high-prevalence populations, adult catch-up vaccination has sometimes been deployed, but an alternative Test and Treat (T&T) approach could be used as an intervention to interrupt transmission. Universal T&T has not been previously evaluated as a population intervention for HBV infection, despite high-profile data supporting its success with human immunodeficiency virus (HIV).

Methods And Findings: We set out to investigate the relationship between prevalence of HBV infection and exposure in Africa, undertaking a systematic literature review in November 2019. We identified published seroepidemiology data representing the period 1995-2019 from PubMed and Web of Science, including studies of adults that reported prevalence of both hepatitis B surface antigen (HBsAg; prevalence of HBV infection) and antibody to hepatitis B core antigen (anti-HBc; prevalence of HBV exposure). We identified 96 studies representing 39 African countries, with a median cohort size of 370 participants and a median participant age of 34 years. Using weighted linear regression analysis, we found a strong relationship between the prevalence of infection (HBsAg) and exposure (anti-HBc) (R2 = 0.45, p < 0.001). Region-specific differences were present, with estimated CHB prevalence in Northern Africa typically 30% to 40% lower (p = 0.007) than in Southern Africa for statistically similar exposure rates, demonstrating the need for intervention strategies to be tailored to individual settings. We applied a previously published mathematical model to investigate the effect of interventions in a high-prevalence setting. The most marked and sustained impact was projected with a T&T strategy, with a predicted reduction of 33% prevalence by 20 years (95% CI 30%-37%) and 62% at 50 years (95% CI 57%-68%), followed by routine neonatal vaccination and prevention of mother to child transmission (PMTCT; at 100% coverage). In contrast, the impact of catch-up vaccination in adults had a negligible and transient effect on population prevalence. The study is constrained by gaps in the published data, such that we could not model the impact of antiviral therapy based on stratification by specific clinical criteria and our model framework does not include explicit age-specific or risk-group assumptions regarding force of transmission.

Conclusions: The unique data set collected in this study highlights how regional epidemiology data for HBV can provide insights into patterns of transmission, and it provides an evidence base for future quantitative research into the most effective local interventions. In combination with robust neonatal immunisation programmes, ongoing PMTCT efforts, and the vaccination of high-risk groups, diagnosing and treating HBV infection is likely to be of most impact in driving advances towards elimination targets at a population level.
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http://dx.doi.org/10.1371/journal.pmed.1003068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173646PMC
April 2020

Dual prognostic role of 2-oxoglutarate-dependent oxygenases in ten cancer types: implications for cell cycle regulation and cell adhesion maintenance.

Cancer Commun (Lond) 2019 04 29;39(1):23. Epub 2019 Apr 29.

Nuffield Department of Medicine, University of Oxford, Old Road Campus, Oxford, OX37FZ, UK.

Background: Tumor hypoxia is associated with metastasis and resistance to chemotherapy and radiotherapy. Genes involved in oxygen-sensing are clinically relevant and have significant implications for prognosis. In this study, we examined the pan-cancer prognostic significance of oxygen-sensing genes from the 2-oxoglutarate-dependent oxygenase family.

Methods: A multi-cohort, retrospective study of transcriptional profiles of 20,752 samples of 25 types of cancer was performed to identify pan-cancer prognostic signatures of 2-oxoglutarate-dependent oxygenase gene family (a family of oxygen-dependent enzymes consisting of 61 genes). We defined minimal prognostic gene sets using three independent pancreatic cancer cohorts (n = 681). We identified two signatures, each consisting of 5 genes. The ability of the signatures in predicting survival was tested using Cox regression and receiver operating characteristic (ROC) curve analyses.

Results: Signature 1 (KDM8, KDM6B, P4HTM, ALKBH4, ALKBH7) and signature 2 (KDM3A, P4HA1, ASPH, PLOD1, PLOD2) were associated with good and poor prognosis. Signature 1 was prognostic in 8 cohorts representing 6 cancer types (n = 2627): bladder urothelial carcinoma (P = 0.039), renal papillary cell carcinoma (P = 0.013), liver cancer (P = 0.033 and P = 0.025), lung adenocarcinoma (P = 0.014), pancreatic adenocarcinoma (P < 0.001 and P = 0.040), and uterine corpus endometrial carcinoma (P < 0.001). Signature 2 was prognostic in 12 cohorts representing 9 cancer types (n = 4134): bladder urothelial carcinoma (P = 0.039), cervical squamous cell carcinoma and endocervical adenocarcinoma (P = 0.035), head and neck squamous cell carcinoma (P = 0.038), renal clear cell carcinoma (P = 0.012), renal papillary cell carcinoma (P = 0.002), liver cancer (P < 0.001, P < 0.001), lung adenocarcinoma (P = 0.011), pancreatic adenocarcinoma (P = 0.002, P = 0.018, P < 0.001), and gastric adenocarcinoma (P = 0.004). Multivariate Cox regression confirmed independent clinical relevance of the signatures in these cancers. ROC curve analyses confirmed superior performance of the signatures to current tumor staging benchmarks. KDM8 was a potential tumor suppressor down-regulated in liver and pancreatic cancers and an independent prognostic factor. KDM8 expression was negatively correlated with that of cell cycle regulators. Low KDM8 expression in tumors was associated with loss of cell adhesion phenotype through HNF4A signaling.

Conclusion: Two pan-cancer prognostic signatures of oxygen-sensing genes were identified. These genes can be used for risk stratification in ten diverse cancer types to reveal aggressive tumor subtypes.
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http://dx.doi.org/10.1186/s40880-019-0369-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489267PMC
April 2019

A novel signature derived from immunoregulatory and hypoxia genes predicts prognosis in liver and five other cancers.

J Transl Med 2019 01 9;17(1):14. Epub 2019 Jan 9.

Nuffield Department of Medicine, University of Oxford, Old Road Campus, Oxford, OX3 7FZ, UK.

Background: Despite much progress in cancer research, its incidence and mortality continue to rise. A robust biomarker that would predict tumor behavior is highly desirable and could improve patient treatment and prognosis.

Methods: In a retrospective bioinformatics analysis involving patients with liver cancer (n = 839), we developed a prognostic signature consisting of 45 genes associated with tumor-infiltrating lymphocytes and cellular responses to hypoxia. From this gene set, we were able to identify a second prognostic signature comprised of 8 genes. Its performance was further validated in five other cancers: head and neck (n = 520), renal papillary cell (n = 290), lung (n = 515), pancreas (n = 178) and endometrial (n = 370).

Results: The 45-gene signature predicted overall survival in three liver cancer cohorts: hazard ratio (HR) = 1.82, P = 0.006; HR = 1.84, P = 0.008 and HR = 2.67, P = 0.003. Additionally, the reduced 8-gene signature was sufficient and effective in predicting survival in liver and five other cancers: liver (HR = 2.36, P = 0.0003; HR = 2.43, P = 0.0002 and HR = 3.45, P = 0.0007), head and neck (HR = 1.64, P = 0.004), renal papillary cell (HR = 2.31, P = 0.04), lung (HR = 1.45, P = 0.03), pancreas (HR = 1.96, P = 0.006) and endometrial (HR = 2.33, P = 0.003). Receiver operating characteristic analyses demonstrated both signatures superior performance over current tumor staging parameters. Multivariate Cox regression analyses revealed that both 45-gene and 8-gene signatures were independent of other clinicopathological features in these cancers. Combining the gene signatures with somatic mutation profiles increased their prognostic ability.

Conclusions: This study, to our knowledge, is the first to identify a gene signature uniting both tumor hypoxia and lymphocytic infiltration as a prognostic determinant in six cancer types (n = 2712). The 8-gene signature can be used for patient risk stratification by incorporating hypoxia information to aid clinical decision making.
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http://dx.doi.org/10.1186/s12967-019-1775-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327401PMC
January 2019

Glucose and glutamine availability regulate HepG2 transcriptional responses to low oxygen.

Wellcome Open Res 2018 26;3:126. Epub 2018 Sep 26.

Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK.

Little is known about the impact of nutrients on cellular transcriptional responses, especially in face of environmental stressors such as oxygen deprivation. Hypoxia-inducible factors (HIF) coordinate the expression of genes essential for adaptation to oxygen-deprived environments. A second family of oxygen-sensing genes known as the alpha-ketoglutarate-dependent dioxygenases are also implicated in oxygen homeostasis and epigenetic regulation. The relationship between nutritional status and cellular response to hypoxia is understudied. cell culture systems frequently propagate cells in media that contains excess nutrients, and this may directly influence transcriptional response in hypoxia. We studied the effect of glucose and glutamine concentration on HepG2 hepatoma transcriptional response to low oxygen and expression of hypoxia inducible factor-1α (HIF-1α). Mass spectrometry confirmed low oxygen perturbation of dioxygenase transcripts resulted in changes in DNA methylation. Under normoxic conditions, we observed a significant upregulation of both HIF-target genes and oxygen-dependent dioxygenases in HepG2 cells cultured with physiological levels of glucose or glutamine relative to regular DMEM media, demonstrating that excess glutamine/glucose can mask changes in gene expression. Under hypoxic conditions, was the most upregulated gene in physiological glutamine media while and dioxygenases were downregulated in physiological glucose. Hypoxic regulation of these transcripts did not associate with changes in HIF-1α protein expression. Downregulation of suggests a potential for epigenetic modulation. Mass-spectrometry quantification of modified DNA bases confirmed our transcript data. Hypoxia resulted in decreased DNA hydroxymethylation, which correlated with downregulation. Additionally, we observed that expression was significantly downregulated in patients with hepatocellular carcinoma, suggesting that tumour hypoxia may deregulate expression resulting in global changes in DNA hydroxymethylation.   Given the dramatic effects of nutrient availability on gene expression, future experiments should be aware of how excess levels of glutamine and glucose may perturb transcriptional responses.
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http://dx.doi.org/10.12688/wellcomeopenres.14839.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178907PMC
September 2018

Acute parvovirus B19 infection in identical twins unmasking previously unidentified hereditary spherocytosis.

BMJ Case Rep 2014 Jul 29;2014. Epub 2014 Jul 29.

Department of Infectious Disease and Tropical Medicine, Royal Hallamshire Hospital, Sheffield, UK.

Identical Caucasian male twins, previously fit, presented 1 week apart with short histories of fever and lethargy. The twins were febrile at presentation with profound pancytopaenia and evidence of haemolysis. There was no rash or arthralgia. Both required multiple red cell transfusions. The twins had positive IgM serology for Epstein-Barr virus (EBV), cytomegalovirus (CMV) and parvovirus B19. EBV viral capsid antigen and Epstein-Barr nuclear antigen IgGs were also positive however, suggesting past EBV exposure. Parvovirus B19 DNA was detected from peripheral blood PCR; CMV and EBV DNA PCRs were negative. Convalescent serology demonstrated no evolution of the CMV serological response, that is no IgG to CMV developed which implies an initial non-specific polyclonal IgM response. The twins recovered fully over 7 days, the first with a course of prednisolone and the second spontaneously. They were diagnosed with hereditary spherocytosis on convalescent blood films. On further questioning, a family history of hereditary spherocytosis was eventually revealed. The twins' maternal grandmother was known to have the condition asymptomatically. Their mother had prior to this never been tested, but later bloods would reveal a compatible biochemical picture.
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http://dx.doi.org/10.1136/bcr-2013-202957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4120043PMC
July 2014

Undergraduate teaching on biological weapons and bioterrorism at medical schools in the UK and the Republic of Ireland: results of a cross-sectional study.

BMJ Open 2013 Jun 20;3(6). Epub 2013 Jun 20.

Infection and Tropical Medicine, Royal Hallamshire Hospital-Sheffield Teaching Hospitals, Sheffield, South Yorkshire, UK.

Objective: To determine if individual undergraduate schools of medicine in the UK and the Republic of Ireland provide any teaching to medical students about biological weapons, bioterrorism, chemical weapons and weaponised radiation, if they perceive them to be relevant issues and if they figure them in their future plans.

Design: A cross-sectional study utilising an internet-based questionnaire sent to key figures responsible for leading on the planning and delivery of undergraduate medical teaching at all schools of medicine in the UK and Ireland.

Setting: All identified undergraduate schools of medicine in the UK and Ireland between August 2012 and December 2012.

Outcome Measures: Numerical data and free text feedback about relevant aspects of undergraduate teaching.

Results: Of the 38 medical schools approached, 34 (28 in UK, 6 in Ireland) completed the questionnaire (89.47%). 4 (all in UK) chose not to complete it. 6/34 (17.65%) included some specific teaching on biological weapons and bioterrorism. 7/34 (20.59%) had staff with bioterrorism expertise (mainly in microbiological and syndromic aspects). 4/34 (11.76%) had plans to introduce some specific teaching on bioterrorism. Free text responses revealed that some felt that because key bodies (eg, UK's General Medical Council) did not request teaching on bioterrorism, then it should not be included, while others regarded this field of study as a postgraduate subject and not appropriate for undergraduates, or argued that the curriculum was too congested already. 4/34 (11.76%) included some specific teaching on chemical weapons, and 3/34 (8.82%) on weaponised radiation.

Conclusions: This study provides evidence that at the present time there is little teaching at the undergraduate level in the UK and Ireland on the subjects of biological weapons and bioterrorism, chemical weapons and weaponised radiation and signals that this situation is unlikely to change unless there were to be high-level policy guidance.
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http://dx.doi.org/10.1136/bmjopen-2013-002744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669729PMC
June 2013

Hypoglycaemia associated with co-trimoxazole use in a 56-year-old Caucasian woman with renal impairment.

BMJ Case Rep 2012 Nov 9;2012. Epub 2012 Nov 9.

Department of Infection and Tropical Medicine, Sheffield Teaching Hospital, Sheffield, UK.

Here we present a case of refractory hypoglycaemia associated with use of the antibiotic trimethoprim-sulfamethoxazole (TMP-SMX). This was used to treat Pneumocystis jirovecii pneumonia (PCP) infection. The patient had significant pre-existing renal impairment with a kidney transplant in situ. Refractory hypoglycaemia occurred 5 days after starting the antibiotic and persisted for 36 h after its cessation. SMX contains the same sulphanilamide structural group as the oral hypoglycaemic agents called sulphonureas. SMX could therefore act as an insulin secretagogue. The inappropriately raised insulin and c-peptide levels seen in our patient support this theory. The 5-day asymptomatic period would allow sufficient time for the drug to accumulate and the extended period seen after its cessation would be seen in a dose-dependent side effect. Following 3 days of observation and continuous glycaemic support on the High Dependency Unit she was discharged back to the ward, with no further occurrence of hypoglycaemia.
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http://dx.doi.org/10.1136/bcr-2012-007215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544489PMC
November 2012

Potentially avoidable inpatient nights among warfarin receiving patients; an audit of a single university teaching hospital.

BMC Res Notes 2009 Mar 13;2:41. Epub 2009 Mar 13.

The School of Medicine, University College Cork, Cork, Ireland.

Background: Warfarin is an oral anticoagulant (OAT) that needs active management to ensure therapeutic range. Initial management is often carried out as an inpatient, though not requiring inpatient facilities. This mismatch results in financial costs which could be directed more efficaciously. The extent of this has previously been unknown. Here we aim to calculate the potential number of bed nights which may be saved among those being dose optimized as inpatients and examine associated factors.

Methods: A 6 week prospective audit of inpatients receiving OAT, at Cork University Hospital, was carried out. The study period was from 11th June 2007 to 20th July 2007. Data was collected from patient's medications prescription charts, medical record files, and computerised haematology laboratory records. The indications for OAT, the patient laboratory coagulation results and therapeutic intervals along with patient demographics were analysed. The level of potentially avoidable inpatient nights in those receiving OAT in hospital was calculated and the potential cost savings quantified. Potential avoidable bed nights were defined as patients remaining in hospital for the purpose of optimizing OAT dosage, while receiving subtherapeutic or therapeutic OAT (being titred up to therapeutic levels) and co-administered covering low molecular weight heparin, and requiring no other active care. The average cost of euro638 was taken as the per night hospital stay cost for a non-Intensive Care bed. Ethical approval was granted from the Ethical Committee of the Cork Teaching Hospitals, Cork, Ireland.

Results: A total of 158 patients were included in the audit. There was 94 men (59.4%) and 64 women (40.6%). The mean age was 67.8 years, with a median age of 70 years.Atrial Fibrillation (43%, n = 70), followed by aortic valve replacement (15%, n = 23) and pulmonary emboli (11%, n = 18) were the commonest reasons for prescribing OAT. 54% had previously been prescribed OAT prior to current admission.It was confirmed that, there are potentially avoidable nights in patients receiving OAT. The majority of this group were those being commenced on OAT for the first time (p = 0.00002), in the specialities of Cardiology, Cardiothoracic surgery and Care of the Elderly. The potential number of bed nights to be saved is 13 per week for the hospital or 1.1 bed nights per 10,000 general hospital admissions. These were predominantly weekday nights. The estimated cost of avoidable inpatient OAT dose optimization was approximately euro8300 per week.

Conclusion: With rising costs and the increasing demands for acute hospital beds, alterations to inpatient management for this group of patients should be considered. Alternatives include increasing the size of current anticoagulation clinics, introduction of POCT (point of care testing) devices and increased GP management. POCT can be justified based upon the publication by Gardiner et al, who showed that 87% of patients find self testing straightforward, 87% were confident in the result they obtained using the devices and 77% preferred self testing.
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http://dx.doi.org/10.1186/1756-0500-2-41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2657894PMC
March 2009
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