Faculty Bibliography

INTRODUCTION: Coupled plasma filtration and adsorption (CPFA) has been used in the treatment of severe sepsis with the intention of removing the proinflammatory and anti-inflammatory mediators from the systemic circulation. It is believed that this interrupts and moderates the septic cascade, but there is uncertainty about the benefits of this therapy. METHODS: A systematic review and meta-analysis were performed to estimate the effects of CPFA on mortality in severe sepsis. The Cochrane CENTRAL Register of Controlled Trials, CINAHL, EMBASE, MEDLINE-EBSCO-Host, MEDLINE and ProQuest, were searched from 1997 to 2013. Randomised controlled trials, prospective cohort studies and retrospective cohort studies were included using the Centre for Reviews and Dissemination (CRD) framework. Data were abstracted using standard pro forma, and studies independently reviewed by two authors to confirm inclusion criteria. Quality of studies and risk of bias were assessed using the Grading of Recommendations, Assessment, Development and Evaluation Working Group (GRADE) and Critical Appraisal Skills (CASP) criteria, respectively. Meta-analysis was performed using Review Manager (RevMan V.5.1) software. The primary outcome was 28-day mortality. Secondary outcomes were mediator adsorption (picograms/mL), mean arterial BP (mm Hg) and oxygenation ratio. RESULTS: 17 studies met the inclusion criteria (n=441 patients, 242 CPFA). 14 studies reported the primary outcome of 28-day mortality. There were 88 deaths in CPFA patients versus 118 in those receiving haemofiltration: OR 0.34 (95% CI 0.24 to 0.13). Point estimates of effect on the secondary outcomes of mean arterial pressure and oxygen ratio favoured CPFA. Studies were small and heterogenous. CONCLUSIONS: Evidence for CPFA in severe sepsis is sparse, of poor quality and further research is required, however, this meta-analysis noted improvements in survival rates of those patients treated with CPFA.

BACKGROUND: In breast cancer patients undergoing sentinel lymph node biopsy (SLNB) analysis using one-step nucleic acid amplification (OSNA), clarity is required as to the risk factors for non-sentinel lymph node (NSLN) involvement upon axillary lymph node dissection (ALND). This study aims to identify these factors, including categorising by extent of sentinel node positivity: solitary positive node (solitary), multiple nodes with some positive (multiple incomplete positive), or multiple nodes all of which are positive (multiple all positive). METHODS: We conducted a cohort study using prospectively collected data on 856 SLNBs analysed using OSNA, from patients with cT1-3 clinically node-negative invasive breast cancer. ALND was performed for 289 positive SLNBs. RESULTS: NSLN metastases were identified in 73 (25.3%) ALNDs. Significant factors for NSLN involvement on multivariate analysis were: SLNB macrometastases (cytokeratin-19 mRNA count >5000 copies/mul) (adj.OR = 3.01; 95% CI, 1.61-5.66; p = 0.0006), multiple all positive vs. multiple incomplete positive SLNB (adj.OR = 2.92; 95% CI, 1.38-6.19; p = 0.0050), and undergoing mastectomy (adj.OR = 1.89; 95% CI, 1.00-3.55; p = 0.0486). Amongst multiple incomplete positive SLNBs, an 8.8% NSLN risk was identified when only micrometastases were present. CONCLUSION: Extent of sentinel lymph node positivity measured using OSNA predicts NSLN metastasis risk, aiding decisions surrounding axillary treatment.

Modern theories of economic growth emphasise the key role of human capital and technological progress in determining a society's standard of living. In some advanced countries, however, higher education costs and the level of indebtedness among graduates have increased dramatically during recent years. This phenomenon is particularly evident in the United States, and within the biomedical sciences sector. In this paper, we develop a basic model of economic growth in order to investigate the effects of biomedical graduate indebtedness on the allocation of human resources in R&D activities and hence on the growth process. In particular, we derive a 'science-growth curve', i.e., a relation between the share of pure researchers and the economy's rate of growth, and we find two possible effects of student indebtedness on economic growth: a composition effect and a productivity effect. (C) 2015 Elsevier B.V. All rights reserved.

OBJECTIVES: Antibiotic prophylaxis (AP) administration prior to invasive dental procedures has been a leading focus of infective endocarditis prevention. However, there have been long-standing concerns about the risk of adverse drug reactions as a result of this practice. The objective of this study was to identify the incidence and nature of adverse reactions to amoxicillin and clindamycin prophylaxis to prevent infective endocarditis. METHODS: We obtained AP prescribing data for England from January 2004 to March 2014 from the NHS Business Services Authority, and adverse drug reaction data from the Medicines and Healthcare Products Regulatory Agency's Yellow Card reporting scheme for prescriptions of the standard AP protocol of a single 3 g oral dose of amoxicillin or a single 600 mg oral dose of clindamycin for those allergic to penicillin. RESULTS: The reported adverse drug reaction rate for amoxicillin AP was 0 fatal reactions/million prescriptions (in fact 0 fatal reactions for nearly 3 million prescriptions) and 22.62 non-fatal reactions/million prescriptions. For clindamycin, it was 13 fatal and 149 non-fatal reactions/million prescriptions. Most clindamycin adverse drug reactions were Clostridium difficile infections. CONCLUSIONS: AP adverse drug reaction reporting rates in England were low, particularly for amoxicillin, and lower than previous estimates. This suggests that amoxicillin AP is comparatively safe for patients without a history of amoxicillin allergy. The use of clindamycin AP was, however, associated with significant rates of fatal and non-fatal adverse drug reactions associated with C. difficile infections. These were higher than expected and similar to those for other doses, durations and routes of clindamycin administration.

BACKGROUND: Indian Asians, who make up a quarter of the world's population, are at high risk of developing type 2 diabetes. We investigated whether DNA methylation is associated with future type 2 diabetes incidence in Indian Asians and whether differences in methylation patterns between Indian Asians and Europeans are associated with, and could be used to predict, differences in the magnitude of risk of developing type 2 diabetes. METHODS: We did a nested case-control study of DNA methylation in Indian Asians and Europeans with incident type 2 diabetes who were identified from the 8-year follow-up of 25 372 participants in the London Life Sciences Prospective Population (LOLIPOP) study. Patients were recruited between May 1, 2002, and Sept 12, 2008. We did epigenome-wide association analysis using samples from Indian Asians with incident type 2 diabetes and age-matched and sex-matched Indian Asian controls, followed by replication testing of top-ranking signals in Europeans. For both discovery and replication, DNA methylation was measured in the baseline blood sample, which was collected before the onset of type 2 diabetes. Epigenome-wide significance was set at p<1 x 10(-7). We compared methylation levels between Indian Asian and European controls without type 2 diabetes at baseline to estimate the potential contribution of DNA methylation to increased risk of future type 2 diabetes incidence among Indian Asians. FINDINGS: 1608 (11.9%) of 13 535 Indian Asians and 306 (4.3%) of 7066 Europeans developed type 2 diabetes over a mean of 8.5 years (SD 1.8) of follow-up. The age-adjusted and sex-adjusted incidence of type 2 diabetes was 3.1 times (95% CI 2.8-3.6; p<0.0001) higher among Indian Asians than among Europeans, and remained 2.5 times (2.1-2.9; p<0.0001) higher after adjustment for adiposity, physical activity, family history of type 2 diabetes, and baseline glycaemic measures. The mean absolute difference in methylation level between type 2 diabetes cases and controls ranged from 0.5% (SD 0.1) to 1.1% (0.2). Methylation markers at five loci were associated with future type 2 diabetes incidence; the relative risk per 1% increase in methylation was 1.09 (95% CI 1.07-1.11; p=1.3 x 10(-17)) for ABCG1, 0.94 (0.92-0.95; p=4.2 x 10(-11)) for PHOSPHO1, 0.94 (0.92-0.96; p=1.4 x 10(-9)) for SOCS3, 1.07 (1.04-1.09; p=2.1 x 10(-10)) for SREBF1, and 0.92 (0.90-0.94; p=1.2 x 10(-17)) for TXNIP. A methylation score combining results for the five loci was associated with future type 2 diabetes incidence (relative risk quartile 4 vs quartile 1 3.51, 95% CI 2.79-4.42; p=1.3 x 10(-26)), and was independent of established risk factors. Methylation score was higher among Indian Asians than Europeans (p=1 x 10(-34)). INTERPRETATION: DNA methylation might provide new insights into the pathways underlying type 2 diabetes and offer new opportunities for risk stratification and prevention of type 2 diabetes among Indian Asians. FUNDING: The European Union, the UK National Institute for Health Research, the Wellcome Trust, the UK Medical Research Council, Action on Hearing Loss, the UK Biotechnology and Biological Sciences Research Council, the Oak Foundation, the Economic and Social Research Council, Helmholtz Zentrum Munchen, the German Research Center for Environmental Health, the German Federal Ministry of Education and Research, the German Center for Diabetes Research, the Munich Center for Health Sciences, the Ministry of Science and Research of the State of North Rhine-Westphalia, and the German Federal Ministry of Health.

BACKGROUND: An algorithm that detects errors in diagnosis, classification or coding of diabetes in primary care computerised medial record (CMR) systems is currently available. However, this was developed on CMR systems that are episode orientated medical records (EOMR); and do not force the user to always code a problem or link data to an existing one. More strictly problem orientated medical record (POMR) systems mandate recording a problem and linking consultation data to them. OBJECTIVE: To compare the rates of detection of diagnostic accuracy using an algorithm developed in EOMR with a new POMR specific algorithm. METHOD: We used data from The Health Improvement Network (THIN) database (N = 2,466,364) to identify a population of 100,513 (4.08%) patients considered likely to have diabetes. We recalibrated algorithms designed to classify cases of diabetes to take account of that POMR enforced coding consistency in the computerised medical record systems [In Practice Systems (InPS) Vision] that contribute data to THIN. We explored the different proportions of people classified as having type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) and with diabetes unclassifiable as either T1DM or T2DM. We compared proportions using chi-square tests and used Tukey's test to compare the characteristics of the people in each group. RESULTS: The prevalence of T1DM using the original EOMR algorithm was 0.38% (9,264/2,466,364), and for T2DM 3.22% (79,417/2,466,364). The prevalence using the new POMR algorithm was 0.31% (7,750/2,466,364) T1DM and 3.65% (89,990/2,466,364) T2DM. The EOMR algorithms also left more people unclassified 11,439 (12%), as to their type of diabetes compared with 2,380 (2.4%), for the new algorithm. Those people who were only classified by the EOMR system differed in terms of older age, and apparently better glycaemic control, despite not being prescribed medication for their diabetes (p < 0.005). CONCLUSION: Increasing the degree of problem orientation of the medical record system can improve the accuracy of recording of diagnoses and, therefore, the accuracy of using routinely collected data from CMRs to determine the prevalence of diabetes mellitus; data processing strategies should reflect the degree of problem orientation.

The aims of supervised machine learning (ML) applications fall into three broad categories: classification, ranking, and calibration/probability estimation. Many ML methods and evaluation techniques relate to the first two. Nevertheless, there are many applications where having an accurate probability estimate is of great importance. Deriving accurate probabilities from the output of a ML method is therefore an active area of research, resulting in several methods to turn a ranking into class probability estimates. In this manuscript we present a method, splined empirical probabilities, based on the receiver operating characteristic (ROC) to complement existing algorithms such as isotonic regression. Unlike most other methods it works with a cumulative quantity, the ROC curve, and as such can be tagged onto an ROC analysis with minor effort. On a diverse set of measures of the quality of probability estimates (Hosmer-Lemeshow, Kullback-Leibler divergence, differences in the cumulative distribution function) using simulated and real health care data, our approach compares favourably with the standard calibration method, the pool adjacent violators algorithm used to perform isotonic regression.

BACKGROUND: Antibiotic prophylaxis given before invasive dental procedures in patients at risk of developing infective endocarditis has historically been the focus of infective endocarditis prevention. Recent changes in antibiotic prophylaxis guidelines in the USA and Europe have substantially reduced the number of patients for whom antibiotic prophylaxis is recommended. In the UK, guidelines from the National Institute for Health and Clinical Excellence (NICE) recommended complete cessation of antibiotic prophylaxis for prevention of infective endocarditis in March, 2008. We aimed to investigate changes in the prescribing of antibiotic prophylaxis and the incidence of infective endocarditis since the introduction of these guidelines. METHODS: We did a retrospective secular trend study, analysed as an interrupted time series, to investigate the effect of antibiotic prophylaxis versus no prophylaxis on the incidence of infective endocarditis in England. We analysed data for the prescription of antibiotic prophylaxis from Jan 1, 2004, to March 31, 2013, and hospital discharge episode statistics for patients with a primary diagnosis of infective endocarditis from Jan 1, 2000, to March 31, 2013. We compared the incidence of infective endocarditis before and after the introduction of the NICE guidelines using segmented regression analysis of the interrupted time series. FINDINGS: Prescriptions of antibiotic prophylaxis for the prevention of infective endocarditis fell substantially after introduction of the NICE guidance (mean 10,900 prescriptions per month [Jan 1, 2004, to March 31, 2008] vs 2236 prescriptions per month [April 1, 2008, to March 31, 2013], p<0.0001). Starting in March, 2008, the number of cases of infective endocarditis increased significantly above the projected historical trend, by 0.11 cases per 10 million people per month (95% CI 0.05-0.16, p<0.0001). By March, 2013, 35 more cases per month were reported than would have been expected had the previous trend continued. This increase in the incidence of infective endocarditis was significant for both individuals at high risk of infective endocarditis and those at lower risk. INTERPRETATION: Although our data do not establish a causal association, prescriptions of antibiotic prophylaxis have fallen substantially and the incidence of infective endocarditis has increased significantly in England since introduction of the 2008 NICE guidelines. FUNDING: Heart Research UK, Simplyhealth, and US National Institutes of Health.

This article revolves around the assessment of corporate social responsibility in relation to pharmaceutical firms. Corporate social responsibility (CSR) is becoming an increasingly important dimension in the corporate landscape. The rise of ethical awareness of stakeholders has prompted many global corporations to adopt CSR policies. This study shines the light on pharmaceutical firms to gauge the level of CSR in this industry. Five of the largest pharmaceutical firms were evaluated using the global reporting initiative (GRI) guidelines as a benchmark. The results showed an unexpectedly large variety in the performance of the companies, with some areas of CSR being emphasised, while others were largely ignored. This is partly due to lack of relevance of certain GRI performance metrics to the pharmaceutical industry. We conclude that the pharmaceutical industry's CSR initiatives require much improvement to be deemed comprehensive. Current major CSR guidelines, including GRI, are largely not industry specific so there needs to be a move to construct relevant CSR guidelines that target issues pertaining to the pharmaceutical industry. There should also be a focus on impact-orientated CSR guidelines, as opposed to simple reportability, in order to promote more meaningful CSR initiatives