Medical graduate views on statistical learning needs for clinical practice: a comprehensive survey.

BACKGROUND: This paper seeks to contribute to a reputable evidence base for required competencies across different topics in statistics and probability (statistical topics) in preparing medical graduates for clinical practice. This is in order to inform the prioritization of statistical topics within future undergraduate medical curricula, while exploring the need for preparing tomorrow's doctors to be producers, and not merely consumers, of statistics. METHODS: We conducted a comprehensive online survey from July 2013 to August 2014 for a target group of 462 medical graduates with current or prior experience of teaching undergraduate medical students of the University of Edinburgh of whom 278 (60.2%) responded. Statistical topics were ranked by proportion of respondents who identified the practice of statistics, performing statistical procedures or calculations using appropriate data, as a required competency for medical schools to provide in preparing undergraduate medical students for clinical practice. Mixed effects analyses were used to identify potential predictors for selection of the above competency and to compare the likelihood of this selection for a range of statistical topics versus critical appraisal. RESULTS: Evidence was gleaned from medical graduates' experiences of clinical practice for the need for, not only a theoretical understanding of statistics and probability but also, the ability to practice statistics. Nature of employment and statistical topic were highly significant predictors of choice of the practice of statistics as a required competency ((F = 3.777, p < 0.0005) and (F = 45.834, p < 0.0005), respectively). The most popular topic for this competency was graphical presentation of data (84.3% of respondents) in contrast to cross-over trials for the competency understanding the theory only (70.5% of respondents). Several topics were found to be more popular than critical appraisal for competency in the practice of statistics. CONCLUSIONS: The model of medical graduates as mere consumers of statistics is oversimplified. Contrary to what has been suggested elsewhere, statistical learning opportunities in undergraduate medicine should not be restricted to development of critical appraisal skills. Indeed, our findings support development of learning opportunities for undergraduate medical students as producers of statistics across a wide range of statistical topics.

Prescribing Safety Assessment 2016: Delivery of a national prescribing assessment to 7343 UK final-year medical students.

AIMS: Newly graduated doctors write a large proportion of prescriptions in UK hospitals but recent studies have shown that they frequently make prescribing errors. The prescribing safety assessment (PSA) has been developed as an assessment of competence in relation to prescribing and supervising the use of medicines. This report describes the delivery of the PSA to all UK final-year medical students in 2016 (PSA2016). METHODS: The PSA is a 2-hour online assessment comprising eight sections which cover various aspects of prescribing defined within the outcomes of undergraduate education identified by the UK General Medical Council. Students sat one of four PSA 'papers', which had been standard-set using a modified Angoff process. RESULTS: A total of 7343 final-year medical students in all 31 UK medical schools sat the PSA. The overall pass rate was 95% with the pass rates for the individual papers ranging from 93 to 97%. The PSA was re-sat by 261 students who had failed and 80% of those candidates passed. The internal consistency (Cronbach's alpha) of the four papers ranged from 0.74 to 0.77 (standard error of measurement 4.13-4.24%). There was a statistically significant variation in performance between medical school cohorts (F = 32.6, P < 0.001) and a strongly positive correlation in performance for individual schools between PSA2015 and PSA2016 (r = 0.79, 95% CI 0.61-0.90; P < 0.01). CONCLUSIONS: PSA2016 demonstrated the feasibility of delivering a standardized national prescribing assessment online. The vast majority of UK final-year medical students were able to meet a prespecified standard of prescribing competence.

Junior doctor-led 'near-peer' prescribing education for medical students.

AIMS: Prescribing errors are common and inadequate preparation of prescribers appears to contribute. A junior doctor-led prescribing tutorial programme has been developed for Edinburgh final year medical students to increase exposure to common prescribing tasks. The aim of this study was to assess the impact of these tutorials on students and tutors. METHODS: One hundred and ninety-six tutorials were delivered to 183 students during 2010-2011. Each student completed a questionnaire after tutorial attendance which explored their previous prescribing experiences and the perceived benefits of tutorial attendance. Tutors completed a questionnaire which evaluated their teaching experiences and the impact on their prescribing practice. Student tutorial attendance was compared with end-of-year examination performance using linear regression analysis. RESULTS: The students reported increased confidence in their prescribing knowledge and skills after attending tutorials. Students who attended more tutorials also tended to perform better in end-of-year examinations (Drug prescribing: r = 0.16, P = 0.015; Fluid prescribing: r = 0.18, P = 0.007). Tutors considered that participation enhanced their own prescribing knowledge and skills. Although they were occasionally unable to address student uncertainties, 80% of tutors reported frequently correcting misconceptions and deficits in student knowledge. Ninety-five percent of students expressed a preference for prescribing training delivered by junior doctors over more senior doctors. CONCLUSIONS: A 'near-peer' junior doctor-led approach to delivering prescribing training to medical students was highly valued by both students and tutors. Although junior doctors have relatively less clinical experience of prescribing, we believe that this can be addressed by training and academic supervision and is outweighed by the benefits of these tutorials.

How should teaching of undergraduates in clinical pharmacology and therapeutics be delivered and assessed?

Clinical pharmacology and therapeutics is the academic discipline that informs rational prescribing of medicines. There is accumulating evidence that a significant minority of prescriptions in the UK National Health Service contain errors. This comes at a time when the approach to and success of undergraduate education in this area has been called into question. Various stakeholders are now in agreement that this challenging area of undergraduate education needs to be strengthened. The principles that should form the basis of future educational strategy include greater visibility of clinical pharmacology and therapeutics in the curriculum, clear learning outcomes that are consistent with national guidance, strong and enthusiastic leadership, a student formulary, opportunities to practice prescribing, a robust assessment of prescribing competencies and external quality control. Important new developments in the UK are Prescribe, a repository of e-learning materials to support education in clinical pharmacology and prescribing, and the Prescribing Skills Assessment, a national online assessment designed to allow medical students to demonstrate that they have achieved the core competencies required to begin postgraduate training.

eDrugCalc: an online self-assessment package to enhance medical students' drug dose calculation skills.

AIMS: Dose calculation errors can cause serious life-threatening clinical incidents. We designed eDrugCalc as an online self-assessment tool to develop and evaluate calculation skills among medical students. METHODS: We undertook a prospective uncontrolled study involving 1727 medical students in years 1-5 at the University of Edinburgh. Students had continuous access to eDrugCalc and were encouraged to practise. Voluntary self-assessment was undertaken by answering the 20 questions on six occasions over 30 months. Questions remained fixed but numerical variables changed so each visit required a fresh calculation. Feedback was provided following each answer. RESULTS: Final-year students had a significantly higher mean score in test 6 compared with test 1 [16.6, 95% confidence interval (CI) 16.2, 17.0 vs. 12.6, 95% CI 11.9, 13.4; n= 173, P < 0.0001 Wilcoxon matched pairs test] and made a median of three vs. seven errors. Performance was highly variable in all tests with 2.7% of final-year students scoring < 10/20 in test 6. Graduating students in 2009 (30 months' exposure) achieved significantly better scores than those in 2007 (only 6 months): mean 16.5, 95% CI 16.0, 17.0, n= 184 vs. 15.1, 95% CI 14.5, 15.6, n= 187; P < 0.0001, Mann-Whitney test. Calculations based on percentage concentrations and infusion rates were poorly performed. Feedback showed that eDrugCalc increased confidence in calculating doses and was highly rated as a learning tool. CONCLUSIONS: Medical student performance of dose calculations improved significantly after repeated exposure to an online formative dose-calculation package and encouragement to develop their numeracy. Further research is required to establish whether eDrugCalc reduces calculation errors made in clinical practice.

Prevention of medication errors: teaching and training.

1. Poor prescribing is probably the most common cause of preventable medication errors in hospitals, and many of these events involve junior doctors who have recently graduated. Prescribing is a complex skill that depends on a sound knowledge of medicines, an understanding of the principles of clinical pharmacology, the ability to make judgements concerning risks and benefits, and ideally experience. It is not surprising that errors occur. 2. The challenge of being a prescriber is probably greater now than ever before. Medical education has changed radically in the last 20 years, reflecting concerns about an overburdened curriculum and lack of focus on social sciences. In the UK, these changes have resulted in less teaching in clinical pharmacology and practical prescribing as guaranteed features of undergraduate training and assessment. There has been growing concern, not least from students, that medical school training is not sufficient to prepare them for the pressures of becoming prescribers. Similar concerns are being expressed in other countries. While irrefutable evidence that these changes are related to medication errors identified in practice, there is circumstantial evidence that this is so. 3. Systems analysis of errors suggests that knowledge and training are relevant factors in causation and that focused education improves prescribing performance. We believe that there is already sufficient evidence to support a careful review of how students are trained to become prescribers and how these skills are fostered in the postgraduate years. We provide a list of guiding principles on which training might be based.

The availability of prescription-only analgesics purchased from the internet in the UK.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Increasing numbers of people are accessing medicines from the internet. This online market is poorly regulated and represents a potential threat to the health of patients and members of the public. WHAT THIS STUDY ADDS: Prescription-only analgesics, including controlled opioids, are readily available to the UK public through internet pharmacies that are easily identified by popular search engines. The majority of websites do not require the customer to possess a valid prescription for the drug. Less than half provide an online health screen to assess suitability for supply. The majority have no registered geographical location. Analgesic medicines are usually purchased at prices significantly above British National Formulary prices and are often supplied in large quantities. These findings are of particular relevance to pain-management specialists who are trying to improve the rational use of analgesic drugs. AIMS: To explore the availability to the UK population of prescription-only analgesics from the internet. METHODS: Websites were identified by using several keywords in the most popular internet search engines. From 2000 websites, details of 96 were entered into a database. RESULTS: Forty-six (48%) websites sold prescription analgesics, including seven opioids, two non-opioids and 18 nonsteroidal anti-inflammatory drugs. Thirty-five (76%) of these did not require the customer to possess a valid prescription. CONCLUSION: Prescription-only analgesics, including controlled opioids, are readily available from internet websites, often without a valid prescription.

Morphine is an arteriolar vasodilator in man.

AIM: The mechanisms of action of morphine on the arterial system are not well understood. The aim was to report forearm vascular responses, and their mediation, to intra-arterial morphine in healthy subjects. METHODS: Three separate protocols were performed: (i) dose ranging; (ii) acute tolerance; (iii) randomized crossover mechanistic study on forearm blood flow (FBF) responses to intrabrachial infusion of morphine using venous occlusion plethysmography. Morphine was infused either alone (study 1 and 2), or with an antagonist: naloxone, combined histamine-1 and histamine-2 receptor blockade or during a nitric oxide clamp. RESULTS: Morphine caused an increase in FBF at doses of 30 microg min(-1)[3.25 (0.26) ml min(-1) 100 ml(-1)][mean (SEM)] doubling at 100 microg min(-1) to 5.23 (0.53) ml min(-1) 100 ml(-1). Acute tolerance was not seen to 50 microg min(-1) morphine, with increased FBF [3.96 (0.35) ml min(-1) 100 ml(-1)] (P = 0.003), throughout the 30-min infusion period. Vasodilatation was abolished by pretreatment with antihistamines (P = 0.008) and the nitric oxide clamp (P < 0.001), but not affected by naloxone. The maximum FBF with pretreatment with combined H1/H2 blockade was 3.06 (0.48) and 2.90 (0.17) ml min(-1) 100 ml(-1) after 30 min, whereas with morphine alone it reached 4.3 (0.89) ml min(-1) 100 ml(-1). CONCLUSIONS: Intra-arterial infusion of morphine into the forearm circulation causes vasodilatation through local histamine-modulated nitric oxide release. Opioid receptor mechanisms need further exploration.

Medication errors: problems and recommendations from a consensus meeting.

Here we discuss 15 recommendations for reducing the risks of medication errors: 1. Provision of sufficient undergraduate learning opportunities to make medical students safe prescribers. 2. Provision of opportunities for students to practise skills that help to reduce errors. 3. Education of students about common types of medication errors and how to avoid them. 4. Education of prescribers in taking accurate drug histories. 5. Assessment in medical schools of prescribing knowledge and skills and demonstration that newly qualified doctors are safe prescribers. 6. European harmonization of prescribing and safety recommendations and regulatory measures, with regular feedback about rational drug use. 7. Comprehensive assessment of elderly patients for declining function. 8. Exploration of low-dose regimens for elderly patients and preparation of special formulations as required. 9. Training for all health-care professionals in drug use, adverse effects, and medication errors in elderly people. 10. More involvement of pharmacists in clinical practice. 11. Introduction of integrated prescription forms and national implementation in individual countries. 12. Development of better monitoring systems for detecting medication errors, based on classification and analysis of spontaneous reports of previous reactions, and for investigating the possible role of medication errors when patients die. 13. Use of IT systems, when available, to provide methods of avoiding medication errors; standardization, proper evaluation, and certification of clinical information systems. 14. Nonjudgmental communication with patients about their concerns and elicitation of symptoms that they perceive to be adverse drug reactions. 15. Avoidance of defensive reactions if patients mention symptoms resulting from medication errors.

Phosphodiesterase type 5 inhibition reverses impaired forearm exercise-induced vasodilatation in hypertensive patients.

OBJECTIVE: Established hypertension is characterized by increased peripheral vascular resistance and endothelial dysfunction, features that may underlie the reduced exercise-induced vasodilatation seen in hypertensive patients. Sildenafil citrate is a phosphodiesterase type 5 (PDE5) inhibitor used clinically for the treatment of male erectile dysfunction. Its vasodilating properties are due to the inhibition of cyclic guanosine monophosphate (cGMP) breakdown and prolongation of the signalling actions of the nitric oxide (NO)-cGMP pathway in vascular smooth muscle cells. Sildenafil has beneficial effects on endothelial function and exercise tolerance in congestive heart failure and pulmonary hypertension, and we hypothesized that it would improve exercise-induced vasodilatation in hypertensive patients. METHODS AND RESULTS: Ten hypertensive patients and ten matched normotensive subjects were studied in a three-way, randomized, single-blind and placebo-controlled study. On each study day, forearm blood flow (FBF) responses to handgrip exercise were assessed before and after intra-arterial (brachial) infusion of sildenafil, verapamil (a control, cGMP-independent vasodilator), and saline (placebo). Preinfusion exercise-induced vasodilatation was significantly reduced in hypertensive patients compared to normotensive controls. Sildenafil and verapamil infusions both caused a similar increase in baseline FBF. However, while verapamil did not affect the vasodilator response to handgrip exercise in either group, sildenafil substantially enhanced this response in hypertensive patients, but not in normotensive subjects. CONCLUSIONS: Our data suggest that sildenafil, through an increase in cGMP levels in the vasculature, substantially and selectively improves the vasodilator response to handgrip exercise in hypertensive patients. These findings represent an essential first step in support of further studies exploring the potentially beneficial effects of PDE5 inhibition on impaired exercise capacity in hypertension.

Undergraduate preparation for prescribing: the views of 2413 UK medical students and recent graduates.

AIMS: To gather opinions from UK medical students and recent graduates about their undergraduate training to prescribe and their confidence about meeting the relevant competencies identified by the General Medical Council (GMC). METHODS: We designed a web-based survey that was distributed to UK medical students and first year Foundation doctors (graduation years 2006-2008) via medical schools and postgraduate networks. RESULTS: Analysis was restricted to 2413 responses from students graduating in 2006-2008 from the 25 UK medical schools (mean 96.5 per school) with a complete undergraduate curriculum. Distinct courses and assessments in 'clinical pharmacology & therapeutics (or equivalent)' were identified by 17% and 13%, respectively, with mode of learning described most commonly as 'opportunistic learning during clinical attachments' (41%). Only 38% felt 'confident' about prescription writing and only a minority (35%) had filled in a hospital prescription chart more than three times during training. The majority (74%) felt that the amount of teaching in this area was 'too little' or 'far too little', and most tended to disagree or disagreed that their assessment 'thoroughly tested knowledge and skills' (56%). When asked if they were confident that they would be able to achieve the prescribing competencies set out by the GMC, 42% disagreed or tended to disagree, whereas only 29% agreed or tended to agree. CONCLUSIONS: Many respondents clearly perceived a lack of learning opportunities and assessment related to the safe and effective use of drugs and had little confidence that they would meet the competencies identified by the GMC. There is an urgent need to review undergraduate training in this area.

Key Learning Outcomes for Clinical Pharmacology and Therapeutics Education in Europe: A Modified Delphi Study.

Harmonizing clinical pharmacology and therapeutics (CPT) education in Europe is necessary to ensure that the prescribing competency of future doctors is of a uniform high standard. As there are currently no uniform requirements, our aim was to achieve consensus on key learning outcomes for undergraduate CPT education in Europe. We used a modified Delphi method consisting of three questionnaire rounds and a panel meeting. A total of 129 experts from 27 European countries were asked to rate 307 learning outcomes. In all, 92 experts (71%) completed all three questionnaire rounds, and 33 experts (26%) attended the meeting. 232 learning outcomes from the original list, 15 newly suggested and 5 rephrased outcomes were included. These 252 learning outcomes should be included in undergraduate CPT curricula to ensure that European graduates are able to prescribe safely and effectively. We provide a blueprint of a European core curriculum describing when and how the learning outcomes might be acquired.

Uric acid restores endothelial function in patients with type 1 diabetes and regular smokers.

Endothelial dysfunction is a characteristic finding in both patients with type 1 diabetes and in regular smokers and is an important precursor to atherosclerosis. The urate molecule has antioxidant properties, which could influence endothelial function. The impact of acutely raising uric acid concentrations on endothelial function was studied in eight men with type 1 diabetes, eight healthy regular smokers, and eight age-matched healthy control subjects in a randomized, four-way, double-blind, placebo-controlled study. Subjects received 1,000 mg uric acid i.v. in vehicle, 1,000 mg vitamin C as a control antioxidant, vehicle alone, or 0.9% saline on separate occasions over 1 h. Forearm blood flow responses to intrabrachial acetylcholine and sodium nitroprusside were assessed using venous occlusion plethysmography. Responses to acetylcholine, but not sodium nitroprusside, were impaired in patients with diabetes (P < 0.001) and in smokers (P < 0.005) compared with control subjects. Administration of uric acid and vitamin C selectively improved acetylcholine responses in patients with type 1 diabetes (P < 0.01) and in regular smokers (P < 0.05). Uric acid administration improved endothelial function in the forearm vascular bed of patients with type 1 diabetes and smokers, suggesting that high uric acid concentrations in vivo might serve a protective role in these and other conditions associated with increased cardiovascular risk.

A generalized arterial transfer function derived at rest underestimates augmentation of central pressure after exercise.

OBJECTIVES: Peripheral exercise blood pressure and resting central blood pressure are considered more relevant to cardiovascular health than resting peripheral blood pressure. Central exercise blood pressure may well be an even more useful measure, but there is no simple non-invasive means of determining it. The aim of the present study was to establish whether the estimation of central blood pressure from peripheral blood pressure using a transfer function derived at rest, would hold after aerobic exercise. METHODS: Thirty healthy young men were studied before and immediately (< 1 min) and 10 min after 15 min bicycle exercise at 65-70% of maximum heart rate. Simultaneous carotid and radial artery waveforms were recorded, and radial-to-carotid generalized transfer functions (GTF) were calculated using Fourier analysis for rest and immediately postexercise. Central systolic blood pressure (SBP) and augmentation index (AIx) were calculated for measured and derived waves. RESULTS: The resting GTF underestimated central SBP and AIx immediately (-5.8 +/- 2.1 mmHg, P = 0.01; -8.3 +/- 2.9%, P = 0.008) and 10 min after (-2.0 +/- 0.7 mmHg, P = 0.008; -7.0 +/- 2.1%, P = 0.003) exercise. No significant bias was found between measured and derived (using resting GTF) carotid values at rest. The use of an exercise-specific GTF resulted in no specific bias immediately or 10 min after exercise, although it overestimated blood pressure and AIx at rest (2.5 +/- 1.0 mmHg, P = 0.02; 11.3 +/- 3.0%, P = 0.001). CONCLUSION: A peripheral-to-central arterial GTF derived at rest significantly underestimates key measures of central arterial pressure immediately after exercise, and pressure estimations may be improved by the use of an exercise-specific GTF.

Endogenous urate production augments plasma antioxidant capacity in healthy lowland subjects exposed to high altitude.

BACKGROUND: Both tissue hypoxia in vitro, and whole-body hypoxia in vivo, have been found to promote the release of reactive oxygen species (ROS) that are potentially damaging to the cardiovascular system. Antioxidant systems protect against oxidative damage by ROS and may exhibit some degree of responsiveness to oxidative stimuli. Production of urate, a potent soluble antioxidant, is increased in hypoxic conditions. We aimed to determine whether urate is an important antioxidant defense in healthy subjects exposed to hypoxia. METHODS: We conducted a cohort study of 25 healthy lowland volunteers during acute exposure to high altitude (4 days at 3,600 m, followed by 10 days at 5,200 m) on the Apex high-altitude research expedition to Bolivia. We measured markers of oxidative stress (8-isoprostane F2), serum urate concentration, and total plasma antioxidant activity by two techniques: 2,2'-amino-di-[3-ethylbenzthiazole sulfonate] spectrophotometry (total antioxidant status [TAS]) and enhanced chemiluminescence (ECL). RESULTS: On ascent, F2-isoprostane levels were significantly elevated compared with those at sea level (p < 0.01). After 1 week at high altitude, plasma antioxidant capacity (AOC) by both TAS and ECL, and serum urate concentration were significantly elevated (each p < 0.01 vs sea level), and F2-isoprostane levels were reduced to values at sea level. There was a highly significant correlation between plasma urate and AOC at this stage (ECL, r(2) = 0.59, p = 0.0001; TAS, r(2) = 0.30, p = 0.0062). CONCLUSIONS: Our results support the hypothesis that urate may act as a responsive endogenous antioxidant in high-altitude hypoxia.

The influence of primary care prescribing rates for new drugs on spontaneous reporting of adverse drug reactions.

INTRODUCTION: Adverse drug reaction (ADR) reporting makes a vital contribution to pharmacovigilance, although the factors that influence the reporting rate remain unclear. The aim of this study was to investigate whether the variation in the rate of reporting of suspected ADRs in different regions of Scotland was explained by differences in local prescribing practice and to quantify the extent of this influence. METHODS: Population and primary care prescribing data were obtained for ten geographical areas based on the 15 administrative regions of the National Health Service in Scotland. All reports of suspected ADRs received from within Scotland for 2000 and 2001 were available from the regional monitoring centre (Committee on Safety of Medicines, Scotland). The primary analysis was based on 14 medications that appeared in the 'top ten' list for the frequency of reported ADRs for either year. Reporting rates for each area were expressed both in terms of population (reports per million people) and in terms of estimated exposure to those medications in primary care (reports per 1000 prescriptions). For each analysis, the Pearson correlation coefficient between reporting and prescribing data was calculated using SPSS software. RESULTS: The 'top ten' medications accounted for 1715 of 2817 (60.9%, 95% CI 59.1, 62.7) ADR reports but only 2.2 million out of a total of 128 million primary care prescriptions (1.7%). Although there was a 3-fold geographical variation in the per-population ADR reporting rate, there was a close correlation between local reporting of ADRs and prescribing of the index medications (p = 0.66, p = 0.04, respectively). This implies that 44% of the observed variation in reporting rate can be attributed to variation in prescribing within the same population. DISCUSSION: Spontaneous ADR reporting in Scotland over the 2 years studied was highly concentrated on a small number of medications that were under intensive surveillance. Although there was a 3-fold variation in reporting rates from individual geographic areas when corrected for the size of the population, primary care prescribing data showed nearly half of this local variation in reporting rates could be explained by differences in prescribing. This study highlights the importance of considering prescribing practice when interpreting spontaneous ADR reporting data.

Effects of short-term isocapnic hyperoxia and hypoxia on cardiovascular function.

Both hypoxia and hyperoxia have major effects on cardiovascular function. However, both states affect ventilation and many previous studies have not controlled CO(2) tension. We investigated whether hemodynamic effects previously attributed to modified O(2) tension were still apparent under isocapnic conditions. In eight healthy men, we studied blood pressure (BP), heart rate (HR), cardiac index (CI), systemic vascular resistance index (SVRI) and arterial stiffness (augmentation index, AI) during 1 h of hyperoxia (mean end-tidal O(2) 79.6 +/- 2.0%) or hypoxia (pulse oximeter oxygen saturation 82.6 +/- 0.3%). Hyperoxia increased SVRI (18.9 +/- 1.9%; P < 0.001) and reduced HR (-10.3 +/- 1.0%; P < 0.001), CI (-10.3 +/- 1.7%; P < 0.001), and stroke index (SI) (-7.3 +/- 1.3%; P < 0.001) but had no effect on AI, whereas hypoxia reduced SVRI (-15.2 +/- 1.2%; P < 0.001) and AI (-10.7 +/- 1.1%; P < 0.001) and increased HR (18.2 +/- 1.2%; P < 0.001), CI (20.2 +/- 1.8%; P < 0.001), and pulse pressure (13.2 +/- 2.3%; P = 0.02). The effects of hyperoxia on CI and SVRI, but not the other hemodynamic effects, persisted for up to 1 h after restoration of air breathing. Although increased oxidative stress has been proposed as a cause of the cardiovascular response to altered oxygenation, we found no significant changes in venous antioxidant or 8-iso-prostaglandin F(2alpha) levels. We conclude that both hyperoxia and hypoxia, when present during isocapnia, cause similar changes in cardiovascular function to those described with poikilocapnic conditions.

Prediction of serum total antioxidant activity from the concentration of individual serum antioxidants.

BACKGROUND: Redox mechanisms are implicated in the pathogenesis of many diseases and several assays of total antioxidant capacity (TAOC) have been reported. Large epidemiological databases contain information on individual serum antioxidants as well as disease-specific phenotypic data. However, antioxidants work co-operatively in biological systems and it is important to be able to translate individual antioxidant measures into those of global antioxidant defence. Models therefore need developing to quantify contributions made by individual species to global antioxidant defence. OBJECTIVE: To develop a predictive model that translates individual antioxidant concentrations into an index of TAOC, enabling interrogation of epidemiological databases that contain information about individual antioxidants, but not about TAOC. METHODS: Sera from 256 volunteers were simultaneously assayed for key antioxidants and TAOC by enhanced chemiluminescence (TAOC(ECL)). A predictive model was developed for serum TAOC using multiple linear regression analysis. RESULTS: The model explained 86% of TAOC(ECL) variability in serum. The strongest predictor of TAOC(ECL) was uric acid (1 SD increase associated with TAOC(ECL) increase of 103 micromol/l Teq-95% CI: 96.8-109), followed by vitamins A, C, E. CONCLUSIONS: The reported model represents a powerful tool for interrogating databases where individual serum antioxidant concentrations are known, and TAOC measures are required.