Exploration of reasons for primary care testing (the Why Test study): a UK-wide audit using the Primary care Academic CollaboraTive.

BACKGROUND: Rates of blood testing have increased over the past two decades. Reasons for testing cannot easily be extracted from electronic health record databases. AIM: To explore who requests blood tests and why, and what the outcomes of testing are in UK primary care. DESIGN AND SETTING: A retrospective audit of electronic health records in general practices in England, Wales, Scotland, and Northern Ireland was undertaken. METHOD: Fifty-seven clinicians from the Primary care Academic CollaboraTive (PACT) each reviewed the electronic health records of 50 patients who had blood tests in April 2021. Anonymised data were extracted including patient characteristics, who requested the tests, reasons for testing, test results, and outcomes of testing. RESULTS: Data were collected from 2572 patients across 57 GP practices. The commonest reasons for testing in primary care were investigation of symptoms (43.2%), monitoring of existing disease (30.1%), monitoring of existing medications (10.1%), and follow up of previous abnormalities (6.8%); patient requested testing was rare in this study (1.5%). Abnormal and borderline results were common, with 26.6% of patients having completely normal test results. Around one-quarter of tests were thought to be partially or fully unnecessary when reviewed retrospectively by a clinical colleague. Overall, 6.2% of tests in primary care led to a new diagnosis or confirmation of a diagnosis. CONCLUSION: The utilisation of a national collaborative model (PACT) has enabled a unique exploration of the rationale and outcomes of blood testing in primary care, highlighting areas for future research and optimisation.

Concussion in the UK: a contemporary narrative review.

Concussion has been receiving an increasing amount of media exposure following several high-profile professional sports controversies and multimillion-dollar lawsuits. The potential life-changing sequalae of concussion and the rare, but devasting, second impact syndrome have also gained much attention. Despite this, our knowledge of the pathological processes involved is limited and often extrapolated from research into more severe brain injuries. As there is no objective diagnostic test for concussion. Relying on history and examination only, the diagnosis of concussion has become the rate-limiting step in widening research into the disease. Clinical study protocols therefore frequently exclude the most vulnerable groups of patients such as those with existing cognitive impairment, concurrent intoxication, mental health issues or learning difficulties. This up-to-date narrative review aims to summarize our current concussion knowledge and provides an insight into promising avenues for future research.

Concussion in Non-athletes: Assessment of Cognition and Symptomatology (CONTACTS) study protocol - an exploratory cohort study investigating the utility of sports concussion assessment tools and salivary microRNAs to diagnose concussion in NHS patients.

INTRODUCTION: Concussion is a complex pathophysiological process with a wide range of non-specific signs and symptoms. There are currently no objective diagnostic tests to identify concussion, and diagnosis relies solely on history and examination. Recent research has identified a unique panel of microRNAs (miRNAs) that distinguish between concussed and non-concussed rugby players. This study aims to assess the diagnostic utility of salivary miRNAs in concussion for a sample of UK National Health Service patients and whether well-established sports-related concussion (SRC) assessment tools may be translated into the emergency department (ED). METHODS AND ANALYSIS: Concussion in Non-athletes: Assessment of Cognition and Symptomatology is a single-centre, prospective, two-phase cohort study. The concussed cohort will consist of participants with maxillofacial trauma and concurrent concussion. The control cohort will consist of participants with isolated limb trauma and no evidence of concussion. Participants will be recruited in the ED and saliva samples will be taken to identify the presence of miRNAs. The SRC assessments being investigated include the Sports Concussion Assessment Test, Fifth Edition (SCAT5), the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) and the ImPACT Quick. Follow-up will be at 24-48 hours in-hospital and remotely via telephone and email at 14 days and 6 months. ETHICS AND DISSEMINATION: Ethical approval was granted in February 2021 by the West Midlands Coventry & Warwickshire Research Ethics Committee (ref 20/WM/0299). The investigators intend to submit their study findings for publication in peer-reviewed journals and to disseminate study findings via presentation at academic meetings. The results will also form part of a doctorate thesis, registered at the University of Birmingham.

Transferability of genetic loci and polygenic scores for cardiometabolic traits in British Pakistani and Bangladeshi individuals.

Individuals with South Asian ancestry have a higher risk of heart disease than other groups but have been largely excluded from genetic research. Using data from 22,000 British Pakistani and Bangladeshi individuals with linked electronic health records from the Genes & Health cohort, we conducted genome-wide association studies of coronary artery disease and its key risk factors. Using power-adjusted transferability ratios, we found evidence for transferability for the majority of cardiometabolic loci powered to replicate. The performance of polygenic scores was high for lipids and blood pressure, but lower for BMI and coronary artery disease. Adding a polygenic score for coronary artery disease to clinical risk factors showed significant improvement in reclassification. In Mendelian randomisation using transferable loci as instruments, our findings were consistent with results in European-ancestry individuals. Taken together, trait-specific transferability of trait loci between populations is an important consideration with implications for risk prediction and causal inference.

Why Test study protocol: a UK-wide audit using the Primary Care Academic CollaboraTive (PACT) to explore the reasons for primary care testing.

BACKGROUND: The number of blood tests done in primary care has been increasing over the past 20 years. Some estimates suggest that up to one-quarter of these tests may not have been needed. This could lead to a cascade effect of further investigations, appointments, or referrals, as well as anxiety for patients, increased workload, and costs to the health service. To better understand the impact and sequelae of blood tests on patients, it is necessary to know why blood tests are requested and what is done with the results. AIM: To explore who orders blood tests and why, and how test results are actioned in primary care. DESIGN & SETTING: Retrospective audit of electronic health records in general practices across the UK. METHOD: The Primary care Academic CollaboraTive (PACT), a UK-wide network of primary care health professionals, will be utilised to collect data from individual practices. PACT members will be asked to review the electronic health records of 50 patients who had recent blood tests in their practice, and manually extract anonymised data on who requested the test, the indication, the result, and subsequent actions. Data will also be collected from PACT members to assess the feasibility of the collaborative model. CONCLUSION: PACT offers a unique opportunity to extract clinical data which cannot otherwise be obtained. Understanding the indications for tests will help identify priority areas for research to optimise testing and patient safety in primary care.

Characterisation of type 2 diabetes subgroups and their association with ethnicity and clinical outcomes: a UK real-world data study using the East London Database.

BACKGROUND: Subgroups of type 2 diabetes (T2DM) have been well characterised in experimental studies. It is unclear, however, whether the same approaches can be used to characterise T2DM subgroups in UK primary care populations and their associations with clinical outcomes. AIM: To derive T2DM subgroups using primary care data from a multi-ethnic population, evaluate associations with glycaemic control, treatment initiation, and vascular outcomes, and to understand how these vary by ethnicity. DESIGN AND SETTING: An observational cohort study in the East London Primary Care Database from 2008 to 2018. METHOD: Latent-class analysis using age, sex, glycated haemoglobin, and body mass index at diagnosis was used to derive T2DM subgroups in white, South Asian, and black groups. Time to treatment initiation and vascular outcomes were estimated using multivariable Cox-proportional hazards regression. RESULTS: In total, 31 931 adults with T2DM were included: 47% South Asian (n = 14 884), 26% white (n = 8154), 20% black (n = 6423). Two previously described subgroups were replicated, 'mild age-related diabetes' (MARD) and 'mild obesity-related diabetes' (MOD), and a third was characterised 'severe hyperglycaemic diabetes' (SHD). Compared with MARD, SHD had the poorest long-term glycaemic control, fastest initiation of antidiabetic treatment (hazard ratio [HR] 2.02, 95% confidence interval [CI] = 1.76 to 2.32), and highest risk of microvascular complications (HR 1.38, 95% CI = 1.28 to 1.49). MOD had the highest risk of macrovascular complications (HR 1.50, 95% CI = 1.23 to 1.82). Subgroup differences in treatment initiation were most pronounced for the white group, and vascular complications for the black group. CONCLUSION: Clinically useful T2DM subgroups, identified at diagnosis, can be generated in routine real-world multi-ethnic populations, and may offer a pragmatic means to develop stratified primary care pathways and improve healthcare resource allocation.

Integrating polygenic risk scores in the prediction of type 2 diabetes risk and subtypes in British Pakistanis and Bangladeshis: A population-based cohort study.

BACKGROUND: Type 2 diabetes (T2D) is highly prevalent in British South Asians, yet they are underrepresented in research. Genes & Health (G&H) is a large, population study of British Pakistanis and Bangladeshis (BPB) comprising genomic and routine health data. We assessed the extent to which genetic risk for T2D is shared between BPB and European populations (EUR). We then investigated whether the integration of a polygenic risk score (PRS) for T2D with an existing risk tool (QDiabetes) could improve prediction of incident disease and the characterisation of disease subtypes. METHODS AND FINDINGS: In this observational cohort study, we assessed whether common genetic loci associated with T2D in EUR individuals were replicated in 22,490 BPB individuals in G&H. We replicated fewer loci in G&H (n = 76/338, 22%) than would be expected given power if all EUR-ascertained loci were transferable (n = 101, 30%; p = 0.001). Of the 27 transferable loci that were powered to interrogate this, only 9 showed evidence of shared causal variants. We constructed a T2D PRS and combined it with a clinical risk instrument (QDiabetes) in a novel, integrated risk tool (IRT) to assess risk of incident diabetes. To assess model performance, we compared categorical net reclassification index (NRI) versus QDiabetes alone. In 13,648 patients free from T2D followed up for 10 years, NRI was 3.2% for IRT versus QDiabetes (95% confidence interval (CI): 2.0% to 4.4%). IRT performed best in reclassification of individuals aged less than 40 years deemed low risk by QDiabetes alone (NRI 5.6%, 95% CI 3.6% to 7.6%), who tended to be free from comorbidities and slim. After adjustment for QDiabetes score, PRS was independently associated with progression to T2D after gestational diabetes (hazard ratio (HR) per SD of PRS 1.23, 95% CI 1.05 to 1.42, p = 0.028). Using cluster analysis of clinical features at diabetes diagnosis, we replicated previously reported disease subgroups, including Mild Age-Related, Mild Obesity-related, and Insulin-Resistant Diabetes, and showed that PRS distribution differs between subgroups (p = 0.002). Integrating PRS in this cluster analysis revealed a Probable Severe Insulin Deficient Diabetes (pSIDD) subgroup, despite the absence of clinical measures of insulin secretion or resistance. We also observed differences in rates of progression to micro- and macrovascular complications between subgroups after adjustment for confounders. Study limitations include the absence of an external replication cohort and the potential biases arising from missing or incorrect routine health data. CONCLUSIONS: Our analysis of the transferability of T2D loci between EUR and BPB indicates the need for larger, multiancestry studies to better characterise the genetic contribution to disease and its varied aetiology. We show that a T2D PRS optimised for this high-risk BPB population has potential clinical application in BPB, improving the identification of T2D risk (especially in the young) on top of an established clinical risk algorithm and aiding identification of subgroups at diagnosis, which may help future efforts to stratify care and treatment of the disease.

Primary care service utilisation and outcomes in type 2 diabetes: a longitudinal cohort analysis.

OBJECTIVES: To describe primary care utilisation patterns among adults with type 2 diabetes and to quantify the association between utilisation and long-term health outcomes. DESIGN: Retrospective cohort study. SETTING: 168 primary care practices in Southern England within the Electronic Care and Health Information Analytics database between 2013 and 2020. PARTICIPANTS: 110 240 adults with Quality and Outcomes Framework read code of type 2 diabetes diagnosis; age greater than 18 years; linked and continuous records available from April 2013 until April 2020 (or death). PRIMARY AND SECONDARY OUTCOME MEASURES: (1) Rates of service utilisation (total number of primary care contacts per quarter) across the study period; (2) participant characteristics associated with higher and lower rates of service utilisation; and (3) associations between service utilisation and (A) cardiovascular disease (CVD events) and (B) all-cause mortality. RESULTS: Mean (SD) number of primary care attendances per quarter in the cohort of 110 240 went from 2.49 (2.01) in 2013 to 2.78 (2.06) in 2020. Patients in the highest usage tertile were more likely to be female, older, more frail, white, from the least deprived quintile and to have five or more comorbidities. In adjusted models, higher rates of service utilisation (per consultation) were associated with higher rates of CVD events (OR 1.0058; 95% CI 1.0053 to 1.0062; p<0.001) and mortality (OR 1.0057; 95% CI 1.0051 to 1.0064; p<0.001). CONCLUSIONS: People with type 2 diabetes are using primary care services more frequently, but increased volume of clinical care does not correlate with better outcomes, although this finding may be driven by more unwell patients contacting services more frequently. Further research on the nature and content of contacts is required to understand how to tailor services to deliver effective care to those at greatest risk of complications.

Population stratification in type 2 diabetes mellitus: A systematic review.

AIMS: There is increasing interest in using stratification in type 2 diabetes to target resources, individualise care and improve outcomes. We aim to systematically review and collate literature that has utilised population stratification methods in the study of adults with type 2 diabetes; and to describe and compare stratification methodologies, population characteristics, variables used to stratify and outcome variables. METHODS: The MEDLINE, EMBASE, CINAHL and Cochrane databases were searched from inception to July 2020. Studies included adults with type 2 diabetes using population stratification methods. The review protocol was registered on PROSPERO (ID: CRD42020206604) and conducted in line with PRISMA guidance. Extracted data included study aims; study setting (primary or secondary care); population characteristics; stratification variables and outcomes; and methodological approach to stratification. RESULTS: Across 348 included studies, there were a total of 10,776,009 participants with a mean age of 61.0 years (SD 5.94). 6.7% of studies used data-driven methods and the rest employed expert-driven approaches using pre-defined stratification criteria. The commonest variable used to stratify populations was HbA1c (n = 57, 16.4%); few studies stratified using clinically important non-traditional variables such as health behaviours and beliefs. CONCLUSIONS: Most studies performing population stratification in type 2 diabetes used expert-driven approaches with the aim of predicting outcomes in glycaemic control, mortality and cardiovascular complications. We identified relatively few studies using data-driven approaches, which offer opportunities generate hypotheses beyond current expert knowledge. We describe important research gaps including stratification with regard to disease remission.

Integrating primary care and social services for older adults with multimorbidity: a qualitative study.

BACKGROUND: Growing demand from an increasingly ageing population with multimorbidity has resulted in complex health and social care needs requiring more integrated services. Integrating primary care with social services could utilise resources more efficiently, and improve experiences for patients, their families, and carers. There is limited evidence on progress including key barriers to and drivers of integration to inform large-scale national change. AIM: To elicit stakeholder views on drivers and barriers of integrated primary care and social services, and highlight opportunities for successful implementation. DESIGN AND SETTING: A qualitative interview study. METHOD: Semi-structured interviews with maximum variation sampling to capture stakeholder views across services and professions. RESULTS: Thirty-seven interviews were conducted across England with people including GPs, nurses, social care staff, commissioners, local government officials, voluntary and private sector workers, patients, and carers. Drivers of integration included groups of like-minded individuals supported by good leadership, expanded interface roles to bridge gaps between systems, and co-location of services. Barriers included structural and interdisciplinary tension between professions, organisational self-interest, and challenges in record sharing. CONCLUSION: Drivers and barriers to integration identified in other contexts are also present in primary care and social services. Benefits of integration are unlikely to be realised if these are not addressed in the design and execution of new initiatives. Efforts should go beyond local- and professional-level change to include wider systems- and policy-level initiatives. This will support a more systems-wide approach to integrated care reform, which is necessary to meet the complex and growing needs of an ageing multimorbid population.

Analysis of the trend in community prescribing of RAAS inhibitors during the COVID-19 pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has sparked novel research and insights, but also concerns and anxiety regarding established practices. Early into the pandemic, public and scientific concern was raised regarding the role of renin-angiotensin- aldosterone system (RAAS) inhibitors on the susceptibility to COVID-19 given their effect on angiotensin-converting enzyme 2 (ACE-2), the host receptor for the virus. This gathered media attention globally, despite several health boards encouraging the ongoing use of these medications. We aimed to investigate whether, despite advice supporting continued use of these medications, there was a change in prescribing practices for RAAS inhibitors in general practice. Data were collated from the NHS digital platform, which provides monthly practice-level prescribing information for all primary care practices in England. We performed an interrupted time-series analysis on national-level prescribing data comparing time-series coefficients pre- and post-March 2020 with metformin used as a control. We find that from March to December 2020, prescribing rates of RAAS inhibitors were reduced relative to the previous time-series trend. This finding persisted after adjustment for rates of metformin prescription. This suggests that there was a change in prescribing behaviour during the COVID-19 pandemic, which may be linked to the public and scientific concerns during this time.

Currently prescribed drugs in the UK that could upregulate or downregulate ACE2 in COVID-19 disease: a systematic review.

OBJECTIVE: To review evidence on routinely prescribed drugs in the UK that could upregulate or downregulate ACE2 and potentially affect COVID-19 disease. DESIGN: Systematic review. DATA SOURCE: MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science. STUDY SELECTION: Any design with animal or human models examining a currently prescribed UK drug compared with a control, placebo or sham group, and reporting an effect on ACE2 level, activity or gene expression. DATA EXTRACTION AND SYNTHESIS: MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science and OpenGrey from inception to 1 April 2020. Methodological quality was assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool for animal studies and Cochrane risk-of-bias tool for human studies. RESULTS: We screened 3360 titles and included 112 studies with 21 different drug classes identified as influencing ACE2 activity. Ten studies were in humans and one hundred and two were in animal models None examined ACE2 in human lungs. The most frequently examined drugs were angiotensin receptor blockers (ARBs) (n=55) and ACE inhibitors (ACE-I) (n=22). More studies reported upregulation than downregulation with ACE-I (n=22), ARBs (n=55), insulin (n=8), thiazolidinedione (n=7) aldosterone agonists (n=3), statins (n=5), oestrogens (n=5) calcium channel blockers (n=3) glucagon-like peptide 1 (GLP-1) agonists (n=2) and Non-steroidal anti-inflammatory drugs (NSAIDs) (n=2). CONCLUSIONS: There is an abundance of the academic literature and media reports on the potential of drugs that could attenuate or exacerbate COVID-19 disease. This is leading to trials of repurposed drugs and uncertainty among patients and clinicians concerning continuation or cessation of prescribed medications. Our review indicates that the impact of currently prescribed drugs on ACE2 has been poorly studied in vivo, particularly in human lungs where the SARS-CoV-2 virus appears to enact its pathogenic effects. We found no convincing evidence to justify starting or stopping currently prescribed drugs to influence outcomes of COVID-19 disease.

Drug treatments affecting ACE2 in COVID-19 infection: a systematic review protocol.

BACKGROUND: The SARS-CoV-2 virus causing COVID-19 binds human angiotensin-converting enzyme 2 (ACE2) receptors in human tissues. ACE2 expression may be associated with COVID-19 infection and mortality rates. Routinely prescribed drugs that up- or down-regulate ACE2 expression are, therefore, of critical research interest as agents that might promote or reduce risk of COVID-19 infection in a susceptible population. AIM: To collate evidence on routinely prescribed drug treatments in the UK that could up- or down-regulate ACE2, and thus potentially affect COVID-19 infection. DESIGN & SETTING: Systematic review of studies published in MEDLINE, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature), the Cochrane Library, and Web of Science from inception to 1 April 2020. METHOD: A systematic review will be conducted in line with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Inclusion criteria will be: (1) assesses the effect of drug exposure on ACE2 level of expression or activity; (2) the drug is included in the British National Formulary (BNF) and, therefore, available to prescribe in the UK; and (3) a control, placebo, or sham group is included as comparator. Exclusion criteria will be: (1) ACE2 measurement in utero; (2) ACE2 measurement in children aged <18 years; (3) drug not in the BNF; and (4) review article. Quality will be assessed using the Cochrane risk of bias tool for human studies, and the SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) risk of bias tool for animal studies. RESULTS: Data will be reported in summary tables and narrative synthesis. CONCLUSION: This systematic review will identify drug therapies that may increase or decrease ACE2 expression. This might identify medications increasing risk of COVID-19 transmission, or as targets for intervention in mitigating transmission.

Inequalities in suicide rates associated with deprivation in England from 2004 to 2019.

BACKGROUND: Although addressing inequality has been a public and political priority for decades, inequalities in health, wealth, and other societal domains persist in England. In Ireland, rates of suicide are twice as high in the most deprived decile of society compared with the least deprived. Trends in the association between deprivation and suicide in England are unclear. AIM: To describe the relationship between deprivation and suicide in England in 2019 and analyse trends in this relationship over time. METHOD: Data on rate of suicide and Index of Multiple Deprivation (IMD) for each local authority in England for 2018 and 2004 were obtained from the Office for National Statistics' publicly available databases. The mean suicide rate for each quintile of deprivation was calculated, and means compared using ANOVA. The correlation coefficients between IMD and suicide rate were calculated for both 2004 and 2019. Steiger's test was used to compare coefficients over time. RESULTS: In 2019, the suicide rate in the least deprived quintile was 8.7 per 100 000 person-years, compared with 8.3 in 2004. This increased across each quintile to 11.1 suicides per 100 000 person-years in the most deprived quintile in 2019 (ANOVA: P<0.001), and to 11.7 in 2004 (ANOVA: P<0.001). The correlation coefficient between IMD and suicide rate in 2004 was 0.43, compared with 0.33 in 2019. Steiger's test demonstrated no significant difference between coefficients over time (P = 0.16). CONCLUSION: Suicide is associated with deprivation in England. Despite significant research and policy effort, there has been no improvement in this association between 2004 and 2019.

Loneliness, social isolation, cardiovascular disease and mortality: a synthesis of the literature and conceptual framework.

To conduct a systematic review and develop a conceptual framework on the mechanisms linking loneliness, social isolation, health outcomes and mortality. Electronic databases were systematically searched (PubMed, MEDLINE, Scopus and EMBASE) from inception to October 2018 followed by manual searching to identify research on loneliness, social isolation and mortality in adults published in the English language. Articles were assessed for quality and synthesised into a conceptual framework using meta-ethnographical approaches. A total of 122 articles were included. These collated observational designs examining mediators and moderations of the association in addition to qualitative studies exploring potential mechanisms were included. A framework incorporating 18 discrete factors implicated in the association between loneliness, social isolation and mortality was developed. Factors were categorised into societal or individual, and sub-categorised into biological, behavioural and psychological. These findings emphasise the complex multidirectional relationship between loneliness, social isolation and mortality. Our conceptual framework may allow development of more holistic interventions, targeting many of the interdependent factors that contribute to poor outcomes for lonely and socially isolated people.

Do trauma courses change practice? A qualitative review of 20 courses in East, Central and Southern Africa.

BACKGROUND: Trauma courses have been shown to improve clinical knowledge and patient outcomes. However, little is known about the individual drivers of change in practice amongst course participants in their home clinic environment. METHODS: Front-line healthcare workers participated in a two-day Primary Trauma Care (PTC) course. Immediately after the course participants completed an evaluation survey on intended change in the management of trauma patients. Six months after the course, participants completed a survey on actual changes that had occurred. RESULTS: A total of 451 participants were sampled, with 321 responding at 6 months, from 40 courses across East, Central and Southern Africa. The most commonly reported intended change was the adoption of an ABCDE/systematic approach (53%). Six months after the course, 92.7% of respondents reported that they had made changes in their management, with adoption of an ABCDE/systematic approach (50.0%) remaining most common. 77% of participants reported an improvement in departmental trauma management, 26% reported an increase in staffing, 29% an increase in equipment and 68% of participants had gone on to train other healthcare workers in PTC. CONCLUSION: The findings suggest that PTC courses not only improve individual management of trauma patients but also but is also associated with beneficial effects for participants' host institutions with regards to staffing, equipment and training.

What dose of tranexamic acid is most effective and safe for adult patients undergoing cardiac surgery?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: what dose of tranexamic acid is most effective and safe for adult patients undergoing cardiac surgery? Altogether 586 papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Current evidence shows clinical benefit of using high-dose tranexamic acid (>80 mg/kg total dose) as opposed to low-dose tranexamic acid (<50 mg/kg total dose) in cardiac surgery with cardiopulmonary bypass. Evidence from a large randomized controlled trial shows that patients receiving high-dose tranexamic acid lose less blood postoperatively than patients receiving low-dose tranexamic acid (590 vs 820 ml, P = 0.01). Patients receiving high-dose tranexamic acid also require fewer units of blood product transfusion (2.5 units vs 4.1 units; P = 0.02) and are less likely to undergo repeat surgery to achieve haemostasis. This effect is larger in those who are at high risk of bleeding. Several prospective studies comparing doses found no difference in clinical outcomes between high- and low-dose regimens, but excluded patients at high risk of bleeding. However, data from numerous observational studies demonstrate that tranexamic acid use is associated with an increased risk of postoperative seizure; one analysis showed tranexamic acid use to be a very strong independent predictor (odds ratio = 14.3, P < 0.001). There is also evidence that this risk of seizure is dose-dependent, with the greatest risk at higher doses of tranexamic acid. We conclude that, in general, patients with a high risk of bleeding should receive high-dose tranexamic acid, while those at low risk of bleeding should receive low-dose tranexamic acid with consideration given to potential dose-related seizure risk. We recommend the regimens of high-dose (30 mg kg(-1) bolus + 16 mg kg(-1) h(-1) + 2 mg kg(-1) priming) and low-dose (10 mg kg(-1) bolus + 1 mg kg(-1) h(-1) + 1 mg kg(-1) priming) tranexamic acid, as these are well established in terms of safety profile and have the strongest evidence for efficacy.

Towards computational modelling of the human foetal electrocardiogram: normal sinus rhythm and congenital heart block.

AIMS: We aim to engineer a computational model of propagation during normal sinus rhythm in the foetal human heart, by modifying models for adult cardiac tissue to match foetal electrocardiogram (fECG) characteristics. The model will be partially validated by fECG data, and applied to explore possible mechanisms of arrhythmogenesis in the foetal heart. METHODS AND RESULTS: Foetal electrocardiograms have been recorded during pregnancy, with P- and T-waves, and the QRS complex, identified by averaging and signal processing. Intervals of the fECG are extracted and used to modify currently available human adult cardiomyocyte models. RR intervals inform models of the pacemaking cells by constraining their rate, the QT interval and its rate dependence constrain models of ventricular cells, and the width of the P-wave, the QR and PR intervals constrain propagation times, conduction velocities, and intercellular coupling. These cell models are coupled into a one-dimensional (1D) model of propagation during normal sinus rhythm in the human foetal heart. We constructed a modular, heterogeneous 1D model for propagation in the foetal heart, and predicted the effects of reduction in L-type Ca(++) current. These include bradycardia and atrioventricular conduction blocks. These may account quantitatively for congenital heart block produced by positive IgG antibodies. CONCLUSION: The fECG can be interpreted mechanistically and quantitatively by using a simple computational model for propagation. After further validation, by clinical recordings of the fECG and the electrophysiological experiments on foetal cardiac cells and tissues, the model may be used to predict the effects of maternally administered pharmaceuticals on the fECG.