Modernizing Medical Research to Benefit People and Animals

In the context of widespread public and political concern around the use of animals in research, we sought to examine the scientific, ethical, and economic arguments around the replacement of animals with New Approach Methodologies (NAMs) and to situate this within a regulatory context. We also analyzed the extent to which animal replacement aligns with British public and policymakers’ priorities and explored global progress towards this outcome. The global context is especially relevant given the international nature of regulatory guidance on the safety testing of new medicines. We used a range of evidence to analyze this area, including scientific papers; expert economic analysis; public opinion polls and the Hansard of the UK Parliament. We found evidence indicating that replacing animals with NAMs would benefit animal welfare, public health and the economy. The majority of the British public is in favor of efforts to replace animals and focusing on this area would help to support the British Government’s current policy priorities. We believe that this evidence underlines the need for strong action from policymakers to accelerate the transition from animal experiments to NAMs. The specific measure we suggest is to introduce a new ministerial to coordinate and accelerate the replacement of animals with NAMs

An Evaluation of the Use of a New Virtual Learning Environment for a Postgraduate Hospital Pharmacist Programme

As part of the collaboration with the University of Brighton a new VLE has been developed. This case study describes what was required of the VLE and how it has been developed and used to date.Requirements that the new VLE needed to address included:Students based externally being able to access course materials.Students on the same course being registered at two universities.Academic staff based at two universities being able to share teaching materials.Work-based tutors working across twelve hospital NHS Trusts being able to access course materials

International students' expectations of a twelve week IELTS Preparation Course

The International English Language Testing System (IELTS) English proficiency test has been the focus of increasing research since its inception in 1989. While research has contributed to a better understanding of test construction and has highlighted the limitations of individual test scores for predicting academic success, few studies have focused on students’ perceptions of the academic module of IELTS. The present study attempts to address this gap in the research by investigating student expectations of an IELTS preparation course. The study, adopting a multi-method approach using surveys and interviews, investigated ten international students enrolled in a twelve-week academic IELTS preparation course in a language school affiliated to a university in Auckland, New Zealand. The study found that students have high expectations not only of an IELTS preparation course, but of the IELTS band score they will achieve. The study also found that student expectations of the course were met at least to some extent. Various factors contributed to the fulfilment of students’ expectations including a focus on speaking and listening activities and the use of formative practice tests. Although all four language skills were recognised by the students prior to the course as being important, speaking and listening were identified as those most expected to be improved. By the end of the course, however, reading and writing skills were acknowledged to be most important, suggesting a growing awareness of the importance of literacy skills, both for achieving an appropriate IELTS score and for further academic study. Although limited by the number of participants, the findings have significance for the development and delivery of academic IELTS preparation courses. Firstly, although there is value in focusing on listening and speaking skills, given the change in students’ perceptions, academic literacy skills perhaps need a predominant focus. Related to this focus, challenging reading activities and related vocabulary development should be an integral part of the course. Secondly, the inclusion of practice IELTS tests provides an important formative component of preparation courses. Finally, the study suggests that administration staff and teachers need to better prepare students to have realistic expectations of an achievable IELTS band score

Development of directed global inhibition, competitive inhibition and behavioural inhibition during the transition between infancy and toddlerhood.

Inhibitory control (IC) is a core executive function integral to self-regulation and cognitive control, yet is itself multi-componential. Directed global inhibition entails stopping an action on demand. Competitive inhibition is engaged when an alternative response must also be produced. Related, but not an executive function, is temperamentally-driven wariness of novelty, known as behavioural inhibition. Understanding early development of these components has been hampered by a shortage of suitable measures. We combine established and novel measures to capture directed global inhibition (Toy Prohibition, Touchscreen Prohibition), competitive inhibition (A-not-B, Early Childhood Inhibitory Touchscreen Task; ECITT) and behavioural inhibition (Touchscreen Approach) in 113 10- and 16-month-olds (73 seen longitudinally). ECITT performance shows good 1-week test-retest reliability at 10-months (r = 0.30-0.60) but little stability to 16-months. Directed global inhibition performance shows developmental progression but little stability of individual differences from 10 to 16 months. Performance on measures targeting similar IC components shows greater coherence at 16-months (r = 0.23-0.59) compared with 10-months (r = 0.09-0.35). Probing of ECITT condition effects indicates toddlers are more able, compared with infants, to override immediate prepotencies; indicative of increasingly flexible control over behaviour. However, exerting IC over cumulative prepotencies appears just as challenging for toddlers as infants. Exploratory analyses show little evidence for cross-sectional or longitudinal associations between behavioural, directed global and competitive inhibition. In combination, these findings indicate that IC is not yet a stable, unidimensional construct during the transition between infancy and toddlerhood, and highlight the need for careful selection of multiple measures for those interested in capturing early variation in IC

Estimating Household and Community Transmission of Ocular Chlamydia trachomatis

Trachoma is a major cause of blindness worldwide and results from ocular infection with the bacterium Chlamydia trachomatis. Mass distribution of antibiotics in communities is part of the strategy to eliminate blindness due to trachoma. Targeted treatment of infected households could be more efficient, but the success of such a strategy will depend on the extent of transmission of infection between members of the same household and between members of the community. In this work, we estimated the magnitude of household and community transmission in four populations, two from The Gambia and two from Tanzania. We found that, in general, transmission of the bacteria within households is very efficient. In three of the four populations, persistent infection within households was predicted by the high level of household transmission (a phenomenon observed in longitudinal studies of trachoma). In all of the studied populations, individuals who live in households with more individuals contribute more to the number of new infections in the community than those who live with fewer individuals. Further studies are required to identify and examine household-targeted approaches to treatment

Targeting Antibiotics to Households for Trachoma Control

Repeated ocular infection with the bacterium Chlamydia trachomatis leads to the development of trachoma, a major cause of infectious blindness worldwide. Mass distribution of antibiotics, a component of the current trachoma control strategy, has had success in reducing infection in some areas, but results in a large number of uninfected people receiving antibiotics. We have previously shown that transmission of the bacteria between people in the same household is very efficient. Here, we investigated the effectiveness and cost-effectiveness of targeting antibiotics to households with active trachoma (inflammatory disease) compared to mass distribution, using data from four trachoma-endemic populations and a mathematical model of transmission. We found a high correspondence between households with active trachoma and infected households. In all populations the household targeted approach was predicted to be as effective as mass distribution, but it reduced the number of uninfected individuals receiving antibiotics, making the targeted strategy more cost-effective when antibiotics are not donated. Assuming antibiotics are donated, we predicted the targeted strategy to be more cost effective if it increases the proportion of infected individuals receiving treatment. Further work to address the feasibility and the cost variability in implementing the targeted approach in different settings is now required

The Development of an Age-Structured Model for Trachoma Transmission Dynamics, Pathogenesis and Control

Trachoma is the worldwide leading infectious cause of blindness and is due to repeated conjunctival infection with Chlamydia trachomatis bacteria. The effects of control interventions on population levels of infection and active disease can be promptly measured, but the effects on severe ocular disease outcomes require long-term monitoring. We present a mathematical model of trachoma transmission and disease to predict the impact of interventions on blinding trachoma. The model is based on the concept of multiple re-infections leading to progressive scarring of the eye and the potentially blinding disease sequelae. It includes aspects of trachoma natural history such as an increasing rate of recovery from infection, and a decreasing chlamydial load with subsequent infections. The model reproduces key features of trachoma epidemiology such as the age-profile of infection prevalence; a shift in the prevalence peak toward younger ages in higher-transmission environments; and a rising profile of the prevalence of the severe sequelae (scarring, trichiasis), as well as estimates of the number of infections experienced before these sequelae appear. The model can be used to examine the outcomes of various control strategies on infection and disease and can help to plan treatment interventions for different endemic settings

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial