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BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection.METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis.RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives.CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).

Purpose We evaluated the impact of personal melanoma genomic risk information on sun-related behaviors and psychological outcomes. Methods In this parallel group, open, randomized controlled trial, 1,025 Australians of European ancestry without melanoma and aged 18–69 years were recruited via the Medicare database (3% consent). Participants were randomized to the intervention (n = 513; saliva sample for genetic testing, personalized melanoma risk booklet based on a 40-variant polygenic risk score, telephone-based genetic counseling, educational booklet) or control (n = 512; educational booklet). Wrist-worn ultraviolet (UV) radiation dosimeters (10-day wear) and questionnaires were administered at baseline, 1 month postintervention, and 12 months postbaseline. Results At 12 months, 948 (92%) participants completed dosimetry and 973 (95%) the questionnaire. For the primary outcome, there was no effect of the genomic risk intervention on objectively measured UV exposure at 12 months, irrespective of traditional risk factors. For secondary outcomes at 12 months, the intervention reduced sunburns (risk ratio: 0.72, 95% confidence interval: 0.54–0.96), and increased skin examinations among women. Melanoma-related worry was reduced. There was no overall impact on general psychological distress. Conclusion Personalized genomic risk information did not influence sun exposure patterns but did improve some skin cancer prevention and early detection behaviors, suggesting it may be useful for precision prevention. There was no evidence of psychological harm.

Background Decisions on funding new healthcare technologies assume that all health improvements are valued equally. However, public reaction to health technology assessment (HTA) decisions suggests there are health attributes that matter deeply to them but are not currently accounted for in the assessment process. We aimed to determine the relative importance of attributes of illness that influence the value placed on alleviating that illness. Method We conducted a discrete choice experiment survey that presented general public respondents with 15 funding decisions between hypothetical health conditions. The conditions were defined by five attributes that characterise serious illnesses, plus the health gain from treatment. Respondent preferences were modelled using conditional logistic regression and latent class analysis. Results 905 members of the UK public completed the survey in November 2017. Respondents generally preferred to provide treatments for conditions with ‘better’ characteristics. The exception was treatment availability, where respondents preferred to provide treatments for conditions where there is no current treatment, and were prepared to accept lower overall health gain to do so. A subgroup of respondents preferred to prioritise ‘worse’ health states. Conclusion This study suggests a preference among the UK public for treating an unmet need; however, it does not suggest a preference for prioritising other distressing aspects of health conditions, such as limited life expectancy, or where patients are reliant on care. Our results are not consistent with the features currently prioritised in UK HTA processes, and the preference heterogeneity we identify presents a major challenge for developing broadly acceptable policy.

Objectives: To estimate the hospital costs among persons with obesity undergoing bariatric surgery compared with those without bariatric surgery. Methods: We analysed the UK Biobank Cohort study linked to Hospital Episode Statistics, for all adults with obesity undergoing bariatric surgery at National Health Service hospitals in England, Scotland, or Wales from 2006 to 2017. Surgery patients were matched with controls who did not have bariatric surgery using propensity scores approach with a ratio of up to 1-to-5 by year. Inverse probability of censoring weighting was used to correct for potential informative censoring. Annual and cumulative hospital costs were assessed for the surgery and control groups. Results: We identified 348 surgical patients (198 gastric bypass, 73 sleeve gastrectomy, 77 gastric banding) during the study period. In total, 324 surgical patients and 1506 matched control participants were included after propensity score matching. Mean 5-year cumulative hospital costs were €11,659 for 348 surgical patients. Compared with controls, surgical patients (n = 324) had significantly higher inpatient expenditures in the surgery year (€7289 vs. €2635, P Conclusions: Bariatric surgery significantly increased the inpatient costs in the surgery year, but was associated with decreased costs in the subsequent 4 years. However, any cost savings made up to 4 years were not enough to compensate for the initial surgical expenditure.

Objectives Health economics analysis plans (HEAPs) currently lack consistency, with uncertainty surrounding appropriate content. We aimed to develop a list of essential items that should be included in HEAPs for economic evaluations conducted alongside randomized trials. Methods A list of potential items for inclusion was developed by examining existing HEAPs. An electronic Delphi survey was conducted among professional health economists. Respondents were asked to rate potential items from 1 (least important) to 9 (most important), suggest additional items, and comment on proposed items (round 1). A second survey (round 2) was emailed to participants, including the participant’s own scores from round 1 along with summary results from the whole panel; participants were asked to rerate each item. Consensus criteria for inclusion in the final list were predefined as >70% of participants rating an item 7-9 and, Highlights • Health economics analysis plans (HEAPs) are becoming best practice for economic evaluations conducted alongside randomized controlled trials; however, they are currently implemented inconsistently. • This study used Delphi consensus techniques to identify a list of items that should be included in a HEAP. • A standardized HEAP will contribute to the transparency and reproducibility of economic evaluations and to the minimization of bias.

Background In the UK, consultations for prescription medicines are available via private providers such as online pharmacies. However, these providers may have lower thresholds for prescribing certain drugs. This is a particular concern for antibiotics, given the increasing burden of antimicrobial resistance. Public preferences for consultations with online providers are unknown, hence the impact of increased availability of online consultations on antibiotic use and population health is unclear. Objective To conduct a discrete choice experiment survey to understand UK public preferences for seeking online consultations, and the factors that influence these preferences, in the context of having symptoms for which antibiotics may be appropriate. Methods In a survey conducted between July and August 2018, general population respondents completed 16 questions in which they chose a primary care consultation via either their local medical centre or an online provider. Consultations were described in terms of five attributes, including cost and similarity to traditional ‘face-to-face’ appointments. Choices were modelled using regression analysis. Results Respondents (n = 734) placed a high value on having a consultation via their local medical centre rather than an online provider, and a low value on consultations by phone or video. However, respondents characterised as ‘busy young professionals’ showed a lower strength of preference for traditional consultations, with a higher concern for convenience. Conclusion Before COVID-19, the UK public had limited appetite for consultations with online providers, or for consultations that were not face-to-face. Nevertheless, prescriptions from online providers should be monitored going forward, particularly for antibiotics, and in key patient groups. Supplementary Information The online version contains supplementary material available at 10.1007/s40258-021-00642-8.

Aim Optimal airway management during out-of-hospital cardiac arrest (OHCA) is uncertain. Complications from tracheal intubation (TI) may be avoided with supraglottic airway (SGA) devices. The AIRWAYS-2 cluster randomised controlled trial (ISRCTN08256118) compared the i-gel SGA with TI as the initial advanced airway management (AAM) strategy by paramedics treating adults with non-traumatic OHCA. This paper reports the trial cost-effectiveness analysis. Methods A within-trial cost-effectiveness analysis of the i-gel compared with TI was conducted, with a 6-month time horizon, from the perspective of the UK National Health Service (NHS) and personal social services. The primary outcome measure was quality-adjusted life years (QALYs), estimated using the EQ-5D-5L questionnaire. Multilevel linear regression modelling was used to account for clustering by paramedic when combining costs and outcomes. Results 9,296 eligible patients were attended by 1,382 trial paramedics and enrolled in the AIRWAYS-2 trial (4410 TI, 4886 i-gel). Mean QALYs to 6 months were 0.03 in both groups (i-gel minus TI difference -0.0015, 95% CI –0.0059 to 0.0028). Total costs per participant up to 6 months post-OHCA were £3,570 and £3,413 in the i-gel and TI groups respectively (mean difference £157, 95% CI –£270 to £583). Based on mean difference point estimates, TI was more effective and less costly than i-gel; however differences were small and there was great uncertainty around these results. Conclusion The small differences between groups in QALYs and costs shows no difference in the cost-effectiveness of the i-gel and TI when used as the initial AAM strategy in adults with non-traumatic OHCA.

Background To reduce inappropriate antibiotic use, public health campaigns often provide fear-based information about antimicrobial resistance (AMR). Meta-analyses have found that fear-based campaigns in other contexts are likely to be ineffective unless respondents feel confident they can carry out the recommended behaviour (‘self-efficacy’). This study aimed to test the likely impact of fear-based messages, with and without empowering self-efficacy elements, on patient consultations/antibiotic requests for influenza-like illnesses, using a randomised design. Methods We hypothesised that fear-based messages containing empowering information about self-management without antibiotics would be more effective than fear alone, particularly in a pre-specified subgroup with low AMR awareness. Four thousand respondents from an online panel, representative of UK adults, were randomised to receive three different messages about antibiotic use and AMR, designed to induce fear about AMR to varying degrees. Two messages (one ‘strong-fear’, one ‘mild-fear’) also contained empowering information regarding influenza-like symptoms being easily self-managed without antibiotics. The main outcome measures were self-reported effect of information on likelihood of visiting a doctor and requesting antibiotics, for influenza-like illness, analysed separately according to whether or not the AMR information was ‘very/somewhat new’ to respondents, pre-specified based on a previous (non-randomised) survey. Results The ‘fear-only’ message was ‘very/somewhat new’ to 285/1000 (28.5%) respondents, ‘mild-fear-plus-empowerment’ to 336/1500 (22.4%), and ‘strong-fear-plus-empowerment’ to 388/1500 (25.9%) (p = 0.002). Of those for whom the respective information was ‘very/somewhat new’, only those given the ‘strong-fear-plus-empowerment’ message said they would be less likely to request antibiotics if they visited a doctor for an influenza-like illness (p p p Conclusions Fear could be effective in public campaigns to reduce inappropriate antibiotic use, but should be combined with messages empowering patients to self-manage symptoms effectively without antibiotics.

Polygenic risk is known to influence susceptibility to cancer. The use of data on polygenic risk, in conjunction with other predictors of future disease status, may offer significant potential for preventative care through risk-stratified screening programmes. An important element in the evaluation of screening programmes is their cost-effectiveness.We undertook a systematic review of papers evaluating the cost-effectiveness of screening interventions informed by polygenic risk scores compared to more conventional screening modalities. We included papers reporting cost-effectiveness outcomes in the English language published as articles or uploaded onto preprint servers with no restriction on date, type of cancer or form of polygenic risk modelled. We excluded papers evaluating screening interventions that did not report cost-effectiveness outcomes or which had a focus on monogenic risk. We evaluated studies using the Quality of Health Economic Studies checklist.Ten studies were included in the review, which investigated three cancers: prostate (n=5), colorectal (n=3) and breast (n=2). All study designs were cost-utility papers implemented as Markov models (n=6) or microsimulations (n=4). Nine of ten papers scored highly (score >75 on a 0-100) scale) when assessed using the Quality of Health Economic Studies checklist. Eight of ten studies concluded that polygenic risk informed cancer screening was likely to be more cost-effective than alternatives. However, the included studies lacked robust external data on the cost of polygenic risk stratification, did not account for how very large volumes of polygenic risk data on individuals would be collected and used, did not consider ancestry-related differences in polygenic risk, and did not fully account for downstream economic sequalae stemming from the use of polygenic risk data in these ways. These topics merit attention in future research on how polygenic risk data might contribute to cost-effective cancer screening.FundingThis work was supported by Cancer Research UK under grant number C18281/A29019. PD and RM are members of the MRC Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council and the University of Bristol (MC_UU_12013/1, MC_UU_12013/9). PD, EK ad RMM received support from a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). SW and JCT receive funding from the Oxford NIHR Biomedical Research Centre.RegistrationProspectively registered on PROSPERO database before searches commenced. Available at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=243659

Choice models in health are almost exclusively based on the neoclassical economic paradigm of utility maximization. Recently developed choice models have captured and shown empirical support for regret minimization as an alternative decision rule. In health economics, recent applications of RRM models indicate that individuals making health-based choices may exhibit regret minimization-type behavior. In this paper, we build on this research using a more flexible model that allows for heterogeneous decision rules, separately from preference heterogeneity, and comparing it to models that assume single decision rules. We use four datasets from diverse settings in which individuals make health choices: tobacco markets, genomic testing, and HIV prevention. We found that, if a one-size-fits-all rule is applied, then utility maximization was preferable to regret minimization for these datasets. However, we also find that individuals apply varying decision rules in similar proportions in these health settings, suggesting that models for heterogeneous decision rules were needed to capture these behaviors in these settings.

ObjectivesTo evaluate the benefit of combining polygenic risk scores (PRS) with the QCancer-10 (colorectal cancer) non-genetic risk prediction model to identify those at highest risk of colorectal cancer (CRC).DesignPopulation based cohort study. Six different PRS for CRC were developed (using LDpred2 PRS software, clumping and thresholding approaches, and genome-wide significant models). The top-performing genome-wide and GWAS-significant PRS were then combined with QCancer-10 and performance compared to QCancer-10 alone. Case-control (logistic regression) and time-to-event (Cox proportional hazards) analyses were used to evaluate risk model performance in men and women.Setting and participantsUK Biobank Study. A total of 434587 individuals with complete genetic and QCancer-10 predictor data were included in the QCancer-10+PRS modelling cohorts.Main outcome measuresPrediction of colorectal cancer diagnosis by genetic, non-genetic and combined risk models.FindingsPRS derived using the LDpred2 program performed best, with an odds-ratio per standard deviation of 1.58, and top age- and sex-adjusted C-statistic of 0.733 (95% confidence interval 0.710 to 0.753) in logistic regression models in the validation cohort. Integrated QCancer-10+PRS models out-performed QCancer-10 alone. In men, the integrated LDpred2 (QCancer-10+LDP) model produced a C-statistic of 0.730 (0.720 to 0.741) and explained variation of 28.1% (26.3% to 30.0%), compared with 0.693 (0.682 to 0.704) and 21.0% (18.9% to 23.1%) for QCancer-10 alone. Performance improvements in women were similar. In the top 20% of individuals at highest absolute risk, the sensitivity of QCancer-10+LDP models for predicting CRC diagnosis within 5 years was 47.6% in men and 42.5% in women, with respective 3.49-fold and 2.75-fold absolute increases in the top 5% of risk compared to average. Decision curve analysis showed that adding PRS to QCancer-10 improved net-benefit and interventions avoided, across most probability thresholds.ConclusionsIntegrating PRS with QCancer-10 significantly improves risk prediction over QCancer-10 alone. Evaluation of risk stratified population screening using this approach is warranted.Summary BoxWhat is already known on this topicRisk stratification based on genetic or environmental risk factors could improve cancer screening outcomesNo previously published study has examined integrated models combining genome-wide PRS and non-genetic risk factors beyond ageQCancer-10 (colorectal cancer) is the top-performing non-genetic risk prediction model for CRCWhat this study addsAdding PRS to the QCancer-10 (colorectal cancer) risk prediction model improves performance and clinical benefit, with greatest gain from the LDpred2 genome-wide PRS, to a level that suggests utility in stratifying CRC screening and prevention

BACKGROUND:Exposure to ultraviolet radiation from sunlight is directly associated with melanoma skin cancer, however reducing sun-exposure can be difficult to achieve at a population level. METHODS:Using a genomic risk information behaviour change trial for melanoma prevention, we classified participants as risk-seeking, risk-neutral or risk-averse for domain-specific risk taking (DOSPERT). One-way ANOVA determined the association between socio-demographic characteristics and risk-taking score, and multivariable linear regression ascertained impact of an individual's underlying risk propensity on an objective measure of sun-exposure, standard erythemal dose (SED), at 3-months follow-up. RESULTS:Of 119 participants, mean age 53 years; 50% males, 87% had a personal/family history of cancer; 19% were classified risk-seeking, 57% risk-neutral. The mean risk-taking score was significantly higher in younger participants (≤50 years: 13.86 vs. >50 years: 11.11, p = 0.003); and lower in those with a personal/family history of skin cancer versus without (10.55 vs 13.33, p = 0.009). Risk averse individuals had lower weekly mean SEDs at 3-months than risk neutral and risk seeking individuals (2.56, 5.81, 4.81 respectively, p = 0.01). Risk seekers showed fewer sun protective habits (p

Genomic testing is becoming routine for diagnosing rare childhood genetic disease. Evidence underlying sustainable implementation is limited, focusing on short-term endpoints such as diagnostic yield, unable to fully characterize patient and family valued outcomes. Although genomic testing is becoming widely available, evidentiary and outcomes uncertainty persist as key challenges for implementation. We examine whether the current evidence base reflects public tolerance for uncertainty for genomics to diagnose rare childhood genetic disease. We conducted focus groups with general population parents in Vancouver, Canada, and Oxford, United Kingdom, to discuss expectations and concerns related to genomic testing to diagnose rare childhood genetic disease. Applying a purposive sampling technique, recruitment continued until thematic saturation was reached. Transcripts were analysed using thematic analysis. Thirty-three parents participated across four focus groups. Participants valued causal diagnoses alongside management strategies to improve patient health and wellbeing. Further, participants valued expanding the evidence base to reduce evidentiary uncertainty while ensuring security of information. Willingness to pay out of pocket for testing reflected perceived familial health benefit. Diagnostic yield fails to fully capture valued outcomes, and efforts to resolve uncertainty better reflect public priorities. Evaluations of genomic testing that fully integrate valued endpoints are necessary to ensure consistency with best practices and public willingness to accept the uncertain familial benefit.

Genomic testing is becoming routine for diagnosing rare childhood genetic disease. Evidence underlying sustainable implementation is limited, focusing on short-term endpoints such as diagnostic yield, unable to fully characterize patient and family valued outcomes. Although genomic testing is becoming widely available, evidentiary and outcomes uncertainty persist as key challenges for implementation. We examine whether the current evidence base reflects public tolerance for uncertainty for genomics to diagnose rare childhood genetic disease. We conducted focus groups with general population parents in Vancouver, Canada, and Oxford, United Kingdom, to discuss expectations and concerns related to genomic testing to diagnose rare childhood genetic disease. Applying a purposive sampling technique, recruitment continued until thematic saturation was reached. Transcripts were analysed using thematic analysis. Thirty-three parents participated across four focus groups. Participants valued causal diagnoses alongside management strategies to improve patient health and wellbeing. Further, participants valued expanding the evidence base to reduce evidentiary uncertainty while ensuring security of information. Willingness to pay out of pocket for testing reflected perceived familial health benefit. Diagnostic yield fails to fully capture valued outcomes, and efforts to resolve uncertainty better reflect public priorities. Evaluations of genomic testing that fully integrate valued endpoints are necessary to ensure consistency with best practices and public willingness to accept the uncertain familial benefit.

The emergence of next-generation genomic sequencing (NGS) tests for use in clinical care has generated widespread interest around the globe, but little is known about the availability and funding of these tests worldwide. We examined NGS availability across world regions and countries, with a particular focus on availability of three key NGS tests—Whole-Exome Sequencing or Whole-Genome Sequencing for diagnosis of suspected genetic diseases such as intellectual disability disorders or rare diseases, non-invasive prenatal testing for common genetic abnormalities in fetuses and tumor sequencing for therapy selection and monitoring of cancer treatment. We found that these NGS tests are available or becoming available in every major region of the world. This includes both high-income countries with robust genomic programmes such as the USA and the UK, and growing availability in countries with upper-middle-income economies. We used exploratory case studies across three diverse health care systems (publicly funded/national (UK), publicly funded/provincial (Canada) and mixed private/public system (USA)) to illustrate the funding challenges and approaches used to address those challenges that might be adopted by other countries. We conclude by assessing what type of data and initiatives will be needed to better track and understand the use of NGS around the world as such testing continues to expand.

Precision diagnostics is one of the two pillars of precision medicine. Sequencing efforts in the past decade have firmly established cancer as a primarily genetically driven disease. This concept is supported by therapeutic successes aimed at particular pathways that are perturbed by specific driver mutations in protein-coding domains and reflected in three recent FDA tissue agnostic cancer drug approvals. In addition, there is increasing evidence from studies that interrogate the entire genome by whole-genome sequencing that acquired global and complex genomic aberrations including those in non-coding regions of the genome might also reflect clinical outcome. After addressing technical, logistical, financial and ethical challenges, national initiatives now aim to introduce clinical whole-genome sequencing into real-world diagnostics as a rational and potentially cost-effective tool for response prediction in cancer and to identify patients who would benefit most from 'expensive' targeted therapies and recruitment into clinical trials. However, so far, this has not been accompanied by a systematic and prospective evaluation of the clinical utility of whole-genome sequencing within clinical trials of uniformly treated patients of defined clinical outcome. This approach would also greatly facilitate novel predictive biomarker discovery and validation, ultimately reducing size and duration of clinical trials and cost of drug development. This manuscript is the third in a series of three to review and critically appraise the potential and challenges of clinical whole-genome sequencing in solid tumors and hematological malignancies.

IntroductionGabapentin is an antiepileptic drug currently licensed to treat epilepsy and neuropathic pain but has been used off-label to treat acute postoperative pain. The GAP study will compare the effectiveness, cost-effectiveness and safety of gabapentin as an adjunct to standard multimodal analgesia versus placebo for the management of pain after major surgery.Methods and analysisThe GAP study is a multicentre, double-blind, randomised controlled trial in patients aged 18 years and over, undergoing different types of major surgery (cardiac, thoracic or abdominal). Patients will be randomised in a 1:1 ratio to receive either gabapentin (600 mg just before surgery and 600 mg/day for 2 days after surgery) or placebo in addition to usual pain management for each type of surgery. Patients will be followed up daily until hospital discharge and then at 4 weeks and 4 months after surgery. The primary outcome is length of hospital stay following surgery. Secondary outcomes include pain, total opioid use, adverse health events, health related quality of life and costs.Ethics and disseminationThis study has been approved by the Research Ethics Committee . Findings will be shared with participating hospitals and disseminated to the academic community through peer-reviewed publications and presentation at national and international meetings. Patients will be informed of the results through patient organisations and participant newsletters.Trial registration numberISRCTN63614165.

AimThe AIRWAYS-2 cluster randomised controlled trial compared the i-gel supraglottic airway device (SGA) with tracheal intubation (TI) as the first advanced airway management (AAM) strategy used by Emergency Medical Service clinicians (paramedics) treating adult patients with non-traumatic out-of-hospital cardiac arrest (OHCA). It showed no difference between the two groups in the primary outcome of modified Rankin Scale (mRS) score at 30 days/hospital discharge. This paper reports outcomes to 6 months.MethodsParamedics from four ambulance services in England were randomised 1:1 to use an i-gel SGA (759 paramedics) or TI (764 paramedics) as their initial approach to AAM. Adults who had a non-traumatic OHCA and were attended by a participating paramedic were enrolled automatically under a waiver of consent. Survivors were invited to complete questionnaires at three and six months after OHCA. Outcomes were analysed using regression methods.Results767/9296 (8.3%) enrolled patients survived to 30 days/hospital discharge and 317/767 survivors (41.3%) consented and were followed-up to six months. No significant differences were found between the two treatment groups in the primary outcome measure (mRS score: 3 months: odds ratio (OR) for good recovery (i-gel/TI, OR) 0.89, 95% CI 0.69–1.14; 6 months OR 0.91, 95% CI 0.71–1.16). EQ-5D-5L scores were also similar between groups and sensitivity analyses did not alter the findings.ConclusionThere were no statistically significant differences between the TI and i-gel groups at three and six months. We therefore conclude that the initially reported finding of no significant difference between groups at 30 days/hospital discharge was sustained when the period of follow-up was extended to six months.

Background Deciding whether to discontinue antibiotics at early review is a cornerstone of hospital antimicrobial stewardship practice worldwide. In England, this approach is described in government guidance (‘Start Smart then Focus’). However, Methods We conducted an online choice experiment, a survey method to elicit preferences. Acute/general hospital prescribers in England were asked if they would continue or discontinue antibiotic treatment in 15 hypothetical scenarios. Scenarios were described according to six attributes, including patients’ presenting symptoms and whether discontinuation would conflict with local prescribing guidelines. Respondents’ choices were analysed using conditional logistic regression. Results One hundred respondents completed the survey. Respondents were more likely to continue antibiotics when discontinuation would ‘strongly conflict’ with local guidelines (average marginal effect (AME) on the probability of continuing + 0.194 (p p p p Conclusions Guidelines that conflict with antibiotic discontinuation (e.g. pre-specify fixed durations) may discourage safe discontinuation at review. In contrast, guidelines conditional on patient factors/treatment response could help hospital prescribers discontinue antibiotics if diagnostic information suggesting they are no longer needed is available.

Background Acute Kidney Injury (AKI) adversely affects outcomes after cardiac surgery. A major mediator of AKI is the activation of leukocytes through exposure to the cardiopulmonary bypass circuit. We evaluate the use of leukodepletion filters throughout bypass to protect against post-operative AKI by removing activated leukocytes during cardiac surgery. Methods This is a single-centre, double-blind, randomized controlled trial comparing the use of leukodepletion versus a standard arterial filter throughout bypass. Elective adult patients undergoing heart valve surgery with or without concomitant procedures were investigated. The primary clinical outcome measured was the development of AKI according to the KDIGO criteria. Secondary measures included biomarkers of renal tubular damage (urinary Retinol Binding Protein and Kidney Injury Molecule-1), glomerular kidney injury (urinary Micro Albumin and serum Cystatin C) and urinary Neutrophil Gelatinase Associated Lipocalin, as well as the length of hospital stay and quality of life measures through EQ-5D-5L questionnaires. Results The ROLO trial randomized 64 participants with a rate of recruitment higher than anticipated (57% achieved, 40% anticipated). The incidence of AKI was greater in the leukodepletion filter group (44% versus 23%, risk difference 21, 95% CI − 2 to 44%). This clinical finding was supported by biomarker levels especially by a tendency toward glomerular insult at 48 h, demonstrated by a raised serum Cystatin C (mean difference 0.11, 95% CI 0.00 to 0.23, p = 0.068) in the leukodepleted group. There was however no clear association between the incidence or severity of AKI and length of hospital stay. On average, health related quality of life returned to pre-operative levels in both groups within 3 months of surgery. Conclusions Leukocyte depletion during cardiopulmonary bypass does not significantly reduce the incidence of AKI after valvular heart surgery. Other methods to ameliorate renal dysfunction after cardiac surgery need to be investigated. Trial registration The trial was registered by the International Standard Randomized Controlled Trial Number Registry ISRCTN42121335. Registered on the 18 February 2014. The trial was run by the Bristol Clinical Trials and Evaluation Unit. This trial was financially supported by the National Institute of Health Research (Research for Patient Benefit), award ID: PB-PG-0711-25,090.

Background The Melanoma Genomics Managing Your Risk Study is a randomised controlled trial that aims to evaluate the efficacy of providing information on personal genomic risk of melanoma in reducing ultraviolet radiation (UV) exposure, stratified by traditional risk group (low or high phenotypic risk) in the general population. The primary outcome is objectively measured total daily Standard Erythemal Doses at 12 months. Secondary outcomes include UV exposure at specific time periods, self-reported sun protection and skin-examination behaviours, psychosocial outcomes, and ethical considerations surrounding offering genomic testing at a population level. A within-trial and modelled economic evaluation will be undertaken from an Australian health system perspective to assess the cost-effectiveness of the intervention. Objective To publish the pre-determined statistical analysis plan (SAP) before database lock and the start of analysis. Methods This SAP describes the data synthesis, analysis principles and statistical procedures for analysing the outcomes from this trial. The SAP was approved after closure of recruitment and before completion of patient follow-up. It outlines the planned primary analyses and a range of subgroup and sensitivity analyses. Health economic outcomes are not included in this plan but will be analysed separately. The SAP will be adhered to for the final data analysis of this trial to avoid potential analysis bias that may arise from knowledge of the outcome data. Results This SAP is consistent with best practice and should enable transparent reporting. Conclusion This SAP has been developed for the Melanoma Genomics Managing Your Risk Study and will be followed to ensure high-quality standards of internal validity and to minimise analysis bias. Trial registration Prospectively registered with the Australian New Zealand Clinical Trials Registry, ID: ACTR N12617000691347. Registered on 15 May 2017.

Background Studies estimating excess length of stay (LOS) attributable to nosocomial infections have failed to address time-varying confounding, likely leading to overestimation of their impact. We present a methodology based on inverse probability–weighted survival curves to address this limitation. Methods A case study focusing on intensive care unit–acquired bacteremia using data from 2 general intensive care units (ICUs) from 2 London teaching hospitals were used to illustrate the methodology. The area under the curve of a conventional Kaplan-Meier curve applied to the observed data was compared with that of an inverse probability–weighted Kaplan-Meier curve applied after treating bacteremia as censoring events. Weights were based on the daily probability of acquiring bacteremia. The difference between the observed average LOS and the average LOS that would be observed if all bacteremia cases could be prevented was multiplied by the number of admitted patients to obtain the total excess LOS. Results The estimated total number of extra ICU days caused by 666 bacteremia cases was estimated at 2453 (95% confidence interval [CI], 1803–3103) days. The excess number of days was overestimated when ignoring time-varying confounding (2845 [95% CI, 2276–3415]) or when completely ignoring confounding (2838 [95% CI, 2101–3575]). Conclusions ICU-acquired bacteremia was associated with a substantial excess LOS. Wider adoption of inverse probability–weighted survival curves or alternative techniques that address time-varying confounding could lead to better informed decision making around nosocomial infections and other time-dependent exposures., This study illustrates how to estimate the excess length of stay due to nosocomial infections in the presence of time-varying confounding. The number of excess days was substantially overestimated when ignoring time-varying confounding, suggesting that future studies should adopt similar methodology.

Background 10%–15% of early-stage colon cancers harbour either deficient mismatch repair (dMMR), microsatellite instability high (MSI-H) or POLE exonuclease domain mutations, and are characterised by high tumour mutational burden and increased lymphocytic infiltrate. Metastatic dMMR colon cancers are highly sensitive to immune checkpoint inhibition, and recent data show POLE-mutant tumours are similarly responsive. We are conducting a phase III randomised trial to determine if the addition of the anti-PD-L1 antibody avelumab following adjuvant chemotherapy improves disease-free survival (DFS) in patients with stage III dMMR/MSI-H or POLE mutant colon cancer and is a cost-effective approach for the UK National Health Service (NHS). Methods We are recruiting patients with completely resected, stage III colon cancer confirmed to have dMMR/MSI-H, locally or POLE exonuclease domain mutation on central testing. Eligible patients are randomised in a 1:1 ratio to standard fluoropyrimidine-based chemotherapy (capecitabine, oxaliplatin for 12 weeks or capecitabine for 24 weeks) or chemotherapy, followed by avelumab (10 mg/kg, 2 weekly for 24 weeks). Stratification is by chemotherapy received and MMR/MSI-H status. The primary endpoint is DFS. Secondary endpoints include overall survival, toxicity, quality of life and health resource use. The 3-year DFS rate in the control arm is expected to be ~75%. Avelumab is expected to improve the 3-year DFS rate by 12% (ie, 87%). Target accrual is 402 patients, which provides 80% power to detect an HR of 0.48 for DFS at a two-sided alpha of 0.05. This national, multicentre phase III trial is sponsored by the Royal Marsden NHS Foundation Trust and it is anticipated that approximately 40 centres in the UK will participate. This study opened to recruitment in August 2018. Trial registration number NCT03827044

Background Dual antiplatelet therapy (DAPT) is the recommended preventative treatment for secondary ischaemic events, but increases the risk of bleeding, potentially affecting patients’ health-related quality-of-life (HRQoL). Varied utility decrements have been used in cost-effectiveness models assessing alternative DAPT regimens, but it is unclear which of these decrements are most appropriate. Therefore, we reviewed existing sources of utility decrements for bleeds in patients receiving DAPT and undertook primary research to estimate utility decrements through a patient elicitation exercise using vignettes and the EuroQol EQ-5D. Methods MEDLINE, PubMed and references of included studies were searched. Primary research and decision analytic modelling studies reporting utility decrements for bleeds related to DAPT were considered. For the primary research study, 21 participants completed an elicitation exercise involving vignettes describing minor and major bleeds and the EQ-5D-3 L and EQ-5D-5 L. Utility decrements were derived using linear regression and compared to existing estimates. Results Four hundred forty-two citations were screened, of which 12 studies were included for review. Reported utility decrements ranged from − 0.002 to − 0.03 for minor bleeds and − 0.007 to − 0.05 for major bleeds. Data sources used to estimate the decrements, however, lacked relevance to our population group and few studies adequately reported details of their measurement and valuation approaches. No study completely adhered to reimbursement agency requirements in the UK according to the National Institute for Health and Care Excellence reference case. Our primary research elicited utility decrements overlapped existing estimates, ranging from − 0.000848 to − 0.00828 for minor bleeds and − 0.0187 to − 0.0621 for major bleeds. However, the magnitude of difference depended on the instrument, estimation method and valuation approach applied. Conclusions Several sources of utility decrements for bleeds are available for use in cost-effectiveness analyses, but are of limited quality and relevance. Our elicitation exercise has derived utility decrements from a relevant patient population, based on standardised definitions of minor and major bleeding events, using a validated HRQoL instrument and have been valued using general population tariffs. We suggest that our utility decrements be used in future cost-effectiveness analyses of DAPT.

Background Reducing ultraviolet radiation (UV) exposure and improving early detection may reduce melanoma incidence, mortality and health system costs. This study aims to evaluate the efficacy and cost-effectiveness of providing information on personal genomic risk of melanoma in reducing UV exposure at 12 months, according to low and high traditional risk. Methods In this randomized controlled trial, participants (target sample = 892) will be recruited from the general population, and randomized (1:1 ratio, intervention versus control). Intervention arm participants provide a saliva sample, receive personalized melanoma genomic risk information, a genetic counselor phone call, and an educational booklet on melanoma prevention. Control arm participants receive only the educational booklet. Eligible participants are aged 18–69 years, have European ancestry and no personal history of melanoma. All participants will complete a questionnaire and wear a UV dosimeter to objectively measure their sun exposure at baseline, 1- and 12-month time-points, except 1-month UV dosimetry will be limited to ~250 participants. The primary outcome is total daily Standard Erythemal Doses at 12 months. Secondary outcomes include objectively measured UV exposure for specific time periods (e.g. midday hours), self-reported sun protection and skin-examination behaviors, psycho-social outcomes, and ethical considerations surrounding offering genomic testing at a population level. A within-trial and modelled economic evaluation will be undertaken from an Australian health system perspective to assess the intervention costs and outcomes. Discussion This trial will inform the clinical and personal utility of introducing genomic testing into the health system for melanoma prevention and early detection at a population-level. Trial registration. Australian New Zealand Clinical Trials Registry ACTRN12617000691347.

Background In an environment of limited health care resources, it is crucial for health care systems which provide blood transfusion to have accurate and comprehensive information on the costs of transfusion, incorporating not only the costs of blood products, but also their administration. Unfortunately, in many countries accurate costs for administering blood are not available. Our study aimed to generate comprehensive estimates of the costs of administering transfusions for the UK National Health Service. Study design and methods A detailed microcosting study was used to cost two key inputs into transfusion: transfusion laboratory and nursing inputs. For each input, data collection forms were developed to capture staff time, equipment, and consumables associated with each step in the transfusion process. Costing results were combined with costs of blood product wastage to calculate the cost per unit transfused, separately for different blood products. Data were collected in 2014/15 British pounds and converted to US dollars. Results A total of 438 data collection forms were completed by 74 staff. The cost of administering blood was $71 (£49) per unit for red blood cells, $84 (£58) for platelets, $55 (£38) for fresh-frozen plasma, and $72 (£49) for cryoprecipitate. Conclusions Blood administration costs add substantially to the costs of the blood products themselves. These are frequently incurred costs; applying estimates to the blood components supplied to UK hospitals in 2015, the annual cost of blood administration, excluding blood products, exceeds $175 (£120) million. These results provide more accurate estimates of the total costs of transfusion than those previously available.

Background Delayed (or “backup”) antibiotic prescription, where the patient is given a prescription but advised to delay initiating antibiotics, has been shown to be effective in reducing antibiotic use in primary care. However, this strategy is not widely used in the United Kingdom. This study aimed to identify factors influencing preferences among the UK public for delayed prescription, and understand their relative importance, to help increase appropriate use of this prescribing option. Methods and findings We conducted an online choice experiment in 2 UK general population samples: adults and parents of children under 18 years. Respondents were presented with 12 scenarios in which they, or their child, might need antibiotics for a respiratory tract infection (RTI) and asked to choose either an immediate or a delayed prescription. Scenarios were described by 7 attributes. Data were collected between November 2018 and February 2019. Respondent preferences were modelled using mixed-effects logistic regression. The survey was completed by 802 adults and 801 parents (75% of those who opened the survey). The samples reflected the UK population in age, sex, ethnicity, and country of residence. The most important determinant of respondent choice was symptom severity, especially for cough-related symptoms. In the adult sample, the probability of choosing delayed prescription was 0.53 (95% confidence interval (CI) 0.50 to 0.56, p < 0.001) for a chesty cough and runny nose compared to 0.30 (0.28 to 0.33, p < 0.001) for a chesty cough with fever, 0.47 (0.44 to 0.50, p < 0.001) for sore throat with swollen glands, and 0.37 (0.34 to 0.39, p < 0.001) for sore throat, swollen glands, and fever. Respondents were less likely to choose delayed prescription with increasing duration of illness (odds ratio (OR) 0.94 (0.92 to 0.96, p < 0.001)). Probabilities of choosing delayed prescription were similar for parents considering treatment for a child (44% of choices versus 42% for adults, p = 0.04). However, parents differed from the adult sample in showing a more marked reduction in choice of the delayed prescription with increasing duration of illness (OR 0.83 (0.80 to 0.87) versus 0.94 (0.92 to 0.96) for adults, p for heterogeneity p < 0.001) and a smaller effect of disruption of usual activities (OR 0.96 (0.95 to 0.97) versus 0.93 (0.92 to 0.94) for adults, p for heterogeneity p < 0.001). Females were more likely to choose a delayed prescription than males for minor symptoms, particularly minor cough (probability 0.62 (0.58 to 0.66, p < 0.001) for females and 0.45 (0.41 to 0.48, p < 0.001) for males). Older people, those with a good understanding of antibiotics, and those who had not used antibiotics recently showed similar patterns of preferences. Study limitations include its hypothetical nature, which may not reflect real-life behaviour; the absence of a “no prescription” option; and the possibility that study respondents may not represent the views of population groups who are typically underrepresented in online surveys. Conclusions This study found that delayed prescription appears to be an acceptable approach to reducing antibiotic consumption. Certain groups appear to be more amenable to delayed prescription, suggesting particular opportunities for increased use of this strategy. Prescribing choices for sore throat may need additional explanation to ensure patient acceptance, and parents in particular may benefit from reassurance about the usual duration of these illnesses., Liz Morrell and co-workers investigate individual preferences for immediate or delayed antimicrobial prescriptions., Author summary Why was this study done? Antibiotic resistance is a growing threat to global public health, and reduction of unnecessary antibiotic consumption is essential. An effective strategy to reduce antibiotic prescribing in primary care is delayed prescribing, where the patient is given a prescription but told to “wait and see” and take the antibiotics if their condition gets worse or does not improve; however, despite supporting evidence from randomised trials, this approach is not widely used in UK primary care. As doctor’s prescribing decisions can be influenced by factors such as patient concerns, our study aimed to understand which factors affect patients’ acceptance of delayed prescription and the relative importance of these factors. What did the researchers do and find? We designed an online choice experiment that had 12 possible situations a patient might encounter if they went to see their doctor about a respiratory tract infection (RTI). For each, we asked whether they would prefer an immediate or a delayed antibiotic prescription. A total of 802 adult members of the public and a further 801 adults who were parents of at least 1 child under 18 completed the survey. The most important features affecting prescription preference were the symptoms and how long they (or their child) had been ill. Respondents were most likely to choose the delayed prescription for minor symptoms like a common cold (probability of 53%) or minor sore throat (47%) and less likely for a serious chest infection (30%); only 37% chose delayed prescription for a sore throat, swollen glands, and fever, although this is likely to be a viral illness. We identified groups of respondents—for example, females and people who are knowledgeable about antibiotics—who were the most amenable to delayed prescription. What do these findings mean? The general public have some understanding that immediate antibiotics are not needed for colds, but better education on their (lack of) a role in viral sore throats may be helpful. Primary care doctors wishing to use more delayed prescription, but concerned about patient acceptance, could increase use among the more amenable groups. Patients will need reassurance that delayed prescription is appropriate for the more serious symptoms such as fever and on the typical duration of these illnesses.

Background Policies such as the Cancer Drugs Fund in England assumed a societal preference to fund cancer care relative to other conditions, even if that resulted in lower health gain for the population overall. Objective The aim of this study was to investigate the evidence for such a preference among the UK public. Methods The MEDLINE, PubMed and Econlit electronic databases were searched for studies relating to preferences for prioritising cancer treatment, as well as studies relating to preferences for the characteristics of cancer (severity of disease, end-of-life). The searches were run in November 2015 and updated in March 2017. Empirical preference studies, studies of public views, and studies in English were included. Results We identified 24 studies relating to cancer preferences. Two directly addressed health trade-offs in the UK—one showed a preference for health gain in cancer, while the other found no such preference but provided results consistent with population health maximisation. Other studies mostly showed support for cancer but did not require a direct health trade-off. Severity and end-of-life searches identified 12 and 6 papers, respectively, which were additional to existing reviews. There is consistent evidence that people give priority to severe illness, while results for end-of-life are mixed. Conclusion We did not find consistent support for a preference for health gains to cancer patients in the context of health maximisation. The evidence base is small and the results are highly sensitive to study design. There remains a contradiction between these findings and the popular view of cancer, and further work is required to determine the features of cancer which contribute to that view. Electronic supplementary material The online version of this article (doi:10.1007/s40273-017-0511-7) contains supplementary material, which is available to authorized users.

Genetic disorders are clinically diverse and genetically heterogeneous, and are traditionally diagnosed based on an iterative phenotype-guided genetic assessment. However, such diagnostic approaches are long (diagnostic odysseys are common), misdiagnoses occur frequently, and diagnostic rates are low. Massively parallel sequencing (MPS) technologies may improve diagnostic rates and reduce the time to diagnosis for patients with suspected genetic disorders; however, MPS technologies are expensive and the health economic evidence base to support their use is limited. Several studies have compared the costs of traditional and MPS diagnostic pathways for patients with suspected genetic disorders, however costing methods and diagnostic scenarios are heterogeneous across studies. We conducted a literature review to identify and summarise information on these costing methods and diagnostic scenarios. Relevant studies were identified in MEDLINE, EMBASE, EconLit, University of York Centre for Reviews and Dissemination and the Cochrane Library, from 2010 to 2018. Twenty-four articles were included in the review. We observed considerable heterogeneity across studies with respect to the selection of items of resource use used to derive total diagnostic pathway cost estimates. We also observed structural differences in the diagnostic scenarios used to compare the traditional and MPS diagnostic pathways. There is a need for guidelines on the costing of diagnostic pathways to encourage the use of consistent methods. More micro-costing studies that evaluate diagnostic service delivery are also required. Greater homogeneity in costing approaches would facilitate more reliable comparisons between studies and improve the transferability of cost estimates across countries.

IntroductionLung cancer is a leading cause of cancer deaths worldwide and surgery remains the main treatment for early stage disease. Prior to the introduction of video-assisted thoracoscopic surgery (VATS), lung resection for cancer was undertaken through an open thoracotomy. To date, the evidence base supporting the different surgical approaches is based on non-randomised studies, small randomised trials and is focused mainly on short-term in-hospital outcomes.Methods and analysisThe VIdeo assisted thoracoscopic lobectomy versus conventional Open LobEcTomy for lung cancer study is a UK multicentre parallel group randomised controlled trial (RCT) with blinding of outcome assessors and participants (to hospital discharge) comparing the effectiveness, cost-effectiveness and acceptability of VATS lobectomy versus open lobectomy for treatment of lung cancer. We will test the hypothesis that VATS lobectomy is superior to open lobectomy with respect to self-reported physical function 5 weeks after randomisation (approximately 1 month after surgery). Secondary outcomes include assessment of efficacy (hospital stay, pain, proportion and time to uptake of chemotherapy), measures of safety (adverse health events), oncological outcomes (proportion of patients upstaged to pathologic N2 (pN2) disease and disease-free survival), overall survival and health related quality of life to 1 year. The QuinteT Recruitment Intervention is integrated into the trial to optimise recruitment.Ethics and disseminationThis trial has been approved by the UK (Dulwich) National Research Ethics Service Committee London. Findings will be written-up as methodology papers for conference presentation, and publication in peer-reviewed journals. Many aspects of the feasibility work will inform surgical RCTs in general and these will be reported at methodology meetings. We will also link with lung cancer clinical studies groups. The patient and public involvement group that works with the Respiratory Biomedical Research Unit at the Brompton Hospital will help identify how we can best publicise the findings.Trial registration numberISRCTN13472721

Background Cardiovascular magnetic resonance (CMR) is increasingly used in patients who activate the primary percutaneous coronary intervention (PPCI) pathway to assess heart function. It is uncertain whether having CMR influences patient management or the risk of major adverse cardiovascular events in these patients. Objective To determine whether or not it is feasible to set up a national registry, linking routinely collected data from hospital information systems (HISs), to investigate the role of CMR in patients who activate the PPCI pathway. Design A feasibility prospective cohort study. Setting Four 24/7 PPCI hospitals in England and Wales (two with and two without a dedicated CMR facility). Participants Patients who activated the PPCI pathway and underwent an emergency coronary angiogram. Interventions CMR either performed or not performed within 10 weeks of the index event. Main outcome measures A. Feasibility parameters – (1) patient consent implemented at all hospitals, (2) data extracted from more than one HIS and successfully linked for > 90% of consented patients at all four hospitals, (3) HIS data successfully linked with Hospital Episode Statistics (HES) and Patient Episode Database Wales (PEDW) for > 90% of consented patients at all four hospitals and (4) CMR requested and carried out for ≥ 10% of patients activating the PPCI pathway in CMR hospitals. B. Key drivers of cost-effectiveness for CMR (identified from simple cost-effectiveness models) in patients with (1) multivessel disease and (2) unobstructed coronary arteries. C. A change in clinical management arising from having CMR (defined using formal consensus and identified using HES follow-up data in the 12 months after the index event). Results A. (1) Consent was implemented (for all hospitals, consent rates were 59–74%) and 1670 participants were recruited. (2) Data submission was variable – clinical data available for ≥ 82% of patients across all hospitals, biochemistry and echocardiography (ECHO) data available for ≥ 98%, 34% and 87% of patients in three hospitals and medications data available for 97% of patients in one hospital. (3) HIS data were linked with hospital episode data for 99% of all consented patients. (4) At the two CMR hospitals, 14% and 20% of patients received CMR. B. In both (1) multivessel disease and (2) unobstructed coronary arteries, the difference in quality-adjusted life-years (QALYs) between CMR and no CMR [‘current’ comparator, stress ECHO and standard ECHO, respectively] was very small [0.0012, 95% confidence interval (CI) –0.0076 to 0.0093 and 0.0005, 95% CI –0.0050 to 0.0077, respectively]. The diagnostic accuracy of the ischaemia tests was the key driver of cost-effectiveness in sensitivity analyses for both patient subgroups. C. There was consensus that CMR leads to clinically important changes in management in five patient subgroups. Some changes in management were successfully identified in hospital episode data (e.g. new diagnoses/procedures, frequency of outpatient episodes related to cardiac events), others were not (e.g. changes in medications, new diagnostic tests). Conclusions A national registry is not currently feasible. Patients were consented successfully but conventional consent could not be implemented nationally. Linking HIS and hospital episode data was feasible but HIS data were not uniformly available. It is feasible to identify some, but not all, changes in management in the five patient subgroups using hospital episode data. The delay in obtaining hospital episode data influenced the relevance of some of our study objectives. Future work To test the feasibility of conducting the study using national data sets (e.g. HES, British Cardiovascular Intervention Society audit database, Diagnostic Imaging Dataset, Clinical Practice Research Datalink). Funding The National Institute for Health Research (NIHR) Health Services and Delivery Research programme. This study was designed and delivered in collaboration with the Clinical Trials and Evaluation Unit, a UK Clinical Research Collaboration-registered clinical trials unit that, as part of the Bristol Trials Centre, is in receipt of NIHR clinical trials unit support funding.

Background: To ensure patients continue to get early access to antibiotics at admission, while also safely reducing antibiotic use in hospitals, one needs to target the continued need for antibiotics as more diagnostic information becomes available. UK Department of Health guidance promotes an initiative called ‘Start Smart then Focus’: early effective antibiotics followed by active ‘review and revision’ 24–72 h later. However in 2017, Methods/design: Antibiotic Review Kit for Hospitals (ARK-Hospital) is a complex ‘review and revise’ behavioural intervention targeting healthcare professionals involved in antibiotic prescribing or administration in inpatients admitted to acute/general medicine (the largest consumers of non-prophylactic antibiotics in hospitals). The primary study objective is to evaluate whether ARK-Hospital can safely reduce the total antibiotic burden in acute/general medical inpatients by at least 15%. The primary hypotheses are therefore that the introduction of the behavioural intervention will be non-inferior in terms of 30-day mortality post-admission (relative margin 5%) for an acute/general medical inpatient, and superior in terms of defined daily doses of antibiotics per acute/general medical admission (co-primary outcomes). The unit of observation is a hospital organisation, a single hospital or group of hospitals organised with one executive board and governance framework (National Health Service trusts in England; health boards in Northern Ireland, Wales and Scotland). The study comprises a feasibility study in one organisation (phase I), an internal pilot trial in three organisations (phase II) and a cluster (organisation)-randomised stepped-wedge trial (phase III) targeting a minimum of 36 organisations in total. Randomisation will occur over 18 months from November 2017 with a further 12 months follow-up to assess sustainability. The behavioural intervention will be delivered to healthcare professionals involved in antibiotic prescribing or administration in adult inpatients admitted to acute/general medicine. Outcomes will be assessed in adult inpatients admitted to acute/general medicine, collected through routine electronic health records in all patients.Discussion: ARK-Hospital aims to provide a feasible, sustainable and generalisable mechanism for increasing antibiotic stopping in patients who no longer need to receive them at ‘review and revise’.Trial registration: ISRCTN Current Controlled Trials, ISRCTN12674243. Registered on 10 April 2017.

Background For many infectious conditions, the optimal antibiotic course length remains unclear. The estimation of course length must consider the important trade-off between maximising short- and long-term efficacy and minimising antibiotic resistance and toxicity. Main body Evidence on optimal treatment durations should come from randomised controlled trials. However, most antibiotic randomised controlled trials compare two arbitrarily chosen durations. We argue that alternative trial designs, which allow allocation of patients to multiple different treatment durations, are needed to better identify optimal antibiotic durations. There are important considerations when deciding which design is most useful in identifying optimal treatment durations, including the ability to model the duration–response relationship (or duration–response ‘curve’), the risk of allocation concealment bias, statistical efficiency, the possibility to rapidly drop arms that are clearly inferior, and the possibility of modelling the trade-off between multiple competing outcomes. Conclusion Multi-arm designs modelling duration–response curves with the possibility to drop inferior arms during the trial could provide more information about the optimal duration of antibiotic therapies than traditional head-to-head comparisons of limited numbers of durations, while minimising the probability of assigning trial participants to an ineffective treatment regimen.

ObjectiveTo identify the key drivers of cost-effectiveness for cardiovascular magnetic resonance (CMR) when patients activate the primary percutaneous coronary intervention (PPCI) pathway.DesignEconomic decision models for two patient subgroups populated from secondary sources, each with a 1 year time horizon from the perspective of the National Health Service (NHS) and personal social services in the UK.SettingUsual care (with or without CMR) in the NHS.ParticipantsPatients who activated the PPCI pathway, and for Model 1: underwent an emergency coronary angiogram and PPCI, and were found to have multivessel coronary artery disease. For Model 2: underwent an emergency coronary angiogram and were found to have unobstructed coronary arteries.InterventionsModel 1 (multivessel disease) compared two different ischaemia testing methods, CMR or fractional flow reserve (FFR), versus stress echocardiography. Model 2 (unobstructed arteries) compared CMR with standard echocardiography versus standard echocardiography alone.Main outcome measuresKey drivers of cost-effectiveness for CMR, incremental costs and quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios.ResultsIn both models, the incremental costs and QALYs between CMR (or FFR, Model 1) versus no CMR (stress echocardiography, Model 1 and standard echocardiography, Model 2) were small (CMR: −£64 (95% CI −£232 to £187)/FFR: £360 (95% CI −£116 to £844) and CMR/FFR: 0.0012 QALYs (95% CI −0.0076 to 0.0093)) and (£98 (95% CI −£199 to £488) and 0.0005 QALYs (95% CI −0.0050 to 0.0077)), respectively. The diagnostic accuracy of the tests was the key driver of cost-effectiveness for both patient groups.ConclusionsIf CMR were introduced for all subgroups of patients who activate the PPCI pathway, it is likely that diagnostic accuracy would be a key determinant of its cost-effectiveness. Further research is needed to definitively answer whether revascularisation guided by CMR or FFR leads to different clinical outcomes in acute coronary syndrome patients with multivessel disease.

Introduction‘Real world’ bleeding in patients exposed to different regimens of dual antiplatelet therapy (DAPT) and triple therapy (TT, DAPT plus an anticoagulant) have a clinical and economic impact but have not been previously quantified.Methods and analysisWe will use linked Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) data to assemble populations eligible for three ‘target trials’ in patient groups: percutaneous coronary intervention (PCI); coronary artery bypass grafting (CABG); conservatively managed (medication only) acute coronary syndrome (ACS). Patients ≥18 years old will be eligible if, in CPRD records, they have: ≥1 year of data before the index event; no prescription for DAPT or anticoagulants in the preceding 3 months; a prescription for aspirin or DAPT within 2 months after discharge from the index event. The primary outcome will be any bleeding event (CPRD or HES) up to 12 months after the index event. We will estimate adjusted HR for time to first bleeding event comparing: aspirin and clopidogrel (reference) versus aspirin and prasugrel or aspirin and ticagrelor after PCI; and aspirin (reference) versus aspirin and clopidogrel after CABG and ACS. We will describe rates of bleeding in patients prescribed TT (DAPT plus an anticoagulant). Potential confounders will be identified systematically using literature review, semistructured interviews with clinicians and a short survey of clinicians. We will conduct sensitivity analyses addressing the robustness of results to the study’s main limitation—that we will not be able to identify the intervention group for patients whose bleeding event occurs before a DAPT prescription in CPRD.Ethics and disseminationThis protocol was approved by the Independent Scientific Advisory Committee for the UK Medicines and Healthcare Products Regulatory Agency Database Research (protocol 16_126R) and the South West Cornwall and Plymouth Research Ethics Committee (17/SW/0092). The findings will be presented in peer-reviewed journals, lay summaries and briefing papers to commissioners/other stakeholders.Trial registration number76607611; Pre-results.