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BackgroundAnthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by elevations in cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin-system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy.MethodsIn a multicenter prospective randomized open label blinded endpoint trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent serial high-sensitivity cardiac troponin testing and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Patients at high risk of cardiotoxicity (cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomized to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary outcome was adjusted change in left ventricular ejection fraction at 6 months. In low-risk non-randomized patients with cardiac troponin I concentrations in the lower two tertiles, we hypothesised the absence of a 6-month change in left ventricular ejection fraction (±2%).ResultsBetween October 2017 and June 2021, 175 patients (mean age 53 years; 87% female; 71% breast cancer) were recruited. Patients randomized to cardioprotection (n=29) or standard care (n=28) had left ventricular ejection fractions of 69.4±7.4% and 69.1±6.1% at baseline and 65.7±6.6% and 64.9±5.9% 6 months after completion of chemotherapy respectively. After adjusting for age, pre-treatment left ventricular ejection fraction and planned anthracycline dose, the estimated mean difference in 6-month left ventricular ejection fraction between cardioprotection and standard care groups was -0.37% (95% confidence interval, -3.59 to 2.85%; P=0.82). In low-risk non-randomized patients, baseline and 6-month left ventricular ejection fractions were 69.3±5.7% and 66.4±6.3% respectively: estimated mean difference, 2.87% (95% confidence interval, 1.63 to 4.10%; P=0.92, not equivalent)ConclusionsCombination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment cardiac troponin I concentrations. Low-risk non-randomized patients had similar declines in left ventricular ejection fraction questioning the utility of routine cardiac troponin monitoring. Furthermore, the modest declines in left ventricular ejection fraction suggest that the value and clinical impact of early cardioprotection therapy needs to be better defined in patients receiving high-dose anthracycline regimes.REGISTRATIONEudraCT 2017-000896-99, ISRCTN24439460Clinical PerspectiveWhat is new?In this randomized controlled trial of patients at high risk of anthracycline cardiotoxicity, combined candesartan and carvedilol therapy did not protect against decline in 6-month left ventricular ejection fraction after completion of chemotherapy.Overall decline in 6-month left ventricular ejection fraction occurred irrespective of changes in cardiac troponin concentration during chemotherapy.What are the clinical implications?The Cardiac CARE trial findings do not support recent guideline recommendations advocating the use of cardiac troponin monitoring and early preventive neurohormonal blockade in patients at risk of anthracycline cardiotoxicity.Future studies should focus on factors determining transition to subsequent development of heart failure from initial mild and asymptomatic changes in cardiac function following anthracycline chemotherapy.

Objective To test the feasibility of a telephone delivered intervention, informed by cognitive behavioural principles, for post-stroke fatigue, and estimated its effect on fatigue and other outcomes. Design Randomised controlled parallel group trial. Setting Three Scottish stroke services. Subjects Stroke survivors with fatigue three months to two years post-stroke onset. Interventions Seven telephone calls (fortnightly then a ‘booster session’ at 16 weeks) of a manualised intervention, plus information about fatigue, versus information only. Main measures Feasibility of trial methods, and collected outcome measures (fatigue, mood, anxiety, social participation, quality of life, return to work) just before randomisation, at the end of treatment (four months after randomisation) and at six months after randomisation. Results Between October 2018 and January 2020, we invited 886 stroke survivors to participate in postal screening: 188/886 (21%) returned questionnaires and consented, of whom 76/188 (40%) were eligible and returned baseline forms; 64/76 (84%) returned six month follow-up questionnaires. Of the 39 allocated the intervention, 23 (59%) attended at least four sessions. At six months, there were no significant differences between the groups (adjusted mean differences in Fatigue Assessment Scale −0.619 (95% CI −4.9631, 3.694; p = 0.768), the Generalised Anxiety Disorder 7 −0.178 (95% CI −3.823, 3.467, p = 0.92), and the Patient Health Questionnaire −0.247 (95% CI −2.935, 2.442, p = 0.851). There were no between-group differences in quality of life, social participation or return to work. Conclusion Patients can be recruited to a trial of this design. These data will inform the design of further trials in post-stroke fatigue.

Background: Anthracyclines are effective cytotoxic drugs used in the treatment of breast cancer and lymphoma but are associated with myocardial injury, left ventricular dysfunction, and heart failure. Anthracycline-induced cardiotoxicity is highly variable in severity and without a proven therapeutic intervention. β-Adrenergic receptor blockers and renin-angiotensin-system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients. Methods: The Cardiac CARE trial is a multicentre prospective randomized open-label blinded end point trial of combination β-adrenergic receptor blocker and renin-angiotensin-system inhibitor therapy in patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy that is associated with myocardial injury. Patients at higher risk of cardiotoxicity with plasma high-sensitivity cTnI (cardiac troponin I) concentrations in the upper tertile at the end of chemotherapy are randomized to standard of care plus combination candesartan and carvedilol therapy or standard of care alone. All patients undergo cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. The primary end point is the change in left ventricular ejection fraction at 6 months after chemotherapy. In low-risk nonrandomized patients, left ventricular ejection fraction before and 6 months after anthracycline will be compared with define the specificity of the high-sensitivity cTnI assay for identifying low-risk participants who do not develop left ventricular systolic dysfunction. Discussion: Cardiac CARE will examine whether cardiac biomarker monitoring identifies patients at risk of left ventricular dysfunction following anthracycline chemotherapy and whether troponin-guided treatment with combination candesartan and carvedilol therapy prevents the development of left ventricular dysfunction in these high-risk patients.

Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB), but little is known about the clinical characteristics of those with early disease. Radionuclide bone scans, biochemical markers of bone turnover, and clinical characteristics were analyzed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study. We studied 222 individuals, of whom 54.9% were female, with mean ± SE age of 50.1 ± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu, which was present in 141 of 222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%), ten of whom (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 versus 49.8 ± 8.9; p = .07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years versus 59 years, p = .17). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalized to the upper limit of normal in each center were higher in those with lesions (0.75 ± 0.69 versus 0.42 ± 0.29 arbitary units; p

BACKGROUND Treatment advances have improved cancer-related outcomes and shifted interest towards minimising long-term iatrogenic complications, particularly chemotherapy-related cardiotoxicity. High-sensitivity cardiac troponin I (hs-cTnI) assays accurately quantify very low concentrations of plasma troponin and enable early detection of cardiomyocyte injury prior to development of myocardial dysfunction. The profile of hs-cTnI in response to anthracycline-based treatment has not previously been described. PATIENTS AND METHODS This was a multi-centre prospective observational cohort study. Female patients with newly-diagnosed invasive breast cancer scheduled to receive adjuvant or neo-adjuvant anthracycline-based (epirubicin) chemotherapy were recruited. Blood sampling was performed before, during and 24 hours after each treatment cycle. Plasma hs-cTnI concentrations were measured using the Abbott ARCHITECTSTAT assay (limit of detection 1.2 ng/L, coefficient of variation ≤10% at 4.7 ng/L, 99th centile upper reference limit in women 16 ng/L). RESULTS We recruited 78 women with a mean (standard deviation) age of 53.6 (9.6). The median (IQR) baseline troponin concentration was 1 (1 to 4) ng/L and median (IQR) cumulative epirubicin dose was 394 (300 to 405) mg/m2. Following an initial 33% fall 24 hours following anthracycline dosing (p Citation Format: Olga Oikonomidou, Evangelos Tzolos, Philip D Adamson, Peter S Hall, Iain R MacPherson, Morag MacLean, Steff Lewis, Heather McVicars, David E Newby, Nicholas L Mills, Ninian Lang, Peter A Henriksen. Dynamic changes in high-sensitivity cardiac troponin I in response to anthracycline-based chemotherapy-The Cardiac Care Trial pilot data [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-13-02.

Background and Purpose: Stroke is the second commonest cause of death worldwide and a leading cause of severe disability, yet there are no published trials of palliative care in stroke. To design and evaluate palliative care interventions for people with stroke, researchers need to know what measurable outcomes matter most to patients and families, stroke professionals, and other service providers. Methods: A multidisciplinary steering group of professionals and laypeople managed the study. We synthesized recommendations from respected United Kingdom and international consensus documents to generate a list of outcome domains and then performed a rapid scoping literature review to identify potential outcome measures for use in future trials of palliative care after stroke. We then completed a 3-round, online Delphi survey of professionals, and service users to build consensus about outcome domains and outcome measures. Finally, we held a stakeholder workshop to review and finalize this consensus. Results: We generated a list of 36 different outcome domains from 4 key policy documents. The rapid scoping review identified 43 potential outcome measures that were used to create a shortlist of 16 measures. The 36 outcome domains and 16 measures were presented to a Delphi panel of diverse healthcare professionals and lay service users. Of 48 panelists invited to take part, 28 completed all 3 rounds. Shared decision-making and quality of life were selected as the most important outcome domains for future trials of palliative care in stroke. Additional comments highlighted the need for outcomes to be feasible, measurable, and relevant beyond the initial, acute phase of stroke. The stakeholder workshop endorsed these results. Conclusions: Future trials of palliative care after stroke should include pragmatic outcome measures, applicable to the evolving patient and family experiences after stroke and be inclusive of shared decision-making and quality of life.

Summary Background Oral anticoagulation reduces the rate of systemic embolism for patients with atrial fibrillation by two-thirds, but its benefits for patients with previous intracranial haemorrhage are uncertain. In the Start or STop Anticoagulants Randomised Trial (SoSTART), we aimed to establish whether starting is non-inferior to avoiding oral anticoagulation for survivors of intracranial haemorrhage who have atrial fibrillation. Methods SoSTART was a prospective, randomised, open-label, assessor-masked, parallel-group, pilot phase trial done at 67 hospitals in the UK. We recruited adults (aged ≥18 years) who had survived at least 24 h after symptomatic spontaneous intracranial haemorrhage, had atrial fibrillation, and had a CHA2DS2-VASc score of at least 2. Web-based computerised randomisation incorporating a minimisation algorithm allocated participants (1:1) to start or avoid long-term (≥1 year) full treatment dose open-label oral anticoagulation. The participants assigned to start oral anticoagulation received either a direct oral anticoagulant or vitamin K antagonist, and the group assigned to avoid oral anticoagulation received standard clinical practice (antiplatelet agent or no antithrombotic agent). The primary outcome was recurrent symptomatic spontaneous intracranial haemorrhage, and was adjudicated by an individual masked to treatment allocation. All outcomes were ascertained for at least 1 year after randomisation and assessed in the intention-to-treat population of all randomly assigned participants, using Cox proportional hazards regression adjusted for minimisation covariates. We planned a sample size of 190 participants (one-sided p=0·025, power 90%, allowing for non-adherence) based on a non-inferiority margin of 12% (or adjusted hazard ratio [HR] of 3·2). This trial is registered with ClinicalTrials.gov (NCT03153150) and is complete. Findings Between March 29, 2018, and Feb 27, 2020, consent was obtained at 61 sites for 218 participants, of whom 203 were randomly assigned at a median of 115 days (IQR 49–265) after intracranial haemorrhage onset. 101 were assigned to start and 102 to avoid oral anticoagulation. Participants were followed up for median of 1·2 years (IQR 0·97–1·95; completeness 97·2%). Starting oral anticoagulation was not non-inferior to avoiding oral anticoagulation: eight (8%) of 101 in the start group versus four (4%) of 102 in the avoid group had intracranial haemorrhage recurrences (adjusted HR 2·42 [95% CI 0·72–8·09]; p=0·152). Serious adverse events occurred in 17 (17%) participants in the start group and 15 (15%) in the avoid group. 22 (22%) patients in the start group and 11 (11%) patients in the avoid group died during the study. Interpretation Whether starting oral anticoagulation was non-inferior to avoiding it for people with atrial fibrillation after intracranial haemorrhage was inconclusive, although rates of recurrent intracranial haemorrhage were lower than expected. In view of weak evidence from analyses of three composite secondary outcomes, the possibility that oral anticoagulation might be superior for preventing symptomatic major vascular events should be investigated in adequately powered randomised trials. Funding British Heart Foundation, Medical Research Council, Chest Heart & Stroke Scotland.

Introduction – Randomised controlled trials (RCTs) have shown that antiplatelet and anticoagulant (antithrombotic) agents reduce the risk of stroke and other major vascular events for a variety of patients despite increasing the risk of bleeding. However, patients with intracranial haemorrhage were not included in these RCTs, so the risks and benefits of antithrombotic agents after intracranial haemorrhage are uncertain. Methods and analysis – The Collaboration Of Controlled Randomised trials of long-term Oral Antithrombotic drugs after spontaneous intraCranial Haemorrhage (COCROACH) aims to perform an individual participant data meta-analysis (IPDMA) in order to provide reliable information about the effects of antithrombotic agents on the risks of major vascular events after spontaneous intracranial haemorrhage overall, and in clinically important sub-groups. The protocol of the corresponding Cochrane Review (8 April 2016) specified the methods used by this IPDMA for searching the Cochrane Stroke Group Trials Register, the Cochrane Central Register of Controlled Trials, Ovid MEDLINE, Ovid Embase, and online registries of RCTs. RCTs are eligible for inclusion in this IPDMA if they are registered with a trial registry, include participants with spontaneous intracranial haemorrhage who are allocated at random to long-term use of any oral antithrombotic agent(s) or to placebo, open control, another antithrombotic agent, or another intervention for the prevention of major vascular events, and their chief investigator agrees to share participant-level de-identified data. COCROACH was initiated at the European Stroke Organisation Conference on 17 May 2017 before the results of any RCTs were known. This protocol was agreed after the publication of one RCT of antiplatelet agents (RESTART ISRCTN71907627) and the presentation of one trial of an oral anticoagulant agent (NASPAF-ICH NCT02998905), but before the majority of RCT results were known. We will perform two-step IPDMA of included RCTs using their intention-to-treat datasets using fixed effects models as the primary analysis. We will conduct separate IPDMAs, grouping RCTs into distinct dyads of intervention (antithrombotic agent class) and comparator, as allocated by randomisation. The primary outcome for each IPDMA will be a composite outcome of major vascular events that are appropriate to the intervention-comparator dyad. Secondary outcomes will include major ischaemic events and major haemorrhagic events. We will assess interactions with the effects of antithrombotic agents on the primary outcome in demographic, clinical, imaging, and treatment-related sub-groups. Ethics and dissemination – All participant data will be shared with the University of Edinburgh by included RCTs with the intention of addressing the same research question for which they were acquired. Participant-level data will be de-identified and shared unless forbidden by individual participants or regulatory authorities. We will disseminate the results of this IPDMA in peer-reviewed journals.

Aim Making an accurate diagnosis of asthma can be challenging. Approaches used to assess the probability of asthma vary between clinicians; a prediction model could help to standardise clinical assessment. We aimed to derive and internally validate a clinical prediction model to support health professionals in primary care to assess the probability of an asthma diagnosis in children and young people presenting with symptoms suggestive of asthma. Methods We created a dataset from the Avon Longitudinal Study of Parents and Children (ALSPAC) enhanced with data from linked primary care electronic health records. Individuals with at least three inhaled corticosteroid prescriptions in one year and a ‘specific’ asthma Read code were designated as having asthma. Potential candidate predictors were included if data were available in at least 60% of participants. Remaining missing data were handled using multiple imputation. The prediction model was derived using logistic regression. Bootstrap re-sampling was used to internally validate the model. Results 11972 individuals aged Conclusion Information readily available from a patient’s electronic health records can support primary care clinicians weigh up the likelihood of a child/young person having asthma. We plan to externally validate the prediction model in a dataset created from primary care electronic health records. We will then develop the prediction model into a clinical decision support system (CDSS), co-produced with clinicians and patients, and test the feasibility of using the CDSS in clinical practice prior to prospective evaluation.

Objectives To establish if the use of early computed tomography (CT) coronary angiography improves one year clinical outcomes in patients presenting to the emergency department with acute chest pain and at intermediate risk of acute coronary syndrome and subsequent clinical events. Design Randomised controlled trial. Setting 37 hospitals in the UK. Participants Adults with suspected or a provisional diagnosis of acute coronary syndrome and one or more of previous coronary heart disease, raised levels of cardiac troponin, or abnormal electrocardiogram. Interventions Early CT coronary angiography and standard of care compared with standard of care only. Main outcome measures Primary endpoint was all cause death or subsequent type 1 or 4b myocardial infarction at one year. Results Between 23 March 2015 and 27 June 2019, 1748 participants (mean age 62 years (standard deviation 13), 64% men, mean global registry of acute coronary events (GRACE) score 115 (standard deviation 35)) were randomised to receive early CT coronary angiography (n=877) or standard of care only (n=871). Median time from randomisation to CT coronary angiography was 4.2 (interquartile range 1.6-21.6) hours. The primary endpoint occurred in 51 (5.8%) participants randomised to CT coronary angiography and 53 (6.1%) participants who received standard of care only (adjusted hazard ratio 0.91 (95% confidence interval 0.62 to 1.35), P=0.65). Invasive coronary angiography was performed in 474 (54.0%) participants randomised to CT coronary angiography and 530 (60.8%) participants who received standard of care only (adjusted hazard ratio 0.81 (0.72 to 0.92), P=0.001). There were no overall differences in coronary revascularisation, use of drug treatment for acute coronary syndrome, or subsequent preventive treatments between the two groups. Early CT coronary angiography was associated with a slightly longer time in hospital (median increase 0.21 (95% confidence interval 0.05 to 0.40) days from a median hospital stay of 2.0 to 2.2 days). Conclusions In intermediate risk patients with acute chest pain and suspected acute coronary syndrome, early CT coronary angiography did not alter overall coronary therapeutic interventions or one year clinical outcomes, but reduced rates of invasive angiography while modestly increasing length of hospital stay. These findings do not support the routine use of early CT coronary angiography in intermediate risk patients with acute chest pain and suspected acute coronary syndrome. Trial registration ISRCTN19102565 , NCT02284191 .

Background: Making a diagnosis of asthma can be challenging. Guidelines recommend identification of patients at high probability of asthma, but this is not defined numerically. Aim: We sought consensus on what constitutes high probability of asthma: defined as the probability at which there is enough information to add a diagnostic code of asthma and a subsequent negative test would not alter clinical opinion. Methods: A consensus workshop (modified Nominal Group Technique) was held with international health professionals with primary care knowledge/experience. After facilitated discussion, participants voted over three rounds, answering: At what numerical probability would you consider someone to be at high probability of asthma diagnosis? The result was summarised using mean/SD. The workshop discussion was recorded, transcribed and analysed qualitatively. Results: 10 participants (9 GPs, 1 asthma/allergy physician) from nine countries took part. Using final votes, the mean for a high probability of asthma was 75% (SD 7.6), indicating a trade-off between limiting false positives (more likely if a lower threshold was used) and pragmatism (on the grounds that first line preventive treatment with inhaled corticosteroids is relatively low risk). The need to review treatment response was strongly emphasised to check the diagnosis and detect non-responders. Conclusion: 75% was the probability at which participants felt confident to establish a diagnosis of asthma in primary care, albeit with the caveat that a review of treatment response was essential. Contextual factors such as availability of tests and the ease that patients could be reviewed influenced participants threshold choice.

Background Approximately, half of stroke survivors experience fatigue. Fatigue may persist for many months and interferes with participation in everyday activities and has a negative impact on social and family relationships, return to work, and quality of life. Fatigue is among the top 10 priorities for ‘Life after Stroke’ research for stroke survivors, carers, and clinicians. We previously developed and tested in a small uncontrolled pilot study a manualised, clinical psychologist-delivered, face-to-face intervention, informed by cognitive behavioural therapy (CBT). We then adapted it for delivery by trained therapists via telephone. We now aim to test the feasibility of this approach in a parallel group, randomised controlled feasibility trial (Post Stroke Intervention Trial In Fatigue, POSITIF). Methods/design POSITIF aims to recruit 75 stroke survivors between 3 months and 2 years post-stroke who would like treatment for their fatigue. Eligible consenting stroke survivors will be randomised to either a 7-session manualised telephone-delivered intervention based on CBT principles plus information about fatigue, or information only. The aims of the intervention are to (i) provide an explanation for post-stroke fatigue, in particular that it is potentially reversible (an educational approach), (ii) encourage participants to overcome the fear of taking physical activity and challenge negative thinking (a cognitive approach) and (iii) promote a balance between daily activities, rest and sleep and then gradually increase levels of physical activity (a behavioural approach). Fatigue, mood, quality of life, return to work and putative mediators will be assessed at baseline (just before randomisation), at the end of treatment and 6 months after randomisation. POSITIF will determine the feasibility of recruitment, adherence to the intervention and the resources required to deliver the intervention in a larger trial. Discussion The POSITIF feasibility trial will recruit until 31 January 2020. Data will inform the utility and design of a future adequately powered randomised controlled trial. Trial registration ClinicalTrials.gov, NCT03551327. Registered on 11 June 2018.

Aims Treatment advances have improved cancer-related outcomes and shifted interest towards minimising long-term iatrogenic complications, particularly chemotherapy-related cardiotoxicity. High-sensitivity cardiac troponin I (hs-cTnI) assays accurately quantify very low concentrations of plasma troponin and enable early detection of cardiomyocyte injury prior to the development of myocardial dysfunction. The profile of hs-cTnI in response to anthracycline-based treatment has not previously been described. Materials and methods This was a multicentre prospective observational cohort study. Female patients with newly diagnosed invasive breast cancer scheduled to receive anthracycline-based (epirubicin) chemotherapy were recruited. Blood sampling was carried out before and 24 h after each cycle. Hs-cTnI concentrations were measured using the Abbott ARCHITECTSTAT assay. Results We recruited 78 women with a median (interquartile range) age of 52 (49–61) years. The median baseline troponin concentration was 1 (1–4) ng/l and the median cumulative epirubicin dose was 394 (300–405) mg/m2. Following an initial 33% fall 24 h after anthracycline dosing (P, Highlights • Plasma hs-cTnI concentrations showed an anthracycline dose-dependent increase. • Hs-cTnI could act as an early and sensitive anthracycline cardiotoxicity prediction tool. • Hs-cTnI measurement should happen before rather than after each cycle.

The effectiveness of carotid endarterectomy (CEA) for stroke prevention depends on low procedural risks. The aim of this study was to assess the frequency and timing of procedural complications after CEA, which may clarify underlying mechanisms and help inform safe discharge policies.Individual-patient data were obtained from four large carotid intervention trials (VACS, ACAS, ACST-1 and GALA; 1983-2007). Patients undergoing CEA for asymptomatic carotid artery stenosis directly after randomization were used for the present analysis. Timing of procedural death and stroke was divided into intraoperative day 0, postoperative day 0, days 1-3 and days 4-30.Some 3694 patients were included in the analysis. A total of 103 patients (2·8 per cent) had serious procedural complications (18 fatal strokes, 68 non-fatal strokes, 11 fatal myocardial infarctions and 6 deaths from other causes) [Correction added on 20 April, after first online publication: the percentage value has been corrected to 2·8]. Of the 86 strokes, 67 (78 per cent) were ipsilateral, 17 (20 per cent) were contralateral and two (2 per cent) were vertebrobasilar. Forty-five strokes (52 per cent) were ischaemic, nine (10 per cent) haemorrhagic, and stroke subtype was not determined in 32 patients (37 per cent). Half of the strokes happened on the day of CEA. Of all serious complications recorded, 44 (42·7 per cent) occurred on day 0 (20 intraoperative, 17 postoperative, 7 with unclear timing), 23 (22·3 per cent) on days 1-3 and 36 (35·0 per cent) on days 4-30.At least half of the procedural strokes in this study were ischaemic and ipsilateral to the treated artery. Half of all procedural complications occurred on the day of surgery, but one-third after day 3 when many patients had been discharged.La efectividad de la endarterectomía carotídea (carotid endarterectomy, CEA) en la prevención de un accidente cerebrovascular depende de que este procedimiento tenga pocos riesgos. El objetivo de este estudio fue evaluar la frecuencia y el momento de aparición de las complicaciones tras una CEA, lo que podría clarificar los mecanismos subyacentes y ayudar a establecer una política de altas hospitalarias segura. MÉTODOS: Se utilizaron los datos de los pacientes incluidos en cuatro grandes ensayos de intervención carotídea (VACS, ACAS, ACST-1 y GALA; 1983-2007). Para el presente análisis se utilizaron los datos de pacientes sometidos a CEA por estenosis de la arteria carótida asintomática recogidos inmediatamente tras la aleatorización. Se consideraron diferentes intervalos entre el procedimiento, la muerte o el accidente cerebrovascular: intraoperatorio día 0, postoperatorio día 0, postoperatorio días 1-3 y postoperatorio días 4-30.En el análisis se incluyeron 3.694 pacientes. Se detectaron complicaciones graves relacionadas con el procedimiento en 103 (2,8%) pacientes (18 accidentes cerebrovasculares fatales, 68 accidentes cerebrovasculares no fatales, 11 infartos de miocardio fatales y 6 muertes por otras causas). De los 86 accidentes cerebrovasculares, 67 (78%) fueron ipsilaterales, 17 (20%) contralaterales y dos (2%) vertebrobasilares. Los accidentes cerebrovasculares fueron isquémicos en 45 (52%) casos, hemorrágicos en 9 (10%) y no se pudo determinar el subtipo de ictus en 32 (37%). La mitad de los accidentes cerebrovasculares ocurrieron el día de la CEA. De todas las complicaciones graves registradas, 44 (43%) ocurrieron en el día 0 (20 intraoperatorias, 17 postoperatorias y 7 en períodos poco definidos), 23 (22%) entre los días 1-3 y 36 (35%) entre los días 4-30. CONCLUSIÓN: En este estudio, al menos la mitad de los accidentes cerebrovasculares relacionados con la CEA fueron isquémicos e ipsilaterales respecto a la arteria tratada. La mitad de todas las complicaciones de la CEA ocurrieron el día de la cirugía, pero un tercio de los casos se presentaron después del día 3, cuando muchos pacientes ya habían sido dados de alta.

ObjectiveMaking the diagnosis of asthma is challenging. Guidelines recommend that clinicians identify a group at ‘high probability’ of asthma. High probability, however, is not numerically defined giving rise to uncertainty. The aim of this work was to build consensus on what constitutes a high probability of asthma in primary care. High probability was defined as the probability threshold at which there is enough information to make a firm diagnosis of asthma, and a subsequent negative test would not alter that opinion (assumed to be a false negative).DesignMixed-methods study.SettingA consensus workshop using modified nominal group technique was held during an international respiratory conference.ParticipantsInternational conference attendees eligible if they had knowledge/experience of working in primary care, respiratory medicine and spoke English.MethodsParticipants took part in facilitated discussions and voted over three rounds on what constituted a high probability of asthma diagnosis. The workshop was audio-recorded, transcribed and qualitatively analysed.ResultsBased on final votes, the mean value for a high probability of asthma in primary care was 75% (SD 7.6), representing a perceived trade-off between limiting the number of false positives (more likely if a lower threshold was used) and pragmatism on the basis that first-line preventive therapies (ie, low-dose inhaled corticosteroids) are relatively low risk. The need to review response to treatment was strongly emphasised for detecting non-responders and reviewing the diagnosis.ConclusionA consensus probability of 75% was the threshold at which the primary care participants in this workshop felt confident to establish the diagnosis of asthma, albeit with the caveat that a review of treatment response was essential. Contextual factors, including availability and timing of tests and the ease with which patients could be reviewed, influenced participants’ decision making.

Background: Accurately diagnosing asthma can be challenging. Uncertainty about the best combination of clinical features and investigations for asthma diagnosis is reflected in conflicting recommendations from international guidelines. One solution could be a clinical prediction model to support health professionals estimate the probability of an asthma diagnosis. However, systematic review evidence identifies that existing models for asthma diagnosis are at high risk of bias and unsuitable for clinical use. Being mindful of previous limitations, this protocol describes plans to derive and validate a prediction model for use by healthcare professionals to aid diagnostic decision making during assessment of a child or young person with symptoms suggestive of asthma in primary care. Methods: A prediction model will be derived using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and linked primary care electronic health records (EHR). Data will be included from study participants up to 25 years of age where permissions exist to use their linked EHR. Participants will be identified as having asthma if they received at least three prescriptions for an inhaled corticosteroid within a one-year period and have an asthma code in their EHR. To deal with missing data we will consider conducting a complete case analysis. However, if the exclusion of cases with missing data substantially reduces the total sample size, multiple imputation will be used. A multivariable logistic regression model will be fitted with backward stepwise selection of candidate predictors. Apparent model performance will be assessed before internal validation using bootstrapping techniques. The model will be adjusted for optimism before external validation in a dataset created from the Optimum Patient Care Research Database. Discussion: This protocol describes a robust strategy for the derivation and validation of a prediction model to support the diagnosis of asthma in children and young people in primary care.

Primary research question For adults surviving spontaneous (non-traumatic) symptomatic intracranial haemorrhage with persistent/paroxysmal atrial fibrillation/flutter (AF), does starting full treatment dose oral anticoagulation (OAC) result in a beneficial net reduction of all serious vascular events compared with not starting OAC? Trial design Investigator-led, multicentre, randomised, open, assessor-masked, parallel group, clinical trial of investigational medicinal product (CTIMP) prescribing strategies. We plan for a pilot phase, followed by a safety phase. Objectives Pilot phase: ~30 hospital sites keep screening logs and recruit at least 60 participants >24 hours after spontaneous symptomatic intracranial haemorrhage with AF and a CHA2DS2-VASc score ≥2 to determine the acceptability and feasibility of recruiting the target sample size in a definitive trial in an acceptable timescale. Safety phase: ~60 hospital sites will recruit at least 190 participants to determine whether the risk of recurrent symptomatic intracranial haemorrhage is sufficiently low (non-inferior) to justify a definitive trial. Eligibility criteria Inclusion: Spontaneous symptomatic intracranial haemorrhage, AF and a CHA2DS2-VASc score ≥2. Exclusion: Patient age

Background: Rapid identification of coronary heart disease may improve clinical outcomes in patients presenting with acute chest pain. We aimed to establish whether early CT coronary angiography in intermediate-risk patients presenting to the Emergency Department with acute chest pain could improve one-year clinical outcomes. Methods: In a prospective randomised open blinded-endpoint parallel-group clinical trial, adults with suspected acute coronary syndrome and prior coronary heart disease, elevated cardiac troponin or ischaemic electrocardiogram, were randomised 1:1 to early CT coronary angiography plus standard of care or standard of care alone in 37 UK hospitals. The primary endpoint was one-year all-cause death or subsequent type 1 or 4b myocardial infarction. Findings: Between 23rd March 2015 and 27th June 2019, 1748 participants (mean age 62 (SD 13) years, 64% male, mean GRACE score 115 (SD 35)) were randomised to early CT coronary angiography (n=877) or to standard of care alone (n=871). The primary endpoint occurred in 51 (5·8%) participants randomised to CT coronary angiography and 53 (6·1%) participants with standard of care (adjusted hazard ratio 0·91 (95% confidence interval, 0·62 to 1·35), P=0·65). CT coronary angiography was associated with reduced invasive coronary angiography (adjusted hazard ratio 0·81 (95% confidence interval, 0·72 to 0·92), P=0·001) but no change in coronary revascularisation or preventative therapies. Early CT coronary angiography was associated with longer hospitalisations (median increase 0·21 (95% confidence interval 0·05 to 0·40) days) and higher costs (£561 more per patient). Interpretation: In patients with suspected acute coronary syndrome, CT coronary angiography did not alter overall coronary therapeutic interventions or one-year clinical outcomes but increased length of hospital stay and healthcare costs. These findings do not support the routine use of early CT coronary angiography in intermediate-risk patients with acute chest pain. Trial Registration: ISRCTN19102565 and NCT02284191. Funding Statement: National Institute for Health Research HTA Programme (13/04/108). Declaration of Interests: SG was deputy director of the National Institute for Health Research Health Technology Assessment Programme and chairs the NIHR HTA commissioning committee. NC reports Unrestricted research grants from HeartFlow, Boston Scientific, Haemonetics, Beckmann Coulter Speaker fees and Consultancy from HeartFlow, Boston Scientific, Abbott, Haemonetics Travel sponsorship from Haemonetics, Boston Scientific, HeartFlow, Biosensors, Edwards, Medtronic. DEN reports grant support from Siemens. All other authors report no conflicts of interest. Ethics Approval Statement: The trial was approved by the South East Scotland Research Ethics Committee 01.

Background and Purpose— This analysis was performed to assess the association between perioperative and clinical variables and the 30-day risk of stroke or death after carotid endarterectomy for symptomatic carotid stenosis. Methods— Individual patient-level data from the 5 largest randomized controlled carotid trials were pooled in the Carotid Stenosis Trialists’ Collaboration database. A total of 4181 patients who received carotid endarterectomy for symptomatic stenosis per protocol were included. Determinants of outcome included carotid endarterectomy technique, type of anesthesia, intraoperative neurophysiological monitoring, shunting, antiplatelet medication, and clinical variables. Stroke or death within 30 days after carotid endarterectomy was the primary outcome. Adjusted risk ratios (aRRs) were estimated in multilevel multivariable analyses using a Poisson regression model. Results— Mean age was 69.5±9.2 years (70.7% men). The 30-day stroke or death rate was 4.3%. In the multivariable regression analysis, local anesthesia was associated with a lower primary outcome rate (versus general anesthesia; aRR, 0.70 [95% CI, 0.50–0.99]). Shunting (aRR, 1.43 [95% CI, 1.05–1.95]), a contralateral high-grade carotid stenosis or occlusion (aRR, 1.58 [95% CI, 1.02–2.47]), and a more severe neurological deficit (mRS, 3–5 versus 0–2: aRR, 2.51 [95% CI, 1.30–4.83]) were associated with higher primary outcome rates. None of the other characteristics were significantly associated with the perioperative stroke or death risk. Conclusions— The current results indicate lower perioperative stroke or death rates in patients operated upon under local anesthesia, whereas a more severe neurological deficit and a contralateral high-grade carotid stenosis or occlusion were identified as potential risk factors. Despite a possible selection bias and patients not having been randomized, these findings might be useful to guide surgeons and anesthetists when treating patients with symptomatic carotid disease.

Purpose. Despite WHO recommendations there is currently no national screening and eradication policy for the detection of methicillin-sensitive Staphylococcus aureus (MSSA) in the UK prior to elective orthopaedic surgery. This study aimed to evaluate the effectiveness of current standard methicillin-resistant S. aureus (MRSA) eradication therapies in the context of S. aureus (both MRSA and MSSA) decolonisation in an elective orthopaedic population. Methodology. A total of 100 patients awaiting joint replacement surgery who were positive for S. aureus on PCR nasal screening underwent the current standard MRSA pre-operative decolonisation regimen for five days. Prior to commencement of the eradication therapy swabs of the anterior nares, throat, and perineum were taken for culture. Further culture swabs were taken at 48-96 hours following treatment, at hospital admission for surgery, and at hospital discharge. Following completion of treatment patients were asked to provide feedback on their experience using Likert rating scales. The primary outcome of this study was S. aureus clearance 48-96 hours following eradication treatment. Results/Key Findings. Clearance of S. aureus 48-96 hours following treatment was 94% anterior nares, 66% throat, and 88% groin. Mean completion with nasal mupirocin was 98%. There was no statistically significant recolonisation effect between the end of the eradication treatment period and the day of surgery (p>0.05) at a median time of 10 days. Conclusion. Current MRSA decolonisation regimens are well-tolerated and effective for MSSA decolonisation for the anterior nares and groin. The decolonisation effect is preserved for at least 10 days following treatment.

Diagnosing asthma is challenging. Misdiagnosis can lead to untreated symptoms, incorrect treatment and avoidable deaths. The best combination of clinical features and tests to achieve a diagnosis of asthma is unclear. As asthma is usually diagnosed in non-specialist settings, a clinical prediction model to aid the assessment of the probability of asthma in primary care may improve diagnostic accuracy. We aimed to identify and describe existing prediction models to support the diagnosis of asthma in children and adults in primary care. We searched Medline, Embase, CINAHL, TRIP and US National Guidelines Clearinghouse databases from 1 January 1990 to 23 November 17. We included prediction models designed for use in primary care or equivalent settings to aid the diagnostic decision-making of clinicians assessing patients with symptoms suggesting asthma. Two reviewers independently screened titles, abstracts and full texts for eligibility, extracted data and assessed risk of bias. From 13,798 records, 53 full-text articles were reviewed. We included seven modelling studies; all were at high risk of bias. Model performance varied, and the area under the receiving operating characteristic curve ranged from 0.61 to 0.82. Patient-reported wheeze, symptom variability and history of allergy or allergic rhinitis were associated with asthma. In conclusion, clinical prediction models may support the diagnosis of asthma in primary care, but existing models are at high risk of bias and thus unreliable for informing practice. Future studies should adhere to recognised standards, conduct model validation and include a broader range of clinical data to derive a prediction model of value for clinicians.

Introduction High-risk coronary atherosclerotic plaque is associated with higher plasma troponin concentrations suggesting ongoing myocardial injury that may be a target for dual antiplatelet therapy. The aim of this study is to determine whether ticagrelor reduces high-sensitivity troponin I concentrations in patients with established coronary artery disease and high-risk coronary plaque using coronary 18F-fluoride positron emission tomography-computed tomography. Methods In a randomised double-blind placebo-controlled trial, patients with multivessel coronary artery disease underwent coronary 18F-fluoride positron emission tomography-computed tomography and measurement of high-sensitivity cardiac troponin I and were randomised (1:1) to ticagrelor 90 mg twice daily or matched placebo. The primary endpoint was troponin I concentration at 30 days in patients with increased coronary 18F-fluoride uptake. Results In total, 202 patients were randomized and 191 met the pre-specified criteria for inclusion in the primary analysis. In patients with increased coronary 18F-fluoride uptake (n=120/191) there was no evidence that ticagrelor had an effect on plasma troponin concentrations at 30 days (ratio of geometric means for ticagrelor versus placebo, 1.11, [95% confidence interval 0.90 to 1.36], p=0.32). Over 1 year, ticagrelor had no effect on troponin concentrations in patients with increased coronary 18F-fluoride uptake (ratio of geometric means, 0.86, 95% confidence interval 0.63 to 1.17, p=0.33). Conclusion Dual antiplatelet therapy with ticagrelor does not reduce plasma troponin concentrations in patients with coronary 18F-fluoride uptake. This suggests that subclinical plaque thrombosis does not contribute to ongoing myocardial injury in this setting.

Objectives The goal of this study was to determine whether ticagrelor reduces high-sensitivity troponin I concentrations in patients with established coronary artery disease and high-risk coronary plaque. Background High-risk coronary atherosclerotic plaque is associated with higher plasma troponin concentrations suggesting ongoing myocardial injury that may be a target for dual antiplatelet therapy. Methods In a randomized, double-blind, placebo-controlled trial, patients with multivessel coronary artery disease underwent coronary 18F-fluoride positron emission tomography/coronary computed tomography scanning and measurement of high-sensitivity cardiac troponin I. Patients were randomized (1:1) to receive ticagrelor 90 mg twice daily or matched placebo. The primary endpoint was troponin I concentration at 30 days in patients with increased coronary 18F-fluoride uptake. Results In total, 202 patients were randomized to treatment, and 191 met the pre-specified criteria for inclusion in the primary analysis. In patients with increased coronary 18F-fluoride uptake (120 of 191), there was no evidence that ticagrelor had an effect on plasma troponin concentrations at 30 days (ratio of geometric means for ticagrelor vs. placebo: 1.11; 95% confidence interval: 0.90 to 1.36; p = 0.32). Over 1 year, ticagrelor had no effect on troponin concentrations in patients with increased coronary 18F-fluoride uptake (ratio of geometric means: 0.86; 95% confidence interval: 0.63 to 1.17; p = 0.33). Conclusions Dual antiplatelet therapy with ticagrelor did not reduce plasma troponin concentrations in patients with high-risk coronary plaque, suggesting that subclinical plaque thrombosis does not contribute to ongoing myocardial injury in this setting. (Dual Antiplatelet Therapy to Reduce Myocardial Injury [DIAMOND]; NCT02110303), Central Illustration

Background and Purpose— The FOCUS trial (Fluoxetine or Control Under Supervision) showed that fluoxetine did not improve modified Rankin Scale scores (mRS) but increased the risk of fractures. We aimed to describe the fractures, their impact on mRS and factors associated with fracture risk. Methods— A United Kingdom, multicenter, parallel-group, randomized, placebo-controlled trial. Patients ≥18 years with a clinical stroke and persisting deficit assessed 2 to 15 days after onset were eligible. Consenting patients were allocated fluoxetine 20 mg or matching placebo for 6 months. The primary outcome was the mRS at 6 months and secondary outcomes included fractures. Results— Sixty-five of 3127 (2.1%) patients had 67 fractures within 6 months of randomization; 43 assigned fluoxetine and 22 placebo. Fifty-nine (90.8%) had fallen and 26 (40%) had fractured their neck of femur. The effect of fluoxetine on mRS (common odds ratio =0.951) was not significantly altered by excluding fracture patients (common odds ratio =0.961). Cox proportional hazards modeling showed that only age >70 year (hazard ratio =1.97; 95% CI, 1.13–3.45; P =0.017), female sex (hazard ratio =2.13; 95% CI, 1.29–3.51; P =0.003), and fluoxetine (hazard ratio =2.00; 95% CI, 1.20–3.34; P =0.008) were independently associated with fractures. Conclusions— Most fractures resulted from falls. Although many fractures were serious, and likely to impair patients’ function, the increased fracture risk did not explain the lack of observed effect of fluoxetine on mRS. Only increasing age, female sex, and fluoxetine were independent predictors of fractures. Clinical Trial Registration— URL: http://www.controlled-trials.com . Unique identifier: ISRCTN83290762.

Background CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome.Methods In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1,2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 mu m(2)/s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0-2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered.Findings We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0.47 [95% CI 0.30-0.72], p=0.0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0.77 [0.69-0.86] per 10 mL, p(interaction)=0.29; diffusion MRI OR 0.87 [0.81-0.94] per 10 mL, p(interaction)=0.94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low.Interpretation Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imagingto-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions. Copyright (C) 2018 Elsevier Ltd. All rights reserved.

Introduction and objectives Misdiagnosis of asthma is common and substantial. As asthma is mostly diagnosed in non-specialist settings, a clinical prediction model to support structured assessment of the probability of asthma in primary care may help improve diagnostic accuracy. We aimed to identify and describe existing clinical prediction models to support the diagnosis of asthma in children and adults in primary care. Methods We searched Medline, Embase, CINAHL, TRIP and Guidelines Clearinghouse databases from 1/1/1990 to 23/11/17. We included clinical prediction models designed for use in primary care or equivalent settings, to aid the diagnostic decision-making of a healthcare professional during the assessment of an individual with symptoms suggesting asthma. A quantifiable probability of asthma diagnosis was the primary outcome. Two reviewers independently screened titles/abstracts and full texts for eligibility, extracted data, and assessed risk of bias for included papers. Results From 13 788 records, 53 full-text articles were reviewed. Eight articles, from seven modelling studies were included. Risk of bias within studies was moderate to high; only three studies validated their models, and the reporting of model development and measures of model performance was generally poor. Logistic regression was the most common modelling technique. One study created a decision tree. Three studies used symptoms as the only variables in their models. Two studies incorporated results of clinical tests (spirometry and fractional exhaled nitric oxide respectively) in their models but only one study used clinical examination findings. Wheeze was the most commonly used predictor variable followed by night-time cough and past history of allergic/atopic diseases. Variability of symptoms (including exercise induced symptoms) was an important predictor for asthma diagnosis in four of the models. Conclusions Few clinical prediction models have been developed to support the diagnosis of asthma in primary care. Most, but not all had limitations in study design. Wheeze, symptom variability and results of clinical tests were valuable in predicting asthma diagnosis. The results of this systematic review will inform the development of a clinical prediction model for asthma diagnosis in primary care.

Background: In recent years, there has been increasing focus on the earlier detection of deterioration in the clinical condition of hospital patients with the aim of instigating earlier treatment to reverse this deterioration and preventadverse outcomes. This is especially important in the ED, a dynamic environment with large volumes of undifferentiated patients, which carries inherent patient risk. SNAP40 is an innovative medical-grade device that can be worn on the upper arm that continuously monitors patients’ vital signs including relative changes in systolic blood pressure, respiratory rate, heart rate, movement, blood oxygen saturation and temperature. It uses automated risk analysis to potentially allow clinical staff to easily and quickly identify high-risk patients. The aim of this study is to investigate whether the SNAP40 device is able to identify deterioration in the vital sign physiology of an ED patient earlier than current standard monitoring and observation charting techniques.Methods/design: Single centre, teaching hospital ED open label, prospective, observational cohort study recruiting 250 high acuity participants aged 16 years or over presenting to the ED. Participants will be approached and enrolledin the ED and after consent will have the SNAP40 wearable monitoring device attached which will be used alongside standard care monitoring. Participants will be observed throughout their time in the ED. Any SNAP40 device alarm, standard monitoring alarms or standard practice vital sign observations indicating a deterioration in a patient’s vital sign physiology (defined as an increase in NEWS score) will be recorded. Primary outcome is time to detection of deterioration. Secondary outcomes include staff time spent performing observations and responding to standard monitoring alarms, clinical escalation of care when deterioration is detected and participants and staff rating ofexperience of both SNAP40 and current monitoring.Discussion: The SNAP40-ED study aims to recruit 250 patients. It will be the first study to compare the ability of a novel ambulatory monitoring device to detect deterioration compared to standard care in the ED. It may allow the earlier detection of deterioration in the clinical condition of ED patients and therefore earlier treatment to reverse this deterioration and prevent adverse outcomes.Trial registration: NCT03179267 ClinicalTrials.gov. Registered on June 17, 2017

The optimal timing of aortic valve replacement in asymptomatic patients with aortic stenosis is uncertain. Replacement fibrosis, as assessed by midwall (nonischemic) late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging, is an irreversible marker of left ventricular decompensation in aortic stenosis. Once established, it progresses rapidly and is associated with poor long-term prognosis in a dose-dependent manner.The objective of this multicenter prospective randomized controlled trial is to determine whether early aortic valve replacement in asymptomatic patients with severe aortic stenosis can improve the adverse prognosis associated with midwall LGE. Patients will be screened for likelihood of having LGE with electrocardiography or high-sensitivity troponin I. Those at high risk will proceed to CMR imaging. Approximately 400 patients with midwall LGE will be randomized 1:1 to early valve replacement or routine care. Those who do not exhibit midwall LGE will continue with routine care and be randomized to a study registry or no further follow-up. Follow-up will be annual for approximately 3 years until the number of required outcome events is achieved. The primary endpoint is a composite of all-cause mortality and unplanned aortic stenosis-related hospitalization. The expected event rate is 25.0% in the routine care arm and 13.4% in the early intervention arm over the first 2 years; 88 observed primary outcome events will give 90% power at 5% significance level. Key secondary endpoints include all-cause mortality, sudden cardiac death, stroke, and symptomatic status.The EVOLVED trial is the first multicenter randomized controlled trial to compare early aortic valve replacement to routine care in asymptomatic patients with severe aortic stenosis and midwall LGE.

Background: Improving the accuracy with which asthma is diagnosed requires methodologically robust evaluation of diagnostic tests. This is complicated in asthma due to the lack of a true reference ‘gold standard’. Aims: We investigated how the diagnostic accuracy of a test for asthma varies when compared against two reference standards: bronchial provocation assessed by 1) spirometry 2) whole body plethysmography (WBP). Methods: We conducted a secondary analysis of a diagnostic study. Individuals with symptoms suggestive of asthma were enrolled and completed a symptom questionnaire, lung function tests, Fractional exhaled Nitric Oxide (FeNO) and bronchial provocation. Index tests were 12 symptoms and FeNO. Diagnostic accuracy of every index test was calculated against both reference standards. Results: 393 participants (158 men) completed the study. Using these alternative reference standards made no difference to the estimates of sensitivity for each of the 12 symptoms. Using WBP as the reference standard, 11 of 12 symptoms had a higher specificity (not statistically significant) than spirometry. For FeNO, area under the receiver operating characteristic curve was non-significantly greater when WBP (0.66 95%CI 0.60 to 0.71) was used as the reference standard instead of spirometry (0.62 95%CI 0.55 to 0.69). Conclusions: Overall, no statistical difference in diagnostic accuracy of clinical symptoms or FeNO was found when spirometry or WBP reference standards were used. Measures of diagnostic accuracy were non-significantly greater with WBP as reference standard. Accurate evaluation of new tests and diagnostic algorithms for asthma requires careful consideration of the reference standard used.

Introduction 18F-Fluoride is a highly sensitive positron emission tomography tracer that binds to microcalcification. When combined with computed tomography angiography (PET-CT), it enables simultaneous anatomical and metabolic imaging that non-invasively identifies high-risk plaques in coronary arteries. Uncertainty persists regarding the optimal parameter to quantify metabolic activity in coronary arteries and reliably discriminate 18F-fluoride from the surrounding myocardium. This prospective clinical study evaluates the precision of 18F-fluoride quantification. Methods Thirty patients with multi-vessel coronary artery disease underwent serial 18F-fluoride coronary PET-CT within 2 weeks. Coronary 18F-fluoride maximum activity (SUVMAX) was referenced to left atrial activity (TBRMAX) to evaluate the accuracy of repeated measures. Coefficient of variance of 18F-fluoride was calculated to establish a threshold of precision measurement. Results Twenty patients with stable coronary artery disease and ten patients with recent acute coronary syndrome. All coronary artery segments (n=171) were measured in sextuplicate with diagnostic precision of 18F-fluoride activity (coefficient of variation 0.9. A single plaque TBRMAX >0.9 was present in 90% (n=9/10) of acute coronary syndrome patients and 60% (n=12/20) of stable coronary artery disease patients. On a per-patient level, the overall agreement for visual assessment of 18F-fluoride uptake was good (κ=0.64) and was significantly improved with the application of a quantitative threshold (κ=0.84). Conclusion 18F-fluoride PET-CT provides a precise measurement of calcification activity in the coronary vasculature. These assessment techniques will support prospective trials of this radiotracer as a non-invasive imaging biomarker of plaque vulnerability.

BACKGROUND: General anaesthesia (GA) during endovascular thrombectomy has been associated with worse patient outcomes in observational studies compared with patients treated without GA. We assessed functional outcome in ischaemic stroke patients with large vessel anterior circulation occlusion undergoing endovascular thrombectomy under GA, versus thrombectomy not under GA (with or without sedation) versus standard care (ie, no thrombectomy), stratified by the use of GA versus standard care.METHODS: For this meta-analysis, patient-level data were pooled from all patients included in randomised trials in PuMed published between Jan 1, 2010, and May 31, 2017, that compared endovascular thrombectomy predominantly done with stent retrievers with standard care in anterior circulation ischaemic stroke patients (HERMES Collaboration). The primary outcome was functional outcome assessed by ordinal analysis of the modified Rankin scale (mRS) at 90 days in the GA and non-GA subgroups of patients treated with endovascular therapy versus those patients treated with standard care, adjusted for baseline prognostic variables. To account for between-trial variance we used mixed-effects modelling with a random effect for trials incorporated in all models. Bias was assessed using the Cochrane method. The meta-analysis was prospectively designed, but not registered.FINDINGS: Seven trials were identified by our search; of 1764 patients included in these trials, 871 were allocated to endovascular thrombectomy and 893 were assigned standard care. After exclusion of 74 patients (72 did not undergo the procedure and two had missing data on anaesthetic strategy), 236 (30%) of 797 patients who had endovascular procedures were treated under GA. At baseline, patients receiving GA were younger and had a shorter delay between stroke onset and randomisation but they had similar pre-treatment clinical severity compared with patients who did not have GA. Endovascular thrombectomy improved functional outcome at 3 months both in patients who had GA (adjusted common odds ratio (cOR) 1·52, 95% CI 1·09-2·11, p=0·014) and in those who did not have GA (adjusted cOR 2·33, 95% CI 1·75-3·10, pINTERPRETATION: Worse outcomes after endovascular thrombectomy were associated with GA, after adjustment for baseline prognostic variables. These data support avoidance of GA whenever possible. The procedure did, however, remain effective versus standard care in patients treated under GA, indicating that treatment should not be withheld in those who require anaesthesia for medical reasons.FUNDING: Medtronic.

Importance: While guidance on statistical principles for clinical trials exists, there is an absence of guidance covering the required content of statistical analysis plans (SAPs) to support transparency and reproducibility.Objective: To develop recommendations for a minimum set of items that should be addressed in SAPs for clinical trials, developed with input from statisticians, previous guideline authors, journal editors, regulators, and funders.Design: Funders and regulators (n = 39) of randomized trials were contacted and the literature was searched to identify existing guidance; a survey of current practice was conducted across the network of UK Clinical Research Collaboration–registered trial units (n = 46, 1 unit had 2 responders) and a Delphi survey (n = 73 invited participants) was conducted to establish consensus on SAPs. The Delphi survey was sent to statisticians in trial units who completed the survey of current practice (n = 46), CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guideline authors (n = 16), pharmaceutical industry statisticians (n = 3), journal editors (n = 9), and regulators (n = 2) (3 participants were included in 2 groups each), culminating in a consensus meeting attended by experts (N = 12) with representatives from each group. The guidance subsequently underwent critical review by statisticians from the surveyed trial units and members of the expert panel of the consensus meeting (N = 51), followed by piloting of the guidance document in the SAPs of 5 trials.Findings: No existing guidance was identified. The registered trials unit survey (46 responses) highlighted diversity in current practice and confirmed support for developing guidance. The Delphi survey (54 of 73, 74% participants completing both rounds) reached consensus on 42% (n = 46) of 110 items. The expert panel (N = 12) agreed that 63 items should be included in the guidance, with an additional 17 items identified as important but may be referenced elsewhere. Following critical review and piloting, some overlapping items were combined, leaving 55 items.Conclusions and Relevance: Recommendations are provided for a minimum set of items that should be addressed and included in SAPs for clinical trials. Trial registration, protocols, and statistical analysis plans are critically important in ensuring appropriate reporting of clinical trials.