Short email with attachment versus long email without attachment when contacting authors to request unpublished data for a systematic review: a nested randomised trial

Objective Systematic reviews often rely on the acquisition of unpublished analyses or data. We carried out a nested randomised trial comparing two different approaches for contacting authors to request additional data for a systematic review. Participants Participants were authors of published reports of prevention or treatment trials in stroke in which there was central adjudication of events. A primary and secondary research active author were selected as contacts for each trial. Interventions Authors were randomised to be sent either a short email with a protocol of the systematic review attached (‘Short’) or a longer email that contained detailed information and without the protocol attached (‘Long’). A maximum of two emails were sent to each author to obtain a response. The unit of analysis was trial, accounting for clustering by author. Primary and secondary outcome measures The primary outcome was whether a response was received from authors. Secondary outcomes included time to response, number of reminders needed before a response was received and whether authors agreed to collaborate. Results 88 trials with 76 primary authors were identified in the systematic review, and of these, 36 authors were randomised to Short (trials=45) and 40 to Long (trials=43). Responses were received for 69 trials. There was no evidence of a difference in response rate between trial arms (Short vs Long, OR 1.10, 95%CI 0.36 to 3.33). There was no evidence of a difference in time to response between trial arms (Short vs Long, HR 0.91, 95%CI 0.55 to 1.51). In total, 27% of authors responded within a day and 22% of authors never responded. Conclusions There was no evidence to suggest that email format had an impact on the number of responses received when acquiring data for a systematic review involving stroke trials or the time taken to receive these responses

Outcome assessment by central adjudicators in randomised stroke trials: Simulation of differential and non-differential misclassification

INTRODUCTION: Adjudication of the primary outcome in randomised trials is thought to control misclassification. We investigated the amount of misclassification needed before adjudication changed the primary trial results. Patients (or materials) and methods: We included data from five randomised stroke trials. Differential misclassification was introduced for each primary outcome until the estimated treatment effect was altered. This was simulated 1000 times. We calculated the between-simulation mean proportion of participants that needed to be differentially misclassified to alter the treatment effect. In addition, we simulated hypothetical trials with a binary outcome and varying sample size (1000–10,000), overall event rate (10%–50%) and treatment effect (0.67–0.90). We introduced non-differential misclassification until the treatment effect was non-significant at 5% level. RESULTS: For the five trials, the range of unweighted kappa values were reduced from 0.89–0.97 to 0.65–0.85 before the treatment effect was altered. This corresponded to 2.1%–6% of participants misclassified differentially for trials with a binary outcome. For the hypothetical trials, those with a larger sample size, stronger treatment effect and overall event rate closer to 50% needed a higher proportion of events non-differentially misclassified before the treatment effect became non-significant. DISCUSSION: We found that only a small amount of differential misclassification was required before adjudication altered the primary trial results, whereas a considerable proportion of participants needed to be misclassified non-differentially before adjudication changed trial conclusions. Given that differential misclassification should not occur in trials with sufficient blinding, these results suggest that central adjudication is of most use in studies with unblinded outcome assessment. CONCLUSION: For trials without adequate blinding, central adjudication is vital to control for differential misclassification. However, for large blinded trials, adjudication is of less importance and may not be necessary

The Effects of Midline Cerebellar rTMS on Human Pharyngeal Cortical Activity in the Intact Swallowing Motor System

We sought to compare the effects of 10 Hz cerebellar vermis (vs. unilateral hemispheric and sham) repetitive transcranial magnetic stimulation (rTMS) on cortical neuroelectrical activity and thereafter 10 Hz cerebellar vermis (vs. sham) rTMS on swallowing behaviour. Healthy participants (n = 25) were randomly allocated to receive vermis, unilateral hemisphere or sham 10 Hz cerebellar rTMS. Recordings were made using pharyngeal electromyography and manometry catheters, obtaining motor-evoked potentials (MEPs) and pressure recordings. The amplitudes of MEPs elicited using single-pulse TMS delivered to the pharyngeal areas of the motor cortex bilaterally were measured pre- and post-cerebellar stimulation. As in previous studies, abductor policis brevis (APB) MEPs were measured to assess post-rTMS modulation specificity. Swallowing was assessed using a swallowing accuracy task. Measurements were made at baseline and 15-min intervals for an hour post-intervention. Measurements involved TMS being used to elicit 10 MEPs bilaterally over the pharyngeal areas of the motor cortex, over the APB cortical representation adjacent to the pharyngeal area with the lowest resting motor threshold and 5 MEPs bilaterally over pharyngeal areas of the cerebellar hemispheres. Swallowing accuracy was assessed by giving participants 10 attempts to swallow and hit a digital target. Cerebellar vermis rTMS caused significant suppression of cortical pharyngeal MEP amplitudes compared with unilateral rTMS and sham (P = 0.0005, 0.002). APB and cerebellar MEP amplitudes were unaffected as were pharyngeal and APB MEP latencies. Following cerebellar vermis rTMS there was a significant reduction in swallowing accuracy compared with sham (P = 0.001). Our findings demonstrate cerebellar vermis rTMS exerts a suppressive effect on pharyngeal motor cortical activity and swallowing behaviour

Therapeutic potential of transdermal glyceryl trinitrate in the management of acute stroke

The nitric oxide donor, glyceryl trinitrate (GTN), is a candidate treatment for the management of acute stroke with haemodynamic and potential reperfusion and neuroprotective effects. When administered as a transdermal patch during the acute and subacute phases after stroke, GTN was safe, lowered blood pressure, maintained cerebral blood flow, and did not induce cerebral steal or alter functional outcome. However, when given within 6 h of stroke onset, GTN reduced death and dependency (odds ratio 0.52; 95% confidence interval 0.34–0.78), death, disability, cognitive impairment and mood disturbance, and improved quality of life (data from two trials, n = 312). In a pooled analysis of four studies (n = 186), GTN reduced between-visit systolic blood pressure variability over days 1–7 compared with no GTN (mean difference -2.09; 95% confidence interval -3.83 to -0.35; p = 0.019). The efficacy of GTN given in the ultra-acute/pre-hospital setting is currently being assessed and, if found to be beneficial, the implications for hyperacute stroke practice are significant. Here, we discuss the evidence to date, potential mechanisms of action and future possibilities, including unanswered questions, for the therapeutic potential of GTN in acute stroke

The incidence of first stroke in pregnant and non-pregnant women of childbearing age: a population-based cohort study from England

Background: Pregnant women may have an increased risk of stroke compared to non-pregnant women of similar age, but the magnitude and the timing of such risk are unclear. We examined the risk of first stroke event in women of childbearing age and compared the risk during pregnancy and in the early postpartum period to background risk outside these periods. Methods and Results: We conducted an open cohort study of 2,046,048 women aged 15-49 years between 1st April 1997 and 31th March 2014 using linked primary (Clinical Practice Research Datalink) and secondary (Hospital Episode Statistics) care records in England. Risk of first stroke was assessed by calculating the incidence rate of stroke in antepartum, peripartum (2 days before until 1 day after delivery), early (first six weeks) and late (second six weeks) postpartum periods, compared with non-pregnant time using a Poisson regression model with adjustment for maternal age, socioeconomic group and calendar time. A total of 2,511 women had a first stroke. The incidence rate of stroke was 25.0 per 100,000 person-years (95% confidence interval 24.0-26.0) in non-pregnant time. The rate was lower antepartum (10.7/100,000 person-years, 7.6-15.1), but 9-fold higher peripartum (161.1/100,000 person-years, 80.6-322.1) and 3-fold higher early postpartum (47.1/100,000 person-years, 31.3-70.9). Rates of ischaemic and haemorrhagic stroke both increased peripartum and early postpartum. Conclusions: Although the absolute risk of first stroke is low in women of childbearing age, health care professionals should be aware of a considerable increase in relative risk during the peripartum and early postpartum periods

Statistical analysis plan for the ‘Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke’ (TARDIS) trial

Rationale: Antiplatelet agents such as aspirin, clopidogrel and dipyridamole are effective in reducing the risk of recurrence after a stroke. Importantly, the risk of recurrence is highest immediately after the index event while antiplatelets cause bleeding. Aims and/or hypothesis: The ‘Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke’ (TARDIS) trial is testing whether short-term intensive antiplatelet therapy is safe and effective in reducing the early risk of recurrence as compared with standard guideline-based therapy. Design: TARDIS is an international multi-center prospective randomized open-label blinded–end-point trial, with funding from the UK Health Technology Assessment program. Patients with acute ischemic stroke or transient ischemic attack are randomized within 48 h to intensive/triple antiplatelet therapy or guideline antiplatelets taken for one-month. Patients or relatives give written informed (proxy) consent and all sites have research ethics approval. Analyses will be done by intention-to-treat. Study Outcome: The primary outcome is shift in stroke recurrent events and their severity, assessed using the modified Rankin Scale, at three-months. Discussion: This paper and attachment describe the trial’s statistical analysis plan, as developed from the protocol during recruitment and prior to unblinding of data. The statistical analysis plan contains design and methods for analyses, and unpopulated tables and figures for the primary and baseline publications. The data from the trial will provide the first large-scale randomized evidence for the use of intensive antiplatelet therapy for preventing recurrence after acute stroke and transient ischemic attack

The Landscape of Videofluoroscopy in the UK: A Web-Based Survey

Videofluoroscopy (VFS) is considered one of the gold-standard assessments of swallowing. Whilst guidelines for the application and conduct of VFS exist, their translation into clinical practice remain challenging. To build a greater understanding on how VFS clinics operate in the UK. A web-based survey was shared with speech and language therapists (SLTs) working in VFS clinics via professional networks and social media from October 2018 to January 2019. 101 responses were received. Two thirds of clinics were SLT-led, with the majority of clinics being run by two SLTs (73.6%) and a radiographer (95.5%) also known as radiologic technologists, diagnostic radiographers and medical radiation technologists. Less than 50% of radiographers had received specialist training. Around half of the clinics used a standard assessment or analysis protocol and 88.1% a rating scale. Set recipes for a range of textures were used in 53.4% of VFS clinics. Barium and water soluble contrasts were used, but only 15.8% knew the concentration of contrast used. The most commonly reported VFS pulse and frame rate was 15 per second. There was evidence of a lack of SLT knowledge regarding technical operation of VFS. Screening times varied from 0.7–10 min (median 3 min, IQR 2.5–3.5). Around 50% of respondents reported quality issues affecting analysis. In a survey of UK SLTs, translation of VFS guidance into practice was found to be limited which may impact on the quality of assessment and analysis. Collaboration with radiology, strengthening of guidelines and greater uptake of specialist training is deemed essential

Reprint: Good laboratory practice: preventing introduction of bias at the bench

As a research community, we have failed to show that drugs, which show substantial efficacy in animal models of cerebral ischemia, can also improve outcome in human stroke. Accumulating evidence suggests this may be due, at least in part, to problems in the design, conduct, and reporting of animal experiments which create a systematic bias resulting in the overstatement of neuroprotective efficacy. Here, we set out a series of measures to reduce bias in the design, conduct and reporting of animal experiments modeling human stroke