Statistical analysis plan for the ‘Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage’ (TICH-2) trial

Rationale Aside from blood pressure lowering, treatment options for intracerebral haemorrhage remain limited and a proportion of patients will undergo early haematoma expansion with resultant significant morbidity and mortality. Tranexamic acid (TXA), an anti-fibrinolytic drug, has been shown to significantly reduce mortality in patients, who are bleeding following trauma, when given rapidly. TICH-2 is testing whether TXA is effective at improving outcome in spontaneous intracerebral haemorrhage (SICH). Methods and design TICH-2 is a pragmatic, phase III, prospective, double-blind, randomised placebo-controlled trial. Two thousand adult (aged ≥ 18 years) patients with an acute SICH, within 8 h of stroke onset, will be randomised to receive TXA or the placebo control. The primary outcome is ordinal shift of modified Rankin Scale score at day 90. Analyses will be performed using intention-to-treat. Results This paper and its attached appendices describe the statistical analysis plan (SAP) for the trial and were developed and published prior to database lock and unblinding to treatment allocation. The SAP includes details of analyses to be undertaken and unpopulated tables which will be reported in the primary and key secondary publications. The database will be locked in early 2018, ready for publication of the results later in the same year. Discussion The SAP details the analyses that will be done to avoid bias arising from prior knowledge of the study findings. The trial will determine whether TXA can improve outcome after SICH, which currently has no definitive therapy. Trial registration ISRCTN registry, ID: ISRCTN93732214. Registered on 17 January 2013

Statistical analysis plan for the ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial

High blood pressure is common during the acute phase of stroke and is associated with a poor outcome. However, the management of high blood pressure remains unclear. The ‘Efficacy of Nitric Oxide in Stroke’ trial tested whether transdermal glyceryl trinitrate, a nitric oxide donor that lowers blood pressure, is safe and effective in improving outcome after acute stroke. Efficacy of Nitric Oxide in Stroke is an international multicenter, prospective, randomized, single-blind, blinded endpoint trial, with funding from the UK Medical Research Council. Patients with acute ischemic stroke or intracerebral hemorrhage and systolic blood pressure 140–220 mmHg were randomized to glyceryl trinitrate or no glyceryl trinitrate and, where relevant, to continue or stop prestrike antihypertensive therapy. The primary outcome is shift in modified Rankin Scale at three-months. Patients or relatives gave written informed (proxy) consent, and all sites had research ethics approval. Analyses will be done by intention to treat. This paper and attachment describe the trial’s statistical analysis plan, developed prior to unblinding of date. The statistical analysis plan contains design and methods for analyses, and unpopulated tables and figures for the two primary publications and some secondary publications. The database will be locked in late February 2014 in preparation for presentation of the results in May 2014. The data from the trial will improve the precision of the estimates of the overall treatment effects (efficacy and safety) of results from completed trials of blood pressure management in acute stroke, and provide the first large-scale randomized evidence on transdermal glyceryl trinitrate, and of continuing (vs. stopping) prestroke antihypertensive medications, in acute stroke

A Large Web-Based Observer Reliability Study of Early Ischaemic Signs on Computed Tomography. The Acute Cerebral CT Evaluation of Stroke Study (ACCESS)

BACKGROUND: Early signs of ischaemic stroke on computerised tomography (CT) scanning are subtle but CT is the most widely available diagnostic test for stroke. Scoring methods that code for the extent of brain ischaemia may improve stroke diagnosis and quantification of the impact of ischaemia. METHODOLOGY AND PRINCIPAL FINDINGS: We showed CT scans from patients with acute ischaemic stroke (n = 32, with different patient characteristics and ischaemia signs) to doctors in stroke-related specialties world-wide over the web. CT scans were shown twice, randomly and blindly. Observers entered their scan readings, including early ischaemic signs by three scoring methods, into the web database. We compared observers' scorings to a reference standard neuroradiologist using area under receiver operator characteristic curve (AUC) analysis, Cronbach's alpha and logistic regression to determine the effect of scales, patient, scan and observer variables on detection of early ischaemic changes. Amongst 258 readers representing 33 nationalities and six specialties, the AUCs comparing readers with the reference standard detection of ischaemic signs were similar for all scales and both occasions. Being a neuroradiologist, slower scan reading, more pronounced ischaemic signs and later time to CT all improved detection of early ischaemic signs and agreement on the rating scales. Scan quality, stroke severity and number of years of training did not affect agreement. CONCLUSIONS: Large-scale observer reliability studies are possible using web-based tools and inform routine practice. Slower scan reading and use of CT infarct rating scales improve detection of acute ischaemic signs and should be encouraged to improve stroke diagnosis

Myofascial force transmission in dynamic muscle conditions: effects of dynamic shortening of a single head of multi-tendoned rat extensor digitorum longus muscle

This study investigated the effects of myofascial force transmission during dynamic shortening of head III of rat extensor digitorum longus muscle (EDL III). The anterior crural compartment was left intact. Force was measured simultaneously at the distal EDL III tendon, the proximal EDL tendon and the distal tendons of tibialis anterior and extensor hallucis longus muscles (TA+EHL). Two types of distal shortening of EDL III were studied: (1) sinusoidal shortening (2 mm) and (2) isokinetic shortening (8 mm). Sinusoidal shortening of EDL III caused a decrease in force exerted at the distal tendon of EDL III: from 0.58 (0.08) N to 0.26 (0.04) N. In contrast, hardly any changes in proximal EDL force and distal TA+EHL force were found. Maximal concentric force exerted at the distal tendon of EDL III was higher than maximal isometric force expected on the basis of the physiological cross-sectional area of EDL III muscle fibers (Maas et al. 2003). Therefore, a substantial fraction of this force must originate from sources other than muscle fibers of EDL III. Isokinetic shortening of EDL III caused high changes in EDL III force from 0.97 (0.15) N to zero. In contrast, changes in proximal EDL force were much smaller: from 2.44 (0.25) N to 1.99 (0.19) N. No effects on TA+EHL force could be shown. These results are explained in terms of force transmission between the muscle belly of EDL III and adjacent tissues. Thus, also in dynamic muscle conditions, muscle fiber force is transmitted via myofascial pathways. © Springer-Verlag 2005

Effect of X-Ray Attenuation of Arterial Obstructions on Intravenous Thrombolysis and Outcome after Ischemic Stroke

<div><p>Objective</p><p>To assess whether the x-ray attenuation of intra-arterial obstruction measured on non-contrast CT in ischemic stroke can predict response to thrombolysis and subsequent functional outcome.</p><p>Methods</p><p>The Third International Stroke Trial (IST-3) was a multicenter randomized-controlled trial of intravenous thrombolysis (rt-PA) given within six hours of ischemic stroke. Ethical approval and informed consent were obtained. In a subgroup of 109 IST-3 patients (38 men, median age 82 years), a single reader, masked to all clinical and other imaging data, manually measured x-ray attenuation (Hounsfield Units, HU) on non-contrast CT at the location of angiographically-proven intra-arterial obstructions, pre-randomization and at 24–48 hour follow-up. We calculated change in attenuation between scans. We assessed the impact of pre-randomization arterial obstruction attenuation on six-month functional outcome.</p><p>Results</p><p>Most arterial obstructions (64/109, 59%) were hyperattenuating (mean 51.0 HU). Compared with control, treatment with rt-PA was associated with a greater, but non-significant, reduction in obstruction attenuation at follow-up (-8.0 HU versus -1.4 HU in patients allocated control, p = 0.117). In multivariable ordinal regression analysis controlled for patient age, stroke severity, location and extent of obstruction, time from stroke onset to baseline scan and rt-PA treatment allocation, the attenuation of pre-randomization arterial obstruction was not independently associated with six-month outcome (odds ratio = 0.99, 95% confidence interval = 0.94–1.03, p = 0.516).</p><p>Conclusions</p><p>In ischemic stroke, the x-ray attenuation of the arterial obstruction may decline more rapidly from baseline to 24–48 hours following treatment with thrombolysis but we found no evidence that baseline arterial obstruction attenuation predicts six-month outcome.</p></div

Retrospective harm benefit analysis of pre-clinical animal research for six treatment interventions

The harm benefit analysis (HBA) is the cornerstone of animal research regulation and is considered to be a key ethical safeguard for animals. The HBA involves weighing the anticipated benefits of animal research against its predicted harms to animals but there are doubts about how objective and accountable this process is.i. To explore the harms to animals involved in pre-clinical animal studies and to assess these against the benefits for humans accruing from these studies; ii. To test the feasibility of conducting this type of retrospective HBA.Data on harms were systematically extracted from a sample of pre-clinical animal studies whose clinical relevance had already been investigated by comparing systematic reviews of the animal studies with systematic reviews of human studies for the same interventions (antifibrinolytics for haemorrhage, bisphosphonates for osteoporosis, corticosteroids for brain injury, Tirilazad for stroke, antenatal corticosteroids for neonatal respiratory distress and thrombolytics for stroke). Clinical relevance was also explored in terms of current clinical practice. Harms were categorised for severity using an expert panel. The quality of the research and its impact were considered. Bateson's Cube was used to conduct the HBA.The most common assessment of animal harms by the expert panel was 'severe'. Reported use of analgesia was rare and some animals (including most neonates) endured significant procedures with no, or only light, anaesthesia reported. Some animals suffered iatrogenic harms. Many were kept alive for long periods post-experimentally but only 1% of studies reported post-operative care. A third of studies reported that some animals died prior to endpoints. All the studies were of poor quality. Having weighed the actual harms to animals against the actual clinical benefits accruing from these studies, and taking into account the quality of the research and its impact, less than 7% of the studies were permissible according to Bateson's Cube: only the moderate bisphosphonate studies appeared to minimise harms to animals whilst being associated with benefit for humans.This is the first time the accountability of the HBA has been systematically explored across a range of pre-clinical animal studies. The regulatory systems in place when these studies were conducted failed to safeguard animals from severe suffering or to ensure that only beneficial, scientifically rigorous research was conducted. Our findings indicate a pressing need to: i. review regulations, particularly those that permit animals to suffer severe harms; ii. reform the processes of prospectively assessing pre-clinical animal studies to make them fit for purpose; and iii. systematically evaluate the benefits of pre-clinical animal research to permit a more realistic assessment of its likely future benefits

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

Predation and infanticide influence ideal free choice by a parrot occupying heterogeneous tropical habitats

The ideal free distribution (IFD) predicts that organisms will disperse to sites that maximize their fitness based on availability of resources. Habitat heterogeneity underlies resource variation and influences spatial variation in demography and the distribution of populations. We relate nest site productivity at multiple scales measured over a decade to habitat quality in a box-nesting population of Forpus passerinus (green-rumped parrotlets) in Venezuela to examine critical IFD assumptions. Variation in reproductive success at the local population and neighborhood scales had a much larger influence on productivity (fledglings per nest box per year) than nest site or female identity. Habitat features were reliable cues of nest site quality. Nest sites with less vegetative cover produced greater numbers of fledglings than sites with more cover. However, there was also a competitive cost to nesting in high-quality, low-vegetative cover nest boxes, as these sites experienced the most infanticide events. In the lowland local population, water depth and cover surrounding nest sites were related with F. passerinus productivity. Low vegetative cover and deeper water were associated with lower predation rates, suggesting that predation could be a primary factor driving habitat selection patterns. Parrotlets also demonstrated directional dispersal. Pairs that changed nest sites were more likely to disperse from poor-quality nest sites to high-quality nest sites rather than vice versa, and juveniles were more likely to disperse to, or remain in, the more productive of the two local populations. Parrotlets exhibited three characteristics fundamental to the IFD: habitat heterogeneity within and between local populations, reliable habitat cues to productivity, and active dispersal to sites of higher fitness

Nitric oxide donors (nitrates), L-arginine, or nitric oxide synthase inhibitors for acute stroke

Background:Nitric oxide (NO) has multiple effects that may be beneficial in acute stroke, including lowering blood pressure, and promoting reperfusion and cytoprotection. Some forms of nitric oxide synthase inhibition (NOS-I) may also be beneficial. However, high concentrations of NO are likely to be toxic to brain tissue. This is an update of a Cochrane review first published in 1998, and last updated in 2002. Objectives:To assess the safety and efficacy of NO donors, L-arginine, and NOS-I in people with acute stroke. Search methods: We searched the Cochrane Stroke Group Trials Register (last searched 6 February 2017), MEDLINE (1966 to June 2016), Embase (1980 to June 2016), ISI Science Citation Indexes (1981 to June 2016), Stroke Trials Registry (searched June 2016), International Standard Randomised Controlled Trial Number (ISRCTN) (searched June 2016), Clinical Trials registry (searched June 2016), and International Clinical Trials Registry Platform (ICTRP) (searched June 2016). Previously, we had contacted drug companies and researchers in the field. Selection criteria: Randomised controlled trials comparing nitric oxide donors, L-arginine, or NOS-I versus placebo or open control in people within one week of onset of confirmed stroke. Data collection and analysis: Two review authors independently applied the inclusion criteria, assessed trial quality and risk of bias, and extracted data. The review authors cross-checked data and resolved issues through discussion. We obtained published and unpublished data, as available. Data were reported as mean difference (MD) or odds ratio (OR) with 95% confidence intervals (CI). Main results: We included five completed trials, involving 4197 participants; all tested transdermal glyceryl trinitrate (GTN), an NO donor. The assessed risk of bias was low across the included studies; one study was double-blind, one open-label and three were single-blind. All included studies had blinded outcome assessment. Overall, GTN did not improve the primary outcome of death or dependency at the end of trial (modified Rankin Scale (mRS) > 2, OR 0.97, 95% CI 0.86 to 1.10, 4195 participants, high-quality evidence). GTN did not improve secondary outcomes, including death (OR 0.78, 95% CI 0.40 to 1.50) and quality of life (MD -0.01, 95% CI -0.17 to 0.15) at the end of trial overall (high-quality evidence). Systolic/diastolic blood pressure (BP) was lower in people treated with GTN (MD -7.2 mmHg (95% CI -8.6 to -5.9) and MD -3.3 (95% CI -4.2 to -2.5) respectively) and heart rate was higher (MD 2.0 beats per minute (95% CI 1.1 to 2.9)). Headache was more common in those randomised to GTN (OR 2.37, 95% CI 1.55 to 3.62). We did not find any trials assessing other nitrates, L-arginine, or NOS-I. Authors' conclusions: There is currently insufficient evidence to recommend the use of NO donors, L-arginine or NOS-I in acute stroke, and only one drug (GTN) has been assessed. In people with acute stroke, GTN reduces blood pressure, increases heart rate and headache, but does not alter clinical outcome (all based on high-quality evidence)

Developing a Citizen Social Science approach to understand urban stress and promote wellbeing in urban communities

This paper sets out the future potential and challenges for developing an interdisciplinary, mixed-method Citizen Social Science approach to researching urban emotions. It focuses on urban stress, which is increasingly noted as a global mental health challenge facing both urbanised and rapidly urbanising societies. The paper reviews the existing use of mobile psychophysiological or biosensing within urban environments—as means of ‘capturing’ the urban geographies of emotions. Methodological reflections are included on primary research using biosensing in a study of workplace and commuter stress for university employees in Birmingham (UK) and Salzburg (Austria) for illustrative purposes. In comparing perspectives on the conceptualisation and measurement of urban stress from psychology, neuroscience and urban planning, the difficulties of defining scientific constructs within Citizen Science are discussed to set out the groundwork for fostering interdisciplinary dialogue. The novel methods, geo-located sensor technologies and data-driven approaches to researching urban stress now available to researchers pose a number of ethical, political and conceptual challenges around defining and measuring emotions, stress, human behaviour and urban space. They also raise issues of rigour, participation and social scientific interpretation. Introducing methods informed by more critical Citizen Social Science perspectives can temper overly individualised forms of data collection to establish more effective ways of addressing urban stress and promoting wellbeing in urban communities