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Objectives Informing research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.Design In the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.Setting UK stroke services.Participants 3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.Results Of those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.Conclusion It is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration number ISRCTN83290762; Post-results.

The aim of this pilot study was to evaluate the effectiveness of the U.K. Change4Life Sugar Swaps campaign for improving nutritional intake in a small sample of families prior to the 2015 nationwide launch. A total of 49 participants from 14 families received information and materials during a two-week intervention period in November 2014 encouraging them to swap high sugar foods and drinks for low sugar alternatives. Daily dietary intake was reported with online food diaries over four stages, each two weeks in length: (i) baseline (no information provided), (ii) intervention when Sugar Swaps materials were accessible, (iii) immediate follow-up, and (iv) one year on from baseline. Data were analysed for sugar, glucose, fructose, sucrose, lactose, fat, saturated fat, carbohydrate, protein, salt, fibre, vitamin C, and energy. During the intervention, significant daily reductions of 32 g sugar, 11 g fat, and 236 kcal for each family member were observed, among others, and 61% of benefits achieved during the intervention period were maintained at immediate follow-up. Encouragingly, for children, reductions in sugar, sucrose, fat, saturated fat, carbohydrate, and energy were observed one year on. The Sugar Swaps Campaign is potentially an effective public health intervention for improving short- and long-term dietary behaviour for the whole family.

Objective: To determine whether the presence of diffusion-weighted imaging-positive (DWI+) lesions is associated with recurrent stroke after intracerebral haemorrhage (ICH)., Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) assessed the effect of restarting versus avoiding antiplatelet therapy after ICH on major vascular events for up to 5 years. We rated DWI sequences of MRI done before randomisation for DWI+ lesion presence, masked to outcome and antiplatelet use. Cox proportional hazards regression models were used to quantify associations., Results: Of 537 participants in RESTART, 247 (median (IQR) age 75.7 (69.6-81.1) years; 170 men (68.8%); 120 started vs 127 avoided antiplatelet therapy) had DWI sequences on brain MRI at a median of 57 days (IQR 19-103) after ICH, of whom 73 (30%) had one or more DWI+ lesion. During a median follow-up of 2 years (1-3), 18 participants had recurrent ICH and 21 had ischaemic stroke. DWI+ lesion presence was associated with all stroke, (adjusted HR 2.2 (95% CI 1.1 to 4.2)) and recurrent ICH (4.8 (95% CI 1.8 to 13.2)), but not ischaemic stroke (0.9 (95% CI 0.3 to 2.5)). DWI+ lesion presence (0.5 (95% CI 0.2 to 1.3)) vs absence (0.6 (95% CI 0.3 to 1.5), p interaction =0.66) did not modify the effect of antiplatelet therapy on a composite outcome of recurrent stroke., Conclusions: DWI+ lesion presence in ICH survivors is associated with recurrent ICH, but not with ischaemic stroke. We found no evidence of modification of effects of antiplatelet therapy on recurrent stroke after ICH by DWI+ lesion presence. These findings provide a new perspective on the significance of DWI+ lesions, which may be markers of microvascular mechanisms associated with recurrent ICH., Trial Registration Number: ISRCTN71907627., Competing Interests: Competing interests: MdCVH and JW are supported by the Row Fogo Charitable Trust who funds the Row Fogo Charitable Trust Centre for Research into the Ageing and the Brain Re No: AD.ROW4.35.BRO-D.FID 3668413. DJW reports personal fees from Bayer and JFB Consulting, outside the submitted work (no award/grant number). F-EdL was supported by a clinical established investigator grant of the Dutch Heart Foundation (grant 2014T060), and by a VIDI innovational grant from The Netherlands Organisation for Health Research and Development, ZonMw (grant 016126351). CJMK is supported by a clinical established investigator grant of the Dutch Heart Foundation (grant no. 2012 T077) and an Aspasia grant from The Netherlands Organization for Health Research and Development (ZonMw grant no. 015.008.048). RA-SS reports a grant from the British Heart Foundation (SP/12/2/29422) paid to the University of Edinburgh for the conduct of RESTART, and grants from the Stroke Association, Chest Heart and Stroke Scotland and GE Healthcare Limited, outside the submitted work (no award/grant number). PW reports personal fees from Stryker Global Advisory Board on Hemorrhagic Stroke and MicroVention-Terumo, and a grant from MicroVention-Terumo outside the submitted work (no award/grant number). JW is supported by European Union Horizon 2020, PHC-03-15, project No 666881, ‘SVDs@Target’, Fondation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease, ref no. 16 CVD 05, the UK Dementia Research Institute which receives its funding from DRI, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK, and by grants from the EU Framework 7, Medical Research Council and the British Heart Foundation, outside the submitted work (no award/grant number)., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: For adults surviving stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, it is unclear whether starting antiplatelet drugs results in an increase in the risk of recurrent ICH or a beneficial net reduction of all serious vascular events compared to avoiding antiplatelet drugs., Methods/design: The REstart or STop Antithrombotics Randomised Trial (RESTART) is an investigator-led, randomised, open, assessor-blind, parallel-group, randomised trial comparing starting versus avoiding antiplatelet drugs for adults surviving antithrombotic-associated ICH at 122 hospital sites in the United Kingdom. RESTART uses a central, web-based randomisation system using a minimisation algorithm, with 1:1 treatment allocation to which central research staff are masked. Central follow-up includes annual postal or telephone questionnaires to participants and their general (family) practitioners, with local provision of information about adverse events and outcome events. The primary outcome is recurrent symptomatic ICH. The secondary outcomes are: symptomatic haemorrhagic events; symptomatic vaso-occlusive events; symptomatic stroke of uncertain type; other fatal events; modified Rankin Scale score; adherence to antiplatelet drug(s). The magnetic resonance imaging (MRI) sub-study involves the conduct of brain MRI according to a standardised imaging protocol before randomisation to investigate heterogeneity of treatment effect according to the presence of brain microbleeds. Recruitment began on 22 May 2013. The target sample size is at least 720 participants in the main trial (at least 550 in the MRI sub-study)., Discussion: Final results of RESTART will be analysed and disseminated in 2019., Trial Registration: ISRCTN71907627 ( www.isrctn.com/ISRCTN71907627 ). Prospectively registered on 25 April 2013.

Background: Few interventions are proven to increase recruitment in clinical trials. Recruitment to RESTART, a randomised controlled trial of secondary prevention after stroke due to intracerebral haemorrhage, has been slower than expected. Therefore, we sought to investigate an intervention to boost recruitment to RESTART., Methods/design: We conducted a stepped-wedge, cluster randomised trial of a complex intervention to increase recruitment, embedded within the RESTART trial. The primary objective was to investigate if the PRIME complex intervention (a recruitment co-ordinator who conducts a recruitment review, provides access to bespoke stroke audit data exports, and conducts a follow-up review after 6 months) increases the recruitment rate to RESTART. We included 72 hospital sites located in England, Wales, or Scotland that were active in RESTART in June 2015. All sites began in the control state and were allocated using block randomisation stratified by hospital location (Scotland versus England/Wales) to start the complex intervention in one of 12 different months. The primary outcome was the number of patients randomised into RESTART per month per site. We quantified the effect of the complex intervention on the primary outcome using a negative binomial, mixed model adjusting for site, December/January months, site location, and background time trends in recruitment rate., Results: We recruited and randomised 72 sites and recorded their monthly recruitment to RESTART over 24 months (March 2015 to February 2017 inclusive), providing 1728 site-months of observations for the primary analysis. The adjusted rate ratio for the number of patients randomised per month after allocation to the PRIME complex intervention versus control time before allocation to the PRIME complex intervention was 1.06 (95% confidence interval 0.55 to 2.03, p = 0.87). Although two thirds of respondents to the 6-month follow-up questionnaire agreed that the audit reports were useful, only six patients were reported to have been randomised using the audit reports. Respondents frequently reported resource and time pressures as being key barriers to running the audit reports., Conclusion: The PRIME complex intervention did not significantly improve the recruitment rate to RESTART. Further research is needed to establish if PRIME might be beneficial at an earlier stage in a prevention trial or for prevention dilemmas that arise more often in clinical practice.

Background: The effect of alteplase on patient survival after ischaemic stroke is the subject of debate. We report the effect of intravenous alteplase on long-term survival after ischaemic stroke of participants in the Third International Stroke Trial (IST-3)., Methods: In IST-3, done at 156 hospitals in 12 countries (Australia, Europe, and the UK), participants (aged >18 years) were randomly assigned with a telephone voice-activated or web-based system in a 1:1 ratio to treatment with intravenous 0·9 mg/kg alteplase plus standard care or standard care alone within 6 h of ischaemic stroke. We followed up participants in the UK and Scandinavia (Sweden and Norway) for survival up to 3 years after randomisation using data from national registries and compared survival in the two groups with proportional hazards survival analysis, adjusting for key prognostic variables. IST-3 is registered with the ISRCTN registry, number ISRCTN25765518., Findings: Between May 5, 2000, and July 27, 2011, 3035 participants were enrolled in IST-3. Of these, 1948 (64%) of 3035 participants were scheduled for analysis of 3 year survival, and 1946 (>99%) of these were included in the analysis (967 [50%] in the alteplase plus standard care group and 979 [50%] in the standard care alone group). By 3 years after randomisation, 453 (47%) of 967 participants in the alteplase plus standard care group and 494 (50%) of 979 in the standard care alone group had died (risk difference 3·6% [95% CI -0·8 to 8·1]). Participants allocated to alteplase had a significantly higher hazard of death during the first 7 days (99 [10%] of 967 died in the alteplase plus standard care group vs 65 [7%] of 979 in the standard care alone group; hazard ratio 1·52 [95% CI 1·11-2·08]; p=0·004) and a significantly lower hazard of death between 8 days and 3 years (354 [41%] of 868 vs 429 [47%] of 914; 0·78 [0·68-0·90]; p=0·007)., Interpretation: Alteplase treatment within 6 h after ischaemic stroke was associated with a small, non-significant reduction in risk of death at 3 years, but among individuals who survived the acute phase, treatment was associated with a significant increase in long-term survival. These results are reassuring for clinicians who have expressed concerns about the effect of alteplase on survival., Funding: Heart and Stroke Scotland, UK Medical Research Council, Health Foundation UK, Stroke Association UK, Research Council of Norway, AFA Insurance, Swedish Heart Lung Fund, Foundation of Marianne and Marcus Wallenberg, Polish Ministry of Science and Education, Australian Heart Foundation, Australian National Health and Medical Research Council, Swiss National Research Foundation, Swiss Heart Foundation, Assessorato alla Sanita (Regione dell'Umbria), and Danube University., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Some types of human sequential memory, e.g. the acquisition of a new composition by a trained musician, seem to be very efficient in extending the length of a memorized sequence and in flexible reuse of known subsequences in a newly acquired sequential context. This implies that interference between known and newly acquired subsequences can be avoided even when learning a sequence which is a partial mutation of a known sequence. It is known that established motor sequences do not have such flexibility. Using learning of deferred imitation, the current study investigates the flexibility of explicit spatial memory by quantifying the interferences between successively acquired, partially overlapping sequences. After learning a spatial sequence on day 1, this sequence was progressively modified on day 2. On day 3, a retention test was performed with both the initial and the modified sequence. The results show that subjects performed very well on day 1 and day 2. No spatial interference between changed and unchanged targets was observed during the stepwise progressive modification of the reproduced sequence. Surprisingly, subjects performed well on both sequences on day 3. Comparison with a control experiment without intermediate mutation training showed that the initial training on day 1 did not proactively interfere with the retention of the modified sequence on day 3. Vice versa, the mutation training on day 2 did not interfere retroactively with the retention of the original sequence as tested on day 3. The results underline the flexibility in acquiring explicit spatial memory., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Sequence learning has been the subject of research in various paradigms but has not been investigated for learning deferred imitation of long spatial sequences. In this task no guiding stimuli support the sequence reproduction and all sequence information has to be recalled from memory. We investigate this kind of imitation learning with a task in which a long sequence of spatial positions has to be reproduced without guiding stimuli, either by manual pointing or by ocular fixations. Sequences consisting of 20 positions were acquired after only 25 training trials. The persistence of learned sequences over several days showed that the sequence was retained in long-term memory. A transfer test revealed that the learned sequence was independent of the effector. A detailed analysis of the error distributions of pointing and ocular fixations was performed to characterize the guiding control signal. The independence of the variable position errors from the movement directions as well as the lack of error propagation between successive targets suggest that the reproduction in this learning task was guided by sequential positions rather than sequential displacements., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Studying imitation learning of long sequences requires the evaluation of inaccurately and incompletely reproduced movement sequences. In order to evaluate the movement reproduction, it has to be assigned to the original stimulus. We developed an assignment algorithm that considers the Spatial Neighborhood and Order of reproduction (SNOA). To evaluate the features of this analysis it was applied to human performance during learning of long pointing sequences under two conditions: stimulus-guided reproduction with high spatial accuracy and imitation learning with low spatial accuracy. The results were compared with a simple assignment considering Spatial Neighborhood only (SNA) and with a Manual Assignment (MA). In the stimulus-guided reproduction the error measures did not differ between the algorithms. In contrast, with imitation learning, SNOA and MA generated higher estimates of order and omission errors than SNA. The results show that SNOA can be used to automatically quantify the similarity of both movement structure and metric information between long target sequences and inaccurate and incomplete movement reproductions.

MIIND (Multiple Interacting Instantiations of Neural Dynamics) is a highly modular multi-level C++ framework, that aims to shorten the development time for models in Cognitive Neuroscience (CNS). It offers reusable code modules (libraries of classes and functions) aimed at solving problems that occur repeatedly in modelling, but tries not to impose a specific modelling philosophy or methodology. At the lowest level, it offers support for the implementation of sparse networks. For example, the library SparseImplementationLib supports sparse random networks and the library LayerMappingLib can be used for sparse regular networks of filter-like operators. The library DynamicLib, which builds on top of the library SparseImplementationLib, offers a generic framework for simulating network processes. Presently, several specific network process implementations are provided in MIIND: the Wilson-Cowan and Ornstein-Uhlenbeck type, and population density techniques for leaky-integrate-and-fire neurons driven by Poisson input. A design principle of MIIND is to support detailing: the refinement of an originally simple model into a form where more biological detail is included. Another design principle is extensibility: the reuse of an existing model in a larger, more extended one. One of the main uses of MIIND so far has been the instantiation of neural models of visual attention. Recently, we have added a library for implementing biologically-inspired models of artificial vision, such as HMAX and recent successors. In the long run we hope to be able to apply suitably adapted neuronal mechanisms of attention to these artificial models.

The solubility of toluene has been measured in distilled water, and in various inorganic salt solutions. Values of the Setschenow constant, K(S), which quantify toluene solubility versus salt concentration, have been determined for each salt. Values of K(S) are compared to the activity of water for the salt solutions. Data from this study, consistent with earlier data, suggests that the effects of salts upon toluene solubility are non-additive. This contrasts the additive behavior of inorganic salts upon the solubility of nonpolar organic compounds, such as benzene and naphthalene, reported in the literature. Specific interaction between slightly polar toluene and ions in solution is suggested as a possible explanation for the non-additive effect of salts on the solubility of toluene.