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Background: High blood pressure is common in acute stroke and is a predictor of poor outcome; however, large trials of lowering blood pressure have given variable results, and the management of high blood pressure in ultra-acute stroke remains unclear. We investigated whether transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), a nitric oxide donor, might improve outcome when administered very early after stroke onset.Methods: We did a multicentre, paramedic-delivered, ambulance-based, prospective, randomised, sham-controlled, blinded-endpoint, phase 3 trial in adults with presumed stroke within 4 h of onset, face-arm-speech-time score of 2 or 3, and systolic blood pressure 120 mm Hg or higher. Participants were randomly assigned (1:1) to receive transdermal GTN (5 mg once daily for 4 days; the GTN group) or a similar sham dressing (the sham group) in UK-based ambulances by paramedics, with treatment continued in hospital. Paramedics were unmasked to treatment, whereas participants were masked. The primary outcome was the 7-level modified Rankin Scale (mRS; a measure of functional outcome) at 90 days, assessed by central telephone follow-up with masking to treatment. Analysis was hierarchical, first in participants with a confirmed stroke or transient ischaemic attack (cohort 1), and then in all participants who were randomly assigned (intention to treat, cohort 2) according to the statistical analysis plan. This trial is registered with ISRCTN, number ISRCTN26986053.Findings: Between Oct 22, 2015, and May 23, 2018, 516 paramedics from eight UK ambulance services recruited 1149 participants (n=568 in the GTN group, n=581 in the sham group). The median time to randomisation was 71 min (IQR 45–116). 597 (52%) patients had ischaemic stroke, 145 (13%) had intracerebral haemorrhage, 109 (9%) had transient ischaemic attack, and 297 (26%) had a non-stroke mimic at the final diagnosis of the index event. In the GTN group, participants' systolic blood pressure was lowered by 5·8 mm Hg compared with the sham group (pvs 3 [2–5]; n=558, in the sham group; 1·04 [0·84–1·29]; p=0·69). We found no difference in secondary outcomes, death (treatment-related deaths: 36 in the GTN group vs 23 in the sham group [p=0·091]), or serious adverse events (188 in the GTN group vs 170 in the sham group [p=0·16]) between treatment groups.Interpretation: Prehospital treatment with transdermal GTN does not seem to improve functional outcome in patients with presumed stroke. It is feasible for UK paramedics to obtain consent and treat patients with stroke in the ultra-acute prehospital setting.Funding: British Heart Foundation.

Background Lacunar stroke, a form of small vessel disease (SVD), differs pathologically from other ischaemic stroke subtypes and has no specific long-term secondary prevention. Licenced drugs, isosorbide mononitrate (ISMN) and cilostazol, have relevant actions to prevent SVD progression. Methods We recruited independent patients with clinically confirmed lacunar ischaemic stroke without cognitive impairment to a prospective randomised clinical trial, LACunar Intervention-1 (LACI-1). We randomised patients using a central web-based system, 1:1:1:1 with minimisation, to masked ISMN 25mg bd, cilostazol 100md bd, both ISMN and cilostazol started immediately, or both with start delayed. We escalated doses to target over two weeks, sustained for eight weeks. Primary outcome was the proportion achieving target dose. Secondary outcomes included symptoms, safety (haemorrhage, recurrent vascular events), cognition, haematology and vascular function. LACI-1 was powered (80%, alpha 0·05) to detect 35% (90% versus 55%) difference between the proportion reaching target dose on one versus both drugs at 55 patients. Registration ISRCTN12580546. Findings LACI-1 enrolled 57 participants between March 2016 and August 2017: 18 (32%) female, mean age 66 (SD 11, range 40-85) years, onset-randomisation 203 (range 6-920) days. Most achieved full (64%) or over half (87%) dose, with no difference between cilostazol vs ISMN, single vs dual drugs. Headache and palpitations increased initially then declined similarly with dual versus single drugs. There was no between-group difference in BP, pulse-wave velocity, haemoglobin or platelet function, but pulse rate was higher (mean difference, MD, 6·4, 95%CI 1·2-11·7, p=0·02), platelet count higher (MD 35·7, 95%CI 2·8, 68·7, p=0·03) and white matter hyperintensities reduced more (p=0·007) with cilostazol versus no cilostazol. Interpretation Cilostazol and ISMN are well tolerated when the dose is escalated, without safety concerns, in patients with lacunar stroke. Larger trials with longer term follow-up are justified. Trial Registration Number: ISRCTN12580546 Funding: Alzheimer's Society (AS-PG-14-033) Declaration of Interest: JMW, PB, NS, FD, GB, KF, RD, MJT, IG received funding from the Alzheimer’s Society (ASPG-14-033); FD, PB, NS, JMW report funding from the UK Stroke Association; FD also reports funding from NHS Research Scotland; GB also received funding from Edinburgh and Lothians Health Foundation and the Stroke Association Princess Margaret Research Development Fellowship scheme; YS received funding from the China Scholarships Council; MJT also received funding from NHS Lothian Research and Development Office; JMW also received funding from the Scottish Funding Council; JMW, FD, MJT, MS and GB also received funding from European Union Horizon 2020 (666881, ‘SVDs@Target’) and the Fondation Leducq (16 CVD 05). NS, PB, JMW, JPA also received funding from the British Heart Foundation; PB, NS, JPA, also received funding from the National Institutes of Health Research (NIHR) HTA Programme; PB, NS, CR also received funding from the NIHR Clinical Research network (CRN) East Midlands PB is a NIHR Senior Investigator. Ethical Approval: The trial was approval by the Scotland A Research Ethics Committee (Ref 15/SS/0154), the Medicines and Healthcare Regulatory Agency (Ref 01384/0244/001-0001) and NHS R D (Ref 2015/0354/TMF) and all participants gave written informed consent.

Scientific studies (1990–2000) on the impacts of channel maintenance on the river corridor biota and habitat of Irish arterially drained channels identified strategies that would reduce adverse impact or provide benefit. A 10‐point training programme was developed from these strategies and was rolled out to all Office of Public Work (OPW) field staff, engaged in channel maintenance, during 2003. Follow‐up site visits indicated a strong degree of implementation in respect of particular actions. It was also apparent that there was a low level of uptake of value‐added options, particularly those where strong liaison with fisheries was feasible. It was evident that some of the ‘enhanced maintenance’ diggings in the cross‐section would enhance hydromorphology elements in the channel, consistent with Water Framework Directive requirements. All 10 elements are now being pursued in a new 5‐year programme (2008–2012).

We have developed a small, special-purpose analog computer for automatically calculating the shunt impedance of a resonant cavity from phase-shift perturbation data. Accuracy is limited by the size of the perturbing bead and precision is about 2% for a fixed experimental configuration.

Rationale The pathophysiology of most lacunar stroke, a form of small vessel disease, is thought to differ from large artery atherothrombo- or cardio-embolic stroke. Licensed drugs, isosorbide mononitrate and cilostazol, have promising mechanisms of action to support their testing to prevent stroke recurrence, cognitive impairment, or radiological progression after lacunar stroke. Aim LACI-1 will assess the tolerability, safety, and efficacy, by dose, of isosorbide mononitrate and cilostazol, alone and in combination, in patients with ischemic lacunar stroke. Sample size A sample of 60 provides 80+% power (significance 0.05) to detect a difference of 35% (90% versus 55%) between those reaching target dose on one versus both drugs. Methods and design LACI-1 is a phase IIa partial factorial, dose-escalation, prospective, randomized, open label, blinded endpoint trial. Participants are randomized to isosorbide mononitrate and/or cilostazol for 11 weeks with dose escalation to target as tolerated in two centers (Edinburgh, Nottingham). At three visits, tolerability, safety, blood pressure, pulse wave velocity, and platelet function are assessed, plus magnetic resonance imaging to assess cerebrovascular reactivity in a subgroup. Study outcomes Primary: proportion of patients completing study achieving target maximum dose. Secondary symptoms whilst taking medications; safety (hemorrhage, recurrent vascular events, falls); blood pressure, platelet function, arterial stiffness, and cerebrovascular reactivity. Discussion This study will inform the design of a larger phase III trial of isosorbide mononitrate and cilostazol in lacunar stroke, whilst providing data on the drugs’ effects on vascular and platelet function. Trial registration ISRCTN (ISRCTN12580546) and EudraCT (2015-001953-33).