Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions

Small vessel disease encompasses lacunar stroke, white matter hyperintensities, lacunes and microbleeds. It causes a quarter of all ischemic strokes, is the commonest cause of vascular dementia, and the cause is incompletely understood. Vascular prophylaxis, as appropriate for large artery disease and cardioembolism, includes antithrombotics, and blood pressure and lipid lowering; however, these strategies may not be effective for small vessel disease, or are already used routinely so precluding further detailed study. Further, intensive antiplatelet therapy is known to be hazardous in small vessel disease through enhanced bleeding. Whether acetylcholinesterase inhibitors, which delay the progression of Alzheimer's dementia, are relevant in small vessel disease remains unclear. Potential prophylactic and treatment strategies might be those that target brain microvascular endothelium and the blood brain barrier, microvascular function and neuroinflammation. Potential interventions include endothelin antagonists, neurotrophins, nitric oxide donors and phosphodiesterase 5 inhibitors, peroxisome proliferator-activated receptor-gamma agonists, and prostacyclin mimics and phosphodiesterase 3 inhibitors. Several drugs that have relevant properties are licensed for other disorders, offering the possibility of drug repurposing. Others are in development. Since influencing multiple targets may be most effective, using multiple agents and/or those that have multiple effects may be preferable. We focus on potential small vessel disease mechanistic targets, summarize drugs that have relevant actions, and review data available from randomized trials on their actions and on the available evidence for their use in lacunar stroke

Statistical analysis of the primary outcome in acute stroke trials

Common outcome scales in acute stroke trials are ordered categorical or pseudocontinuous in structure but most have been analyzed as binary measures. The use of fixed dichotomous analysis of ordered categorical outcomes after stroke (such as the modified Rankin Scale) is rarely the most statistically efficient approach and usually requires a larger sample size to demonstrate efficacy than other approaches. Preferred statistical approaches include sliding dichotomous, ordinal, or continuous analyses. Because there is no best approach that will work for all acute stroke trials, it is vital that studies are designed with a full understanding of the type of patients to be enrolled (in particular their case mix, which will be critically dependent on their age and severity), the potential mechanism by which the intervention works (ie, will it tend to move all patients somewhat, or some patients a lot, and is a common hazard present), a realistic assessment of the likely effect size, and therefore the necessary sample size, and an understanding of what the intervention will cost if implemented in clinical practice. If these approaches are followed, then the risk of missing useful treatment effects for acute stroke will diminish

On the Correlated X-ray and Optical Evolution of SS Cygni

We have analyzed the variability and spectral evolution of the prototype dwarf nova system SS Cygni using RXTE data and AAVSO observations. A series of pointed RXTE/PCA observations allow us to trace the evolution of the X-ray spectrum of SS Cygni in unprecedented detail, while 6 years of optical AAVSO and RXTE/ASM light curves show long-term patterns. Employing a technique in which we stack the X-ray flux over multiple outbursts, phased according to the optical light curve, we investigate the outburst morphology. We find that the 3-12 keV X-ray flux is suppressed during optical outbursts, a behavior seen previously, but only in a handful of cycles. The several outbursts of SS Cygni observed with the more sensitive RXTE/PCA also show a depression of the X-rays during optical outburst. We quantify the time lags between the optical and X-ray outbursts, and the timescales of the X-ray recovery from outburst. The optical light curve of SS Cygni exhibits brief anomalous outbursts. During these events the hard X-rays and optical flux increase together. The long-term data suggest that the X-rays decline between outburst. Our results are in general agreement with modified disk instability models (DIM), which invoke a two-component accretion flow consisting of a cool optically thick accretion disk truncated at an inner radius, and a quasi-spherical hot corona-like flow extending to the surface of the white dwarf. We discuss our results in the framework of one such model, involving the evaporation of the inner part of the optically thick accretion disk, proposed by Meyer & Meyer-Hofmeister (1994).Comment: 24 pages, 8 figures, 2 tables, accepted for publication in Ap

Dipyridamole plus aspirin versus aspirin alone in the secondary prevention after TIA or stroke: a meta-analysis by risk

Objectives: Our aim was to study the effect of combination therapy with aspirin and dipyridamole (A+D) over aspirin alone (ASA) in secondary prevention after transient ischemic attack or minor stroke of presumed arterial origin and to perform subgroup analyses to identify patients that might benefit most from secondary prevention with A+D. Data sources: The previously published meta-analysis of individual patient data was updated with data from ESPRIT (N=2,739); trials without data on the comparison of A+D versus ASA were excluded. Review methods: A meta-analysis was performed using Cox regression, including several subgroup analyses and following baseline risk stratification. Results: A total of 7,612 patients (5 trials) were included in the analyses, 3,800 allocated to A+D and 3,812 to ASA alone. The trial-adjusted hazard ratio for the composite event of vascular death, non-fatal myocardial infarction and non-fatal stroke was 0.82 (95% confidence interval 0.72-0.92). Hazard ratios did not differ in subgroup analyses based on age, sex, qualifying event, hypertension, diabetes, previous stroke, ischemic heart disease, aspirin dose, type of vessel disease and dipyridamole formulation, nor across baseline risk strata as assessed with two different risk scores. A+D were also more effective than ASA alone in preventing recurrent stroke, HR 0.78 (95% CI 0.68 – 0.90). Conclusion: The combination of aspirin and dipyridamole is more effective than aspirin alone in patients with TIA or ischemic stroke of presumed arterial origin in the secondary prevention of stroke and other vascular events. This superiority was found in all subgroups and was independent of baseline risk. ---------------------------7dc3521430776 Content-Disposition: form-data; name="c14_creators_1_name_family" Halke

Stroke outcome in clinical trial patients deriving from different countries

<p><b>Background and Purpose:</b> Stroke incidence and outcome vary widely within and across geographical locations. We examined whether differences in index stroke severity, stroke risk factors, mortality, and stroke outcome across geographical locations remain after adjusting for case mix.</p> <p><b>Methods:</b> We analyzed 3284 patients from the Virtual International Stroke Trials Archive (VISTA). We used logistic regression to examine the incidence of mild index stroke, functional, and neurological outcomes after accounting for age, medical history, year of trial recruitment, and initial stroke severity in the functional and neurological outcome analyses. We examined mortality between geographical regions using a Cox proportional hazards model, accounting for age, initial stroke severity, medical history, and year of trial recruitment.</p> <p><b>Results</b> Patients enrolled in the USA and Canada had the most severe index strokes. Those recruited in Austria and Switzerland had the best functional and neurological outcomes at 90 days (P<0.05), whereas those enrolled in Germany had the worst functional outcome at 90 days (P=0.013). Patients enrolled in Austria, Switzerland, Belgium, Netherlands, Finland, Germany, Greece, Israel, Spain, and Portugal had a significantly better survival rate when compared with those enrolled in USA and Canada. Patients enrolled in trials after 1998 had more severe index strokes, with no significant difference in outcome compared with those enrolled before 1998.</p> <p><b>Conclusion:</b> We identified regional variations in index stroke severity, outcome, and mortality for patients enrolled in ischemic stroke clinical trials over the past 13 years that were not fully explained by case mix. Index stroke severity was greater in patients enrolled after 1998, with no significant improvement in outcomes compared to those enrolled before 1998.</p&gt

The Stationary Phase Method for a Wave Packet in a Semiconductor Layered System. The applicability of the method

Using the formal analysis made by Bohm in his book, {\em "Quantum theory"}, Dover Publications Inc. New York (1979), to calculate approximately the phase time for a transmitted and the reflected wave packets through a potential barrier, we calculate the phase time for a semiconductor system formed by different mesoscopic layers. The transmitted and the reflected wave packets are analyzed and the applicability of this procedure, based on the stationary phase of a wave packet, is considered in different conditions. For the applicability of the stationary phase method an expression is obtained in the case of the transmitted wave depending only on the derivatives of the phase, up to third order. This condition indicates whether the parameters of the system allow to define the wave packet by its leading term. The case of a multiple barrier systems is shown as an illustration of the results. This formalism includes the use of the Transfer Matrix to describe the central stratum, whether it is formed by one layer (the single barrier case), or two barriers and an inner well (the DBRT system), but one can assume that this stratum can be comprise of any number or any kind of semiconductor layers.Comment: 15 pages, 4 figures although figure 4 has 5 graph

Understanding the lived experiences of Mexican informal caregivers with Ambient Assisted Living Technologies

Ambient Assisted Living (AAL) Technologies, have the potential to support the people with dementia living in their homes for longer. Dementia is a major public health concern. It currently affects approximately 46.8 million people worldwide and by 2050 this figure will increase to 131.5 million. Low-and-middle income countries (LMIC) will be particularly affected by this situation as their poor health infrastructures and governmental support will mean that they have to rely on the informal caregiver (IC) sector. ICs are people who care for a dependent or disabled family member, commonly spouses or daughters. Mexico was the first Spanish speaking country in the world to recognise dementia as a public health priority. In-home technologies, such as AAL Technologies, are used in dementia care in order to improve patients’ and caregivers’ quality of life. This paper explores the way in which Mexican ICs of people with dementia (PWD) make sense of their lived experiences with AAL technologies

Swallowing therapy for dysphagia in acute and subacute stroke

Background: Dysphagia (swallowing problems), which is common after stroke, is associated with increased risk of death or dependency, occurrence of pneumonia, poor quality of life, and longer hospital stay. Treatments provided to improve dysphagia are aimed at accelerating recovery of swallowing function and reducing these risks. This is an update of the review first published in 1999 and updated in 2012.Objectives: To assess the effects of swallowing therapy on death or dependency among stroke survivors with dysphagia within six months of stroke onset.Search methods: We searched the Cochrane Stroke Group Trials Register (26 June 2018), the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 6) in the Cochrane Library (searched 26 June 2018), MEDLINE (26 June 2018), Embase (26 June 2018), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (26 June 2018),Web of Science Core Collection (26 June 2018), Speech BITE (28 June 2016), ClinicalTrials.Gov (26 June 2018), and the World Health Organization International Clinical Trials Registry Platform (26 June 2018). We also searched Google Scholar (7 June 2018) and the reference lists of relevant trials and review articles.Selection criteria: We sought to include randomised controlled trials (RCTs) of interventions for people with dysphagia and recent stroke (within six months).Data collection and analysis: Two review authors independently applied the inclusion criteria, extracted data, assessed risk of bias, used the GRADE approach to assess the quality of evidence, and resolved disagreements through discussion with the third review author (PB). We used random effects models to calculate odds ratios (ORs), mean differences (MDs), and standardised mean differences (SMDs), and provided 95% confidence intervals (CIs) for each. The primary outcome was functional outcome, defined as death or dependency (or death or disability), at the end of the trial. Secondary outcomes were case fatality at the end of the trial, length of inpatient stay, proportion of participants with dysphagia at the end of the trial, swallowing ability, penetration aspiration score, or pneumonia, pharyngeal transit time, institutionalisation, and nutrition.Main results: We added 27 new studies (1777 participants) to this update to include a total of 41 trials (2660 participants). We assessed the efficacy of swallowing therapy overall and in subgroups by type of intervention: acupuncture (11 studies), behavioural interventions (nine studies), drug therapy (three studies), neuromuscular electrical stimulation (NMES; six studies), pharyngeal electrical stimulation (PES; four studies), physical stimulation (three studies), transcranial direct current stimulation (tDCS; two studies), and transcranial magnetic stimulation (TMS; nine studies). Swallowing therapy had no effect on the primary outcome (death or dependency/disability at the end of the trial) based on data from one trial (two data sets) (OR 1.05, 95% CI 0.63 to 1.75; 306 participants; 2 studies; I² = 0%; P = 0.86; moderate-quality evidence). Swallowing therapy had no effect on case fatality at the end of the trial (OR 1.00, 95% CI 0.66 to 1.52; 766 participants; 14 studies; I² = 6%; P = 0.99; moderate-quality evidence). Swallowing therapy probably reduced length of inpatient stay (MD -2.9, 95% CI -5.65 to -0.15; 577 participants; 8 studies; I² = 11%; P = 0.04; moderate-quality evidence). Researchers found no evidence of a subgroup effect based on testing for subgroup differences (P = 0.54). Swallowing therapy may have reduced the proportion of participants with dysphagia at the end of the trial (OR 0.42, 95% CI 0.32 to 0.55; 1487 participants; 23 studies; I² = 0%; P = 0.00001; low-quality evidence). Trial results show no evidence of a subgroup effect based on testing for subgroup differences (P = 0.91). Swallowing therapy may improve swallowing ability (SMD -0.66, 95% CI -1.01 to -0.32; 1173 participants; 26 studies; I² = 86%; P = 0.0002; very low quality evidence).We found no evidence of a subgroup effect based on testing for subgroup differences (P = 0.09). We noted moderate to substantial heterogeneity between trials for these interventions. Swallowing therapy did not reduce the penetration aspiration score (i.e. it did not reduce radiological aspiration) (SMD -0.37, 95% CI -0.74 to -0.00; 303 participants; 11 studies; I² = 46%; P = 0.05; low-quality evidence). Swallowing therapy may reduce the incidence of chest infection or pneumonia (OR 0.36, 95% CI 0.16 to 0.78; 618 participants; 9 studies; I² = 59%; P = 0.009; very low-quality evidence).Authors’ conclusions: Moderate- and low-quality evidence suggests that swallowing therapy did not have a significant effect on the outcomes of death or dependency/disability, case fatality at the end of the trial, or penetration aspiration score. However, swallowing therapy may have reduced length of hospital stay, dysphagia, and chest infections, and may have improved swallowing ability. However, these results are based on evidence of variable quality, involving a variety of interventions. Further high-quality trials are needed to test whether specific interventions are effective

Should we adjudicate outcomes in stroke trials? A systematic review

BACKGROUND: Central adjudication of outcomes is common in randomized clinical trials in stroke. The rationale for adjudication is clear; centrally adjudicated outcomes should have less random and systematic errors than outcomes assessed locally by site investigators. However, adjudication brings added complexities to a clinical trial and can be costly. AIM: To assess the evidence for outcome adjudication in stroke trials. SUMMARY OF REVIEW: We identified 12 studies evaluating central adjudication in stroke trials. The majority of these were secondary analyses of trials, and the results of all of these would have remained unchanged had central adjudication not taken place, even for trials without sufficient blinding. The largest differences between site-assessed and adjudicator-assessed outcomes were between the most subjective outcomes, such as causality of serious adverse events. We found that the cost of adjudication could be upward of £100,000 for medium to large prevention trials. These findings suggest that the cost of central adjudication may outweigh the advantages it brings in many cases. However, through simulation, we found that only a small amount of bias is required in site investigators’ outcome assessments before adjudication becomes important. CONCLUSION: Central adjudication may not be necessary in stroke trials with blinded outcome assessment. However, for open-label studies, central adjudication may be more important