Effects of low-dose alteplase and intensive blood pressure control on brain (micro-) circulation: imaging analyses from the ENCHANTED trial

Background and aims: Worldwide, the burden of acute ischaemic stroke (AIS) is high in terms of disability-adjusted life-years lost. Prior research shows that imaging features of brain frailty (atrophy and severe leucoaraiosis) and acute ischaemia (visible ischaemic lesions, hypoattenuation, large ischaemic lesion, swelling, and hyper-attenuated arteries) on non-contrast computerised tomography (CT) scans are associated with symptomatic intracerebral haemorrhage (sICH) and mortality in thrombolysis-treated AIS patients. This thesis aimed to elucidate other CT and magnetic resonance imaging (MRI) factors related to abnormalities in the brain (micro-) circulation (including fluid-attenuated inversion recovery hyperintense arteries [FLAIR-HAs], a single penetrating artery occlusion presented as a lacunar infarct, and vascular obstruction at different sites) that determine prognosis in thrombolysis-treated AIS patients, and that may modify the effects of treatment with either intravenous alteplase by dose or in the control of blood pressure (BP) according to intensity. Methods: Secondary analyses of datasets from the international randomised trial - Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) - were conducted after central classification of brain scan images. Results: FLAIR-HAs on MRI are frequently present in AIS due to presumed cardioembolism. They indicate a favourable prognosis in such thrombolysis-treated AIS patients, despite also being associated with an increased risk of intracerebral haemorrhage within the region of infarction. A meta-analysis of the ENCHANTED data with similar studies shows that FLAIR-HAs are not associated with the functional outcome overall but are associated with recovery, specifically in patients with endovascular therapy for AIS. FLAIR-HAs are also associated with early recanalisation or haemorrhagic complications, and early neurologic deterioration. My studies on lacunar AIS show no differences in the treatment effect of low- versus standard-dose alteplase, and early intensive versus guideline-recommended BP lowering, on functional recovery and sICH across lacunar and non-lacunar cases of AIS. Furthermore, functional recovery by alteplase dose or BP lowering intensity is not modified by the degree or site of vascular obstruction in cerebral vessels noted on CT or MRI angiography. Conclusions: My thesis has established that several CT/MRI brain imaging features of brain (micro-) circulation are important prognostic markers of functional recovery and sICH in thrombolysis-treated AIS patients. However, these imaging markers do not appear to modify the treatment effects of randomised alteplase dose and degree of BP-lowering among participants of the ENCHANTED trial

In ovo serial skeletal muscle diffusion tractography of the developing chick embryo using DTI: feasibility and correlation with histology

Abstract Background Magnetic resonance imaging is a noninvasive method of evaluating embryonic development. Diffusion tensor imaging (DTI), based on the directional diffusivity of water molecules, is an established method of evaluating tissue structure. Yet embryonic motion degrades the in vivo acquisition of long-duration DTI. We used a dual-cooling technique to avoid motion artifact and aimed to investigate whether DTI can be used to monitor chick embryonic skeletal muscle development in ovo, and to investigate the correlation between quantitative DTI parameters fractional anisotropy (FA) and fiber length and quantitative histologic parameters fiber area percentage (FiberArea%) and limb length. Results From 84 normally developing chick embryos, 5 were randomly chosen each day from incubation days 5 to 18 and scanned using 3.0 Tesla magnetic resonance imaging. A dual-cooling technique is used before and during imaging. Eggs were cracked for making histological specimen after imaging. 3 eggs were serially imaged from days 5 to 18. We show that skeletal muscle fibers can be tracked in hind limb in DTI beginning with incubation day 8. Our data shows a good positive correlation between quantitative DTI and histologic parameters (FA vs FiberArea%: r= 0.943, p\u3c0.0001; Fiber_length vs Limb_length: r=0.974, p\u3c0.0001). The result of tracked fibers in DTI during incubation corresponds to the development of chick embryonic skeletal muscle as reported in the literature. Conclusion Diffusion tensor imaging can provide a noninvasive means of evaluating skeletal muscle development in ovo

Effectiveness and Safety of Antibiotics for Preventing Pneumonia and Improving Outcome after Acute Stroke: Systematic Review and Meta-analysis

Pneumonia is a common complication after stroke which increases morbidity and mortality. This systematic review was conducted to evaluate the efficacy and safety of antibiotics for the prevention of pneumonia after acute stroke. Medline, EMBASE, and Cochrane databases were searched for randomized controlled trials comparing preventive antibiotics to placebo or no antibiotics after acute stroke. The primary outcome was poststroke pneumonia. Secondary outcomes were all infections, urinary tract infections, death, dependency, length of hospital stay, and adverse events. Treatment effects were summarized using random effects metaanalysis. Six trials (4111 patients) were eligible for inclusion. The median National Institute of Health Stroke Scale score in included trials ranged from 5 to 16.5. The proportion of dysphagia ranged from 26% to 100%. Preventive antibiotics were commenced within 48 hours after acute stroke. Compared to control, preventive antibiotics reduced the risk of poststroke pneumonia (RR .75, 95%CI ·.57-.99), and all infections (RR .58, 95%CI .48-.69). There was no significant difference in the risks of dependency (RR 0.99, 95%CI 0·80-1·11), or mortality (RR .96, 95%CI .78-1.19) between the preventive antibiotics and control groups. Preventive antibiotics did not increase the risk of elevated liver enzymes (RR 1.20, 95% CI .97-1.49). Preventive antibiotics had uncertain effects on the risks of other adverse events. Preventive antibiotics reduced the risk of post-stroke pneumonia. However, there is insufficient evidence to currently recommend routine use of preventive antibiotics after acute stroke. [Abstract copyright: Copyright © 2018. Published by Elsevier Inc.

In Ovo Monitoring of Smooth Muscle Fiber Development in the Chick Embryo: Diffusion Tensor Imaging with Histologic Correlation

, and to determine the correlation between histologically-derived muscle fiber fraction, day of incubation and diffusion tensor imaging fractional anisotropy values and length of tracked fibers.From a set of 82 normally developing fertile chicken eggs, 5 eggs were randomly chosen each day from incubation days 5 to 18 and cooled using a dual-cooling technique prior to and during magnetic resonance imaging at 3.0 Tesla. Smooth muscle fibers of the gizzard were tracked using region of interests placed over the gizzard. Following imaging, the egg was cracked and the embryo was fixated and sectioned, and a micrograph most closely corresponding to the acquired magnetic resonance image was made. Smooth muscle fiber fraction was determined using an automated computer algorithm. development of smooth muscle tissue

Comparison of Treatment Rates of Depression After Stroke Versus Myocardial Infarction: A Systematic Review and Meta-Analysis of Observational Data

Objective: Depression after stroke and myocardial infarction (MI) is common but often assumed to be undertreated without reliable evidence being available. Thus, we aimed to determine treatment rates and investigate the application of guidelines in these conditions. Methods: Databases MEDLINE, EMBASE, PsycInfo, Web of Science, CINAHL, and Scopus were systematically searched without language restriction from inception to June 30, 2017. Prospective observational studies with consecutive recruitment reporting any antidepressant treatment in adults with depression after stroke or MI were included. Random-effects models were used to calculate pooled estimates of treatment rates. Results: Fifty-five studies reported 32 stroke cohorts (n = 8938; pooled frequency of depression = 34%, 95% confidence interval [CI] = 29%–38%) and 17 MI cohorts (n = 10,767; pooled frequency of depression = 24%, 95% CI = 20%–28%). In 29 stroke cohorts, 24% (95% CI = 20%–27%) of 2280 depressed people used antidepressant medication. In 15 MI cohorts, 14% (95% CI = 8%–19%) of 2381 depressed people used antidepressant medication indicating a lower treatment rate than in stroke. Two studies reported use of psychosocial interventions, indicating that less than 10% of participants were treated. Conclusions: Despite the high frequency of depression after stroke and MI and the existence of efficacious treatment strategies, people often remain untreated. Innovative strategies are needed to increase the use of effective antidepressive interventions in patients with cardiovascular disease

An exploration of the heterogeneity in effects of SGLT2 inhibition on cardiovascular and all-cause mortality in the EMPA-REG OUTCOME, CANVAS Program, DECLARE-TIMI 58, and CREDENCE trials

Background: Large-scale outcome trials of sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes have identified consistent effects on major adverse cardiovascular events, heart failure, and progression of kidney disease. However, the magnitude of effects on cardiovascular and all-cause death appeared to vary between some of the studies. Methods: We explored the impact of differences in trial methodologies, participant characteristics, types of deaths, follow-up duration, effects on intermediate markers of risk, and drug selectivity for SGLT2 on the magnitude of the protective effect against fatal events achieved in the 4 trials. Results: The trial populations differed substantively in the proportions with baseline atherosclerotic cardiovascular disease history (99.2% in EMPA-REG OUTCOME to 40.6% in DECLARE-TIMI 58), and macroalbuminuria (88.0% in CREDENCE to 7.6% in the CANVAS Program). Meta-regression analyses identified no clear effect of these (both P > 0.09) or other participant characteristics on mortality benefits (all P > 0.55). Other differences between the trials (duration, selectivity of the SGLT2 inhibitor, or effects on intermediate markers of risk) also did not explain the heterogeneity in effects on mortality observed (all P > 0.30). Conclusion: No clear explanation for the statistical evidence of heterogeneity in effects of SGLT2 inhibition on fatal outcomes between the trials could be identified. While the analyses had limited statistical power, these results raise the possibility that the observed variations in treatment effects on fatal outcomes between trials may be at least partly due to chance

Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease:Results From the CREDENCE Trial and Meta-Analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus.METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis.RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (&lt;45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]).CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791.</p