Recurrent stroke risk and cerebral microbleed burden in ischemic stroke and TIA A meta-analysis

OBJECTIVE: To determine associations between cerebral microbleed (CMB) burden with recurrent ischemic stroke (IS) and intracerebral hemorrhage (ICH) risk after IS or TIA. METHODS: We identified prospective studies of patients with IS or TIA that investigated CMBs and stroke (ICH and IS) risk during $3 months follow-up. Authors provided aggregate summary-level data on stroke outcomes, with CMBs categorized according to burden (single, 2–4, and$5 CMBs) and distribution. We calculated absolute event rates and pooled risk ratios (RR) using randomeffects meta-analysis. RESULTS: We included 5,068 patients from 15 studies. There were 115/1,284 (9.6%) recurrent IS events in patients with CMBs vs 212/3,781 (5.6%) in patients without CMBs (pooled RR 1.8 for CMBs vs no CMBs; 95% confidence interval [CI] 1.4–2.5). There were 49/1,142 (4.3%) ICH events in those with CMBs vs 17/2,912 (0.58%) in those without CMBs (pooled RR 6.3 for CMBs vs no CMBs; 95% CI 3.5–11.4). Increasing CMB burden increased the risk of IS (pooled RR [95% CI] 1.8 [1.0–3.1], 2.4 [1.3–4.4], and 2.7 [1.5–4.9] for 1 CMB, 2–4 CMBs, and $5 CMBs, respectively) and ICH (pooled RR [95 CMB, 2–4 CMBs, and$5 CMBs, respectively). CONCLUSIONS: CMBs are associated with increased stroke risk after IS or TIA. With increasing CMB burden (compared to no CMBs), the risk of ICH increases more steeply than that of IS. However, IS absolute event rates remain higher than ICH absolute event rates in all CMB burden categories

Protocol for the 'e-Nudge trial' : a randomised controlled trial of electronic feedback to reduce the cardiovascular risk of individuals in general practice [ISRCTN64828380]

Background: Cardiovascular disease (including coronary heart disease and stroke) is a major cause of death and disability in the United Kingdom, and is to a large extent preventable, by lifestyle modification and drug therapy. The recent standardisation of electronic codes for cardiovascular risk variables through the United Kingdom's new General Practice contract provides an opportunity for the application of risk algorithms to identify high risk individuals. This randomised controlled trial will test the benefits of an automated system of alert messages and practice searches to identify those at highest risk of cardiovascular disease in primary care databases. Design: Patients over 50 years old in practice databases will be randomised to the intervention group that will receive the alert messages and searches, and a control group who will continue to receive usual care. In addition to those at high estimated risk, potentially high risk patients will be identified who have insufficient data to allow a risk estimate to be made. Further groups identified will be those with possible undiagnosed diabetes, based either on elevated past recorded blood glucose measurements, or an absence of recent blood glucose measurement in those with established cardiovascular disease. Outcome measures: The intervention will be applied for two years, and outcome data will be collected for a further year. The primary outcome measure will be the annual rate of cardiovascular events in the intervention and control arms of the study. Secondary measures include the proportion of patients at high estimated cardiovascular risk, the proportion of patients with missing data for a risk estimate, and the proportion with undefined diabetes status at the end of the trial

Long-term prognosis of symptomatic isolated middle cerebral artery disease in Korean stroke patients

<p>Abstract</p> <p>Background</p> <p>This study aimed to investigate the long-term mortality and recurrence rate of stroke in first-time stroke patients with symptomatic isolated middle cerebral artery disease (MCAD) under medical management.</p> <p>Methods</p> <p>We identified 141 first ever stroke patients (mean age, 64.4 ± 12.5 years; 53% male) with symptomatic isolated MCAD. MCAD was defined as significant stenosis of more than 50% or occlusion of the MCA as revealed by MR angiography. The median follow-up was 27.7 months. We determined a cumulative rate of stroke recurrence and mortality by Kaplan-Meier survival analyses and sought predictors using the Cox proportional hazard model.</p> <p>Results</p> <p>The cumulative composite outcome rate (stroke recurrence or any-cause death) was 14%, 19%, 22%, and 28% at years 1, 2, 3, and 5, respectively. The annual recurrence rate of stroke was 4.1%. The presence of diabetes mellitus was the only significant independent predictor of stroke recurrence or any cause of death in multivariate analyses of Cox proportional hazard model adjusted for any plausible potential confounding factors.</p> <p>Conclusions</p> <p>We estimated the long-term prognosis of stroke patients with isolated symptomatic MCAD under current medical management in Korea. Diabetes mellitus was found to be a significant predictor for stroke recurrence and mortality.</p

Transcranial Doppler ultrasonography predicts cardiovascular events after TIA

<p>Abstract</p> <p>Background</p> <p>Transient ischemic attack (TIA) patients are at high vascular risk. We assessed the value of extracranial (ECD) and transcranial (TCD) Doppler and duplex ultrasonography to predict clinical outcome after TIA.</p> <p>Methods</p> <p>176 consecutive TIA patients admitted to the Stroke Unit were recruited in the study. All patients received diffusion-weighted imaging, standardized ECD and TCD. At a median follow-up of 27 months, new vascular events were recorded.</p> <p>Results</p> <p>22 (13.8%) patients experienced an ischemic stroke or TIA, 5 (3.1%) a myocardial infarction or acute coronary syndrome, and 5 (3.1%) underwent arterial revascularization. ECD revealed extracranial ≥ 50% stenosis or occlusions in 34 (19.3%) patients, TCD showed intracranial stenosis in 15 (9.2%) and collateral flow patterns due to extracranial stenosis in 5 (3.1%) cases. Multivariate analysis identified these abnormal ECD and TCD findings as predictors of new cerebral ischemic events (ECD: hazard ratio (HR) 4.30, 95% confidence interval (CI) 1.75 to 10.57, P = 0.01; TCD: HR 4.73, 95% CI 1.86 to 12.04, P = 0.01). Abnormal TCD findings were also predictive of cardiovascular ischemic events (HR 18.51, 95% CI 3.49 to 98.24, P = 0.001).</p> <p>Conclusion</p> <p>TIA patients with abnormal TCD findings are at high risk to develop further cerebral and cardiovascular ischemic events.</p

Pan-cancer analysis of pre-diagnostic blood metabolite concentrations in the European Prospective Investigation into Cancer and Nutrition

BACKGROUND: Epidemiological studies of associations between metabolites and cancer risk have typically focused on specific cancer types separately. Here, we designed a multivariate pan-cancer analysis to identify metabolites potentially associated with multiple cancer types, while also allowing the investigation of cancer type-specific associations. METHODS: We analysed targeted metabolomics data available for 5828 matched case-control pairs from cancer-specific case-control studies on breast, colorectal, endometrial, gallbladder, kidney, localized and advanced prostate cancer, and hepatocellular carcinoma nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. From pre-diagnostic blood levels of an initial set of 117 metabolites, 33 cluster representatives of strongly correlated metabolites and 17 single metabolites were derived by hierarchical clustering. The mutually adjusted associations of the resulting 50 metabolites with cancer risk were examined in penalized conditional logistic regression models adjusted for body mass index, using the data-shared lasso penalty. RESULTS: Out of the 50 studied metabolites, (i) six were inversely associated with the risk of most cancer types: glutamine, butyrylcarnitine, lysophosphatidylcholine a C18:2, and three clusters of phosphatidylcholines (PCs); (ii) three were positively associated with most cancer types: proline, decanoylcarnitine, and one cluster of PCs; and (iii) 10 were specifically associated with particular cancer types, including histidine that was inversely associated with colorectal cancer risk and one cluster of sphingomyelins that was inversely associated with risk of hepatocellular carcinoma and positively with endometrial cancer risk. CONCLUSIONS: These results could provide novel insights for the identification of pathways for cancer development, in particular those shared across different cancer types

Pre-referral rectal artesunate in severe malaria: flawed trial

<p>Abstract</p> <p>Background</p> <p>Immediate injectable treatment is essential for severe malaria. Otherwise, the afflicted risk lifelong impairment or death. In rural areas of Africa and Asia, appropriate care is often miles away. In 2009, Melba Gomes and her colleagues published the findings of a randomized, placebo-controlled trial of rectal artesunate for suspected severe malaria in such remote areas. Enrolling nearly 18,000 cases, the aim was to evaluate whether, as patients were in transit to a health facility, a pre-referral artesunate suppository blocked disease progression sufficiently to reduce these risks. The affirmative findings of this, the only trial on the issue thus far, have led the WHO to endorse rectal artesunate as a pre-referral treatment for severe malaria. In the light of its public health importance and because its scientific quality has not been assessed for a systematic review, our paper provides a detailed evaluation of the design, conduct, analysis, reporting, and practical features of this trial.</p> <p>Results</p> <p>We performed a checklist-based and an in-depth evaluation of the trial. The evaluation criteria were based on the CONSORT statement for reporting clinical trials, the clinical trial methodology literature, and practice in malaria research. Our main findings are: The inclusion and exclusion criteria and the sample size justification are not stated. Many clearly ineligible subjects were enrolled. The training of the recruiters does not appear to have been satisfactory. There was excessive between center heterogeneity in design and conduct. Outcome evaluation schedule was not defined, and in practice, became too wide. Large gaps in the collection of key data were evident. Primary endpoints were inconsistently utilized and reported; an overall analysis of the outcomes was not done; analyses of time to event data had major flaws; the stated intent-to-treat analysis excluded a third of the randomized subjects; the design-indicated stratified or multi-variate analysis was not done; many improper subgroups were analyzed in a post-hoc fashion; the analysis and reporting metric was deficient. There are concerns relating to patient welfare at some centers. Exclusion of many cases from data analysis compromised external validity. A bias-controlled reanalysis of available data does not lend support to the conclusions drawn by the authors.</p> <p>Conclusions</p> <p>This trial has numerous serious deficiencies in design, implementation, and methods of data analysis. Interpretation and manner of reporting are wanting, and the applicability of the findings is unclear. The trial conduct could have been improved to better protect patient welfare. The totality of these problems make it a flawed study whose conclusions remain subject to appreciable doubt.</p

No short-cut in assessing trial quality: a case study

Assessing the quality of included trials is a central part of a systematic review. Many check-list type of instruments for doing this exist. Using a trial of antibiotic treatment for acute otitis media, Burke et al., BMJ, 1991, as the case study, this paper illustrates some limitations of the check-list approach to trial quality assessment. The general verdict from the check list type evaluations in nine relevant systematic reviews was that Burke et al. (1991) is a good quality trial. All relevant meta-analyses extensively used its data to formulate therapeutic evidence. My comprehensive evaluation, on the other hand, brought to the surface a series of serious problems in the design, conduct, analysis and report of this trial that were missed by the earlier evaluations. A check-list or instrument based approach, if used as a short-cut, may at times rate deeply flawed trials as good quality trials. Check lists are crucial but they need to be augmented with an in-depth review, and where possible, a scrutiny of the protocol, trial records, and original data. The extent and severity of the problems I uncovered for this particular trial warrant an independent audit before it is included in a systematic review

Chicken CRTAM Binds Nectin-Like 2 Ligand and Is Upregulated on CD8⁺ αβ and γδ T Lymphocytes with Different Kinetics

During a search for immunomodulatory receptors in the chicken genome, we identified a previously cloned chicken sequence as CRTAM homologue by its overall identity and several conserved sequence features. For further characterization, we generated a CRTAM specific mab. No staining was detectable in freshly isolated cell preparations from thymus, bursa, caecal tonsils, spleen, blood and intestine. Activation of splenocytes with recombinant IL-2 increased rapid CRTAM expression within a 2 h period on about 30% of the cells. These CRTAM+ cells were identified as CD8+ γδ T lymphocytes. In contrast, CRTAM expression could not be stimulated on PBL with IL-2, even within a 48 h stimulation period. As a second means of activation, T cell receptor (TCR) crosslinking using an anti-αβ-TCR induced CRTAM on both PBL and splenocytes. While CRTAM expression was again rapidly upregulated on splenocytes within 2 h, it took 48 h to reach maximum levels of CRTAM expression in PBL. Strikingly, albeit the stimulation of splenocytes was performed with anti-αβ-TCR, CRTAM expression after 2 h was mainly restricted to CD8+ γδ T lymphocytes, however, the longer anti-TCR stimulation of peripheral blood lymphocytes (PBL) resulted in CRTAM expression on αβ T lymphocytes. In order to characterize the potential ligand we cloned and expressed chicken Necl-2, a member of the nectin and nectin-like family which is highly homologous to its mammalian counterpart. Three independent assays including a reporter assay, staining with a CRTAM-Ig fusion protein and a cell conjugate assay confirmed the interaction of CRTAM with Necl-2 which could also be blocked by a soluble CRTAM-Ig fusion protein or a CRTAM specific mab. These results suggest that chicken CRTAM represents an early activation antigen on CD8+ T cells which binds to Necl-2 and is upregulated with distinct kinetics on αβ versus γδ T lymphocytes

Exploring diurnal variation using piecewise linear splines:an example using blood pressure

Background: There are many examples of physiological processes that follow a circadian cycle and researchers are interested in alternative methods to illustrate and quantify this diurnal variation. Circadian blood pressure (BP) deserves additional attention given uncertainty relating to the prognostic significance of BP variability in relation to cardiovascular disease. However, the majority of studies exploring variability in ambulatory blood pressure monitoring (ABPM) collapse the data into single readings ignoring the temporal nature of the data. Advanced statistical techniques are required to explore complete variation over 24 h. Methods: We use piecewise linear splines in a mixed-effects model with a constraint to ensure periodicity as a novel application for modelling daily blood pressure. Data from the Mitchelstown Study, a cross-sectional study of Irish adults aged 47–73 years (n = 2047) was utilized. A subsample (1207) underwent 24-h ABPM. We compared patterns between those with and without evidence of subclinical target organ damage (microalbuminuria). Results: We were able to quantify the steepest rise and fall in SBP, which occurred just after waking (2.23 mmHg/30 min) and immediately after falling asleep (−1.93 mmHg/30 min) respectively. The variation about an individual’s trajectory over 24 h was 12.3 mmHg (standard deviation). On average those with microalbuminuria were found to have significantly higher SBP (7.6 mmHg, 95% CI 5.0–10.1) after adjustment for age, sex and BMI. Including an interaction term between each linear spline and microalbuminuria did not improve model fit. Conclusion: We have introduced a practical method for the analysis of ABPM where we can determine the rate of increase or decrease for different periods of the day. This may be particularly useful in examining chronotherapy effects of antihypertensive medication. It offers new measures of short-term BP variability as we can quantify the variation about an individual’s trajectory but also allows examination of the variation in slopes between individuals (random-effects)