Campbell, B. C.V. et al. (2019) Penumbral imaging and functional outcome in patients with anterior circulation ischaemic stroke treated with endovascular thrombectomy versus medical therapy: a meta-analysis of individual patient-level data.ABSTRACT Background: CT-perfusion (CTP) and MRI may assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of ischaemic core and penumbra volumes were associated with functional outcomes and treatment effect.

Campbell, B. C. V. et al. (2018) Effect of general anaesthesia on functional outcome in patients with anterior circulation ischaemic stroke having endovascular thrombectomy versus standard care: a meta-analysis of individual patient data. Lancet Neurology, 17(1), pp. 47-53. (doi:10.1016/S1474-4422(17)30407-6) This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/149670/ variables. An alternative approach using propensity-score stratification was also used. To account for between-trial variance we used mixed-effects modeling with a random effect for trial incorporated in all models. Bias was assessed using the Cochrane tool.Findings: Of 1764 patients in 7 trials, 871 were allocated to endovascular thrombectomy. After exclusion of 74 patients (72 who did not undergo the procedure and 2 with missing data on anaesthetic strategy), 236/797 (30%) of endovascular patients were treated under GA. At baseline, GA patients were younger and had shorter time to randomisation but similar pre-treatment clinical severity compared to non-GA. Endovascular thrombectomy improved functional outcome at 3 months versus standard care in both GA (adjusted common odds ratio (cOR) 1·52, 95%CI 1·09-2·11, p=0·014) and non-GA (adjusted cOR 2·33, 95%CI 1·75-3·10, p<0·001) patients. However, outcomes were significantly better for those treated under non-GA versus GA (covariate-adjusted cOR 1·53, 95%CI 1·14-2·04, p=0·004; propensitystratified cOR 1·44 95%CI 1·08-1·92, p=0·012). The risk of bias and variability among studies was assessed to be low.Interpretation: Worse outcomes after endovascular thrombectomy were associated with GA, after adjustment for baseline prognostic variables. These data support avoidance of GA whenever possible. The procedure did, however, remain effective versus standard care in patients treated under GA, indicating that treatment should not be withheld in those who require anaesthesia for medical reasons. Funding:The HERMES collaboration was funded by an unrestricted grant from Medtronic to the University of Calgary. Research in contextEvidence before this study between abolition of the thrombectomy treatment effect in MR CLEAN and no effect in THRACE. Three single-centre randomised trials of general anaesthesia versus conscious sedation found either no difference in functional outcome between groups or a slight benefit of general anaesthesia. Added value of this studyThese data from contemporary, high quality randomised trials form the largest study to date of the association between general anesthesia and the benefit of endovascular thrombectomy versus standard care. We used two different approaches to adjust for baseline imbalances (multivariable logistic regression and propensity-score stratification). We found that GA for endovascular thrombectomy, as practiced in contemporary clinical care across a wide range of expert centres during the rand...

Objectives To determine the associations between local (pericardial) fat and incident CV disease (CVD) events and cardiac remodeling independent of markers of overall adiposity. Background The impact of pericardial fat—a local fat depot encasing the heart—on myocardial function and long-term cardiovascular (CV) prognosis independent of systemic consequences of adiposity or hepatic fat is an area of active debate. Methods We studied 4,234 participants enrolled in the Multi-Ethnic Study of Atherosclerosis with concomitant cardiac magnetic resonance (CMR) imaging and computed tomographic (CT) measurements for pericardial fat volume and hepatic attenuation (a measure of liver fat). Poisson and Cox regression were used to estimate the annualized risk of incident hard atherosclerotic CVD (ASCVD), all-cause death, heart failure, all-cause CVD, hard CHD and stroke as a function of pericardial and hepatic fat. Generalized additive models were used to assess the association between CMR indices of left ventricular (LV) structure and function and pericardial fat. Models were adjusted for relevant clinical, demographic, and cardiometabolic covariates. Results MESA participants with higher pericardial and hepatic fat were more likely to be older, more frequently male, and had a higher prevalence of cardiometabolic risk factors (including dysglycemia, dyslipdemia, hypertension), as well as adiposity-associated inflammation. Over a median 12.2-year follow-up (IQR 11.6–12.8 years), pericardial fat was associated with a higher rate of incident hard ASCVD (standardized hazard ratio [SHR] 1.22, 95% confidence interval [CI] 1.10–1.35, P=0.0001; hepatic fat by CT was not significantly associated with hard ASCVD (SHR 0.96, 95% CI 0.86–1.08, P=0.52). Higher pericardial fat was associated with greater indexed LV mass (37.8 vs. 33.9 g/m2.7, highest vs. lowest quartile, P<0.01), LV mass-to-volume ratio (1.2 vs. 1.1, highest vs. lowest quartile, P<0.01). In adjusted models, a higher pericardial fat volume was associated with greater LV mass (P<0.0001) and concentricity (P<0.0001). Conclusion Pericardial fat is associated with poorer CVD prognosis and LV remodeling, independent of insulin resistance, inflammation and CT measures of hepatic fat.

Cytotoxic CD8 T lymphocytes play a central role in the tissue destruction of many autoimmune disorders. In type 1 diabetes (T1D), insulin and its precursor preproinsulin are major self-antigens targeted by T cells. We comprehensively examined preproinsulin specificity of CD8 T cells obtained from pancreatic islets of organ donors with and without T1D and identified epitopes throughout the entire preproinsulin protein and defective ribosomal products derived from preproinsulin messenger RNA. The frequency of preproinsulin-reactive T cells was significantly higher in T1D donors than nondiabetic donors and also differed by individual T1D donor, ranging from 3 to over 40%, with higher frequencies in T1D organ donors with HLA-A*02:01. Only T cells reactive to preproinsulin-related peptides isolated from T1D donors demonstrated potent autoreactivity. Reactivity to similar regions of preproinsulin was also observed in peripheral blood of a separate cohort of new-onset T1D patients. These findings have important implications for designing antigen-specific immunotherapies and identifying individuals that may benefit from such interventions.

To determine whether concentrations of potentially toxic lipids in the aqueous phase of human stool are responsive to changes in dietary fat, calcium, and fiber, 20 male volunteers were placed on a high-fat, low-calcium, low-fiber or a low-fat, high-calcium, high-fiber diet for 4 days. To assess toxicity of the fecal fractions, we examined the ability of fecal supernatants to lyse human erythrocytes. Bile acid concentrations in fecal water from the low-fat group were reduced significantly from 180 +/- 60 microM to 100 +/- 70 microM; in the high-fat group, increased from 190 +/- 60 microM to 250 +/- 100 microM. Erythrocyte lysis was 76% for the high-fat group, 37% for the low-fat group. There was a significant weak correlation between aqueous bile acid concentration and cell lysis. Results suggest that diet can influence concentrations of detergents in the aqueous phase of human stool and the potential toxicity of this fraction to cell membranes.