Stroke penumbra defined by an MRI-based oxygen challenge technique: 2. Validation based on the consequences of reperfusion

Magnetic resonance imaging (MRI) with oxygen challenge (T2* OC) uses oxygen as a metabolic biotracer to define penumbral tissue based on CMRO2 and oxygen extraction fraction. Penumbra displays a greater T2* signal change during OC than surrounding tissue. Since timely restoration of cerebral blood flow (CBF) should salvage penumbra, T2* OC was tested by examining the consequences of reperfusion on T2* OC-defined penumbra. Transient ischemia (109±20 minutes) was induced in male Sprague-Dawley rats (n=8). Penumbra was identified on T2*-weighted MRI during OC. Ischemia and ischemic injury were identified on CBF and apparent diffusion coefficient maps, respectively. Reperfusion was induced and scans repeated. T2 for final infarct and T2* OC were run on day 7. T2* signal increase to OC was 3.4% in contralateral cortex and caudate nucleus and was unaffected by reperfusion. In OC-defined penumbra, T2* signal increased by 8.4%±4.1% during ischemia and returned to 3.25%±0.8% following reperfusion. Ischemic core T2* signal increase was 0.39%±0.47% during ischemia and 0.84%±1.8% on reperfusion. Penumbral CBF increased from 41.94±13 to 116.5±25 mL per 100 g per minute on reperfusion. On day 7, OC-defined penumbra gave a normal OC response and was located outside the infarct. T2* OC-defined penumbra recovered when CBF was restored, providing further validation of the utility of T2* OC for acute stroke management

Stroke penumbra defined by an MRI-based oxygen challenge technique: 1. validation using [14C]2-deoxyglucose autoradiography

Accurate identification of ischemic penumbra will improve stroke patient selection for reperfusion therapies and clinical trials. Current magnetic resonance imaging (MRI) techniques have limitations and lack validation. Oxygen challenge T2* MRI (T2* OC) uses oxygen as a biotracer to detect tissue metabolism, with penumbra displaying the greatest T2* signal change during OC. [14C]2-deoxyglucose (2-DG) autoradiography was combined with T2* OC to determine metabolic status of T2*-defined penumbra. Permanent middle cerebral artery occlusion was induced in anesthetized male Sprague-Dawley rats (n=6). Ischemic injury and perfusion deficit were determined by diffusion- and perfusion-weighted imaging, respectively. At 147±32 minutes after stroke, T2* signal change was measured during a 5-minute 100% OC, immediately followed by 125 μCi/kg 2-DG, intravenously. Magnetic resonance images were coregistered with the corresponding autoradiograms. Regions of interest were located within ischemic core, T2*-defined penumbra, equivalent contralateral structures, and a region of hyperglycolysis. A T2* signal increase of 9.22%±3.9% (mean±s.d.) was recorded in presumed penumbra, which displayed local cerebral glucose utilization values equivalent to contralateral cortex. T2* signal change was negligible in ischemic core, 3.2%±0.78% in contralateral regions, and 1.41%±0.62% in hyperglycolytic tissue, located outside OC-defined penumbra and within the diffusion abnormality. The results support the utility of OC-MRI to detect viable penumbral tissue follow

Efforts at the Frontlines: Implementing a Hepatitis C Testing and Linkage-to-Care Program at the Local Public Health Level

The national Viral Hepatitis Action Plan recommends strengthening partnerships among health departments, community-based organizations, and health-care providers for hepatitis services. We implemented a hepatitis C virus (HCV) testing and linkage-to-care program through a local health department using similar strategies reported for HIV care

Impact of computed tomography perfusion imaging on the response to tenecteplase in ischemic stroke: analysis of two randomized controlled trials

Background: We pooled 2 clinical trials of tenecteplase compared with alteplase for the treatment of acute ischemic stroke, 1 that demonstrated superiority of tenecteplase and the other that showed no difference between the treatments in patient clinical outcomes. We tested the hypotheses that reperfusion therapy with tenecteplase would be superior to alteplase in improving functional outcomes in the group of patients with target mismatch as identified with advanced imaging. Methods: We investigated whether tenecteplase-treated patients had a different 24-hour reduction in the National Institutes of Health Stroke Scale and a favorable odds ratio of a modified Rankin scale score of 0 to 1 versus 2 to 6 compared with alteplase-treated patients using linear regression to generate odds ratios. Imaging outcomes included rates of vessel recanalization and infarct growth at 24 hours and occurrence of large parenchymal hematoma. Baseline computed tomography perfusion was analyzed to assess whether patients met the target mismatch criteria (absolute mismatch volume >15 mL, mismatch ratio >1.8, baseline ischemic core <70 mL, and volume of severely hypoperfused tissue <100 mL). Patients meeting target mismatch criteria were analyzed as a subgroup to identify whether they had different treatment responses from the pooled group. Results: Of 146 pooled patients, 71 received alteplase and 75 received tenecteplase. Tenecteplase-treated patients had greater early clinical improvement (median National Institutes of Health Stroke Scale score change: tenecteplase, 7; alteplase, 2; P=0.018) and less parenchymal hematoma (2 of 75 versus 10 of 71; P=0.02). The pooled group did not show improved patient outcomes when treated with tenecteplase (modified Rankin scale score 0–1: odds ratio, 1.77; 95% confidence interval, 0.89–3.51; P=0.102) compared with alteplase therapy. However, in patients with target mismatch (33 tenecteplase, 35 alteplase), treatment with tenecteplase was associated with greater early clinical improvement (median National Institutes of Health Stroke Scale score change: tenecteplase, 6; alteplase, 1; P<0.001) and better late independent recovery (modified Rankin scale score 0–1: odds ratio, 2.33; 95% confidence interval, 1.13–5.94; P=0.032) than those treated with alteplase. Conclusions: Tenecteplase may offer an improved efficacy and safety profile compared with alteplase, benefits possibly exaggerated in patients with baseline computed tomography perfusion–defined target mismatch. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01472926. URL: https://www.anzctr.org.au. Unique identifier: ACTRN12608000466347

Comparing mismatch strategies for patients being considered for ischemic stroke tenecteplase trials

Background: Currently there are multiple variations of imaging-based patient selection mismatch methods in ischemic stroke. In the present study, we sought to compare the two most common mismatch methods and identify if there were different effects on the outcome of a randomized clinical trial depending on the mismatch method used. Aims: Investigate the effect of clinical and imaging-based mismatch criteria on patient outcomes of a pooled cohort from randomized trials of intravenous tenecteplase versus alteplase. Methods: Baseline clinical and imaging scores were used to categorize patients as meeting either the DAWN mismatch (baseline NIHSS ≥ 10, and age cut-offs for ischemic core volume) or DEFUSE 2 mismatch criteria (mismatch volume > 15 mL, mismatch ratio > 1.8 and ischemic core < 70 mL). We then investigated whether tenecteplase-treated patients had favorable odds of less disability (on modified Rankin scale, mRS) compared to those treated with alteplase, for clinical and imaging mismatch, respectively. Results: From 146 pooled patients, 71 received alteplase and 75 received tenecteplase. The overall pooled group did not show improved patient outcomes when treated with tenecteplase (mRS 0-1 OR 1.77, 95% CI 0.89–3.51, p = 0.102) compared with alteplase. A total of 39 (27%) patients met both clinical and imaging mismatch criteria, 25 (17%) patients met only imaging criteria, 36 (25%) met only clinical mismatch criteria and, finally, 46 (31%) did not meet either of imaging or mismatch criteria. Patients treated with tenecteplase had more favorable outcomes when they met either imaging mismatch (mRS 0–1, OR 2.33, 95% CI 1.13–5.94, p = 0.032) or clinical mismatch criteria (mRS 0–1, OR 2.15, 95% CI 1.142, 8.732, p = 0.027) but with differing proportions. Conclusion: Target mismatch selection was more inclusive and exhibited in a larger treatment effect between tenecteplase and alteplase

Patterns in the limnology of lakes and ponds across multiple local and regional environmental gradients in the eastern Canadian Arctic

This study examined water chemistry from 113 lakes and ponds across the eastern Canadian Arctic to address the lack of limnological data and understanding of relationships among limnological variables across key local and regional gradients. Environmental and geochemical variables were compared at both the local and regional scale with the use of multivariate analysis. A principal components analysis indicated that there was a primary gradient in temperature, nutrients, and conductivity between sampled regions. In addition, there were significant regional differences observed for nutrients total nitrogen (TN) and total phosphorus (TP), chlorophyll a, and dissolved major ions determined via canonical variates analysis. Across all regions TN:TP ratios were high, indicating phosphorus limitation, and mid-summer surface water temperature was strongly correlated to dissolved nitrogen concentrations. Local landscape characteristics were also examined, with multiple samples from lakes of varying elevations, surface area, and depth within the same area. Shallow pond systems (<2 m depth) were found to have significantly higher variability for major ions, especially in areas with influences from local geology. Likewise, the concentration of nutrients and ions in ponds were strongly correlated to concentrations of dissolved organic carbon, likely indicating the influence of watershed inputs and resuspended sediments on the limnology of ponds. Although there was higher regional variation in the limnology of pond systems than lakes, the general patterns within each region were similar

Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression

Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease

Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke

Background: Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers. Methods: We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials. Results: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p < 0.01) interaction of perceived endovascular equipoise shift on the association between sonothrombolysis and 3 month functional outcome [adjusted common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95% CI 0.06–0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95% CI 0.89–1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, patients randomized to sonothrombolysis had higher odds of 3 month functional independence (mRS scores 0–2) compared with patients treated with tPA only (adjusted OR: 1.53; 95% CI 1.01–2.31; p = 0.04). Conclusion: Our experience in CLOTBUST-ER indicates that increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies