Advance Consent in Acute Stroke Trials: Survey of Canadian Stroke Physicians.

Advance consent presents a potential solution to the challenge of obtaining informed consent for participation in acute stroke trials. Clinicians in stroke prevention clinics are uniquely positioned to identify and seek consent from potential stroke trial participants. To assess the acceptability of advance consent to Canadian stroke clinic physicians, we performed an online survey. We obtained 58 respondents (response rate 35%): the vast majority (82%) expressed comfort with obtaining advance consent and 92% felt that doing so would not be a significant disruption to clinic workflow. These results support further study of advance consent for acute stroke trials.

Advance Consent in Acute Stroke Trials: Survey of Canadian Research Ethics Board Chairs.

Advance consent could allow individuals at high risk of stroke to provide consent before they might become eligible for enrollment in acute stroke trials. This survey explores the acceptability of this novel technique to Canadian Research Ethics Board (REB) chairs that review acute stroke trials. Responses from 15 REB chairs showed that majority of respondents expressed comfort approving studies that adopt advance consent. There was no clear preference for advance consent over deferral of consent, although respondents expressed significant concern with broad rather than trial-specific advance consent. These findings shed light on the acceptability of advance consent to Canadian ethics regulators.

PRMT1-mediated FLT3 arginine methylation promotes maintenance of FLT3-ITD+ acute myeloid leukemia.

The presence of FMS-like receptor tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukemia (AML) is associated with poor clinical outcome. FLT3 tyrosine kinase inhibitors (TKIs), although effective in kinase ablation, do not eliminate primitive FLT3-ITD+ leukemia cells, which are potential sources of relapse. Thus, understanding the mechanisms underlying FLT3-ITD+ AML cell persistence is essential to devise future AML therapies. Here, we show that expression of protein arginine methyltransferase 1 (PRMT1), the primary type I arginine methyltransferase, is increased significantly in AML cells relative to normal hematopoietic cells. Genome-wide analysis, coimmunoprecipitation assay, and PRMT1-knockout mouse studies indicate that PRMT1 preferentially cooperates with FLT3-ITD, contributing to AML maintenance. Genetic or pharmacological inhibition of PRMT1 markedly blocked FLT3-ITD+ AML cell maintenance. Mechanistically, PRMT1 catalyzed FLT3-ITD protein methylation at arginine 972/973, and PRMT1 promoted leukemia cell growth in an FLT3 methylation-dependent manner. Moreover, the effects of FLT3-ITD methylation in AML cells were partially due to cross talk with FLT3-ITD phosphorylation at tyrosine 969. Importantly, FLT3 methylation persisted in FLT3-ITD+ AML cells following kinase inhibition, indicating that methylation occurs independently of kinase activity. Finally, in patient-derived xenograft and murine AML models, combined administration of AC220 with a type I PRMT inhibitor (MS023) enhanced elimination of FLT3-ITD+ AML cells relative to AC220 treatment alone. Our study demonstrates that PRMT1-mediated FLT3 methylation promotes AML maintenance and suggests that combining PRMT1 inhibition with FLT3 TKI treatment could be a promising approach to eliminate FLT3-ITD+ AML cells.

Peripheral Nerve Blocks and Potentially Attributable Adverse Events in Older People with Hip Fracture: A Retrospective Population-based Cohort Study.

BACKGROUND: Peripheral nerve blocks are being used with increasing frequency for management of hip fracture-related pain. Despite converging evidence that nerve blocks may be beneficial, safety data are lacking. This study hypothesized that peripheral nerve block receipt would not be associated with adverse events potentially attributable to nerve blocks, as well as overall patient safety incidents while in hospital. METHODS: This was a preregistered, retrospective population-based cohort study using linked administrative data. This study identified all hip fracture admissions in people 50 yr of age or older and identified all nerve blocks (although we were unable to ascertain the specific anatomic location or type of block), potentially attributable adverse events (composite of seizures, fall-related injuries, cardiac arrest, nerve injury), and any patient safety events using validated codes. The study also estimated the unadjusted and adjusted association of nerve blocks with adverse events; adjusted absolute risk differences were also calculated. RESULTS: In total, 91,563 hip fracture patients from 2009 to 2017 were identified; 15,631 (17.1%) received a nerve block, and 5,321 (5.8%; 95% CI, 5.7 to 6.0%) patients experienced a potentially nerve block-attributable adverse event: 866 (5.5%) in patients with a block and 4,455 (5.9%) without a block. Before and after adjustment, nerve blocks were not associated with potentially attributable adverse events (adjusted odds ratio, 1.05; 95% CI, 0.97 to 1.15; and adjusted risk difference, 0.3%, 95% CI, -0.1 to 0.8). CONCLUSIONS: The data suggest that nerve blocks in hip fracture patients are not associated with higher rates of potentially nerve block-attributable adverse events, although these findings may be influenced by limitations in routinely collected administrative data.

S100B protein level for the detection of clinically significant intracranial haemorrhage in patients with mild traumatic brain injury: a subanalysis of a prospective cohort study.

BACKGROUND: Clinical assessment of patients with mild traumatic brain injury (mTBI) is challenging and overuse of head CT in the ED is a major problem. Several studies have attempted to reduce unnecessary head CTs following a mTBI by identifying new tools aiming to predict intracranial bleeding. Higher levels of S100B protein have been associated with intracranial haemorrhage following a mTBI in previous literature. The main objective of this study is to assess whether plasma S100B protein level is associated with clinically significant brain injury and could be used to reduce the number of head CT post-mTBI. METHODS: Study design: secondary analysis of a prospective multicentre cohort study conducted between 2013 and 2016 in five Canadian EDs. Inclusion criteria: non-hospitalised patients with mTBI with a GCS score of 13-15 in the ED and a blood sample drawn within 24 hours after the injury. Data collected: sociodemographic and clinical data were collected in the ED. S100B protein was analysed using ELISA. All CT scans were reviewed by a radiologist blinded to the biomarker results. Main outcome: the presence of clinically important brain injury. RESULTS: 476 patients were included. Mean age was 41±18 years old and 150 (31.5%) were women. Twenty-four (5.0%) patients had a clinically significant intracranial haemorrhage. Thirteen patients (2.7%) presented a non-clinically significant brain injury. A total of 37 (7.8%) brain injured patients were included in our study. S100B median value (Q1-Q3) was: 0.043 µg/L (0.008-0.080) for patients with clinically important brain injury versus 0.039 µg/L (0.023-0.059) for patients without clinically important brain injury. Sensitivity and specificity of the S100B protein level, if used alone to detect clinically important brain injury, were 16.7% (95% CI 4.7% to 37.4%) and 88.5% (95% CI 85.2% to 91.3%), respectively. CONCLUSION: Plasma S100B protein level was not associated with clinically significant intracranial lesion in patients with mTBI.

The effect of early in-hospital medication review on health outcomes: a systematic review.

AIMS: Adverse drug events are an important cause of emergency department visits, unplanned admissions and prolonged hospital stays. Our objective was to synthesize the evidence on the effect of early in-hospital pharmacist-led medication review on patient-oriented outcomes based on observed data. METHODS: We systematically searched eight bibliographic reference databases, electronic grey literature, medical journals, conference proceedings, trial registries and bibliographies of relevant papers. We included studies that employed random or quasi-random methods to allocate subjects to pharmacist-led medication review or control. Medication review had to include, at a minimum, obtaining a best possible medication history and reviewing medications for appropriateness and adverse drug events. The intervention had to be initiated within 24 h of emergency department presentation or 72 h of admission. We extracted data in duplicate and pooled outcomes from clinically homogeneous studies of the same design using random effects meta-analysis. RESULTS: We retrieved 4549 titles of which seven were included, reporting the outcomes of 3292 patients. We pooled data from studies of the same design, and found no significant differences in length of hospital admission (weighted mean difference [WMD] -0.04 days, 95% confidence interval [CI] -1.63, 1.55), mortality (odds ratio [OR] 1.09, 95% CI 0.69, 1.72), readmissions (OR 1.15, 95% CI 0.81, 1.63) or emergency department revisits at 3 months (OR 0.60, 95% CI 0.27, 1.32). Two large studies reporting reductions in readmissions could not be included in our pooled estimates due to differences in study design. CONCLUSIONS: Wide confidence intervals suggest that additional research is likely to influence the effect size estimates and clarify the effect of medication review on patient-oriented outcomes. This systematic review failed to identify an effect of pharmacist-led medication review on health outcomes.

Stratified, urgent care for transient ischemic attack results in low stroke rates.

BACKGROUND AND PURPOSE: Transient ischemic attack (TIA) is a marker for early risk of stroke. No previous studies have assessed the use of urgent stroke prevention clinics for emergency department (ED) patients with TIA. We hypothesized that an ABCD2-based ED triaging tool for TIA with outpatient management would be associated with lower 90-day stroke rate than that predicted by ABCD2. METHODS: A cohort of prospectively identified patients presenting with symptoms suggestive of TIA seen in 2 tertiary-care EDs. These patients were divided into 3 strata based on their ACBD2 score, and triage targets were set for each stratum. All patients received the same standard of care in the Stroke Clinic regardless of their risk score. Primary outcome was stroke by 90 days of index TIA. Secondary outcomes were subsequent TIA, myocardial infarction, or death. RESULTS: One-thousand ninety-three patients met the inclusion criteria; 982 patients completed 90-day follow-up and comprised the final cohort. After stratification, 32%, 49%, and 19% of patients were categorized as low-, moderate-, or high-risk, respectively. The overall 90-day risk of stroke in all patients was 3.2%, compared with the ABCD2-predicted risk of 9.2%. Only 1.6% of patients with TIA/minor stroke were admitted from the ED. The risk of subsequent TIA, myocardial infarction, or death by 90 days was 5.5%, 0.1%, and 1.7%, respectively. CONCLUSIONS: Outpatient care in a rapid-access stroke prevention clinic using the ABCD2 score for triage resulted in a low 90-day stroke rate for patients in the ED with TIA. Benefit occurred without requiring admission for most patients.

Phase 1 Safety, Pharmacokinetics, and Fluorescence Imaging Study of Tozuleristide (BLZ-100) in Adults With Newly Diagnosed or Recurrent Gliomas.

BACKGROUND: Fluorescence-guided surgery (FGS) can improve extent of resection in gliomas. Tozuleristide (BLZ-100), a near-infrared imaging agent composed of the peptide chlorotoxin and a near-infrared fluorophore indocyanine green, is a candidate molecule for FGS of glioma and other tumor types. OBJECTIVE: To perform a phase 1 dose-escalation study to characterize the safety, pharmacokinetics, and fluorescence imaging of tozuleristide in adults with suspected glioma. METHODS: Patients received a single intravenous dose of tozuleristide 3 to 29 h before surgery. Fluorescence images of tumor and cavity in Situ before and after resection and of excised tissue ex Vivo were acquired, along with safety and pharmacokinetic measures. RESULTS: A total of 17 subjects received doses between 3 and 30 mg. No dose-limiting toxicity was observed, and no reported adverse events were considered related to tozuleristide. At doses of 9 mg and above, the terminal serum half-life for tozuleristide was approximately 30 min. Fluorescence signal was detected in both high- and low-grade glial tumors, with high-grade tumors generally showing greater fluorescence intensity compared to lower grade tumors. In high-grade tumors, signal intensity increased with increased dose levels of tozuleristide, regardless of the time of dosing relative to surgery. CONCLUSION: These results support the safety of tozuleristide at doses up to 30 mg and suggest that tozuleristide imaging may be useful for FGS of gliomas.

Real-time Visualization of Breast Carcinoma in Pathology Specimens From Patients Receiving Fluorescent Tumor-Marking Agent Tozuleristide.

CONTEXT.­: Resection of breast carcinoma with adequate margins reduces the risk of local recurrence and reoperation. Tozuleristide (BLZ-100) is an investigational peptide-fluorophore agent that may aid in intraoperative tumor detection and margin assessment. In this study, fluorescence imaging was conducted ex vivo on gross breast pathology specimens. OBJECTIVES.­: To determine the potential of tozuleristide to detect breast carcinoma in fresh pathology specimens and the feasibility of fluorescence-guided intraoperative pathology assessment of surgical margins. DESIGN.­: Twenty-three patients received an intravenous bolus dose of 6 or 12 mg of tozuleristide at least 1 hour before surgery. Fifteen lumpectomy and 12 mastectomy specimens were evaluated for fluorescence by the site's clinical pathology staff using the SIRIS, an investigational near-infrared imaging device. The breast tissue was then processed per usual procedures. Fluorescent patterns were correlated with the corresponding hematoxylin-eosin-stained sections. Clinical pathology reports were used to correlate fluorescent signal to grade, histotype, prognostic marker status, and margin measurements. RESULTS.­: Tozuleristide fluorescence was readily observed in invasive and in situ breast carcinoma specimens. Most invasive carcinomas were bright and focal, whereas in situ lesions demonstrated a less intense, more diffuse pattern. Tozuleristide was detected in ductal and lobular carcinomas with a similar fluorescent pattern. Fluorescence was detected in high- and low-grade lesions, and molecular marker/hormone receptor status did not affect signal. Fluorescence could be used to identify the relationship of carcinoma to margins intraoperatively. CONCLUSIONS.­: Tumor targeting with tozuleristide allowed visual real-time distinction between pathologically confirmed breast carcinoma and normal tissue.

Do beta-blockers reduce short-term mortality following acute myocardial infarction? A systematic review and meta-analysis.

OBJECTIVE: Acute myocardial infarction (AMI) remains a major cause of death and beta-blockers are known to reduce long-term mortality in post-AMI patients. We sought to determine whether patients receiving beta-blockers acutely (within 72 h) following AMI had a lower mortality rate at 6 weeks than patients receiving placebo. METHODS: We conducted a systematic review of randomized controlled clinical trials that assessed 6-week mortality and compared beta-blockers with placebo in patients randomized within the first 72 hours following AMI. We searched these databases: MEDLINE (1966-2006), EMBASE (1980-2007), Cochrane Central Register of Controlled Trials, Health Star (1966-2007), Cochrane Database for Systematic Reviews, ACP Journal Club (1991-2007), Database of Abstracts of Reviews of Effect (< 1st quarter 2007) and Conference Papers Index (1984-2007). Two blinded reviewers extracted the data and rated study quality using the Jadad score and the adequacy of allocation concealment score, which was adopted by the Cochrane group. We calculated pooled odds ratios (ORs) using a random effect model and performed sensitivity analyses to explore the stability of the overall treatment effect. RESULTS: We included 18 studies (13 were rated high-quality) with 74 643 enrolled participants and had 5095 deaths. Compared with placebo, adding beta-blockers to other interventions within 72 hours after AMI did not result in a statistically significant reduction in 6-week mortality (OR 0.95, 95% confidence interval [CI] 0.90-1.01). When restricted to high quality studies, the OR for 6-week mortality reduction was 0.96 (95% CI 0.91-1.02). We found similar results including studies that enrolled patients within 24 hours after AMI. However, a subgroup analysis that excluded high-risk patients with Killip class III and above showed that beta-blockers resulted in a significant reduction in short-term mortality (OR 0.93, 95% CI 0.88-0.99). CONCLUSION: Acute intervention with beta-blockers does not result in a statistically significant short-term survival benefit following AMI but may be beneficial for low-risk (Killip class I) patients.

Canadian†Stroke†Best†Practice†Recommendations: Hyperacute Stroke Care Guidelines, Update 2015.

The 2015 update of the Canadian Stroke Best Practice Recommendations Hyperacute Stroke Care guideline highlights key elements involved in the initial assessment, stabilization, and treatment of patients with transient ischemic attack (TIA), ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and acute venous sinus thrombosis. The most notable change in this 5th edition is the addition of new recommendations for the use of endovascular therapy for patients with acute ischemic stroke and proximal intracranial arterial occlusion. This includes an overview of the infrastructure and resources required for stroke centers that will provide endovascular therapy as well as regional structures needed to ensure that all patients with acute ischemic stroke that are eligible for endovascular therapy will be able to access this newly approved therapy; recommendations for hyperacute brain and enhanced vascular imaging using computed tomography angiography and computed tomography perfusion; patient selection criteria based on the five trials of endovascular therapy published in early 2015, and performance metric targets for important time-points involved in endovascular therapy, including computed tomography-to-groin puncture and computed tomography-to-reperfusion times. Other updates in this guideline include recommendations for improved time efficiencies for all aspects of hyperacute stroke care with a movement toward a new median target door-to-needle time of 30 min, with the 90th percentile being 60 min. A stronger emphasis is placed on increasing public awareness of stroke with the recent launch of the Heart and Stroke Foundation of Canada FAST signs of stroke campaign; reinforcing the public need to seek immediate medical attention by calling 911; further engagement of paramedics in the prehospital phase with prehospital notification to the receiving emergency department, as well as the stroke team, including neuroradiology; updates to the triage and same-day assessment of patients with transient ischemic attack; updates to blood pressure recommendations for the hyperacute phase of care for ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. The goal of these recommendations and supporting materials is to improve efficiencies and minimize the absolute time lapse between stroke symptom onset and reperfusion therapy, which in turn leads to better outcomes and potentially shorter recovery times.

Initial emergency department trauma scores from the OPALS study: the case for the motor score in blunt trauma.

OBJECTIVES: To compare the predictive accuracy of the Revised Trauma Score (RTS), the Glasgow Coma Scale (GCS), and their components in blunt trauma patients. METHODS: This multicenter prospective cohort study was conducted in 20 communities as part of the Ontario Prehospital Advanced Life Support (OPALS) Study. It included adult trauma patients with Injury Severity Scores >12. The assessments made by trauma team leaders for the RTS, GCS, and their subscales were analyzed: 1) receiver operating characteristic (ROC) curve areas and Kendall's tau c correlation coefficient (Tc) for survival to hospital discharge, 2) Mann-Whitney U test and Tc correlations for intensive care unit admission, and 3) Spearman correlations with the disability measure Glasgow Outcome Scale. RESULTS: The authors analyzed data from 795 blunt trauma patients with these characteristics: median age of 40 years, 70% male, and 18% mortality. The scores that best predicted survival were the RTS (ROC = 0.83, Tc = 0.39), the GCS (ROC = 0.82, Tc = 0.38), the motor component of the GCS (ROC = 0.81, Tc = 0.37), and the verbal component of the GCS (ROC = 0.81, Tc = 0.36). Only scores for the RTS (p = 0.03), the GCS (p = 0.02), and the motor component of the GCS (p = 0.03) showed a significant association with admission to the intensive care unit. The associations with disability were weak in all scores. CONCLUSIONS: The initial emergency department motor score showed the highest predictive validity among all of the other components. These results suggest its validity for blunt trauma triage when compared with the GCS or RTS.

Wrist buckle fractures: a survey of current practice patterns and attitudes toward immobilization.

OBJECTIVES: Buckle fractures are the most common wrist fractures in children, yet there is little literature regarding their management. This study examined the management of these fractures and attitudes toward their immobilization by pediatric emergency department (ED) physicians and pediatric orthopedic surgeons. METHODS: A standardized survey was mailed to all pediatric orthopedic surgeons and pediatric ED physicians at 8 Canadian children's hospitals. RESULTS: Eighty-seven percent of physicians responded, including 33 of 39 pediatric orthopedic surgeons and 84 of 96 pediatric ED physicians. Sixty-four percent of respondents believe that wrist buckle fractures always need to be immobilized; pain control was most frequently cited for this belief. Physicians who did not believe that all buckle fractures need to be immobilized indicated that these fractures are inherently stable and have a low risk of refracture. Forty-eight percent of the orthopedic surgeons prefer below-elbow casts, 30% prefer a combination (splint and cast) and 12% prefer backslabs. Sixty percent of ED physicians "usually or always" use casts and 31% "usually or always" use backslabs. Although there was variation among the orthopedic surgeons regarding the recommended length of immobilization, most (70%) recommended 2 to 4 weeks, although some (12%) treated only until pain free. ED physicians showed greater diversity regarding length of immobilization. CONCLUSIONS: Although many physicians believe that wrist buckle fractures need to be immobilized, a significant number do not. There is substantial variability in the type and length of immobilization used. This variability suggests that the optimal management strategy for wrist buckle fractures is unclear and should be determined in future prospective studies.