Search

Critically ill patients infected with SARS-CoV-2 display adaptive immunity, but it is unknown if they develop cross-reactivity to variants of concern (VOCs). We profiled cross-immunity against SARS-CoV-2 VOCs in naturally infected, non-vaccinated, critically ill COVID-19 patients. Wave-1 patients (wild-type infection) were similar in demographics to Wave-3 patients (wild-type/alpha infection), but Wave-3 patients had higher illness severity. Wave-1 patients developed increasing neutralizing antibodies to all variants, as did patients during Wave-3. Wave-3 patients, when compared to Wave-1, developed more robust antibody responses, particularly for wild-type, alpha, beta and delta variants. Within Wave-3, neutralizing antibodies were significantly less to beta and gamma VOCs, as compared to wild-type, alpha and delta. Patients previously diagnosed with cancer or chronic obstructive pulmonary disease had significantly fewer neutralizing antibodies. Naturally infected ICU patients developed adaptive responses to all VOCs, with greater responses in those patients more likely to be infected with the alpha variant, versus wild-type.

Introduction Anticoagulation may improve outcomes in patients with COVID-19 when started early in the course of illness. Materials and methods This was a population-based cohort study using linked administrative datasets of outpatients aged ≥65 years old testing positive for SARS-CoV-2 between January 1 and December 31, 2020 in Ontario, Canada. The key exposure was anticoagulation with warfarin or direct oral anticoagulants before COVID-19 diagnosis. We calculated propensity scores and used matching weights (MWs) to reduce baseline differences between anticoagulated and non-anticoagulated patients. The primary outcome was a composite of death or hospitalization within 60 days of a positive SARS-CoV-2 test. We used the Kaplan-Meier method and cumulative incidence functions to estimate risk of the primary and component outcomes at 60 days. Results We studied 23,159 outpatients (mean age 78.5 years; 13,474 [58.2%] female), among whom 3200 (13.8%) deaths and 3183 (13.7%) hospitalizations occurred within 60 days of the SARS-CoV-2 test. After application of MWs, the 60-day risk of death or hospitalization was 29.2% (95% CI 27.4%–31.2%) for anticoagulated individuals and 32.1% (95% CI 30.7%–33.5%) without anticoagulation (absolute risk difference [ARD], −2.9%; p = 0.005). Anticoagulation was also associated with a lower risk of death: 18.6% (95% CI 17.0%–20.2%) with anticoagulation and 20.9% (95% CI 19.7%–22.2%) in non-anticoagulated patients (ARD -2.3%; p = 0.005). Conclusions Among outpatients aged ≥65 years, oral anticoagulation at the time of a positive SARS-CoV-2 test was associated with a lower risk of a composite of death or hospitalization within 60 days.

Massive hemorrhage protocols (MHP) are critical to standardized delivery of timely, safe, and resource-effective coordinated care for patients with life-threatening bleeding.A standardized MHP survey was sent to all hospitals (n = 150) in Ontario with a transfusion service. This study aim was to determine the proportion of hospitals with an MHP and assess for variability.The overall survey completion rate was 133 of 150 hospitals (89%) (remaining 17 providing negative affirmation that they did not have an MHP). An MHP was in place at 97 of 150 (65%) hospitals (60% of small (5000 red cell units/year) vs. 91% of medium/large). A total of 10 different names of protocols were reported, with "Massive Transfusion Protocol" (68%) predominating. Activation criteria were present in 82 of 97 (85%); commonly activated based on volume of blood loss (70%). Blood work was drawn at the discretion of the physician (37%) or at predefined intervals (31%; majority every 60 min). Common routine laboratory tests performed were CBC (87%) and INR (84%). Fibrinogen testing was available at 88 (66%) of 133 reporting hospitals and part of the standard testing at 73 of 97 (75%) hospitals with an MHP. Median targets of hemostatic resuscitations, stated in the protocol at 49% of hospitals with an MHP, were: platelets50 × 10A third of hospitals lack formal MHPs, with the majority lacking in smaller hospitals. The survey results indicate that there is marked variability in all key aspects of the reported MHPs. This may be due to differences in hospital resources and personnel, lack of supporting evidence to dictate requirements, and differences in knowledge base of the individuals involved in protocol setting.

Background Free Open-Access Medical education (FOAM) use among residents continues to rise. However, it often lacks quality assurance processes and residents receive little guidance on quality assessment. The Academic Life in Emergency Medicine Approved Instructional Resources tool (AAT) was created for FOAM appraisal by and for expert educators and has demonstrated validity in this context. It has yet to be evaluated in other populations. Objectives We assessed the AAT's usability in a diverse population of practicing emergency medicine (EM) physicians, residents, and medical students; solicited feedback; and developed a revised tool. Methods As part of the Medical Education Translational Resources: Impact and Quality (METRIQ) study, we recruited medical students, EM residents, and EM attendings to evaluate five FOAM posts with the AAT and provide quantitative and qualitative feedback via an online survey. Two independent analysts performed a qualitative thematic analysis with discrepancies resolved through discussion and negotiated consensus. This analysis informed development of an initial revised AAT, which was then further refined after pilot testing among the author group. The final tool was reassessed for reliability. Results Of 330 recruited international participants, 309 completed all ratings. The Best Evidence in Emergency Medicine (BEEM) score was the component most frequently reported as difficult to use. Several themes emerged from the qualitative analysis: for ease of use-understandable, logically structured, concise, and aligned with educational value. Limitations include deviation from questionnaire best practices, validity concerns, and challenges assessing evidence-based medicine. Themes supporting its use include evaluative utility and usability. The author group pilot tested the initial revised AAT, revealing a total score average measure intraclass correlation coefficient (ICC) of moderate reliability (ICC = 0.68, 95% confidence interval [CI] = 0 to 0.962). The final AAT's average measure ICC was 0.88 (95% CI = 0.77 to 0.95). Conclusions We developed the final revised AAT from usability feedback. The new score has significantly increased usability, but will need to be reassessed for reliability in a broad population.

Background Online educational resources are criticized as being teacher-centred, failing to address learner’s needs. Needs assessments are an important precursor to inform curriculum development, but these are often overlooked or skipped by developers of online educational resources due to cumbersome measurement tools. Novel methods are required to identify perceived and unperceived learning needs to allow targeted development of learner-centred curricula. Objectives To evaluate the feasibility of performing a novel technique dubbed the Massive Online Needs Assessment (MONA) for the purpose of emergency haematology online educational curricular planning, within an online learning community (affiliated with the Free Open Access Medical education movement). Methods An online survey was launched on CanadiEM.org using an embedded Google Forms survey. Participants were recruited using the study website and a social media campaign (utilizing Twitter, Facebook, Blogs, and a poster) targeting a specific online community. Web analytics were used to monitor participation rates in addition to survey responses. Results The survey was open from 20 September to 10 December 2016 and received 198 complete responses representing 6 medical specialties from 21 countries. Most survey respondents identified themselves as staff physicians (n = 109) and medical trainees (n = 75). We identified 17 high-priority perceived needs, 17 prompted needs, and 10 topics with unperceived needs through our MONA process. Conclusions A MONA is a feasible, novel method for collecting data on perceived, prompted, and unperceived learning needs to inform an online emergency haematology educational blog. This methodology could be useful to the developers of other online education resources. Electronic supplementary material The online version of this article (10.1007/s40037-018-0406-0) contains supplementary material, which is available to authorized users.

ObjectiveIn 2015 and 2016, the Canadian Journal of Emergency Medicine (CJEM) Social Media (SoMe) Team collaborated with established medical websites to promote CJEM articles using podcasts and infographics while tracking dissemination and readership.MethodsCJEM publications in the “Original Research” and “State of the Art” sections were selected by the SoMe Team for podcast and infographic promotion based on their perceived interest to emergency physicians. A control group was composed retrospectively of articles from the 2015 and 2016 issues with the highest Altmetric score that received standard Facebook and Twitter promotions. Studies on SoMe topics were excluded. Dissemination was quantified by January 1, 2017 Altmetric scores. Readership was measured by abstract and full-text views over a 3-month period. The number needed to view (NNV) was calculated by dividing abstract views by full-text views.ResultsTwenty-nine of 88 articles that met inclusion were included in the podcast (6), infographic (11), and control (12) groups. Descriptive statistics (mean, 95% confidence interval) were calculated for podcast (Altmetric: 61, 42-80; Abstract: 1795, 1135-2455; Full-text: 431, 0-1031), infographic (Altmetric: 31.5, 19-43; Abstract: 590, 361-819; Full-text: 65, 33-98), and control (Altmetric: 12, 8-15; Abstract: 257, 159-354; Full-Text: 73, 38-109) articles. The NNV was 4.2 for podcast, 9.0 for infographic, and 3.5 for control articles.DiscussionLimitations included selection bias, the influence of SoMe promotion on the Altmetric scores, and a lack of generalizability to other journals.ConclusionCollaboration with established SoMe websites using podcasts and infographics was associated with increased Altmetric scores and abstract views but not full-text article views.

Background: Massive hemorrhage protocols (MHPs) streamline the complex logistics required for prompt care of the bleeding patient, but their uptake has been variable and few regions have a system to measure outcomes from these events. Aim Statement: We aim to implement a standardized MHP with uniform quality improvement (QI) metrics to increase uptake of evidence-based MHPs across 150-hospitals in Ontario between 2017 and 2021. Measures & Design: We performed ongoing PDSA cycles; 1) stakeholder analysis by surveying the Ontario Regional Blood Coordinating Network (ORBCoN), 2) problem characterization and Ishikawa analysis for key QI metrics based on areas of MHP variability in 150 Ontario hospitals using a web-based survey, 3) creation of a consensus MHP via a modified Delphi process, 4) problem characterization at ORBCoN for the design of a freely available toolkit for provincial implementation by expert working groups, 5) design of 8 key QI metrics by a modified Delphi process, and 6) identification of process measures for QI data collection by implementation metrics. Evaluation/Results: PDSA1-2; 150-hospitals were surveyed. 33% of hospitals lacked MHPs, mostly in smaller sites. Major areas for QI were related to activation criteria, hemostatic agents, protocolized hypothermia management, variable MHP naming, QI metrics and serial blood work requirements. PDSA3; 3 Delphi rounds were held to reach 100% expert consensus for 42 statements and 8 CQI metrics. Major areas for modification were protocol name, laboratory resuscitation targets, cooler configurations, and role of factor VIIa. PDSA4; adaptable toolkit is under development by the steering committee and expert working groups. Implementation is scheduled for Spring 2020. PDSA5; the 8 CQI metrics are: TXA administration < 1 h, RBC transfusion < 15 min, call to transfer for definitive care < 60 min, temp >35°C at end of protocol, Hgb kept between 60-110g/L, transition to group-specific RBC by 90 min, appropriate activation defined by ≥6 units RBC in the first 24 hours, and any blood component wastage. Discussion/Impact: MHP uptake, content, and tracking is variable. A standardized MHP that is adaptable to diverse settings decreases complexity, improves use of evidence-based practices, and provides a platform for continuous QI. PDSA6 will occur after implementation; we will complete an implementation survey, and design a pilot and feasibility study for prospective tracking of patient outcomes using existing prospectively collected inter-hospital and provincial databases.

Introduction: Many cardiac arrest survivors die later due to hemorrhage or thromboembolism, thought to be caused by acquired coagulopathy in post-cardiac arrest syndrome (PCAS) from shock and reperfusion injury. Understanding PCAS is a priority identified by the AHA for the prevention of complications in cardiac arrest survivors. Shock dysregulates both coagulation and fibrinolysis. The key effector enzyme thrombin (Th), is responsible for both up- and down-regulating coagulation and fibrinolysis. Measuring early Th activity may allow for predicting PCAS coagulopathy, and early medical intervention in the ED. Therefore, we aimed to characterize the time-course profile of early coagulation using an established pig model of cardiac arrest. Methods: Yorkshire pigs were anaesthetised and intubated, had VF-arrest induced by pacing, and were resuscitated per ACLS. Rotational thromboelastometry (ROTEM) was performed on whole blood at four times: baseline, intra-arrest, post-arrest, and death, using the fibrin-based test with tissue factor to initiate clotting in the presence of a platelet inhibitor cytochalasin D (FIBTEM). Clot time (CT), clot formation time (CFT), alpha-angle during clot formation (Alpha), clot amplitude at 10 min (A10), maximum clot firmness (MCF), and maximum lysis as total percentage (ML%) were quantified. The primary outcome is the overall coagulation initiation measured by CFT, while secondary outcomes include ROTEM parameters reflecting Th activity. Parameters are compared over time in SPSS using repeated measures ANOVA and Bonferroni correction. Results: Pilot data from one experiment show that cardiac arrest causes immediate early changes to coagulation that subsequently normalized with ROSC (Figure 1). CFT was impaired immediately upon cardiac arrest (2.3-fold increase), normalized with ROSC, and impaired again at death when compared with baseline. Consistent with clotting impairment, A10, Alpha, and MCF were all reduced with cardiac arrest, normalized with ROSC, and impaired again at death. Conclusion: Higher initial indices of coagulopathy in patients with cardiac arrest appear to correlate with death and thromboembolism. In this pilot, CFT is acutely modified by cardiac arrest. Since CFT is affected by overall Th activity, early Th dysregulation may be a critical driver of coagulopathy. Th may therefore be a lead target that is modifiable in the emergency post-arrest setting to decrease morbidity and mortality from PCAS in cardiac arrest survivors.

Background A massive hemorrhage protocol (MHP) enables rapid delivery of blood components in a patient who is exsanguinating pending definitive hemorrhage control, but there is variability in MHP implementation rates, content and compliance owing to challenges presented by infrequent activation, variable team performance and patient acuity. The goal of this project was to identify the key evidence-based principles and quality indicators required to develop a standardized regional MHP. Methods A modified Delphi consensus technique was performed in the spring and summer of 2018. Panellists used survey links to independently review and rate (on a 7-point Likert scale) 43 statements and 8 quality indicators drafted by a steering committee composed of transfusion medicine specialists and technologists, and trauma physicians. External stakeholder input from all hospitals in Ontario was sought. Results Three rounds were held with 36 experts from diverse clinical backgrounds. Consensus was reached for 42 statements and 8 quality indicators. Additional modifications from external stakeholders were incorporated to form the foundation for the proposed MHP. Interpretation This MHP template will provide the basis for the design of an MHP toolkit, including specific recommendations for pediatric and obstetrical patients, and for hospitals with limited availability of blood components or means to achieve definitive hemorrhage control. We believe that harmonization of MHPs in our region will simplify training, increase uptake of evidence-based interventions, enhance communication, improve patient comfort and safety, and, ultimately, improve patient outcomes.

OBJECTIVE Journals use social media to increase the awareness of their publications. Infographics show research findings in a concise and visually appealing manner, well suited for dissemination on social media platforms. We hypothesized that infographic abstracts promoted on social media would increase the dissemination and online readership of the parent research articles. METHODS Twenty-four articles were chosen from the six issues of CJEM published between July 2016 and June 2017 and randomized to infographic or control groups. All articles were disseminated through the journal’s social media accounts (Twitter and Facebook). Control articles were promoted using a screen capture image of each article’s abstract on the journal’s social media accounts. Infographic articles were promoted similarly using a visual infographic. Infographics were also published and promoted on the CanadiEM.org’s website and social media channels. Abstract views, full-text views, and the change in Altmetric score were compared between groups using unpaired two-tailed t-tests. RESULTS There were no significant differences in the groups at baseline. Abstract views (mean, 95% CI) were higher in the infographics (379, 287-471) than the control group (176, 136-215, p

Rivaroxaban and apixaban are both small molecules that reversibly inhibit factor Xa. Compared with rivaroxaban, apixaban has minimal effects on the prothrombin time and activated partial thromboplastin time. To investigate this phenomenon, we used a factor Xa-directed substrate in a buffer system. Although rivaroxaban and apixaban inhibited factor Xa with similar Ki values at equilibrium, kinetic measurements revealed that rivaroxaban inhibited factor Xa up to 4-fold faster than apixaban (p

The non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin for many indications. These agents include dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. All 4 agents are licensed in the United States for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism and rivaroxaban and apixaban are approved for thromboprophylaxis after elective hip or knee arthroplasty. The NOACs are at least as effective as warfarin, but are not only more convenient to administer because they can be given in fixed doses without routine coagulation monitoring but also are safer because they are associated with less intracranial bleeding. As part of a theme series on the NOACs, this article (1) compares the pharmacological profiles of the NOACs with that of warfarin, (2) identifies the doses of the NOACs for each approved indication, (3) provides an overview of the completed phase III trials with the NOACs, (4) briefly discusses the ongoing studies with the NOACs for new indications, (5) reviews the emerging real-world data with the NOACs, and (6) highlights the potential opportunities for the NOACs and identifies the remaining challenges.

Thrombin activity, inhibition, and localization are regulated by two exosites that flank the active site. Substrates, cofactors, and inhibitors bind to exosite 1 to promote active site access, whereas exosite 2 interactions hold thrombin on cells, platelets, and proteins. The exosites also serve allosteric roles, whereby ligand binding alters thrombin activity. Previously, we showed that ligands that bind exosite 2 attenuate the exosite 1-mediated interaction of thrombin with fibrin, demonstrating allosteric connection between the exosites. To determine the functional consequences of these inter-exosite interactions, we examined the effect of exosite 2 ligands on thrombin's interaction with thrombomodulin, a key cofactor that binds exosite 1 and redirects thrombin activity to the anticoagulant protein C pathway. Exosite 2-directed ligands, which included the HD22 aptamer, glycoprotein 1bα-derived peptide, and fibrinogen γ'-chain peptide, reduced the level of exosite 1-mediated thrombin binding to the thrombomodulin peptide consisting of the fourth, fifth, and sixth epidermal-like growth factor-like domains, decreasing affinity by10-fold, and attenuated thrombomodulin-dependent activation of protein C by 60-80%. The ligands had similar effects on thrombin-mediated protein C activation with intact soluble thrombomodulin and with thrombomodulin on the surface of cultured endothelial cells. Their activity was exosite 2-specific because it was attenuated when RA-thrombin, a variant lacking exosite 2, was used in place of thrombin. These results indicate that additional reactions mediated by exosite 1 are amenable to regulation by exosite 2 ligation, providing further evidence of inter-exosite allosteric regulation of thrombin activity.

The new oral anticoagulants (NOACs), which include dabigatran, rivaroxaban, apixaban, and edoxaban, are poised to replace warfarin for treatment of the majority of patients with venous thromboembolism (VTE). With a rapid onset of action and the capacity to be administered in fixed doses without routine coagulation monitoring, NOACs streamline VTE treatment. In phase 3 trials in patients with acute symptomatic VTE, NOACs have been shown to be noninferior to conventional anticoagulant therapy for prevention of recurrence and are associated with less bleeding. Rivaroxaban and dabigatran are already licensed for VTE treatment in the United States, and apixaban and edoxaban are under regulatory consideration for this indication. As the number of approved drugs increases, clinicians will need to choose the right anticoagulant for the right VTE patient. To help with this decision, this review (1) compares the pharmacologic profiles of the NOACs, (2) outlines the unique design features of the phase 3 trials that evaluated the NOACs for VTE treatment, (3) reviews the results of these trials highlighting similarities and differences in the findings, (4) provides perspective about which VTE patients should receive conventional treatment or are candidates for NOACs, and (5) offers suggestions about how to choose among the NOACs.

Background: The cornerstone of a massive hemorrhage protocol (MHP) is the rapid delivery of blood components to mitigate the consequences of hemorrhagic shock, coagulopathy, and hypothermia in the exsanguinating patient pending definitive hemorrhage control. MHPs are used to facilitate protocol activation/termination, mobilize an interdisciplinary team, provide immediate access to blood, prioritize rapid blood testing, and commence hypothermia-prevention strategies. Non-randomized, before-after implementation studies have found an association between MHPs and improved patient outcomes, including mortality. There is variability in MHP implementation rates, content, and protocol compliance due to challenges presented by infrequent activation, variable team performance, and patient acuity. Methods: We used a modified Delphi technique to establish the framework for a standardized Provincial MHP toolkit and develop quality indicators. We assembled a panel of 36 content experts to represent relevant stakeholders at 150 Ontario hospitals. Panelists included physicians, nurses, and technologists from anesthesia, trauma, obstetrics, hematology, transfusion, emergency, transport, critical care, as well as representation by blood suppliers and patients. The group represented the diverse geographic healthcare program including academic, pediatric, suburban, and small rural hospitals. Panelists were required to attend a two-day MHP forum and complete all rounds of the Delphi. Panelists used digital surveys (LimeSurvey, Hamburg, Germany) to independently review 43 statements and 8 quality indicators drafted by a steering committee. Each statement was rated on a 7-point Likert scale from "definitely should not" to "definitely should include". Disposition of items was based on critieria determined a priori on the median Likert score. Round 1: (1) score at least >5.5 incorporated as written, (2) 2.6-5.4, discussed at the forum with all panelists, with a 2nd round revision, (3) 5.5, accepted, (2) 2.4-5.4, rewritten and sent for round 3, (3) Results: After 3 rounds, consensus was reached for 42 statements and 8 quality indicators. A 100% response rate was achieved from panelists in all three rounds. There were four main areas that required additional rounds and major modifications: (1) selection of the name of the protocol; (2) selection of the laboratory resuscitation targets; (3) determination of the pack configurations; and, (4) clarification of the role of rVIIa. The obstacle to selecting a unified name for the protocol was that many of the hospitals already had longstanding MHPs with specific names. Consensus on the laboratory targets and pack configuration was achieved by splitting statements into sub-sections. The rVIIa statement required three rounds of review to ensure the phrasing satisfied all the panelists for this controversial therapy. Interpretation: We believe that harmonization of MHPs in our region will simplify training, increase uptake of evidence-based interventions, enhance communication, improve patient safety, and ultimately improve outcomes. We highlight areas that need additional study: (1) RCTs are needed to determine if MHPs improve patient outcomes. (2) A "streamlined" version for community hospitals for stabilization before transfer to a tertiary care centre must be tested. (3) Activation and termination criteria have not been validated. (4) The frequency and type of laboratory testing has not been investigated. (5) Laboratory targets for resuscitation must be tested. (6) Does maintaining normothermia decrease transfusion? (7) Can fibrinogen concentrates and PCCs can be considered equivalent to cryoprecipitate and plasma, respectively? (8) Does compliance with the selected quality indicators result in improved outcome? These MHP recommendations will provide the basis for the design of local MHPs including specific recommendations for pediatric patients and for hospitals where definitive hemorrhage control may not be available. Disclosures Arnold: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Rigel: Consultancy, Research Funding; Principia: Consultancy. Pai:Novartis: Honoraria. Sholzberg:Takeda: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding; Baxter: Honoraria, Research Funding. Zeller:Canadian Blood Services: Consultancy; Pfizer: Other: Advisory Board; Ontario Ministry of Health and Long Term Care: Consultancy. Pavenski:Ablynx: Honoraria, Research Funding; Bioverativ: Research Funding; Shire: Honoraria; Alexion: Honoraria, Research Funding; Octapharma: Research Funding.

Although new oral anticoagulants are replacing warfarin for stroke prevention in atrial fibrillation and for the prevention and treatment of venous thromboembolism, the lack of antidotes is a concern. Consequently, the development of a potential antidote for oral factor Xa inhibitors, such as rivaroxaban and apixaban, represents a major breakthrough. For decades, vitamin K antagonists (VKAs), such as warfarin, were the only orally available anticoagulants. This situation changed with the recent introduction of oral direct thrombin and factor Xa inhibitors. Designed to be given in fixed doses without laboratory monitoring, the new oral anticoagulants (NOACs) are more convenient to administer than warfarin. When compared with warfarin in large phase III clinical trials, NOACs were at least as effective as warfarin, but were associated with less intracranial bleeding. Despite these advantages, however, some clinicians are reluctant to use NOACs because specific antidotes are lacking. In a recent report in Nature Medicine , Lu et al have taken the first step to addressing this unmet medical need. These investigators developed a bioengineered recombinant variant of factor Xa that serves as an antidote for oral and parenteral factor Xa inhibitors. Not only does the antidote reverse the anticoagulant effect of oral factor Xa inhibitors in vitro and in animals, but it also reduces blood loss induced by these agents in rat tail transection and rabbit liver laceration bleeding models. Based on these promising results, the antidote is now undergoing phase II evaluation in humans. If the preclinical findings are confirmed in humans, this antidote has the potential to increase usage of the oral factor Xa inhibitors and streamline their management in situations where rapid reversal is needed in preparation for urgent surgery or intervention, or in patients with serious bleeding. Oral anticoagulants are used for long-term prevention and treatment of venous and arterial …

Thrombin is a highly plastic molecule whose activity and specificity are regulated by exosites 1 and 2, positively-charged domains that flank the active site. Exosite binding by substrates and cofactors regulates thrombin activity by localizing thrombin, guiding substrates, and by inducing allosteric changes at the active site. Although inter-exosite and exosite-to-active-site allostery have been demonstrated, the impact of active site ligation on exosite function has not been examined. To address this gap, we used surface plasmon resonance to determine the effects of dabigatran and argatroban, active site-directed inhibitors, on thrombin binding to immobilized γA/γA-fibrin or glycoprotein Ibα peptide via exosite 1 and 2, respectively, and thrombin binding to γA/γ'-fibrin or factor Va, which is mediated by both exosites. Whereas dabigatran attenuated binding, argatroban increased thrombin binding to γA/γA- and γA/γ'-fibrin and to factor Va. The results with immobilized fibrin were confirmed by examining the binding of radiolabeled thrombin to fibrin clots. Thus, dabigatran modestly accelerated the dissociation of thrombin from γA/γA-fibrin clots, whereas argatroban attenuated dissociation. Dabigatran had no effect on thrombin binding to glycoprotein Ibα peptide, whereas argatroban promoted binding. These findings not only highlight functional effects of thrombin allostery, but also suggest that individual active site-directed thrombin inhibitors uniquely modulate exosite function, thereby identifying potential novel mechanisms of action.

Vitamin K antagonists, such as warfarin, have been the mainstay of oral anticoagulation for many decades. Although effective, warfarin has numerous limitations, including a variable dose requirement from patient to patient because of differences in dietary vitamin K intake, common genetic polymorphisms, and multiple drug interactions that affect its pharmacodynamics and metabolism. Consequently, warfarin requires frequent monitoring to ensure that a therapeutic anticoagulant effect has been achieved because excessive anticoagulation can lead to bleeding, and because insufficient anticoagulation can result in thrombosis. Such monitoring is burdensome for patients and physicians and is costly for the health care system. These limitations have prompted the development of new oral anticoagulants that target either factor Xa or thrombin. Although the path to the development of these drugs has been long, the new drugs are at least as effective and safe as warfarin, but they streamline clinical care because they can be administered in fixed doses without routine coagulation monitoring. This article focuses on rivaroxaban, apixaban, and edoxaban, the oral factor Xa inhibitors in the most advanced stages of development. After 20 years of discovery research, these agents are already licensed for several indications. Thus, the long path to finding replacements for warfarin has finally reached fruition. Therefore, development of the oral factor Xa inhibitors represents a translational science success story.

Introduction: Developing structured online educational curricula that meet learner needs is challenging. Thrombosis and bleeding are areas of innovation and change in emergency medicine. We aimed to determine the learning needs of the Free Open Access Medical education (FOAM) community with the subsequent goal of developing structured curricula to meet them. Methods: A Massive Online Needs Assessment (MONA) was conducted to determine the perceived and unperceived educational needs in thrombosis and bleeding. The survey was designed by a multidisciplinary team of experts and was open from September 20 to December 10, 2016. The survey requested limited demographic information and contained questions to identify topics of interest. Respondents’ baseline knowledge and unperceived needs were assessed using 5 case scenarios containing 3 questions each. Knowledge gaps were defined a priori as topics where Results: We received 198 complete responses by staff physicians (n=109), residents (n=46), medical students (n=29) and allied health professionals (n=14) from 20 countries. 116/198 responses were from people working in emergency medicine. Topics of interest to participants included choice of anticoagulants, interruption of anticoagulation, management of bleeding and monitoring anticoagulation. Knowledge gaps were identified in 4 main areas including interruption of anticoagulation, management of bleeding (including reversal of anticoagulation and massive transfusion), inherited thrombophilia, and screening for malignancy in acute thrombosis. Conclusion: We have identified six priority topics to cover in our future online Thrombosis and Bleeding curriculum by surveying the online medical community. Although perceived and unperceived needs showed high congruence, two priority topics were only identified by assessing unperceived needs.

Introduction/Innovation Concept: The boom in online educational resources for medical education over the past decade has changed how physicians learn and keep up to date with new literature. While nearly all emergency medicine residents use online resources, few of these resources were designed to target knowledge gaps. Novel methods are required to identify learning needs to allow the targeted development of learner-centered curricula. Methods: A multidisciplinary team attempted to determine the feasibility of conducting a Massive Online Needs Assessment (MONA) to assess the perceived and unperceived educational needs in thrombosis and bleeding. An open, online survey was launched via Google Forms and disseminated using the online educational resource CanadiEM.org and social media platforms Twitter and Facebook with the goal of reaching participants of the Free Open Access Medical education (FOAM) community. Curriculum, Tool, or Material: The survey was designed to identify knowledge gaps and contained demographic, free text, and multiple choice questions. It took individuals approximately 30 minutes to complete and was incentivized with entry into a draw for one of four $250 Amazon Gift cards. Feasibility was defined a priori as 150 responses from at least 4 specialties in 4 or more countries. This sample was deemed the minimum number required to identify knowledge gaps (defined as Conclusion: It is feasible to use a MONA to collect data on the perceived and unperceived needs of an online community. Such needs assessments could be used to make online resources more learner-centered.

Introduction: With the increasing volume of medical literature published each year, it is difficult for clinicians to translate the latest research into practice. Awareness is the first step of knowledge translation and journals have begun using social media to increase the dissemination and awareness of their publications. Infographics can describe research findings visually, are shared broadly on social media, and may be a more effective way to convey information. We hypothesized that infographic abstracts would increase the social media dissemination and online readership of research articles relative to traditional abstracts. Methods: In this randomized controlled trial, 24 original research articles were chosen from the six issues of the Canadian Journal of Emergency Medicine (CJEM) published between July 2016 and May 2017 (4 articles per issue). Half were randomized to the infographic and control groups within each issue. Infographic articles were promoted using a visual infographic outlining the findings of the article. Control articles were promoted using a screen capture image of each articles abstract. Both were disseminated through the journals social media accounts (Twitter and Facebook) along with the link to the selected article. Infographics were also published on CanadiEM.org. Abstract views, full text views, and the change in Altmetric score were tracked for 30 days and compared between groups. Unpaired two-tailed t-tests were used to detect significant differences. Results: Abstract views (mean, SD) were significantly higher for infographic articles (378.9, 162.0) than control articles (175.5, 69.2, pConclusion: CJEM articles promoted on social media using infographics had higher abstract viewership and Altmetric scores than those promoted with traditional abstracts. Although there was no difference in full-text readership, our results suggest that infographic abstracts may have a role in increasing the dissemination of medical literature.

Introduction: The CJEM Social Media Team was created in 2014 to assist the journal with the dissemination of its research online. It consists of two Social Media Editors (Junior and Senior) and a team of volunteer medical students and residents to assist their work. Collaborative promotional agreements were developed to promote CJEM articles on the Skeptics’ Guide to Emergency Medicine (SGEM) podcast through the ‘Hot off the Press’ (HOP) series and the CanadiEM blog through an infographic series. Methods: CJEM papers were selected for promotion by the Team based on their perceived interest to the online community of emergency physicians. Altmetric scores, which are a measure of online dissemination derived from a weighted algorithm of social media metrics, were collated for articles promoted using the SGEM HOP or CanadiEM blogs. A control group was created using the articles with the top two Altmetric scores in each CJEM issue in 2015 and 2016. Erratum, Letters, and articles written by the social media editors were excluded from the control groups. The success of the social media promotion was quantified through the measurement of Altmetric scores as of January 1, 2017. Unpaired two-tailed t-tests with unequal variance were used to test for significant differences. Results: 106 and 82 eligible articles were published in 2015 and 2016, respectively. Four articles in 2015 and two articles in 2016 were excluded from the control groups because they were written by the social media editors. SGEM HOP podcasts promoted one article in 2015 and five articles in 2016. CanadiEM infographics promoted three articles in 2015 and eight articles in 2016. No articles were promoted in both series. The average Altmetric score was higher for SGEM HOP (61.0) than CanadiEM Infographics (31.5, pConclusion: The results suggest that collaborating with established social media websites to promote CJEM articles using podcasts and infographics increases their social media dissemination. Given the nonrandomized design of these results, causative conclusions cannot be drawn. A randomized study of the impact of social media promotion on readership is underway.