Co-designing and piloting educational materials with patients and healthcare providers for syncope in the emergency department.

Objective: The purpose of this study was to identify barriers and design interventions to promote adherence to 2017 Guideline for Syncope Evaluation and Management. Methods: Focus groups and interviews were conducted to understand preferences, needs and barriers from patients and providers. Educational materials for patients were developed following a co-design, iterative process with patients, providers and hospital staff. The academic medical center's (AMC) Patient Education Department and Patient & Family Advisory Council reviewed materials to ensure health literacy. We piloted usability and feasibility of delivering the materials to a small cohort of patients. Results: From Feb to March 2020, 24 patients were asked to watch the video. Twenty-two watched the intake video; of those 8 watched the discharge video. 95% of participants found the intake video informational and 86% would recommend it to others; 100% found the discharge video informational and would recommend it to others. Patients who watched both videos reported the videos improved their overall stay. Conclusion: Our study described a patient-clinician-researcher codesign process and demonstrated feasibility of tools developed to communicate risk and uncertainty with patients and facilitate shared decision making in syncope evaluation. Innovation: Engaging end users in developing interventions is critical for sustained practice change.

Extracellular Histones Trigger Disseminated Intravascular Coagulation by Lytic Cell Death.

Histones are cationic nuclear proteins that are essential for the structure and functions of eukaryotic chromatin. However, extracellular histones trigger inflammatory responses and contribute to death in sepsis by unknown mechanisms. We recently reported that inflammasome activation and pyroptosis trigger coagulation activation through a tissue-factor (TF)-dependent mechanism. We used a combination of various deficient mice to elucidate the molecular mechanism of histone-induced coagulation. We showed that histones trigger coagulation activation in vivo, as evidenced by coagulation parameters and fibrin deposition in tissues. However, histone-induced coagulopathy was neither dependent on intracellular inflammasome pathways involving caspase 1/11 and gasdermin D (GSDMD), nor on cell surface receptor TLR2- and TLR4-mediated host immune response, as the deficiency of these genes in mice did not protect against histone-induced coagulopathy. The incubation of histones with macrophages induced lytic cell death and phosphatidylserine (PS) exposure, which is required for TF activity, a key initiator of coagulation. The neutralization of TF diminished the histone-induced coagulation. Our findings revealed lytic cell death as a novel mechanism of histone-induced coagulation activation and thrombosis.

KL2 scholars' perceptions of factors contributing to sustained translational science career success.

Introduction: Identifying the most effective ways to support career development of early stage investigators in clinical and translational science should yield benefits for the biomedical research community. Institutions with Clinical and Translational Science Awards (CTSA) offer KL2 programs to facilitate career development; however, the sustained impact has not been widely assessed. Methods: A survey comprised of quantitative and qualitative questions was sent to 2144 individuals that had previously received support through CTSA KL2 mechanisms. The 547 responses were analyzed with identifying information redacted. Results: Respondents held MD (47%), PhD (36%), and MD/PhD (13%) degrees. After KL2 support was completed, physicians' time was divided 50% to research and 30% to patient care, whereas PhD respondents devoted 70% time to research. Funded research effort averaged 60% for the cohort. Respondents were satisfied with their career progression. More than 95% thought their current job was meaningful. Two-thirds felt confident or very confident in their ability to sustain a career in clinical and translational research. Factors cited as contributing to career success included protected time, mentoring, and collaborations. Conclusion: This first large systematic survey of KL2 alumni provides valuable insight into the group's perceptions of the program and outcome information. Former scholars are largely satisfied with their career choice and direction, national recognition of their expertise, and impact of their work. Importantly, they identified training activities that contributed to success. Our results and future analysis of the survey data should inform the framework for developing platforms to launch sustaining careers of translational scientists.

Lipid phosphate phosphatase 3 in smooth muscle cells regulates angiotensin II-induced abdominal aortic aneurysm formation.

Genetic variants that regulate lipid phosphate phosphatase 3 (LPP3) expression are risk factors for the development of atherosclerotic cardiovascular disease. LPP3 is dynamically upregulated in the context of vascular inflammation with particularly heightened expression in smooth muscle cells (SMC), however, the impact of LPP3 on vascular pathology is not fully understood. We investigated the role of LPP3 and lysophospholipid signaling in a well-defined model of pathologic aortic injury and observed Angiotensin II (Ang II) increases expression of PLPP3 in SMCs through nuclear factor kappa B (NF-κB) signaling Plpp3 global reduction (Plpp3+/-) or SMC-specific deletion (SM22-Δ) protects hyperlipidemic mice from AngII-mediated aneurysm formation. LPP3 expression regulates SMC differentiation state and lowering LPP3 levels promotes a fibroblast-like phenotype. Decreased inactivation of bioactive lysophosphatidic acid (LPA) in settings of LPP3 deficiency may underlie these phenotypes because deletion of LPA receptor 4 in mice promotes early aortic dilation and rupture in response to AngII. LPP3 expression and LPA signaling influence SMC and vessel wall responses that are important for aortic dissection and aneurysm formation. These findings could have important implications for therapeutics targeting LPA metabolism and signaling in ongoing clinical trials.

Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium.

Coronavirus disease 2019 (COVID-19) predisposes patients to thrombotic and thromboembolic events, owing to excessive inflammation, endothelial cell activation and injury, platelet activation and hypercoagulability. Patients with COVID-19 have a prothrombotic or thrombophilic state, with elevations in the levels of several biomarkers of thrombosis, which are associated with disease severity and prognosis. Although some biomarkers of COVID-19-associated coagulopathy, including high levels of fibrinogen and D-dimer, were recognized early during the pandemic, many new biomarkers of thrombotic risk in COVID-19 have emerged. In this Consensus Statement, we delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thrombosis in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine thrombosis with thrombocytopenia syndrome. We then make consensus recommendations for the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombotic risk and in-hospital mortality. A thorough understanding of these biomarkers might aid risk stratification and prognostication, guide interventions and provide a platform for future research.

Developing and Demonstrating the Viability and Availability of the Multilevel Implementation Strategy for Syncope Optimal Care Through Engagement (MISSION) Syncope App: Evidence-Based Clinical Decision Support Tool.

BACKGROUND: Syncope evaluation and management is associated with testing overuse and unnecessary hospitalizations. The 2017 American College of Cardiology/American Heart Association (ACC/AHA) Syncope Guideline aims to standardize clinical practice and reduce unnecessary services. The use of clinical decision support (CDS) tools offers the potential to successfully implement evidence-based clinical guidelines. However, CDS tools that provide an evidence-based differential diagnosis (DDx) of syncope at the point of care are currently lacking. OBJECTIVE: With input from diverse health systems, we developed and demonstrated the viability of a mobile app, the Multilevel Implementation Strategy for Syncope optImal care thrOugh eNgagement (MISSION) Syncope, as a CDS tool for syncope diagnosis and prognosis. METHODS: Development of the app had three main goals: (1) reliable generation of an accurate DDx, (2) incorporation of an evidence-based clinical risk tool for prognosis, and (3) user-based design and technical development. To generate a DDx that incorporated assessment recommendations, we reviewed guidelines and the literature to determine clinical assessment questions (variables) and likelihood ratios (LHRs) for each variable in predicting etiology. The creation and validation of the app diagnosis occurred through an iterative clinician review and application to actual clinical cases. The review of available risk score calculators focused on identifying an easily applied and valid evidence-based clinical risk stratification tool. The review and decision-making factors included characteristics of the original study, clinical variables, and validation studies. App design and development relied on user-centered design principles. We used observations of the emergency department workflow, storyboard demonstration, multiple mock review sessions, and beta-testing to optimize functionality and usability. RESULTS: The MISSION Syncope app is consistent with guideline recommendations on evidence-based practice (EBP), and its user interface (UI) reflects steps in a real-world patient evaluation: assessment, DDx, risk stratification, and recommendations. The app provides flexible clinical decision making, while emphasizing a care continuum; it generates recommendations for diagnosis and prognosis based on user input. The DDx in the app is deemed a pragmatic model that more closely aligns with real-world clinical practice and was validated using actual clinical cases. The beta-testing of the app demonstrated well-accepted functionality and usability of this syncope CDS tool. CONCLUSIONS: The MISSION Syncope app development integrated the current literature and clinical expertise to provide an evidence-based DDx, a prognosis using a validated scoring system, and recommendations based on clinical guidelines. This app demonstrates the importance of using research literature in the development of a CDS tool and applying clinical experience to fill the gaps in available research. It is essential for a successful app to be deliberate in pursuing a practical clinical model instead of striving for a perfect mathematical model, given available published evidence. This hybrid methodology can be applied to similar CDS tool development.

Passive antipyretic therapy is not as effective as invasive hypothermia for maintaining normothermia after cardiac arrest.

AIM OF THE STUDY: Targeted temperature management is a class I indication in comatose patients after a cardiac arrest. While the literature has primarily focused on innovative methods to achieve target temperatures, pharmacologic therapy has received little attention. We sought to examine whether pharmacologic therapy using antipyretics is effective in maintaining normothermia in post cardiac arrest patients. MATERIALS AND METHODS: Patients ≥18 years who were resuscitated after an in-hospital or out-of-hospital cardiac arrest and admitted at our institution from January 2012 to September 2015 were retrospectively included. Patients were divided into groups based on the method of temperature control that was utilized. The primary outcome was temperature control <38 °C during the first 48 h after the cardiac arrest. RESULTS: 671 patients were identified in Group 1 (no hypothermia), 647 in Group 2 (antipyretics), 44 in Group 3 (invasive hypothermia), and 51 in Group 4 (invasive hypothermia and antipyretics). Mean patient age was 59 (SD ±15.7) years with 40.6% being female. Using Group 1 as the control arm, 57.7% of patients maintained target temperature with antipyretics alone (p < 0.001), compared to 69.3% in the control group and 82.1% in the combined hypothermia groups 3&4 (p = 0.01). Patients receiving both invasive hypothermia and antipyretics (Group 4), had the greatest mean temperature decrease of 5.2 °C. CONCLUSIONS: Among patients undergoing targeted temperature management, relying solely on as needed use of antipyretics is not sufficient to maintain temperatures <38 °C. However, antipyretics could be used as an initial strategy if given regularly and/or in conjunction with more aggressive cooling techniques.

Planning Implementation Success of Syncope Clinical Practice Guidelines in the Emergency Department Using CFIR Framework.

Background and Objectives: Overuse and inappropriate use of testing and hospital admission are common in syncope evaluation and management. Though guidelines are available to optimize syncope care, research indicates that current clinical guidelines have not significantly impacted resource utilization surrounding emergency department (ED) evaluation of syncope. Matching implementation strategies to barriers and facilitators and tailoring strategies to local context hold significant promise for a successful implementation of clinical practice guidelines (CPG). Our team applied implementation science principles to develop a stakeholder-based implementation strategy. Methods and Materials: We partnered with patients, family caregivers, frontline clinicians and staff, and health system administrators at four health systems to conduct quantitative surveys and qualitative interviews for context assessment. The identification of implementation strategies was done by applying the CFIR-ERIC Implementation Strategy Matching Tool and soliciting stakeholders' inputs. We then co-designed with patients and frontline teams, and developed and tested specific strategies. Results: A total of 114 clinicians completed surveys and 32 clinicians and stakeholders participated in interviews. Results from the surveys and interviews indicated low awareness of syncope guidelines, communication challenges with patients, lack of CPG protocol integration into ED workflows, and organizational process to change as major barriers to CPG implementation. Thirty-one patients and their family caregivers participated in interviews and expressed their expectations: clarity regarding their diagnosis, context surrounding care plan and diagnostic testing, and a desire to feel cared about. Identifying change methods to address the clinician barriers and patients and family caregivers expectations informed development of the multilevel, multicomponent implementation strategy, MISSION, which includes patient educational materials, mentored implementation, academic detailing, Syncope Optimal Care Pathway and a corresponding mobile app, and Lean quality improvement methods. The pilot of MISSION demonstrated feasibility, acceptability and initial success on appropriate testing. Conclusions: Effective multifaceted implementation strategies that target individuals, teams, and healthcare systems can be employed to plan successful implementation and promote adherence to syncope CPGs.

Inflammasome activation promotes venous thrombosis through pyroptosis.

Crosstalk between coagulation and innate immunity contributes to the progression of many diseases, including infection and cardiovascular disease. Venous thromboembolism (VTE), including pulmonary embolism and deep vein thrombosis (DVT), is among the most common causes of cardiovascular death. Here, we show that inflammasome activation and subsequent pyroptosis play an important role in the development of venous thrombosis. Using a flow restriction-induced mouse venous thrombosis model in the inferior vena cava (IVC), we show that deficiency of caspase-1, but not caspase-11, protected against flow restriction-induced thrombosis. Interleukin-1ß expression increased in the IVC following ligation, indicating that inflammasome is activated during injury. Deficiency of gasdermin D (GSDMD), an essential mediator of pyroptosis, protected against restriction-induced venous thrombosis. After induction of venous thrombosis, fibrin was deposited in the veins of wild-type mice, as detected using immunoblotting with a monoclonal antibody that specifically recognizes mouse fibrin, but not in the caspase-1-deficient or GSDMD-deficient mice. Depletion of macrophages by gadolinium chloride or deficiency of tissue factor also protected against venous thrombosis. Our data reveal that tissue factor released from pyroptotic monocytes and macrophages following inflammasome activation triggers thrombosis.

"Passing Out is a Serious Thing": Patient Expectations for Syncope Evaluation and Management.

PURPOSE: Syncope is a complex symptom requiring thoughtful evaluation. The ACC/AHA/HRS published syncope management guidelines in 2017. Effective guideline implementation hinges on overcoming multilevel barriers, including providers' perceptions that patients prefer aggressive diagnostic testing when presenting to the emergency department (ED) with syncope, which conflicts with the 2017 Guideline on Syncope. To better understand this perceived barrier, we explored patient and family caregiver expectations and preferences when presenting to the ED with syncope. PATIENTS AND METHODS: We conducted semi-structured focus groups (N=12) and in-depth interviews (N=19) with patients presenting to the ED with syncope as well as with their family caregivers. Interviews were recorded, transcribed verbatim, and analyzed by a team of researchers following a directed content analysis. Results were reviewed and shared iteratively with all team members to confirm mutual understanding and agreement. RESULTS: Syncope patients and caregivers discussed three main desires when presenting to the ED with syncope: 1) clarity regarding their diagnosis,; 2) context surrounding their care plan and diagnostic approach; and 3) to feel seen, heard and cared about by their health care team. CONCLUSION: Clinicians have cited patient preferences for aggressive diagnostic testing as a barrier to adhering to the 2017 Guideline on Syncope, which recommends against routine administration of imaging testing (eg, echocardiograms). Our results suggest that while participants preferred diagnostic testing as a means to achieve clarity and even a feeling of being cared for, other strategies, such as a patient-engaged approach to communication and shared decision-making, may address the spectrum of patient expectations when presenting to the ED with syncope while adhering to guideline recommendations.

Depression After Open Heart Surgery: Influences of Optimism, Sex, and Event-Related Medical Factors.

ABSTRACT: Postoperative depression is a multifaceted condition that can limit quality of life and potentially decrease the survival benefits of open heart surgery (OHS). We postulated that sex, pre-event character strengths, medical, and certain surgery indicators would predict post-event/myocardial infarction depression. To identify predictors, we collected three-wave survey data from 481 OHS patients at a large academic referral institution (age, 62+; female, 42%) and included key medical and surgical information. The final model (F[7, N = 293] = 28.15, p < 0.001, R2 = 0.408) accounted for over two fifths of the variance in post-OHS depression. Pre-event/OHS optimism mitigated post-OHS depression. Being female, older, living alone, longer surgical perfusion time, absence of left main disease greater than 50%, and pre-OHS depression were associated with the increased likelihood of post-OHS depression. Our findings suggest that teaching optimism to OHS patients might be beneficial in reducing the risk of postoperative depression and that female patients should be monitored more closely for the development of depression through an interdisciplinary approach.

Value-based assessment of implementing a Pulmonary Embolism Response Team (PERT).

PERTs are a new, multidisciplinary approach to PE care. They were conceived to efficiently identify and risk stratify PE patients and standardize care delivery. More research needs to be conducted to assess the effects that PERTs have had on PE care. This study sought to determine the effects of a PERT on quality and overall value of care. This was a retrospective study of all patients 18 years of age or older who presented with a principal diagnosis of an acute PE based on available ICD codes from January 1, 2010 to December 31, 2018. Patients who did not have an imaging study, i.e., CTPA or ECHO, available were excluded. Patients were divided into pre- (before October 2015) and post-PERT eras (after October 2015) and stratified based on the presence of right heart strain/dysfunction on imaging. All quality outcomes were extracted from the EMR, and cost outcomes were provided by the financial department. 530 individuals (226 pre-PERT and 304 post-PERT) were identified for analysis. Quality outcomes improved between the eras; most notably in-hospital mortality decreased (16.5 vs. 9.6) and hospital LOS decreased (7.7 vs. 4.4) (p < 0.05). Total cost of care also decreased a statistically significant amount between the eras. The implementation of a PERT improved quality and cost of care, resulting in improved value. We hypothesize that this may be due to more timely identification and risk stratification leading to earlier interventions and streamlined decision making, but further research is required to validate these findings in larger cohorts.

Cangrelor in addition to standard therapy reduces cardiac damage and inflammatory markers in patients with ST-segment elevation myocardial infarction.

Although P2Y12 receptor blockers have become a standard, adjunctive therapy in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI), the optimal regimen has not been established. We performed a prospective, open-label, randomized study to investigate the effect of cangrelor administration on platelet function and inflammation in patients with primary PCI (PPCI). Twenty-two patients were randomized to receive either cangrelor and ticagrelor or ticagrelor alone (standard group) before PPCI. Platelet reactivity was evaluated at baseline (before PCI), 10 min and the end of the procedure. At baseline, there was no significant difference in platelet reactivity between both groups, whereas platelets were significantly inhibited at 10 min after initiating cangrelor vs. standard (adenosine-diphosphate-induced aggregation 102.2 ± 24.88 vs. 333.4 ± 63.3, P < 0.05 and thrombin-receptor-activating-peptide-induced aggregation 285.8 ± 86.1 vs. 624.8 ± 106.0, P < 0.05). Lower platelet aggregation in the cangrelor group persisted but the difference was reduced by the end of the procedure. Circulating inflammatory cells, pro-inflammatory cytokines, total elastase, and surrogates of neutrophil extracellular traps (total elastase-myeloperoxidase complexes) were significantly lower in the cangrelor compared to the standard therapy group at 6 h after randomization. There was a trend towards reduction in cardiac damage in the cangrelor group as reflected by the changes in late gadolinium enhancement between 48 h and 3 months after STEMI. Early administration of cangrelor in STEMI patients was associated with more effective platelet inhibition during PPCI and significantly dampened the deleterious inflammatory response compared to standard therapy (NCT03043274).

Calcium Ion Chelation Preserves Platelet Function During Cold Storage.

OBJECTIVE: Platelet transfusion is a life-saving therapy to prevent or treat bleeding in patients with thrombocytopenia or platelet dysfunction. However, for >6 decades, safe and effective strategies for platelet storage have been an impediment to widespread use of platelet transfusion. Refrigerated platelets are cleared rapidly from circulation, precluding cold storage of platelets for transfusion. Consequently, platelets are stored at room temperature with an upper limit of 5 days due to risks of bacterial contamination and loss of platelet function. This practice severely limits platelet availability for transfusion. This study is to identify the mechanism of platelet clearance after cold storage and develop a method for platelet cold storage. Approach and Results: We found that rapid clearance of cold-stored platelets was largely due to integrin activation and apoptosis. Deficiency of integrin ß3 or caspase-3 prolonged cold-stored platelets in circulation. Pretreatment of platelets with EGTA, a cell impermeable calcium ion chelator, reversely inhibited cold storage-induced platelet activation and consequently prolonged circulation of cold-stored platelets. Moreover, transfusion of EGTA-treated, cold-stored platelets, but not room temperature-stored platelets, into the mice deficient in glycoprotein Ibα significantly shortened tail-bleeding times and diminished blood loss. CONCLUSIONS: Integrin activation and apoptosis is the underlying mechanism of rapid clearance of platelets after cold storage. Addition of a cell impermeable calcium ion chelator to platelet products is potentially a simple and effective method to enable cold storage of platelets for transfusion.

Preoperative Optimism Related to Low Anxiety in Patients 1 Month After Open Heart Surgery.

Anxiety can contribute to poor prognosis in cardiac patients. Few studies have examined the role of optimism in anxiety after open heart surgery (OHS). This study investigated the influence of preoperative optimism on post-OHS anxiety, adjusting cardiac indices used by cardiac surgeons. Data were collected before and 1 month after OHS in 481 patients (58% men; age, 62.4 ± 11.94 years). Optimism was measured using the Life Orientation Test. Anxiety was measured using the Trait Anxiety Inventory. Medical and cardiac indices were retrieved from the Society of Thoracic Surgeon's national database. Multiple regression analyses showed that greater pre-OHS optimism was associated with lower levels of post-OHS anxiety (F[6, N = 306] = 50.18, p < 0.001, R = 0.502). No other factors showed similar protection. Pre-OHS anxiety, younger age, and minority status were associated with anxiety in the critical recovery month. The findings demonstrate the potential benefit of optimism against post-OHS anxiety, which may have clinical implications for improving disease management.

Autotaxin inhibition reduces cardiac inflammation and mitigates adverse cardiac remodeling after myocardial infarction.

OBJECTIVE: Acute myocardial infarction (AMI) initiates pathological inflammation which aggravates tissue damage and causes heart failure. Lysophosphatidic acid (LPA), produced by autotaxin (ATX), promotes inflammation and the development of atherosclerosis. The role of ATX/LPA signaling nexus in cardiac inflammation and resulting adverse cardiac remodeling is poorly understood. APPROACH AND RESULTS: We assessed autotaxin activity and LPA levels in relation to cardiac and systemic inflammation in AMI patients and C57BL/6 (WT) mice. Human and murine peripheral blood and cardiac tissue samples showed elevated levels of ATX activity, LPA, and inflammatory cells following AMI and there was strong correlation between LPA levels and circulating inflammatory cells. In a gain of function model, lipid phosphate phosphatase-3 (LPP3) specific inducible knock out (Mx1-Plpp3Δ) showed higher systemic and cardiac inflammation after AMI compared to littermate controls (Mx1-Plpp3fl/fl); and a corresponding increase in bone marrow progenitor cell count and proliferation. Moreover, in Mx1- Plpp3Δ mice, cardiac functional recovery was reduced with corresponding increases in adverse cardiac remodeling and scar size (as assessed by echocardiography and Masson's Trichrome staining). To examine the effect of ATX/LPA nexus inhibition, we treated WT mice with the specific pharmacological inhibitor, PF8380, twice a day for 7 days post AMI. Inhibition of the ATX/LPA signaling nexus resulted in significant reduction in post-AMI inflammatory response, leading to favorable cardiac functional recovery, reduced scar size and enhanced angiogenesis. CONCLUSION: ATX/LPA signaling nexus plays an important role in modulating inflammation after AMI and targeting this mechanism represents a novel therapeutic target for patients presenting with acute myocardial injury.

Securing the Future for a Major Academic Cardiovascular Program: Hardwiring a Referral Network and Preparing for a Transition to Value-Based Reimbursement.

The University of Kentucky College of Medicine and Albert B. Chandler Hospital opened over 50 years ago to serve Kentucky. After initial growth and expansion, both were struggling clinically, academically, and financially in the early 2000s. Difficulties were apparent in cardiovascular (CV) services, which captured only 11% of the regional patients hospitalized for cardiac disease. Over the next 15 years, CV services dynamically transformed to become the leading provider with a large network of regional partners, garnering 42% of market share. This article describes strategic plans and initiatives leading to clinical and academic growth. Future value-based initiatives are also described.