Current and Future Roles of Glycoprotein IIb-IIIa Inhibitors in Primary Angioplasty for ST-Segment Elevation Myocardial Infarction.

Acute myocardial infarction still represents the major cause of mortality in high-income countries. Therefore, considerable efforts have been focused on the treatment of myocardial infarctions in the acute and long-term phase, with special attention being paid to reperfusion strategies and adjunctive antithrombotic therapies. In fact, despite the successful mechanical recanalization of the epicardial conduit, a substantial percentage of patients still experience poor myocardial reperfusion or acute/subacute in-stent thrombosis.

Long-Term Impact of a Medical School Course on the Intersection of Art and Medical History.

Background: One recent trend in medical education is the integration of humanities into the curriculum, including viewing works of art in museums, with analysis of short-term, but not long-term, impact. We developed a course for medical students, trainees, and faculty at the Icahn School of Medicine at Mount Sinai co-taught by an art historian and a physician/medical historian that features images of great works of art to make connections between art and medical history with the following goals: 1. To encourage the students to make careful and systematic observations, describe what they see to others in the group, and exchange their views respectfully, 2.

Pregnancy and childbirth in patients with Glanzmann Thrombasthenia.

Glanzmann thrombasthenia (GT) is a rare inherited platelet bleeding disorder caused by a quantitative and/or qualitative defect of the αIIbβ3 integrin. Pregnancy and delivery pose special challenges as they entail increased risks of both maternal and foetal bleeding that may be life-threatening. Multidisciplinary management throughout the preconception, intrapartum and peripartum periods is vital to optimize pregnancy outcomes.

Evidence That Anemia Accelerates AS Progression Via Shear-Induced TGF-β1 Activation: Heyde's Syndrome Comes Full Circle.

The severity of aortic stenosis (AS) is associated with acquired von Willebrand syndrome (AVWS) and gastrointestinal bleeding, leading to anemia (Heyde's syndrome). We investigated how anemia is linked with AS and AVWS using the LA100 mouse model and patients with AS. Induction of anemia in LA100 mice increased transforming growth factor (TGF)-β1 activation, AVWS, and AS progression.

Critical Analysis of Thrombocytopenia Associated With Glycoprotein IIb/IIIa Inhibitors and Potential Role of Zalunfiban, a Novel Small Molecule Glycoprotein Inhibitor, in Understanding the Mechanism(s).

Thrombocytopenia is a rare but serious complication of the intravenous glycoprotein IIb/IIIa (GPIIb/IIIa; integrin αIIbβ3) receptor inhibitors (GPIs), abciximab, eptifibatide, and tirofiban. The thrombocytopenia ranges from mild (50 000-100 000 platelets/μL), to severe (20 000 to <50 000/μL), to profound (<20 000/μL). Profound thrombocytopenia appears to occur in <1% of patients receiving their first course of therapy.

Building an infrastructure to support the development, conduct, and reporting of informative clinical studies: The Rockefeller University experience.

Introduction: Clinical trials are a vital component of translational science, providing crucial information on the efficacy and safety of new interventions and forming the basis for regulatory approval and/or clinical adoption. At the same time, they are complex to design, conduct, monitor, and report successfully. Concerns over the last two decades about the quality of the design and the lack of completion and reporting of clinical trials, characterized as a lack of "informativeness," highlighted by the experience during the COVID-19 pandemic, have led to several initiatives to address the serious shortcomings of the United States clinical research enterprise.

Variability in International Society on Thrombosis and Haemostasis-Scientific and Standardization Committee endorsed Bleeding Assessment Tool (ISTH-BAT) score with normal aging in healthy females: contributory factors and clinical significance.

Background: Bleeding assessment tools are key screening tests used in the evaluation of patients with suspected inherited bleeding disorders. The International Society on Thrombosis and Haemostasis-Scientific and Standardization Committee endorsed Bleeding Assessment Tool (ISTH-BAT) has differing reference ranges for adult males (0-3), adult females (0-5), and children (0-2), reflecting differing bleeding symptoms and exposure to hemostatic challenges in these healthy population subgroups. Age is known to markedly impact bleeding score in individuals with von Willebrand disease.

Prehospital treatment with zalunfiban (RUC-4) in patients with ST- elevation myocardial infarction undergoing primary percutaneous coronary intervention: Rationale and design of the CELEBRATE trial.

Background: Early and complete restoration of target vessel patency in ST-elevation myocardial infarction (STEMI) is associated with improved outcomes. Oral P2Y inhibitors have failed to demonstrate either improved patency or reduced mortality when administered in the prehospital setting. Thus, there is a need for antiplatelet agents that achieve prompt and potent platelet inhibition, and that restore patency in the prehospital setting.

Structure-Based Discovery of a Novel Class of Small-Molecule Pure Antagonists of Integrin αVβ3.

Inhibitors of integrin αVβ3 have therapeutic promise for a variety of diseases. Most αVβ3-targeting small molecules patterned after the RGD motif are partial agonists because they induce a high-affinity, ligand-binding conformation and prime the receptor to bind the ligand without an activating stimulus, in part a charge-charge interaction between their aspartic acid carboxyl group and the metal ion in the metal-ion-dependent adhesion site (MIDAS). Building upon our previous studies on the related integrin αIIbβ3, we searched for pure αVβ3 antagonists that lack this typical aspartic acid carboxyl group and instead engage through direct binding to one of the coordinating residues of the MIDAS metal ion, specifically β3 E220.

It's the water! The open and shut case of drug-induced integrin activation.

Integrin receptors are established drug targets, but many of the drugs that have been developed act as partial agonists, inducing the receptor into a high-affinity, ligand-binding state. Lin et al. discovered a general mechanism to circumvent this problem-stabilizing a key water molecule that prevents receptor activation.

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.

Stakeholder Engagement In a Comparative Effectiveness/Implementation Study to Prevent Infection Recurrence: CA-MRSA Project (CAMP2).

Background: Methicillin-resistant or methicillin-sensitive Staphylococcus aureus skin and soft tissue infections pose serious clinical and public health challenges. Few protocols exist for outpatient education, decolonization and decontamination.

Objectives: This trial implemented infection prevention protocols in homes via community health workers/Promotoras.

The Rockefeller Team Science Leadership training program: Curriculum, standardized assessment of competencies, and impact of returning assessments.

The ability to effectively lead an interdisciplinary translational team is a crucial component of team science success. Most KL2 Clinical Scholars have been members of scientific teams, but few have been team science leaders. There is a dearth of literature and outcome measures of effective Team Science Leadership in clinical and translational research.

Platelet binding to polymerizing fibrin is avidity driven and requires activated αIIbβ3 but not fibrin cross-linking.

The molecular basis of platelet-fibrin interactions remains poorly understood despite the predominance of fibrin in thrombi. We have studied the interaction of platelets with polymerizing fibrin by adding thrombin to washed platelets in the presence of the peptide RGDW, which inhibits the initial platelet aggregation mediated by fibrinogen binding to αIIbβ3 but leaves intact a delayed increase in light transmission (delayed wave; DW) as platelets interact with the polymerizing fibrin. The DW was absent in platelets from a patient with Glanzmann thrombasthenia, indicating a requirement for αIIbβ3.

Application of Auxiliary VerifyNow Point-of-Care Assays to Assess the Pharmacodynamics of RUC-4, a Novel αIIbβ3 Receptor Antagonist.

 Prehospital therapy of ST-elevation myocardial infarction (STEMI) with αIIbβ3 antagonists improves clinical outcomes, but they are difficult to use in prehospital settings. RUC-4 is a novel αIIbβ3 antagonist being developed for prehospital therapy of STEMI that rapidly achieves high-grade platelet inhibition after subcutaneous administration. Standard light transmission aggregometry (LTA) is difficult to perform during STEMI, so we applied VerifyNow (VN) assays to assess the pharmacodynamics of RUC-4 relative to aspirin and ticagrelor.

Comparative Effectiveness Study of Home-Based Interventions to Prevent CA-MRSA Infection Recurrence.

Recurrent skin and soft tissue infections (SSTI) caused by Community-Associated Methicillin-Resistant (CA-MRSA) or Methicillin-Sensitive (CA-MSSA) present treatment challenges. This community-based trial examined the effectiveness of an evidence-based intervention (CDC Guidelines, topical decolonization, surface decontamination) to reduce SSTI recurrence, mitigate household contamination/transmission, and improve patient-reported outcomes. Participants (n = 186) were individuals with confirmed MRSA(+)/MSSA(+) SSTIs and their household members.

CTSA pharmacies: Contribution to research and public health during the COVID-19 pandemic.

Introduction: In March 2020, academic medical center (AMC) pharmacies were compelled to implement practice changes in response to the COVID-19 pandemic. These changes were described by survey data collected by the Clinical and Translational Science Awards (CTSA) program which were interpreted by a multi-institutional team of AMC pharmacists and physician investigators.

Methods: The CTSA program surveyed 60 AMC pharmacy departments.

Re-engineering The Clinical Research Enterprise in Response to COVID-19: The Clinical Translational Science Award (CTSA) experience and proposed playbook for future pandemics.

The 2020 COVID-19 pandemic has had a profound impact on the clinical research enterprises at the 60 Clinical and Translational Science Award (CTSA) Hubs throughout the nation. There was simultaneously a need to expand research to obtain crucial data about disease prognosis and therapy and enormous limitations on conducting research as localities and institutions limited travel and person-to-person contact. These imperatives resulted in major changes in the way research was conducted, including expediting Institutional Review Board review, shifting to remote interactions with participants, centralizing decision-making in prioritizing research protocols, establishing biobanks, adopting novel informatics platforms, and distributing study drugs in unconventional ways.