Broadening the Categories of Patients Eligible for Extended Venous Thromboembolism Treatment.

Traditionally, venous thromboembolism (VTE) resulting from major transient risk factors (e.g., surgery or trauma) or a major persistent risk factor such as cancer, has been defined as being provoked, whereas unprovoked VTE encompasses events without an identifiable cause. These categorizations influence anticoagulant treatment duration; unlike VTE provoked by major transient risk factors, extended anticoagulation beyond 3 months is advised for patients with cancer or unprovoked VTE due to risk persistence after treatment cessation. However, some patients with VTE provoked by minor transient or minor persistent risk factors may also be candidates for extended anticoagulation therapy due to the continuing risk of recurrence. In patients who require extended therapy, vitamin K antagonists (VKAs) are effective but are associated with an increased risk of bleeding and various treatment burdens (e.g., anticoagulation monitoring and dose adjustment). Evaluations of extended VTE treatment with the less-burdensome direct oral anticoagulants such as apixaban, dabigatran, edoxaban, and rivaroxaban show that they are at least as safe and effective as VKAs in a broad range of patients. In addition, apixaban and rivaroxaban offer more than one dosing option, allowing tailoring of treatment to the patient's specific risk factor profile. Analysis of more granular definitions for risk factor groupings has also yielded vital information on the most appropriate strategies for the treatment of patients with specific risk factors, highlighting that extended anticoagulation treatment may benefit those with minor transient and persistent environmental and nonenvironmental risk factors who commonly receive shorter-duration therapy

Optimal allocation of selected T-series advanced base functional component equipment packages

Advanced Base Functional Components (ABFCs) are pre-planned modular units of equipment and personnel designed to extend or create the logistic infrastructure required to support naval expeditionary operations. The ABFC program is structured to combine trained personnel with the equipment needed to perform a particular logistic mission such as seaport operations and cargo handling, warehousing, or freight terminal operations. If the ABFC must deploy to a theater of operations, individual equipment packages containing material handling equipment and/or civil engineering support equipment (CESE) vehicles tailored to the operational situation are required. This thesis presents an optimization model that determines the minimum number and type of ABFC equipment packages required for the land-based naval logistic requirements of several hypothetical scenarios, some of which illustrate dual major theater war scenarios. The model quickly and efficiently provides the user with the minimum required number of material handling equipment and CESE vehicles for selected T- series ABFCs.http://archive.org/details/optimalllocation109459337U.S. Navy (U.S.N.) author.Approved for public release; distribution is unlimited

Recent Developments in Minnesota Corporate Law

This article summarizes a number of select cases and statutory amendments involving various topics in Minnesota corporate law. Sections I and II address 2003 statutory changes and cases decided in 2003, respectively. Sections III and IV address 2004 statutory changes and cases decided in the first half of 2004, respectively. The purpose of this article is to provide the practitioner with an overview of recent developments in Minnesota corporate law

Antibody-Based Ticagrelor Reversal Agent in Healthy Volunteers.

BACKGROUND: Ticagrelor is an oral P2Y12 inhibitor that is used with aspirin to reduce the risk of ischemic events among patients with acute coronary syndromes or previous myocardial infarction. Spontaneous major bleeding and bleeding associated with urgent invasive procedures are concerns with ticagrelor, as with other antiplatelet drugs. The antiplatelet effects of ticagrelor cannot be reversed with platelet transfusion. A rapid-acting reversal agent would be useful. METHODS: In this randomized, double-blind, placebo-controlled, phase 1 trial, we evaluated intravenous PB2452, a monoclonal antibody fragment that binds ticagrelor with high affinity, as a ticagrelor reversal agent. We assessed platelet function in healthy volunteers before and after 48 hours of ticagrelor pretreatment and again after the administration of PB2452 or placebo. Platelet function was assessed with the use of light transmission aggregometry, a point-of-care P2Y12 platelet-reactivity test, and a vasodilator-stimulated phosphoprotein assay. RESULTS: Of the 64 volunteers who underwent randomization, 48 were assigned to receive PB2452 and 16 to receive placebo. After 48 hours of ticagrelor pretreatment, platelet aggregation was suppressed by approximately 80%. PB2452 administered as an initial intravenous bolus followed by a prolonged infusion (8, 12, or 16 hours) was associated with a significantly greater increase in platelet function than placebo, as measured by multiple assays. Ticagrelor reversal occurred within 5 minutes after the initiation of PB2452 and was sustained for more than 20 hours (P\u3c0.001 after Bonferroni adjustment across all time points for all assays). There was no evidence of a rebound in platelet activity after drug cessation. Adverse events related to the trial drug were limited mainly to issues involving the infusion site. CONCLUSIONS: In healthy volunteers, the administration of PB2452, a specific reversal agent for ticagrelor, provided immediate and sustained reversal of the antiplatelet effects of ticagrelor, as measured by multiple assays. (Funded by PhaseBio Pharmaceuticals; ClinicalTrials.gov number, NCT03492385.)

Cell Migration Driven by Cooperative Substrate Deformation Patterns

Most eukaryotic cells sense and respond to the mechanical properties of their surroundings. This can strongly influence their collective behavior in embryonic development, tissue function, and wound healing. We use a deformable substrate to measure collective behavior in cell motion due to substrate mediated cell-cell interactions. We quantify spatial and temporal correlations in migration velocity and substrate deformation, and show that cooperative cell-driven patterns of substrate deformation mediate long-distance mechanical coupling between cells and control collective cell migration

Elastase-mediated fibrinogenolysis by chemoattractant-stimulated neutrophils occurs in the presence of physiologic concentrations of antiproteinases.

Plasma levels of the HNE-derived fibrinopeptide A alpha 1-21 reflect in vivo enzyme activity. To provide a possible explanation for the presence of circulating A alpha 1-21 in individuals with normal plasma antiproteinase concentrations we investigated whether PMN-associated HNE is more resistant to inhibition than the free enzyme. PMN were stimulated to migrate across 125I-fibrinogen-coated nitrocellulose filters in response to 10(-7) M FMLP, and the extent of fibrinogenolysis was determined by measuring release of A alpha 1-21 and 125I-labeled fibrinogen degradation products. The fibrinogenolytic activity of migrating PMN was then compared with that of free HNE present in PMN lysates or secreted by PMN stimulated with FMLP. Whereas the fibrinogenolytic activity of soluble HNE was completely inhibited by low concentrations (1%) of plasma or serum and macromolecular antiproteinase (alpha 1 proteinase-inhibitor and soybean trypsin-inhibitor), even in the presence of undiluted plasma or serum the activity of the migrating PMN was incompletely blocked (81-85%). Further, concentrations of alpha 1 proteinase-inhibitor and soybean trypsin-inhibitor that totally inhibited free HNE activity also incompletely blocked (88-89%) the fibrinogenolytic activity of migrating PMN, indicating that FMLP-stimulated PMN demonstrate significant fibrinogenolytic activity in the presence of antiproteinases as small as 20,000 mol wt. A specific low molecular weight HNE inhibitor (MeO-Suc-Ala2-Pro-ValCH2Cl), however, totally blocked PMN-mediated fibrinogenolysis without affecting intracellular HNE activity, HNE secretion from PMN, or PMN migration in response to FMLP. These findings support the hypothesis that PMN migrating on a fibrinogen-coated surface form zones of close contact with fibrinogen, thus preventing access of plasma antiproteinases to HNE released at the cell-substrate interface. The occurrence of this phenomenon in vivo would explain the presence of circulating A alpha 1-21 in individuals with normal antiproteinase concentrations

characteristics and outcomes in patients with venous thromboembolism taking concomitant anti platelet agents and anticoagulants in the amplify trial

AbstractThe double-blind, randomized, AMPLIFY trial compared 6 months' treatment with apixaban (10 mg twice daily for 7 days and 5 mg twice daily thereafter) versus conventional treatment (subcutaneous enoxaparin [1 mg/kg twice daily for ≥ 5 days] overlapped and followed by warfarin [international normalized ratio = 2.0–3.0]) in patients with acute venous thromboembolism (VTE). This post hoc analysis of AMPLIFY compared outcomes among those taking or not taking concomitant anti-platelet therapy. The primary efficacy outcome was recurrent VTE or VTE-related death; the principal safety outcome was major bleeding. Of 5,365 (apixaban, n = 2,676; enoxaparin/warfarin, n = 2,689) randomized patients, 813 (apixaban, n = 402 [15%]; enoxaparin/warfarin, n = 411 [15%]) took concomitant anti-platelet therapy, of which 92% consisted of low-dose aspirin. Rates of VTE or VTE-related death were similar whether or not anti-platelet agents were taken (apixaban: 3.6 and 2.0%; enoxaparin/warfarin: 3.0 and 2.6%; anti-platelet use: relative risk [RR], 1.23; 95% confidence interval [CI], 0.58–2.62; no anti-platelet use: RR, 0.77; 95% CI, 0.52–1.13); interaction p-value = 0.299. Major bleeding rates were threefold higher in those taking versus those not taking anti-platelet agents (apixaban: 1.2 and 0.4%; enoxaparin/warfarin: 4.1 and 1.4%; anti-platelet use: RR, 0.30; 95% CI, 0.11–0.81; no anti-platelet use: RR, 0.31; 95% CI, 0.15–0.63); interaction p-value = 0.924. Concomitant anti-platelet therapy produced a proportionally similar increase in major bleeding in patients randomized to apixaban or conventional therapy, but there were fewer major bleeds with apixaban. Therefore, the overall safety of apixaban over conventional therapy was maintained in patients receiving anti-platelet therapy. Clinicaltrials.gov: NCT00643201

Trends in Prescribing Oral Anticoagulants in Canada, 2008–2014

AbstractPurposeThe non–vitamin K antagonist oral anticoagulants (NOACs), dabigatran, rivaroxaban, and apixaban, provide several advantages over vitamin K antagonists, such as warfarin. Little is known about the trends of prescribing OACs in Canada. In this study we analyzed changes in prescription volumes for OAC drugs since the introduction of the NOACs in Canada overall, by province and by physician specialty.MethodsCanadian prescription volumes for warfarin, dabigatran, rivaroxaban, and apixaban from January 2008 to June 2014 were obtained from the Canadian Compuscript Audit of IMS Health Canada Inc and were analyzed by physician specialty at the national and provincial levels. Total prescriptions by indication were calculated based on data from the Canadian Disease and Therapeutic Index for all OAC indications and for each commonly prescribed dose of dabigatran (75, 110, and 150 mg), rivaroxaban (10, 15, and 20 mg), and apixaban (2.5 and 5 mg).FindingsThe overall number of OAC prescriptions in Canada has increased annually since 2008. With the availability of the NOACs, the proportion of total OAC prescriptions attributable to warfarin has steadily decreased, from 99% in 2010 to 67% by June 2014, and the absolute number of warfarin prescriptions has been decreasing since February 2011. The greatest decline in proportionate warfarin prescriptions was in Ontario. In general, the increase of NOAC prescriptions coincided with the introduction of provinces’ reimbursement of NOAC prescription costs. The proportion of total OAC prescriptions represented by the NOACs varied by specialty, with the greatest proportionate prescribing found among orthopedic surgeons, cardiologists, and neurologists.ImplicationsSince their approval, the NOACs have represented a growing share of total OAC prescriptions in Canada. This trend is expected to continue because the NOACs are given preference over warfarin in guidelines on stroke prevention in patients with atrial fibrillation, because of growing physician experience, and due to the emergence of potential new indications. An understanding of the current prescribing patterns will help to encourage knowledge translation and possibly influence policy/reimbursement strategies