The Impact of Community Use of Novel Oral Anticoagulants on an Academic Medical Center

Warfarin has been a mainstay of therapy for treatment and prevention of venous thromboembolic disease (VTED) and prevention of stroke and systemic embolism for over 50 years. Recent FDA approval of several novel oral anticoagulants has offered more extensive treatment options for management of these disease states. The availability of the novel anticoagulants offers an attractive alternative to warfarin therapy for patients due to their convenience of use. In comparison to warfarin, dabigatran, rivaroxaban and apixaban offer: - a fixed dosage regimen - a relatively small potential drug interaction profile - minimal laboratory monitoring - little to no dietary restrictions. Although these agents offer a relatively fixed dose regimen, dosage adjustment is required in moderate renal dysfunction, and use is contraindicated in severe renal dysfunction. Currently there are no specific reversal agents in the event of a nov- el anticoagulant associated bleed. These concerns led to the development of an anticoagulation stewardship program at our institution to monitor and guide the usage of these agents

Surgical Pulmonary Embolectomy Outcomes for Acute Pulmonary Embolism

Introduction: Acute pulmonary embolism (PE) is associated with significant mortality. Surgical embolectomy is a viable treatment option; however, it remains controversial due to variable outcomes. This review investigates patient outcomes following surgical embolectomy for acute PE. Methods: Electronic search was performed to identify articles reporting surgical embolectomy for treatment of PE. 32 studies were included comprising 936 patients. Demographic, perioperative, and outcome data were extracted and pooled for systematic review. Results: Mean patient age was 56.3 [95% CI 52.5; 60.1] years and 50% [46; 55] were male. 82% had right ventricular dysfunction [62; 93], 80% [67; 89] had unstable hemodynamics, and 9% [5; 16] experienced cardiac arrest. Massive PE and submassive PE were present in 83% of patients [43; 97] and 13% [2; 56], respectively. Before embolectomy, 33% of patients [14; 60] underwent systemic thrombolysis and 14% [8; 24] catheter embolectomy. Preoperatively, 47% of patients were ventilated [26; 70] and 36% had percutaneous cardiopulmonary support [11; 71]. Mean operative time and mean cardiopulmonary bypass time were 170 [101; 239] and 56 [42; 70] minutes, respectively. Intraoperative mortality was 4% [2; 8]. Mean hospital and ICU stay were 10 [6; 14] and 2 [1; 3] days, respectively. Mean postoperative systolic pulmonary artery pressure (sPAP) was significantly decreased from preoperative (sPAP 57.8 mmHg [53; 62.7]) to postoperative period (sPAP 31.3 mmHg [24.9; 37.8]), p \u3c0.01). In-hospital mortality was 16% [12; 21]. Overall survival at five years was 73% [64; 81]. Discussion: Surgical embolectomy is an acceptable treatment option with favorable outcomes

Coarse-grained reconfigurable array architectures

Coarse-Grained Reconfigurable Array (CGRA) architectures accelerate the same inner loops that benefit from the high ILP support in VLIW architectures. By executing non-loop code on other cores, however, CGRAs can focus on such loops to execute them more efficiently. This chapter discusses the basic principles of CGRAs, and the wide range of design options available to a CGRA designer, covering a large number of existing CGRA designs. The impact of different options on flexibility, performance, and power-efficiency is discussed, as well as the need for compiler support. The ADRES CGRA design template is studied in more detail as a use case to illustrate the need for design space exploration, for compiler support and for the manual fine-tuning of source code

Phage typing or CRISPR typing for epidemiological surveillance of Salmonella Typhimurium?

Objective: Salmonella Typhimurium is the most dominant Salmonella serovar around the world. It is associated with foodborne gastroenteritis outbreaks but has recently been associated with invasive illness and deaths. Characterization of S. Typhimurium is therefore very crucial for epidemiological surveillance. Phage typing has been used for decades for subtyping of S. Typhimurium to determine the epidemiological relation among isolates. Recent studies however have suggested that high throughput clustered regular interspaced short palindromic repeats (CRISPR) typing has the potential to replace phage typing. This study aimed to determine the efficacy of highthroughput CRISPR typing over conventional phage typing in epidemiological surveillance and outbreak investigation of S. Typhimurium. Results: In silico analysis of whole genome sequences (WGS) of well-documented phage types of S. Typhimurium reveals the presence of different CRISPR type among strains belong to the same phage type. Furthermore, different phage types of S. Typhimurium share identical CRISPR type. Interestingly, identical spacers were detected among outbreak and non-outbreak associated DT8 strains of S. Typhimurium. Therefore, CRISPR typing is not useful for the epidemiological surveillance and outbreak investigation of S. Typhimurium and phage typing, until it is replaced by WGS, is still the gold standard method for epidemiological surveillance of S. Typhimurium

Prospective cohort study of radiotherapy with concomitant and adjuvant temozolomide chemotherapy for glioblastoma patients with no or minimal residual enhancing tumor load after surgery

Survival of glioblastoma patients has been linked to the completeness of surgical resection. Available data, however, were generated with adjuvant radiotherapy. Data confirming that extensive cytoreduction remains beneficial to patients treated with the current standard, concomitant temozolomide radiochemotherapy, are limited. We therefore analyzed the efficacy of radiochemotherapy for patients with little or no residual tumor after surgery. In this prospective, non-interventional multicenter cohort study, entry criteria were histological diagnosis of glioblastoma, small enhancing or no residual tumor on post-operative MRI, and intended temozolomide radiochemotherapy. The primary study objective was progression-free survival; secondary study objectives were survival and toxicity. Furthermore, the prognostic value of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation was investigated in a subgroup of patients. One-hundred and eighty patients were enrolled. Fourteen were excluded by patient request or failure to initiate radiochemotherapy. Twenty-three patients had non-evaluable post-operative imaging. Thus, 143 patients qualified for analysis, with 107 patients having residual tumor diameters ≤1.5 cm. Median follow-up was 24.0 months. Median survival or patients without residual enhancing tumor exceeded the follow-up period. Median survival was 16.9 months for 32 patients with residual tumor diameters >0 to ≤1.5 cm (95% CI: 13.3–20.5, p = 0.039), and 13.9 months (10.3–17.5, overall p < 0.001) for 36 patients with residual tumor diameters >1.5 cm. Patient age at diagnosis and extent of resection were independently associated with survival. Patients with MGMT promoter methylated tumors and complete resection made the best prognosis. Completeness of resection acts synergistically with concomitant and adjuvant radiochemotherapy, especially in patients with MGMT promoter methylation

A Dynamical Systems Model for Combinatorial Cancer Therapy Enhances Oncolytic Adenovirus Efficacy by MEK-Inhibition

Oncolytic adenoviruses, such as ONYX-015, have been tested in clinical trials for currently untreatable tumors, but have yet to demonstrate adequate therapeutic efficacy. The extent to which viruses infect targeted cells determines the efficacy of this approach but many tumors down-regulate the Coxsackievirus and Adenovirus Receptor (CAR), rendering them less susceptible to infection. Disrupting MAPK pathway signaling by pharmacological inhibition of MEK up-regulates CAR expression, offering possible enhanced adenovirus infection. MEK inhibition, however, interferes with adenovirus replication due to resulting G1-phase cell cycle arrest. Therefore, enhanced efficacy will depend on treatment protocols that productively balance these competing effects. Predictive understanding of how to attain and enhance therapeutic efficacy of combinatorial treatment is difficult since the effects of MEK inhibitors, in conjunction with adenovirus/cell interactions, are complex nonlinear dynamic processes. We investigated combinatorial treatment strategies using a mathematical model that predicts the impact of MEK inhibition on tumor cell proliferation, ONYX-015 infection, and oncolysis. Specifically, we fit a nonlinear differential equation system to dedicated experimental data and analyzed the resulting simulations for favorable treatment strategies. Simulations predicted enhanced combinatorial therapy when both treatments were applied simultaneously; we successfully validated these predictions in an ensuing explicit test study. Further analysis revealed that a CAR-independent mechanism may be responsible for amplified virus production and cell death. We conclude that integrated computational and experimental analysis of combinatorial therapy provides a useful means to identify treatment/infection protocols that yield clinically significant oncolysis. Enhanced oncolytic therapy has the potential to dramatically improve non-surgical cancer treatment, especially in locally advanced or metastatic cases where treatment options remain limited.National Institutes of Health (U.S.) (Grant R01 CA118545)National Institutes of Health (U.S.) (Grant R01 CA095701)National Institutes of Health (U.S.) (Grant U54 CA11297)National Institutes of Health (U.S.) (Grant U54-CA112967

A Model of a MAPK•Substrate Complex in an Active Conformation: A Computational and Experimental Approach

The mechanisms by which MAP kinases recognize and phosphorylate substrates are not completely understood. Efforts to understand the mechanisms have been compromised by the lack of MAPK-substrate structures. While MAPK-substrate docking is well established as a viable mechanism for bringing MAPKs and substrates into close proximity the molecular details of how such docking promotes phosphorylation is an unresolved issue. In the present study computer modeling approaches, with restraints derived from experimentally known interactions, were used to predict how the N-terminus of Ets-1 associates with ERK2. Interestingly, the N-terminus does not contain a consensus-docking site ((R/K)2-3-X2-6-ΦA-X-ΦB, where Φ is aliphatic hydrophobic) for ERK2. The modeling predicts that the N-terminus of Ets-1 makes important contributions to the stabilization of the complex, but remains largely disordered. The computer-generated model was used to guide mutagenesis experiments, which support the notion that Leu-11 and possibly Ile-13 and Ile-14 of Ets-1 1-138 (Ets) make contributions through binding to the hydrophobic groove of the ERK2 D-recruiting site (DRS). Based on the modeling, a consensus-docking site was introduced through the introduction of an arginine at residue 7, to give the consensus 7RK-X2-ΦA-X-ΦB13. This results in a 2-fold increase in kcat/Km for the phosphorylation of Ets by ERK2. Similarly, the substitution of the N-terminus for two different consensus docking sites derived from Elk-1 and MKK1 also improves kcat/Km by two-fold compared to Ets. Disruption of the N-terminal docking through deletion of residues 1-23 of Ets results in a 14-fold decrease in kcat/Km, with little apparent change in kcat. A peptide that binds to the DRS of ERK2 affects Km, but not kcat. Our kinetic analysis suggests that the unstructured N-terminus provides 10-fold uniform stabilization of the ground state ERK2•Ets•MgATP complex and intermediates of the enzymatic reaction

Primary gliosarcoma: key clinical and pathologic distinctions from glioblastoma with implications as a unique oncologic entity

This report presents the historical experience, clinical presentation, treatment, prognosis, and pathogenesis of gliosarcoma described to date in the English literature. PubMed query of term “gliosarcoma” was performed, followed by a rigorous review of cited literature. Articles selected for analysis included: (1) case reports of gliosarcoma, (2) review articles of gliosarcoma, and (3) studies of the pathogenesis or genetics of gliosarcoma in humans. Our review identified 219 cases of gliosarcoma in 34 reports and eight articles addressing the pathogenesis. Survival in larger series ranged 4–11.5 months. Features unique to gliosarcoma compared to glioblastoma (GBM) include their temporal lobe predilection, potential to appear similar to a meningioma at surgery, repeated reports of extracranial metastases, and infrequency of EGFR mutations. Published experience is limited to small case series, and the pathogenesis remains unclear. Clinical and pathologic characteristics distinct from GBM suggest that they may warrant specific treatment, separate from conventional GBM therapy