Analysis and Simulation of Tandem Charge

In the present work, the PG-7 (40mm) anti-tank hollow charge has been developed to double (tandem) hollow charge warhead by using a simulation program. The interaction of the precursor warhead with the Explosive Reactive Armor ERA was studied and the delayed time between the precursor head and the main charge was found which about 50 µs is with 350 mm penetration depth. The effect of precursor charge on the main charge was also studied and this effect was isolated in the delay period, in addition to the effect of precursor warhead jetting on the rear warhead the optimum delay time was found. This study was carried out using the ANSYS AUTODYN simulation program. And the model worked in several ways to reach these goals.

Is There a Higher Incidence of Graft Failure or Delayed Time to Engraftment in Patients Undergoing Autologous Stem Cell Transplantation Who Receive Olanzapine for Anti-Emetic Prophylaxis?

Olanzapine has been shown to significantly decrease nausea and emetic episodes associated with chemotherapy in patients undergoing hematopoietic stem cell transplant (Monson, Greer, Kreikemeier, & Liewer, 2020). Additionally, Olanzapine has been shown to improve clinical outcomes in autologous stem cell transplant patients when added to triplet anti-emetic therapy of ondansetron, fosaprepitant and dexamethasone without any negative effects on time to engraftment (Clemmons, et al., 2018). Although this study did not show any delay in time to engraftment, there is only a small amount of data looking at this question, including Clemmons et al. (2016) and Trifilio et al. (2017). Other studies (Navari et al., 2016) demonstrated a decrease in chemotherapy related nausea and vomiting in patients receiving Olanzapine, but did not provide data on engraftment times as this was in standard chemotherapy recipients. At Colorado Blood Cancer Institute (CBCI), Olanzapine was used for a period of time for anti-emetic prophylaxis both pre and post autologous stem cell transplant. There was concern regarding whether or not Olanzapine was causing delays in time to engraftment or even potentially graft failure and use of the drug in transplant anti-emetic regimens was discontinued. We hypothesized that Olanzapine does not cause higher incidence of graft failure, as compared to patients who do not receive Olanzapine as part of their anti-emetic regimen during the pre and post autologous stem cell transplant period. A retrospective analysis (n = 272) was conducted on patients who underwent autologous stem cell transplant between 2019 and 2020. 134 of these patients received Olanzapine during conditioning and up until time of engraftment, and 138 patients had no Olanzapine exposure throughout their conditioning and transplant. Conditioning regimens were equal between the two groups (Table 1). The average number of days on Olanzapine was 10.7, and the average dose was 7.5mg daily. For the purposes of this study engraftment was defined as the first day post stem cell infusion that the patient had an absolute neutrophil count (ANC) of greater than or equal to 500. Findings showed that the mean day of engraftment in the patients with Olanzapine exposure was 14.69; in the non-Olanzapine group, the mean day of engraftment was 12.64 (Table 2). Using the two-sample t-test, this difference (2.05 days, 95% CI (1.60-2.51)) is significant (p<.0001). Based on our findings, there is evidence to support Olanzapine causing a slightly delayed time to engraftment in autologous stem cell transplant patients, but not a higher incidence of graft failure, although a randomized controlled trial would be needed to fully investigate. There is clear data showing increased ability to manage chemo therapy induced nausea and vomiting. While a randomized controlled trial would be needed to fully investigate, given there is not a proven increase in graft failure, Olanzapine should be considered as a desirable option to treat and prevent chemotherapy induced nausea and vomiting in autologous stem cell transplant patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Olanzapine (Zyprexa) - Used off-label for the treatment and prevention of chemotherapy induced nausea and vomiting

Protection of β2GPI Deficient Mice from Thrombosis May Reflect a Platelet Activation Defect

Introduction Antiphospholipid syndrome (APS) is an autoimmune disorder caused by "antiphospholipid" antibodies (aPL) directed against β2-glycoprotein I (β2GPI). Although β2GPI is proposed to have both anti- and procoagulant properties in vitro, its physiological role in coagulation in vivo is not well understood. Previous studies have shown that β2GPI deficient mice display impaired thrombin generation but failed to demonstrate an anticoagulant role in vivo. Recent findings from our laboratory demonstrated that β2GPI-deficient mice (APOH -/-) developed by CRISPR/Cas9 had shown delayed time to thrombosis as evidenced by prolonged clotting times in carotid artery occlusion models. However, no mechanism was identified for the delayed time to thrombosis phenotype. Methods Venous thrombosis by complete occlusion of the IVC was performed as described previously (Wrobleski et al., 2011). In brief, an abdominal incision was made on anesthetized mice to visualize IVC. The activated partial thromboplastin time (aPTT); prothrombin time (PT) and Tissue factor-induced thrombin generation time (TGT) were performed as described previously (Stavrou et al., 2014). Protein C activity was performed according to manufacturer's recommendations (Chromogenix Coamatic® Protein C, Diapharma). To assess platelet activation, platelets were isolated under resting conditions using retro-orbital blood and the final washed platelet pellet was resuspended in Tyrodes solution. Platelets were stimulated with 0.25 U/ml thrombin and incubated with 1 µL of CD62P-FITC or Oregon Green conjugated-fibrinogen for 30 minutes. Platelets were fixed with 100 μL 2% formalin, and quantification of platelet surface P-selectin and fibrinogen binding to activated platelet GPIIb/IIIa was performed by flow cytometry (Accuri Flow Cytometer, BD Biosciences). For mouse tail vein bleeding time assays, mice were anesthetized and the tail transected approximately 5 mm from the tip. The tail was then placed in a 50 ml falcon tube containing saline pre-warmed to 37°C. The time to cessation of bleeding was determined visually. All experiments were performed on 8-12 week old mice. Results aPTT and PT results for APOH +/+ and APOH -/- mice were 41.82 ± 1.174 and 41.38 ± 2.026 seconds, and 14.55 ± 2.262 and 11.30 ± 0.578 seconds, respectively (NS). After IVC ligation, thrombi in APOH -/- mice had a mean weight of 16.94 ± 1.782 mg compared to 27.69 ± 1.725 mg in APOH +/+ mice littermates (P = 0.0002, Figure A). Thrombin generation induced by either tissue factor or aPPT reagent showed peak thrombin generation at 15 min with no difference between APOH +/+ and APOH -/- mice. Likewise, no significant differences were observed in percent Protein C activity levels between APOH +/+ (8.058 ± 1.433) and APOH -/- (6.453 ± 0.924). Stimulation with 0.25 U/ml thrombin resulted in significantly greater expression of P-selectin) on platelets of APOH +/+ (161.3 ± 30.62 MFI) compared to those from APOH -/- mice (54.47 ± 9.721 MFI) (P= 0.0101;Figure 1B). Likewise, there was significantly greater fibrinogen binding to stimulated platelets from APOH +/+ (129.7 ± 32.21 MFI) compared to APOH-/- mice (35.30 ± 2.144 MFI) with P = 0.0111 (Figure 1C). Finally, consistent with platelet activation studies, tail vein bleeding times were mildly, but significantly prolonged in APOH -/- mice (192.3 ± 45.86 sec) compared to APOH+/+ mice (95.14 ± 9.582 sec) with P = 0.. Conclusion The effects of β2GPI, if any, on coagulation processes is controversial, and has not been thoroughly studied in β2GPI deficient animals. The results presented here suggest that the smaller thrombi that form in mice deficient in β2GPI following IVC occlusion may reflect a mild platelet function defect. This hypothesis is supported by diminished P-selectin expression and fibrinogen binding in response to 0.25 U/ml thrombin by platelets from β2GPI deficient mice compared to wild-type littermates. Moreover, tail vein bleeding times were mildly prolonged in β2GPI deficient mice. Taken together, these studies suggest that β2GPI may actually contribute to hemostasis by supporting platelet responses to low concentrations of thrombin. Additional studies are needed to characterize these effects in detail. Figure 1 Figure 1. Disclosures McCrae: Sanofi, Novartis, Alexion, and Johnson & Johnson: Consultancy, Honoraria; Dova, Novartis, Rigel, and Sanofi Genzyme: Consultancy.

Time-Based Decision Making for Reperfusion in Acute Ischemic Stroke

Decision making in the extended time windows for acute ischemic stroke can be a complex and time-consuming process. The process of making the clinical decision to treat has been compounded by the availability of different imaging modalities. In the setting of acute ischemic stroke, time is of the essence and chances of a good outcome diminish by each passing minute. Navigating the plethora of advanced imaging modalities means that treatment in some cases can be inefficaciously delayed. Time delays and individually based non-programmed decision making can prove challenging for clinicians. Visual aids can assist such decision making aimed at simplifying the use of advanced imaging. Flow charts are one such visual tool that can expedite treatment in this setting. A systematic review of existing literature around imaging modalities based on site of occlusion and time from onset can be used to aid decision making; a more program-based thought process. The use of an acute reperfusion flow chart helping navigate the myriad of imaging modalities can aid the effective treatment of patients.

Genetics, Immunity and Nutrition Boost the Switching from NASH to HCC

Nonalcoholic fatty liver disease (NAFLD) is the leading contributor to the global burden of chronic liver diseases. The phenotypic umbrella of NAFLD spans from simple and reversible steatosis to nonalcoholic steatohepatitis (NASH), which may worsen into cirrhosis and hepatocellular carcinoma (HCC). Notwithstanding, HCC may develop also in the absence of advanced fibrosis, causing a delayed time in diagnosis as a consequence of the lack of HCC screening in these patients. The precise event cascade that may precipitate NASH into HCC is intricate and it entails diverse triggers, encompassing exaggerated immune response, endoplasmic reticulum (ER) and oxidative stress, organelle derangement and DNA aberrancies. All these events may be accelerated by both genetic and environmental factors. On one side, common and rare inherited variations that affect hepatic lipid remodeling, immune microenvironment and cell survival may boost the switching from steatohepatitis to liver cancer, on the other, diet-induced dysbiosis as well as nutritional and behavioral habits may furtherly precipitate tumor onset. Therefore, dietary and lifestyle interventions aimed to restore patients’ health contribute to counteract NASH progression towards HCC. Even more, the combination of therapeutic strategies with dietary advice may maximize benefits, with the pursuit to improve liver function and prolong survival.

Indeterminate and Enriched Propositions in Context Linger: Evidence From an Eye-Tracking False Memory Paradigm

A sentence such as We finished the paper is indeterminate with regards to what we finished doing with the paper. Indeterminate sentences constitute a test case for two major issues regarding language comprehension: (1) how we compose sentence meaning; and (2) what is retained in memory about what we read in context over time. In an eye-tracking experiment, participants read short stories that were unexpectedly followed by one of three recognition probes: (a) an indeterminate sentence (Lisa began the book), that is identical to the one in the story; (b) an enriched but false probe (Lisa began reading the book); and (c) a contextually unrelated probe (Lisa began writing the book). The probes were presented either at the offset of the original indeterminate sentence in context or following additional neutral discourse. We measured accuracy, probe recognition time, and reading times of the probe sentences. Results showed that, at the immediate time point, participants correctly accepted the identical probes with high accuracy and short recognition times, but that this effect reversed to chance-level accuracy and significantly longer recognition times at the delayed time point. We also found that participants falsely accept the enriched probe at both time points 50% of the time. There were no reading-time differences between identical and enriched probes, suggesting that enrichment might not be an early, mandatory process for indeterminate sentences. Overall, results suggest that while context produces an enriched proposition, an unenriched proposition true to the indeterminate sentence also lingers in memory.