Repeated extreme heatwaves result in higher leaf thermal tolerances and greater safety margins

2021 ◽  
Author(s):  
Collin W Ahrens ◽  
Anthea Challis ◽  
Margaret Byrne ◽  
Andrea Leigh ◽  
Adrienne B. Nicotra ◽  
...  
Keyword(s):  
Safety Margins

Accuracy of robot-assisted versus optical frameless navigated stereoelectroencephalography electrode placement in children

2019 ◽  
Vol 23 (3) ◽  
pp. 297-302 ◽  
Author(s):  
Julia D. Sharma ◽  
Kiran K. Seunarine ◽  
Muhammad Zubair Tahir ◽  
Martin M. Tisdall
Keyword(s):  
Soft Tissue ◽  
Entry Point ◽  
Electrode Placement ◽  
Target Point ◽  
Localization Error ◽  
Bone Thickness ◽  
Tissue Thickness ◽  
Robot Assisted ◽  
Soft Tissue Thickness ◽  
Safety Margins

OBJECTIVEThe aim of this study was to compare the accuracy of optical frameless neuronavigation (ON) and robot-assisted (RA) stereoelectroencephalography (SEEG) electrode placement in children, and to identify factors that might increase the risk of misplacement.METHODSThe authors undertook a retrospective review of all children who underwent SEEG at their institution. Twenty children were identified who underwent stereotactic placement of a total of 218 electrodes. Six procedures were performed using ON and 14 were placed using a robotic assistant. Placement error was calculated at cortical entry and at the target by calculating the Euclidean distance between the electrode and the planned cortical entry and target points. The Mann-Whitney U-test was used to compare the results for ON and RA placement accuracy. For each electrode placed using robotic assistance, extracranial soft-tissue thickness, bone thickness, and intracranial length were measured. Entry angle of electrode to bone was calculated using stereotactic coordinates. A stepwise linear regression model was used to test for variables that significantly influenced placement error.RESULTSBetween 8 and 17 electrodes (median 10 electrodes) were placed per patient. Median target point localization error was 4.5 mm (interquartile range [IQR] 2.8–6.1 mm) for ON and 1.07 mm (IQR 0.71–1.59) for RA placement. Median entry point localization error was 5.5 mm (IQR 4.0–6.4) for ON and 0.71 mm (IQR 0.47–1.03) for RA placement. The difference in accuracy between Stealth-guided (ON) and RA placement was highly significant for both cortical entry point and target (p < 0.0001 for both). Increased soft-tissue thickness and intracranial length reduced accuracy at the target. Increased soft-tissue thickness, bone thickness, and younger age reduced accuracy at entry. There were no complications.CONCLUSIONSRA stereotactic electrode placement is highly accurate and is significantly more accurate than ON. Larger safety margins away from vascular structures should be used when placing deep electrodes in young children and for trajectories that pass through thicker soft tissues such as the temporal region.

scholarly journals Bootstrap and Order Statistics for Quantifying Thermal-Hydraulic Code Uncertainties in the Estimation of Safety Margins

2008 ◽  
Vol 2008 ◽  
pp. 1-9 ◽  
Author(s):  
Enrico Zio ◽  
Francesco Di Maio
Keyword(s):  
Confidence Interval ◽  
Order Statistics ◽  
Nuclear Reactor ◽  
Safety Margin ◽  
Fuel Cladding ◽  
Complete Group ◽  
Bootstrap Technique ◽  
Safety Margins ◽  
Group Distribution

In the present work, the uncertainties affecting the safety margins estimated from thermal-hydraulic code calculations are captured quantitatively by resorting to the order statistics and the bootstrap technique. The proposed framework of analysis is applied to the estimation of the safety margin, with its confidence interval, of the maximum fuel cladding temperature reached during a complete group distribution blockage scenario in a RBMK-1500 nuclear reactor.

613 HER2-XPAT, a novel protease-activatable prodrug T cell engager (TCE), with potent T-cell activation and efficacy in solid tumors and large predicted safety margins in non-human primate (NHP)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A649-A649
Author(s):  
Fiore Cattaruzza ◽  
Ayesha Nazeer ◽  
Zachary Lange ◽  
Caitlin Koski ◽  
Mikhail Hammond ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytokine Production ◽  
Antigenic Specificity ◽  
The Core ◽  
Protease Cleavage ◽  
Safety Margins

BackgroundTCEs are effective in leukemias but have been challenging in solid tumors due to on-target, off-tumor toxicity. Attempts to circumvent CRS include step-up dosing and/or complex designs but are unsuccessful due to toxicity and/or enhanced immunogenicity. HER2-XPAT, or XTENylated Protease-Activated bispecific T-Cell Engager, is a prodrug TCE that exploits the protease activity present in tumors vs. healthy tissue to expand the therapeutic index (TI). The core of the HER2-XPAT (PAT) consists of 2 tandem scFvs targeting CD3 and HER2. Attached to the core, two unstructured polypeptide masks (XTEN) sterically reduce target engagement and extend T1/2. Protease cleavage sites at the base of the XTEN masks enable proteolytic activation of XPATs in the tumor microenvironment, unleashing a potent TCE with short T1/2, further improving the TI. HER2-XPAT, a tumor protease-activatable prodrug with wide safety margins, can co-opt T-cells regardless of antigenic specificity to induce T-cell killing of HER2+ tumors.MethodsPreclinical studies were conducted to characterize the activity of HER2-XPAT, HER2-PAT (cleaved XPAT), and HER2-NonClv (a non-cleavable XPAT) for cytotoxicity in vitro, for anti-tumor efficacy in xenograft models, and for safety in NHPs.ResultsHER2-PAT demonstrated potent in vitro T-cell cytotoxicity (EC50 1-2pM) and target-dependent T-cell activation and cytokine production by hPBMCs. HER2-XPAT provided up to 14,000-fold protection against killing of HER2 tumor cells and no cytotoxicity against cardiomyocytes up to 1uM. In vivo, HER2-XPAT induced complete tumor regressions in BT-474 tumors with equimolar dosing to HER2-PAT, whereas HER2-NonClv had no efficacy, supporting requirement of protease cleavage for T-cell activity. In NHP, HER2-XPAT has been dose-escalated safely up to 42mg/kg (MTD). HER2-XPAT demonstrated early T-cell margination at 2 mg/kg but largely spared CRS, cytokine production, and tissue toxicity up to 42 mg/kg. PK profiles of HER2-XPAT and HER2-NonClv were comparable, consistent with ex vivo stability for cleavage when incubated in cancer pts plasma for 7 days at 37°C. HER2-PAT by continuous infusion induced lethal CRS and cytokine spikes at 0.3 mg/kg/d but was tolerated at 0.25 mg/kg/d, providing HER2-XPAT with >1300-fold protection in tolerability vs. HER2-PAT, >4 logs over cytotoxicity EC50s for HER2 cell lines, and a 20-fold safety margin over the dose required for pharmacodynamic activity.ConclusionsHER2-XPAT is a potent prodrug TCE with no CRS and a wide TI based on NHPs. With XTEN’s clinical data demonstrating low immunogenicity, the XPATs are a promising solution. IND studies are ongoing. Additional PK/PD, cytokines, safety, and efficacy data will be presented.

scholarly journals A Novel Benzopyrane Derivative Targeting Cancer Cell Metabolic and Survival Pathways

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2840
Author(s):  
Dana M. Zaher ◽  
Wafaa S. Ramadan ◽  
Raafat El-Awady ◽  
Hany A. Omar ◽  
Fatema Hersi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cancer Cell ◽  
Xenograft Model ◽  
Mitochondrial Metabolism ◽  
High Dose ◽  
Anticancer Effect ◽  
Safety Margins ◽  
Wide Range

(1) Background: Today, the discovery of novel anticancer agents with multitarget effects and high safety margins represents a high challenge. Drug discovery efforts indicated that benzopyrane scaffolds possess a wide range of pharmacological activities. This spurs on building a skeletally diverse library of benzopyranes to identify an anticancer lead drug candidate. Here, we aim to characterize the anticancer effect of a novel benzopyrane derivative, aiming to develop a promising clinical anticancer candidate. (2) Methods: The anticancer effect of SIMR1281 against a panel of cancer cell lines was tested. In vitro assays were performed to determine the effect of SIMR1281 on GSHR, TrxR, mitochondrial metabolism, DNA damage, cell cycle progression, and the induction of apoptosis. Additionally, SIMR1281 was evaluated in vivo for its safety and in a xenograft mice model. (3) Results: SIMR1281 strongly inhibits GSHR while it moderately inhibits TrxR and modulates the mitochondrial metabolism. SIMR1281 inhibits the cell proliferation of various cancers. The antiproliferative activity of SIMR1281 was mediated through the induction of DNA damage, perturbations in the cell cycle, and the inactivation of Ras/ERK and PI3K/Akt pathways. Furthermore, SIMR1281 induced apoptosis and attenuated cell survival machinery. In addition, SIMR1281 reduced the tumor volume in a xenograft model while maintaining a high in vivo safety profile at a high dose. (4) Conclusions: Our findings demonstrate the anticancer multitarget effect of SIMR1281, including the dual inhibition of glutathione and thioredoxin reductases. These findings support the development of SIMR1281 in preclinical and clinical settings, as it represents a potential lead compound for the treatment of cancer.

Component and Integration Test of an FPGA-Based PWR Protection Sub-System Using UVM

2017 ◽  
Author(s):  
Xuanxuan Shui ◽  
Yichun Wu ◽  
Junyi Zhou ◽  
Yuanfeng Cai
Keyword(s):  
Nuclear Power ◽  
Power Industry ◽  
Nuclear Power Industry ◽  
Normal Operation ◽  
Static Timing Analysis ◽  
Specific Test ◽  
Pressurized Water ◽  
Safety Margins ◽  
Integration Test ◽  
Test Process

Field programmable gate arrays (FPGAs) have drawn wide attention from nuclear power industry for digital instrument and control applications (DI&C), because it’s much easier and simpler than microprocessor-based applications, which makes it more reliable. FPGAs can also enhance safety margins of the plant with potential possibility for power upgrading at normal operation. For these reasons, more and more nuclear power corporations and research institutes are treating FPGA-based protection system as a technical alternative. As nuclear power industry requires high reliability and safety for DI&C Systems, the development method and process should be fully verified and validated. For this reason, to improve the application of FPGA in NPP I&C system, the specific test methods are critical for the developers and regulators. However, current international standards and research reports, like IEC 62566 and NUREG/CR-7006, which have demonstrated the life circle of the development of FPGA-based safety critical DI&C in NPPs, but the specific test requirements and methods which are significant to the developers are not provided. In this paper, the whole test process of a pressurized water reactor (PWR) protection sub-system (Primary Coolant Flow Low Protection, Over Temperature Delta T Protection, Over Power Delta T Protection) is described, including detail component and integration tests. The Universal Verification Methodology (UVM) based on System Verilog class libraries is applied to establish the verification test platform. All these tests are conducted in a simulation environment. The test process is driven by the test coverage which includes code coverages (i.e., Statement, Branch, Condition and Expression, Toggle, Finite State Machine) and function coverage. Specifically, Register Transaction Level (RTL) simulation is conducted for Component tests, while RTL simulation, Gate Level simulation, Timing simulation and Static timing analysis are conducted for the integration test. The issues (e.g., the floating point calculation, FPGA resource allocation and optimization) arose in the test process are also analyzed and discussed, which can be references for the developers in this area. The component and integration tests are part of the Verification and Validation (V&V) work, which should be done by the V&V team separated from the development team. The testing method could assure the test results reliable and authentic. It is practical and useful for the development and V&V of FPGA-based safety DI&C systems.

Pharmacokinetic and toxicology assessment of INTERCEPT (S-59 and UVA treated) platelets

2001 ◽  
Vol 20 (10) ◽  
pp. 533-550 ◽  
Author(s):  
V Ciaravino ◽  
T McCullough ◽  
A D Dayan
Keyword(s):  
Ex Vivo ◽  
Reproductive Toxicity ◽  
In Vivo Studies ◽  
Pathogen Inactivation ◽  
Platelet Concentrates ◽  
Baxter Healthcare ◽  
Safety Margins ◽  
Toxicology Assessment

The pathogen inactivation process developed by Cerus and Baxter Healthcare Corporations uses the psoralen, S-59 (amotosalen) in an ex vivo photochemical treatment (PCT) process to inactivate viruses, bacteria, protozoans, and leukocytes in platelet concentrates and plasma. Studies were performed by intravenous infusion of S-59 PCT formulations-compound adsorption device (CAD) treatment and with non-UVA illuminated S-59, using doses that were multiples of potential clinical exposures. The studies comprised full pharmacokinetic, single and repeated-dose (up to 13 weeks duration) toxicity, safety pharmacology (CNS, renal, and cardiovascular), reproductive toxicity, genotoxicity, carcinogenicity testing in the p53- mouse, vein irritation, and phototoxicity. No specific target organ toxicity (clinical or histopathological), reproductive toxicity, or carcinogenicity was observed. S-59 and/or PCT formulations demonstrated CNS, ECG, and phototoxicity only at supraclinical doses. Based on the extremely large safety margins (>30,000 fold expected clinical exposures), the CNS and ECG observations are not considered to have any toxicological relevance. Additionally, after a complete assessment, mutagenicity and phototoxicity results are not considered relevant for the proposed use of INTERCEPT platelets. Thus, the results of an extensive series of in vitro and in vivo studies have not demonstrated any toxicologically relevant effects of platelet concentrates prepared by the INTERCEPT system.

scholarly journals Combining Response Surface Optimization and Stochastic Analysis for Crashworthiness Design – an Introductory Study

2001 ◽  
Vol 8 (1) ◽  
pp. 21-31 ◽  
Author(s):  
Lars A. Fredriksson ◽  
Uwe Schramm
Keyword(s):  
Response Surface ◽  
Stochastic Analysis ◽  
Cost Effective ◽  
Initial Study ◽  
Dynamic Responses ◽  
Stochastic Methods ◽  
Explicit Finite Element ◽  
Transient Dynamic ◽  
Response Surface Optimization ◽  
Safety Margins

Objective of the design process are cost effective designs that meet certain expectations with respect to functionality and appearance. Designs are created in an iterative process where analyses of the structural behavior lead to changes in the design. The use of optimization technology makes design changes to be driven directly by analysis results. The application of optimization allows an efficient search for the right combination of design variables for a certain design. Additional use of stochastic methods in order to analyze the design from a statistical standpoint adds robustness to the design and prevents unpleasant surprises in later physical testing.This paper discusses methodology to optimize structures that undergo impact loading. Objective and constraints are transient dynamic responses. The optimization problem is solved using a sequential response surface method. An explicit finite element code is used to solve the transient dynamic problem. The optimization is not performed on results from single simulations but on statistical results from a stochastic analysis. The stochastic analysis is driven using a Monte Carlo method. Commercial software is used for the implementation of the methodology.The results from the study indicate that a combination of optimization and stochastic analysis can add safety margins to a design with respect to robustness against physical errors in the design itself and against changes in load levels and load cases. However, this initial study must be followed up by more in-depth investigations to fully understand the benefits of combined optimization-stochastic analysis.

Rational Design of Novel Materials From Polymer Microrheology

2010 ◽  
Author(s):  
Rodrigo E. Teixeira ◽  
Richard S. Graham
Keyword(s):  
Rational Design ◽  
Molecular Level ◽  
Pressure Vessels ◽  
Novel Materials ◽  
Entangled Polymers ◽  
Stochastic Fluctuations ◽  
Safety Margins ◽  
Polymer Liquids ◽  
Entangled Polymer ◽  
High Degree

The visco-elastic properties of entangled polymer liquids arise from molecular-scale topological interactions and stochastic fluctuations under flow. Here, the evolutions of individual entangled polymers were observed in rheologically relevant shear flow histories. We uncover a high degree of molecular individualism and broad conformational distributions resulting from incessant stretch-collapse cycles. The data and insights of the present study may lead to improved molecular-level models and constitutive equations. These tools, in turn, may enable the rational design of novel materials with properties tailored to accomplish specific tasks such as high-pressure vessels and piping with greater safety margins and cost-effectiveness.

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