DLR Contribution to the First High Lift Prediction Workshop

DLR’s contribution to the first AIAA High Lift Prediction Workshop (HiLiftPW-1) covers computations of all three scheduled test cases for the NASA trapezoidal wing in high lift configuration. The DLR finite volume code TAU has been employed as the flow solver. In a standard set-up the one-equation turbulence model of Spalart and Allmaras in the original formulation is used to model effects of turbulence. For selected grids and flow conditions, the k-ω SST model of Menter and a differential Reynolds stress model (SSG/LLR-ω ) developed by DLR have been considered. DLR contributed with two hybrid unstructured grid families to the workshop. The grids have been generated with the grid generation packages Centaur and Solar. A grid family with three Solar grids has been generated and provided to the workshop featuring grids of 12·10^6 , 37·10^6 , and 111·10^6 points for test case 1. In addition, a Solar grid of 37·10^6 points has been provided for test case 2, and a grid of 40·10^6 for the configuration including the slat and flap brackets (test case 3). DLR didn’t succeed in generating a fine-grid with the Centaur package. In order to complete a Centaur grid family with three grid levels an extra-coarse grid has been provided. Thus, the three levels of the Centaur grid family are realized by grids of 13·10^6 , 16·10^6 , and 32·10^6 points. In general a go o d agreement between the experimental evidence and the polar computations on the Solar and Centaur grids is found in terms of forces, moments and wing pressure distributions. The wing tip area with the rearward part of the main wing and the flap represents the most challenging part of the configuration, especially at angles of attack around maximum lift. The deviations between the TAU solutions and the experimental data in this area are only weakly influenced by the different grid topologies or turbulence models used. The influence of the grid resolution of both grid families is comparable, taking into account the different absolute resolution levels of both grid families. Including the slat and flap brackets leads to the expected lift decrease. Concerning the convergence properties, a strong dependence on the numerical start-up procedure has been detected in many of the computations at higher angles of attack

Analysis procedures and subjective flight results of a simulator validation and cue fidelity experiment

A joint experiment to investigate simulator validation and cue fidelity was conducted by the Dryden Flight Research Facility of NASA Ames Research Center (Ames-Dryden) and NASA Langley Research Center. The primary objective was to validate the use of a closed-loop pilot-vehicle mathematical model as an analytical tool for optimizing the tradeoff between simulator fidelity requirements and simulator cost. The validation process includes comparing model predictions with simulation and flight test results to evaluate various hypotheses for differences in motion and visual cues and information transfer. A group of five pilots flew air-to-air tracking maneuvers in the Langley differential maneuvering simulator and visual motion simulator and in an F-14 aircraft at Ames-Dryden. The simulators used motion and visual cueing devices including a g-seat, a helmet loader, wide field-of-view horizon, and a motion base platform

A new pharmacogenetic algorithm to predict the most appropriate dosage of acenocoumarol for stable anticoagulation in a mixed Spanish population

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.There is a strong association between genetic polymorphisms and the acenocoumarol dosage requirements. Genotyping the polymorphisms involved in the pharmacokinetics and pharmacodynamics of acenocoumarol before starting anticoagulant therapy would result in a better quality of life and a more efficient use of healthcare resources. The objective of this study is to develop a new algorithm that includes clinical and genetic variables to predict the most appropriate acenocoumarol dosage for stable anticoagulation in a wide range of patients. We recruited 685 patients from 2 Spanish hospitals and 1 primary healthcare center. We randomly chose 80% of the patients (n = 556), considering an equitable distribution of genotypes to form the generation cohort. The remaining 20% (n = 129) formed the validation cohort. Multiple linear regression was used to generate the algorithm using the acenocoumarol stable dosage as the dependent variable and the clinical and genotypic variables as the independent variables. The variables included in the algorithm were age, weight, amiodarone use, enzyme inducer status, international normalized ratio target range and the presence of CYP2C9∗2 (rs1799853), CYP2C9∗3 (rs1057910), VKORC1 (rs9923231) and CYP4F2 (rs2108622). The coefficient of determination (R2) explained by the algorithm was 52.8% in the generation cohort and 64% in the validation cohort. The following R2 values were evaluated by pathology: atrial fibrillation, 57.4%; valve replacement, 56.3%; and venous thromboembolic disease, 51.5%. When the patients were classified into 3 dosage groups according to the stable dosage (<11 mg/week, 11-21 mg/week, >21 mg/week), the percentage of correctly classified patients was higher in the intermediate group, whereas differences between pharmacogenetic and clinical algorithms increased in the extreme dosage groups. Our algorithm could improve acenocoumarol dosage selection for patients who will begin treatment with this drug, especially in extreme-dosage patients. The predictability of the pharmacogenetic algorithm did not vary significantly between diseases.This study was funded by a grant from the Spanish Ministry of Health and Social Policy (Instituto de Salud Carlos III, PI07/0710) and the Andalusian Regional Ministry of Health (Progress and Health Foundation, PI-0717-2013

The use of intravascular ultrasound imaging to improve use of inferior vena cava filters in a high-risk bariatric population

ObjectivePulmonary embolism is the leading cause of death after gastric bypass procedures for obesity, approximating 0.5% to 4%. All bariatric patients, but especially the super-obese, which have a body mass index (BMI) >50 kg/m2, are at significant risk for postoperative venous thromboembolism (VTE). Visualization and weight limitations of fluoroscopy tables exclude most bariatric and all super-obese patients from inferior vena cava (IVC) filter placement using fluoroscopy. Intravascular ultrasound (IVUS)-guided IVC filter placement is the only modality that allows these high-risk patients to have an IVC filter placed.MethodsHospital and outpatient records of the 494 patients who underwent gastric bypass procedures from January 1, 2004, to May 31, 2006, were reviewed. All patients who had concurrent IVC filter placement with the use of IVUS guidance were selected. Comorbidities, outcomes, and complications were recorded.ResultsWe identified 27 patients with mean BMI of 70 ± 3 kg/m2; of these, 25 were super-obese (BMI >50 kg/m2). Procedures included five laparoscopic and 22 open gastric bypass operations. All patients underwent concurrent IVC filter placement using IVUS guidance. In addition to super-obesity, indications for IVC filter placement included history of VTE (n = 4), known hypercoagulable state (n = 2), and profound immobility (n = 21). Mean follow up was 293 ± 40 days. Technical success rate was 96.3%. There were no catheter site complications. In one surviving patient, a nonfatal pulmonary embolism was detected by computed tomography 2 months postoperatively. Two patients died, and autopsy excluded VTE as the cause of death in both.ConclusionThis study suggests efficacy of IVUS-guided IVC filter placement in preventing mortality from pulmonary embolism in high-risk bariatric patients, including the super-obese. IVUS-guided IVC filter placement can be safely performed with an excellent success rate in all bariatric patients, including the super-obese, who otherwise would not be candidates for IVC filter placement due to the limitations imposed by their large body habitus

Network Meta-analysis on Disconnected Evidence Networks When Only Aggregate Data Are Available:Modified Methods to Include Disconnected Trials and Single-Arm Studies while Minimizing Bias

BACKGROUND: Network meta-analysis (NMA) requires a connected network of randomized controlled trials (RCTs) and cannot include single-arm studies. Regulators or academics often have only aggregate data. Two aggregate data methods for analyzing disconnected networks are random effects on baseline and aggregate-level matching (ALM). ALM has been used only for single-arm studies, and both methods may bias effect estimates. METHODS: We modified random effects on baseline to separate RCTs connected to and disconnected from the reference and any single-arm studies, minimizing the introduction of bias. We term our modified method reference prediction. We similarly modified ALM and extended it to include RCTs disconnected from the reference. We tested these methods using constructed data and a simulation study. RESULTS: In simulations, bias for connected treatments for ALM ranged from −0.0158 to 0.051 and for reference prediction from −0.0107 to 0.083. These were low compared with the true mean effect of 0.5. Coverage ranged from 0.92 to 1.00. In disconnected treatments, bias of ALM ranged from −0.16 to 0.392 and of reference prediction from −0.102 to 0.40, whereas coverage of ALM ranged from 0.30 to 0.82 and of reference prediction from 0.64 to 0.94. Under fixed study effects for disconnected evidence, bias was similar, but coverage was 0.81 to 1.00 for reference prediction and 0.18 to 0.76 for ALM. Trends of similar bias but greater coverage for reference prediction with random study effects were repeated in constructed data. CONCLUSIONS: Both methods with random study effects seem to minimize bias in treatment connected to the reference. They can estimate treatment effects for disconnected treatments but may be biased. Reference prediction has greater coverage and may be recommended overall. HIGHLIGHTS: Two methods were modified for network meta-analysis on disconnected networks and for including single-arm observational or interventional studies in network meta-analysis using only aggregate data and for minimizing the bias of effect estimates for treatments only in trials connected to the reference. Reference prediction was developed as a modification of random effects on baseline that keeps analyses of trials connected to the reference separately from those disconnected from the reference and from single-arm studies. The method was further modified to account for correlation in trials with more than 2 arms and, under random study effects, to estimate variance in heterogeneity separately in connected and disconnected evidence. Aggregate-level matching was extended to include trials disconnected from the reference, rather than only single-arm studies. The method was further modified to separately estimate treatment effects and heterogeneity variance in the connected and disconnected evidence and to account for the correlation between arms in trials with more than 2 arms. Performance was assessed using a constructed data example and simulation study. The methods were found to have similar, and sometimes low, bias when estimating the relative effects for disconnected treatments, but reference prediction with random study effects had the greatest coverage. The use of reference prediction with random study effects for disconnected networks is recommended if no individual patient data or alternative real-world evidence is available

Directly Acting Oral Anticoagulants for the Prevention of Stroke in Atrial Fibrillation in England and Wales:Cost-Effectiveness Model and Value of Information Analysis

Objectives. Determine the optimal, licensed, first-line anticoagulant for prevention of ischemic stroke in patients with non-valvular atrial fibrillation (AF) in England and Wales from the UK National Health Service (NHS) perspective and estimate value to decision making of further research. Methods. We developed a cost-effectiveness model to compare warfarin (international normalized ratio target range 2–3) with directly acting (or non–vitamin K antagonist) oral anticoagulants (DOACs) apixaban 5 mg, dabigatran 150 mg, edoxaban 60 mg, and rivaroxaban 20 mg, over 30 years post treatment initiation. In addition to death, the 17-state Markov model included the events stroke, bleed, myocardial infarction, and intracranial hemorrhage. Input parameters were informed by systematic literature reviews and network meta-analysis. Expected value of perfect information (EVPI) and expected value of partial perfect information (EVPPI) were estimated to provide an upper bound on value of further research. Results. At willingness-topay threshold £20,000, all DOACs have positive expected incremental net benefit compared to warfarin, suggesting they are likely cost-effective. Apixaban has highest expected incremental net benefit (£7533), followed by dabigatran (£6365), rivaroxaban (£5279), and edoxaban (£5212). There was considerable uncertainty as to the optimal DOAC, with the probability apixaban has highest net benefit only 60%. Total estimated population EVPI was £17.94 million (17.85 million, 18.03 million), with relative effect between apixaban versus dabigatran making the largest contribution with EVPPI of £7.95 million (7.66 million, 8.24 million). Conclusions. At willingness-to-pay threshold £20,000, all DOACs have higher expected net benefit than warfarin but there is considerable uncertainty between the DOACs. Apixaban had the highest expected net benefit and greatest probability of having highest net benefit, but there is considerable uncertainty between DOACs. A head-to-head apixaban versus dabigatran trial may be of value

Novel antiviral strategies for feline coronavirus and feline calicivirus

Feline coronavirus (FCoV) and feline calicivirus (FCV) commonly infect domestic cats, and are an important cause of morbidity and mortality. There are currently no effective antiviral agents for these pathogens. Studies reported herein attempt address this therapeutic shortfall through the testing of a panel of small molecule compounds and specifically designed small interfering RNAs (siRNAs) for antiviral effects against both viruses. Initial compound screening identified chloroquine, mefloquine, and hexamethylene amiloride as effective inhibitors of FCoV, whilst mefloquine effectively inhibited FCV. Efficacy at low micromolar concentration was confirmed with orthogonal testing, albeit with relatively narrow selective indices. Preliminary experiments performed to inform the antiviral mechanism of the compounds against FCoV demonstrated all three compounds acted at an early stage of viral replication. For FCV, mefloquine exhibited potent inhibition of a panel of recent field isolates and demonstrated additive effects in combination with recombinant feline interferon omega. For both FCoV and FCV, a number of siRNAs demonstrated potent and specific inhibition of viral replication. These were effective at low nanomolar concentrations, when used in combination, and against high viral loads. A structural siRNA variant, Dicer-substrate siRNA, demonstrated similar or better efficacy, depending on the target, over canonical siRNAs directed at the same FCoV motif. Limitations of antiviral siRNAs in terms of antiviral resistance were investigated. FCoV serially passaged through siRNA treated cells rapidly acquired resistance, however combination therapy with three siRNAs was able to delay this considerably. For FCV, siRNAs effective against the reference strain were broadly efficacious against field isolates, although some variability was noted. Taken together these results provide important information regarding potential antiviral therapies against these important pathogens

Novel antiviral strategies for feline coronavirus and feline calicivirus

Feline coronavirus (FCoV) and feline calicivirus (FCV) commonly infect domestic cats, and are an important cause of morbidity and mortality. There are currently no effective antiviral agents for these pathogens. Studies reported herein attempt address this therapeutic shortfall through the testing of a panel of small molecule compounds and specifically designed small interfering RNAs (siRNAs) for antiviral effects against both viruses. Initial compound screening identified chloroquine, mefloquine, and hexamethylene amiloride as effective inhibitors of FCoV, whilst mefloquine effectively inhibited FCV. Efficacy at low micromolar concentration was confirmed with orthogonal testing, albeit with relatively narrow selective indices. Preliminary experiments performed to inform the antiviral mechanism of the compounds against FCoV demonstrated all three compounds acted at an early stage of viral replication. For FCV, mefloquine exhibited potent inhibition of a panel of recent field isolates and demonstrated additive effects in combination with recombinant feline interferon omega. For both FCoV and FCV, a number of siRNAs demonstrated potent and specific inhibition of viral replication. These were effective at low nanomolar concentrations, when used in combination, and against high viral loads. A structural siRNA variant, Dicer-substrate siRNA, demonstrated similar or better efficacy, depending on the target, over canonical siRNAs directed at the same FCoV motif. Limitations of antiviral siRNAs in terms of antiviral resistance were investigated. FCoV serially passaged through siRNA treated cells rapidly acquired resistance, however combination therapy with three siRNAs was able to delay this considerably. For FCV, siRNAs effective against the reference strain were broadly efficacious against field isolates, although some variability was noted. Taken together these results provide important information regarding potential antiviral therapies against these important pathogens