On the adjoint solution of the quasi-1D Euler equations: the effect of boundary conditions and the numerical flux function

This work compares a numerical and analytical adjoint equation method with respect to boundary condition treatments applied to the quasi-1D Euler equations. The effect of strong and weak boundary conditions and the effect of flux evaluators on the numerical adjoint solution near the boundaries are discussed

Rolofylline, an adenosine A1−receptor antagonist, in acute heart failure

Background: Worsening renal function, which is associated with adverse outcomes, often develops in patients with acute heart failure. Experimental and clinical studies suggest that counterregulatory responses mediated by adenosine may be involved. We tested the hypothesis that the use of rolofylline, an adenosine A1−receptor antagonist, would improve dyspnea, reduce the risk of worsening renal function, and lead to a more favorable clinical course in patients with acute heart failure. Methods: We conducted a multicenter, double-blind, placebo-controlled trial involving patients hospitalized for acute heart failure with impaired renal function. Within 24 hours after presentation, 2033 patients were randomly assigned, in a 2:1 ratio, to receive daily intravenous rolofylline (30 mg) or placebo for up to 3 days. The primary end point was treatment success, treatment failure, or no change in the patient’s clinical condition; this end point was defined according to survival, heart-failure status, and changes in renal function. Secondary end points were the post-treatment development of persistent renal impairment and the 60-day rate of death or readmission for cardiovascular or renal causes. Results: Rolofylline, as compared with placebo, did not provide a benefit with respect to the primary end point (odds ratio, 0.92; 95% confidence interval, 0.78 to 1.09; P=0.35). Persistent renal impairment developed in 15.0% of patients in the rolofylline group and in 13.7% of patients in the placebo group (P=0.44). By 60 days, death or readmission for cardiovascular or renal causes had occurred in similar proportions of patients assigned to rolofylline and placebo (30.7% and 31.9%, respectively; P=0.86). Adverse-event rates were similar overall; however, only patients in the rolofylline group had seizures, a known potential adverse effect of A1-receptor antagonists. Conclusions: Rolofylline did not have a favorable effect with respect to the primary clinical composite end point, nor did it improve renal function or 60-day outcomes. It does not show promise in the treatment of acute heart failure with renal dysfunction. (Funded by NovaCardia, a subsidiary of Merck; ClinicalTrials.gov numbers, NCT00328692 and NCT00354458.

Comparison of two adjoint equation approaches with respect to boundary-condition treatments for the quasi-1D Euler equations

For computation of nonlinear aeroelastic problems, an efficient error estimation and grid adaptation algorithm is highly desirable, but traditional error estimation or grid adaptation do not suffice, since they are insufficiently related to relevant engineering variables and are incapable of significantly reducing the computing time. The dual formulation however, can be used as an a-posteriori error estimation in the quantity of interest. However, derivation of the dual problem, especially the accompanying boundary conditions, is not a trivial task. This document compares a discrete and analytical ad joint equation method with respect to boundary-condition treatments applied on the quasi-1D Euler equations. Flux evaluation of the primal problem is do ne by a Linearised Godunov scheme. For our future goal, solving ftuid-structure problems, the discrete approach seems preferable

Effects of rapid prey evolution on predator-prey cycles

We study the qualitative properties of population cycles in a predator-prey system where genetic variability allows contemporary rapid evolution of the prey. Previous numerical studies have found that prey evolution in response to changing predation risk can have major quantitative and qualitative effects on predator-prey cycles, including: (i) large increases in cycle period, (ii) changes in phase relations (so that predator and prey are cycling exactly out of phase, rather than the classical quarter-period phase lag), and (iii) "cryptic" cycles in which total prey density remains nearly constant while predator density and prey traits cycle. Here we focus on a chemostat model motivated by our experimental system [Fussmann et al. 2000,Yoshida et al. 2003] with algae (prey) and rotifers (predators), in which the prey exhibit rapid evolution in their level of defense against predation. We show that the effects of rapid prey evolution are robust and general, and furthermore that they occur in a specific but biologically relevant region of parameter space: when traits that greatly reduce predation risk are relatively cheap (in terms of reductions in other fitness components), when there is coexistence between the two prey types and the predator, and when the interaction between predators and undefended prey alone would produce cycles. Because defense has been shown to be inexpensive, even cost-free, in a number of systems [Andersson and Levin 1999, Gagneux et al. 2006,Yoshida et al. 2004], our discoveries may well be reproduced in other model systems, and in nature. Finally, some of our key results are extended to a general model in which functional forms for the predation rate and prey birth rate are not specified.Comment: 35 pages, 8 figure

Natriuretic peptide-based inclusion criteria in a heart failure clinical trial: insights from COMMANDER HF

Objectives: This study investigated the effects of a mid-trial protocol amendment requiring elevated natriuretic peptides for inclusion in the COMMANDER-HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure) trial. Background: Heart failure (HF) trials that select patients based on history of HF hospitalization alone are susceptible to regional variations in event rates. Elevated plasma concentrations of natriuretic peptides (NPs) as selection criteria may help HF ascertainment and risk enrichment. In the COMMANDER-HF trial, B-type natriuretic peptide greater than or equal to 200 ng/l or N-terminal pro–B-type natriuretic peptide greater than or equal to 800 ng/l were added to inclusion criteria as a mid-trial protocol amendment, providing a unique case-study of NP-based inclusion criteria. Methods: We compared the baseline characteristics, event rates, and treatment effects for patients enrolled before and after the NP protocol amendment. The primary endpoint was all-cause death, myocardial infarction, or stroke. Secondary endpoints included HF rehospitalization and cardiovascular death. Results: A total of 5,022 patients with left ventricular ejection fraction less than or equal to 40% and coronary artery disease were included. Compared to patients enrolled before the NP protocol amendment, those enrolled post-amendment (n = 3,867, 77%) were older, more often had diabetes, and had lower values for body mass index, left ventricular ejection fraction, and estimated glomerular filtration rate, higher heart rate, and higher event rates: primary endpoint (hazard ratio [HR]: 1.32; 95% confidence interval [CI]: 1.16 to 1.50), cardiovascular death (HR: 1.29; 95% CI: 1.11 to 1.50), HF rehospitalization (HR: 1.31; 95% CI: 1.15 to 1.49), and major bleeding (HR: 1.71; 95% CI: 1.11 to 2.65). Differences between pre- and post-amendment rates were confined to and driven by Eastern Europe. This protocol amendment did not modify the neutral effect of rivaroxaban on the primary endpoint (p interaction = 0.36) or secondary endpoints. Conclusions: In a global event-driven trial of rivaroxaban in HF, requiring elevated NPs for inclusion increased event rates allowing earlier completion of the trial but did not modify treatment effect. These data inform future HF trials regarding the expected impact of NP-based inclusion criteria on patient characteristics and event rates. (COMMANDER HF [A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure] NCT01877915

Effects of serelaxin in patients with acute heart failure

Background: Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure. Methods: In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 μg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days. Results: A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P=0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P=0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups. Conclusions: In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778. opens in new tab.

Effect of nesiritide in patients with acute decompensated heart failure

Background Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. Methods We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. Results Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P = 0.03) and 24 hours (68.2% vs. 66.1%, P = 0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, −0.7 percentage points; 95% confidence interval [CI], −2.1 to 0.7; P = 0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, −0.4 percentage points; 95% CI, −1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P = 0.11). Conclusions Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.