Analyzing intramolecular vibrational energy redistribution via the overlap intensity-level velocity correlator

Numerous experimental and theoretical studies have established that intramolecular vibrational energy redistribution (IVR) in isolated molecules has a heirarchical tier structure. The tier structure implies strong correlations between the energy level motions of a quantum system and its intensity-weighted spectrum. A measure, which explicitly accounts for this correaltion, was first introduced by one of us as a sensitive probe of phase space localization. It correlates eigenlevel velocities with the overlap intensities between the eigenstates and some localized state of interest. A semiclassical theory for the correlation is developed for systems that are classically integrable and complements earlier work focusing exclusively on the chaotic case. Application to a model two dimensional effective spectroscopic Hamiltonian shows that the correlation measure can provide information about the terms in the molecular Hamiltonian which play an important role in an energy range of interest and the character of the dynamics. Moreover, the correlation function is capable of highlighting relevant phase space structures including the local resonance features associated with a specific bright state. In addition to being ideally suited for multidimensional systems with a large density of states, the measure can also be used to gain insights into the phase space transport and localization. It is argued that the overlap intensity-level velocity correlation function provides a novel way of studying vibrational energy redistribution in isolated molecules. The correlation function is ideally suited to analyzing the parametric spectra of molecules in external fields.Comment: 16 pages, 13 figures (low resolution

High-Precision Entropy Values for Spanning Trees in Lattices

Shrock and Wu have given numerical values for the exponential growth rate of the number of spanning trees in Euclidean lattices. We give a new technique for numerical evaluation that gives much more precise values, together with rigorous bounds on the accuracy. In particular, the new values resolve one of their questions.Comment: 7 pages. Revision mentions alternative approach. Title changed slightly. 2nd revision corrects first displayed equatio

Spanning tree generating functions and Mahler measures

We define the notion of a spanning tree generating function (STGF) $\sum a_n z^n$, which gives the spanning tree constant when evaluated at $z=1,$ and gives the lattice Green function (LGF) when differentiated. By making use of known results for logarithmic Mahler measures of certain Laurent polynomials, and proving new results, we express the STGFs as hypergeometric functions for all regular two and three dimensional lattices (and one higher-dimensional lattice). This gives closed form expressions for the spanning tree constants for all such lattices, which were previously largely unknown in all but one three-dimensional case. We show for all lattices that these can also be represented as Dirichlet $L$-series. Making the connection between spanning tree generating functions and lattice Green functions produces integral identities and hypergeometric connections, some of which appear to be new.Comment: 26 pages. Dedicated to F Y Wu on the occasion of his 80th birthday. This version has additional references, additional calculations, and minor correction

Rationale and design for the development of a novel nitroxyl donor in patients with acute heart failure

Hospitalisation for acute heart failure remains a major public health problem with high prevalence, morbidity, mortality, and cost. Prior attempts to develop new therapies for this condition have not been successful. Nitroxyl (HNO) plays a unique role in cardiovascular physiology by direct post‐translational modification of thiol residues on target proteins, specifically SERCA2a, phospholamban, the ryanodine receptor and myofilament proteins in cardiomyocytes. In animal models, these biological effects lead to vasodilatation, increased inotropy and lusitropy, but without tachyphylaxis, pro‐arrhythmia or evidence of increased myocardial oxygen demand. BMS‐986231 is an HNO donor being developed as a therapy for heart failure, and initial studies in patients with heart failure support the potential clinical value of these physiological effects. In this manuscript, we describe the ongoing phase II development programme for BMS‐986231, which consists of three related randomised placebo‐controlled clinical trials, StandUP‐AHF, StandUP‐Imaging and StandUP‐Kidney, which are designed to provide evidence of tolerability and efficacy as well as confirm the anticipated physiological effects in patients with heart failure with reduced ejection fraction. These studies will set the stage for the further study of BMS‐986231 in future phase III clinical trials

Acute treatment with omecamtiv mecarbil to increase contractility in acute heart failure

Background: Omecamtiv mecarbil (OM) is a selective cardiac myosin activator that increases myocardial function in healthy volunteers and in patients with chronic heart failure. Objectives: This study evaluated the pharmacokinetics, pharmacodynamics, tolerability, safety, and efficacy of OM in patients with acute heart failure (AHF). Methods: Patients admitted for AHF with left ventricular ejection fraction ≤40%, dyspnea, and elevated plasma concentrations of natriuretic peptides were randomized to receive a double-blind, 48-h intravenous infusion of placebo or OM in 3 sequential, escalating-dose cohorts. Results: In 606 patients, OM did not improve the primary endpoint of dyspnea relief (3 OM dose groups and pooled placebo: placebo, 41%; OM cohort 1, 42%; cohort 2, 47%; cohort 3, 51%; p = 0.33) or any of the secondary outcomes studied. In supplemental, pre-specified analyses, OM resulted in greater dyspnea relief at 48 h (placebo, 37% vs. OM, 51%; p = 0.034) and through 5 days (p = 0.038) in the high-dose cohort. OM exerted plasma concentration-related increases in left ventricular systolic ejection time (p < 0.0001) and decreases in end-systolic dimension (p < 0.05). The adverse event profile and tolerability of OM were similar to those of placebo, without increases in ventricular or supraventricular tachyarrhythmias. Plasma troponin concentrations were higher in OM-treated patients compared with placebo (median difference at 48 h, 0.004 ng/ml), but with no obvious relationship with OM concentration (p = 0.95). Conclusions: In patients with AHF, intravenous OM did not meet the primary endpoint of dyspnea improvement, but it was generally well tolerated, it increased systolic ejection time, and it may have improved dyspnea in the high-dose group. (Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure [ATOMIC-AHF]; NCT01300013)

Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: The IRONOUT HF Randomized Clinical Trial.

Importance: Iron deficiency is present in approximately 50% of patients with heart failure with reduced left ventricular ejection fraction (HFrEF) and is an independent predictor of reduced functional capacity and mortality. However, the efficacy of inexpensive readily available oral iron supplementation in heart failure is unknown. Objective: To test whether therapy with oral iron improves peak exercise capacity in patients with HFrEF and iron deficiency. Design, Setting, and Participants: Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with HFrEF ( Interventions: Oral iron polysaccharide (n = 111) or placebo (n = 114), 150 mg twice daily for 16 weeks. Main Outcomes and Measures: The primary end point was a change in peak oxygen uptake (V̇o2) from baseline to 16 weeks. Secondary end points were change in 6-minute walk distance, plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and health status as assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ, range 0-100, higher scores reflect better quality of life). Results: Among 225 randomized participants (median age, 63 years; 36% women) 203 completed the study. The median baseline peak V̇o2 was 1196 mL/min (interquartile range [IQR], 887-1448 mL/min) in the oral iron group and 1167 mL/min (IQR, 887-1449 mL/min) in the placebo group. The primary end point, change in peak V̇o2 at 16 weeks, did not significantly differ between the oral iron and placebo groups (+23 mL/min vs -2 mL/min; difference, 21 mL/min [95% CI, -34 to +76 mL/min]; P = .46). Similarly, at 16 weeks, there were no significant differences between treatment groups in changes in 6-minute walk distance (-13 m; 95% CI, -32 to 6 m), NT-proBNP levels (159; 95% CI, -280 to 599 pg/mL), or KCCQ score (1; 95% CI, -2.4 to 4.4), all P \u3e .05. Conclusions and Relevance: Among participants with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks. These results do not support use of oral iron supplementation in patients with HFrEF. Trial Registration: clinicaltrials.gov Identifier: NCT02188784

Permutation criteria to evaluate multiple clinical endpoints in a proof-of-concept study: lessons from Pre-RELAX-AHF

Clinically relevant endpoints cannot be routinely targeted with reasonable power in a small study. Hence, proof-of-concept studies are often powered to a primary surrogate endpoint. However, in acute heart failure (AHF) effects on surrogates have not translated into clinical benefit in confirmatory studies. Although observing an effect on one of many endpoints due to chance is likely, observing concurrent positive trends across several outcomes by chance is usually unlikely. Pre-RELAX-AHF, which compared 4 relaxin doses with placebo in AHF, has shown favourable trends versus placebo (one-sided P <0.10) on six of nine clinical endpoints in the 30 mu g/kg/day group. To illustrate evaluation of multiple, correlated clinical endpoints for evidence of efficacy and for dose selection, a permutation method was applied retrospectively. By randomly re-assigning the treatment group to the actual data for each of the 229 subjects, 20,000 permutation samples were constructed. The permutation P value for at least six favourable trends among nine endpoints in any dose groups was 0.0073 (99.9% CI 0.0053-0.0093). This is higher than would be expected if the endpoints were uncorrelated (0.00026), but much lower than the probability of observing one of nine comparisons significant at the traditional two-sided P <0.05 (0.74). Thus, the result was unlikely due to correlated endpoints or to chance. Examining consistency of effect across multiple clinical endpoints in a proof-of-concept study may identify efficacious therapies and enable dose selection for confirmatory trials. The merit of the approach described requires confirmation through prospective application in designing future studies

Wing-Body Aeroelasticity Using Finite-Difference Fluid/Finite-Element Structural Equations on Parallel Computers

This paper presents a procedure for computing the aeroelasticity of wing-body configurations on multiple-instruction, multiple-data (MIMD) parallel computers. In this procedure, fluids are modeled using Euler equations discretized by a finite difference method, and structures are modeled using finite element equations. The procedure is designed in such a way that each discipline can be developed and maintained independently by using a domain decomposition approach. A parallel integration scheme is used to compute aeroelastic responses by solving the coupled fluid and structural equations concurrently while keeping modularity of each discipline. The present procedure is validated by computing the aeroelastic response of a wing and comparing with experiment. Aeroelastic computations are illustrated for a High Speed Civil Transport type wing-body configuration

Rationale and design of the GUIDE-IT study: Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure.

OBJECTIVES: The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) study is designed to determine the safety, efficacy, and cost-effectiveness of a strategy of adjusting therapy with the goal of achieving and maintaining a target N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of BACKGROUND: Elevations in natriuretic peptide (NP) levels provide key prognostic information in patients with HF. Therapies proven to improve outcomes in patients with HF are generally associated with decreasing levels of NPs, and observational data show that decreases in NP levels over time are associated with favorable outcomes. Results from smaller prospective, randomized studies of this strategy thus far have been mixed, and current guidelines do not recommend serial measurement of NP levels to guide therapy in patients with HF. METHODS: GUIDE-IT is a prospective, randomized, controlled, unblinded, multicenter clinical trial designed to randomize approximately 1,100 high-risk subjects with systolic HF (left ventricular ejection fraction ≤40%) to either usual care (optimized guideline-recommended therapy) or a strategy of adjusting therapy with the goal of achieving and maintaining a target NT-proBNP level of CONCLUSIONS: The GUIDE-IT study is designed to definitively assess the effects of an NP-guided strategy in high-risk patients with systolic HF on clinically relevant endpoints of mortality, hospitalization, quality of life, and medical resource use. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure [GUIDE-IT]; NCT01685840)