Search

ObjectivesThis study sought to determine clinician and scientist involvement in heart failure (HF) clinical research and to describe the challenges of conducting clinical trials in the United States.BackgroundImprovements in the current capability, potential, and deficiencies of the HF clinical research infrastructure in the United States are needed in order to enhance efficiency and impact.MethodsThe Heart Failure Society of America (HFSA) distributed an electronic survey regarding HF clinical trial activity for the purpose of understanding the barriers that exist to conducting high-quality HF clinical research.ResultsOverall, 1,794 HFSA members were queried, and 434 members (24%) completed surveys, whereas a total of 7,589 individuals with interest in HF were queried, and 615 completed surveys. Of the respondents, 410 (67%) were actively engaged in HF research and 120 (20%) were interested in research. Most respondents, 270, were physicians (44%); 311 of the total (76% of the total and 80% of physicians) practiced in academic institutions; 333 respondents (81%) had served as principal investigators and 73 (18%) as site coordinators. Respondents active in clinical research usually participated in 1 to 5 trials and enrolled 1 to 20 patients annually. Institutional review board (IRB) approval typically required 3 months, and contract completion required 3 to 6 months per site. The greatest barriers to research were insufficient site budgets, delay in contracting, inability to find participants meeting trial entry criteria, and unavailability of qualified study coordinators.ConclusionsMany U.S. clinical research sites are constrained by budgetary, staffing, and contractual issues. The HFSA Research Network seeks to unify interested sites and deconstruct barriers to permit high-value HF research.

Alloys of Ag and small amounts of Pd are promising as bifunctional catalysts, potentially combining the inherent selectivity of the noble Ag with that of the more reactive Pd. Stable PdAg surface alloys are prepared via evaporation of Pd onto Ag(111) at room temperature followed by annealing at 400 K to create a model system. Using this procedure, the most stable form of the surface alloy under vacuum was determined to be a Ag-capped PdAg surface alloy, on the basis of a combination of X-ray photoelectron spectroscopy (XPS), scanning tunneling microscopy (STM), and density functional theory (DFT). Extensive roughening of the surface was apparent in STM images, characterized by islands of the Ag/PdAg/Ag(111) alloy of several layers thickness. The roughening is attributed to transport of Ag from the Ag(111) surface into the alloy islands. Within these islands, there is a driving force for Pd to be dispersed, surrounded by Ag, on the basis of DFT modeling. Exposure of these Ag/PdAg/Ag(111) islands to CO (0.5 Torr) at 300 K induces migration of Pd to the surface, driven by the energetic stabilization of the Pd-CO bond based on ambient-pressure XPS. Once the Pd is drawn to the surface by higher pressures of CO at room temperature, it remains stable even under very low CO partial pressures at temperatures of 300 K and below, on the basis of DFT-modeled phase behavior. Exposure to 1 Torr of O2 at 400 K also causes Pd to resurface, and the resulting structure persists even at low pressures and temperatures below 300 K. These results establish that the state of the PdAg catalyst surface depends strongly on pretreatment and operational conditions. Hence, exposure of an alloy catalyst to CO or O2 at moderate temperatures and pressures can lead to catalyst activation by bringing Pd to the surface. Furthermore, these results demonstrate that exposure to CO at room temperature, which is often used as a proxy for evaluating the Pd coordination sites available in a catalyst, changes the surface structure. Therefore, the CO vibrational frequencies measured with diffuse-reflectance infrared Fourier-transform spectroscopy (DRIFTS) on PdAg catalyst materials do not necessarily provide information about their working state, and fundamental understanding of the CO-PdAg alloy is crucial.

BackgroundPrevious systematic reviews have indicated that exercise-based cardiac rehabilitation (ExCR) for patients with heart failure (HF) has a beneficial effect on health-related quality-of-life (HRQoL) and exercise capacity. However, there is uncertainty regarding potential differential effects of ExCR across HF patient subgroups.ObjectivesThe authors sought to undertake an individual participant data (IPD) meta-analysis to: 1) assess the impact of ExCR on HRQoL and exercise capacity in patients with HF; and 2) investigate differential effects of ExCR according to a range of patient characteristics: age, sex, ethnicity, New York Heart Association functional class, ischemic etiology, ejection fraction, and exercise capacity.MethodsA single dataset was produced, comprising randomized trials where ExCR (delivered for 3 weeks or more) was compared with a no exercise control group. Each trial provided IPD on HRQoL or exercise capacity (or both), with follow-up of 6 months or more. One- and 2-stage meta-analysis models were used to investigate the effect of ExCR overall and the interactions between ExCR and participant characteristics.ResultsIPD was obtained from 13 trials for 3,990 patients, predominantly (97%) with reduced ejection fraction HF. Compared with the control group, there was a statistically significant difference in favor of ExCR for HRQoL and exercise capacity. At 12-month follow-up, improvements were seen in 6-min walk test (mean 21.0 m; 95% confidence interval: 1.57 to 40.4 m; p = 0.034) and Minnesota Living With HF score (mean improvement 5.9; 95% confidence interval: 1.0 to 10.9; p = 0.018). No consistent evidence was found of differential intervention effects across patient subgroups.ConclusionsThese results, based on an IPD meta-analysis of randomized trials, confirm the benefit of ExCR on HRQoL and exercise capacity and support the Class I recommendation of current international clinical guidelines that ExCR should be offered to all HF patients. (Exercise Training for Chronic Heart Failure [ExTraMATCH II]: protocol for an individual participant data meta-analysis; PROSPERO: international database of systematic reviews CRD42014007170).

AimsTo undertake an individual patient data (IPD) meta-analysis to assess the impact of exercise-based cardiac rehabilitation (ExCR) in patients with heart failure (HF) on mortality and hospitalisation, and differential effects of ExCR according to patient characteristics: age, sex, ethnicity, New York Heart Association functional class, ischaemic aetiology, ejection fraction, and exercise capacity.Methods and resultsRandomised trials of exercise training for at least 3 weeks compared with no exercise control with 6-month follow-up or longer, providing IPD time to event on mortality or hospitalisation (all-cause or HF-specific). IPD were combined into a single dataset. We used Cox proportional hazards models to investigate the effect of ExCR and the interactions between ExCR and participant characteristics. We used both two-stage random effects and one-stage fixed effect models. IPD were obtained from 18 trials including 3912 patients with HF with reduced ejection fraction. Compared to control, there was no statistically significant difference in pooled time to event estimates in favour of ExCR although confidence intervals (CIs) were wide [all-cause mortality: hazard ratio (HR) 0.83, 95% CI 0.67-1.04; HF-specific mortality: HR 0.84, 95% CI 0.49-1.46; all-cause hospitalisation: HR 0.90, 95% CI 0.76-1.06; and HF-specific hospitalisation: HR 0.98, 95% CI 0.72-1.35]. No strong evidence was found of differential intervention effects across patient characteristics.ConclusionExercise-based cardiac rehabilitation did not have a significant effect on the risk of mortality and hospitalisation in HF with reduced ejection fraction. However, uncertainty around effect estimates precludes drawing definitive conclusions.

The structure and dynamics of water on solid surfaces critically affect the chemistry of materials in ambient and aqueous environments. Here, we investigate the hydrogen bonding network of water adsorbed on the majority (101) surface of anatase TiO2, a widely used photocatalyst, using polarization- and azimuth-resolved infrared spectroscopy combined with neural network potential molecular dynamics simulations. Our results show that one monolayer of water saturates the undercoordinated titanium (Ti5c) sites, forming one-dimensional chains of molecule hydrogen bonded to surface undercoordinated bridging oxygen (O2c) atoms. As the coverage increases, water adsorption on O2c sites leads to significant restructuring of the water monolayer and the formation of a two-dimensional hydrogen bond network characterized by tightly bound pairs of water molecules on adjacent Ti5c and O2c sites. This structural motif likely persists at ambient conditions, influencing the reactions occurring there. The results reported here provide critical details of the structure of the water–anatase (101) interface that were previously hypothesized but unconfirmed experimentally. [ABSTRACT FROM AUTHOR]

Our ability to rationalise the activity of heterogeneous catalytic materials relies on a precise understanding of both the structure and composition of the catalyst under reaction conditions to resolve active sites. Their highly dynamic nature means that catalysis suffers from an observer effect, where the act of measuring activity and/or structure will modify the structure itself. Herein, we present a well-defined catalyst consisting of 2 nm Pt nanoparticles supported on SiO2 that can be dynamically modified and regenerated without irreversibly changing the underlying structure or activity of the catalyst. Using in situ diffuse reflectance infrared Fourier transform spectroscopy and transmission electron microscopy we identify that the catalyst is resistant to oxidative and reductive treatments, but irreversibly restructures in reactive environments (CO + O2) at moderate pressures and temperatures. We show that by using transient pressure pulse experiments it is possible to minimise the restructuring in reactive environments, which when coupled with kinetic modelling can be used to identify site and state dependent activity while simultaneously quantifying the number of active sites. The well-defined nature of this 2 nm Pt/SiO2 catalyst means it can be utilised to gain molecular insight into catalytic processes and act as a new material for use in heterogeneous catalytic surface science. Further, the rapid restructuring of the catalyst during CO oxidation demonstrates that it is not a benign characterisation tool for comparison of catalysts. [ABSTRACT FROM AUTHOR]

With few notable exceptions, drug development for heart failure (HF) has become progressively more challenging, and there remain no definitively proven therapies for patients with acute HF or HF with preserved ejection fraction. Inspection of temporal trends suggests an increasing rate of disagreement between early-phase and phase III trial end points. Preliminary results from phase II HF trials are frequently promising, but increasingly followed by disappointing phase III results. Given this potential disconnect, it is reasonable to carefully re-evaluate the purpose, design, and execution of phase II HF trials, with particular attention directed toward the surrogate end points commonly used by these studies. In this review, we offer a critical reappraisal of the role of phase II HF trials and surrogate end points, highlighting challenges in their use and interpretation, lessons learned from past experiences, and specific strengths and weaknesses of various surrogate outcomes. We conclude by proposing a series of approaches that should be considered for the goal of optimizing the efficiency of HF drug development. This review is based on discussions between scientists, clinical trialists, industry and government sponsors, and regulators that took place at the Cardiovascular Clinical Trialists Forum in Washington, DC, on December 2, 2016.

OBJECTIVES:As the largest acute heart failure (AHF) trial conducted to date, the global ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial database presented an opportunity to systematically describe the relationship among time of hospital presentation, clinical profile, inpatient management, and outcomes among patients admitted with AHF. BACKGROUND:Time of hospital presentation has been shown to impact outcomes among patients hospitalized with many conditions. However, the association among time of presentation and patient characteristics, management, and clinical outcomes among patients hospitalized with AHF has not been well characterized. METHODS:A post hoc analysis of the ASCEND-HF trial was performed, which enrolled 7,141 patients hospitalized for AHF. Patients were divided based on when they presented to the hospital; regular hours were defined as 9 am to 5 pm, Monday through Friday, and off hours were defined as 5 pm to 9 am, Monday through Friday and weekends. Clinical characteristics and outcomes were compared by time of presentation. RESULTS:Overall, 3,298 patients (46%) presented during off hours. Off-hour patients were more likely to have orthopnea (80% vs. 74%, respectively) and rales (56% vs. 49%, respectively) than regular-hour patients. Off-hour patients were more likely to receive intravenous (IV) nitroglycerin (18% vs. 11%, respectively) and IV loop diuretics (92% vs. 86%, respectively) as initial therapy and reported greater relief from dyspnea at 24 h (odds ratio [OR]: 1.14; 95% confidence interval [CI]: 1.04 to 1.24; p = 0.01) than regular-hour patients. After adjustment, off-hour presentation was associated with significantly lower 30-day mortality (OR: 0.74; 95% CI: 0.57 to 0.96; p = 0.03) and 180-day mortality (hazard ratio [HR]: 0.82; 95% CI: 0.72 to 0.94; p = 0.01) but similar 30-day rehospitalization rates (p = 0.40). CONCLUSIONS:In this AHF trial, patients admitted during off hours exhibited a distinct clinical profile, experienced greater dyspnea relief, and had lower post-discharge mortality than regular-hour patients. These findings have implications for future AHF trials.

The molecular mechanisms of sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) remain incompletely understood. Single-cell RNA sequencing and morphometric data were collected from research kidney biopsies donated by young persons with type 2 diabetes (T2D), aged 12 to 21 years, and healthy controls (HCs). Participants with T2D were obese and had higher estimated glomerular filtration rates and mesangial and glomerular volumes than HCs. Ten T2D participants had been prescribed SGLT2i (T2Di[+]) and 6 not (T2Di[-]). Transcriptional profiles showed SGLT2 expression exclusively in the proximal tubular (PT) cluster with highest expression in T2Di(-) patients. However, transcriptional alterations with SGLT2i treatment were seen across nephron segments, particularly in the distal nephron. SGLT2i treatment was associated with suppression of transcripts in the glycolysis, gluconeogenesis, and tricarboxylic acid cycle pathways in PT, but had the opposite effect in thick ascending limb. Transcripts in the energy-sensitive mTORC1-signaling pathway returned toward HC levels in all tubular segments in T2Di(+), consistent with a diabetes mouse model treated with SGLT2i. Decreased levels of phosphorylated S6 protein in proximal and distal tubules in T2Di(+) patients confirmed changes in mTORC1 pathway activity. We propose that SGLT2i treatment benefits the kidneys by mitigating diabetes-induced metabolic perturbations via suppression of mTORC1 signaling in kidney tubules., Introduction The incedence of youth-onset type 2 diabetes (T2D) is rapidly rising among children and adolescents globally (1). It is associated with a more severe clinical course than youth-onset type [...]

BackgroundOver the last 50 years, clinical trials of novel interventions for acute heart failure (AHF) have, with few exceptions, been neutral or shown harm. We hypothesize that this might be related to a differential response to pharmacological therapy.MethodsWe studied the magnitude of treatment effect of rolofylline across clinical characteristics and plasma biomarkers in 2033 AHF patients and derived a biomarker-based responder sum score model. Treatment response was survival from all-cause mortality through day 180.ResultsIn the overall study population, rolofylline had no effect on mortality (HR 1.03, 95% CI 0.82-1.28, p = 0.808). We found no treatment interaction across clinical characteristics, but we found interactions between several biomarkers and rolofylline. The biomarker-based sum score model included TNF-R1α, ST2, WAP four-disulfide core domain protein HE4 (WAP-4C), and total cholesterol, and the score ranged between 0 and 4. In patients with score 4 (those with increased TNF-R1α, ST2, WAP-4C, and low total cholesterol), treatment with rolofylline was beneficial (HR 0.61, 95% CI 0.40-0.92, p = 0.019). In patients with score 0, treatment with rolofylline was harmful (HR 5.52, 95% CI 1.68-18.13, p = 0.005; treatment by score interaction p

The increasing burden and the continued suboptimal outcomes for patients with heart failure underlines the importance of continued research to develop novel therapeutics for this disorder. This can only be accomplished with successful translation of basic science discoveries into direct human application through effective clinical trial design and execution that results in a substantially improved clinical course and outcomes. In this respect, phase II clinical trials play a pivotal role in determining which of the multitude of potential basic science discoveries should move to the large and expansive registration trials in humans. A critical examination of the phase II trials in heart failure reveals multiple shortcomings in their concept, design, execution, and interpretation. To further a dialogue on the challenges and potential for improvement and the role of phase II trials in patients with heart failure, the Food and Drug Administration facilitated a meeting on October 17, 2016, represented by clinicians, researchers, industry members, and regulators. This document summarizes the discussion from this meeting and provides key recommendations for future directions.

ObjectivesThis study sought to examine the relationships between in-hospital and post-discharge body weight changes and outcomes among patients hospitalized for acute heart failure (AHF).BackgroundBody weight changes during and after hospitalization for AHF and the relationships with outcomes have not been well characterized.MethodsA post hoc analysis was performed of the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure) trial, which enrolled patients admitted for AHF regardless of ejection fraction. In-hospital body weight change was defined as the difference between baseline and discharge/day 10, whereas post-discharge body weight change was defined as the difference between discharge/day 10 and day 30. Spearman rank correlations of weight change, urine output (UOP), and dyspnea relief as assessed by a 7-point Likert scale are described. Logistic and Cox proportional hazards regression was used to evaluate the relationship between weight change and outcomes.ResultsStudy participants with complete body weight data (n = 4,172) had a mean age of 65 ± 14 years, and 66% were male. Ischemic heart disease was reported in 60% of patients and the average ejection fraction was 30 ± 13%. The median change in body weight was -1.0 kg (interquartile range: -2.1 to 0.0 kg) at 24 h and -2.3 kg (interquartile range: -5.0 to -0.7 kg) by discharge/day 10. At hour 24, there was a weak correlation between change in body weight and UOP (r = -0.381), and minimal correlation between body weight change and dyspnea relief (r = -0.096). After risk adjustment, increasing body weight during hospitalization was associated with a 16% increase per kg in the likelihood of 30-day mortality or HF readmission for patients showing weight loss ≤1 kg or weight gain during hospitalization (odds ratio per kg increase 1.16, 95% confidence interval [CI]: 1.09 to 1.27; p < 0.001). Among the subset of patients experiencing >1-kg increase in body weight post-discharge, increasing body weight was associated with higher risk of 180-day mortality (hazard ratio per kg increase 1.16; 95% CI: 1.09 to 1.23; p < 0.001).ConclusionsA substantial number of patients experienced minimal weight loss or frank weight gain in the context of an AHF trial, and increasing body weight in this subset of patients was independently associated with a worse post-discharge prognosis.