Development of a composite model derived from cardiopulmonary exercise tests to predict mortality risk in patients with mild-to-moderate heart failure

Objective: Cardiopulmonary exercise testing (CPET) is used to predict outcome in patients with mild-to-moderate heart failure (HF). Single CPET-derived variables are often used, but we wanted to see if a composite score achieved better predictive power. Methods: Retrospective analysis of patient records at the Department of Cardiology, Castle Hill Hospital, Kingston-upon-Hull. 387 patients [median (25th-75th percentile)] [age 65 (56-72) years; 79% males; LVEF 34 (31-37) %] were included. Patients underwent a symptomlimited, maximal CPET on a treadmill. During a median follow up of 8.6 ± 2.1 years in survivors, 107 patients died. Survival models were built and validated using a hybrid approach between the bootstrap and Cox regression. Nine CPET-derived variables were included. Z-score defined each variable's predictive strength. Model coefficients were converted to a risk score. Results: Four CPET-related variables were independent predictors of all-cause mortality in the survival model: the presence of exertional oscillatory ventilation (EOV), increasing slope of the relation between ventilation and carbon dioxide production (VE/VCO2 slope), decreasing oxygen uptake efficiency slope (OUES), and an increase in the lowest ventilatory equivalent for carbon dioxide (VEqCO2 nadir). Individual predictors of mortality ranged from 0.60 to 0.71 using Harrell’s C-statistic, but the optimal combination of EOV + VE/VCO2 slope + OUES + VEqCO2 nadir reached 0.75. The Hull CPET risk score had a significantly higher area under the curve (0.78) when compared to the Heart Failure Survival Score (AUC=0.70;

Utah’s Watershed Restoration Initiative: Restoring Watersheds at a Landscape Scale

Abstract: The Utah Watershed Restoration Initiative (WRI) is a partnership-based program, administered by the Utah Department of Natural Resources, which seeks to improve the functional capacity of high priority watersheds throughout the state. Since its inception in 2006, the WRI partnership has completed nearly 1,500 projects to restore and rehabilitate over 526,091 ha in Utah watersheds. The WRI program is unique to the west, in that it transcends jurisdictional boundaries, and local, state, and federal management authority to focus finite resources on completing high priority conservation projects. We surveyed selected WRI selected participants in 2015 to determine what factors they believed most contributed to the overall success of the program. Survey respondents attributed the success of the WRI program to: 1) engaged leadership at multiple levels, 2) a bottom-up hierarchy, 3) a history of collaboration, 4) practice partnerships, 5) a science-based approach, 6) operating at a meaningful spatial scale, 7) being solution minded, not problem focused, and 8) unselfish sharing of resources. In this paper we discuss these success factors and provide recommendations to those desiring to implement voluntary incentive-based landscape conservation strategies

Influence of case definition on incidence and outcome of acute coronary syndromes

© 2016, BMJ Publishing Group. All rights reserved. Objective: Acute coronary syndromes (ACS) are common, but their incidence and outcome might depend greatly on how data are collected. We compared case ascertainment rates for ACS and myocardial infarction (MI) in a single institution using several different strategies. Methods: The Hull and East Yorkshire Hospitals serve a population of ∼560 000. Patients admitted with ACS to cardiology or general medical wards were identified prospectively by trained nurses during 2005. Patients with a death or discharge code of MI were also identified by the hospital information department and, independently, from Myocardial Infarction National Audit Project (MINAP) records. The hospital laboratory identified all patients with an elevated serum troponin-T (TnT) by contemporary criteria ( > 0.03 μg/L in 2005). Results: The prospective survey identified 1731 admissions (1439 patients) with ACS, including 764 admissions (704 patients) with MIs. The hospital information department reported only 552 admissions (544 patients) with MI and only 206 admissions (203 patients) were reported to the MINAP. Using all 3 strategies, 934 admissions (873 patients) for MI were identified, for which TnT was > 1 μg/L in 443, 0.04-1.0 μg/L in 435, =0.03 μg/L in 19 and not recorded in 37. A further 823 patients had TnT > 0.03 μg/L, but did not have ACS ascertained by any survey method. Of the 873 patients with MI, 146 (16.7%) died during admission and 218 (25.0%) by 1 year, but ranging from 9% for patients enrolled in the MINAP to 27% for those identified by the hospital information department. Conclusions: MINAP and hospital statistics grossly underestimated the incidence of MI managed by our hospital. The 1-year mortality was highly dependent on the method of ascertainment

Ecosystem carbon 7 dioxide fluxes after disturbance in forests of North America

Disturbances are important for renewal of North American forests. Here we summarize more than 180 site years of eddy covariance measurements of carbon dioxide flux made at forest chronosequences in North America. The disturbances included stand-replacing fire (Alaska, Arizona, Manitoba, and Saskatchewan) and harvest (British Columbia, Florida, New Brunswick, Oregon, Quebec, Saskatchewan, and Wisconsin) events, insect infestations (gypsy moth, forest tent caterpillar, and mountain pine beetle), Hurricane Wilma, and silvicultural thinning (Arizona, California, and New Brunswick). Net ecosystem production (NEP) showed a carbon loss from all ecosystems following a stand-replacing disturbance, becoming a carbon sink by 20 years for all ecosystems and by 10 years for most. Maximum carbon losses following disturbance (g C m−2y−1) ranged from 1270 in Florida to 200 in boreal ecosystems. Similarly, for forests less than 100 years old, maximum uptake (g C m−2y−1) was 1180 in Florida mangroves and 210 in boreal ecosystems. More temperate forests had intermediate fluxes. Boreal ecosystems were relatively time invariant after 20 years, whereas western ecosystems tended to increase in carbon gain over time. This was driven mostly by gross photosynthetic production (GPP) because total ecosystem respiration (ER) and heterotrophic respiration were relatively invariant with age. GPP/ER was as low as 0.2 immediately following stand-replacing disturbance reaching a constant value of 1.2 after 20 years. NEP following insect defoliations and silvicultural thinning showed lesser changes than stand-replacing events, with decreases in the year of disturbance followed by rapid recovery. NEP decreased in a mangrove ecosystem following Hurricane Wilma because of a decrease in GPP and an increase in ER

Development of a human model for the study of effects of hypoxia, exercise, and sildenafil on cardiac and vascular function in chronic heart failure

Background: Pulmonary hypertension is associated with poor outcome in patients with chronic heart failure (CHF) and may be a therapeutic target. Our aims were to develop a noninvasive model for studying pulmonary vasoreactivity in CHF and characterize sildenafil's acute cardiovascular effects. Methods and Results: In a crossover study, 18 patients with CHF participated 4 times [sildenafil (2 × 20 mg)/or placebo (double-blind) while breathing air or 15% oxygen] at rest and during exercise. Oxygen saturation (SaO2) and systemic vascular resistance were recorded. Left and right ventricular (RV) function and transtricuspid systolic pressure gradient (RVTG) were measured echocardiographically. At rest, hypoxia caused SaO2 (P = 0.001) to fall and RVTG to rise (5 ± 4 mm Hg; P = 0.001). Sildenafil reduced SaO2 (−1 ± 2%; P = 0.043), systemic vascular resistance (−87 ± 156 dyn·s−1·cm−2; P = 0.034), and RVTG (−2 ± 5 mm Hg; P = 0.05). Exercise caused cardiac output (2.1 ± 1.8 L/min; P < 0.001) and RVTG (19 ± 11 mm Hg; P < 0.0001) to rise. The reduction in RVTG with sildenafil was not attenuated by hypoxia. The rise in RVTG with exercise was not substantially reduced by sildenafil. Conclusions: Sildenafil reduces SaO2 at rest while breathing air, this was not exacerbated by hypoxia, suggesting increased ventilation–perfusion mismatching due to pulmonary vasodilation in poorly ventilated lung regions. Sildenafil reduces RVTG at rest and prevents increases caused by hypoxia but not by exercise. This study shows the usefulness of this model to evaluate new therapeutics in pulmonary hypertension

Liver ‘organ on a chip’

© 2017 The liver plays critical roles in both homeostasis and pathology. It is the major site of drug metabolism in the body and, as such, a common target for drug-induced toxicity and is susceptible to a wide range of diseases. In contrast to other solid organs, the liver possesses the unique ability to regenerate. The physiological importance and plasticity of this organ make it a crucial system of study to better understand human physiology, disease, and response to exogenous compounds. These aspects have impelled many to develop liver tissue systems for study in isolation outside the body. Herein, we discuss these biologically engineered organoids and microphysiological systems. Keywords: Microphysiologic systems; Organoids; 3D culture systemsNational Institutes of Health (U.S.) (Grant UH3TR000496)National Institutes of Health (U.S.) (Grant UH3TR000503

Integration of systems biology with organs-on-chips to humanize therapeutic development

"Mice are not little people" - a refrain becoming louder as the gaps between animal models and human disease become more apparent. At the same time, three emerging approaches are headed toward integration: powerful systems biology analysis of cell-cell and intracellular signaling networks in patient-derived samples; 3D tissue engineered models of human organ systems, often made from stem cells; and micro-fluidic and meso-fluidic devices that enable living systems to be sustained, perturbed and analyzed for weeks in culture. Integration of these rapidly moving fields has the potential to revolutionize development of therapeutics for complex, chronic diseases, including those that have weak genetic bases and substantial contributions from gene-environment interactions. Technical challenges in modeling complex diseases with "organs on chips" approaches include the need for relatively large tissue masses and organ-organ cross talk to capture systemic effects, such that current microfluidic formats often fail to capture the required scale and complexity for interconnected systems. These constraints drive development of new strategies for designing in vitro models, including perfusing organ models, as well as "mesofluidic" pumping and circulation in platforms connecting several organ systems, to achieve the appropriate physiological relevance. Keywords: organs-on-chips; 3D liver culture; perfusion; drug development; inflammation; organ crosstalk; tissue chip; intestineUnited States. Defense Advanced Research Projects Agency (Award W911NF-12-2- 0039))National Institutes of Health (U.S.) (Grant UH3TR000496