Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients The ROADMAP Study 2-Year Results

OBJECTIVES The authors sought to provide the pre-specified primary endpoint of the ROADMAP (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients) trial at 2 years. BACKGROUND The ROADMAP trial was a prospective nonrandomized observational study of 200 patients (97 with a left ventricular assist device [LVAD], 103 on optimal medical management [OMM]) that showed that survival with improved functional status at 1 year was better with LVADs compared with OMM in a patient population of ambulatory New York Heart Association functional class IIIb/IV patients. METHODS The primary composite endpoint was survival on original therapy with improvement in 6-min walk distance \u3e= 75 m. RESULTS Patients receiving LVAD versus OMM had lower baseline health-related quality of life, reduced Seattle Heart Failure Model 1-year survival (78% vs. 84%; p = 0.012), and were predominantly INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profile 4 (65% vs. 34%; p \u3c 0.001) versus profiles 5 to 7. More LVAD patients met the primary endpoint at 2 years: 30% LVAD versus 12% OMM (odds ratio: 3.2 [95% confidence interval: 1.3 to 7.7]; p = 0.012). Survival as treated on original therapy at 2 years was greater for LVAD versus OMM (70 +/- 5% vs. 41 +/- 5%; p \u3c 0.001), but there was no difference in intent-to-treat survival (70 +/- 5% vs. 63 +/- 5%; p = 0.307). In the OMM arm, 23 of 103 (22%) received delayed LVADs (18 within 12 months; 5 from 12 to 24 months). LVAD adverse events declined after year 1 for bleeding (primarily gastrointestinal) and arrhythmias. CONCLUSIONS Survival on original therapy with improvement in 6-min walk distance was superior with LVAD compared with OMM at 2 years. Reduction in key adverse events beyond 1 year was observed in the LVAD group. The ROADMAP trial provides risk-benefit information to guide patient- and physician-shared decision making for elective LVAD therapy as a treatment for heart failure. (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients [ROADMAP]; NCT01452802

Percutaneous Coronary Intervention and Drug-Eluting Stent Use Among Patients ≥85 Years of Age in the United States

ObjectivesThis study assessed the comparative effectiveness of drug-eluting stents (DES) versus bare-metal stents (BMS) among patients ≥85 years of age.BackgroundDespite an aging population, little is known about the comparative effectiveness of DES versus BMS among patients age ≥85 years undergoing percutaneous coronary intervention (PCI).MethodsWe examined 471,006 PCI patients age ≥65 years at 947 hospitals in the National Cardiovascular Data Registry between 2004 and 2008 and linked to Medicare claims data. Long-term outcomes (median follow-up 640.8 ± 423.5 days) were compared between users of DES and BMS.ResultsPatients age ≥85 years comprise an increasing proportion of PCIs performed among elderly subjects, yet rates of DES use declined the most in this age group. Compared with BMS, use of DES was associated with lower mortality: age ≥85 years, 29% versus 38% (adjusted hazard ratio [HR]: 0.80 [95% confidence interval (CI): 0.77 to 0.83]); age 75 to 84 years, 17% versus 25% (HR: 0.77 [95% CI: 0.75 to 0.79]); and age 65 to 74 years, 10% versus 16% (HR: 0.73 [95% CI: 0.71 to 0.75]). However, the adjusted mortality difference narrowed with increasing age (pinteraction <0.001). In contrast, the adjusted HR for myocardial infarction rehospitalization associated with DES use was significantly lower with increasing age: age ≥85 years, 9% versus 12% (HR: 0.77 [95% CI: 0.71 to 0.83]); age 75 to 84 years, 7% versus 9% (HR: 0.81 [95% CI: 0.77 to 0.84]); and age 65 to 74 years, 7% versus 8% (HR: 0.84 [95% CI: 0.80 to 0.88]) (pinteraction <0.001).ConclusionsIn this national study of older patients undergoing PCI, declines in DES use were most pronounced among those aged ≥85 years, yet lower adverse-event rates associated with DES versus BMS use were observed

A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation

Like Bcl-2, Mcl-1 is an important survival factor for many cancers, its expression contributing to chemoresistance and disease relapse. However, unlike other prosurvival Bcl-2–like proteins, Mcl-1 stability is acutely regulated. For example, the Bcl-2 homology 3 (BH3)–only protein Noxa, which preferentially binds to Mcl-1, also targets it for proteasomal degradation. In this paper, we describe the discovery and characterization of a novel BH3-like ligand derived from Bim, BimS2A, which is highly selective for Mcl-1. Unlike Noxa, BimS2A is unable to trigger Mcl-1 degradation, yet, like Noxa, BimS2A promotes cell killing only when Bcl-xL is absent or neutralized. Furthermore, killing by endogenous Bim is not associated with Mcl-1 degradation. Thus, functional inactivation of Mcl-1 does not always require its elimination. Rather, it can be efficiently antagonized by a BH3-like ligand tightly engaging its binding groove, which is confirmed here with a structural study. Our data have important implications for the discovery of compounds that might kill cells whose survival depends on Mcl-1

Colors of 2625 Quasars at 0<z<5 Measured in the Sloan Digital Sky Survey Photometric System

We present an empirical investigation of the colors of quasars in the Sloan Digital Sky Survey (SDSS) photometric system. The sample studied includes 2625 quasars with SDSS photometry. The quasars are distributed in a 2.5 degree wide stripe centered on the Celestial Equator covering $\sim529$ square degrees. Positions and SDSS magnitudes are given for the 898 quasars known prior to SDSS spectroscopic commissioning. New SDSS quasars represent an increase of over 200% in the number of known quasars in this area of the sky. The ensemble average of the observed colors of quasars in the SDSS passbands are well represented by a power-law continuum with $\alpha_{\nu} = -0.5$ ($f_{\nu} \propto \nu^{\alpha}$). However, the contributions of the $3000 {\rm \AA}$ bump and other strong emission lines have a significant effect upon the colors. The color-redshift relation exhibits considerable structure, which may be of use in determining photometric redshifts for quasars. The range of colors can be accounted for by a range in the optical spectral index with a distribution $\alpha_{\nu}=-0.5\pm0.65$ (95% confidence), but there is a red tail in the distribution. This tail may be a sign of internal reddening. Finally, we show that there is a continuum of properties between quasars and Seyfert galaxies and we test the validity of the traditional division between the two classes of AGN.Comment: 66 pages, 15 figures (3 color), accepted by A

THE DRIFT SCALE HEATER TEST AT YUCCA MOUNTAIN, NEVADA

The Drift Scale Heater Test (DST) is an integral part of the program of testing and studies being conducted by the U.S. Department of Energy to evaluate the suitability of Yucca Mountain, Nevada as a site of a deep geologic repository for the permanent disposal of spent nuclear fuel and high-level nuclear waste. The DST is a large-scale, in situ thermal test to be conducted over nearly a decade in the Exploratory Studies Facility at Yucca Mountain (Figure 1). The overall objective of the DST is to acquire a more indepth understanding of the physical processes that will occur in the rock surrounding the emplaced waste. There are four principal processes of concern: thermal, mechanical, hydrological, and chemical. These processes will be intensified because of the decay heat from the emplaced waste and their interaction or coupling. An understanding of these coupled processes is essential for the assessment of the long-term (over thousands of years) performance of the repository

North-south dipole in winter hydroclimate in the western United States during the last deglaciation

During the termination of the last glacial period the western U.S. experienced exceptionally wet conditions, driven by changes in location and strength of the mid-latitude winter storm track. The distribution of modern winter precipitation is frequently characterized by a north-south wet/dry dipole pattern, controlled by interaction of the storm track with ocean-atmosphere conditions over the Pacific and Atlantic Oceans. Here we show that a dipole pattern of similar geographic extent persisted and switched sign during millennial-scale abrupt climate changes of the last deglaciation, based on a new lake level reconstruction for pluvial Lake Chewaucan (northwestern U.S.), and a compilation of regional paleoclimate records. This suggests the dipole pattern is robust, and one mode may be favored for centuries, thereby creating persistent contrasting wet/dry conditions across the western U.S. The TraCE-21k climate model simulation shows an equatorward enhancement of winter storm track activity in the northeastern Pacific, favoring wet conditions in southwestern U.S. during the second half of Heinrich Stadial 1(16.1-14.6 ka) and consistent with paleoclimate evidence. During the Bolling/Allerod (14.6-12.8 ka), the northeastern Pacific storm track contracted poleward, consistent with wetter conditions concentrated poleward toward the northwest U.S.Desert Research Institute Jonathan O. Davis grant; Comer Science and Education Foundation; Tides FoundationOpen access journal.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Herschel-ATLAS: Far-infrared properties of radio-loud and radio-quiet quasars

This is pre-copyedited, author-produced pdf of an article accepted for publication in Monthly Notices of the Royal Astronomical Society following peer review. The version of record, E. Kalfountzou, et al., ‘Herschel-ATLAS: Far-infrared properties of radio-loud and radio-quiet quasars’, MNRAS, Vol 42(2): 1181-1196, first published online June 11, 2014, is available online via doi: 10.1093/mnras/stu782 Published by Oxford University Press on behalf of the Royal Astronomical Society.We have constructed a sample of radio-loud and radio-quiet quasars from the Faint Images Radio Sky at Twenty-one centimetres and the Sloan Digital Sky Survey Data Release 7, over the Herschel-ATLAS Phase 1 area (9h, 12h and 14 h . 5 ). Using a stacking analysis, we find a significant correlation between the far-infrared (FIR) luminosity and 1.4-GHz luminosity for radio-loud quasars. Partial correlation analysis confirms the intrinsic correlation after removing the redshift contribution, while for radio-quiet quasars, no partial correlation is found. Using a single-temperature grey-body model, we find a general trend of lower dust temperatures in case of radio-loud quasars compared to radio-quiet quasars. Also, radio-loud quasars are found to have almost constant mean values of dust mass along redshift and optical luminosity bins. In addition, we find that radio-loud quasars at lower optical luminosities tend to have on average higher FIR and 250-μm luminosity with respect to radio-quiet quasars with the same optical luminosites. Even if we use a two-temperature grey-body model to describe the FIR data, the FIR luminosity excess remains at lower optical luminosities. These results suggest that powerful radio jets are associated with star formation especially at lower accretion ratesPeer reviewe

Resourcefulness, reciprocity and reflexivity: the three Rs of partnership in sport for public health research

This paper explores the dynamics of research–policy–practice (RPP) partnerships in sport. Such partnerships, involving a diverse range of groups, have emerged as a response to: (1) a contemporary political prioritisation in the use of sport for health and wellbeing and (2) a parallel requirement for robust evidence of effectiveness and cost-effectiveness. A conceptual framework for understanding such RPP partnerships is proposed and discussed in relation to three overlapping characteristics; resourcefulness, reciprocity and reflexivity. The paper concludes that understanding these three Rs of RPP partnerships is a way to demythologise the role of sport in public health and present theoretically informed analyses about processes of knowledge production, dissemination and use. It is a conceptual framework which might also further an understanding of, and make public, issues concerning the legitimation of some forms of evidence over others, and potentially maximise the impact of the co-production of knowledge about sport for public health and wellbeing

Human Antibodies that Slow Erythrocyte Invasion Potentiate Malaria-Neutralizing Antibodies.

The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is the leading target for next-generation vaccines against the disease-causing blood-stage of malaria. However, little is known about how human antibodies confer functional immunity against this antigen. We isolated a panel of human monoclonal antibodies (mAbs) against PfRH5 from peripheral blood B cells from vaccinees in the first clinical trial of a PfRH5-based vaccine. We identified a subset of mAbs with neutralizing activity that bind to three distinct sites and another subset of mAbs that are non-functional, or even antagonistic to neutralizing antibodies. We also identify the epitope of a novel group of non-neutralizing antibodies that significantly reduce the speed of red blood cell invasion by the merozoite, thereby potentiating the effect of all neutralizing PfRH5 antibodies as well as synergizing with antibodies targeting other malaria invasion proteins. Our results provide a roadmap for structure-guided vaccine development to maximize antibody efficacy against blood-stage malaria. Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved