Plasma Proteomic Profile Predicts Survival in Heart Failure With Reduced Ejection Fraction

BACKGROUND: It remains unclear whether the plasma proteome adds value to established predictors in heart failure (HF) with reduced ejection fraction (HFrEF). We sought to derive and validate a plasma proteomic risk score (PRS) for survival in patients with HFrEF (HFrEF-PRS). Methods: Patients meeting Framingham criteria for HF with EF\u3c50% were enrolled (n=1017) and plasma underwent SOMAscan® profiling (4453 targets). Patients were randomly divided 2:1 into derivation and validation cohorts. The HFrEF-PRS was derived using Cox regression of all-cause mortality adjusted for clinical score and N-Terminal pro-B-Type Natriuretic Peptide (NTproBNP), then was tested in the validation cohort. Risk stratification improvement was evaluated by C-statistic, integrated discrimination index (IDI), continuous net reclassification index (NRI), and median improvement in risk score (MIRS) for 1-year and 3-year mortality. Results: Participants\u27 mean age was 68 years, 48% identified as African American, 35% were female and 296 deaths occurred. In derivation (n=681), 128 proteins associated with mortality, 8 comprising the optimized HFrEF-PRS. In validation (n=336) the HFrEF-PRS associated with mortality (hazard ratio (HR) =2.27 [95% Confidence interval (95%CI) 1.84-2.82], p=6.3x10(-14)), Kaplan-Meier curves differed significantly between HFrEF-PRS quartiles (p=2.2x10(-6)), and it remained significant after adjustment for clinical score and NTproBNP (HR=1.37, 95%CI 1.05-1.79, p=0.021). The HFrEF-PRS improved metrics of risk stratification (C-statistic change=0.009, p=0.612; IDI=0.041, p=0.010; NRI=0.391, p=0.078; MIRS=0.039, p=0.016) and associated with cardiovascular death and HF phenotypes (e.g. 6-minute walk distance, EF change). Most HFrEF-PRS proteins had little known connection to HFrEF. Conclusions: A plasma multi-protein score improved risk stratification in HFrEF patients and identified novel candidates

The Degenerate Parametric Oscillator and Ince's Equation

We construct Green's function for the quantum degenerate parametric oscillator in terms of standard solutions of Ince's equation in a framework of a general approach to harmonic oscillators. Exact time-dependent wave functions and their connections with dynamical invariants and SU(1,1) group are also discussed.Comment: 10 pages, no figure

Phylogenetic relationships of cone snails endemic to Cabo Verde based on mitochondrial genomes

Background: Due to their great species and ecological diversity as well as their capacity to produce hundreds of different toxins, cone snails are of interest to evolutionary biologists, pharmacologists and amateur naturalists alike. Taxonomic identification of cone snails still relies mostly on the shape, color, and banding patterns of the shell. However, these phenotypic traits are prone to homoplasy. Therefore, the consistent use of genetic data for species delimitation and phylogenetic inference in this apparently hyperdiverse group is largely wanting. Here, we reconstruct the phylogeny of the cones endemic to Cabo Verde archipelago, a well-known radiation of the group, using mitochondrial (mt) genomes. Results: The reconstructed phylogeny grouped the analyzed species into two main clades, one including Kalloconus from West Africa sister to Trovaoconus from Cabo Verde and the other with a paraphyletic Lautoconus due to the sister group relationship of Africonus from Cabo Verde and Lautoconus ventricosus from Mediterranean Sea and neighboring Atlantic Ocean to the exclusion of Lautoconus endemic to Senegal (plus Lautoconus guanche from Mauritania, Morocco, and Canary Islands). Within Trovaoconus, up to three main lineages could be distinguished. The clade of Africonus included four main lineages (named I to IV), each further subdivided into two monophyletic groups. The reconstructed phylogeny allowed inferring the evolution of the radula in the studied lineages as well as biogeographic patterns. The number of cone species endemic to Cabo Verde was revised under the light of sequence divergence data and the inferred phylogenetic relationships. Conclusions: The sequence divergence between continental members of the genus Kalloconus and island endemics ascribed to the genus Trovaoconus is low, prompting for synonymization of the latter. The genus Lautoconus is paraphyletic. Lautoconus ventricosus is the closest living sister group of genus Africonus. Diversification of Africonus was in allopatry due to the direct development nature of their larvae and mainly triggered by eustatic sea level changes during the Miocene-Pliocene. Our study confirms the diversity of cone endemic to Cabo Verde but significantly reduces the number of valid species. Applying a sequence divergence threshold, the number of valid species within the sampled Africonus is reduced to half.Spanish Ministry of Science and Innovation [CGL2013-45211-C2-2-P, CGL2016-75255-C2-1-P, BES-2011-051469, BES-2014-069575, Doctorado Nacional-567]info:eu-repo/semantics/publishedVersio

Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for <i>CYP2D6, ADRB1, ADRB2, ADRA2C, GRK4</i>, and <i>GRK5 </i>Genotypes and Beta-Blocker Therapy

Beta-blockers are widely used medications for a variety of indications, including heart failure, myocardial infarction, cardiac arrhythmias, and hypertension. Genetic variability in pharmacokinetic (e.g., CYP2D6) and pharmacodynamic (e.g., ADRB1, ADRB2, ADRA2C, GRK4, GRK5) genes have been studied in relation to beta-blocker exposure and response. We searched and summarized the strength of the evidence linking beta-blocker exposure and response with the six genes listed above. The level of evidence was high for associations between CYP2D6 genetic variation and both metoprolol exposure and heart rate response. Evidence indicates that CYP2D6 poor metabolizers experience clinically significant greater exposure and lower heart rate in response to metoprolol compared with those who are not poor metabolizers. Therefore, we provide therapeutic recommendations regarding genetically predicted CYP2D6 metabolizer status and metoprolol therapy. However, there was insufficient evidence to make therapeutic recommendations for CYP2D6 and other beta-blockers or for any beta-blocker and the other five genes evaluated (updates at www.cpicpgx.org).</p

The Minimum-Uncertainty Squeezed States for for Atoms and Photons in a Cavity

We describe a six-parameter family of the minimum-uncertainty squeezed states for the harmonic oscillator in nonrelativistic quantum mechanics. They are derived by the action of corresponding maximal kinematical invariance group on the standard ground state solution. We show that the product of the variances attains the required minimum value 1/4 only at the instances that one variance is a minimum and the other is a maximum, when the squeezing of one of the variances occurs. The generalized coherent states are explicitly constructed and their Wigner function is studied. The overlap coefficients between the squeezed, or generalized harmonic, and the Fock states are explicitly evaluated in terms of hypergeometric functions. The corresponding photons statistics are discussed and some applications to quantum optics, cavity quantum electrodynamics, and superfocusing in channeling scattering are mentioned. Explicit solutions of the Heisenberg equations for radiation field operators with squeezing are found.Comment: 27 pages, no figures, 174 references J. Phys. B: At. Mol. Opt. Phys., Special Issue celebrating the 20th anniversary of quantum state engineering (R. Blatt, A. Lvovsky, and G. Milburn, Guest Editors), May 201

Clinical and Research Considerations for Patients with Hypertensive Acute Heart Failure

Management approaches for patients in the emergency department (ED) who present with acute heart failure (AHF) have largely focused on intravenous diuretics. Yet, the primary pathophysiologic derangement underlying AHF in many patients is not solely volume overload. Patients with hypertensive AHF (H-AHF) represent a clinical phenotype with distinct pathophysiologic mechanisms that result in elevated ventricular filling pressures. To optimize treatment response and minimize adverse events in this subgroup, we propose that clinical management be tailored to a conceptual model of disease based on these mechanisms. This consensus statement reviews the relevant pathophysiology, clinical characteristics, approach to therapy, and considerations for clinical trials in ED patients with H-AHF

Monocot plastid phylogenomics, timeline, net rates of species diversification, the power of multiâ gene analyses, and a functional model for the origin of monocots

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/1/ajb21178-sup-0009-AppendixS9.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/2/ajb21178-sup-0020-AppendixS20.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/3/ajb21178.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/4/ajb21178-sup-0019-AppendixS19.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/5/ajb21178-sup-0010-AppendixS10.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/6/ajb21178-sup-0002-AppendixS2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/7/ajb21178-sup-0006-AppendixS6.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/8/ajb21178-sup-0012-AppendixS12.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/9/ajb21178-sup-0017-AppendixS17.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/10/ajb21178-sup-0007-AppendixS7.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/11/ajb21178-sup-0001-AppendixS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/12/ajb21178-sup-0003-AppendixS3.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/13/ajb21178-sup-0016-AppendixS16.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/14/ajb21178_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/15/ajb21178-sup-0008-AppendixS8.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/16/ajb21178-sup-0004-AppendixS4.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/17/ajb21178-sup-0018-AppendixS18.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/18/ajb21178-sup-0014-AppendixS14.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/19/ajb21178-sup-0011-AppendixS11.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/20/ajb21178-sup-0005-AppendixS5.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146610/21/ajb21178-sup-0015-AppendixS15.pd

Effect of a Hospital and Postdischarge Quality Improvement Intervention on Clinical Outcomes and Quality of Care for Patients With Heart Failure With Reduced Ejection Fraction: The CONNECT-HF Randomized Clinical Trial

Importance: Adoption of guideline-directed medical therapy for patients with heart failure is variable. Interventions to improve guideline-directed medical therapy have failed to consistently achieve target metrics, and limited data exist to inform efforts to improve heart failure quality of care. Objective: To evaluate the effect of a hospital and postdischarge quality improvement intervention compared with usual care on heart failure outcomes and care. Design, Setting, and Participants: This cluster randomized clinical trial was conducted at 161 US hospitals and included 5647 patients (2675 intervention vs 2972 usual care) followed up after a hospital discharge for acute heart failure with reduced ejection fraction (HFrEF). The trial was performed from 2017 to 2020, and the date of final follow-up was August 31, 2020. Interventions: Hospitals (n = 82) randomized to a hospital and postdischarge quality improvement intervention received regular education of clinicians by a trained group of heart failure and quality improvement experts and audit and feedback on heart failure process measures (eg, use of guideline-directed medical therapy for HFrEF) and outcomes. Hospitals (n = 79) randomized to usual care received access to a generalized heart failure education website. Main Outcomes and Measures: The coprimary outcomes were a composite of first heart failure rehospitalization or all-cause mortality and change in an opportunity-based composite score for heart failure quality (percentage of recommendations followed). Results: Among 5647 patients (mean age, 63 years; 33% women; 38% Black; 87% chronic heart failure; 49% recent heart failure hospitalization), vital status was known for 5636 (99.8%). Heart failure rehospitalization or all-cause mortality occurred in 38.6% in the intervention group vs 39.2% in usual care (adjusted hazard ratio, 0.92 [95% CI, 0.81 to 1.05). The baseline quality-of-care score was 42.1% vs 45.5%, respectively, and the change from baseline to follow-up was 2.3% vs -1.0% (difference, 3.3% [95% CI, -0.8% to 7.3%]), with no significant difference between the 2 groups in the odds of achieving a higher composite quality score at last follow-up (adjusted odds ratio, 1.06 [95% CI, 0.93 to 1.21]). Conclusions and Relevance: Among patients with HFrEF in hospitals randomized to a hospital and postdischarge quality improvement intervention vs usual care, there was no significant difference in time to first heart failure rehospitalization or death, or in change in a composite heart failure quality-of-care score. Trial Registration: ClinicalTrials.gov Identifier: NCT03035474

Population structure, connectivity, and demographic history of an apex marine predator, the bull shark <i>Carcharhinus leucas</i>

Knowledge of population structure, connectivity, and effective population size remains limited for many marine apex predators, including the bull shark Carcharhinus leucas. This large‐bodied coastal shark is distributed worldwide in warm temperate and tropical waters, and uses estuaries and rivers as nurseries. As an apex predator, the bull shark likely plays a vital ecological role within marine food webs, but is at risk due to inshore habitat degradation and various fishing pressures. We investigated the bull shark\u27s global population structure and demographic history by analyzing the genetic diversity of 370 individuals from 11 different locations using 25 microsatellite loci and three mitochondrial genes (CR, nd4, and cytb). Both types of markers revealed clustering between sharks from the Western Atlantic and those from the Western Pacific and the Western Indian Ocean, with no contemporary gene flow. Microsatellite data suggested low differentiation between the Western Indian Ocean and the Western Pacific, but substantial differentiation was found using mitochondrial DNA. Integrating information from both types of markers and using Bayesian computation with a random forest procedure (ABC‐RF), this discordance was found to be due to a complete lack of contemporary gene flow. High genetic connectivity was found both within the Western Indian Ocean and within the Western Pacific. In conclusion, these results suggest important structuring of bull shark populations globally with important gene flow occurring along coastlines, highlighting the need for management and conservation plans on regional scales rather than oceanic basin scale