bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serial hemoglobin monitoring in adult patients with blunt solid organ injury: less is more
Authors: Madbak Firas , Price Dustin , Skarupa David , Yorkgitis Brian , Ebler David , Hsu Albert , Kerwin Andrew James , Crandall Marie 
Published: May 2020

BackgroundPatients who sustain blunt solid organ injury to the liver, spleen, or kidney and are treated nonoperatively frequently undergo serial monitoring of their hemoglobin (Hb). We hypothesized that among initially hemodynamically stable patients with blunt splenic, hepatic, or renal injuries treated without an operation, scheduled monitoring of serum Hb values may be unnecessary as hemodynamic instability, not merely Hb drop, would prompt intervention.MethodsWe performed a retrospective review of patients admitted to our urban Level 1 trauma center following blunt trauma with any grade III, IV, or V liver, spleen, or kidney injury from January 1, 2016 to December 31, 2016. Patients who were hemodynamically unstable and went directly to the operating room or interventional radiology were excluded. Patients who required any urgent or unplanned operative or angiographic intervention were compared with patients who did not require an intervention. Routine demographic and outcome variables were obtained and bivariate and multivariate regression statistics were performed using Stata V.10.ResultsA total of 138 patients were included in the study. Age (39.3 vs 41.4, p=0.51), mean injury severity score (26.7 vs 22.1, p=0.12), and admission Hb (11.9 vs 12.8, p=0.06) did not differ significantly between the two groups. The number of Hb draws (9.2 vs 10, p=0.69) and the associated change in Hb (3.7 vs 3.5, p=0.71) did not differ significantly between the two groups. Only splenic grade predicted need for urgent intervention (3.5 vs 2, p<0.001). All patients who required an operative or radiologic intervention did so based on change in hemodynamics or severity of splenic grade, per our institutional protocol, and not Hb trend.DiscussionAmong patients with blunt solid organ injury, a need for emergent intervention in the form of laparotomy or angioembolization occurs within the first hours of injury. Routine scheduled Hb measurements did not change management in our cohort.Level of evidenceLevel III.
Variability in subcutaneous fat composition of Iberian pigs reared in free-range conditions in the southwest of the Iberian Peninsula
Authors: Tejeda J.F. , Hernández-Matamoros A. , García-Cascos J.M. , González E. 
Published: May 2020

A total of 80 free-range Iberian pigs reared with acorns and grass in eight different free-range systems (n = 10) in the southwest of the Iberian Peninsula were used to determine the relationship between fatty acid, tocopherol, and neophytadiene subcutaneous fat composition. The pigs were fed extensively for 79.1 ± 9.5 d from 110.9 ± 11.9 kg live weight at the beginning of the final fattening phase to 175.0 ± 15.9 kg slaughtered weight. Quercus suber and Quercus rotundifolia acorns were characterised by a high content of C18:1n-9 (58.3 and 63.1%, respectively) and γ-tocopherol [43.7 and 43.0 mg kg−1 dry matter (DM), respectively], while grass exhibited a high content of C18:3n-3 (42.5%), α-tocopherol (366.5 mg kg−1 DM) and neophytadiene (136.2 relative area units). The C18:1n-9 (54.4%–57.7%) and γ-tocopherol (2.7–4.1 mg kg−1 DM) contents in subcutaneous fat from Iberian pigs differed (p < 0.001) between the free-range systems studied. Pasture intake had a significant effect (p < 0.01) on subcutaneous fat content of C18:3n-3 (0.5%–0.8%), α-tocopherol (7.8–13.1 mg kg−1 DM) and neophytadiene (2.6–6.3 relative area units). However, the results demonstrated no correlations between accumulated levels of these compounds throughout the free-range period. In conclusion, the absence of correlations corroborated the heterogeneity of extensive rearing systems, with variations between years and geographical areas where the Iberian pigs were reared.
Mixed state entanglement for holographic axion model
Authors: Huang Yi-fei , Shi Zi-jian , Niu Chao , Zhang Cheng-yong , Liu Peng 
Published: May 2020

AbstractWe study the mixed state entanglement in a holographic axion model. We find that the holographic entanglement entropy (HEE), mutual information (MI) and entanglement of purification (EoP) exhibit very distinct behaviors with system parameters. The HEE exhibits universal monotonic behavior with system parameters, while the behaviors of MI and EoP relate to the specific system parameters and configurations. We find that MI and EoP can characterize mixed state entanglement better than HEE since they are less affected by thermal effects. Specifically, the MI partly cancels out the thermal entropy contribution, while the holographic EoP is not dictated by the thermal entropy in any situation. Moreover, we argue that EoP is more suitable for describing mixed state entanglement than MI. Because the MI of large configurations are still dictated by the thermal entropy, while the EoP will never be controlled only by the thermal effects.
Positivity in the effective field theory of cosmological perturbations
Authors: Ye Gen , Piao Yun-Song 
Published: May 2020

AbstractRequiring the existence of a unitary, causal and local UV-completion places a set of positivity bounds on the corresponding effective field theories (EFTs). We discuss the obstructions and possibility in applying the positivity bound to cosmology, in particular the EFT of cosmological perturbations. Taking a $$c_T=1$$cT=1 beyond-Horndeski EFT as an illustrative example, we derive such bounds, which incorporate the cosmological correction of order $$H^2/\Lambda ^2$$H2/Λ2, $$\Lambda $$Λ being the cutoff scale. The derived bounds are applied to slow-roll inflation with beyond Horndeski operators. It is found that the cosmological positivity bounds may be either stronger or weaker than their flat space counterpart.
Comparison of topological charge definitions in Lattice QCD
Authors: Alexandrou Constantia , Athenodorou Andreas , Cichy Krzysztof , Dromard Arthur , Garcia-Ramos Elena , Jansen Karl , Wenger Urs , Zimmermann Falk 
Published: May 2020

AbstractIn this paper, we show a comparison of different definitions of the topological charge on the lattice. We concentrate on one small-volume ensemble with 2 flavours of dynamical, maximally twisted mass fermions and use three more ensembles to analyze the approach to the continuum limit. We investigate several fermionic and gluonic definitions. The former include the index of the overlap Dirac operator, the spectral flow of the Wilson–Dirac operator and the spectral projectors. For the latter, we take into account different discretizations of the topological charge operator and various smoothing schemes to filter out ultraviolet fluctuations: the gradient flow, stout smearing, APE smearing, HYP smearing and cooling. We show that it is possible to perturbatively match different smoothing schemes and provide a well-defined smoothing scale. We relate the smoothing parameters for cooling, stout and APE smearing to the gradient flow time $$\tau $$τ. In the case of hypercubic smearing the matching is performed numerically. We investigate which conditions have to be met to obtain a valid definition of the topological charge and susceptibility and we argue that all valid definitions are highly correlated and allow good control over topology on the lattice.
Artificial Intelligence Will Not Replace Health Professionals, but the Proper Use of Artificial Intelligence Will Make Health Professionals Better
Authors: Rodriguez-Antolin Carlos 
Published: May 2020

Abstract
Deep learning has enabled great advances to be made in cancer research with regards to diagnosis, prognosis, and treatment. The study by Wang and colleagues in this issue of Cancer Research develops a deep learning algorithm with the ability to digitally stain histologic images, achieving reliable nuclei segmentation and cell classification. They use this tool to study the tumor morphologic microenvironment in tissue pathology images of patients with lung adenocarcinoma. On the basis of the image features, they develop a prognostic model and find correlations with the transcriptional activities of biological pathways.
See related article by Wang et al., p. 2056
Preclinical and Dose-Finding Phase I Trial Results of Combined Treatment with a TORC1/2 Inhibitor (TAK-228) and Aurora A Kinase Inhibitor (Alisertib) in Solid Tumors
Authors: Davis S. Lindsey , Ionkina Anastasia A. , Bagby Stacey M. , Orth James D. , Gittleman Brian , Marcus Joshua M. , Lam Elaine T. , Corr Bradley R. , O'Bryant Cindy L. , Glode Ashley E. , Tan Aik-Choon , Kim Jihye , Tentler John J. , Capasso Anna , Lopez Kyrie L. , Gustafson Daniel L. , Messersmith Wells A. , Leong Stephen , Eckhardt S. Gail , Pitts Todd M. , Diamond Jennifer R. 
Published: May 2020

Abstract

Purpose:
The purpose of this study was to evaluate the rational combination of TORC1/2 inhibitor TAK-228 and Aurora A kinase inhibitor alisertib in preclinical models of triple-negative breast cancer (TNBC) and to conduct a phase I dose escalation trial in patients with advanced solid tumors.

Experimental Design:
TNBC cell lines and patient-derived xenograft (PDX) models were treated with alisertib, TAK-228, or the combination and evaluated for changes in proliferation, cell cycle, mTOR pathway modulation, and terminal cellular fate, including apoptosis and senescence. A phase I clinical trial was conducted in patients with advanced solid tumors treated with escalating doses of alisertib and TAK-228 using a 3+3 design to determine the maximum tolerated dose (MTD).

Results:
The combination of TAK-228 and alisertib resulted in decreased proliferation and cell-cycle arrest in TNBC cell lines. Treatment of TNBC PDX models resulted in significant tumor growth inhibition and increased apoptosis with the combination. In the phase I dose escalation study, 18 patients with refractory solid tumors were enrolled. The MTD was alisertib 30 mg b.i.d. days 1 to 7 of a 21-day cycle and TAK-228 2 mg daily, continuous dosing. The most common treatment-related adverse events were neutropenia, fatigue, nausea, rash, mucositis, and alopecia.

Conclusions:
The addition of TAK-228 to alisertib potentiates the antitumor activity of alisertib in vivo, resulting in increased cell death and apoptosis. The combination is tolerable in patients with advanced solid tumors and should be evaluated further in expansion cohorts with additional pharmacodynamic assessment.
FGFR2c Mesenchymal Isoform Expression Is Associated with Poor Prognosis and Further Refines Risk Stratification within Endometrial Cancer Molecular Subtypes
Authors: Sengal Asmerom T. , Patch Ann-Marie , Snell Cameron E. , Smith Deborah S. , Leung Samuel C.Y. , Talhouk Aline , Williams Elizabeth D. , McAlpine Jessica N. , Pollock Pamela M. 
Published: May 2020

Abstract

Purpose:
The two most common molecular subtypes of endometrial cancers, mismatch repair deficient (MMRd) and p53 wild-type (p53wt) comprise the majority of endometrial cancers and have intermediate prognoses where additional risk stratification biomarkers are needed. Isoform switching of FGFR2 from FGFR2b to FGFR2c (normally expressed in mesenchymal cells), has been reported in other solid carcinomas. The objective of this study was to investigate the role of FGFR2c in risk stratification of endometrial cancer.

Experimental Design:
We have developed and optimized a BaseScope RNA ISH assay to detect FGFR2c. FGFR2c expression was determined in a preliminary screening cohort of 78 endometrial cancers and a clinically and molecularly annotated Vancouver cohort (n = 465). Cox regression model analyses were performed to assess the prognostic value of FGFR2c.

Results:
Univariate and multivariate analyses revealed FGFR2c expression was significantly associated with shorter disease-specific survival (DSS) and progression-free survival (PFS) in endometrioid endometrial cancer (EEC, n = 302). Notably, FGFR2c expression was significantly associated with shorter PFS and DSS in patients with grade 3 EECs (P &lt; 0.003 and P &lt; 0.002) and the European Society Medical Oncology (ESMO) high-risk group (P &lt; 0.0001 and P &lt; 0.002), respectively. Moreover, within the MMRd subtype, FGFR2c expression was significantly associated with shorter PFS (P &lt; 0.048) and DSS (P &lt; 0.001).

Conclusions:
FGFR2c expression appears an independent prognostic biomarker in patients with EEC and further discerns the outcomes within grade 3 tumors, ESMO high-risk groups, as well as within the MMRd and p53wt subtypes. FGFR2c inclusion into future molecular subtyping can further refine risk stratification of EEC.
PKC (Protein Kinase C)-δ Modulates AT (Antithrombin) Signaling in Vascular Endothelial Cells
Authors: Panicker Sumith R. , Biswas Indranil , Giri Hemant , Cai Xiaofeng , Rezaie Alireza R. 
Published: May 2020

Objective:
Native and latent conformers of AT (antithrombin) induce anti-inflammatory and proapoptotic signaling activities, respectively, in vascular endothelial cells by unknown mechanisms. Synd-4 (syndecan-4) has been identified as a receptor that is involved in transmitting signaling activities of AT in endothelial cells.

Approach and Results:
In this study, we used flow cytometry, signaling assays, immunoblotting and confocal immunofluorescence microscopy to investigate the mechanism of the paradoxical signaling activities of high-affinity heparin (native) and low-affinity heparin (latent) conformers of AT in endothelial cells. We discovered that native AT binds to glycosaminoglycans on vascular endothelial cells via its heparin-binding D-helix to induce anti-inflammatory signaling responses by recruiting PKC (protein kinase C)-δ to the plasma membrane and promoting phosphorylation of the Synd-4 cytoplasmic domain at Ser179. By contrast, the binding of latent AT to endothelial cells to a site(s), which is not competed by the native AT, induces a proapoptotic effect by localizing PKC-δ to the perinuclear/nuclear compartment in endothelial cells. Overexpression of a dominant-negative form of PKC-δ resulted in inhibition of anti-inflammatory and proapoptotic signaling activities of both native and latent AT.

Conclusions:
These results indicate that the native and latent conformers of AT may exert their distinct intracellular signaling effects through differentially modulating the subcellular localization of PKC-δ in endothelial cells.
Aptamer-Based Proteomic Platform Identifies Novel Protein Predictors of Incident Heart Failure and Echocardiographic Traits
Authors: Nayor Matthew , Short Meghan I. , Rasheed Humaira , Lin Honghuang , Jonasson Christian , Yang Qiong , Hveem Kristian , Felix Janine F. , Morrison Alanna C. , Wild Philipp S. , Morley Michael P. , Cappola Thomas P. , Benson Mark D. ,   CHARGE-Heart Failure Working Group,   CHARGE-EchoGen Consortium, Ngo Debby , Sinha Sumita , Keyes Michelle J. , Shen Dongxiao , Wang Thomas J. , Larson Martin G. , Brumpton Ben M. , Gerszten Robert E. , Omland Torbjørn , Vasan Ramachandran S. 
Published: May 2020

Background:
We used a large-scale, high-throughput DNA aptamer-based discovery proteomic platform to identify circulating biomarkers of cardiac remodeling and incident heart failure (HF) in community-dwelling individuals.

Methods:
We evaluated 1895 FHS (Framingham Heart Study) participants (age 55±10 years, 54% women) who underwent proteomic profiling and echocardiography. Plasma levels of 1305 proteins were related to echocardiographic traits and to incident HF using multivariable regression. Statistically significant protein-HF associations were replicated in the HUNT (Nord-Trøndelag Health) study (n=2497, age 63±10 years, 43% women), and results were meta-analyzed. Genetic variants associated with circulating protein levels (pQTLs) were related to echocardiographic traits in the EchoGen (n=30 201) and to incident HF in the CHARGE (n=20 926) consortia.

Results:

Seventeen proteins associated with echocardiographic traits in cross-sectional analyses (false discovery rate <0.10), and 8 of these proteins had pQTLs associated with echocardiographic traits in EchoGen (
P
<0.0007). In Cox models adjusted for clinical risk factors, 29 proteins demonstrated associations with incident HF in FHS (174 HF events, mean follow-up 19 [limits, 0.2–23.7] years). In meta-analyses of FHS and HUNT, 6 of these proteins were associated with incident HF (
P
<3.8×10
−
5
; 3 with higher risk: NT-proBNP [N-terminal proB-type natriuretic peptide], TSP2 [thrombospondin-2], MBL [mannose-binding lectin]; and 3 with lower risk: ErbB1 [epidermal growth factor receptor], GDF-11/8 [growth differentiation factor-11/8], and RGMC [hemojuvelin]). For 5 of the 6 proteins, pQTLs were associated with echocardiographic traits (
P
<0.0006) in EchoGen, and for RGMC, a protein quantitative trait loci was associated with incident HF (
P
=0.001).

Conclusions:
A large-scale proteomics approach identified new predictors of cardiac remodeling and incident HF. Future studies are warranted to elucidate how biological pathways represented by these proteins may mediate cardiac remodeling and HF risk and to assess if these proteins can improve HF risk prediction.
Relationship Between Left Ventricular Geometry and Invasive Hemodynamics in Pediatric Pulmonary Hypertension
Authors: Burkett Dale A. , Patel Sonali S. , Mertens Luc , Friedberg Mark K. , Ivy D. Dunbar 
Published: May 2020

Background
Ventricular septal flattening, frequently present in pulmonary hypertension (PH), can be quantified using eccentricity index (EI). EI has not been evaluated by concurrent echocardiography and cardiac catheterization and traditionally does not account for postsystolic septal flattening, often seen in PH. We evaluated left ventricular shape, including a novel measure of maximal EI to account for postsystolic septal flattening, to establish the relationship with concurrent invasive hemodynamics.

Methods
Echocardiography was performed at 2 institutions in 78 pediatric PH patients during cardiac catheterization and in 78 matched controls. From midpapillary parasternal short-axis views, EI and right-to-left ventricular diameter ratio were assessed.

Results
EI and right-to-left ventricular measures were significantly increased in PH compared with controls. Shape measures correlated with invasive hemodynamics and PH outcome measures (PH-related hospitalization, functional class, medical therapy escalation, and BNP [brain natriuretic peptide]). End-systolic EI of 1.16 best identified the presence of PH, whereas a maximal EI of 1.42 and 1.94 best identified half-systemic and systemic PH, respectively. A maximal EI of 1.27 was associated with an odds ratio of 16.16 (95% CI, 6.62–39.46) for PH-related hospitalization or escalation of therapy.

Conclusions
Using simultaneous echocardiography and catheterization in the largest study population to date, we demonstrate that EI and right-to-left ventricular ratio correlate with invasive hemodynamics and outcomes measures, and EI can accurately define those with clinically important PH. These measures strengthen the ability of echocardiography to identify and follow pediatric PH patients, especially in the absence of methods to quantify right ventricular systolic pressures.
Diffusion Tensor Cardiovascular Magnetic Resonance in Cardiac Amyloidosis
Authors: Khalique Zohya , Ferreira Pedro F. , Scott Andrew D. , Nielles-Vallespin Sonia , Martinez-Naharro Ana , Fontana Marianna , Hawkins Phillip , Firmin David N. , Pennell Dudley J. 
Published: May 2020

Background
Cardiac amyloidosis (CA) is a disease of interstitial myocardial infiltration, usually by light chains or transthyretin. We used diffusion tensor cardiovascular magnetic resonance (DT-CMR) to noninvasively assess the effects of amyloid infiltration on the cardiac microstructure.

Methods
DT-CMR was performed at diastole and systole in 20 CA, 11 hypertrophic cardiomyopathy, and 10 control subjects with calculation of mean diffusivity, fractional anisotropy, and sheetlet orientation (secondary eigenvector angle).

Results

Mean diffusivity was elevated and fractional anisotropy reduced in CA compared with both controls and hypertrophic cardiomyopathy (
P
<0.001). In CA, mean diffusivity was correlated with extracellular volume (
r
=0.68,
P
=0.004), and fractional anisotropy was inversely correlated with circumferential strain (
r
=−0.65,
P
=0.02). In CA, diastolic secondary eigenvector angle was elevated, and secondary eigenvector angle mobility was reduced compared with controls (both
P
<0.001). Diastolic secondary eigenvector angle was correlated with amyloid burden measured by extracellular volume in transthyretin, but not light chain amyloidosis.

Conclusions
DT-CMR can characterize the microstructural effects of amyloid infiltration and is a contrast-free method to identify the location and extent of the expanded disorganized myocardium. The diffusion biomarkers mean diffusivity and fractional anisotropy effectively discriminate CA from hypertrophic cardiomyopathy. DT-CMR demonstrated that failure of sheetlet relaxation in diastole correlated with extracellular volume in transthyretin, but not light chain amyloidosis. This indicates that different mechanisms may be responsible for impaired contractility in CA, with an amyloid burden effect in transthyretin, but an idiosyncratic effect in light chain amyloidosis. Consequently, DT-CMR offers a contrast-free tool to identify novel pathophysiology, improve diagnostics, and monitor disease through noninvasive microstructural assessment.
Transcriptional and Cellular Diversity of the Human Heart
Authors: Tucker Nathan R. , Chaffin Mark , Fleming Stephen J. , Hall Amelia W. , Parsons Victoria A. , Bedi Kenneth C. , Akkad Amer-Denis , Herndon Caroline N. , Arduini Alessandro , Papangeli Irinna , Roselli Carolina , Aguet François , Choi Seung Hoan , Ardlie Kristin G. , Babadi Mehrtash , Margulies Kenneth B. , Stegmann Christian M. , Ellinor Patrick T. 
Published: May 2020

Background:
The human heart requires a complex ensemble of specialized cell types to perform its essential function. A greater knowledge of the intricate cellular milieu of the heart is critical to increase our understanding of cardiac homeostasis and pathology. As recent advances in low-input RNA sequencing have allowed definitions of cellular transcriptomes at single-cell resolution at scale, we have applied these approaches to assess the cellular and transcriptional diversity of the nonfailing human heart.

Methods:
Microfluidic encapsulation and barcoding was used to perform single nuclear RNA sequencing with samples from 7 human donors, selected for their absence of overt cardiac disease. Individual nuclear transcriptomes were then clustered based on transcriptional profiles of highly variable genes. These clusters were used as the basis for between-chamber and between-sex differential gene expression analyses and intersection with genetic and pharmacologic data.

Results:
We sequenced the transcriptomes of 287 269 single cardiac nuclei, revealing 9 major cell types and 20 subclusters of cell types within the human heart. Cellular subclasses include 2 distinct groups of resident macrophages, 4 endothelial subtypes, and 2 fibroblast subsets. Comparisons of cellular transcriptomes by cardiac chamber or sex reveal diversity not only in cardiomyocyte transcriptional programs but also in subtypes involved in extracellular matrix remodeling and vascularization. Using genetic association data, we identified strong enrichment for the role of cell subtypes in cardiac traits and diseases. Intersection of our data set with genes on cardiac clinical testing panels and the druggable genome reveals striking patterns of cellular specificity.

Conclusions:
Using large-scale single nuclei RNA sequencing, we defined the transcriptional and cellular diversity in the normal human heart. Our identification of discrete cell subtypes and differentially expressed genes within the heart will ultimately facilitate the development of new therapeutics for cardiovascular diseases.