bluuebunny/crossref_metadata_2025 huggingface dataset:
The elastic vacuum
Authors: Mathur Samir D.
Published: July 2021

The quantum gravity vacuum must contain virtual fluctuations of black hole microstates. These extended-sized fluctuations get “crushed” when a closed trapped surface forms, and turn into on-shell “fuzzball” states that resolve the information puzzle. We argue that these same fluctuations can get “stretched” by the anti-trapped surfaces in an expanding cosmology, and that this stretching generates vacuum energy. The stretching happens when the Hubble deceleration reduces quickly, which happens whenever the pressure drops quickly. We thus get an inflation-scale vacuum energy when the heavy GUTS particles become nonrelativistic, and again a small vacuum energy when the radiation phase turns to dust. The expansion law in the radiation phase does not allow stretching, in agreement with the observed irrelevance of vacuum energy in that phase.
Magmatism in the Siang window of the Eastern Himalayan Syntaxis, NE India: a vestige of Kerguelen mantle plume activity
Authors: Singh Athokpam Krishnakanta , Oinam Govind , Chung Sun-Lin , Bikramaditya R. K. , Lee Hao-Yang , Joshi Mallickarjun
Published: July 2021

We report new U–Pb zircon ages for mafic plutonic (gabbro) and volcanic (andesite) rocks, along with the whole-rock chemistry of a mafic–felsic suite of volcanic rocks from the Siang window of the Eastern Himalayan Syntaxis, NE India. Field relationships, and mineralogical and geochemical characteristics, of the studied mafic–intermediate–felsic rocks suggest their co-magmatic linkage that was generated in an extensional tectonic environment. Incompatible trace elements and low concentrations of large ion lithophile elements (LILEs) and REE behaviour reflect both the enriched nature of the mafic rocks and the limited influence of crustal contamination in their genesis. Partial melting and fractional crystallization processes have played a major role during the genesis of these felsic volcanics from the parental mafic magma. The laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) zircon U–Pb ages suggest that the mafic plutonic rock was emplaced at
c.
121.18 ± 1 Ma and intermediate volcanic rock was emplaced at
c.
135.48 ± 0.50 Ma during the Early Cretaceous period. The new ages are consistent with earlier reported zircon U–Pb ages (133.0 ± 1.9–130.7 ± 1.8 Ma) of felsic volcanic rocks from the present study area. Our new field observations, and mineralogical and geochemical characteristics, in conjunction with the U–Pb isotopic database suggest that the major magmatic event in the core of the Siang window of the Eastern Himalaya is coeval with the Rajmahal–Sylhet–Mikir–Shillong flood basalts of eastern and northeastern India, and the Comei–Bunbury Large Igneous Province of southeastern Tibet and SW Australia. These events are related to the break-up of eastern Gondwana and outbreak of the Kerguelen plume.
An Artificial Interface for High Cell Voltage Aqueous-Based Electrochemical Capacitors
Authors: Olarte Marco , Menu Marie-Joelle , Simon Patrice , Gressier Marie , Taberna Pierre-Louis
Published: July 2021

Aqueous electrolytes are very effective for supercapacitor applications but their narrow electrochemical potential window (∼1 V) and associated limited energy currently limits their use. Here, we demonstrate a new strategy to enlarge the potential window by designing an artificial interface (ai). An effective ai was achieved via a mixture of siloxanes doped with an ionic liquid, 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (EMI TFSI). Indeed, the as-deposited ai on the carbon-based electrode hinders the electron charge transfer but not the ionic charge transfer, making the ai ionic conductive. As a result, a cell voltage of about 1.8 V was obtained in aqueous electrolyte-EMI HSO4 1 mol l−1 in water. Used as a membrane, the ai was found to be ionically specific to EMI+; the proton transference number being close to zero. These results show the strategy of developing an ai at the electrode/electrolyte interface could represent a new path for aqueous-based carbon-carbon supercapacitors to reach higher cell voltages, providing both higher specific energy and power.
Northern Long-Eared Bat (Myotis septentrionalis) Day-Roost Loss in the Central Appalachian Mountains following Prescribed Burning
Authors: Ford W. Mark , Johnson Joshua B. , Thomas-Van Gundy Melissa
Published: July 2021

Before the arrival of white-nose syndrome in North America, the northern long-eared bat (Myotis septentrionalis) was a common cavity-roosting bat species in central Appalachian hardwood forests. Two successive prescribed burns on the Fernow Experimental Forest, West Virginia, in 2008 and 2009, were shown to positively affect maternity colony day-roost availability and condition in the near-term. However, whether immediate benefits were temporary and if burned forests actually experienced an accelerated loss of trees and snags possibly suitable for bats more than background loss in unburned forests became an important question following the species’ threatened designation. In 2016, we revisited 81 of 113 northern long-eared bat maternity colony day-roosts initially discovered in 2007–2009 with the objective of ascertaining if these trees and snags were still standing and thus potentially “available” for bat use. Initial tree or snag stage condition class and original year of discovery were contributory factors determining availability by 2016, whereas exposure to prescribed fire and tree/snag species decay resistance were not. Because forest managers may consider using habitat enhancement to improve northern long-eared bat survival, reproduction, and juvenile recruitment and must also protect documented day-roosts during forestry operations, we conclude that initial positive benefits from prescribed burning did not come at the expense of subsequent day-roost loss greater than background rates in these forests at least for the duration we examined.
Factors Associated with Malaria Preventive Measures among Pregnant Women in Guinea
Authors: Diallo Abdourahamane , Touré Almamy Amara , Doumbouya Abdoulaye , Magassouba Aboubacar Sidiki , Traoré Falaye , Cissé Mamady , Barry Ibrahima , Conté Ibrahima , Cissé Diao , Cissé Abdourahim , Camara Gnoume , Bérété Alpha Oumar , Camara Alsény Yarie , Conté Naby Yaya , Beavogui Abdoul Habib
Published: July 2021

Background. Malaria control interventions have been scaled up, particularly those in pregnant women in Guinea. Despite that, coverage of key malaria preventive measure (MPM) indicators remains low. Therefore, it is vital to understand the reasons behind that, especially for the low coverage of sulfadoxine-pyrimethamine (SP) and long-lasting insecticide-treated bed nets (LLIN). Methods. We conducted a cross-sectional survey in nine district hospitals in Guinea. Pregnant women received for delivery were interviewed to collect sociodemographic and obstetrical parameters. Associated factors with MPMs were investigated through univariate analysis and classification and regression tree (CART). Results. A total of 2248 parturients participated in this study. Among pregnant women using mosquito nets (63.5% (61.4%, 65.5%)), only 41.2% (39.1%, 43.3%) had used it regularly during the last two weeks preceding delivery. Similarly, most pregnant women (57.9% (55.8%, 59.9%)) had received less than three doses of SP, and only a few pregnant women (23.9% (22.1%, 25.7%)) have benefited from full MPMs. Parturient’s age, marital status, time spent in residence, place of residence, level of education, distance from home to the health centre, health conditions, occupation, head of the household’s occupation, the presence of garbage and stagnant water in the neighbourhood, source of running water, and the number of pregnancies were significantly statistically associated with MPMs in pregnant women. However, the number of antenatal care visits (ANC), means of transportation used by the pregnant woman to accomplish ANCs, and stagnant water in the neighbourhood were the three preponderant factors. Conclusion. The low coverage of SP and LLINs among pregnant women requires revitalising some strategies, especially improving ANC coverage and more efforts to reduce inequalities in access to those services due to sociodemographic status. Education on the benefits of these MPMs should also be emphasised.
Time until Need for Levodopa among New Users of Dopamine Agonists or MAO-B Inhibitors
Authors: Binde Caroline D. , Tvete Ingunn F. , Klemp Marianne
Published: July 2021

Objective. To investigate the use of dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors in the Norwegian population, between 1 July 2006 and 31 December 2016. Our primary endpoint was time until need for levodopa among new monotherapy users of dopamine agonists and MAO-B inhibitors. Methods. A prospective cohort study including all patients, aged 50 years or above, who had at least one prescription for a dopamine agonist or a MAO-B inhibitor dispensed in the study period. We used data from the Norwegian Prescription Database (NorPD). As we wished to focus on new Parkinson patients, we excluded patients who had levodopa dispensed less than 180 days prior to their first dopamine agonist or MAO-B inhibitor redemption. We explored the demographics and the time until monotherapy was insufficient treatment (defined as need for levodopa prescription). Results. We included 22958 new monotherapy users. Of these, 22108 used dopamine agonists and 850 used MAO-B inhibitors. The mean number of days until the first prescription of levodopa was dispensed was higher among the dopamine agonist users (621 days) compared to the MAO-B inhibitor users (352 days). The proportion of dopamine agonist users who started levodopa treatment during the study period was less than 7%, while the corresponding proportion of MAO-B inhibitor users was almost 59%. Conclusions. We found that new dopamine agonist users had a much greater delay in the need for levodopa than new MAO-B inhibitor users. It seems to be beneficial to initiate treatment with dopamine agonists when starting pharmacological treatment for new Parkinson patients.
An Intragroup and Intergroup Multiple Secret Images’ Sharing Scheme with Each Participant Holding One Shadow Image
Authors: Wang Jiayu , Yan Xuehu , Chen Jia , Yu Yongqiang
Published: July 2021

In some particular situations, participants need to recover different secrets both within a group (i.e., intragroup) and between two groups (i.e., intergroup). However, most of the existing multilevel secret sharing (MLSS) and multigroup secret sharing (MGSS) schemes mainly focus on how to protect a secret between one or more groups. In this paper, we propose a polynomial-based scheme to share multiple secret images both within a group and between groups. The random elements’ utilization model of integer linear programming is used to find polynomial coefficients that meet certain conditions so that each participant holds only one shadow image and some of them can recover secrets of both intergroup and intragroup. In addition, our scheme based on polynomials has the advantage of low computational complexity. Theoretical analysis and experiments show that the proposed scheme is feasible and effective.
Determination of Pendimethalin Dynamic Residual Distribution in Crucian Carp Tissues and Associated Risk Assessment
Authors: Qiao Lu , Yuan Na , Han Gang , Cheng Bo , Zhang Defu , Song Jinlong , Mu Yingchun
Published: July 2021

Pendimethalin has been considered a moderately to extremely toxic compound for fish and aquatic organism. This study developed the determination of dynamic residual distribution for pendimethalin in crucian carp tissues (muscle, liver, kidney, gill, and blood) under semistatic exposure system by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. The pendimethalin residues in various fish tissues increased initially and then decreased, and the residue amount of pendimethalin varied from tissue to tissue of crucian carp. Particularly, the pendimethalin accumulation in most fish tissues made significant decreases at two-time points. Pendimethalin was initially absorbed and enriched by fish body, and then partial pendimethalin was discharged into the outside environment through the metabolism function of crucian carp. The residue levels of pendimethalin distributed in crucian carp were ranked in the following decreasing order: liver > kidney > gill or muscle > blood, attributed to the fact that pendimethalin tends to accumulate in lipid-rich tissues of fish. Risk assessment results indicated that the chronic risk from dietary exposure to pendimethalin through crucian carp consumption for Chinese residents was acceptable, along with a lower estimated exposure dose (EED) than acceptable daily intake (ADI) and risk quotient (RQ) < 1. This study performed the first analysis for pendimethalin residual distribution in crucian carp tissues under semistatic exposure condition and provided a reference for pollution control and risk assessment of pendimethalin aimed at aquatic products.
Suppression of Extracellular Vesicle VEGF-C–mediated Lymphangiogenesis and Pancreatic Cancer Early Dissemination By a Selective HDAC1/2 Inhibitor
Authors: Wang Chu-An , Li Chien-Feng , Huang Rho-Chi , Li Yo-Hua , Liou Jing-Ping , Tsai Shaw-Jenq
Published: July 2021

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer characterized by early dissemination and poor drug response. Therefore, it is an unmet medical need to develop new strategies for treatment. As aberrant activation of ERK due to KRAS activating mutation is a driving force for PDAC, a brake system that can terminate ERK signaling represents an ideal druggable target. Herein, we demonstrate that forced expression of dual specificity phosphatase-2 (DUSP2), a specific ERK phosphatase, abrogated tumor formation and loss of Dusp2 facilitated Kras-driven PDAC progression. We report that a selective HDAC1/2 inhibitor (B390) has multifaceted therapeutic potential in PDAC by restoring the expression and function of DUSP2. In vitro study showed that treatment with B390 inhibited growth and migration abilities of PDAC cells, decreased extracellular vesicle-associated VEGF-C expression, and suppressed lymphatic endothelial cell proliferation. In vivo, B390 not only suppressed tumor growth by increasing tumor cell death, it also inhibited lymphangiogenesis and lymphovascular invasion. Taken together, our data demonstrate that B390 was able to alleviate loss of DUSP2-mediated pathologic processes, which provides the proof-of-concept evidence to demonstrate the potential of using selective HDAC1/2 inhibitors in PDAC treatment and suggests reinstating DUSP2 expression may be a strategy to subside PDAC progression.
In Vivo Gene Transfection With Hepatocyte Growth Factor via the Pulmonary Artery Induces Angiogenesis in the Rat Lung
Authors: Ono Masamichi , Sawa Yoshiki , Matsumoto Kunio , Nakamura Toshikazu , Kaneda Yasufumi , Matsuda Hikaru
Published: July 2021

Background

Recent studies have demonstrated that gene transfer with hepatocyte growth factor (HGF) induces angiogenesis for coronary and peripheral artery diseases. We investigated the ability of gene transfer with human HGF to induce angiogenesis in the rat lung.

Methods and Results

The left lung was selectively transfected with a cDNA encoding human HGF via the left pulmonary artery, using the HVJ-liposome method (H group); rats transfected with the same vector lacking the HGF gene served as controls (C group). HGF gene transfer significantly increased the capillary density in the left lung compared with the C group 7 days after transfection (15.0±1.3 versus 8.0±1.7 mm
2
,
P
<0.01). The left to right average blood perfusion ratio detected by laser Doppler imaging increased significantly in the H group 14 days after transfection (1.12±0.09 versus 0.91±0.11,
P
<0.01). A right pulmonary artery clamp test, in which only the left lung received all the pulmonary blood flow from the right ventricle, revealed that the increase in right ventricular pressure was significantly attenuated in the H group compared with the C group 7 days after transfection (8.6±3.5 versus 15.3±2.8 mm Hg,
P
<0.01).

Conclusions

Trans-pulmonary arterial transfer of the human HGF gene into the left lung increased capillary density and blood perfusion, and decreased vascular resistance when blood flow increased. These results suggest therapeutic angiogenesis induced by HGF gene expression in the lung may be found suitable in treating subjects with decreased pulmonary vasculature or increased pulmonary vascular resistance.
Reduced Mortality and Strokes With Off-Pump Coronary Artery Bypass Grafting Surgery in Octogenarians
Authors: Demaria Roland G. , Carrier Michel , Fortier Simon , Martineau Raymond , Fortier Annick , Cartier Raymond , Pellerin Michel , Hébert Yves , Bouchard Denis , Pagé Pierre , Perrault Louis P.
Published: July 2021

Background

Off-pump coronary artery bypass surgery (OPCAB) has been revived and has gained popularity, although the exact subsets of patients who might benefit most from this technique are unknown. The aim of this retrospective study was to compare the results of coronary artery bypass grafting surgery (CABG) in octogenarians using cardiopulmonary bypass (CPB) or OPCAB techniques.

Methods and Results

Over a 5-year period (1995–1999), 125 patients older than 80 years of age were operated for isolated myocardial revascularization (63 using CPB and 62 with OPCAB). There was no statistically significant difference in preoperative comorbidities between groups or in mean left ventricular ejection fraction (54.5±15.3% in the CPB group and 50.9±13.5% in the OPCAB group, respectively). The mean number of distal anastomosis per patient was 2.9 in CPB group and 2.6 in OPCAB group (
P
=ns). The majority of patients in both groups had unstable angina and were operated on an urgent basis. The operative mortality was 15.9% in the CPB group and 4.8% in the OPCAB group (
P
=0.04). There were 4 postoperative strokes (6.3%) in the CPB group and none (0%) in the OPCAB group (
P
=0.04). The percentage of patients transfused was 92.1% in the CPB group and 72.6% in the OPCAB group (
P
<0.01). Postoperative myocardial infarction occurred in 11.3% in the CPB group and 14.5% in the OPCAB group (
P
=NS). For all the parameters entered in the multivariate analysis with logistic regression model, the type of surgery (CPB or OPCAB) was an independent predictor of operative mortality and stroke (
P
=0.0375). The odds ratio (OR) indicates that operative mortality and stroke occur 4 times (OR=4.171) more often in CPB patients than in OPCAB patients. Follow-up showed no significant difference between the 2 groups in terms of cardiac events and mortality.

Conclusions

This retrospective study suggests a benefit of OPCAB in terms of operative mortality and stroke for octogenarian patients when compared with CPB in our institution.
Abstract 11: Effects of Canakinumab in Patients With Peripheral Artery Disease
Authors: Russell Kerry S , Yates Denise , Feller Andrea , Wang Tianke , Chen Ping , Clough Timothy , Colin Laurence , LaPerna Lucy , Shennak Mustafa M , Lawall Holger , Nikol Sigrid , Smith William , Forst Thomas , Mueller Oliver J , Hoekstra John , Piatek Marek , Ratchford Elizabeth V , Kramer Christopher M , Basson Craig T
Published: July 2021

Background:
Peripheral artery disease (PAD) affects 8.5 million people in the US. PAD patients are at high risk for cardiovascular events, and their quality of life is often significantly impaired by decreased mobility. Interleukin-1β (IL-1β) may play an important role in this disease by promoting inflammatory responses that drive atherosclerotic plaque progression and impair vascular function. We sought to test whether interruption of IL-1β signaling would improve patient mobility and decrease plaque progression in the lower extremities.

Methods:
38 patients (mean age 65; 71% male) with symptomatic PAD (confirmed by ankle-brachial index) were randomized 1:1 to receive Canakinumab (150 mg subcutaneously) or placebo monthly for up to 12 months. Plaque volume in the superficial femoral artery (SFA) was assessed serially using 3.0T MRI. Mobility was assessed serially using the 6-minute walk test (maximum and pain-free walking distance).

Results:
Canakinumab was safe and well-tolerated. 12 patients discontinued (8 placebo, 4 Canakinumab). MRI data (from 31 patients at 3 months; 21 patients at 12 months) showed no evidence of plaque progression in the SFA at either time point in placebo-treated patients; nor was there a change in plaque volume in the Canakinumab-treated group. There was a serial and significant improvement in placebo-adjusted maximum and pain-free walking distance observed as early as 3 months after treatment with Canakinumab (58-meter improvement over placebo in pain-free distance at 3 months, P=0.01). Two placebo-treated patients required peripheral vascular interventions due to progression of disease; however, no Canakinumab-treated patients required revascularization during the study. Canakinumab decreased markers of systemic inflammation (IL-6 and hsCRP).

Conclusions:
Treatment with Canakinumab may improve maximum and pain-free walk distance in patients with symptomatic PAD. In conjunction with results soon to be reported for the CANTOS trial of Canakinumab for secondary prevention of cardiovascular events, additional studies may provide support that inhibition of IL-1β signaling can improve symptoms and function in this patient population with high unmet need.
Abstract 118: Angina Patients Improve Physical Fitness in 18 Days
Authors: Ramirez Francisco E , Nedley Neil , Sanchez Albert
Published: July 2021

Background:
Angina patients can have difficulty with physical activity. It is known that physical exercise could be beneficial for patients suffering from angina. We document the effect that lifestyle interventions have on metabolic equivalents (MetS). MetS is related to oxygen consumed at rest, higher MetS indicates better physical fitness.

Methods:
A medical residential program took place in the Sierra Mountains in Placer County in California. Patients were referred by their physician or came by themselves to the not for profit program. The program included plant-based meals, stress management, spiritual help, chaplaincy, psychological, physical and medical therapies. Every patient was evaluated by a board certified physician who also conducted a stress test on participants. The stress test was done before and after the program. The Bruce protocol was followed for the stress test, the test gave the initial and final MetS measurements. Patients were monitored daily and every patient did some level of physical exercise according their physical condition. For females 60+ years old a MetS of 5 or less are considered very poor fitness while a MetS of 9 is considered good. For males 60+ MetS of 6 are considered very poor while a MetS of 10 is considered good.

Results:
From 12 years of data 2030 patients participated of the program, from those, n=82 had the diagnosis of angina and they also had a before and after stress test results. Those 82, 50% were females, 47.5% were Caucasian, 20.7% Black and 19.5% Hispanic. Average age for males was 62.2, SD 10.4 and mean age for females was 65.6, SD 11.8. For the females baseline MetS were mean 6.1, SD 2.3, median 6, mode 6, min 2, max 11. End MetS were 7.2, SD 2.6, median 7, mode 5, min 3, max 13. T-test reported significant change t(40)=-6.4,
p
<.001. For the males baseline MetS were mean 7.5, SD 2.6, median 7, mode 7, min 2.5, max 12. End MetS were mean 8.9, SD 2.7, median 9, mode 7, min 4.5, max 15.2. T-test indicates significant change t(40)=-4.9,
p
<.001. Many patients reported less angina events during the program.

Conclusion:
The increase in MetS is a clear indication that the fitness level of these patients improved. The end MetS of this group is related to better prognosis since an increase of MetS means better exercise capacity and may decrease mortality.
Abstract 140: Comparison of Major Complication of Oral Anticoagulants in Non-Valvular Atrial Fibrillation: Systematic Review and Meta-Analyses
Authors: Lee Hong Seok
Published: July 2021

Background:
Oral anticoagulants known as a novel oral anticoagulant have been used for the management of non -valvular atrial fibrillation. There was no enough study regarding the efficacy and safety of three major new oral anticoagulants. We assessed major three oral anticoagulants in terms of major bleeding complication and stroke prevention by meta-analyses studies comparing those drugs.

Method:
Relevant studies were identified through electronic literature searches of MEDLINE, EMBASE, Cochrane library, and clinicaltrials.gov (from inception to February 24, 2016). RevMan and ITC software were used for direct comparisons, respectively.

Results:
Apixaban (N=6020), versus dabigatran(N=12038), apixaban versus rivaroxaban(N=8503) and rivaroxaban versus dabigatran were analyzed directly. There was significantly higher major bleeding risks in apixaban compared to dabigatran (both 110mg and 150mg) after adjusting baseline bleeding risk (Relative risk 3.41, 95% confidence interval(2.61 to 4.47) in 110mg, (5.62, 4.83 to 6.54) in 150mg. Intracranial bleeding risk in apixaban was significantly higher than in dabigatran (10.5, 6.10 to18.01). However, apixaban had less GI bleeding risk compared to dabigatran (0.80 , 0.65 to 0.98) and also had less ischemic stroke risk (0.31,0.22 to 0.42). Rivaroxaban showed higher major bleeding risk than dabigatran 110mg (2.34 , 1.81 to 3.03), however, Rivaroxaban had less bleeding risk compared to dabigatran 150mg (0.41, 0.35 to 0.46). Dabigatran 110mg and 150mg had less GI bleeding risk compared to rivaroxaban (0.31 , 0.24 to 0.39) and (0.23,0.17 to 0.29) respectively. Ischemic stroke risk was also decreased in dabigatran110mg (0.46, 0.38 to 0.57). and 150mg (0.66 ,0.52 to 0.83).

Conclusion:
Observed oral anticoagulants were associated with various complications. Overall, apixaban had higher intracranial bleeding risk than dabigatran. The highest GI bleeding risk in rivaroxaban compared to apixaban and dabigatran. Ischemic stroke risk was the highest in dabigatran. In conclusion, we may use those oral anticoagulant based on risks rates, however, a larger study with longer follow-up is needed to corroborate findings.
Abstract 151: Parsimonious Model for the Detection of Acute Coronary Thrombus
Authors: Amraotkar Alok R , Ghafghazi Shahab , Trainor Patrick J , DeFilippis Andrew P
Published: July 2021

Background:
There is limited data to determine accuracy and precision of detecting acute coronary thrombus via angiography.

Objective:
To build a parsimonious model for the prediction of acute coronary thrombus from four commonly used angiographic characteristics (spherical, ovoid, or irregular filling defect; abrupt vessel cutoff with persistence of contrast; intraluminal staining; any coronary filling defect).

Methods:
Angiographic Core Laboratory (Baltimore, Maryland) evaluated angiograms of 80 acute MI / stable CAD subjects in blinded fashion. Outcome was defined as presence of thrombus by histological examination. Multivariable generalized linear modeling was conducted to determine best combinations of characteristics for discriminating between lesions with a histologically confirmed thrombus versus lesions without a histologically confirmed thrombus.

Results:
A best-fit parsimonious model revealed that individual presence of abrupt vessel cutoff with persistence of contrast (O.R=16, P<0.0001) or any coronary filling defect (O.R=84, P<0.0001), or both in concurrence (O.R=105, P<0.0001) (Figure 1 and Table 1), was most significantly associated with the presence of coronary thrombus.

Conclusions:
Modeling suggests that the presence of abrupt vessel cutoff with persistence of contrast or any filling defect, individually or in concurrence, is significantly associated with acute coronary thrombus, and therefore warrants validation in an independent cohort.
Abstract 152: Pre-chemotherapy Lymphocyte Count as a Predictor of Venous Thromboembolism in Patients With Gastric Cancer
Authors: Fuentes Harry E , Paz Luis H , Oramas Diana M , Andrade Xavier A , Al-Ogaili Ahmed , Tafur Alfonso X
Published: July 2021

Background:
VTE is a largely preventable leading cause of mortality among patients with cancer. Gastric cancer (GC) is one of the most pro-thrombotic solid tumors. The use of effective prophylaxis for cancer-associated thrombosis CAT is anchored on reliable VTE risk stratification. Pre-chemotherapy lymphocytes (PCL) are associated with both arterial and venous thrombosis and play an important role in the thrombogenic pathway; however, their clinical significance in GC CAT is unknown.

Aim:
To test PCL as a predictor of VTE in patients with gastric cancer

Methods:
Single institution chart review of GC treated patients (2010-15). VTE events were objectively confirmed in all cases by imaging. Active cancer was defined as biopsy positive metastatic disease or on chemotherapy. Demographic variables, PCL and potential confounding variables were independently extracted. We present continuous variables as median (interquartile range). Categorical variables are expressed as percentages. SPSS version 23 was used and Chi-square, Mann-Whitney U, and logistic regression with forward modeling were applied.

Results:
We included 112 patients in the analysis who were 58 (51-64) year-old, predominantly male (66%), with adenocarcinoma (84%), and advanced disease (59%). The follow-up was 21.3 months (9.5 - 42.6). VTE occurred in 13 (12%) patients: 4 extremity, 4 splanchnic and 5 pulmonary embolisms. Median PCL was 1.6 (1.0 - 2.1). We selected PLC > 1.75 as optimal cutoff based on the ROC performance for new VTE (sensitivity of 70% and specificity of 67%). PCL >1.75 was an independent predictor of VTE (OR: 4.9; 95%CI: 1.3-18.1; p=0.02) after adjusting for body mass index, performance status and cancer stage.

Conclusion:
PCL independently predicted VTE occurrence among patients with GC. Pending external validation, PCL could be implemented in risk stratification strategies specific to GC thromboprophylaxis
Abstract 153: IL-17 Amplifies Thrombosis in a Mouse Model of DVT
Authors: Jacobs Benjamin N , Kanthi Yogen , Petrovic-Djergovic Danica , Liao Hui , Pinsky David J
Published: July 2021

Background:
Immune cells are known to participate in thrombosis. A subset of IL-17 producing T-cells plays a role in the inflammatory dysregulation of inflammatory bowel disease, malignancy, and acute graft rejection. IL-17 resides at the interface between innate and adaptive immunity, exerting pro-inflammatory effects via induction of cytokines and cellular adhesion molecules, with consequent neutrophil activation and mobilization. Inflammatory properties of endothelium itself direct T-cell plasticity, and we have previously demonstrated that endothelial CD39 is an important inflammatory regulator via degradation of pro-inflammatory nucleotides. It is unknown whether IL-17 affects development of thrombosis in deep veins.

Hypothesis:
IL-17 released from T-cells augments deep venous thrombosis, through endothelial CD39-driven T-cell phenotype switching.

Methods:
A uniform non-occluding ligature around the infrarenal IVC was used to model DVT. CD39 haploinsufficient (CD39+/-) mice were used, as full knockouts demonstrate baseline platelet reactivity abnormalities affecting thrombosis. Mice were sacrificed at 48 hours and IVC and thrombus harvested. IL-17 protein was measured using western blotting and immunohistochemistry and inflammatory cells in vein wall were identified by flow cytometry.

Results:
CD39 +/- mice had increased thrombus mass compared to wild-type animals (p=0.02), with a corresponding increase in IL-17. In CD39 +/- mice, immunohistochemistry of thrombus indicated increased inflammatory cell infiltration, expression of VCAM-1 and IL-17. In vitro confirmation of effect of IL-17 dosing of HUVEC induced a 2-fold induction of E-Selectin (p<0.0001) and a 1.25 fold induction of ICAM-1 (p=0.0002) by qPCR; P-Selectin was not different (p=0.6). Flow cytometric analysis of vein wall after thrombus induction indicated increased infiltration of neutrophils (2.5-fold), monocyte-macrophage (2-fold), and T-cells (1.5 fold) in CD39 +/- mice compared with controls.

Conclusion:
Decreased expression of CD39 is associated with a pro-thrombotic phenotype in CD39 haploinsufficient mice, resulting in increased IL-17 within the IVC, inducing Selectin- and CAM-driven pathways of inflammatory cell infiltration after thrombosis.
Abstract 154: Bridging to Warfarin With Direct Oral Anticoagulant Agents
Authors: Diaz Quintero Luis , Tafur Alfonso
Published: July 2021

Background:
Anticoagulation bridging using LMWH remains a common practice to mitigate the Warfarin’s delayed onset of action. However, LMWH often creates resistance from patients given cost, fear to injections, or in patients already on direct oral anticoagulant agents (DOACs), cost coverage that demand agent change. In such circumstances, the possibility of bridging using DOACs has been adopted.

Aim:
To characterize the outcomes and cost benefit for patients who were bridged to Warfarin using a DOAC.

Methods:
We identified a case series of patients who used DOACs for bridging to Warfarin. Primary outcome was major hemorrhage and thrombosis recurrence identified 30 and 60 days after initial bridging therapy was initiated. Categorical variables were presented as percentages, continuous variables as median and range. Chi Square or Student T were used as appropriate.

Results:
A total of nineteen patients were included (Men = 42%, Age = 66.3 (32-93), BMI = 29 (19.5-44.6)). Twelve patients received Apixaban (63%), and seven patients received Rivaroxaban (37%). Reasons to avoid low molecular weigh heparin were patient’s preference (53%), changing indication (32%), interaction (10%), and cost (5%) The average time for successful bridging was 13.2 days (5-29). No episodes of major bleeding, deep venous thrombosis, pulmonary embolism or minor bleeding were registered after 30 and 60 days of initiation of bridging therapy. Average cost of bridging therapy with DOAC was 158.3 USD (Range 21.1-407.9). Estimated cost of bridging therapy with LMWH and current pricing would have been 652.4 US dollars (294-1421).

Conclusion:
Bridging strategy with direct oral anticoagulant agents seems to be a safe, cost-effective approach in patients receiving oral Warfarin. Moreover, this alternative is reasonable for patients with aversion or lack of social support to administer injections. A larger study is necessary to further explore these findings.
Abstract 174: The Use of Next-Generation Sequencing to Detect Copy Number Variation in the Molecular Diagnosis of Familial Hypercholesterolemia
Authors: Iacocca Michael A , Wang Jian , Dron Jacqueline S , Robinson John F , McIntyre Adam D , Ban Matthew R , Cao Henian , Hegele Robert A
Published: July 2021

Background:
Familial hypercholesterolemia (FH) is a common monogenic disorder of lipoprotein metabolism, characterized by elevated LDL cholesterol and increased risk for premature cardiovascular disease. Efforts to provide a molecular diagnosis of FH are trending towards the use of targeted next-generation sequencing (NGS) panels to interrogate canonical FH-associated genes—
LDLR
,
APOB
, and
PCSK9
—for clinically relevant small-scale variants. However, large-scale copy number variants (CNVs) or deldup variants constitute 10-15% of
LDLR
variants in many cohorts. Because these are not routinely accessible by NGS, a second assay, namely multiplex-ligation dependent probe amplification (MLPA), is currently required to screen for them. To increase efficiency and decrease costs associated with identifying the genetic causes for FH, use of a single platform to detect both small and large-scale variants would be extremely beneficial in a clinical setting.

Objective:
Here we determine the accuracy of NGS bioinformatic tools in identifying CNVs.

Methods:
In 313 clinically ascertained, unrelated patients with at least possible FH per the Dutch Lipid Clinic Network (DLCN) criteria, we sequenced canonical FH-associated genes using our targeted NGS panel (LipidSeq
TM
). These patients were also assayed using MLPA. The CNV analysis tool (VarSeq® Golden Helix, Inc.) was run using the NGS data generated for each patient. Concordance between the NGS tool and standard MLPA was subsequently determined.

Results:
We evaluated a subset of 99 FH individuals: 19 were positive while 80 were negative for a
LDLR
mutation using MLPA. Our CNV analysis using bioinformatically processed NGS data compared to MLPA yielded 2 out of 19 false negatives and 0 out of 80 false positives. This translates to a sensitivity of 89% and a specificity of 100% for our NGS approach, considering MLPA as the current ’gold standard’.

Conclusions:
Analysis of deeply resequenced targeted NGS data for the identification of CNVs in FH shows excellent potential to become a standard diagnostic test for those with suspected FH, potentially eliminating the need for secondary MLPA analysis. Future applications of this NGS tool may also allow for novel CNV screening in additional FH-associated genes.
Abstract 19: Selective BET Inhibitors Are Useful for Normalizing Inflammation Leading to Reduced Cardiovascular Disease (CVD) in Humans
Authors: Kulikowski Ewelina , Tsujikawa Laura , Atwell Sarah , Campeau Eric , Wasiak Sylwia , Halliday Christopher , Johansson Jan , Sweeney Mike , Wong Norman C
Published: July 2021

Apabetalone (RVX-208) a bromodomain extra-terminal (BET) inhibitor selectively binds the 2nd ligand domain within a BET protein thus displacing it from acetylated lysine marks on histone tails. In clinical trials of ~1000 patients, many (n=499) of whom with CVD when given 200 mg/d RVX-208 had a 55% relative risk reduction in major adverse cardiac events (MACE) vs placebo. This benefit of RVX-208 may stem from ability of BET inhibition (BETi) to calm inflammation, metabolism, coagulation and complement pathways with well-known roles in CVD risks. These potential benefits of RVX-208 underlie BETonMACE a phase 3 CVD events trial. Of major interest is the anti-inflammatory (AI) effects seen in clinical data showing BETi lowers CRP by 28% in RVX-208 treated patients (n=331). RVX-208 lowered IL-6 and MCP-1 U937 cells exposed to LPS in a dose and time dependent manner by 90 and 85%, respectively within 24 hrs. RVX-208 displaced BET proteins BRD2-4 from chromatin. These AI effects underpin studies of RVX-297 a more potent cousin of RVX-208 that lowered IL-6 and MCP-1 in LPS stimulated U937 cells by 95 and 80% respectively within 24 hrs. In ChIP assays, RVX-297 also displaced BET protein BRD4 and pol II from promoters of cytokine genes IL-6 and IL-1β that mediate inflammation. Together, data from studying RVX-208 and -297 show both BET inhibitors displace transcription factors from promoter DNA that control expression of inflammatory genes (IGs) with key roles in CVD. Importance of BETi displacement of BRD4 and pol II from DNA becomes clear when added to the fact that cellular response to inflammation requires immediate and robust expression of defined set of IGs. For this rapid transcriptional response, the cell places chromatin structures upstream of IGs called super-enhancers (SE) or latent enhancers (LE) that act as molecular sinks for attracting BET proteins such as BRD4. The placement of a SE or LE adjacent to a promoter that controls a IG recruits this gene to the response against an inflammatory insult. Thus targeting BET proteins including BRD4 with a selective BETi may have broad effects on many genes or pathways by crippling SE or LE mediated cellular response to the inflammatory component of CVD. This mechanism may have potential implications to other inflammatory diseases.
Abstract 191: Adipocyte Procollagen C-endopeptidase Enhancer Protein 2 (PCPE2) Influences Lipid Metabolism Secondary to Changes in Expression and Function of Scavenger Receptor Class B Member 1 (SR-BI)
Authors: Maruko Elisa C , Tschannen Michael , Liu Pengyuan , Tsaih Shirng-Wern , Glastonbury Craig A , Small Kerrin , Kaul Sushma , Xu Hao , Fatema Kaniz , Thomas Michael J , Sorci-Thomas Mary G
Published: July 2021

Scavenger receptor class B member 1 (SR-BI) functions as a HDL receptor and stimulates reverse cholesterol transport (RCT) via selective uptake of HDL cholesterol esters (HDL-CE). Procollagen c-endopeptidase enhancer protein 2 (PCPE2) is an extracellular matrix glycoprotein encoded by the PCOLCE2 gene and most highly expressed in adipose tissue, heart, and aorta. PCPE2 has been suggested to be atheroprotective secondary to mechanisms involved in lipid metabolism. Our lab previously reported that SR-BI mediated cholesterol ester uptake is reduced in the absence of PCPE2 despite its increased expression levels. Subsequent HDL turnover studies suggested an overall reduction in catabolism, consistent with larger HDL particles observed, is responsible for the paradox. More recently, human data from the TwinsUK study showed strong correlations between PCOLCE2 and adipose tissue distribution with BMI included as a covariate. Furthermore, despite similar overall body weights, our lab observed a significant reduction in visceral fat pad development in PCPE2-deficient mice fed a Western diet for 25 weeks when compared to wild type mice. In addition, our lab has generated PCPE2 knockout cell lines from murine preadipocyte 3T3-L1 cells (PCPE2
-/-
3T3-L1) and Chinese hamster ovary (CHO) cells using CRISPR-Cas9 and siRNA technology, respectfully. In addition to both cell lines showing increased SR-BI expression, differentiated PCPE2
-/-
3T3-L1 cells have impaired lipid droplet formation. To elucidate the relationship between PCPE2 and SR-BI function and their effects on adipose tissue development, we performed RNA sequencing on visceral adipose tissue from PCPE2-deficient male mice fed a Western diet for 12 weeks. Genes exhibiting significant expression alterations (FDR <0.026) compared to wild type were further analyzed via Ingenuity Pathway Analysis (IPA). Differential expression analysis of diseases and functions related to changes in SR-BI expression highlighted permutations of a number of lipid modulating genes. Overall, changes in SR-BI related metabolic pathways secondary to PCPE2 deficiency appear to play a crucial role linking SR-BI mediated cholesterol ester uptake to adipocyte biology.
Abstract 20: Resolution Phenotype of Monocytes and Macrophages is Altered in Peripheral Arterial Disease
Authors: Schaller Melinda S , Menke Laura , Chen Mian , Gasper Warren J , Grenon S. Marlene , Conte Michael S
Published: July 2021

Introduction:
Peripheral arterial disease (PAD) is a chronic disease characterized by systemic inflammation. Monocytes (Mo) and macrophages play a central role in vascular inflammation and its resolution. We hypothesize that impaired resolution in PAD results in poor clinical outcomes.

Methods:
Resolution phenotype was assessed by phagocytic activity of leukocytes, Mo cell surface markers, and cytokine profiling of Mo-derived macrophages (MDM). Phagocytosis and cell-surface markers were determined by flow cytometry. MDMs were generated from peripheral blood mononuclear cells via density gradient centrifugation. Cytokines were measured by ELISA following MDM differentiation and subsequent stimulation with LPS.

Results:
Circulating Mo and neutrophils (PMN) isolated from PAD patients (n=9) demonstrated significantly lower phagocytic activity (Mo: >30%, p<.001; PMN: >25%, p<.01, Fig. 1) as compared to healthy subjects (HS) (n=14). Cell-surface marker analysis demonstrated a higher proportion of the pro-inflammatory intermediate Mo subset (CD14
++
16
+
, 1.8-fold, p=.04) in PAD compared to HS. MDM from PAD subjects retain their intrinsic inflammatory program by producing more IL-6 (PAD 3138±2676 ng/mL, HS 731±854 ng/mL p=.03) and IL-1β (PAD 244±236 ng/mL, HS 24.1±23.8 ng/mL p=.04) than those from HS. Upon stimulation with LPS, MDM from PAD subjects secrete more IL-6 (PAD 23353±22483 ng/mL, HS 5097±5836 ng/mL p=.05) than those from HS.

Conclusions:
Circulating Mo and PMN in patients with PAD have substantially lower phagocytic activity as well as a greater proportion of the pro-inflammatory intermediate Mo subset compared to HS. MDM preserve their elevated inflammatory state throughout culture and retain a heightened response upon latter stimulatory cues. Collectively these data demonstrate a heightened inflammatory and impaired resolution phenotype in PAD that has potential implications for disease progression and response to interventions.
Abstract 208: Isolevuglandin, a Highly Reactive γ-ketoaldehyde Formed from the Isoprostane Pathway, Induces Deleterious Structural and Functional Consequences to High-density Lipoprotein
Authors: Zhang Linda S , Tao Huan , Pleasent Tiffany , Borja Mark S , Oda Michael N , Jerome W. Gray , Yancey Patricia G , Roberts L. Jackson , Linton MacRae F , Davies Sean S
Published: July 2021

Recent evidence suggest that cardiovascular disease (CVD) risk depends on levels of functional HDL particles, not HDL-cholesterol. In CVD, increased oxidative stress generates reactive lipid species that alter HDL function. Isolevuglandins (isoLGs), generated in parallel to isoprostanes, are extremely reactive to lysine residues of proteins and headgroups of phosphatidylethanolamine (PE). Importantly, IsoLG protein and PE adducts are elevated in atherosclerosis. Recently, our group observed a 42% reduction of atherosclerotic lesion size when salicylamine (SAM), a small molecule scavenger of reactive dicarbonyls including IsoLG, was administered to LDLr
-/-
mice. Little is known about the consequences of IsoLG to HDL function. The aim of this study is to compare effects of IsoLG on apolipoprotein crosslinking, morphology and size of HDL to its functions: cholesterol efflux, apoA-I exchange and anti-inflammation. Human HDL was incubated overnight at 37°C with IsoLG. Thioglycolate-induced intraperitoneal macrophages were harvested from apoE
-/-
mice. IsoLG crosslinked structural apolipoproteins, apoA-I and apoA-II, starting at 0.3 mol IsoLG per mol apoA-I (0.3 eq). HDL modified with 3 eq IsoLG formed subpopulations of two distinct sizes, 6-13 nm and 16-23 nm. A 40.6±0.04% decrease in
3
H-cholesterol efflux from macrophages was observed at 1 eq IsoLG compared to unmodified control HDL. At this IsoLG concentration, HDL-ApoA-I exchange was reduced (P<0.01, n=4), from 47.4±2.8% with control HDL to only 24.8±5.8%, suggesting that IsoLG inhibited apoA-I from disassociating from HDL to interact with ABCA1. Intriguingly, IsoLG inhibited HDL’s protection against LPS-stimulated inflammatory response in macrophages at 0.03 eq as shown by IL-1β and TNFα mRNA expression comparable to LPS alone. At 0.1 eq IsoLG, HDL becomes pro-inflammatory, as indicated by a 927±309% increase in IL-1β mRNA expression (P<0.001). Unlike cholesterol efflux, these effects occurred independent of HDL apolipoprotein crosslinking. We report a novel pathway by which HDL becomes dysfunctional, by mechanisms involving IsoLG-mediated alterations of HDL proteins and structure. Future studies will pinpoint how IsoLG modifies HDL proteins (or lipids) to alter its function.