tbuckley/cabot-search huggingface dataset:
Abstract 14090: Myocardial Infarction Selectively Decreases Cardiac Vagal Afferent Neurotransmission: Implications for Mechanisms Behind Cardiac Parasympathetic Dysfunction
Authors: Zulfiqar Lokhandwala, Asokan Devarajan, Kerry Wang, Kassandra Shannon, John D Tompkins, Marmar Vaseghi
Journal: Circulation (2021)

Introduction: Parasympathetic dysfunction after myocardial infarction (MI) predisposes to arrhythmias and heart failure. Mechanisms behind this dysfunction are unclear. It is known that cardiac sensory afferent neurons in the vagal ganglia sense beat-to-beat changes at the level of the heart. This vagal afferent signaling/activation then increases central cardiac vagal efferent drive. Hypothesis: We hypothesized that MI causes a functional reduction in vagal afferent signaling that subsequently decreases efferent vagal tone, resulting in parasympathetic dysfunction. Methods: A transgenic mouse line was created by crossing mice expressing excitatory vesicular glutamate transporter 2, VGlut-ires-cre, with those expressing channel rhodopsin 2 EYFP (ChR2), resulting in mice with VGlut and ChR2 expression in afferent-specific vagal neurons and fibers. MI was created by left anterior descending artery ligation. Sham animals underwent thoracotomy only. Control animals did not undergo a thoracotomy. Two weeks post-MI or sham, the left cervical vagus nerve was isolated and optically stimulated in vivo using blue light laser (473 nm, 20 Hz, 10 &amp; 20 msec). Heart rate (HR), respiratory rate (RR), and time to activation of efferent vagal effects (time to nadir HR/RR) were assessed. Results: In response to optical stimulation, MI animals (n=5) demonstrated significantly reduced HR responses vs. sham (n=4) and control (n=7) animals at both 10 ms and 20 ms, figure. Time to nadir HR was also increased in MI animals (P&lt;0.05 vs. sham/control). RR decreased in all animals, without significant differences between groups. Conclusions: MI is associated with decreased efferent vagal responses to similar levels of parasympathetic afferent activation. These results suggests that mechanisms behind decreased vagal tone post-MI may be due altered vagal afferent neurotransmission and signaling capabilities. MI selectively affects cardiac, not respiratory, neural responses.
Abstract 14086: A Hybrid Machine Learning Method for Instantaneous Classification of Left Ventricular Filling Pressure Using Femoral Waveforms
Authors: Rashid Alavi, Jing Liu, Melissa Ramos, Antreas Hindoyan, Ray V Matthews, Niema M Pahlevan
Journal: Circulation (2021)

Introduction: Non-invasive and instantaneous evaluation of left ventricular end-diastolic pressure (LVEDP) is of high significance in diagnosis and treatment of heart failure patients. We recently proposed the cardiac triangle mapping (CTM), a systems approach that uses information from arterial pressure waveforms and pre-ejection periods to map the global ventricular function (Pahlevan et al. Fluids 4.1 (2019): 16). Here, we propose a hybrid machine learning (ML) method based on CTM theory that uses pressure waveforms at the iliac bifurcation level and ECG to instantaneously classify the level of LVEDP. Methods: We studied 46 patients (Age: 39-90 (66.4±9.9), BMI: 20.2-36.8 (27.6±4.1), 12 females) who were scheduled for clinical left heart catheterization or coronary angiogram at the Keck Medical Center of USC. Exclusion criteria were valvular heart disease, left bundle branch block, or atrial fibrillation. Invasive LVEDP and pressure waveforms at iliac bifurcation were measured using a 3F Millar transducer tipped catheter, with simultaneous 3 channel ECG. The range of patients’ LVEDP was from 9.3 to 40.5 mmHg. LVEDP=18 mmHg was used as the ML classification cut-off. A random forest classifier (of n=30 grown decision trees, ensemble learning method: bootstrap aggregation, 6 inputs) was trained using data from 36 patients. The model was blindly tested on 10 additional patients. Results: Our ML model showed accuracies of 100.0% and 80.0% for predicting the true class of LVEDP on blind test data (i.e., elevated or normal, respectively) (Fig1). The accuracy on all data was higher than 93.4% for all classes. Conclusions: We demonstrated the proof-of-concept that a physics-based ML model can instantaneously classify the LV filling pressure using information extracted from femoral waveform and ECG. Our study is invasive validation; however, all required ML input parameters can be obtained noninvasively and remotely (i.e., using wearable devices or a smartphone).
Abstract 11067: ABCB10 Overexpression Prevents Acute Doxorubicin-Induced Cardiac Dysfunction
Authors: Ashley J Smuder, Vivian Doerr, Branden L Nguyen
Journal: Circulation (2021)

Introduction: Doxorubicin (DOX) is a highly effective chemotherapy agent used to treat solid tumor cancers and hematological malignancies. However, DOX treatment can cause adverse cardiac events, which can negatively affect patient outcomes by limiting cancer treatment and reducing overall survival. DOX-induced cardiotoxicity occurs due to its off-target accumulation within cardiomyocytes following administration. Within the heart, DOX predominantly localizes within the mitochondria where it promotes cellular injury via the production of reactive oxygen species (ROS). Currently, there is no clinically approved therapy to prevent this debilitating condition. Therefore, work is needed to identify therapeutic countermeasures to prevent DOX cardiotoxicity. In this regard, ABCB10 is a mitochondria-localized ATP-binding cassette transporter that is hypothesized to play a role in the maintenance of mitochondrial redox balance and iron homeostasis. Hypothesis: We hypothesize that cardiac overexpression of ABCB10 would reduce DOX-induced oxidative damage and preserve cardiac function. Methods: Cause and effect were determined by overexpressing ABCB10 in the heart using an AAV9-MHCK7-ABCB10 construct. Acute effects of DOX (20 mg/kg i.p.) on the heart were assessed by echocardiography. Results: Our findings confirm that DOX treatment results in detriments to both cardiac and mitochondrial function 48-hours following administration. Importantly, cardiac overexpression of ABCB10 was sufficient to prevent the DOX-induced reduction in mitochondrial respiratory control ratio. In addition, both left ventricular fractional shortening percentage and myocardial performance index were preserved in ABCB10 overexpressing animals treated acutely with DOX. Conclusions: ABCB10 overexpression in the heart is an effective intervention to prevent cardiotoxicity and mitochondrial dysfunction acutely following DOX chemotherapy treatment.
Risk prediction of covid-19 related death and hospital admission in adults after covid-19 vaccination: national prospective cohort study (vol 374, n2244, 2021)
Authors: J Hippisley-Cox, C A Coupland, N Mehta, R H Keogh, K Diaz-Ordaz, K Khunti, R A Lyons, F Kee, A Sheikh, S Rahman, J Valabhji, E M Harrison, P Sellen, N Haq, M G Semple, Johnson Pwm., A Hayward, J S Nguyen-Van-Tam
Journal: BMJ (2021)
Abstract 11314: <i>Trpm2</i> Deletion Alleviates Atherosclerosis by Inhibiting the Activation of CD36 in Macrophages
Authors: Pengyu Zong, Jianlin Feng, Zhichao Yue, Albert S Yu, Lixia Yue
Journal: Circulation (2021)

Introduction: Atherosclerosis and its complications are the leading cause of death. The central pathological features of atherosclerosis are macrophage infiltration and foam cell formation, in which CD36 is crucial in activating macrophages and mediating the uptake of cholesterol. However, mechanisms regulating the activation of CD36 remain unclear. TRPM2 is an Ca 2+ permeable channel activated by oxidative stress, which occurs in the activation of macrophages. Hypothesis: We hypothesized that during atherosclerosis, TRPM2 is critical for the activation of CD36 in macrophages. Thus, Trpm2 deletion inhibits macrophage activation and foam cell formation. Methods: ApoE -/- mice and ApoE -/- mice with Trpm2 deletion were fed with high-fat food to induce atherosclerosis. Oil red O and immunofluorescence staining were performed to evaluate lipid deposition and macrophage load in aorta. Transwell assay was used to test macrophage infiltration and emigration. Oxidized LDL (oxLDL) or thrombospondin-1 (TSP1) was used to activate CD36. Western blot was used to examine the activation of CD36 signaling. ROS and Ca 2+ imaging were performed to examine the activation of macrophages by CD36. Results: Trpm2 deletion: (1) reduced lesion ratio (0.13 ± 0.02 vs 0.36 ± 0.02) and macrophage load (20.93 ± 4.82 / mm 2 vs 60.20 ± 8.36 / mm 2 ) in aorta; (2) inhibited oxLDL uptake (32.24 ± 7.65 % vs 100 %) by macrophages; (3) suppressed macrophage infiltration (15.83 ± 2.44 / mm 2 vs 46.83 ± 4.62 / mm 2 ) and preserved macrophage emigration (15.5 ± 1.73 / mm 2 vs 5.0 ± 0.73 / mm 2 ); (4) inhibited ROS production (5.32 ± 0.61 % vs 28.82 ± 1.48 %) and increase of intracellular Ca 2+ (2.92 ± 0.86 % vs 11.95 ± 1.60 %) in macrophages induced by oxLDL (n= 6 ~ 8 for all data). Also, oxLDL and TSP1 activated TRPM2 via CD36, and TRPM2 was required for the activation of CD36 signaling in macrophages by oxLDL or TSP1. Conclusions: In summary, TRPM2 and CD36 activated each other in macrophages, which promoted the development of atherosclerosis.
Abstract 10533: Greater Left Ventricular Mass And Abnormal Diastolic Myocardial Function In Neonates Of Pre-eclamptic Pregnancies
Authors: Victor Benvenuto, Melanie Nies, Benjamin Barnes, Rita Long, Allen D Everett, Shelby Kutty
Journal: Circulation (2021)

Introduction: Maternal pre-eclampsia (PEC) is a placental insufficiency syndrome with potential effects on neonatal cardiac function. Hypothesis: We tested the hypothesis that neonatal exposure to maternal PEC results in systolic and diastolic myocardial dysfunction on echocardiogram. Methods: Neonates exposed to maternal PEC (N=142) were matched 1:1 for gestational age and gender (N=142) with neonates concurrently enrolled in our center during the same study period (2009-2019). Echocardiograms performed in first 30 days of life were analyzed. Image analysis was done retrospectively and included LV and RV global peak longitudinal strain, mitral and tricuspid inflow and tissue Doppler, and LV mass indexed to body surface area. Analyses included two-sample t-test, Wilcoxon rank sum, chi-squared, and Bonferroni correction testing. Results: The average gestational age was 28 weeks, with slight male predominance of 54.9%. Birth weight was 885g in PEC group, compared to 1100g in the control (p=0.003). Median age at echocardiogram was 8 days for PEC and 6 days for control.In the PEC group, systolic function demonstrated decreased longitudinal 2-chamber average peak strain and higher mean LV mass. There was no difference in 4-chamber average peak strain, circumferential mid-LV average peak strain, or longitudinal RV 6-segment average strain. Mitral and tricuspid valve E-wave deceleration times were shorter in the PEC group. There were no differences in other markers of diastolic function, including E/A and E/e’ ratio. Conclusions: PEC neonates have increased RV and LV stiffness, indicated by reduced E-wave deceleration time of the mitral and tricuspid valves. This is suggestive of grade 2 diastolic dysfunction. LV mass was increased in the PEC group. We did not find compelling evidence of systolic dysfunction with strain analysis. In conclusion, maternal PEC exposure results in neonatal diastolic abnormalities that may have long term effects on cardiac function.
Abstract 9709: Higher Uric Acid To High Density Lipoprotein Cholesterol Ratio Is Associated With Arterial-ventricular Stiffening In Childhood Obesity
Authors: Kenji Harada, Yukiko Harada
Journal: Circulation (2021)

Background: Uric acid and high density lipoprotein cholesterol are both considered as risk factors of cardiovascular mortality. The ratio of uric acid to high density lipoprotein cholesterol (UH ratio) has been reported to be a good predictor of cardiovascular events. However, few studies have examined UH ratio and cardiovascular function in overweight/obese children. The purpose of this study is to assess the relationship between UH ratio and cardiovascular function in children. Methods: Echocardiography was performed in 453 children aged 7 to 15 years (body mass index 18 to 34 kg/m 2 ). Stroke volume (SV) was measured using aortic diameter and pulsed Doppler velocity profile. SV was indexed for body surface area (SVI). Effective arterial elastance was estimated by end-systolic pressure/SVI. End-systolic elastance was calculated by a modified single-beat method. Lipids, uric acid, fasting glucose, insulin, homeostasis model assessment for insulin resistance (HOMA-IR), and high sensitive C-reactive protein (hs-CRP) were also assessed. Results: Effective arterial elastance and end-systolic elastance increased significantly with body mass index (r = 0.35 and 0.22, p &lt; 0.01, respectively). There were significant relationships between body mass index and UH ratio, HOMA-IR, high density lipoprotein cholesterol, uric acid, triglycerides, and hs-CRP (r = 0.53, 0.52, -0.32, 0.46, 0.37, and 0.38, p &lt; 0.01, respectively). Effective arterial elastance correlated significantly with UH ratio, HOMA-IR, uric acid, high density lipoprotein cholesterol, triglycerides, and hs-CRP (r = 0.24, 0.20, 0.18, -0.11, 0.21, and 0.18, p &lt; 0.05, respectively). There were significant relationships between end-systolic elastance and UH ratio, HOMA-IR, uric acid, and triglycerides (r = 0.25, 0.16, 0.15, and 0.11, p &lt; 0.05, respectively). In multiple regression analysis, UH ratio was independent determinants of effective arterial elastance and end-systolic elastance. Conclusions: The present study demonstrates that UH ratio is a useful indicator reflecting cardiometabolic risk in obese children. Higher UH ratio and combined arterial-ventricular stiffening may contribute to the increased prevalence of later cardiovascular disorder.
STAT proteins: a kaleidoscope of canonical and non-canonical functions in immunity and cancer
Authors: Nagendra Awasthi, Clifford Liongue, Alister C. Ward
Journal: Journal of Hematology & Oncology (2021)

Abstract STAT proteins represent an important family of evolutionarily conserved transcription factors that play key roles in diverse biological processes, notably including blood and immune cell development and function. Classically, STAT proteins have been viewed as inducible activators of transcription that mediate cellular responses to extracellular signals, particularly cytokines. In this ‘canonical’ paradigm, latent STAT proteins become tyrosine phosphorylated following receptor activation, typically via downstream JAK proteins, facilitating their dimerization and translocation into the nucleus where they bind to specific sequences in the regulatory region of target genes to activate transcription. However, growing evidence has challenged this paradigm and identified alternate ‘non-canonical’ functions, such as transcriptional repression and roles outside the nucleus, with both phosphorylated and unphosphorylated STATs involved. This review provides a revised framework for understanding the diverse kaleidoscope of STAT protein functional modalities. It further discusses the implications of this framework for our understanding of STAT proteins in normal blood and immune cell biology and diseases such as cancer, and also provides an evolutionary context to place the origins of these alternative functional modalities.
CSIG-28. REGULATION OF GEMC1 MULTICILIOGENESIS PROGRAM IN CHOROID PLEXUS CARCINOMA
Authors: Haotian Zhao, Thomas Page, Tamanna Sarowar
Journal: Neuro-Oncology (2021)

Abstract Tumors of the choroid plexus (CP) are rare primary brain neoplasms mostly found in children. CP tumors exist in three forms: CP papilloma (CPP), atypical CPP, and CP carcinoma (CPC). Though CPP is more benign, CPC is a highly lethal and little understood cancer with poor survival rate and a tendency for recurrence and metastasis. CP tumors are thought to arise from CP epithelial cells that secrets cerebral spinal fluid and generate multiple cilia on their apical surface. Here we show that aberrant NOTCH and Sonic Hedgehog signaling in mice drive tumors that resemble CPC in humans. In contrast to CP epithelial cells with clusters of multiple cilia, NOTCH-driven CP tumors were monociliated, and disruption of the NOTCH complex restored multiciliation and decreased tumor growth. NOTCH suppressed multiciliation in tumor cells by inhibiting the expression of Geminin Coiled-Coil Domain Containing 1 (GEMC1), and multiciliate differentiation and DNA synthesis associated cell cycle protein (MCIDAS), early transcriptional regulators of multiciliated cell (MCC) differentiation. Consistently, Gemc1-Mcidas deficiency led to a lack of MCCs in the CP, and impaired the correction of the multiciliation defect in tumor cells by a NOTCH inhibitor. Disturbances to the GEMC1 program are commonly observed in human CPCs characterized by solitary cilia and frequent somatic TP53 mutations. Accordingly, CPC driven by deletion of tumor suppressors Trp53 and Rb1 in mice exhibits a cilia deficit consequent to loss of Gemc1-Mcidas expression. Taken together, these findings reveal that the GEMC1-MCIDAS multiciliogenesis program in the CP is critical for inhibiting tumorigenesis, whereas a defective multiciliation program promotes CPC and may represent a therapeutic avenue for this cancer.
Invasive serogroup B meningococci in England following three years of 4CMenB vaccination – First real-world data
Authors: Jay Lucidarme, Xilian Bai, Aiswarya Lekshmi, Stephen A. Clark, Laura Willerton, Sonia Ribeiro, Helen Campbell, Laura Serino, Rosita De Paola, Ann Holland, Jennifer Louth, Mary E. Ramsay, Shamez N. Ladhani, Ray Borrow
Journal: Journal of Infection (2021)

In 2015 the UK became the first country to implement the meningococcal B (MenB) vaccine, 4CMenB, into the national infant program. 4CMenB is expected to cover meningococci expressing sufficient levels of cross-reactive proteins. This study presents clonal complex, 4CMenB antigen genotyping, and 4CMenB coverage data for all English invasive MenB isolates from 2014/15 (1 year pre-vaccine) through 2017/18 and compares data from vaccinated and unvaccinated ≤3 year olds.Vaccine coverage of all invasive MenB isolates from 2014/15 to 2017/18 (n = 784) was analysed using the Meningococcal Antigen Typing System. Genotyping utilised the Meningococcus Genome Library.Among ≤3 year olds, proportionally fewer cases in vaccinees (1, 2 or 3 doses) were associated with well-covered strains e.g. cc41/44 (20.5% versus 36.4%; P<0.01) and antigens e.g. PorA P1.4 (7.2% versus 17.3%; P = 0.02) or fHbp variant 1 peptides (44.6% vs 69.1%; P<0.01). Conversely, proportionally more cases in vaccinees were associated with poorly-covered strains e.g. cc213 (22.9% versus 9.6%; P<0.01) and antigens e.g. variant 2 or 3 fHbp peptides (54.2% versus 30.9%; P<0.01).4CMenB reduces disease due to strains with cross-reactive antigen variants. No increase in absolute numbers of cases due to poorly covered strains was observed in the study period.
Bone targeting antioxidative nano-iron oxide for treating postmenopausal osteoporosis
Authors: Liming Zheng, Zaikai Zhuang, Yixuan Li, Tianshu Shi, Kai Fu, Wenjin Yan, Lei Zhang, Peng Wang, Lan Li, Qing Jiang
Journal: Bioactive Materials (2021)

Osteoporosis is the most common degenerative orthopedic disease in the elderly. Recently, the therapeutic methods for osteoporosis have shifted towards the regulation of local immunity in bone tissues, which could provide a suitable environment for the positive regulation of bone metabolism, promoting osteogenic differentiation and inhibiting osteoclast differentiation. Our previous work demonstrated that iron oxide nanoparticles (IONPs) could positively regulate bone metabolism in vitro. In this study, we further demonstrated that daily administration of IONPs relieved estrogen deficiency-induced osteoporosis via scavenging reactive oxygen species in vivo. Meanwhile, IONPs promoted the osteogenic differentiation of bone marrow mesenchymal stem cells and inhibited the osteoclast differentiation of monocytes from IONPs treated mice. Besides, alendronate, a clinically used anti-osteoporosis bisphosphate, was employed to precisely deliver the IONPs to the bone tissues and played a synergically therapeutic role. Eventually, we verified the bone targeting ability, therapeutic efficiency, and biocompatibility of the novel bone target iron oxides in ovariectomy-induced osteoporotic mice. By applying BTNPs, the OVX-induced osteoporosis was significantly revised in mice models via the positive regulation of bone metabolism.
Abstract 10593: Computationally Modeling Cardiac Growth and Hemodynamics in Healthy Infants
Authors: Ashley Hiebing, Riley Pieper, Colleen Witzenburg
Journal: Circulation (2021)

Introduction: Previous computer models have been developed which predict cardiac growth and remodeling in adults with various pathologies, including hypertension, valvular disease, and myocardial infarction. Applying these models to infants and children is complicated by the fact that they also undergo normal, somatic cardiac growth and remodeling. Objective: Create a computational model to predict ventricular dimensions and hemodynamics in healthy, growing infants. Methods: A left ventricular growth model previously published by our lab for adult canines was modified for healthy infants. The four heart chambers were modeled as time-varying elastances coupled to a circuit model of the circulation. Circulation parameters were allometrically scaled for human infants. Early trends in systemic and pulmonary vascular resistance were fit to clinical data rather than scaled due to the dramatic reduction in pulmonary vascular resistance and marked increase in overall systemic vascular resistance immediately post-birth. Ventricular growth was driven by perturbations in myocyte strain, a non-dimensional metric. Reported heart rate was input directly into the model. Results: The model successfully matched clinically measured values of systemic and pulmonary pressures, end-systolic and end-diastolic left and right ventricular volumes, maximum atrial volumes, and left ventricular end-diastolic thickness within one standard deviation of multiple studies for children aged 0-3 years (Figure). LV end-systolic and right ventricular end-diastolic thicknesses followed clinical trends but were outside of established ranges. Conclusions: Our model predicts hemodynamics and ventricular dimensions for healthy children from birth to 3 years. From this, we can gain a greater understanding of the interplay between somatic and pathological growth in infants and children with congenital heart defects.
The longevity economy
Authors: Andrew J Scott
Journal: The Lancet Healthy Longevity (2021)

The fact that people are on average living healthier, longer lives than previously has the potential to be positive for the economy, offsetting the negative economic effects of an ageing society. A longevity economy will see a shift in the mix of sectors in the economy, with both health and education expanding further and new financial products arising. Such an economy has the potential to contribute to growth in gross domestic product through employment and human capital. Shifting to a longevity economy requires less reliance on policies stated purely in terms of age, and more extension of existing policies aimed at diverse needs and circumstances to older age groups. This shift will be needed to counter inequality within age groups. A life course perspective is also required, to ensure a focus on intergenerational equity and a better understanding of the needs of older individuals that are not health driven.