tbuckley/cabot-search huggingface dataset:
Abstract 16563: FOXO1 Induces Cardiomyocyte-KLF5, Which Drives Oxidative Stress and Diabetic Cardiomyopathy
Authors: Ioannis D Kyriazis, Matthew K Hoffman, Lea Gaignebet, Anna Maria Lucchese, Chao Wang, Thomas Bannister, Melpo Christofidou-Solomidou, Shinichi Oka, Junichi Sadoshima, Walter J Koch, Ira J Goldberg, Vincent W Yang, Agnieszka Bialkowska, Georgios Kararigas, Konstantinos Drosatos
Journal: Circulation (2020)

Introduction: Cardiomyopathy in type 1 diabetes (T1D) is accompanied by impaired mitochondrial function, oxidative stress and lipotoxicity. We showed that cardiomyocyte (CM) Krüppel-like factor 5 (KLF5) is increased in streptozotocin-induced T1D and induces Peroxisome Proliferator Activated Receptor (PPAR)α in mice. Hypothesis: KLF5 upregulation by FOXO1 induces diabetic cardiomyopathy (DbCM). Methods and Results: Analyses in CM from diabetic patients showed higher KLF5 mRNA levels compared to non-diabetic individuals. In vitro mechanistic and in vivo analyses in αMHC- Foxo1 -/- mice revealed that FOXO1 stimulates KLF5 expression via direct promoter binding. Genetic inhibition of CM FOXO1 alleviated DbCM. Additionally, AAV-mediated CM-specific KLF5 overexpression in C57Bl/6 (WT) mice induced cardiac dysfunction. Mice with CM-specific KLF5 constitutive expression (αMHC-rtTA- Klf5 ), which we generated, recapitulated cardiomyopathy without T1D. Moreover, Pparα -/- mice with T1D, had higher CM-KLF5 levels and developed DbCM, suggesting that KLF5-driven DbCM is PPARα-independent. Additionally, CM-KLF5 induced oxidative stress through increased NADPH oxidase (NOX)4 expression and lower mitochondria abundance. Conversely, KLF5 inhibition prevented NOX4 upregulation and superoxide formation. Furthermore, CM-KLF5 promoted NOX4 expression via direct promoter binding. Antioxidant treatment in diabetic WT and αMHC-rtTA- Klf5 mice alleviated cardiac dysfunction partially, suggesting other pathways that contribute in KLF5-induced DbCM. For that, we performed cardiac lipidome analysis where we found clustering of αMHC-rtTA- Klf5 with diabetic WT mice. Of note, KLF5 inhibition in diabetic mice resulted in similar lipidome with non-diabetic WT mice. Individual lipid species analysis showed increased ceramide accumulation in diabetic WT and αMHC-rtTA- Klf5 mice that was reversed upon KLF5 inhibition. Thus, CM-KLF5 activation correlates with cardiac ceramide accumulation, that has been associated with cardiac lipotoxicity. Conclusions: In conclusion, T1D stimulates FOXO1, which induces CM-KLF5 expression that leads to oxidative stress and DbCM in a non-PPARα-dependent manner, as well as to cardiac ceramide accumulation.
ELEVATED SERUM AMINOTRANSFERASE LEVELS AT PRESENTATION ARE ASSOCIATED WITH INTENSIVE CARE UNIT ADMISSION IN PATIENTS WITH COVID-19
Authors: W. Yan, J. J. Jennings, A. R. Montero
Journal: Hepatology (2020)

Background: Abnormal serum aminotransferase levels have been observed in up to 60% of patients with coronavirus disease 2019 (COVID-19) Higher serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have been observed in hospitalized patients with severe disease However, the association between enzyme levels at the time of hospital admission and disease outcomes remains incompletely characterized Studies suggest that the mechanism of liver injury is multifactorial and may involve microvascular thrombosis We aimed to assess the prognostic value of abnormal AST and ALT on admission of patients with COVID-19 and their association with d-dimer in a large urban cohort in the U S Methods: Demographic and clinical data of 532 consecutive patient admissions for COVID-19 in two large, urban tertiary referral hospitals in Washington DC from March 13 to May 21, 2020 were analyzed Independent variables were initial AST and ALT values within 24 hours of presentation Primary outcomes were admission to intensive care unit (ICU) and inpatient mortality Presenting AST and ALT were examined as continuous and as dichotomized (≤2x and >2x upper limit of normal (ULN)) variables with outcomes Secondary analyses included general linear regression between AST/ALT and presenting d-dimer levels Statistical analysis was performed using RStudio (version 4 0 0) Results: Of 532 patients, 50 5% were male, 66 5% were Black, with a mean age of 60 3±16 4 years old Time from symptom onset to presentation was 6 (IQR = 3-8) days Chronic liver disease was observed in 20 patients (3 8%) (Table 1) Ninety-two patients (17 2%) expired and 164 (30 9%) required ICU care Abnormal AST and ALT levels were seen in 368 (70 4%) and 199 (38 0%) patients, respectively The mean presenting AST (95 1 vs 56 1 U/L, p= 0 017) and ALT (66 7 vs 43 9 U/L, p=0 008) levels were higher in patients who required ICU care compared to those who did not Patients with AST >2x ULN (>66 U/L) or ALT >2x ULN (>98 U/L) were more likely to require ICU care (OR 2 10, p=0 001 and OR 2 03, p=0 041, respectively) However, difference in mortality was not observed between those groups Lastly, AST was positively associated with presenting d-dimer (p=0 04) but not ALT (p=0 11) Conclusion: Liver function test should be obtained on admission and elevation in AST and/or ALT should be factored into patient risk stratification, especially when AST >66 U/L and/or ALT >98 U/L  Observed correlation between AST (but not ALT) and d-dimer supports the notion that AST level may reflect the ischemic burden of affected organs as a result of microvascular thrombosis, including but not limited to the liver  However, given the low specificity of d-dimer, its elevation may correlate more so with disease severity rather than true presence of microvascular thrombi within the liver (Table Presented)
血清総及び非高密度リポ蛋白質コレステロール及び心血管イベントのリスク予測-JALS-ECC-
Authors: Tanabe Naohito, Iso Hiroyasu, Okada Katsutoshi, Nakamura Yasuyuki, Harada Akiko, Ohashi Yasuo, Ando Takashi, Ueshima Hirotsugu
Journal: Circulation (2010)
Enhancement of Anticancer Efficacy and Tumor Penetration of Sorafenib by Ionic Liquids
Authors: Yujie Shi, Zongmin Zhao, Kevin Peng, Yongsheng Gao, Debra Wu, Jayoung Kim, Samir Mitragotri
Journal: Advanced Healthcare Materials (2020)

Abstract Ionic liquids (ILs) possess unique solvation and biological properties for drug delivery. Choline and geranic acid (CAGE) in particular, has been successfully formulated to orally deliver insulin and hydrophobic therapeutics such as sorafenib (SRF). However, relatively little is known about the effect of CAGE on intracellular delivery of drugs. Here the effect of low‐concentration CAGE (&lt;2 mg mL −1 ) on the delivery of SRF into cancer cells (4T1, PANC‐1, and HT29) as well as intestine epithelium cells (Caco‐2) is studied. The anti‐cancer effect of SRF is enhanced by up to fivefold in the presence of CAGE (0.5 mg mL −1 ). The effect is mediated not by enhancing the cellular uptake of SRF but by improving intracellular SRF retention by inhibiting exocytosis. Moreover, CAGE improves the anti‐tumor effect of SRF by increasing apoptosis and blocking cell‐cycle progression. Moreover, CAGE significantly enhances the penetration of SRF into and across multicellular constructs with multiple mechanisms involved. Collectively, the administration of ILs such as CAGE combined with SRF may offer a novel therapy to better inhibit tumor progression.
Abstract 13611: Prognostic Value of Shock Index in Patients Admitted With Non ST-Segment Elevation Myocardial Infarction: The ARIC Study Community Surveillance
Authors: Zainali Chunawala, Michael E Hall, Sameer Arora, Xuming Dai, Venu Menon, Kunihiro Matsushita, Melissa Caughey
Journal: Circulation (2020)

Introduction: Shock index (SI), defined as the ratio of heart rate (HR) to systolic blood pressure (SBP), is easily obtained and has been reported to predict all-cause mortality in acute myocardial infarction (AMI) hospitalizations, primarily among patients with STEMI. Large-scale investigations examining the prognostic value of SI in patients with NSTEMI are lacking. Methods: Hospitalizations for acute myocardial infarction were sampled from 4 US areas by the ARIC Study and classified by physician review. HR and SBP at first presentation were abstracted from the medical record. Pulseless patients, those with unobtainable SBP, and transfer patients were excluded. An SI value ≥0.7 was considered high. The TIMI risk score for NSTE-ACS was calculated using the established algorithm. Predictions of all-cause 28-day mortality were analyzed using receiver operating characteristics (ROC). Results: From 2000-2014, 18,301 weighted hospitalizations for NSTEMI patients were sampled and had vitals successfully obtained. Of these, 5753 (31%) had high SI (≥0.7). Patients with high SI were more often female (46% vs 39%) and older (65 vs 63 years), with more prevalent chronic kidney disease (40% vs. 32%), pneumonia (16% vs 8%), and complication by acute heart failure (42% vs 30%). However, the TIMI risk score was comparable for the 2 groups (4.3 vs. 4.2). Angiography (36% vs 58%), revascularization (19% vs 41%), and guideline-directed medications were less often administered to patients with high SI, and the 28-day mortality was nearly 3 times higher (13% vs 5%). Continuous values of SI were more predictive of 28-day mortality than the TIMI risk score, both overall (ROC-AUC: 0.68 vs 0.54; P &lt;0.0001) and among the subset of patients who were revascularized (ROC-AUC: 0.72 vs. 0.56; P &lt;0.0001). Conclusion: The SI outperformed the TIMI risk score for prediction of short-term mortality in patients hospitalized with NSTEMI, and may be useful for risk stratification in emergency settings.
Expression of SARS-CoV-2 Entry Factors in the Pancreas of Normal Organ Donors and Individuals with COVID-19
Authors: Irina Kusmartseva, Wenting Wu, Farooq Syed, Verena Van Der Heide, Marda Jorgensen, Paul Joseph, Xiaohan Tang, Eduardo Candelario-Jalil, Changjun Yang, Harry Nick, Jack L. Harbert, Amanda L. Posgai, John David Paulsen, Richard Lloyd, Sirlene Cechin, Alberto Pugliese, Martha Campbell-Thompson, Richard S. Vander Heide, Carmella Evans-Molina, Dirk Homann, Mark A. Atkinson
Journal: Cell Metabolism (2020)
Abstract 16725: Predicting the Need for a Permanent Pacemaker Device Following Transcatheter Aortic Valve Replacement Using Supervised Machine Learning
Authors: Wasiq Sheikh, Anshul Parulkar, Malik B Ahmed, Suleman Ilyas, Esseim Sharma, Fabio V Lima, Benjamin Rosen, Brian Osler, Gerry Ovide, Antony F Chu
Journal: Circulation (2020)

Introduction: TAVR is approved for use for a range of patients with aortic stenosis. The need for a permanent pacemaker device (PPD) after TAVR varies, but can range from 2 to 51%. Risk factors for requiring PPD after TAVR appear to include being male and having baseline conduction disturbances. Being able to predict who may require PPD could identify at risk patients early and may confer cost savings. Given the advent of machine learning classifier techniques, random forests may aid in better predicting need for PPD after TAVR by using pre-operative variables. Hypothesis: Random Forests offer discriminatory ability in predicting the need for PPD after TAVR using primarily pre-operative variables. Methods: Pre-operative data from a single institution were collected patients undergoing TAVR without a history of PPD between January 2016 and December 2019. EKG data was obtained including underlying rhythm, QRS duration and any underlying conduction abnormality. Other variables included anti-arrhythmic data, comorbidities, and eGFR. Data was imported into Python and a stratified 5 fold cross validation with SMOTE oversampling running at every fold to avoid overfitting was run on the training set. The model that optimized the receiver under the operator curve was exported and applied to a test data set. Precision and recall were calculated to assess classification. Results: A total of 513 patients were identified with nearly 9% eventually requiring PPD. A total of 40 predictor variables were utilized in the modeling. A stratified split of the data resulted in a training set of 384 patients and a test set of 129 patients. A total of 500 trees were used on the training set. The final optimized model had an ROC of 0.71 with the following parameters: gini criterion, max depth of 4, and logarithm max features . When applied to the test set, the model had an ROC of 0.63. Overall accuracy was 0.78, with a precision and recall for no PPD after TAVR being 0.94 and 0.81 and a precision and recall for PPD after TAVR of 0.18 and 0.45. Conclusions: Our results show that machine learning techniques, specifically random forests have discriminatory ability in predicting PPD after TAVR. More tuning of the models are required to achieve better discrimination.
Rising incidence of early-onset colorectal cancer — a call to action
Authors: Naohiko Akimoto, Tomotaka Ugai, Rong Zhong, Tsuyoshi Hamada, Kenji Fujiyoshi, Marios Giannakis, Kana Wu, Yin Cao, Kimmie Ng, Shuji Ogino
Journal: Nature Reviews Clinical Oncology (2020)
SP0022 Low back pain and imaging
Authors: N Boos
Journal: Annals of the Rheumatic Diseases (2001)

<h3></h3> Low-back pain is a very common but benign and in general self-limiting disease indicating that only a small proportion of the patients will require sophisticated imaging studies. Recent studies have highlighted that a simple relation of structural abnormalities to low-back pain is impossible because similar alterations can be found in symptomatic as well as in asymptomatic individuals. These findings question our current criteria for the diagnosis of low-back pain disorders with regard to their discriminative power in differentiating diseased and non-diseased individuals. Structural abnormalities demonstrated by imaging studies should therefore only be interpreted in the light of the clinical findings. This review has shown that only a few studies contribute to our understanding of the clinical efficacy of imaging studies in the evaluation of low-back pain disorders. There is an absolute need for comprehensive well conducted studies on the impact of specific image modalities on diagnosis and treatment of lumbar spinal disease.
Abstract 14933: Brain Emotional Neural Activity is Associated With Complex Plaque Characteristics Resulting Acute Plaque Instability: A Prospective 3D-Rendered 18F FDG-PET/CT Assessment
Authors: Dong Oh Kang, Jae Seon Eo, Eun Jin Park, Hyeong Soo Nam, Joon Woo Song, Cheol Ung Choi, Eung Ju Kim, Seung-woon Rha, Hong Seog Seo, Hongki Yoo, Jin Won Kim
Journal: Circulation (2020)

Introduction: Stress-associated neurobiological activity is associated with future cardiovascular events. However, whether the linkage between brain emotional activity and complex plaque characteristics exists during the phase of acute plaque instability needs to be elucidated. Objectives: We aimed to prospectively estimate brain amygdalar activity (AmygA), arterial inflammation (AI) and macrophage hematopoiesis (HEMA) according to the presence of complex plaque characteristics in patients with acute myocardial infarction (AMI). Methods: In a total of 45 AMI patients (mean 60.0 years, 84.4% male), 18F FDG-PET/CT imaging was performed within 45 days of index episode. Total plaque burden was assessed using the SYNTAX score. The culprit plaque was considered complex, if there were two or more of the following morphologic features: thrombus, ulceration, plaque irregularity, and impaired flow (TIMI&lt;3). The PET signal activities were compared using a customized 3D-rendered PET/CT reconstruction. Results: Average SYNTAX score ranged by 16.3±8.4 and 12 (26.7%) patients had intermediate to high score (≥22). Complex culprit plaque and significant flow limitation were present in 34 (75.6%) and 33 (73.3%) patients, respectively. AmygA increased significantly in those who had higher SYNTAX score (≥22; target-to-background ratio [TBR]: 0.68±0.08 vs. 0.63±0.06; p=0.004), complex culprit plaques (TBR: 0.66±0.05 vs. 0.60±0.04; p&lt;0.001), and significant flow limitation (TBR: 0.66±0.05 vs. 0.61±0.06; p=0.008) as compared to those without complex features (Figure). In contrast, carotid AI, aortic AI, and HEMA merely showed significant differences according to the presence of the aforementioned complex angiographic characteristics. Conclusions: AmygA was markedly enhanced in AMI patients with complex plaque characteristics. These findings suggest that AmygA closely associates with loco-regional disease activity at the level of coronary vasculature.
Abstract 17213: Myocardial Infarction and Stroke Awareness Among US and Foreign-Born Adults in the 2014 and 2017 National Health Interview Survey
Authors: Ivy Mannoh, Ruth Alma N Turkson Ocran, Yvonne Commodore-mensah
Journal: Circulation (2020)

Background: Atherosclerotic cardiovascular disease, defined as nonfatal myocardial infarction (MI), coronary heart disease death, or fatal or nonfatal stroke, is the leading cause of death in the United States (US). MI and stroke symptom awareness reduces delays in hospitalization and mortality. We hypothesized that foreign-born persons will have lower stroke and MI symptom awareness than US-born persons. Methods: We analyzed cross-sectional data from the 2014 and 2017 National Health Interview Surveys (NHIS) on US-born and foreign-born adults from 9 regions of birth (Europe, South America, Mexico/Central America/Caribbean, Russia, Africa, Middle East, Indian subcontinent, Asia, and Southeast Asia). Our outcomes were stroke and MI symptom awareness, and the best action to take during a stroke or MI event. Awareness was defined as knowing all 5 symptoms of MI or stroke respectively, and choosing “call 911” as the best action to take in the event of an MI or stroke. Generalized linear models with Poisson distribution and a logarithmic link was used to assess disparities in awareness between foreign-born and US-born persons. We compared responses from 2014 and 2017 to assess improvement in awareness. Results: We included 63,439 participants, with mean age 38.2 years; 51% were female and 50% had less than high school education. After adjusting for age, sex, and education, we observed significant variation in MI and stroke symptom awareness and best action to take by region of birth [Table]. In comparison to US-born, foreign-born persons were less aware of MI and stroke symptoms and the best action to take. Improvement in awareness was not significant in all groups between 2014 and 2017. Conclusion: These findings suggest a disparity in MI and stroke symptom awareness among immigrants in the US. Culturally tailored public health education and health literacy initiatives are needed to help reduce these disparities in awareness.
SAT0029 The role of microflora in ankent (ankylosing enthesopathy) in mice
Authors: Z Rehakova, J Sinkora, T Hrncir, R Stepankova, J Capkova, P Ivanyi
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Murine ankylosing enthesopathy (ANKENT), an experimental model for human ankylosing spondylitis, is strongly dependent on the contact of ANKENT-prone mice (B10 or B10. BR genetic background) with microbes as no disease is observed under germfree (GF) conditions while about 20% of conventional (CV) males are afflicted. The disease is almost exclusively restricted to male mice, It affects only ankle and tarsal joints. Next risk factor for ANKENT is haplotype. <h3>Objectives</h3> To confirm a hypothesis that ANKENT-triggering agents are intestinal bacteria to identify the ANKENT-triggering strains by technique of controlled association of GF mice. <h3>Methods</h3> B10. BR males from a previously established GF colony were oligoassociated with a cocktail of anaerobic bacteria isolated from a diseased CV male. The mice were checked for ANKENT once a week. Lymphocyte phenotype in afflicted as well as healthy males was determined. <h3>Results</h3> Oligoassociation with the selected cocktail of bacteria resulted in ANKENT in &gt; 20% of ex-GF males, which corresponds to the situation seen under CV conditions and exceeds the ANKENT incidence in specific-pathogen-free mice. <h3>Conclusion</h3> ANKENT-triggering agents are bacteria. The importance of viruses, protozoa and helmints in ANKENT onset can be excluded. Our findings strongly suggest that, similar to other spondylarthropathies, intestinal microflora has a inductive role in ANKENT pathogenesis. Supported by grant GACR 310/00/1371. <h3>Reference</h3> Rehakova, <i>et al</i>. Hum Immunol. 2000;61:555
Potential Cost Implications for All US Food and Drug Administration Oncology Drug Approvals in 2018
Authors: Patrick C. DeMartino, Miloš D. Miljkovic, Vinay Prasad
Journal: JAMA Internal Medicine (2020)

The growth of cancer drug spending in the US has outpaced spending in nearly all other sectors, and an increasing proportion of the drug development pipeline is devoted to oncology. In 2018, there was a record number of drugs entering the US market.
Abstract 14290: Treadmill Exercise Training Reduces the Systolic Blood Pressure Response to Walk Exercise in Patients With Peripheral Artery Disease
Authors: Joshua Slysz, Lu Tian, Lihui Zhao, Dongxue Zhang, Mary M McDermott
Journal: Circulation (2020)

Introduction: Supervised exercise therapy (SET) improves functional capacity in people with peripheral artery disease (PAD). However, the effects of SET on improving cardiovascular health remain unclear. This study investigated the effects of a 6-month SET intervention on the blood pressure (BP) response to walking exercise in patients with PAD. Methods: Participants with PAD randomized to either SET or control group in the NHLBI sponsored PROPEL clinical trial were included. The SET intervention consisted of 3X weekly supervised treadmill exercise for 6 months. Participants in the control group attended weekly education sessions for 6 months. A Gardner-Skinner treadmill test (GSTT) and six-minute walk (6MW) test were completed at baseline and 6-month follow-up. BP was measured at the end of each 2-min stage of the GSTT. Mixed-effects regression models compared the 6-month change in systolic BP (SBP) &amp; diastolic BP (DBP) between groups for each of the first 5 stages of the GSTT. Pearson correlation coefficients were used to relate the average 6-month change in DBP &amp; SBP for the first 5 stages of the GSTT with the 6-month change in 6MW distance. Results: Ninety-seven participants with PAD (67 ± 9 years, 39 (40%) female, 65 (67%) black) completed a 6-month GSTT. Compared to the control group, SET significantly decreased SBP at stage 1, stage 2, stage 3, and stage 4 of the GSTT (Table 1). There were no effects of SET on DBP (Table 1). A greater reduction in SBP during the first 5 stages the GSTT test was associated with significantly greater improvement in 6MW distance at 6-month follow-up of SET (Pearson’s r = -0.37; 95%CI: -0.52, -0.19; p &lt; 0.001). However, there were no associations of reduction in DBP with improvement in 6MW distance. Conclusions: These results show that SET improves cardiovascular health in people with PAD. Furthermore, results suggest that improved CV health in part explains the improved 6MW in response to SET in people with PAD.