tbuckley/cabot-search huggingface dataset:
Abstract 11352: Frailty in Pediatric Patients After Fontan Palliation is Associated with Impaired Quality of Life and Increased Hospitalizations
Authors: Megan Wilde, Kurt Schumacher, Sunkyung Yu, Ray Lowery, Blake P Armstrong, Jessica Stoscup, Karen Uzark, Heang Lim
Journal: Circulation (2021)

Introduction: Frailty is a clinical syndrome common in adults with chronic disease with resultant vulnerability to adverse health outcomes. There is little known about frailty in pediatric patients, including those with congenital heart disease. We hypothesized that the Fontan-palliated population have a high incidence of frailty. Methods: This single center, prospective cohort study assessed frailty in patients (10-21 years old) after Fontan palliation. The five domains of frailty including slowness, weakness, exhaustion, shrinkage, and diminished physical activity were evaluated using a modified Fried frailty assessment comprised of validated pediatric tests. Providers also estimated their patient’s frailty. Quality of life (QOL) was assessed using PedsQL generic and cardiac modules. Standard descriptive statistics and univariate analyses identified risk factors associated with frailty. Results: Of 54 participants (median age 15.3 years, 61% male), 18 (33%) were identified as frail while 26 (48%) were pre-frail. Patients frequently exhibited frailty in the domains of slowness (93%), weakness (41%), and diminished physical activity (39%). There was poor correlation between frailty scores and provider estimates of frailty (Kappa=0.11). Frail subjects were more likely to have lower PedsQL physical functioning scores (mean 62.8 ± SD 18.5 in Frail vs. 75.7 ± 16.0 in No/pre-Frail; p=0.01). Factors associated with frailty included protein losing enteropathy (p=0.03) and at least one hospitalization in the last year (p=0.047). Higher NYHA functional class (p=0.07) and &gt; 4 clinic visits in the last year (p=0.08) trended toward an association with frailty. Conclusion: Frailty was identified in 1/3 of pediatric patients after Fontan palliation with providers inconsistently recognizing it. Frail patients were more likely to have lower physical functioning, and higher healthcare utilization. These findings highlight the need for improved screening and support for an at-risk population that may not be readily apparent to providers. Additional studies are needed to better understand pediatric frailty, its reversibility, and whether it predicts vulnerability to adverse health outcomes as seen in adults.
Abstract 13305: The Relationship of Health Activation to Risk of Future Cardiovascular Disease Among Family Caregivers of Patients With Chronic Illness in Rural Dwellers
Authors: Chin-Yen Lin, Misook L Chung, Frances J Feltner, Mary Kay Rayens, Gia Mudd-Martin, Martha J Biddle, Jennifer L Miller, Terry A Lennie, Debra K Moser
Journal: Circulation (2021)

Background: Rural family caregivers experience high levels of stress, burden, and psychological distress related to caregiving and are at higher risk for cardiovascular disease (CVD) compared to non-caregivers. Health activation (known also as patient activation) is an indicator of engagement in self-care and is defined as an individual’s knowledge, skill, and confidence in managing health. Better health activation is associated with better health outcomes. Because rural individuals are at greater risk of CVD and have fewer supportive resources than those in urban environments, we wanted to determine the relationship of health activation with risk for future CVD in this population. Objective: The purpose of this study was to examine the association of health activation with risk for future CVD among rural family caregivers of patients with chronic illness. Methods: This was a cross-sectional study using baseline data from a randomized controlled trial of an intervention to reduce CVD risk for rural caregivers. We measured health activation using the Patient Activation Measure. The predicted10-year risk of CVD was assessed using the Framingham risk score. Covariates potentially related to cardiovascular risks among caregivers were collected including stress (Perceived Stress Scale-Cohen), anxiety (Brief Symptom Inventory), depressive symptoms (Patient Health Questionnaire-9), and caregiver burden (Zarit Burden Interview). Generalized linear regression was used to analyze data. Results: Of 217 caregivers (mean age 53 ± 13 years, 79% female), 48% were caring for a spouse, 20% were caring for a parent, and the remaining 32% were caring for a sibling, a child, or other relatives. Caregivers with higher health activation had a lower risk of developing CVD in the future based on their Framingham risk score (B = -0.081, SE= 0.039, 95% CI= -0.158 to -0.004, p=0.038), independent of the other covariates. Every 10-point increase in health activation score was associated with a nearly 1-point (0.81) decrease in Framingham risk score. Conclusions: Health activation is a good predictor of future risk for developing CVD. Development and testing of interventions to promote health activation before people develop CVD is suggested to decrease the risk of future CVD.
Abstract 12558: 3-year Outcomes In Stable Coronary Artery Disease Patients With Diabetes Based On A Novel Index: Computational Pressure-flow Dynamics Derived Fractional Flow Reserve
Authors: Kwan Yu LI, Lok Yee Jane Lam, Ka Lam Calvin Leung, Qingwen Ren, Mei Zhen Wu, Yi Kei Stephanie Tse, Si-Yeung Yu, Hang Long Li, Pui Fai Wong, Shuk Yin Yu, Yundi Feng, Yunlong Huo, Kai Hang Yiu
Journal: Circulation (2021)

Introduction: Computational pressure-flow dynamics derived fractional flow reserve (caFFR) has emerged for non-invasive assessment of fractional flow reserve (FFR) in patients with stable coronary artery disease (CAD), without the need for hyperaemic induction and guidewire placement in conventional FFR. The clinical value of caFFR in diabetic patients, who are at risk of microvascular dysfunction, has not been validated. The aim of the study is to evaluate the use of caFFR in diabetic patients with stable CAD. Methods: A total of 212 stable CAD patients with diabetes (mean age=67.6±10.6, 66.5% male) were included. Patients were said to be adherent to caFFR if all ischemic vessels, defined by caFFR≤0.8 were treated with PCI and all nonischemic vessels, defined by caFFR&gt;0.8 were not. Otherwise, they were considered to be non-adherent to caFFR. The primary endpoint was 3-year major adverse cardiac events (MACE), defined as a composite of cardiovascular mortality, non-fatal myocardial infarction (MI), stroke and unplanned revascularization. Results: Among the 212 patients, PCI was performed in 62.3% of them. A total of 26 composite events occurred, including 5 cardiovascular mortality, 5 non-fatal MI, 2 strokes and 14 unplanned revascularization. The incidence rate of MACE was significantly lower in adherent patients than in non-adherent patients (5.4% vs 15.8%; P=0.01). After multivariate adjustment, adherent patients had a significantly lower risk of MACE than non-adherent patients (adjusted hazard ratio [HR], 0.33; 95% confidence interval [Cl], 0.13-0.83; P=0.02). Conclusions: In stable CAD patients with diabetes, caFFR-guided revascularization significantly reduces the risk of MACE in 3 years. The findings support the potential use of caFFR in treatment guidance of diabetic patients.
EXTH-67. THERAPEUTIC EFFICACY OF GC1118, A NOVEL ANTI-EGFR ANTIBODY, AGAINST GLIOBLASTOMA WITH HIGH EGFR AMPLIFICATION IN PATIENT-DERIVED XENOGRAFTS
Authors: Seung Won Choi
Journal: Neuro-Oncology (2021)

Abstract We aimed to evaluate the preclinical efficacy of GC1118, a novel anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), against glioblastoma (GBM) tumors using patient-derived xenograft (PDX) models. A total of 15 distinct GBM PDX models were used to evaluate the therapeutic efficacy of GC1118. Genomic data derived from PDX models were analyzed to identify potential biomarkers associated with the anti-tumor efficacy of GC1118. A patient-derived cell-based high-throughput drug screening assay was performed to further validate the efficacy of GC1118. Compared to cetuximab, GC1118 exerted comparable growth inhibitory effects on the GBM tumors in the PDX models. We confirmed that GC1118 accumulated within the tumor by crossing the blood–brain barrier in in vivo specimens and observed the survival benefit in GC1118-treated intracranial models. Genomic analysis revealed high EGFR amplification as a potent biomarker for predicting the therapeutic efficacy of GC1118 in GBM tumors. In summary, GC1118 exerted a potent anti-tumor effect on GBM tumors in PDX models, and its therapeutic efficacy was especially pronounced in the tumors with high EGFR amplification. Our study supports the importance of patient stratification based on EGFR copy number variation in clinical trials for GBM. The superiority of GC1118 over other EGFR mAbs in GBM tumors should be assessed in future studies.
Response to comment on “Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics”
Authors: Jonas Bovijn, Kristi Krebs, Chia-Yen Chen, Ruth Boxall, Jenny C. Censin, Teresa Ferreira, Sara L. Pulit, Craig A. Glastonbury, Samantha Laber, Iona Y. Millwood, Kuang Lin, Liming Li, Zhengming Chen, Lili Milani, George Davey Smith, Robin G. Walters, Reedik Mägi, Benjamin M. Neale, Cecilia M. Lindgren, Michael V. Holmes
Journal: Science Translational Medicine (2021)

Triangulation of evidence from clinical trials and human genetics suggests a potential excess risk of cardiovascular disease events arising from therapeutic inhibition of sclerostin.
QOLP-03. OBSERVATIONS OF COMPLEMENTARY CANNABIS THERAPY IN MALIGNANT GLIOMA PATIENTS
Authors: Nicholas Blondin
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION As of 5/15/2021, medical marijuana programs exist in 37 states, and marijuana is legal for recreational use in 17 states. In Connecticut, the CT Medical Marijuana Program (MMP) was created in 2012 and I began certifying my patients with malignant glioma (brain cancer) for the program in 2014. I now provide data on my experience with complementary cannabis therapy. PART 1 Between 9/1/2014 and 6/1/2018, 23 patients with malignant glioma were registered in the CT MMP and received a card. Of these 23 patients, 15 patients took a daily cannabis oil supplement for at least 6 months during their treatment, and 7 patients used cannabis products only as needed. 3 patients are still alive, all in the daily cannabis oil group (41, 54 and 77 months). The median overall survival in the daily group was 22.0 months, versus 16.9 months in the as needed group. PART 2 Since 9/1/2014, 71 patients with malignant glioma were certified for the CT MMP. Of these 71 patients, 15 did not complete the patient registration process and did not receive a card for the MMP. As of 5/15/2021, of the 56 registered patients, there are 20 Active patients and 36 Inactive patients. Regarding the Inactive patients, 29 have died and 7 are alive but did not renew their card. Amongst Active patients, 4 are currently taking a daily cannabis oil supplement as a complementary therapy, and 16 are currently using cannabis products only as needed for symptoms. The 4 patients employing complementary therapy currently have a survival of 8, 31, 33, and 35 months. CONCLUSION In my experience, complementary cannabis treatment is well tolerated in malignant glioma patients, and can provide significant palliative benefit to treat insomnia and nausea. Serious adverse events attributed to cannabis products, or decreased survival, have not been observed.
Post-Transplant Blockade of CXCR4 Improves Complete Remission Rates and Donor Stem Cell Engraftment without Aggravating Gvhd
Authors: Long Su, Ming Hui Fang, Jun Zou, Su Jun Gao, Xiao Yi Gu, Xian Di Meng, Xue Wang, Zheng Hu, Yong Guang Yang
Journal: Blood (2021)
NIMG-48. TLR7/8-AGONIST-LOADED NANOPARTICLES REPROGRAM TUMOR-ASSOCIATED MYELOID CELLS FOR EFFECTIVE IMMUNOTHERAPY OF EXPERIMENTAL GLIOMA AND MRI-BASED TREATMENT MONITORING
Authors: Kira Pfleiderer, Verena Turco, Natalie K Horvat, Jessica Hunger, Kianush Karimian-Jazi, Katharina Schregel, Gianluca Brugnara, Duy Nguyen, Kristine Jähne, Manuel Fischer, Abdulrahman Alsasa, Theresa Bunse, Matthias Schlesner, Martina Muckenthaler, Ralph Weissleder, Wolfgang Wick, Sabine Heiland, Philipp Vollmuth, Martin Bendszus, Christopher B Rodell, Michael O Breckwoldt, Michael Platten
Journal: Neuro-Oncology (2021)

Abstract Drivers of glioblastoma progression include the immunosuppressive tumor microenvironment (TME), dominated by tumor-associated myeloid cells. Therefore, we investigated a new approach targeting the myeloid compartment to reprogram myeloid cells in the TME using a β-cyclodextrin nanoparticle (CDNP) formulation encapsulating the toll-like receptor 7 and 8 (TLR7/8) agonist R848. Biodistribution confirmed specific targeting of CDNP-R848 to tumor-associated macrophages (TAMs) (labeling efficiency: 34.0% ± 22.2%), whereas tumor microglia (5.4% ± 4.4%) and splenic macrophages (13.2% ± 0.7%) revealed less uptake. Interestingly, intravenous application of CDNP-R848 induced strong tumor regression with an overall response rate of 80% (2.5% complete response, 52.5% partial response and 25% stable disease, n=40 mice) in Gl261 syngeneic experimental gliomas, while CDNP vehicle treated animals showed exponential tumor growth (100% progressive disease, n=12 mice). As advanced imaging is essential to monitor intracranial disease and possibly predict response and resistance, we performed high resolution magnetic resonance imaging using ultrasmall iron oxide nanoparticles (USPIO) for macrophage tracking. Increased levels of USPIO uptake in vehicle treated animals compared to CDNP-R848 treated animals were found as an early marker of responding mice (ΔT2*: -11.7 ± 4.2 vs -4.0 ± 2.8 ms, p=0.01). This correlated with an increased influx of myeloid cells into the TME of vehicle treated animals and showed a strong correlation of macrophage recruitment and USPIO uptake (R2: 0.78, p=0.004). Mechanistically, phenotyping of macrophages (CD45high/CD11b+) indicated a pro-inflammatory shift of TAMs with an increased infiltration of pro-inflammatory F4/80+/MHCII+ macrophages during CDNP-R848 treatment. Surprisingly, the anti-tumor effect of CDNP-R848 was independent of CD8+ T cells, CD4+ T cells or NK cells during selective depletion experiments. In summary, this work demonstrates the ability of myeloid-targeted therapies to re-shape the tumor microenvironment for an effective immunotherapy of glioma.
Footprints of a microbial toxin from the gut microbiome to mesencephalic mitochondria
Authors: A Raquel Esteves, Mário F Munoz-Pinto, Daniela Nunes-Costa, Emanuel Candeias, Diana F Silva, João D Magalhães, A Raquel Pereira-Santos, I Luisa Ferreira, Susana Alarico, Igor Tiago, Nuno Empadinhas, Sandra Morais Cardoso
Journal: Gut (2021)

Idiopathic Parkinson's disease (PD) is characterised by alpha-synuclein (aSyn) aggregation and death of dopaminergic neurons in the midbrain. Recent evidence posits that PD may initiate in the gut by microbes or their toxins that promote chronic gut inflammation that will ultimately impact the brain. In this work, we sought to demonstrate that the effects of the microbial toxin β-N-methylamino-L-alanine (BMAA) in the gut may trigger some PD cases, which is especially worrying as this toxin is present in certain foods but not routinely monitored by public health authorities.To test the hypothesis, we treated wild-type mice, primary neuronal cultures, cell lines and isolated mitochondria with BMAA, and analysed its impact on gut microbiota composition, barrier permeability, inflammation and aSyn aggregation as well as in brain inflammation, dopaminergic neuronal loss and motor behaviour. To further examine the key role of mitochondria, we also determined the specific effects of BMAA on mitochondrial function and on inflammasome activation.BMAA induced extensive depletion of segmented filamentous bacteria (SFB) that regulate gut immunity, thus triggering gut dysbiosis, immune cell migration, increased intestinal inflammation, loss of barrier integrity and caudo-rostral progression of aSyn. Additionally, BMAA induced in vitro and in vivo mitochondrial dysfunction with cardiolipin exposure and consequent activation of neuronal innate immunity. These events primed neuroinflammation, dopaminergic neuronal loss and motor deficits.Taken together, our results demonstrate that chronic exposure to dietary BMAA can trigger a chain of events that recapitulate the evolution of the PD pathology from the gut to the brain, which is consistent with 'gut-first' PD.
Abstract 13912: ECG-DualNet: A MultiLabel Model for Automated Diagnosis on Both Electrocardiographic Signals and Printed 12-lead Electrocardiograms
Authors: Veer Sangha, Rohan Khera
Journal: Circulation (2021)

Background: Electrocardiograms (ECGs) are frequently stored as printed images, but tools developed for artificial intelligence (AI)-based automated diagnosis and patient phenotyping exclusively rely on signal data, limiting their application. Methods: We developed a model that simultaneously incorporates both signal and image-based ECG data in clinical diagnosis and patient phenotyping. We used all 12-lead ECGs from a large deidentified database from Brazil, with signals transformed to a standard 12-lead ECG image. Both ECG signals and images were randomly subset into training, validation and test sets (90%-5%-5%). We used 6 physician-defined clinical labels spanning rhythm and conduction disorders as labels (atrial fibrillation [AF], sinus tachy/bradycardia [ST/SB], 1 st degree AV block [1dAVB], RBBB, LBBB). In addition, ECG-based identification of patient sex was assessed as a higher dimensional label. Convolutional Neural Networks were constructed with custom Inception net architecture for signals and EfficientNet-B3 for images. Model performance was evaluated in the holdout test set and US-based external validation dataset, PTB-XL. Results: The derivation dataset included 2,228,236 ECGs in 1,506,112 individuals (mean age 54y, 60% female). The ECG-DualNet model successfully labeled all 6 clinical diagnoses and patient gender with a high model performance (AUC of .81-.99 for signal and .92-.99 for images, F1 scores, .31-.78, and .49-82) in the 111,412 held-out test ECGs (Fig A-B). In external validation, with 21,785 ECGs, the model had excellent performance on both ECG signals and images (AUCs .75-.99 and .89-.99, F1 scores, .25-82, and .44-.86) (Fig C-D). Conclusion: A novel multilabel dual signal and image-based model achieved high performance in both clinical diagnosis and higher dimensional phenotypic labels across distinct ECG sources, with the ability to standardize automated diagnosis and patient phenotyping across ECG data formats.
Abstract 10698: Towards a Dialogue Agent to Assist African American and Hispanic/Latino Heart Failure Patients with Dietary Restrictions
Authors: Devika Salunke, Itika Gupta, Barbara Di Eugenio, Paula G Allen-Meares, Carolyn Dickens, Olga Garcia, Andrew D Boyd
Journal: Circulation (2021)

Background: Restricting dietary sodium is a common recommendation to address symptoms in heart failure (HF) patients. However, using the information provided on nutrition labels can be complex, leading to lapses in adherence. This problem is compounded by insufficient information on ethnic preferences in dietary habits. Based on our previous findings we developed a prototype dialogue agent (HF-DA) to assist African American (AA) and Hispanic Latino (H/L) patients with their HF self-care needs, including understanding nutrition labels and providing practical information per FDA recommendations. Objective: Compare HF-DA against existing technology in the public domain in assisting AA and H/L HF patients to make healthy food choices. Methods: We conducted a review of existing technology in two ways. 1: Google search engine: We measured the number of actions (typing, scrolling, clicking) required to find a source for a food’s sodium content matching the U.S. Department of Agriculture’s recommendations and used a calculator to understand the total sodium in a desired serving size. We identified relevant search terms by analyzing the commonly used words in the transcripts from our HF patient education sessions with their health educators (18 AA and 2 H/L) and 1:1 interviews with HF patients (3 AA and 1 H/L). 2: Google Play Store: We downloaded the top 15 apps using the search term “heart failure” and explored their functionality. Results: Google’s search engine required users to perform 1 action to identify the sodium content and percent daily value but then needed 6-8 actions (dependent on query length) to calculate sodium content of total serving size. Our HF-DA provides this information in 4 actions. Of the 15 apps available in the Play Store, none had any features for understanding nutrition labels. Conclusion: Our preliminary analysis revealed there are very few culturally sensitive technological resources available to assist HF patients in understanding nutrition labels. These resources require a patient to understand nutrition labels, perform arithmetic, and recall dietary restrictions. HF-DA is capable of promoting healthy eating habits by aiding HF patients' decision-making process by providing reliable information in fewer steps.
Abstract 10452: Exploring the Role of Mitochondrial Genetic Variants in Coronary Artery Disease
Authors: Baiba Vilne, Bryan Abbo, Uldis Donins, Irina Rudaka
Journal: Circulation (2021)

Introduction: Large-scale genome-wide association studies have identified &gt;200 single-nucleotide variants (SNVs) significantly associated with coronary artery disease (CAD), collectively explaining &lt;20% of the heritability. Hypothesis: Mitochondrial (MT) genetic variants presents an underexplored one potential source of the “missing heritability”. Methods: We analyzed 265 MT-SNVs in ∼500,000 UK Biobank individuals, exploring two different CAD definitions: including (SOFT=34,782) vs. excluding (HARD=20,405) angina, using the array, sex, birth year and first five principal components as covariates. Results: In SOFT cases, four MT-SNVs survived multiple testing correction (at FDR&lt;5%), all conferring increased CAD risk: m.10400C&gt;T (rs28358278, OR=1.28, MAF=0.02, T114T in MT-ND3), m.15301G&gt;A (rs527236045, OR=1.03, MAF=0.04, L185L in MT-CYB), m.11251A&gt;G (rs869096886, OR=1.03, MAF=0.2, L164L in MT-ND4) and m.15452C&gt;A (rs193302994, OR=1.03, MAF=0.2, L236I in MT-CYB), the latter two previously associated with height in the UK Biobank. In HARD cases, no MT-SNVs survived multiple testing correction, the most significant nominal (P &lt;0.05) findings being for four SNVs, whereof m.295C&gt;T (rs41528348, OR=1.05, MAF=0.1, in the D-LOOP) and m.12612A&gt;G (rs28359172, OR=1.05, MAF=0.04, V92V in MT-ND5) could potentially increase CAD risk, whereas m.12372G&gt;A (rs2853499, OR=0.97, MAF=0.22, L12L in MT-ND5), m.11467A&gt;G (rs2853493, OR=0.97, MAF=0.22, L236L in MT-ND4) and m.15301G&gt;A (rs193302991, OR=0.97, MAF=0.04, L185L in MT-CYB) may confer protective effects. Previously, several of these variants have been associated with a number of blood cell traits in the UK Biobank, including the mean corpuscular hemoglobin levels (m.295C&gt;T, m.12612A&gt;G, m.12372G&gt;A) and volume (m.295C&gt;T and m.12612A&gt;G). In addition, m.12372G&gt;A was significantly association with five other blood cell traits, including the mean platelet volume and white/red blood cell count, as well as with several renal biomarkers, and m.12612A&gt;G was associated with height. Conclusions: Our results indicated only spurious associations of the MT-SNV with the occurrence of CAD. More data in larger study cohorts may be needed to conclusively determine the role of MT-DNA in CAD.