tbuckley/cabot-search huggingface dataset:
Abstract 11935: The Index of Microcirculatory Resistance to Predict Subsequent Acute Cellular Rejection and Cardiac Events After Heart Transplantation
Authors: Jung-Min Ahn, Frederik Zimmermann, Lars L Gullestad, Oskar Angerås, Kristjan Karason, Kristoffer Russell, Ketil Lunde, Kozo Okada, Helen Luikart, Kiran K Khush, Yasuhiro Honda, Nico Pijls, Sang Eun Lee, Jae-Joong Kim, Seung-jung Park, Ole-Geir Solberg, William F Fearon
Journal: Circulation (2021)

Introduction: Single center data suggest that the index of microcirculatory resistance (IMR) measured early after heart transplantation predicts subsequent acute cellular rejection. Hypothesis: To validate whether IMR measured early after transplantation can predict subsequent acute cellular rejection and long-term outcome in a large multicenter cohort. Methods: From 5 international heart transplantation cohorts, 237 patients who underwent IMR measurement early after transplantation were enrolled. The primary outcome was biopsy-proven acute cellular rejection of grade 2 or 3 within 1 year after transplantation. A key secondary outcome was major adverse cardiac events (MACE, the composite of death, re-transplantation, myocardial infarction, stroke, graft dysfunction, and readmission due to a cardiac cause) at 10 years. Results: IMR was measured at a median of 7 weeks (interquartile range: 3 to 10 weeks) post-transplantation. Patients with acute cellular rejection grade 2 or 3 at the time of IMR assessment were excluded. At 1 year, the incidence of acute cellular rejection was 14.0%. IMR was associated proportionally with the risk of acute cellular rejection (per increase of 1-unit IMR; adjusted hazard ratio [aHR], 1.04; 95% confidence interval [CI], 1.01-1.06; P=0.002). The incidence of acute cellular rejection in patients with IMR ≥ 18 was 23.8%, while the incidence of acute cellular rejection in those with IMR &lt; 18 was 5.5% (aHR, 4.09; 95% CI, 1.67-10.0; P=0.002). At 10 years, MACE occurred in 86 (36.3%) patients. IMR was significantly associated with the risk of MACE (per increase of 1-unit IMR; aHR, 1.03; 95% CI, 1.01-1.05; P=0.002). Conclusions: IMR measured early after heart transplantation is associated with subsequent acute cellular rejection at 1 year and clinical events at 10 years. Early IMR measurement after transplantation identifies patients at higher risk and may guide personalized post-transplantation management.
Abstract 12260: Reoperation Was an Effective Therapy in Patients with Obstructive Hypertrophic Cardiomyopathy After Septal Reduction Therapy
Authors: Yang Zhang, Changsheng Zhu, Changpeng Song, Kunlun Yin, Jian Zhang, Manyun Huang, Xinxin Zheng, Jie Lu, Xiaonan Fang, Zhou Zhou, WANG Shuiyun, Xiaohong Huang
Journal: Circulation (2021)

Introduction: This study aims to analyze the clinical characteristics of patients with obstructive hypertrophic cardiomyopathy (OHCM) undergoing repeated septal reduction therapy (SRT), and preliminarily describe the genotype in the recruited patients. Methods: Patients with OHCM who received repeated SRT were recruited from 2014 to 2019 in Fuwai Hospital. Patients were divided into septal myectomy (SM) group or alcohol septal ablation (ASA) group according to the primary procedure of SRT. Sixteen of these patients underwent genetic testing. Pathogenic mutations were those mutations identified as pathogenic, likely pathogenic, or variants of uncertain significance according to the ACMG criteria. Results: A total of 31 patients (21 males) was included. The average age was 48.7±12.2 years. There were 7 patients in the SM group and 24 patients in the ASA group. Preoperative electrocardiogram showed that 7 patients in the ASA group presented with complete right bundle branch block (CRBBB). After the operation, 4 patients were implanted with permanent pacemakers due to complete atrioventricular block, of which 3 patients were in the ASA group with CRBBB. Pathogenic mutations were identified in 50.0% (8/16) of the study patients. Pathogenic mutations were mostly located in the MYH7 gene (5/9,55.6%), MYBPC3 gene (3/9,33.3%), and TNNT2 gene (1/9,11.1%). There was no difference between patients carrying pathogenic mutations or not, in terms of interventricular septal thickness and left ventricular outflow tract gradient. During the perioperative period, except for one death caused by electrical storm, the remaining patients had no serious complications. The results of follow-up echocardiography showed that except for 2 patients who had left ventricular outflow tract obstruction again, the thickness of interventricular septum and left ventricular outflow tract gradient was significantly lower compared with preoperative echocardiography. Conclusions: In conclusion, the surgery of SM is an effective treatment in OHCM patients with a history of previous SRT procedures. Patients with the first procedure of ASA are at high risk of developing atrioventricular block after a repeated SM.
Abstract 10627: Benefits of Icosapent Ethyl in Patients with Prior Peripheral Artery Disease: REDUCE-IT PAD
Authors: Deepak L Bhatt, Philippe G Steg, Michael Miller, Eliot A Brinton, Terry A Jacobson, Jean-Claude Tardif, Steven Ketchum, Rebecca Juliano, Lisa Jiao, Christina Copland, Ralph Doyle, Christie M Ballantyne
Journal: Circulation (2021)

Introduction: REDUCE-IT found significant benefit in 8179 statin-treated patients randomized to icosapent ethyl (IPE). Whether that benefit extends to patients with peripheral artery disease (PAD) was unknown. Methods: The primary endpoint was time to cardiovascular (CV) death, myocardial infarction (MI), stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary endpoint was CV death, MI, or stroke. Total (first plus recurrent) events were also assessed. PAD was an inclusion criterion in the established CV disease cohort. Prespecified and post hoc analyses by baseline history of PAD history were performed. Results: Of 5785 (70.7%) REDUCE-IT patients enrolled with established CV disease, 688 had PAD. IPE demonstrated statistically similar risk reduction in first (interaction P [p int ]=0.58) and total (p int =0.78) primary endpoints in patients with established CV disease with or without PAD, though PAD patients had higher first (placebo: 32.8% with vs 24.5% without PAD) and total (placebo: 162.3 vs 101.7 per 1000 patient-years) event rates. The primary endpoint event rate with PAD was 26.2% with IPE vs 32.8% with placebo (HR 0.78; 95% CI 0.59, 1.03; P=0.08) and total events were 112.8 per 1000 patient-years with IPE vs 162.3 with placebo (RR 0.68; 95% CI 0.48, 0.95; P=0.03) (Figure). Primary endpoint absolute risk reductions (ARR) and numbers needed to treat (NNT) suggest benefit for patients with (ARR 6.6%; NNT 15) and without (6.1%; 16) PAD. Safety did not differ substantially by PAD history and was generally consistent with the overall study. Conclusions: In REDUCE-IT, patients with PAD were at very high risk of subsequent ischemic events. IPE provided consistent CV benefit in patients with or without PAD.
Abstract 10137: Functional Brain Imaging Reveals Decreased Cerebellar Volume and Altered Brain Connectivity in Pulmonary Arterial Hypertension
Authors: Timothy S Kim, Theodore Huppert, Omolara Fatukasi, Yassmin Al Aaraj, Timothy Girard, Joseph Mettenburg, James Becker, Seyed Nouraie, Stephen Y Chan
Journal: Circulation (2021)

Introduction: Psychiatric and cognitive deficiencies are increasingly appreciated in pulmonary arterial hypertension (PAH). Brain abnormalities potentially underlying these disease manifestations have been ill-defined. Hypothesis: Altered brain structure and functional connectivity correlate with neurocognitive changes in PAH patients. Methods: PAH patients at UPMC were enrolled from 2017 to 2018. Participants underwent T1/T2 structural and resting functional brain MRI (fMRI) in addition to cognitive testing. Case data were compared in a 1:4 ratio to that of age-, gender-, and education-matched non-PAH controls. Linear regression analysis with clustered sandwich estimator and adjustment for multiple hypothesis testing was used for comparisons. Most recent hemodynamic data for PAH patients were reviewed including pulmonary vascular resistance (PVR). Pearson correlations were computed between PVR and brain volumes. Results: 12 PAH patients (median age, 45 years [range 26-61]; 9 women) were enrolled. T1/T2 MRI analysis identified 18 regions with volumetric differences (q&lt;0.05), with notable involvement of limbic (6/18, 33%) and basal ganglia (4/18, 22%) structures. PAH patients showed decreased left cerebellar cortical (45178 ± 1417 vs 53295 ± 583 mm 3 ; q=0.01) and right cerebellar white matter volumes (16458 ± 727 vs 39675 ± 5846 mm 3 ; q=0.018). Structural changes concorded with results from fMRI analysis: PAH patients had decreased functional connectivity in the left cerebellum (q=0.003). Corresponding with modulation of executive functions by the cerebellum, a trend was seen toward decreased inhibitory control and attention (83 ± 3 vs 95 ± 1; q=0.07) and pattern comparison processing speed (93 ± 5 vs 106 ± 4; q=0.07) in PAH patients. A trend toward negative correlation of PVR with left cerebellar white matter volume (r = -0.82, q = 0.06) was also observed. Conclusion: Limbic, basal ganglia, and cerebellar regions were smaller and less functionally connected in PAH cases than in matched controls. Decreased cerebellar volume may correlate with more severe hemodynamic disease. Any links among brain changes, cognitive dysfunction, and PAH pathophysiology deserve further study and may lead to neurologic modalities to diagnose and treat disease.
DDRE-05. LONG-TERM OUTCOME OF INTRATHECAL CHEMOTHERAPY WITH PEMETREXED IN LEPTOMENINGEAL METASTASIS FROM NON-SMALL CELL LUNG CANCER WITH EGFR-MUTATION: A CASE REPORT
Authors: hui Wang, Jiangfen Zhou, Lei Wen, Weiping Hong, Linbo Cai
Journal: Neuro-Oncology (2021)

Abstract Leptomeningeal metastasis (LM) is fatal complication of non-small cell lung cancer (NSCLC) ,which has a poor prognosis and lacks effective treatments. Pemetrexed, a multitargeted antifolate agent, has demonstrated antitumor activity, a few studies have shown intrathecal pemetrexed (IP) controllable toxicities and potential promising efficacy for LM from NSCLC patients. We report a patient who diagnosed with LM from NSCLC harboring epidermal growth factor receptor (EGFR) mutation in exons 21 via typical neurological symptoms, magnetic resonance imaging (MRI) and positive cerebrospinal fluid (CSF) cytology. The curative effect of tyrosine kinase inhibitor (TKI) targeted drugs was maintained for a short time, the first-generation TKI icotinib was 4 months, and the third-generation osimertinib was 4 months. Then the patient received IP, and osimertinib continued. 30 mg of pemetrexed were implemented on day 1 every weeks for 8 weeks via lumbar puncture, then 50 mg of pemetrexed on day 1 every 4 week for 8 times. This treatment regimen resulted in the alleviation of the neurological symptoms, the CSF level of carcinoembryonic antigen also decresed without obvious side effects. At the time of this manuscript’s submission, she had maintained stable disease (SD) for more than 11 months. To our knowledge, this study provides the first clinical evidence that longterm intrathecal chemotherapy with pemetrexed providing a therapeutic approach against LM from NSCLC.
A Phase 3 Randomized Controlled Trial (MICROCARE) to Evaluate the Efficacy of DAV132 in Preventing Clostridioides Difficile Infection in Patients with Newly Diagnosed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome and Treated with Intensive Chemotherapy
Authors: Maria Vehreschild, Cornelis H. van Werkhoven, Lena Biehl, Aaron Dane, Marlieke E.A. de Kraker, France Mentré, Charles Burdet, Gérald Glupczynski, Leen Timbermont, Elodie Pfender, Frédérique Sablier-Gallis, Antoine Andremont, Jean de Gunzburg, Renaud Buffet, Mark Wilcox, Oliver Cornely, Marc Bonten, Fabien Vitry
Journal: Blood (2021)
Abstract 11929: PAI-1 is Cardioprotective in Human Inflammatory Cardiomyopathy
Authors: Christian Baumeier, Felicitas Escher, Ganna Aleshcheva, Heiko Pietsch, Heinz-Peter Schultheiss
Journal: Circulation (2021)

Introduction: Preclinical data indicate that plasminogen activator inhibitor-1 (PAI-1) is cardioprotective by repressing fibrosis through TGF-β and plasminogen mediated pathways. Moreover, PAI-1 is suggested to be involved in the recruitment and polarization of M2 macrophages. Hypothesis: Elevated myocardial PAI-1 expression protects from fibrosis and acute inflammatory response. Methods: Endomyocardial biopsies (EMBs) of patients with dilated cardiomyopathy (DCM, n=27) and inflammatory dilated cardiomyopathy (DCMi, n=149) were retrospectively analyzed for PAI-1 expression, markers of fibrosis and M1/M2 macrophage polarization. Results: Patients with high-grade myocardial inflammation (DCMi-high, CD3 + lymphocytes &gt; 30 cells/mm 2 ) had significantly increased PAI-1 levels compared to DCM and low-grade DCMi patients (DCMi-low, CD3 + lymphocytes = 14 - 30 cells/mm 2 ) (15.5 ± 0.4 % vs. 1.0 ± 0.1 % and 4.0 ± 0.1 %, p ≤ 0.001). Elevated PAI-1 expression in DCMi-high subjects was associated with a diminished degree of tissue fibrosis, accompanied by decreased levels of TGF-β and a reduced number of cardiac myofibroblasts. In addition, elevation of PAI-1 led to a shift from M1 to M2 macrophages. Conclusions: Our findings give evidence that increased expression of PAI-1 in DCMi patients suppresses cardiac fibrosis and promotes M2 macrophage polarization. Thus, PAI-1 could serve as a potential prognostic biomarker of cardiac fibrosis and inflammation, as well as possible therapeutic target in inflammatory cardiomyopathies.
EXTH-51. DEVELOPMENT OF A NOVEL GENE THERAPY APPROACH TARGETING GLIOBLASTOMA FOLLOWING ARTIFICIAL INTELLIGENCE (AI)-DIRECTED IDENTIFICATION OF THE GBM STATE
Authors: David Tran, Son Le, Bo Ma, Darin Falk, Serge Zolotukhin
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Profound heterogeneity has severely hampered therapeutic advancements in GBM. Remarkably, however, GBM exhibits broad clinical and histopathologic overlaps suggesting the presence of a common state. The GBM state embodies network restructuring forced by founding mutations and perpetuated in subclones of GBM stem-like cells (GSCs). Successful targeting of the GBM state promises to circumvent the heterogeneity. METHODS To decipher the GBM state, we applied NETZEN, an AI suite integrating a deep neural network with gene network-based ranking, to first generate the reference GBM gene network from TCGA’s entire GBM RNAseq collection, and then identify the altered master regulatory gene subnetwork in GBM using a dataset containing &amp;gt;30 diverse patient-derived GSC lines and their paired differentiated cells, 6 astrocyte and 3 neuronal precursor cell lines. To develop a gene therapy against the GBM state, we screened a rAAV capsid library through GBM patient-derived xenografts (PDX) to identify variants with specific tropism for GBM cells that can deliver targeting constructs intratumorally. RESULTS We discovered a putative GBM state anchored by developmentally restricted master regulators. To validate its critical role, we deconstructed it using shRNA in a panel of PDX and uniformly observed improved tumor control and survival compared to controls (p&amp;lt; 0.05 in all lines). More notably, when the core GBM state was forcibly reconstructed in astrocytes, transformation into GSC-like cells occurred, as measured by single-cell analysis, neurosphere formation, and most importantly, development of lethal infiltrating brain tumors in 15/15 mice. Finally, selected novel rAAV capsids with 10-40-fold higher specificity for GBM cells were utilized in a shRNA-based rAAV platform to target key master regulators of the validated GBM state. CONCLUSIONS The GBM state is established by a developmental master regulator subnetwork permitting the creation of a first-of-its-kind, heterogeneity-agnostic GBM therapy. This AI-directed R&amp;D program can be expanded to target other tumors.
Multivariate associative patterns between the gut microbiota and large-scale brain network connectivity
Authors: N. Kohn, J. Szopinska-Tokov, A. Llera Arenas, C.F. Beckmann, A. Arias-Vasquez, E Aarts
Journal: Gut Microbes (2021)

Research on the gut–brain axis has accelerated substantially over the course of the last years. Many reviews have outlined the important implications of understanding the relation of the gut microbiota with human brain function and behavior. One substantial drawback in integrating gut microbiome and brain data is the lack of integrative multivariate approaches that enable capturing variance in both modalities simultaneously. To address this issue, we applied a linked independent component analysis (LICA) to microbiota and brain connectivity data.We analyzed data from 58 healthy females (mean age = 21.5 years). Magnetic Resonance Imaging data were acquired using resting state functional imaging data. The assessment of gut microbial composition from feces was based on sequencing of the V4 16S rRNA gene region. We used the LICA model to simultaneously factorize the subjects' large-scale brain networks and microbiome relative abundance data into 10 independent components of spatial and abundance variation.LICA decomposition resulted in four components with non-marginal contribution of the microbiota data. The default mode network featured strongly in three components, whereas the two-lateralized fronto-parietal attention networks contributed to one component. The executive-control (with the default mode) network was associated to another component. We found that the abundance of Prevotella genus was associated with the strength of expression of all networks, whereas Bifidobacterium was associated with the default mode and frontoparietal-attention networks.We provide the first exploratory evidence for multivariate associative patterns between the gut microbiota and brain network connectivity in healthy humans considering the complexity of both systems.
EPID-10. GLIOMA INCIDENCE AND SURVIVAL BY INCOME LEVEL IN THE UNITED STATES GENERAL POPULATION AGES AND ABOVE FROM 2000-2018
Authors: Jennifer Murillo, Elizabeth Anyanda, Jason Huang
Journal: Neuro-Oncology (2021)

Abstract Gliomas are the most common primary malignant brain tumor in the United States with previous studies showing the incidence varied by age, sex, and race or ethnicity. Survival after diagnosis has also been shown to vary by these factors. Also, socioeconomic status and its association with various cancers have also been studied at length over time. PURPOSE: The purpose of our research was to quantify the differences in incidence and survival rates of gliomas in 15 years and older by income level. METHODS: This population-based study obtained incidence and survival data from the Incidence-SEER Research Database the general population. Average age incidence were generated by glioma groups and grouped by income levels. Survival rates were generated by overall glioma diagnosis grouped by observed survival at 12, 24, 36, 48 and 60 months and by again by income levels. The analysis included 94,207 patients with glioma diagnosed in those aged 15 years or older. RESULTS: Overall, 94, 207 patients diagnosed with glioma were analyzed. Of these, 1,089 (1.16%) fell into the &amp;lt; $35k group, 1,684 (1.79%) in the $35k-$40k group, 3,473 (3.69%) in the $40k-$45k group, 5,647 (5.99%) in the $45k-$50k group, 7,138 (7.58%) in the $50k-$55k group, 6,468 (6.87%) in the $55k-$60k group, 15,348 (16.29%) in the $60k-$65k group, 13,216 (14.03%) in the $65k-$70k group, 9,035 (9.59%) in the $70k-$75k group, and 31,109 (33.02%) fell in &amp;gt; $75k group. The data was also broken further down into survivability showing average survival. CONCLUSION: Incidence of glioma and 12, 24, 36, 48 and 60 month survival rates after diagnosis vary significantly by income level with higher income level greater than $75,000+ having higher incidence and higher survival rates compared with lower income levels. Further research is needed to help determine risk factors and barriers to care to help reveal health disparities.
Abstract 9886: Use of a Smartwatch and App Designed by Stroke Survivors for Atrial Fibrillation Detection in Older Adults After Stroke/Transient Ischemic Event: Preliminary Findings from an Ongoing Randomized Clinical Trial
Authors: Eric Y Ding, Dong Han, Emily L Dickson, Danielle DiMezza, Jessica Scott, Fahimeh Mohagheghian, Andrew Peitzsch, Jane Saczynski, Majaz Moonis, Timothy P Fitzgibbons, Bruce Barton, Ki Chon, David D McManus
Journal: Circulation (2021)

Background: Atrial fibrillation (AF) is a common cause of ischemic stroke that, though critical to diagnose and treat, often goes undetected. Smartwatches are capable of AF detection, but little is known about their use among stroke survivors. In collaboration with stroke survivors and clinicians, we designed a smartphone-smartwatch system for AF detection. In our ongoing clinical trial, we are examining the performance and user experience of the system in older stroke survivors. Hypothesis: The system will be accurate for AF detection among stroke survivors compared to 14-day ECG patch monitoring; participants will find the system usable and will adhere to daily use over 30 days. Methods: The Pulsewatch study is an ongoing two-phased randomized controlled trial with randomization at two timepoints into control or intervention groups. Phase I (14 days) assesses accuracy and usability of the smartwatch and study app. Phase II (30 days) examines watch wear adherence. The intervention group receives a smartwatch with embedded AF detection and a smartphone app for rhythm and symptom tracking. Eligibility criteria are: &gt; 50 years old, ischemic stroke in the past decade, and no major contraindications to anticoagulation therapy. System accuracy for AF detection is compared to an ECG patch monitor, and usability is assessed via the System Usability Scale. Adherence is defined as daily watch wear time over the monitoring period. Results: To date, 69 participants have been randomized into phase I and 36 into phase II (mean age 65, 41% female, 87% White). The smartwatch system demonstrated a sensitivity of 66.7% (95% CI: 9.4 - 99.2) and specificity of 92.6% (95% CI: 82.1 - 97.9) for detection of 3 AF cases over the 14 day period (91.2% accuracy) compared to the ECG patch. The mean usability score was 65/100 and on average, participants wore the watch on 12/30 days for an average of 1.8 hours (SD 0.7) daily. Conclusion: A smartwatch and app dyad demonstrated reasonable accuracy for AF detection and high usability, though adherence was modest. Use of commercial wearables for AF detection among stroke patients shows promise, but additional data from the ongoing Pulsewatch clinical trial will continue to inform strategies to maximize adherence to these devices among older adults.