tbuckley/cabot-search huggingface dataset:
Abstract 8876: Role of Device Temperature Sensor and Impedance in a Rabbit Model of Bacterial Pocket Infection versus Systemic Endotoxemia
Authors: Shailesh Kumar V Musley, Maneesh Shrivastav, Abhijit Kadrolkar, Vinod Sharma
Journal: Circulation (2021)

Introduction: Device infections are associated with considerable morbidity, mortality, and cost. The feasibility of temperature sensor performance and impedance measurements in the dual chamber pacemaker was evaluated. Hypothesis: An infection can cause local temperature to rise around the implanted device. Methods: All rabbits received two subcutaneous pacemaker implants in the thoracic region. The prototype device measured both temperature and local pocket impedance. A control device measured only temperature. After collecting baseline data, rabbits were assigned to either pocket infection (n=6) or systemic infection (n=6) groups. In the pocket infection group, one implant site was inoculated with Staphylococcus aureus suspension (5x106 CFU/mL) and the other control site received saline. In the systemic infection group, each animal received intravenous injections (17.7-35 μg/kg body weight) of E. coli endotoxin for 5 consecutive days. Animals were recovered and monitored for 14 days. The device temperature and pocket impedance data were logged every 10 minutes. Results: The temperature measurements increased significantly in all the rabbits, by 15.4 hours after the bacterial inoculation in the pocket. Compared to 24-hour baseline temperature of 38.83±0.04°C, the temperature increased by 2.03°C (40.86±0.25; P=0.005). The mean pocket impedance decreased significantly by 26 Ohms compared to baseline. In the systemic infection animals, significant increases in temperatures (~1.5 °C; P=&lt;0.01) after each endotoxin challenge were observed, compared to baseline. Conclusions: These results show that shifts in temperature and impedance can be used to detect pocket or systemic infections. It is feasible that an “infection status” may be determined from longitudinal temperature measurements. Prospective data are needed to demonstrate performance of the temperature algorithm following device implantations.
Abstract MP218: Cop9 Signalosome Subunit 6 Restricts Desmosomal Proteome Degradation To Prevent Desmosomal Targeted Cardiac Disease
Authors: Yan Liang, Robert Lyon, Jason Pellman, William Bradford, Stephan Lange, Julijus Bogomolovas, Nancy Dalton, Yusu Gu, Marcus Bobar, Mong-Hong Lee, Tomoo Iwakuma, Vishal Nigam, Angeliki Asimaki, Melvin Scheinman, Kirk L Peterson, Farah Sheikh
Journal: Circulation Research (2021)

Dysregulated protein degradative pathways are increasingly recognized as mediators of human cardiac disease. This pathway may have particular relevance to desmosomal proteins that play critical structural roles in both tissue architecture and cell-cell communication. Genetic mutations in desmosomal genes resulting in the destabilization/breakdown of the desmosomal proteome are a central hallmark of all genetic-based desmosomal-targeted diseases, including the cardiac disease arrhythmogenic right ventricular (RV) dysplasia/cardiomyopathy (ARVD/C). However, no information exists on whether there are resident proteins that regulate desmosomal proteome homeostasis. Here we identified a desmosomal resident regulatory complex, composed of subunit 6 of the COP9 signalosome (CSN6), enzymatically restricted neddylation and targets desmosomal proteome. Pharmacological restoration of CSN enzymatic function (via neddylation inhibitors) could rescue desmosomal protein loss in CSN6 deficient cardiomyocytes. Through the generation of two novel mouse models, we showed that cardiomyocyte-restricted CSN6 loss in mice selectively accelerated desmosomal destruction to trigger classic disease features associated with ARVD/C. We further showed that disruption of CSN6-mediated (neddylation) pathways underlined ARVD/C as CSN6 binding, localization, levels and function were impacted in hearts of classic ARVD/C mouse models and ARVD/C patients impacted by desmosomal loss and mutations, respectively. We anticipate our findings have broad implications towards understanding mechanisms driving desmosome degradation in other desmosomal-based diseases, such as cancers.
BIOM-24. PROTEIN SURFACE SIGNATURE ON SERUM EXTRACELLULAR VESICLES FOR NON-INVASIVE DETECTION OF TUMOR PROGRESSION IN GLIOBLASTOMA PATIENTS
Authors: Theophilos Tzaridis, Johannes Weller, Daniel Bachurski, Farhad Shakheri, Christina Schaub, Peter Hau, Andreas Buness, Uwe Schlegel, Joachim Steinbach, Clemens Seidel, Roland Goldbrunner, Niklas Schäfer, Robert Wechsler-Reya, Björn Scheffler, Martin Glas, Lothar Haeberle, Ulrich Herrlinger, Christoph Coch, Katrin Reiners, Gunther Hartmann
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Detection of tumor progression in glioblastoma patients remains a major challenge for clinicians due to equivocal MRI results. Extracellular vesicles (EVs) are potential biomarkers and can be detected in the blood of tumor patients. In this study, we evaluated the potential of serum-derived EVs from glioblastoma patients to serve as a marker for tumor progression in adjunction with MRI assessment. METHODS Glioblastoma patients from two independent cohorts, one from the multicenter Phase III CeTeG/NOA-09 trial (n=36) and the other from patients treated at the University of Bonn (n=31), were included in this study. EVs from serum of glioblastoma patients and healthy volunteers were separated by size exclusion chromatography and ultracentrifugation. EV markers were defined by using a proximity-extension assay and bead-based flow cytometry. Tumor progression was defined according to modified RANO criteria. RESULTS EVs from the serum of glioblastoma patients (n=67) showed an upregulation of CD29 (p=0.08), CD44 (p&amp;lt; 0.0001), CD81 (p&amp;lt; 0.0001), CD146 (p&amp;lt; 0.0001), C1QA (p=0.003), and histone H3 (p&amp;lt; 0.0001) as compared to serum EVs from healthy volunteers. For both independent cohorts of glioblastoma patients, we noted upregulation of C1QA, CD44, and histone H3 upon tumor progression, but not in patients with stable disease. Notably, six patients with worse survival compared to the median survival of the cohort did not fulfill RANO criteria at the time of suspected progression, yet showed an elevation of at least one out of these three markers. In a multivariable logistic regression analysis, a combination of CD29, CD44, CD81, C1QA, and histone H3 correlated with RANO-defined tumor progression with an AUC of 0.76. CONCLUSION Measurement of CD29, CD44, CD81, C1QA, and histone H3 in serum-derived EVs of glioblastoma patients, along with standard MRI assessment, could improve detection of true tumor progression and thus be a useful tool for clinical decision making.
Abstract 10691: Single Cell Florescence Imaging in Hypertrophic Cardiomyopathy Reveals a Proarrhythmic Substrate: Implications for Arrhythmogenesis and Antiarrhythmic Therapy
Authors: Jonathan Moreno, Druv Bhagavan, Ralph Damiano, Allie Li, Sharon Cresci, Nathaniel Huebsch, Jonathan R Silva
Journal: Circulation (2021)

Introduction: Hypertrophic cardiomyopathy (HCM) is associated with high morbidity and mortality and remains the leading cause of sudden death in young people. Despite 5 decades of research, there is no disease modifying therapy for HCM. The cellular mechanisms leading to a proarrhythmic substrate are not yet fully elucidated but may be patient-specific. Here, we present single cell electrophysiology results of adult cardiomyocytes isolated from a cohort of HCM patients who underwent septal reduction therapy with surgical myectomy. Methods: Freshly isolated surgical specimens from HCM patients were enzymatically digested into single ventricular myocytes and compared to discarded wild-type (WT) donor hearts as controls. Myocytes displayed characteristic rod-shaped morphology, clear sarcolemmal ultrastructure, and intact plasma membranes without significant inclusions. After Ca 2+ readaptation and labeling with both a voltage and Ca 2+ sensitive fluorescent dye, cells were field stimulated at various pacing frequencies to obtain voltage and Ca 2+ tracings. APD restitution, response to drug therapy, and baseline data was compared to patient’s clinical data including electrocardiography, pathology, and multimodality imaging. Results: As compared to WT controls, HCM myocytes displayed significantly prolonged APD and Ca 2+ transients, as well as steeper APD restitution at all pacing frequencies tested. These results correlated with clinical QTc prolongation which was evident in HCM patients’ baseline ECGs that was not seen in controls. Despite genetic diversity in HCM samples, the HCM specimens appeared to share a common proarrhythmic phenotype. Finally, pathologic analysis of the myectomy specimens revealed evidence of myocyte hypertrophy, fibrosis, and cellular disarray, consistent with the clinical diagnosis of HCM. Conclusions: The single cell electrophysiology of HCM is markedly different than WT controls and displays a proarrhythmic phenotype. Single cell fluorescence imaging of a patient’s myocytes is a promising approach to elucidate patient specific electrophysiologic signatures and predict precision therapies for these patients.
Showjumper sues mother’s GP for inadequate advice that led to her spina bifida
Authors: Clare Dyer
Journal: BMJ (2021)

A showjumper with a spinal defect is suing her mother’s GP in a landmark case, arguing that ﻿if he had given proper advice, she would never have been conceived or born.

Evie Toombes, 20, was born with a defect causing spinal cord tethering. She has limited mobility and is doubly incontinent but has become a prominent showjumper who aims to compete in the Paralympic Games.

The law bars children born with disabilities from arguing …
Abstract 11789: Genetic Determinants of Interventricular Septal Anatomy and Risk of Congenital Heart Disease
Authors: Mengyao Yu, Andrew Harper, Matthew Aguirre, Maureen Pittman, Catherine Tcheandjieu, Dulguun Amgalan, Christopher Grace, Anuj Goel, Martin Farrall, Ke Xiao, Jesse Engreitz, Katherine Pollard, Hugh C Watkins, James R Priest
Journal: Circulation (2021)

Background: A large proportion of genetic risk remains unexplained for structural heart disease involving the interventricular septum (IVS) including hypertrophic cardiomyopathy (HCM) and ventricular septal defects (VSD). Methods: We performed machine learning to estimate the cross-sectional area of the interventricular septum (IVS.csad) from the 4-chamber view of cardiac MRI in 32,219 individuals from the UK Biobank. We related IVS.csad to relevant clinical phenotypes, and performed genome-wide association studies and Mendelian Randomization. Results: Automated measures of IVS.csad were highly accurate, and strongly correlated with anthropometric measures, blood pressure, and diagnostic codes related to cardiovascular physiology. A single nucleotide polymorphism in an intron of CDKN1A was associated with IVS.csad (rs2376620, Beta 8.4 mm2, 95% confidence intervals (CI) 5.8 to 11.0, p=2.0e-10), and a common inversion incorporating KANSL1 predicted to disrupt local chromatin structure was associated with an increase in IVS.csad (Beta 8.6 mm2, 95% CI 6.3-10.9, p=1.3e-13). Mendelian Randomization suggested that inheritance of larger IVS.csad was causal for HCM (Beta 2.45 log odds ratio (OR) HCM per increase in SD of IVS.csad, standard error (SE) 0.48, pIVW = 2.8e-7) while inheritance of smaller IVS.csad was causal for VSD (Beta -2.06 log odds ratio (OR) VSD per decrease in SD of IVS.csad, SE 0.75, pIVW = 0.006) Conclusion: Automated derivation of the cross sectional area of the IVS allowed discovery of loci related to cardiac development and Mendelian disease. Inheritance of genetic liability for either large or small interventricular septum, appears to confer risk for HCM or VSD respectively, suggesting that a proportion of risk for structural and congenital heart disease may localize to the common genetic determinants of cardiovascular anatomy.
Evaluation of Site- and Autoantigen-Specific Characteristics of Mucous Membrane Pemphigoid
Authors: Nina van Beek, Khalaf Kridin, Elena Bühler, Anne S. Kochan, Sascha Ständer, Ralf J. Ludwig, Detlef Zillikens, Enno Schmidt, Claudia Günther
Journal: JAMA Dermatology (2021)

Mucous membrane pemphigoid (MMP) is a rare, heterogeneous subepithelial autoimmune bullous disease. The association between its clinical and immunological features is yet to be fully evaluated.To characterize the clinical, immunoserological, and immunopathological characteristics of patients with MMP and to identify site- and autoantigen-specific characteristics.A retrospective cohort study encompassing all consecutive patients diagnosed with MMP from January 2007 through February 2020 in 2 tertiary referral centers in Germany.The clinical, immunoserological, and immunopathological features of eligible patients were evaluated. Associations of different anatomical sites and autoantigens were assessed using a multivariable logistic regression model.The study encompassed 154 patients (96 [62.3%] women and 58 [37.7%] men; mean [SD] age at diagnosis, 66.2 [13.8] years) with MMP, of whom 125 (81.2%), 61 (39.6%), 34 (22.1%), and 16 (10.4%) presented with lesions involving the oral, ocular, nasal, and genital mucosae, respectively, and 35 (22.7%) presented with cutaneous involvement. Among the 154 patients, the most frequently targeted antigen was BP180 (90 patients [58.4%]), followed by laminin 332 (13 patients [8.4%]) and BP230 (3 patients [1.9%]). Ocular disease was inversely associated with oral (adjusted odds ratio [aOR], 0.02; 95% CI, 0.01-0.13) and nasal (aOR, 0.20; 95% CI, 0.04-0.91) involvement and was associated with a 13-fold increased risk of malignant neoplasm (aOR, 13.07; 95% CI, 1.56-109.36). Anti-laminin 332 reactivity was associated with malignant neoplasm (aOR, 23.27; 95% CI, 1.83-296.68), whereas anti-BP180 NC16A immunoglobulin G seropositivity was associated with absence of ocular lesions (aOR, 0.09; 95% CI, 0.01-0.99).In this cohort study of patients with MMP, malignant neoplasms were associated with ocular disease and anti-laminin 332 reactivity, suggesting potential benefit of malignant neoplasm screening in these patients.
Abstract P368: Caveolin-3 Prevents Swelling-induced Cell Lysis Via Regulation Of <i>I</i> <sub>Cl,swell</sub> Expression And Activity
Authors: Daniel G Turner, Leonid Tyan, Sami Stroebel, Frank DeGuire, Di Lang, Alexey Glukhov
Journal: Circulation Research (2021)

Background: Caveolae membrane structures harbor mechanosensitive chloride channels (MCCs) which form a swelling-activated chloride current ( I Cl,swell ) and play an important role in cell volume regulation and mechano-electrical signal transduction. However, the role of muscle-specific caveolar scaffolding protein caveolin-3 (Cav3) in regulation of MCCs expression, activity, and contribution to cell viability in response to mechanical stress remains unclear. We hypothesized that Cav3-based mechano-protection is enabled by complimentary expression of MCCs. Methods and Results: Experiments were performed on native (Cav3-) and Cav3-transfected (Cav3+) HEK-293 cells. Cell stretch was mimicked by light (220 mOsM) or extreme hypoosmotic swelling (&lt;20mOsM). Cav3+ HEK-293 cells were significantly resistant to extreme hypotonic solutions (15 minute incubation) compared to Cav3- HEK-293 cells, and this mechano-protection was significantly reduced when exposed to I Cl,swell selective inhibitor DCPIB (1 μM). We found that three MCCs (ClC-2, ClC-3, and SWELL1, also known as LRRC8A) contain caveolin-binding motifs in their structure, indicating their possible localization in caveolae structures. Co-IP analysis confirmed association of SWELL1 with Cav3. Interestingly, Cav3+ HEK-293 cells showed a significant (by 2-fold) increase of SWELL1 protein level, while ClC-2/3 protein levels remained unchanged. This was accompanied by a 2-fold increase of I Cl,swell , but no change in mRNA expression levels. FRET analysis showed a &lt;10 nm membrane and intracellular association between Cav3 and tested MCCs. Furthermore, Cav3/SWELL1 membrane FRET efficiency was halved in light hypoosmotic solution, as well as after disruption of caveolae structures via cholesterol depletion by 1-hour treatment with 10 μM methyl-β-cyclodextrin. Cav3/ClC-2/3 average membrane FRET efficiency remained unchanged in hypotonic solution. Conclusions: We concluded that of MCCs tested, SWELL1 abundance and activity is regulated by Cav3 and that their association relies on membrane tension and caveolae integrity. The present study highlights the mechano-protective properties of Cav3 which are partially facilitated by complimentary SWELL1 expression and activity.
Impact of Anticonvulsant - Methotrexate Interactions on High Dose Methotrexate Clearance and Outcomes in Patients with Primary CNS Lymphoma
Authors: Ilana N Cypes, Angel Mier-Hicks, Jordan Scott, Adrienne Groman, Pallawi Torka, Catherine Gawronski, Eugene Przespolewski
Journal: Blood (2021)
Broadening symptom criteria improves early case identification in SARS-CoV-2 contacts
Authors: Hamish Houston, Seran Hakki, Timesh D. Pillay, Kieran Madon, Nieves Derqui-Fernandez, Aleksandra Koycheva, Anika Singanayagam, Joe Fenn, Rhia Kundu, Emily Conibear, Robert Varro, Jessica Cutajar, Valerie Quinn, Lulu Wang, Janakan S. Narean, Mica R. Tolosa-Wright, Jack Barnett, Onn Min Kon, Richard Tedder, Graham Taylor, Maria Zambon, Neil Ferguson, Jake Dunning, Jonathan J. Deeks, Ajit Lalvani
Journal: European Respiratory Journal (2021)

The success of case isolation and contact tracing for the control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission depends on the accuracy and speed of case identification. We assessed whether inclusion of additional symptoms alongside three canonical symptoms (CS),
Abstract 9966: Assessment of Wavefront Activation Duration Across the Right Ventricular Outflow Tract in Patients with Idiopathic Premature Ventricular Contractions Using Non Invasive Electrocardiographic Mapping: A Validation Study
Authors: Leonor Parreira, Pedro Carmo, Dinis Mesquita, Catalin Marinescu, Silvia Nunes, Mikhail Chmelevsky, Antonio Ferreira, Rita Marinheiro, Pedro Amador, Margarita Budanova, Pedro Goncalves, Hugo Marques, Pedro Adragao
Journal: Circulation (2021)

Introduction: Previous studies have reported that activation speed across the right ventricular outflow tract (RVOT) can distinguish premature ventricular contractions (PVCs) with a RVOT origin from PVCs with a left ventricular outflow tract (LVOT) origin. Hypothesis: Validate the non-invasive electrocardiographic mapping (ECGI) for assessment of RVOT endocardial activation duration (AD) during PVCs and assess the value of AD as a predictor of the origin of the PVCs. Methods: We studied 15 consecutive patients, 8 males, median age 56 (42-65) years that underwent ablation of frequent (&gt; 10.000 per 24 h) idiopathic PVCs with inferior axis and had an ECGI performed before ablation. The ECGI was performed with the Amycard system, and all ablations were done with Stereotaxis and Carto system. Isochronal activation maps of the PVCs were obtained with the activation direction method (ADM) of the ECGI, and with the Carto isochronal activation map (10 ms isochrones). Total RVOT AD was measured as the time interval between the earliest and the latest activated region. Agreement between the two methods was performed using linear regression and Bland-Altman plot. The cutoff value of AD to predict PVC origin was calculated with ROC curve. Results: PVCs originated from the RVOT in 9 (60%) patients. The median (Q 1 -Q 3 ) RVOT AD measured with ECGI was 50 (36-70) and with Carto 50 (37-72) ms. The agreement between both methods was good with an R 2 of 0.699, p&lt;0.0001, Bland-Altman plot in figure, and example of the same patient measured with Carto and ECGI. The AD was significantly higher in PVCs from the RVOT vs LVOT, both with ECGI and Carto, respectively 67 (54-74) vs 36 (33-40) ms, p&lt;0.0001 and 68 (57-77) vs 35 (30-41) ms, p&lt;0.0001. The cutoff value of 43 ms for AD measured with ECGI predicted the origin of the PVCs with a sensitivity and specificity of 100%. Conclusions: We found good agreement between ECGI and Carto. The AD obtained with ECGI was accurate to predict the origin of the PVCs.
Abstract 12610: Larger Papillary Muscles and Thicker Chords Were Associated With Post-Operative Left Atrioventricular Valve Regurgitation in Partial AVSD, a Quantitative Three-Dimensional Echocardiography Study
Authors: DAVID YOUSSEF, Nee Scze Khoo, JUDITH NAMUYONGA, Lily Lin
Journal: Circulation (2021)

Background: Up to 15% of patients with partial Atrioventricular Septal Defects ( p AVSD) require re-repair of the Left AtrioVentricular Valve (LAVV), with 30% having significant regurgitation. Previous qualitative studies suggest abnormalities in papillary muscles, shortened chordae and thick chords as features associated with LAVVR. We aim to quantitatively assess the sub valvar apparatus in pAVSD using three-Dimensional Echocardiography (3DE) for its association with LAVVR. Hypothesis: We hypothesize that larger papillary muscle and chordal thickness in patients with p AVSD is associated with post-operative LAVVR. Methods: This is a prospective study between 2006 and 2018, of pAVSD aged 0-18 years. All underwent 3DE under sedation using X7-2 probe on a Philips iE33 ultrasound system. Utilizing offline QLAB multi-planar reconstruction (v.10.8.5) we measured anterolateral (APM) and posteromedial papillary (PPM) muscle length; cross sectional area and circumference; chordal length and thickness in mid systole. We measured post-operative vena contracta and LAVV diameter in Apical 4 chamber using 2D color Doppler. Cohort was divided into patients with significant post-operative LAVVR vs. controls based on LAVV vena contracta/LAVV annulus ratio cut off &gt;0.25 (greatest one-third of cohort), LAVVR (n=22) and Controls (n=44). All variables are indexed to Body Surface Area, expressed as median [interquartile range] or mean (standard deviation). Results: LAVVR group were younger at initial surgery, had larger papillary muscles and thicker chords. Table 1 summarizes the variables for Control and LAVVR. Eighteen patients had LAVV re-repair, 14 (63%) were in LAVVR group and 4 (9%) in Controls. Median follow up was 1.5 years. Median time to re-repair was 1.3 years. Conclusion: p AVSD patients with a greater risk of post-operative LAVVR and subsequently re-repair were younger at first repair and had larger papillary muscles length, circumference and thicker chords.
Meaningful Changes in Patient-Reported Outcomes in Relation to Best Clinical Response and Disease Progression: <i>Post Hoc</i> Analyses from MAIA
Authors: Aurore Perrot, Thierry Facon, Shaji Kumar, Torben Plesner, Robert Z. Orlowski, Philippe Moreau, Nizar J. Bahlis, Supratik Basu, Hareth Nahi, Cyrille Hulin, Hang Quach, Hartmut Goldschmidt, Michael E. O'Dwyer, Chris P. Venner, Katja Weisel, Joseph R. Mace, Noopur S. Raje, Mourad Tiab, Magaret Macro, Laurent Frenzel, Xavier Leleu, Kevin Liu, John Fastenau, Katharine S. Gries, Kai Fai Ho, Pankaj Mistry, Brenda Tromp, Maria Delioukina, Jessica Vermeulen, Saad Z. Usmani
Journal: Blood (2021)