tbuckley/cabot-search huggingface dataset:
Chemogenetics as a neuromodulatory approach to treating neuropsychiatric diseases and disorders
Authors: Jingwei Song, Ruchit V. Patel, Massoud Sharif, Anagha Ashokan, Michael Michaelides
Journal: Molecular Therapy (2021)

Chemogenetics enables precise, non-invasive, and reversible modulation of neural activity via the activation of engineered receptors that are pharmacologically selective to endogenous or exogenous ligands. With recent advances in therapeutic gene delivery, chemogenetics is poised to support novel interventions against neuropsychiatric diseases and disorders. To evaluate its translational potential, we performed a scoping review of applications of chemogenetics that led to the reversal of molecular and behavioral deficits in studies relevant to neuropsychiatric diseases and disorders. In this review, we present these findings and discuss the potential and challenges for using chemogenetics as a precision medicine-based neuromodulation strategy.
Abstract 12941: In-Hospital Outcomes Among Diabetics Undergoing Transcarotid Artery Revascularization for Carotid Artery Stenosis
Authors: Ali Hasnie, Ammar Hasnie, James Adefisoye, Kelly Magee, Suhail Allaqaband, M. Fuad Jan, Tanvir Bajwa, Babak Haddadian
Journal: Circulation (2021)

Introduction: Transcarotid artery revascularization (TCAR) is a novel procedure to intervene on clinically significant carotid artery stenosis. Periprocedural rates of stroke have remained exceedingly low in clinical trials (&lt;1.5%). Diabetics are known to have elevated risk of periprocedural adverse events with both carotid endarterectomy and carotid artery stenting. TCAR may offer lower periprocedural rates of cerebrovascular accident given its novel flow reversal technique. However, outcomes among diabetics undergoing TCAR remain unknown. We sought to determine periprocedural cardiovascular and cerebrovascular events (MACCE) among diabetics undergoing the TCAR procedure in a large national database. Methods: The Vascular Quality Initiative database was queried for all TCAR procedures performed from January 2012 to March 2021. Baseline demographic information as well as periprocedural outcomes were obtained. In cases in which a patient had multiple procedures, only the most recent procedure was evaluated. Results: A total of 19,341 patients (median age 74 (IQR 67-80), 63.7% male and 90.3% white) underwent the TCAR procedure. Of this n=7,427 (38.4%) were diabetics. Compared to non-diabetics, the diabetic cohort had a higher risk of stroke (1.7% vs 1.3%, p=.02), transient ischemic attack (0.7% vs 0.4% p =.027), and myocardial infarction (0.7% vs 0.5% p=.064). Death remained a rare outcome, with diabetics having 0.5% periprocedural mortality vs 0.4% among non-diabetics (p=.096). Conclusions: TCAR is a safe revascularization method for significant carotid artery stenosis with an elevated risk of periprocedural MACCE in diabetics compared to non-diabetics. Further study is needed to define optimal patient selection for this novel and less-invasive management strategy for carotid artery disease.
Abstract MP231: Long Non-coding Rna Camirt Plays A Sentinel Role In Aging-related Heart Failure Via Interaction With Phb2 To Modulate Mitophagy Signaling In The Heart
Authors: Xiao-Liang Wang, XIUCHUN LI, Hannah L Ong, Jae-Kyun Ko, Nuo Sun, Joseph M Miano, Jianjie Ma, Chuanxi Cai
Journal: Circulation Research (2021)

Background: Mitochondrial dysfunction is an important risk factor for heart failure in elderly people. Mitophagy, a physiological process that controls the removal of damaged mitochondria, is compromised in aging or failing hearts. In this study, we examined the physiological role of a cardiac-specific lncRNA Camirt that can potentially modulate mitophagy in the heart. Methods and Results: RNA-seq analysis and RT-PCR reveal a lncRNA is highly expressed in both mouse and human hearts, with undetectable levels in other vital organs. Furthermore, Real time qPCR was used to examine the expression of lncRNA in different animal models and in human hearts, which results showed that the expression of this lncRNA is decreased in aging mouse and human hearts, and failing mouse hearts induced by isoproterenol and doxorubicin. RNA pull-down and RNA-binding protein immunoprecipitation assays identify prohibitin-2 (Phb2), a known mitophagy receptor, as a binding partner for this lncRNA. Thus, we name this novel lncRNA as a cardiac-specific mitophagy-associated RNA transcript (Camirt). Camirt conditional (flox) knockout mice were created via CRISPR /Cas9 technology, and subjected to the longitudinal echocardiographic and survival studies. Mice with cardiac specific deletion of Camirt (Camirt-cKO) display progressive heart failure and die within 12 month after birth. RNA sequencing and gene ontology analysis revealed that genes involved in mitophagy signaling were significantly altered in the Camirt-cKO hearts compared with the littermate wild type mice. Transmission electron microscopy were used to examine the mitochondrial morphology in mouse hearts, and reveal excessive accumulation of mitolysosomes in cardiomyocytes derived from the Camirt-cKO mice. In vitro study with Annexin-V/PI staining showed an increased number of live cells and decreased number of apoptotic cells in cultured neonatal cardiomyocytes with overexpression of Camirt following oxidative stress induced by treatment with H2O2. Increased autophagy (or mitophagy) activity was observed in HL-1 cells with stable overexpression of Camirt and in the presence of chloroquine (an inhibitor for the lysosome degradation). While reduced Camirt expression via shRNA knock-down leads to compromised mitophagy activity in HL-1 cells. Further biochemical studies support the function of Camirt/Phb2 in maintenance of mitochondria function and mitophagy signaling under stress conditions. Conclusion: Overall, our results suggested that Camirt plays a sentinel role in aging-related heart failure via interaction with Phb2 to modulate mitophagy signaling in the heart. Future studies will focus on elucidating the in vivo role and mechanisms of Camirt in modulation of mitophagy under natural aging or stress-induced pathologic conditions using the loss- or gain-of-function of Camirt mouse models.
Myeloablative Fractionated Busulfan Conditioning Regimen with Sorafenib in Patients with AML: Results of Phase I Clinical Trial
Authors: Uday R. Popat, Roland Bassett, Peter F. Thall, Amin M. Alousi, Gheath Alatrash, Qaiser Bashir, Chitra Hosing, Jin S. Im, Partow Kebriaei, David Marin, Yago Nieto, Amanda L. Olson, Betul Oran, Jeremy L. Ramdial, Neeraj Saini, Samer A. Srour, Benigno C. Valdez, Katayoun Rezvani, Muzaffar H. Qazilbash, Naval Daver, Farhad Ravandi, Elizabeth J. Shpall, Richard E. Champlin, Borje S. Andersson, Rohtesh S. Mehta
Journal: Blood (2021)
Abstract P422: Sanal Flow Choking Leads To Hemorrhagic Stroke And Other Neurological Disorders In Earth And Human Spaceflight
Authors: Sanal Kumar V R
Journal: Circulation Research (2021)

Background: Evidences are escalating on the diverse neurological disorders associated with COVID-19pandemic due to the nanoscale Sanal-flow-choking (PMC7267099) . The Sanal-flow-chokingoccurs at relatively high and low blood viscosity. Sanal-flow-choking leads to aneurysm andhemorrhagic-stroke and other neurological-disorders if the vessel geometry is having divergence,bifurcation, stenosis and/or occlusion regions (PMC7933821) . Nanoscale Sanal flow choking ismore susceptible at microgravity condition due to altered variations of blood viscosity, turbulenceand the blood pressure ratio (BPR). Astronauts/Cosmonauts experienced neurological disordersduring human spaceflight and thereafter. Methods: Closed-form analytical, in vitro and in silico studies have been carried out for establishing thephenomenon of Sanal-flow-choking. Biofluid/blood heat capacity ratio (BHCR) of various healthysubjects are estimated. Results: The closed-form analytical models reveal that the relatively high and low blood viscosity arerisk factors of Sanal-flow-choking. In vitro study shows that N2, O2, and CO2 gases arepredominant in fresh-blood samples of the healthy human-being and Guinea-pig at a temperaturerange of 37-40 0 C (98.6-104 0 F), which increases the risk of Sanal-flow-choking. In silico resultsshows the Sanal-flow-choking followed by shock-waves and pressure-overshoot in a simulatedartery with the divergence region. Conclusions: As the pressure of the nanoscale biofluid/non-continuum-flows rises, fluid viscosityincreases and average-mean-free-path diminishes and thus, the Knudsen number lowers headingto a zero-slip wall-boundary condition with the compressible flow regime, which increases the riskof Sanal-flow-choking and the shock wave generation causing asymptomatic cardiovasculardisease. Microgravity environment decreases plasma volume and increases the hematocritcompared with the situation on the earth surface, which increases the relative viscosity of bloodcausing an early Sanal-flow-choking. Herein we established that the disproportionate blood-thinning treatment increases the risk of the nanoscale Sanal-flow-choking due to the enhancedboundary-layer-blockage factor. The risk could be diminished by concurrently reducing theviscosity of biofluid/blood and flow-turbulence by increasing thermal-tolerance-level in terms ofBHCR and/or by decreasing the BPR through new drug discovery or using companion medicinewith the traditional blood thinners or other health care management. We recommend allastronauts/cosmonauts should wear ambulatory blood pressure and thermal level monitoringdevices similar to a wristwatch throughout the space travel for the diagnosis, prognosis andprevention of internal flow choking leading to asymptomatic cardiovascular disease includingneurological disorders.
Abstract 11750: Use of a Heart Failure Symptom Monitoring Tool With Individualized Visualizations to Report Longitudinal Patient-Reported Outcome Data
Authors: Sabrina Mangal, Meghan Reading Turchioe, Leslie Park, Annie Myers, Parag Goyal, Kelly Axsom, Ruth M Masterson Creber
Journal: Circulation (2021)

Objective: Evaluate feasibility of using a visualized symptom monitoring tool for patients with heart failure (HF) in a large academic medical center using mixed methods. Introduction: Patients with HF are frequently hospitalized with symptoms such as shortness of breath, fatigue, and swelling, and commonly report persistent symptoms one week after discharge. Many of these hospitalizations are preventable, emphasizing the need for improved methods for symptom monitoring and management. Methods: Quantitative summaries of ten symptoms were measured with the Patient-Reported Outcomes Measurement Information System-29 among patients with HF at baseline, 2, 4, 6, and 8 weeks with automated email follow-up. Symptom summary reports with visualizations previously developed using user-centered design were displayed at each time point to and showed changes in symptoms over time. Qualitative exit interviews were conducted with patients and healthcare professionals and were coded using directed content analysis. Results: 65 participants completed all baseline surveys, and over half (n = 35, 54%) completed at least one follow-up survey (recruitment and follow-up ongoing). Based on mean PROMIS T-scores with a population mean of 50.0, participants reported highest symptom burden for: physical function (36.9 ± 9.0), fatigue (56.9 ± 12.0), and anxiety (55.4 ± 10.0). Interviews with patients (n = 18) and healthcare professionals (n = 5) highlighted that the tool was helpful for understanding health status and prompting communication, which might depend on patient agency. Suggestions for improvement included offering paper copies of symptom reports and follow-up phone calls (Table). Conclusions: Participants found the tool useful for understanding symptoms and prompting communication with the healthcare team. Future work should consider providing actionable symptom summaries to support patient agency and providing multiple options for format and follow-up.
Epidemiological and molecular investigations of a point-source outbreak of Dracunculus medinensis infecting humans and dogs in Chad: a cross-sectional study
Authors: Sarah Anne J Guagliardo, Elizabeth Thiele, Karmen Unterwegner, Ndoyengar Narcisse Nanguita, Laurès Dossou, Philip Tchindebet Ouakou, Hubert Zirimwabagabo, Ernesto Ruiz-Tiben, Donald R Hopkins, Sharon L Roy, Vitaliano Cama, Henry Bishop, Sarah Sapp, Sarah Yerian, Adam J Weiss
Journal: The Lancet Microbe (2021)

<h2>Summary</h2><h3>Background</h3> Dracunculiasis (also known as Guinea worm disease), caused by the <i>Dracunculus medinensis</i> nematode, is progressing towards eradication, with a reduction in cases from 3·5 million cases in the mid-1980s to only 54 human cases at the end of 2019. Most cases now occur in Chad. On April 19, 2019, a 19-year-old woman presented with <i>D medinensis</i> in an area within the Salamat region of Chad, where the disease had not been previously reported. We aimed to investigate the connection between this case and others detected locally and elsewhere in Chad using a combination of epidemiological and genetic approaches. <h3>Methods</h3> In this cross-sectional field study, we conducted household case searches and informal group interviews in the Bogam, Liwi, and Tarh villages in Chad. All community members including children were eligible for participation in the outbreak investigation. Adult female <i>D medinensis</i> associated with this outbreak were collected for genetic analysis (18 from humans and two from dogs). Four mitochondrial genes and 22 nuclear microsatellite markers were used to assess relatedness of worms associated with the outbreak in comparison with other worms from elsewhere in Chad. <h3>Findings</h3> Between April 12 and Sept 6, 2019, we identified 22 human cases and two canine cases of dracunculiasis associated with 15 households. Six (40%) of the 15 affected households had multiple human or canine cases within the household. Most cases of dracunculiasis in people were from three villages in Salamat (21 [95%] of 22 cases), but one case was detected nearly 400 km away in Sarh city (outside the Salamat region). All people with dracunculiasis reported a history of consuming fish and unfiltered water. Worms associated with this outbreak were genetically similar and shared the same maternal lineage. <h3>Interpretation</h3> Molecular epidemiological results suggest a point-source outbreak that originated from a single female <i>D medinensis</i>, rather than newly identified sustained local transmission. The failure of the surveillance system to detect the suspected canine infection in 2018 highlights the challenge of canine <i>D medinensis</i> detection, particularly in areas under passive surveillance. Human movement can also contribute to dracunculiasis spread over long distances. <h3>Funding</h3> The Carter Center.
Abstract 10932: Prediction of 30-Day Hospital Readmission in High-Risk Atherosclerotic Cardiovascular Disease Patients Using Machine Learning Methods on Electronic Health Record Data from Medical Information Mart for Intensive Care-3 Database
Authors: Nitin Kumar Garg, Surajit Ray, Ashwini Mathur
Journal: Circulation (2021)

Introduction: Despite significant therapeutic advancements, Atherosclerotic Cardiovascular Disease (ASCVD) patients require frequent hospitalization. Machine learning (ML) algorithms present an opportunity to develop improved and more generalizable prediction models for 30-day hospital readmission due to ASCVD. Objectives: The current study aims to leverage electronic health record (EHR) data to predict 30-day hospital readmission in high-risk ASCVD patients. Methods: This study utilized the MIMIC III database (a publicly available large, single-centre critical care database of 46,520 patients) comprising of deidentified ~60,000 ICU admissions. Adult patients with the first admission due to ASCVD event and whose length of stay (LOS) in the ICU was &gt;48 hours were included. To develop a prediction model, features representing groups of diagnosis data along with demographics and length of stay in the hospital were used. The performance of ML models was evaluated using the area under the receiver operating characteristic curves (AUCs). Results: Our cohort consisted of 22,666 admissions (mean age 70.1 years) due to an ASCVD event. Out of the 9022 readmissions within 180 days, 60.5% were observed within 30 days of discharge. Among the 17 prospective predictors age, LOS and first hospitalization due to coronary atherosclerosis, heart failure, and haemorrhage issues were the most important factors to predict readmission within 30 days (Fig A). Random Forest was the best performing model with an AUC of 0.66 (Fig B). Conclusions: This model can be helpful in predicting the readmission of high-risk patients after the first ASCVD event which might address the huge unmet need of aiding healthcare resource planning, better patient care, and prevention of rehospitalization and death by intensifying treatment interventions in those patients and taking appropriate decisions to discharge patients based on their age, LOS and ASCVD events resulting in first hopitalization.
DDRE-34. RIBONUCLEOTIDE REDUCTASE REGULATORY SUBUNIT M2 AS A DRIVER OF GLIOBLASTOMA TMZ-RESISTANCE THROUGH MODULATION OF dNTP PRODUCTION
Authors: Ella Perrault, Jack Shireman, Peiyu Lin, Eunus Ali, Andrew Zolp, Shreya Budhiraja, Cheol Park, Shivani Baisiwala, David James, Issam Ben-Sahra, Sebastian Pott, Anindita Basu, Atique Ahmed
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) remains one of the most resistant and fatal forms of cancer. Previous studies examine pre- and post-tumor recurrence; however, it is incredibly difficult to study tumor evolution during therapy where resistance develops. To investigate this, our lab performed a single-cell RNA-sequencing screen before, during, and after temozolomide-based (TMZ) chemotherapy in a patient-derived xenograft (PDX) model in vivo. Our analysis found 149 genes uniquely expressed during TMZ-therapy compared to pre- and post-therapy (p&amp;lt; 0.0001). Of these, the ribonucleotide reductase (RNR) gene family stood out due to the preferential switch to Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) during therapy. Classically, RRM2, or its isoform RRM2B, forms a complex with RRM1 to create an RNR, mediating deoxynucleoside triphosphate (dNTP) production. Our single-cell data revealed that GBM cells rely on RRM1-RRM2 interaction during therapy, but switch to RRM1-RRM2B in post-therapy recurrent GBM. In vitro, RRM2-knockdown cells increased TMZ susceptibility, whereas RRM1- and RRM2B-knockdowns were more resistant to TMZ (p&amp;lt; 0.001). Immunocytochemistry found elevated yH2AX fluorescence in RRM2-knockdowns after TMZ treatment, signifying reduced DNA repair capacity compared to the control (p&amp;lt; 0.001). To understand the mechanism of RRM2-mediated chemoresistance, targeted metabolomics was applied to quantify dNTP signatures during TMZ-therapy. In response to TMZ, dCTP and dGTP production in GBM cells increased 100-fold and 80-fold respectively (p&amp;lt; 0.001). RRM2-knockdowns produced significantly less dCTP and dGTP (p&amp;lt; 0.0001). By supplementing RRM2-knockdowns with dCTP and dGTP, TMZ-susceptibility was rescued, suggesting that RRM2 drives chemoresistance by promoting production of these two nucleotides. In vivo, following intracranial injection of GBM cells, mice treated with the RRM2 inhibitor Triapine with TMZ survived longer than those treated with TMZ alone, indicating promising clinical opportunities in targeting RRM2 (p&amp;lt; 0.0001). Overall, our data present a novel understanding of how RRM2 activity is altered during therapeutic stress to counteract TMZ-induced DNA damage.
Abstract 10208: Quantitative Comparison of Ablation Area Created by the Conventional- and Larger-Sized Visually Guided Laser Balloon
Authors: Takashi Yamasaki, Tetsuhisa Hattori, Misen Pak, Ken Kakita
Journal: Circulation (2021)

Introduction: The visually guided laser balloon (VGLB) ablation catheter has been designed to facilitate pulmonary vein (PV) isolation in patients with atrial fibrillation (AF). Because VGLB is characterized by a compliant and variable diameter balloon, the balloon at the larger inflation size can isolate wider-area circumferential PV antrum. Though the importance of a wider circumferential isolation of PVs, which includes a large portion of the left atrial posterior wall (LAPW), has been suggested in several studies, the extension of the isolation area created by the new VGLB technique remains to be elucidated. We report the quantitative examination of the isolation areas after the conventional- and larger-sized VGLB ablation. Methods: Fifty-five patients with AF who underwent VGLB ablation were enrolled in this prospective study. An electroanatomic map of the left atrium was obtained with the PENTARAY catheter and the CARTO-3 system before and after PV isolation using conventional-sized VGLB. The isolation areas were extended by the larger-sized VGLB ablation and remapped in the same way. As demonstrated in figure, the isolation areas were measured after each ablation. Results: After PV isolation using the conventional-sized VGLB, the mean left- and right-sided antral PV surface areas of ablation were 13.5±2.9 cm 2 and 16.4±3.7 cm 2 , respectively. The total area of LAPW ablation was 10.9±2.1 cm 2 (45.6±9.3% of the posterior wall). On the other hand, they were 18.6±4.0 cm 2 , 23.7±5.2 cm 2 and 16.3±2.8 cm 2 (65.9±11.2%) after ablation with the larger-sized VGLB. These results revealed that the new VGLB technique yielded statistically greater areas of isolation than the conventional-sized VGLB. Conclusions: The larger VGLB ablation technique can create a significantly wider antral PV and LAPW isolation than the conventional-sized VGLB. The resulting LAPW debulking may be greater than the other balloon-based ablation lesions that have been reported previously.
Abstract 13351: New York Heart Association Functional Class Guide Assists With Providers Assessment of Functional Class in Patients With Heart Failure
Authors: Marilyn A Prasun, Thomas P McCoy, Lisa Rathman, Kelly D Stamp
Journal: Circulation (2021)

Background: Correct assignment of New York Heart Association Functional Classification (NYHA-FC) I-IV in patients with heart failure (HF) helps to promote evidence-based guideline directed care. Past research has shown difficulty with providers making consistent decisions about NYHA-FC due to its subjective nature. Therefore, we developed a NYHA-FC Guide to assist with promoting a more accurate NYHA-FC assignment by providers. Objective: Examine the validity, reliability, and accuracy of HF and primary care providers’ assignment of NYHA-FC in patients with HF using the NYHA-FC Guide. Methods: A cross-sectional design was used with validated vignettes after expert review. Advanced practice providers ( n =75) in HF and primary care (PC) utilized a newly developed NYHA-FC Guide to assist in the assignment of NYHA-FC. Known-group validity comparisons, interrater reliability and internal consistency were used to evaluate the validity and reliability of the NYHA-FC Guide. Results: Heart failure providers’ accuracy total mean scores were significantly higher compared to PC providers ( M = 6.0 vs. 5.4, p = 0.020). Primary care providers’ accuracy was higher than anticipated with no significant difference in accuracy of assignment for NYHA-FC II, III and IV relative to HF providers. A majority of HF providers (62%) and primary care providers (80%) reported that the NYHA-FC Guide assisted them with deciding NYHA-FC. Conclusion: Correct assignment of NYHA-FC can promote more objective decision-making regarding prescribing evidence-based treatment to patients with HF. The newly developed NYHA-FC Guide shows promise for facilitating accuracy of NYHA-FC assignment. Further research is warranted to evaluate the accuracy of using the NYHA-FC Guide compared to the gold standard 6 minute walk test and the applicability for use the NYHA-FC Guide in a busy clinical practice.