tbuckley/cabot-search huggingface dataset:
Cognitive preservation following awake mapping-based neurosurgery for low-grade gliomas: A longitudinal, within-patient design study
Authors: Anne-Laure Lemaitre, Guillaume Herbet, Sam Ng, Sylvie Moritz-Gasser, Hugues Duffau
Journal: Neuro-Oncology (2021)

Abstract Background Awake surgery with intraoperative electrical mapping emerged as a gold-standard approach in newly diagnosed diffuse low-grade glioma (DLGG) to optimize the extent of resection (EOR) while sparing critical brain structures. However, no study has assessed to what extent cognitive recovery occurs following awake mapping-guided neurosurgery in a large, longitudinal, and homogeneous series of DLGG. Methods A longitudinal study on the cognitive status of 157 DLGG patients was performed. Neuropsychological assessments were done before and three months after awake mapping-based surgery. Z-scores and variations of Z-scores were computed to determine the number of patients with cognitive deficit(s) or decline. Clinical, surgical, and histopathological variables were studied to investigate factors contributing to neurocognitive outcomes. Results Eighty-seven patients (55.4%) had preoperative cognitive impairments. Statistical analysis between the preoperative (baseline) and postoperative assessments demonstrated a significant difference in three domains (Executive, Psychomotor Speed and Attention, Verbal Episodic Memory). Eighty-six percent of patients exhibited no postoperative cognitive decline, and among them, 10% exhibited cognitive improvement. The mean EOR was 92.3%±7.8%. The EOR, postoperative volume, and tumor lateralization had a significant association with cognitive decline. No patients demonstrated permanent postoperative neurologic deficits, but 5.8% did not resume their preoperative professional activities. The 5-year survival rate was 82.2%. Conclusions This is the largest series ever reported with systematic longitudinal neuropsychological assessment. 86% of patients demonstrated no cognitive decline despite large resections and only 5.8% did not return to work. This work supports the practice of awake surgery with cognitive mapping as safe and effective in DLGG patients.
Abstract 10155: The Atypical Presentation and Clinical Outcomes of Non-ST-Segment Elevation Acute Coronary Syndromes in Chronic Kidney Disease Patients
Authors: Praew Kotruchin, Kodchakorn Tharawadee, Thanat Tangpaisarn, pariwat phingoen
Journal: Circulation (2021)

Introduction: The atypical presentation of acute coronary syndromes (ACS) was a risk factor of unfavorable outcomes. It is not uncommon for chronic kidney disease (CKD) patients with ACS to present atypically. Hypothesis: We hypothesized that the atypical presentation of non-ST-segment elevation ACS (NSTE-ACS) in CKD patients might associate with poor clinical outcomes. Methods: This was a retrospective cohort study in Srinagarind hospital, Thailand, from 2014 to 2017. The CKD patients with NSTE-ACS were enrolled. Clinical data including presenting symptoms, laboratory results, treatments, and outcomes were collected from an electronic database. The atypical presentation was defined as nausea and/or vomiting, dyspepsia, confusion, dyspnea, or no chest pain. The outcome was a composite of all-cause mortality, the over 30-day length of stay, and recurrent ACS underwent PCI or CABG. Results: There were 147 patients enrolled, of those, 77 (52.3%) presented with atypical symptoms. The atypical presentation group had a faster heart rate (HR) compared with those who presented with typical symptoms (87 vs. 78 beats per minute, P=0.005), however, both groups had comparable age, sex, and echocardiographic parameters. The determinant of the atypical presentation was HR (Odds ratio (OR) 1.03, 95%CI: 1.01-1.05). Atypical symptoms and diabetes mellitus were associated with the outcome, adjusted OR 2.62, 95%CI: 1.21-5.67, and adjusted OR 3.54, 95%CI: 1.56-8.03, respectively. Conclusions: ACS should be one of the differential diagnoses in the CKD patients who presented with nausea and/or vomiting, dyspepsia, confusion, dyspnea, or no chest pain. Considered that the atypical presentation was associated with poorer outcomes.
St John Ambulance volunteers prepare to boost capacity in ambulance trusts
Authors: Matthew Limb
Journal: BMJ (2021)

The charity St John Ambulance is in discussions with NHS leaders in England to set up an auxiliary ambulance service to support hard pressed English trusts, The BMJ has learnt.

The service would be part of NHS Reserves, the wider army-style volunteer force whose rollout in England was announced by the health secretary, Sajid Javid, on 28 November.

Some ambulance services in England have been stretched beyond capacity, and paramedics warned in October that services were regularly holding as many as 300 calls at a time, when no ambulances were available.1 Health officials have said that the NHS Reserves scheme is a national extension of pilot work undertaken since the start of the pandemic and that further details will be released “in due course.”

Javid said, “Local hospitals will be able to mobilise a broad range of fully trained staff, from retired doctors to IT experts, giving the NHS additional capacity when it needs it most.”

More than 750 000 people signed up to become NHS volunteer responders in …
Abstract 14271: TLR3 as a Potential Target to Prevent Aortic Valve Stenosis
Authors: Nicola Willemsen, Sven Niepmann, Ann Sophie Boucher, Sebastian Zimmer, Georg Nickenig
Journal: Circulation (2021)

Aortic stenosis (AS) is the most common valvular disease in the western world and is associated with severe morbidity and mortality. Our current concept of disease development suggests that local chronic inflammation drives fibrosis and calcification of the valve cups. It has recently been proposed that activation of pattern recognition receptors may be critical in this context. In a preliminary screening, we found Toll-like receptor 3 expression increased in human AS samples. Aim of this study was to investigate the role of TLR3 in the pathogenesis of AS. Isolated human valvular interstitial cells (VICs) were cultured and stimulated with the TLR3 agonist Poly I:C. To inhibit TLR-3 activation, a knockdown was performed using TLR3 small interfering RNA (siRNA) as well as the TLR3/ RNA Complex inhibitor C4a. Calcification was induced by changing the culturing media. RNA was isolated for gene expression analysis. Calcification was visualized by alizarin red staining. Wild type as well as TLR3 knockout mice underwent an ultrasound guided wire injury. After surgery, C4a was injected in WT mice to suppress TLR3 signaling. Valves were explanted and stained with hematoxylin/eosin or anti CD68. Upon stimulation of TLR3 with PolyI:C, TLR3 expression was consistently upregulated in VICs while incubation of VICs with the TLR3/ RNA complex inhibitor C4a resulted in a downregulation of TLR3. These results suggest that TLR3 may be subject to a potential detrimental positive feedback loop in these cells. Importantly, activation of TLR3 led to a marked increase in expression of the pro-osteogenic markers BMP-2 and RUNX2. TLR3 inhibition or knockdown blunted this response.TLR3 deficient mice revealed a significantly smaller aortic valve leaflet area as well as a reduced intravalvular infiltration with monocytes compared to WT. C4a treatment resulted in lower trans-aortic valve peak velocity levels. Further, C4a mice failed to develop AS upon injury. These findings not only support the endogenous role of TLR3 in the development of AS but suggest that specific TLR3 inhibition might be beneficial for the treatment or prevention of AS. Further studies are required to test this hypothesis and to decipher the exact mechanisms how TLR3 contributes to AS.
Abstract 10952: Increased Hepatic T1 Mapping Prediction of Elevated Right Atrial Pressure in Patients with Dilated Cardiomyopathy
Authors: Tomohiko Watanabe, Yumiko Kanzaki, Kosuke Tsuda, Kazushi Sakane, Ryo Yokoyama, Masaaki Hoshiga
Journal: Circulation (2021)

Introduction: Elevated right atrial pressure (RAP) exhibits residual congestion and poor clinical outcomes in patients with heart failure (HF). In HF patients, persistent high RAP causes liver damage, which leads to liver fibrosis. Recent advances in T1 mapping of the liver using MRI allow the quantification of liver fibrosis. Hypothesis: Hepatic T1 mapping value may predicts high RAP in patients with chronic HF. Methods: We examined the data from the consecutive 40 patients with DCM ( 60 ± 13 years, 27 men) who underwent 3 Tesla cardiac and liver MRI, which were conducted within seven days of right heart catheterization. RV end-diastolic volume (RVEDV), end-systolic volume (RVESV), RV ejection fraction (RVEF), right atrial (RA) and left atrial (LA) volume, left ventricular end-diastolic volume (LVEDV), end-systolic volume (LVESV), LV ejection fraction (LVEF) and LV mass index (LVMI) were calculated from cine cardiac MRI. Native T1 mapping image (T1 short modified look locker inversion recovery-ShMOLLI- sequence) was acquired the heart and the liver (Figure A). Patients were divided into two groups according to RAP; high ( ≥ 8 mmHg; n=10) and low ( &lt;8 mmHg; n=30). Results: Ten patients had high RAP. There were no significant differences in LVEDV,LVESV, LVEF, LVMI, RVEDV, RVESV and RVEF between patients with high RAP group and those without ( 192 ± 54 ml vs 212 ± 57 ml; 136 ± 49 ml vs 154 ± 51 ml; 30 ± 9 % vs 28 ± 8 %; 79 ± 21 g/m 2 vs 81 ± 22 g/m 2 ; 45 ± 27 ml vs 46 ± 19 ml; 27 ± 18 ml vs 25 ± 15 ml; 42 ± 19% vs 46 ± 18%, respectively). The hepatic T1 mapping value was higher in the high RAP group ( 845 ± 47 ms vs 759 ± 90 ms, p &lt; 0.01) and exhibited a positive correlation with RAP ( R = 0.34, P &lt; 0.05). The hepatic T1 mapping value of ≥ 820ms was the optimal cutoff values for identifying high RAP ( T1: sensitivity, 89%; specificity, 72%; AUC, 0.80, Figure B). Conclusion: Increased native T1 mapping value of the liver may be helpful in non-invasively estimating elevated RAP.
Abstract 13314: Development of a Computational Fluid Dynamics Model for Assessing Hemodynamics in Aortic Arches in Human Fetuses
Authors: Steven Evangelos, Zhenglun Wei, Shuping Ge
Journal: Circulation (2021)

Background and Objective: The hemodynamics of fetal circulation and its alterations, as in cases of congenital heart defects (CHD), have been investigated in instrumented animal models or in human fetuses by noninvasive fetal echocardiography and Doppler (FED). There is little data in computational modeling of fetal circulation due to challenges in fetal cardiac imaging and the availability of validation methodologies. This study aims to develop and validate a computational model for assessing hemodynamics in aortic and ductal arches in human fetuses. Methods: Figure 1 shows our computational workflow. The process started by preparing a reconstructed 3D aortic and ductal arch anatomy derived from 3D FED. Then, the computational model was built and validated using clinical data from five human fetuses. The primary output was the velocity waveform at the aortic isthmus (AoI), validated using tracings from spectral Doppler. Results: Upon superimposing the reconstructed fetal aortic arch anatomies onto the original 3D FED stack, our results demonstrated a precise rendering of each subject’s unique vessel structure. Simulations were run for ten cardiac cycles, with each velocity waveform at the AoI showing a discrepancy of less than 15% when compared with the Doppler echocardiography tracings. These findings indicate a good agreement between our computational model and the FED data. Conclusion: This study presents the development and validation of a computational model for assessing patient-specific hemodynamics in the aortic arches of human fetuses. Continued investigation is warranted to further validate and apply this approach to improve the diagnosis, prognosis, and treatment of CHD in human fetuses.
Abstract 12781: Network Medicine-Based Multimodal Omics Discovery and iPSC-Based Validation of Metformin for Potential Treatment of Atrial Fibrillation
Authors: Jessica C Lal, Yadi Zhou, Julie H Rennison, David R Van Wagoner, John Barnard, Feixiong Cheng, Mina K Chung
Journal: Circulation (2021)

Introduction: Atrial Fibrillation (AF) is the most prevalent cardiac arrhythmia in the United States. Effective, safe, and durable therapeutic interventions are lacking. Thus, it is imperative to improve clinical management by utilizing novel approaches for drug repurposing. To date, multimodal omics analysis of genomics, transcriptomics, and protein-protein interactions [PPIs] have not been fully exploited for AF drug repurposing. Hypothesis: We hypothesize that using Network Medicine-based multimodal omics analysis for drug prioritization and functional observations using induced pluripotent stem cell (iPSC) models can help us identify effective therapeutic strategies and elucidate drug’s mechanisms-of-action for restoring normal sinus rhythm. Methods: Here, we used RNA-sequencing data from a biobank of left atrial tissues obtained from cardiac surgery patients to identify testable AF disease modules under the human protein-protein interactome network model. We systematically prioritized repurposable drug candidates for AF using both network proximity and gene-set enrichment analysis approaches by leveraging AF disease module findings, drug-target network, and drug-induced gene signatures in human cell lines. RNAseq was used to assess the transcriptomic impact of a top drug candidate, metformin, on gene expression of atrial myocytes differentiated from human iPSCs (a-iCMs). Results: Via network-based screening of 2,891 FDA-approved or clinical drugs, we found nine putative drug candidates (including Metformin, Furosemide, and Rofecoxib) using both network proximity z-score and GSEA-based enrichment scores. RNA-seq analysis of metformin-treated a-iCMs identified 238 differentially expressed genes following multiple test correction (P&lt; 2.96E-06). Several key cardiovascular or drug-related markers were differentially expressed in Metformin treated a-EHTs. Of note NMRK2 and PCK2 were upregulated, and TGFB1 and TXNIP were downregulated, suggesting an improved energy utilization following metformin treatment. Conclusions: In summary, this study presented state-of-the-art network medicine methodologies for AF drug repurposing and identified metformin as a candidate treatment for AF patients.
Abstract 11571: Defining the Distance Between the His Bundle and Septal Perforator Arteries
Authors: Matthew Bocchese, Michael Gannon, Pravin Patil, William Vandecker, Isaac R Whitman, Edmond Cronin
Journal: Circulation (2021)

Introduction: Left bundle branch pacing (LBBP) is an emerging pacing modality in which the LBBP lead is screwed through the interventricular septum towards the left bundle branch in the left septal subendocardium. Damage to a septal perforating branch of the left anterior descending coronary artery is a potential complication. Objective: To define the distance between the His bundle and the first septal perforator artery to guide safe LBBP lead placement. Methods: Clinically indicated coronary CT angiograms (CCTA) at our institution were reviewed. The intersection of the tricuspid annulus and the base of the non-coronary cusp of the aortic valve represented the location of the His bundle. The intersection of a line joining the His bundle location with the RV apex with the first septal perforator was determined. The distance between the His Bundle and this intersection was measured and recorded. Values were analyzed using standard statistical methods. T-tests were used for continuous variables. Results: A total of 50 consecutive CCTAs were included in this study, 30 men and 20 women, average age 55.4 ± 14.1 years. Medical history included HTN (64%), and diabetes (50%) and CAD (10%). LVH was present in 9 patients (18%) but was mild in all cases. Heart failure was present in 9 patients (18%), 4 of whom had systolic dysfunction with an average EF for the study being 57.0%. The mean left ventricular internal diameter at end diastole (LVIDd) and interventricular septum thickness (IVS) were 46.7 mm and 10.2 mm, respectively. The mean distance from the His Bundle to the first septal perforator was 27.2 ± 7.7 mm, median 26.9 mm, range 13.0 to 44.7 mm. There was no significant difference by gender for mean distance (28.1 mm men vs 25.6 mm women, p=0.26). There was no significant association between LVIDd or IVS and the His Bundle-Septal Perforator distance (r 2 =0.02 and r 2 =0.002, respectively). Conclusions: Using CCTA, we defined the distance between the His bundle and the first septal perforator. Operators implanting LBBP leads can use these measurements to guide safe lead placement.
Abstract 14324: Low Pulmonary Venous Flow Drives Cpc-PH Development in a Pulmonary Venous Banding Swine Model of Cpc-PH
Authors: Betty Allen, Diana Marcela Tabima Martinez, Timothy A Hacker, Daniel Seiter, Thekla Oechtering, Oliver Wieben, Naomi C Chesler
Journal: Circulation (2021)

Introduction: Combined pre- and post-capillary pulmonary hypertension (Cpc-PH) is the most severe form of PH-LHF. While the impact of elevated left atrial and consequently elevated pulmonary venous (PV) pressure on Cpc-PH progression is well studied, little is known about how compromised PV flow secondary to LHF affects disease progression. To assess the hypothesis that decreased PV flow induces Cpc-PH, we developed a large animal model of Cpc-PH by decreasing PV flow independent of LHF. Methods: Survival pulmonary venous banding (PVB) surgery was performed on a large white male pig (9kg), which was then followed for 16 weeks. A pig of the same sex and weight underwent a sham operation as control. Both animals underwent cardiac 4D flow MRI and right heart catheterization (RHC) in a terminal study. Results: At 16 weeks post-surgery, MR imaging demonstrated that PVB decreased mean flow and peak velocity in the right (RIPV) and left inferior pulmonary veins (LIPV) and MPA (figure and table). PVB also decreased MPA relative area change (RAC) (table). RHC demonstrated elevated PCWP, mPAP, PVR, and decreased RV EF (table). Also, Fulton index was increased demonstrating RV hypertrophy (table). Discussion: In conclusion, this study utilized PVB to demonstrate the ability of decreased PV flow to drive Cpc-PH development in the absence of LHF. Our preliminary data suggest a low flow state in the lung can increase RV afterload and induce RV dysfunction. Further studies with a larger sample size are needed to confirm this pathomechanical mechanism. Figure. MRI image of PV confluence narrowing from the PVB. Insert shows flow rates from RIPV and LIPV (blue), across PVB (red), and into LA (green).
TAMI-57. INDUCTION OF FERROPTOSIS PROMOTES IMMUNOGENIC CELL DEATH AND ACTIVATION OF THE IMMUNE MICROENVIRONMENT IN GLIOMA
Authors: Michael Argenziano, Matei Banu, Athanassios Dovas, Wenting Zhao, Julia Furnari, Dominique Higgins, Pavan Upadhyayula, Aayushi Mahajan, Nelson Humala, Peter Sims, Jeffrey N Bruce, Peter Canoll
Journal: Neuro-Oncology (2021)

Abstract Gliomas are immune cold tumors. Effective therapeutic strategies capable of inducing an immune response are lacking.Here we present evidence that ferroptosis, a form of iron-mediated lipid peroxidation-based cell death, may promote anti-tumor immunity via stimulation of phagocytosis and pro-inflammatory activities in microglia. While ferroptosis has shown promise in induction of glioma cell death, the immunogenic and microenvironmental effects of glioma ferroptosis are poorly understood. First, we tested the in vitro effects of the glutathione peroxidase 4 (GPX4) inhibitor RSL3, a ferroptosis inducer, on murine glioma cell lines. Using flow cytometry, we discovered that RSL3 treatment led to membrane translocation of the pro-phagocytic antigen calreticulin, known hallmark of immunogenic cell death, by an average log2-fold-change of 2.53 (p= 0.03) compared to DMSO-treated controls. This effect correlated with lipid peroxidation, as assessed by BODIPY-C11 staining. To further test the effects of ferroptosis on glioma cell-microglia crosstalk, we prepared acute brain tumor slices from both mouse and human glioma samples, and treated them with RSL3. Quantification of immunofluorescent staining from three independent human slice cultures after RSL3 treatment demonstrated a significant increase in calreticulin abundance as compared to control (p &amp;lt; 0.001). Importantly, this effect was significantly diminished with addition of ferrostatin, an inhibitor of ferroptosis, demonstrating that ferroptosis induction was directly responsible for calreticulin translocation. Single-cell RNAseq on mouse and human acute glioma slice cultures treated with RSL3 demonstrated significant overexpression of calreticulin in the tumor population, and positive enrichment of interferon signaling, antigen presentation, and phagocytosis ontologies in both tumor and myeloid compartments. These findings suggest that ferroptosis-induced translocation of calreticulin on the surface of glioma cells promotes activation of the local immune microenvironment by increasing tumor antigen presentation and pro-inflammatory cytokine release by tumor-associated microglia. Thus, ferroptosis-inducing drugs may promote anti-tumor immunity through the activation of immunogenic cell death signals.
Abstract 13615: Mortality Trends And Regional Variations Of Aortic Aneurysm And Dissection In The United States
Authors: Mohsin S Mughal, Ammar Nasir, Ali Ghani, Hasan Mirza, Abdul Aziz A Asbeutah, Hamza Hafeez, Harjot S Jagdey, Talha Ahmad, Khansa Ahmad, Mahboob Alam, Muhammad Khakwani, Mohammed Haris Usman, Najam Wasty, Sergio Waxman
Journal: Circulation (2021)

Introduction: Aortic dissection and aortic aneurysm represent significant health risk as they are associated with very high mortality. Incidence of aortic dissection is low and estimated to be 5-30/100,000 hospitalized patients. Similarly, aortic aneurysms have low incidence (depending upon location) and high mortality (over 80%). Combined mortality associated with aortic aneurysm or dissection and its contemporary trends in the U.S. are not well known. Methods: In this retrospective study death certificate data were retrieved from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (WONDER) database for 1999-2018. Mortality for aortic aneurysm and dissection ICD-10 code-I71 as an underlying cause of death were queried from 1999-2018. This duration was further stratified into five-year periods. WONDER database is publicly available de-identified data collected by CDC that reports the underlying cause of death across the United States. Crude mortality rate and age-adjusted mortality rate per 100,000 were calculated in four U.S census regions (CR1 Northeast, CR2 Midwest, CR3 South, CR4 West). Results: From 1999-2018 AAMR for aortic aneurysm and dissection showed a downward trajectory. Regional variations were observed and are illustrated in figure 1. For Northeast (CR-1) AAMR declined by 54%, for Midwest (CR-2) it declined by 48%; for South (CR-3) it declined by 53%, and for West (CR-4) it declined by 52%. (Table-1) Conclusions: Our study shows a downward trajectory of AAMR for aortic aneurysm and dissection. Which reinforces the continuation of guideline based screening.