tbuckley/cabot-search huggingface dataset:
Abstract 6901: Effect of a Virtual Patient Simulation at Improving VTE Prevention Strategies in Acutely Ill Medical Patients
Authors: Margaret Harris, Jelena Spyropoulos, Michael Lacouture, Doug Blevins, MD, Catherine Capparelli, Mahira Zec Bonomo, MBA, CHCP
Journal: Circulation (2021)

Introduction: Despite evidence and guidelines for VTE prophylaxis in the hospital setting, cardiologists are challenged to implement the latest evidence-based strategies to prevent VTE in clinical care. We sought to determine if an online, virtual patient simulation (VPS)-based continuing medical education intervention could improve performance of cardiologists related to individualized strategies to prevent VTE in these patients. Methods: The intervention comprised two patients presenting in a VPS platform that allows learners to order lab tests, make diagnoses, and prescribe treatments in a manner matching the scope and depth of actual practice. Tailored clinical guidance (CG), based on current evidence and expert recommendation, was provided following each decision, followed by the opportunity for the learner to modify their decisions. Decisions were collected post-CG and compared with each user’s baseline (pre-CG) decisions using a McNemar’s test to determine P values. Data were collected from March 27, 2020 through June 10, 2020. Results: Significant absolute improvements were observed after CG for the following: Case 1 (n= 123) • Diagnose high risk for VTE:44% improvement (15% pre-CG vs 59% post-CG; P&lt;.001) • Order/Initiate o Rivaroxaban: 46% improvement (13% pre-CG vs 59% post-CG; P&lt;.001) o Enoxaparin: 13% improvement (7% pre-CG vs 20% post-CG; P&lt;.001) o Post-discharge VTE assessment risk and counseling: 22% improvement (50% pre-CG vs 72% post-CG; P&lt;.001) o Patient education: 20% improvement (50% pre-CG vs 70% post-CG; P&lt;.001) o Follow-up visits: 20% improvement (48% pre-CG vs 68% post-CG; P&lt;.001) Case 2 (n= 80) • Order/Initiate o Rivaroxaban: 28% improvement (35% pre-CG vs 63% post-CG; P&lt;.001) o Enoxaparin: 10% improvement (4% pre-CG vs 14% post-CG; P&lt;.05) o Post-discharge VTE assessment risk and counseling: 12% improvement (63% pre-CG vs 75% post-CG; P&lt;.01) o Patient education: 11% improvement (60% pre-CG vs 71% post-CG; P&lt;.01) o Follow-up visits: 11% improvement (63% pre-CG vs 74% post-CG; P&lt;.01) Conclusions: VPS that immerses specialists in an authentic, patient-based, practical learning environment can significantly improve evidence-based clinical decision making for the prevention of VTE in acutely ill medical patients.
NIMG-59. RADIOMICS-PREDICTED T CELL DYNAMICS STRATIFY SURVIVAL AFTER DENDRITIC CELL VACCINE THERAPY FOR PRIMARY GLIOBLASTOMA
Authors: Kamila Bond, Andrea Hawkins-Daarud, Gustavo De Leon, Lee Curtin, Javier Urcuyo, Kyle Singleton, Kamala Clark-Swanson, Christopher Sereduk, Nhan Tran, Leland Hu, Ian Parney, Kristin Swanson
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Dendritic cells (DCs) are potent antigen presenting cells that can be exploited to initiate an adaptive anti-tumoral immune response. DC vaccine clinical trials for primary glioblastoma (GBM) have reported prolonged progression-free survival without any impact on overall survival (OS). We report a radiomics approach that identifies a subpopulation of patients with prolonged OS in clinical trial MC1272. METHODS Twenty adults with primary GBM undergoing standard-of-care therapy were enrolled in MC1272. Autologous DCs were pulsed with allogenic GBM cell lines to generate vaccines that were administered for up to twelve cycles. Standard brain imaging was obtained at the initiation of treatment and two months afterwards. An independent cohort of image-localized biopsies underwent RNA sequencing followed by cellular deconvolution to estimate T cell abundance. A machine learning model was trained to predict intratumoral T cell abundance from imaging features, and the model was applied to MC1272 patient imaging. RESULTS Voxelwise predictions of T cell abundance were generated for each patient’s pre- and post-treatment images. The difference in total intratumoral T cell abundance between imaging timepoints classified patients into increasing or decreasing T cell groups. Patients whose T cells increased had longer OS (median, 21 months) than those whose T cells decreased (median, 10 months; p=0.0035). The significance remained in a Cox proportional hazards analysis that adjusted for patient age and sex (p=0.011). CONCLUSIONS A spatially-resolved radiomics model detected that an intratumoral T cell influx after DC vaccine therapy was associated with prolonged OS. The “post-treatment” imaging in this study was obtained a mere two months after DC vaccine initiation, suggesting that our radiomics model can provide an early indication of treatment responsiveness and prognosis in these patients.
Estimated number of deaths directly averted in people 60 years and older as a result of COVID-19 vaccination in the WHO European Region, December 2020 to November 2021
Authors: Margaux MI Meslé, Jeremy Brown, Piers Mook, José Hagan, Roberta Pastore, Nick Bundle, Gianfranco Spiteri, Giovanni Ravasi, Nathalie Nicolay, Nick Andrews, Tetiana Dykhanovska, Joël Mossong, Małgorzata Sadkowska-Todys, Raina Nikiforova, Flavia Riccardo, Hinta Meijerink, Clara Mazagatos, Jan Kyncl, Jim McMenamin, Tanya Melillo, Stella Kaoustou, Daniel Lévy-Bruhl, Freek Haarhuis, Rivka Rich, Meaghan Kall, Dorit Nitzan, Catherine Smallwood, Richard G Pebody
Journal: Eurosurveillance (2021)

Since December 2019, over 1.5 million SARS-CoV-2-related fatalities have been recorded in the World Health Organization European Region - 90.2% in people ≥ 60 years. We calculated lives saved in this age group by COVID-19 vaccination in 33 countries from December 2020 to November 2021, using weekly reported deaths and vaccination coverage. We estimated that vaccination averted 469,186 deaths (51% of 911,302 expected deaths; sensitivity range: 129,851–733,744; 23–62%). Impact by country ranged 6–93%, largest when implementation was early.
EXTH-81. STING ACTIVATION PROMOTES ROBUST IMMUNE RESPONSE AND TUMOR REGRESSION IN GLIOBLASTOMA MODELS
Authors: Gilles Berger, Erik Knelson, Michal Nowicki, David Mooney, E Antonio Chiocca, David Barbie, Sean Lawler
Journal: Neuro-Oncology (2021)

Abstract The immunosuppressive tumor microenvironment in glioblastoma presents a major barrier to effective application of immunotherapeutic approaches in this disease. Although immunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of the disease glioblastoma remains largely refractory to current immunotherapeutic approaches. The cGAS-STING cytoplasmic double stranded DNA sensing pathway has emerged as a next-generation immunotherapy target with potent local immune stimulatory properties, but has not been well investigated in glioblastoma to date. Here we investigated the presence of STING pathway components in glioblastoma patient specimens and cell lines by Western blotting and immunostaining. The functionality of the pathway was determined by ELISA, and immune infiltrates, and animal survival were investigated in mouse glioblastoma models after treatment with the STING agonist ADU-S100. Our data reveal the presence of STING in human GBM specimens, where it stains strongly in the tumor vasculature, and appears to be activated as evidenced by elevated phosphoTBK1 staining. We show that human GBM cells do not respond agonists, but that GBM explants can respond to STING agonist treatment by secretion of inflammatory cytokines. In murine GBM models, we show a profound shift in the tumor immune landscape after STING agonist treatment, with massive infiltration of the tumor-bearing hemisphere with innate immune cells including inflammatory macrophages, neutrophils and NK populations. Treatment of established murine intracranial GL261 and CT-2A tumors by biodegradable ADU-S100-loaded intracranial implants demonstrated a significant increase in survival in both models and long-term survival with immune memory in GL261. This study reveals therapeutic potential and deep remodeling of the TME by STING activation in GBM and warrants the further examination of STING agonists alone or in combination with other immunotherapies such as cancer vaccines, CAR T cells, or immune checkpoint blockade.
Functional capacity at 1 year predicts all‐cause mortality in patients with rheumatoid arthritis: comment on the article by Fatima et al
Authors: Richard K. Jacoby, Johannes J. Rasker
Journal: Arthritis & Rheumatology (2021)

specificity and sensitivity for the identification of early RA, and can be useful as a diagnostic criterion for RA (6).Therefore, if the anti-CCP level had been considered as part of the inclusion criteria in the study by Fatima et al, the study cohort may have been more representative of an early RA population.Second, in the study by Fatima et al, patients who had not completed a HAQ disability index at either baseline or 12 months and patients who had not received treatment with a DMARD or biologic agent in their first year of follow-up were excluded, and therefore selection bias may have had some influence on the results.It is possible that patients with incomplete HAQ information had poorer adherence to treatment and subsequently worse outcomes.As for patients who did not receive DMARDs/biologic agents in the first year of follow-up, this group of patients may have already been experiencing severe symptoms at baseline, and therefore they may have been reluctant to allow the addition of DMARDs to their existing treatment regimen.In summary, the exclusion criteria used in the study by Fatima et al could have overlooked early RA patients who were either poorly adherent to treatment or were experiencing severe underlying disease, making the study sample less representative.Finally, we have some sincere concerns with regard to the potential influence of several residual confounders.Although the authors utilized the Rheumatic Disease Comorbidity Index (7) to minimize the effect of comorbidities on all-cause mortality, there are still a few factors to consider in terms of those that might potentially convey a risk of confounding of the study results, including frequency of alcohol consumption, presence of cirrhosis or chronic kidney disease, and each patient's nutrition status and body mass index at baseline and over follow-up.
Abstract 14260: Suppression and Replacement Gene Therapy for Type 2 Long QT Syndrome
Authors: Sahej Bains, Steven Dotzler, Wei Zhou, CS John Kim, David J Tester, Michael J Ackerman
Journal: Circulation (2021)

Introduction: Type 2 long QT syndrome (LQT2) is caused by loss-of-function variants in the KCNH2 -encoded K v 11.1 potassium channel which is essential for the rapid delayed rectifier channel (I Kr ) that governs phase 3 of cardiac action potential (AP). No current therapies target the molecular cause of LQT2. Methods: A dual-component “suppression-and-replacement” (SupRep) KCNH2 gene therapy was created by cloning into a single construct a custom-designed KCNH2 shRNA that produces ~80% knockdown (suppression) and a “shRNA-immune” (shIMM) KCNH2 cDNA modified by the introduction of synonymous single nucleotide substitutions within the shRNA target site (replacement). The ability of KCNH2-SupRep gene therapy to suppress and replace LQT2-causative variants in KCNH2 was evaluated via heterologous expression in TSA201 cells. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated from two patients with LQT2 (KCNH2-G604S and -N633S). CRISPR-Cas9 corrected isogenic control iPSC-CMs were made. Both lines were treated with KCNH2-SupRep or non-targeting control shRNA (shCT). FluoVolt voltage dye was used to measure the APD. Results: KCNH2-SupRep achieved mutation-independent suppression of wild-type KCNH2 and both LQT2-causative variants with simultaneous replacement of KCNH2-shIMM as measured by allele-specific qRT-PCR. Treatment with KCNH2-SupRep resulted in shortening of the pathologically prolonged APD at 90% repolarization (APD 90 ) to near isogenic control APD 90 levels (G604S: isogenic controls, 424 + 39 ms and N633S: isogenic controls, 433 + 16 ms) compared to treatment with non-targeting shCT (G604S: SupRep treated, 399±105 ms vs. shCT treated, 577±39 ms, p&lt;0.0001; N633S: SupRep treated, 432±85 ms vs. shCT treated, 483±65 ms, p&lt;0.005). Conclusions: We provide the first proof-of-principle gene therapy for correction of LQT2. Like our sentinel discovery of SupRep gene therapy for LQT1, KCNH2-SupRep successfully suppressed and replaced KCNH2 to normal wild-type levels. In TSA201 cells, co-transfection of LQT2 variants and KCNH2-SupRep caused mutation-independent suppression-and-replacement of KCNH2 . In LQT2 iPSC-CMs, KCNH2-SupRep shortened the APD, thereby eliminating the pathognomonic feature of LQT2.
STEM-20. THE ROLE OF HUMAN BETA DEFENSINS IN THE CLONOGENICITY OF GLIOBLASTOMA MULTIFORME
Authors: Peggy Harris, Amber Kerstetter-Fogle, Anthony Sloan, Alankrita Raghavan, Harry Hoffman, Jill Barnholtz-Sloan, Marta Couce, Ge Jin, Aaron Weinberg, Andrew Sloan
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Glioblastoma (GBM) is the most common primary malignant brain tumor with a median overall survival of 12-15months. GBM aggressiveness and poor response to treatment are often attributed to a small population of stem-like cells referred to as glioma stem cells (GSCs). Human Beta-Defensins (HBDs), a family of small molecules initially thought to function as anti-microbials, have been implicated in various cancers with functions that are cancer type specific, including proinflammatory and immunosuppressive roles. GOAL: This study aimed to elucidate HBDs expression in GSCs and differentiated gioma cells (DGSs). METHODS We identified HBD2 and HBD3 in glioma and GSCs and DGSs by immunofluorescence (IF) and immunohistochemistry (IHC). We also assessed the role HBD2/3 play in GBM oncogenesis by investigating their effects on the self-renewal capacity of GSCs. RESULTS HBD2 and HBD3 are found in both bulk tumor and GSCs by IHC and IF. Expression of HBD2 and HBD3 mRNA levels are elevated in GBM patient tissue in comparison to lower grade gliomas by 16.2 &amp; 1.9 fold (respectively; p &amp;lt; 0.0001). Additionally, transcriptional expression of HBD2 and HBD3 are increased by 0.68 and 1.15 fold respectively in GSCs versus autologous DGCs (p &amp;lt; 0.05; p&amp;lt; 0.005 respectively), suggesting a role for HBD 2/3 in oncogenesis. Interestingly however, HBD2 and HBD3 pretreatment of GSC cell lines showed decreased self-renewal capacity by 34.2 and 66.4% (p &amp;lt; 0.001), determined by the reduced number of large neurospheres ( &amp;gt;250mm). CONCLUSIONS Our results demonstrate the presence of HBD2/3 in GBM samples by IHC and IF with increased HBD2/3 mRNA expression in GBM samples. Interestingly DGCs contain less HBD2/3 than their GCS counterparts, and clonogenicity assays demonstrate a decrease in oncogenesis, suggesting that HBD’s role in proliferation and clonogenicity of DGCs and GSCs may be context dependent, leading to additional questions and future studies.
Abstract 10383: Patent Ductus Arteriosus Stent versus Blalock-Thomas-Taussig Shunt for Initial Palliation of Cyanotic Congenital Heart Disease with Ductal Dependent Pulmonary Blood Flow: Results of a Meta-Analysis
Authors: Stephanie Y Tseng, Vien Truong, Daniel Peck, Sneha Kandi, Samuel Brayer, Don P Jason, Wojciech Mazur, Garick D Hill, Awais Ashfaq, Bryan H Goldstein, Tarek Alsaied
Journal: Circulation (2021)

Introduction: In patients with cyanotic congenital heart disease (CHD) and ductal-dependent pulmonary blood flow (DDPBF), initial palliation may include patent ductus arteriosus (PDA) stent or Blalock-Thomas-Taussig shunt (BTTS). This meta-analysis aimed to compare outcomes after PDA stent and BTTS. Methods: A comprehensive search of PubMed and Embase databases was performed. Newcastle-Ottawa tool assessed risk of bias in observational studies. Odds ratios and hazard ratios were pooled. Adjusted hazard ratios controlled for covariates and assessed time to event in survival analysis. Meta-analysis was performed using DerSimonian-Laird random-effects models. Results: Six retrospective observational studies were included, all low risk of bias. Of 757 patients, 243 (32.1%) had PDA stent and 514 (67.9%) had BTTS. There was no significant difference in mortality between PDA stent (HR 0.71; 95% CI: 0.26-1.93, p=0.50; I 2 =54%) and BTTS. PDA stent was associated with lower risk of complications (OR 0.45; 95% CI: 0.25-0.81, p=0.008; I 2 =0%) and post-procedural mechanical circulatory support (OR 0.27; 95% CI: 0.09-0.79, p=0.02; I 2 =0%). PDA stent was associated with shorter intensive care unit (-4.03 days; 95% CI: -5.99 to -2.07, p&lt;0.001; I 2 =66%) length of stay (LOS), hospital LOS (-5.54 days; 95% CI: -9.20 to -1.88, p=0.003; I 2 =78%) and duration of mechanical ventilation (-3.41 days; 95% CI -5.29 to -1.52, p&lt;0.001; I 2 =88%). There were no differences in pulmonary artery growth or hazard of unplanned reinterventions to treat cyanosis between groups. Conclusions: In this large meta-analysis of cyanotic CHD and DDPBF, initial palliation with PDA stent or BTTS demonstrated similar risks of mortality and unplanned reintervention to treat cyanosis. PDA stent was associated with fewer complications and shorter hospital LOS. Given limitations inherent to observational study, this analysis supports the development of a randomized clinical trial in this population.
Clinical Significance of Small PNH-Type Cell Populations in Bone Marrow Failure Syndromes - an Interim Analysis of Japanese Multicentrer Prospective Study -
Authors: Yasutaka Ueda, Kohei Hosokawa, Ken Ishiyama, Hiroyuki Takamori, Yuji Yonemura, Naoshi Obara, Hideyoshi Noji, Kiyoshi Ando, Tsutomu Shichishima, Takayuki Ikezoe, Shigeru Chiba, Haruhiko Ninomiya, Tatsuya Kawaguchi, Jun-ichi Nishimura, Yuzuru Kanakura, Shinji Nakao
Journal: Blood (2021)
NIMG-31. PROPOSED ORIGINS AND PATHWAYS OF DIFFUSE GLIOMAS REVEALED BY LESION COVARIANCE NETWORKS
Authors: Ayan Mandal, Rafael Romero-Garcia, Jakob Seidlitz, Michael Hart, Aaron Alexander-Bloch, John Suckling
Journal: Neuro-Oncology (2021)

Abstract Diffuse gliomas have been hypothesized to originate from neural stem cells in the subventricular zone and develop along previously healthy brain networks. Here, we evaluated these hypotheses by mapping independent sources of glioma localization and determining their relationships with neurogenic niches, genetic markers, and large-scale connectivity networks. Using lesion data from a total of 410 patients with high- and low-grade glioma, we identified – and replicated in an independent sample – three lesion covariance networks (LCNs), which reflect clusters of frequent glioma localization. These three LCNs overlapped with the anterior, posterior, and inferior horns of the lateral ventricles respectively, extending into the frontal, parietal, and temporal cortices. The first LCN, which overlapped with the anterior horn, was associated with low-grade, IDH-mutated/1p19q-codeleted tumors, as well as a neural transcriptomic signature and improved overall survival. Each LCN significantly coincided with multiple structural and functional connectivity networks, with LCN1 bearing an especially strong relationship with brain connectivity, consistent with its neural transcriptomic profile. Finally, we identified subcortical, periventricular structures with functional connectivity patterns to the cortex that significantly matched each LCN. These results build upon prior reports of glioma growth along white matter pathways, as well as evidence for the coordination of glioma stem cell proliferation by neuronal activity. Cumulatively, our findings support a model wherein periventricular brain connectivity guides glioma development from the subventricular zone into distributed brain regions.
Concerts and COVID: can the beat go on?
Authors: Patricia Schlagenhauf, Jeremy Deuel
Journal: The Lancet Infectious Diseases (2021)

time interval for follow-up of 15 days after receiving the second dose was very short.Whether the humoral immune response waned post-vaccination could not be evaluated within such a short period.In February, 2021, Noa and colleagues 8 reported a vaccine efficacy of 46% for BNT162b2 in Israel in a real-world scenario.This waning in vaccine efficacy after 6 months in a fully vaccinated population has been attributed to declining humoral immunity and immune escape due to the delta variant.CVnCoV has been withdrawn from regulatory review by its manufacturer and how it would have performed in the real world will now never be known.Vaccine efficacy could be improved via a heterologous boost regimen using vaccines based on two different platforms; 9,10 Xinxue Liu and colleagues 10 showed that immunogenicity was higher for heterologous schedules of adenovirus vector-based and mRNA-based vaccines compared with homologous prime-boost schedules.Rather than waiting for higher efficacy vaccines or newer vaccines, existing vaccines could be used in combination with vector-based vaccines in a heterologous boost regimen or as a booster dose to enhance vaccine availability in low-income and middle-income countries to help to end the pandemic.We declare no competing interests.
Roadblock: improved annotations do not necessarily translate into new functional insights
Authors: Nicola A. L. Hall, Becky C. Carlyle, Wilfried Haerty, Elizabeth M. Tunbridge
Journal: Genome biology (2021)

The advent of cost-effective high-throughput nucleotide sequencing means that information about the transcriptome is accruing at an exponential rate, rapidly refining our understanding of the diversity of gene products.It is important that these findings are readily accessible to the wider scientific community to maximise their impact.However, there are multiple barriers to their efficient dissemination and their translation into functional insights.Here, we outline how the status quo can result in information becoming siloed and/or ambiguous, using the CACNA1C gene, which encodes a voltage-gated calcium channel, as an example.We highlight three areas that pose potential barriers to effective information transfer and offer suggestions as to how these may be addressed: firstly, a lack of clarity about the strength of the evidence for individual transcripts in current annotations; secondly, limitations to the transfer of information between nucleotide and protein databases; thirdly, challenges relating to the nomenclature used for transcriptional events and RNA modifications, both for genomic researchers and the wider scientific community.