tbuckley/cabot-search huggingface dataset:
<i>Rhoa</i> Mutation Is a Potential Biomarker Associated with Adverse Prognosis and High- Tumor Burden in Patients with Nodal Peripheral Lymphomas with T-Helper Follicular Phenotype (nPTCL-Thf): Data from a Brazilian Retrospective Cohort of Nodal PTCL
Authors: Luis Alberto de Padua Covas Lage, Guilherme Carneiro Barreto, Hebert Fabricio Culler, Jéssica Billar Cavalcanti, Lucas de Oliveira Alves, Luciana Nardinelli, Israel Bendit, Vanderson Rocha, Juliana Pereira
Journal: Blood (2021)
Perceptions on the function of puberty suppression of transgender adolescents who continued or discontinued treatment, their parents, and clinicians
Authors: Lieke J.J.J. Vrouenraets, Martine C. de Vries, Irma M. Hein, Marijn Arnoldussen, Sabine E. Hannema, Annelou L.C. de Vries
Journal: International Journal of Transgender Health (2021)

Purpose: Treatment of transgender adolescents with puberty suppression (PS) was developed to provide time for exploration before pursuing gender affirming medical treatment (GAMT) with irreversible effects. It may also result in a more satisfactory physical outcome for those who continue with GAMT. Despite being the current first choice treatment, little research has examined the function of PS from the perspectives of transgender adolescents, their parents, and clinicians. Insight into the perceived functions of PS will help to adequately support adolescents in their decision-making process and give them the care they need. Methods: Qualitative study using interviews with eight transgender adolescents who proceeded with GAMT after PS ("continuers"), six adolescents who discontinued PS ("discontinuers") and 12 parents, and focus groups with ten clinicians. Results: All informants considered inhibition of development of secondary sex characteristics an important function of PS. Most continuers saw PS as the first step of GAMT. Nevertheless, some were glad that the effects were reversible even if they didn't expect to change their minds. Some discontinuers did experience PS as an expanded diagnostic phase. One continuer used the time on PS to get used to living in the affirmed gender role, and several parents found the time helpful to adapt to their child's new gender role. PS provided clinicians more time for diagnostic assessment. Conclusions: Adolescents, parents and clinicians do not all report the same functions of PS. Although international guidelines emphasize providing time for exploration of gender identity as an important reason for PS, many adolescents nowadays seem to have clear ideas about their gender identity and treatment wishes, and experience PS as the first step of GAMT. For some discontinuers however, PS offered a valued period of exploration. Guidelines could be modified to provide more customized care, taking adolescents' and parents' ideas about the functions of PS into account.
Abstract 14045: Increased Fibrosis and Microvessel Disease in Allograft Endomyocardial Biopsies of Children With Chronic Graft Failure Due to Cardiac Allograft Vasculopathy
Authors: Kae Watanabe, Nicoleta Arva, Jennifer Arzu, Joshua D Robinson, Cynthia K Rigsby, Michael Markl, Nazia Husain
Journal: Circulation (2021)

Introduction: The pathogenesis of chronic graft failure (CGF) in pediatric heart transplant recipients (PHT) is multifactorial and includes cardiac allograft vasculopathy (CAV). Prior research has shown that CGF can present as microvessel disease (MVD) and fibrosis on endomyocardial biopsies (EMB), however, optimal routine surveillance is not established. We analyzed EMB specimens to establish histopathologic findings of CGF represented by PHT with CAV. Hypothesis: PHT recipients with CGF secondary to CAV have increased fibrosis and MVD on EMB. Method: We performed a retrospective case-control study. PHT with moderate to severe (M-S) CAV diagnosed on cardiac catheterization between 2017-2020 were identified. EMB from time of M-S CAV diagnosis (CAV-EMB) was reviewed (excluding those with significant intercurrent rejection) and compared to their EMB prior to any CAV diagnosis (pre-CAV-EMB) and controls that were matched for age at and time since transplant (Tx) . Fibrosis was qualitatively graded on a scale of 0-5 and MVD was scored as number of capillaries with stenotic wall thickening (due to either endothelial cell swelling or medial hypertrophy) per fields of view. Results: Eight PHT with CAV-EMB and pre-CAV-EMB and 8 controls were identified. CAV-EMB group was 2.5 years (IQR: 0.9,8.0) old at time of Tx and 10.6 years post-Tx (8.3,15.5) at EMB. Pre-CAV-EMB was 1.8 years (1.1,2.8) prior to CAV-EMB. In the CAV, pre-CAV, and control groups median fibrosis score was 3.0 (2.0, 3.0) vs 2.0 (2.0, 3.0) vs 1.0 (0, 1.0) (p= 0.001) and MVD score was 2.1 (1.3, 2.9) vs 2.0 (1.6, 2.8) vs 0.5 (0.2, 0.7), respectively (p= 0.007). These were significantly different between pre-CAV-EMB vs controls (fibrosis p=0.003, MVD p=0.007) and CAV-EMB vs controls (fibrosis p=0.001, MVD p=0.005), but not between pre-CAV-EMB vs CAV-EMB. Furthermore, fibrosis and MVD scores were strongly correlated (r=0.78, p&lt;0.001). Conclusion: Histopathological evidence of increased fibrosis and MVD is noted in EMB with CGF secondary to CAV and these findings pre-date angiographic CAV diagnosis. Further studies in larger PHT cohorts are needed to assess time course of fibrosis and MVD to improve surveillance of CAV and CGF.
Abstract 12562: Prasugrel May Be Associated With All-Cause Mortality Benefit in Patients on Chronic Dialysis
Authors: Clayton Davis, Milind Phadnis, Junqiang Dai, Rafia Rasu, Jawahar L Mehta, Nishank Jain
Journal: Circulation (2021)

Introduction: Although prasugrel has been shown to be more effective over other P2Y12 inhibitors (P2Y12-I) in the general population, it remains unclear whether it is also superior in reducing all-cause death in patients on chronic dialysis (ESKD). Methods: This longitudinal analysis included Medicare patients with ESKD on P2Y12-I from the U.S. Renal Data System registry between 2011-2015. Patients were followed from receipt of new prescription until death or censoring. The primary outcome was all-cause death, and the secondary outcome was CV death, as ascertained from the registry. Survival analysis was performed after propensity matching. Results: Our analysis included 44,619 ESKD patients on P2Y12 inhibitors - 95% received clopidogrel (n= 42,523), 3% received prasugrel (n = 1,205), and 2% received ticagrelor (n = 891). During a median follow up of 1 year, there were 2,555 (30.7%), 1,370 (31.1%), and 404 (23.0%) deaths in the prasugrel-clopidogrel, the ticagrelor-clopidogrel, and the prasugrel-ticagrelor matched cohorts, respectively. Similarly, there were 1,266 (15.2%), 667 (15.1%) and 210 (11.9%) CV-deaths in the three cohorts respectively. Prasugrel vs. clopidogrel was associated with reduced risk for death (HR 0.80; 95% CI: 0.70, 0.90). Similar findings were noted when compared to ticagrelor (HR 0.75; 95% CI: 0.57, 0.98). Prasugrel was also associated with a borderline reduced risk for CV-death when compared with clopidogrel (HR 0.85; 95% CI: 0.72, 1.01) and ticagrelor (HR 0.80; 95% CI: 0.60, 1.07). Conclusion: Our findings suggest a benefit in reduction of all-cause death, possibly by reducing CV-death with use of prasugrel over other P2Y12-I in patients on chronic dialysis. Since these results could be limited due to residual confounding, future trials should investigate whether prasugrel is superior to other P2Y12-Is in reducing all-cause death and CV-death among patients on chronic dialysis.
The Molecular Landscape of <i>KMT2A</i>-Rearranged Leukemia from Infancy to Adulthood Reveals Age and Leukemia-Specific Mutational Patterns
Authors: Mattias Pilheden, Ton Falqués, Louise Ahlgren, Helena Sturesson, Michael P Walsh, Guangchun Song, Anders Castor, Cornelis Pronk, Hanne Vibeke Marquart, Birgitte Lausen, Gisela Barbany, Katja Pokrovskaja Tamm, Ullrika Norén-Nyström, Linda Fogelstrand, Olli Lohi, Axel Hyrenius Wittsten, Jinghui Zhang, James R. Downing, Jing Ma, Anna Hagstroem-Andersson
Journal: Blood (2021)
Abstract 10865: Elucidating the Variant-to-Function Relationship for LIPA, a Risk Locus of Coronary Artery Diseases
Authors: Fang Li, Elise Flynn, Chenyi Xue, Yujiao Meng, Ziyi Wang, Xun Wu, Sufang Li, Jian Cui, Jianting Shi, Margot K. Chirikjian, Yizhou Zhu, Annie Rozenblyum, Sophie Shan, Babak Razani, Marit Westerterp, Robert Bauer, Fulai Jin, Yousin Suh, Tuuli Lappalainen, Hanrui Zhang
Journal: Circulation (2021)

Introduction: Genome-wide association studies revealed a robust association between genetic variants at the LIPA (lysosomal acid lipase) locus and coronary artery diseases (CAD). eQTL studies support that the risk alleles of LIPA CAD variants are associated with higher LIPA mRNA and enzyme activity in human monocytes, but not other blood or vascular cells, suggesting that increased myeloid LIPA may confer CAD risk. Herein, we aim to establish the causality of the variant-to-function relationship for the LIPA locus and elucidate how increased myeloid LIPA impact atherosclerosis in vivo. Hypothesis: We hypothesized that causal variants in LIPA lead to increased LIPA expression and enzyme activity in macrophages and myeloid-specific overexpression of Lipa promotes atherosclerosis. Results: We first confirmed that in human monocyte-derived macrophages, LIPA mRNA, protein and enzyme activity are higher in the risk allele carriers of CAD variants. High-resolution HiC revealed an intronic enhancer region showing strong interaction with the LIPA promoter. Within the enhancer region, both rs1320496 and rs1412445 had independent association with CAD and their risk alleles led to increased enhancer activity measured by luciferase assay. Risk allele of rs1320496 also demonstrated increased binding for PU.1, a myeloid-specific transcription factor. To establish how increased myeloid LIPA impact atherosclerosis, we generated myeloid-specific Lipa overexpression mice ( Lipa Tg , Ldlr -/- ). Lipa Tg significantly increased atherosclerotic lesion size without affecting plasma cholesterol level. scRNA-seq analysis showed that Lipa Tg led to reduced lipid-enriched yet increased inflammatory macrophage subsets, and upregulation of genes in chemokine signaling. This is further confirmed by reduced neutral lipid accumulation in both plaque and peritoneal macrophages in Lipa Tg mice. Mechanistically, Lipa Tg led to reduced expression of modified-LDL receptors, increased expression of inflammatory chemokines, and increased circulating IL18 and CXCL2 that likely drive immune cells infiltration during atherosclerosis. Conclusions: We for the first time established that LIPA risks alleles drive increased myeloid LIPA and aggravate atherosclerosis.
EXTH-72. TRANSLATIONAL INVESTIGATION OF TD139 FOR THE TREATMENT OF HIGH-GRADE MENINGIOMA
Authors: Connor Stephenson, Katie Ross, William Vandergrift III, Abhay Varma, Bruce Frankel, Sunil Patel, David Cachia, Scott M Lindhorst, Arabinda Das
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND High-Grade Meningioma (HGM), such as atypical and anaplastic meningiomas, represent a subgroup of meningiomas with histologic and clinical features suggesting aggressive behavior with a penchant for recurrence, even after surgical resection. Here, we postulate that high levels of Galectin-3 (Gal-3) affect the cellular composition and are at the root of the profoundly immunosuppressive tumor microenvironment of HGM. Our study aimed to validate the effect of the Gal-3 inhibitor (TD139) in in vivo. METHODS In vivo MGS2 murine models of HGM were utilized to assess efficacy of treatment with TD139 via intravenous injection. We used ELISA spot, RT-PCR and western blots techniques. MRI and immunohistochemistry -staining methods were used to detect tumor growth in in vivo following TD139 treatments. RESULTS Our results demonstrated a significantly elevated level of Gal-3 in both HGM tissue and serum when compared to non-tumor patients. Furthermore, Epithelial membrane antigen, Ki-67, and Transglutaminase 2 were highly expressed in HGM, whereas the number of observed cytotoxic T-cells in HGM was markedly decreased. When human PBMCs were activated with anti-CD3 (1µg/ml) and anti-CD28 (2µg/ml) antibodies and treated with recombinant Gal-3 protein (500ng/ml) for 96hr, we found reduced expression of T-Box Transcription Factor 21 and RAR Related Orphan Receptor C mRNA with concurrent upregulated expression of GATA Binding protein 3 and Forkhead box P3 mRNA. These findings support the concept that Gal-3 skews the differentiation of CD4+ T cells towards Th2 and Treg cells. In vivo treatment of TD139 (1mg/kg per day for 14 days) showed significant decrease (∼35%) in MGS2 tumor growth in orthotopic allograft model (at Day 41) and increased survival via multiple mechanism. Additionally, we observed an upregulation of CD38 (M1 macrophages) and CD8+ T cells in treated cells. CONCLUSIONS These findings suggest that TD139 may be an effective approach in the treatment of HGM patients.
Supporting NHS staff facing abuse from patients frustrated by long waits for care
Authors: Amit Sinha, Ghulam Abbas, Shabi Ahmad, Ramesh Mehta, Ellen Welch, Ibrahim Bolaji, Arun Baksi
Journal: BMJ (2021)

We are doctors’ associations representing NHS staff and employers. We welcome the concerns about abuse of NHS staff raised by the BMA and other organisations.1 We also wish to emphasise that any form of verbal or physical abuse of health and care staff is completely unacceptable. These distressing incidents should …
Abstract 12265: The Impact of Gestational Age on the Neonatal Electrocardiogram
Authors: Joachim Hartmann, Maria Munk Paerregaard, Jakob Norsk, Adrian Pietersen, Kasper Iversen, Henning Bundgaard, Alex H Christensen
Journal: Circulation (2021)

Objective: The interpretation of the neonatal electrocardiogram (ECG) is challenging and reflects the underlying developing physiology. The possible effects of gestational age (GA) on the ECG has never been evaluated in a large general population study. We aimed at investigating the effect of GA on neonatal electrocardiographic parameters and create GA-specific reference values. Methods: The Copenhagen Baby Heart Study is a prospective, general population study that offered cardiac evaluation of neonates. ECGs and echocardiograms were obtained and systematically analyzed. GA, weight, height, and other baseline variables were registered. Results: We included 16,462 neonates (52% boys) with normal echocardiograms. Median postnatal age was 11 days (range 0-30 days) and median GA was 281 days (range 238-301 days). Analyzing the ECG parameters as a function of GA we found a significant effect of GA on heart rate (HR), PR-, QRS-, and QT intervals, QRS axis, and maximum amplitudes of R-waves in V1/V6 and maximum S-wave in V6 (all p&lt;0.01). The largest percentual effect of GA was on HR, QRS axis, and R-wave in V1. Boys had longer PR- and QRS intervals and more right-shifted QRS axis within multiple GA-intervals (all p&lt;0.01, Figure: Box plots of ECG parameters subdivided by gestational age intervals and sex ). The effect of GA generally persisted after adjustment for HR, weight, postnatal age, and sex. In addition, when comparing HR, PR interval, QRS axis, QRS duration, uncorrected QT interval, and QTcBazett subdivided into postnatal age intervals, we found a significant effect of gestational age on most ECG parameters within these postnatal age intervals. Conclusion: Gestational age was associated with significant differences in multiple neonatal ECG parameters and the effect generally persisted after multifactorial adjustment. Our results indicate a direct effect of GA on the developing neonatal cardiac conduction system. Use of GA-specific reference values may be useful.
Detection of PAX5 Overexpression By RNA-Seq for B-Cell Lineage Detection in Acute Lymphocytic Leukemia
Authors: Abhisek Ghosal, Francys Alarcon, Samuel Koo, Soo Jin Kang, Archana Ramesh, Tibor Gyuris, Segun C Jung, Brad B Thomas, Rudy Fabunan, Christophe Magnan, Hyunjun Nam, Paris Petersen, Fernando Lopez-Diaz, Ryan Bender, Sally Agersborg, Fei Ye, Vincent Funari
Journal: Blood (2021)
Abstract 11210: Trends in Invasive Treatment of Patients Hospitalized with Acute Decompensated Aortic Stenosis and Cardiogenic Shock
Authors: Ahmed Elkaryoni, David J Cohen, John J Lopez, Chetan P Huded, Kevin F Kennedy, Suzanne V Arnold
Journal: Circulation (2021)

Background: Prior to 2012, balloon aortic valvuloplasty (BAV) was the only potential intervention for patients with decompensated aortic stenosis (AS) and cardiogenic shock. Emergent transcatheter aortic valve replacement (TAVR) is now an option and has shown acceptable outcomes compared with elective TAVR. We explored how treatment patterns for AS and cardiogenic shock have shifted since TAVR was introduced. Methods: We identified hospitalizations of patients with AS and cardiogenic shock within the National Readmissions Database, the proportion treated with BAV or TAVR, and in-hospital mortality over the study period by treatment. Due to challenges in determining the timing of surgery vs. onset of shock, patients who underwent surgical AVR were excluded. Results: From 2010-2018, there were 17,297 hospitalizations for AS and cardiogenic shock, which have increased over time (Figure A legend). The proportion of hospitalizations where either BAV or TAVR was used has also increased (BAV 3.9%-&gt;7.1%; TAVR 3.8%-&gt;10.1%; Figure A). In-hospital mortality was very high but has significantly decreased over time for all treatment strategies (no invasive: 46.9%-&gt;35.5%; BAV: 45.7%-&gt;34.2%; TAVR 18.8%-&gt;8.9%; Figure B), with much lower mortality rates the TAVR group at all time points. Compared with BAV, patients treated with TAVR were less likely to require mechanical ventilation (TAVR 34.6% vs BAV 49.1%) or mechanical circulatory support (TAVR 19.9% vs BAV 30.6%; p&lt;0.001 for both). Age and comorbidity burden were similar among groups. Conclusions: Over the past decade, hospitalizations for AS and cardiogenic shock have increased as has the proportion in which BAV or TAVR are emergently used. Although in-hospital mortality has declined over time, it remains very high, particularly among patients treated with BAV or those without intervention. This is likely in part due to the lower severity of cardiogenic shock of the patients treated with TAVR.
Abstract 6993: Electrical Storm in Patients Without an Implantable Cardioverter-Defibrillator is Associated With Higher In-Hospital All-Cause Mortality
Authors: Cameron Incognito, Joshua Parker, Jeffrey Hedley, Venu Menon, Oussama Wazni, John Rickard, Wai Hong Tang
Journal: Circulation (2021)

Introduction: Most data regarding electrical storm (ES) is retrospective from implantable cardioverter-defibrillator (ICD) interrogation, little is known about outcomes in those without an ICD. Objective: Primary outcomes include all-cause in-hospital and 6-month mortality of ES comparing patients with and without ICDs. Secondary outcomes include in-hospital complications. We hypothesize that ES patients without ICDs will have a worse short term prognosis with higher rates of in-hospital complications. Methods: Retrospective single center study including all patients admitted to the coronary ICU with ES between April 2014 - 2020. ES was defined as ≥ 3 isolated sustained ventricular arrhythmias (VA) or ICD therapies within 24 hours. Results: Of 214 patients admitted with ES, 37 did not have an ICD. For those with an ICD, the mean time from implantation to ES was 1101.1 ± 928.4 days. Those without ICD were less likely to be male (70.3% vs. 85.9%; p = 0.029), have known coronary artery disease (37.8% vs. 55.9%; p=0.049), or prior VA (5.4% vs. 84.7%; p&lt;0.0001). Those without ICDs had a higher ejection fraction (39% ± 16% vs. 30% ± 12%; p=0.002), lower PAINESD risk score (14.3 ± 7.3 vs. 17.5 ± 6.2; p=0.004), and were more likely to present with out-of-hospital cardiac arrest (43.2% vs. 5.1%; RR 8.5, 95% CI 4.1 - 17.8; p&lt;0.001). Those without ICDs were more likely to develop complications including SCAI stage D-E cardiogenic shock (RR 2.58, 95% CI 1.9 - 3.5; p&lt;0.001), multiorgan failure (RR 3.78, 95% CI 2.1 - 6.7; p&lt;0.0001), and in-hospital cardiac arrest (RR 4.10, 95% CI 2.7 - 6.2; p&lt;0.0001). Those without ICDs were more likely to have polymorphic ventricular tachycardia (PMVT; 62.2% vs. 23.2%; RR 2.68, 95% CI 1.9 - 3.9; p&lt;0.0001) or ventricular fibrillation (VF; 56.8% vs. 24.9%; RR 2.28, 95% CI 1.6 - 3.3; p=0.0003). In-hospital all-cause (29.7% vs. 13.0%; RR 2.29, 95% CI 1.2 - 4.3; p=0.023) and VA-induced (27.0% vs. 11.3%; RR 2.39, 95% CI 1.2 - 4.7; p=0.019) mortality was higher in patients without ICDs, although 6-month mortality was not significant (Log Rank X 2 1.24; p=0.27). Conclusions: Patients without ICDs were more likely to present following out-of-hospital cardiac arrest with underlying PMVT or VF morphologies. They had higher in-hospital complications and mortality.
Abstract 11481: Non-Invasive Electrocardiographic Mapping of the Human Heart Through a Novel 'Cardiac Magnetic Resonance-Electrocardiographic Imaging' Solution for High Throughput Use
Authors: Matthew Webber, George Joy, Debbie falconer, Xuyuan Tao, Iain Pierce, James Moon, Alun Hughes, Pier Lambiase, Yoram Rudy, Michele Orini, Gabriella Captur
Journal: Circulation (2021)

Background: Electrocardiographic imaging (ECGI) non-invasively maps the heart’s electrical activity through multiple leads on the body surface. Cardiologists need a safe, quick, affordable and re-usable ECGI method to apply to patients undergoing cardiovascular magnetic resonance (CMR), but current solutions are not suitable for high-throughput use. We developed a CMR-ECGI vest for high-throughput use and report the first in vivo results. Methods: We designed and fabricated the CMR-ECGI vest from cotton, containing 256 square (2x2cm) dry textile electrodes each tagged with a localisation marker ( Fig 1 ). Body surface potentials were recorded and co-registered with heart-torso geometries obtained from CMR ( Fig 2 ). Epicardial unipolar potentials were reconstructed using state-of-the-art ECGI algorithms (YR Lab) and local activation and repolarization times were computed using standard methods. Results: Ten healthy volunteers with normal resting ECGs were recruited (34±10years; 60% male). A recumbent 5-minute ECGI recording was performed (preparation time ~15 minutes for montage and doffing). 3 Tesla CMR provided baseline parameters (left ventricular ejection fraction [LVEF] 75±5%, right ventricular [RV] EF 57±5%, native T1 1275±23ms, T2 42±1ms) and showed no clinically significant late gadolinium enhancement. ECGI showed that the sites of earliest and latest activation were the basal RV ( Fig 3A ) and basal-lateral LV respectively ( Fig 3B ). Total duration of epicardial activation and repolarization was 73.3±8.9ms and 195±35.2ms, respectively. These epicardial activation patterns in health are in line with previously described ECGI data. Conclusions: We have developed a re-usable and high-throughput CMR-ECGI solution that is safe and well-tolerated in vivo . This technology is now available for large-scale clinical research use to provide deeper insights into the pathophysiology of arrhythmogenesis, through seamless integration with CMR.