tbuckley/cabot-search huggingface dataset:
Abstract 10840: Direct Admission versus Inter-Hospital Transfer of Hospitalized Patients with Acute Myocardial Infarction in China: Findings from the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome Project
Authors: Danqing Hu, Yongchen Hao, Jun Liu, Na Yang, Yong Huo, Sidney C Smith, Junbo Ge, Gregg Fonarow, Louise Morgan, Chang-Sheng Ma, Han Yaling, Dong Zhao, Jing Liu
Journal: Circulation (2021)

Introduction: Although percutaneous coronary intervention (PCI) is the preferred reperfusion strategy for AMI, a substantial proportion of patients initially arrive at non-PCI hospitals. The impact of direct admission to a PCI-capable hospital and inter-hospital transfer on prognosis of AMI with relatively long ischemia time in real-world practice is still debated. We aimed to compare the in-hospital outcomes associated with direct admission versus inter-hospital transfer of hospitalized patients with AMI in China. Methods: From November 2014 to December 2019, 94,623 patients with AMI were enrolled from 159 tertiary hospitals and 82 secondary hospitals in 30 provinces in China in the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome (CCC-ACS) Project. Patients were divided into those directly admitted or inter-hospital transferred to a PCI hospital. Associations of direct admission versus inter-hospital transfer with in-hospital major adverse cardiovascular events (MACE) were examined by multivariable Cox regression, propensity score matching (PSM), and inverse probability of treatment weighting (IPTW) analysis. Results: Among the 94,623 patients, 53,653 (56.7%) were directly admitted to PCI hospitals, and 40,970 (43.3%) were inter-hospital transferred. Compared with inter-hospital transfer, direct admission was associated with a shorter time from symptom onset to reperfusion (6.0h vs.9.8h for STEMI and 54.4h vs.83.3h for NSTEMI), and higher rates of reperfusion for STEMI (63.4% vs. 50.7%) and timely PCI for NSTEMI (41.1% vs. 34.7%). No significant associations were found between direct admission relative to inter-hospital transfer and the risk of in-hospital MACE in Cox regression (HRs [95%CIs] were 1.17 [0.95-1.42] for STEMI and 0.81 [0.55-1.19] for NSTEMI), in PSM (1.17 [0.94-1.45] for STEMI and 0.79 [0.49-1.27] for NSTEMI), and in IPTW analysis (1.22 [0.95-1.58] for STEMI and 0.87 [0.55-1.37] for NSTEMI). Conclusions: There was no significant difference in the risk of in-hospital MACE between directly admitted and transferred patients with AMI in China. Therefore, when direct admission is not feasible, timely transfer to PCI-capable hospitals maybe an alternative in real-world practice.
Abstract 11518: Association of Individual- and Neighborhood-Level Determinants Across Young Adulthood with Racial Disparity in Premature Cardiovascular Disease: The Coronary Artery Risk Development in Young Adults Study
Authors: Nilay S Shah, Hongyan Ning, Lucia Petito, Kiarri N Kershaw, Michael Bancks, Reis P Jared, Stephen Sidney, Jamal S Rana, David R Jacobs, Catarina I KIEFE, Mercedes Carnethon, Don Lloyd-jones, Norrina Allen, Sadiya Khan
Journal: Circulation (2021)

Introduction: Black adults experience higher rates of cardiovascular disease (CVD) compared with White adults, particularly across young adulthood. To identify intervention targets to reduce disparities, we quantified the contribution of individual- and neighborhood-level determinants across young adulthood to Black-White differences in incidence of premature CVD. Methods: In Black and White adults (baseline age 18-30 years) in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, the associations of clinical, lifestyle, psychosocial, socioeconomic, and neighborhood determinants with racial disparities in incident CVD were evaluated with sex-stratified Cox proportional hazards models adjusted for time-updated risk factors. Percent reduction in the ß estimate (log-hazard ratio [HR]) for race quantified the contribution of each risk factor group, individually and combined, to incident CVD racial disparities. Results: In 1707 Black and 2001 White young adults followed for median 33.9 (IQR 33.7-34.0) years, Black adults had higher risk of incident CVD than White adults (Figure). The fully adjusted model yielded significant attenuation of the disparity: HR 1.22 (0.68-2.21) for Black vs. White women, HR 1.42 (0.91-2.23) for Black vs. White men. In women, clinical risk factors were associated with the largest percent reduction in the ß estimate (83%) for race. In men, socioeconomic, lifestyle and clinical risk factors were each associated with significant percent reductions in ß estimates (45%, 37%, and 28%, respectively). Conclusions: In CARDIA, risk for premature CVD was no longer significantly higher in Black vs. White adults after adjustment for upstream determinants across multiple domains. The largest contribution to racial disparities was from clinical factors in women and socioeconomic factors in men. These findings may inform earlier-life interventions to reduce disparities in premature CVD.
Coordinated missplicing of TMEM14C and ABCB7 causes ring sideroblast formation in SF3B1-mutant myelodysplastic syndrome
Authors: Courtnee A. Clough, Joseph Pangallo, Martina Sarchi, Janine O. Ilagan, Khrystyna North, Rochelle Bergantinos, Massiel C. Stolla, Jasmine Naru, Patrick Nugent, Eunhee Kim, Derek L. Stirewalt, Arvind R. Subramaniam, Omar Abdel-Wahab, Janis L. Abkowitz, Robert K. Bradley, Sergei Doulatov
Journal: Blood (2021)

SF3B1 splicing factor mutations are near-universally found in myelodysplastic syndromes (MDS) with ring sideroblasts (RS), a clonal hematopoietic disorder characterized by abnormal erythroid cells with iron-loaded mitochondria. Despite this remarkably strong genotype-to-phenotype correlation, the mechanism by which mutant SF3B1 dysregulates iron metabolism to cause RS remains unclear due to an absence of physiological models of RS formation. Here, we report an induced pluripotent stem cell model of SF3B1-mutant MDS that for the first time recapitulates robust RS formation during in vitro erythroid differentiation. Mutant SF3B1 induces missplicing of ∼100 genes throughout erythroid differentiation, including proposed RS driver genes TMEM14C, PPOX, and ABCB7. All 3 missplicing events reduce protein expression, notably occurring via 5' UTR alteration, and reduced translation efficiency for TMEM14C. Functional rescue of TMEM14C and ABCB7, but not the non-rate-limiting enzyme PPOX, markedly decreased RS, and their combined rescue nearly abolished RS formation. Our study demonstrates that coordinated missplicing of mitochondrial transporters TMEM14C and ABCB7 by mutant SF3B1 sequesters iron in mitochondria, causing RS formation.
Project Stella: Development and Preclinical Assessment of FOLR1-Directed Chimeric Antigen Receptor T Cells in CBF2AT3-GLIS2/RAM AML
Authors: Quy Le, Sommer Castro, Thao T. Tang, Cynthia Nourigat-Mckay, LaKeisha Perkins, Tiffany A. Hylkema, Laura Pardo, Jenny L. Smith, Amanda R. Leonti, Rhonda E. Ries, Lisa Eidenschink Brodersen, Michael R. Loken, Soheil Meshinchi
Journal: Blood (2021)
Abstract 102: Time-of-intake Regulates Glucocorticoid Pharmacology Of Cardiac Bioenergetics
Authors: Mattia Quattrocelli, Michelle Wintzinger, Karen Miz
Journal: Circulation Research (2021)

Glucocorticoid steroids are circadian regulators of energy balance. However, the specific direct effects of glucocorticoids on heart metabolism remain unresolved. Moreover, the impact of circadian time-of-intake on glucocorticoid pharmacology is still unknown. Here, we investigated whether circadian time of exposure gates the effects of synthetic glucocorticoids on heart bioenergetics. We compared the effects of diurnal versus nocturnal glucocorticoids in heart tissue and mitochondria from wildtype mice, controlling the subjective circadian time of drug injection. To avoid interferences from other tissues, we developed an ex vivo system to interrogate the mitochondrial respiratory capacity rate (state III/state IV) in isolated hearts. We found that diurnal but not nocturnal pulse of the glucocorticoid prednisone increased the mitochondrial respiratory capacity rate in heart. This correlated with circadian-restricted effects on mitochondrial abundance. This was remarkable as it contrasts the circadian fluctuations of endogenous glucocorticoids. Using transgenic mice with inducible cardiac-specific gene knockout, we found that the bioenergetic effects of diurnal-restricted prednisone were dependent on the glucocorticoid receptor and its co-factor Kruppel-like factor 15. Considering the bioenergetic decline that hallmarks the aging heart, we asked whether these circadian-gated effects were applicable to aged mice. We therefore treated 24 months-old mice for 12 weeks with a diurnal-restricted regimen of prednisone. Compared to vehicle, diurnal prednisone increased mitochondrial respiration along with NAD + and ATP content in aged hearts. Moreover, lipidomic profiling of myocardial tissue showed that the vast majority of lipids were downregulated after treatment, including triacylglycerols, suggesting a functional coupling between lipid utilization and mitochondrial oxidation in treated hearts. We also found that diurnal-restricted prednisone rescued bioenergetics and improved function in diabetic hearts from db/db mice. In summary, our data indicate that glucocorticoids regulate cardiac bioenergetics according to circadian-time of intake, supporting a role for chrono-pharmacology in aged and diabetic hearts.
Neutralizing Antibody Testing in Patients With Multiple Myeloma Following COVID-19 Vaccination
Authors: Evangelos Terpos, S. Vincent Rajkumar, Nelson Leung
Journal: JAMA Oncology (2021)

This Viewpoint discusses the benefits of titer testing for anti–SARS-CoV-2 antibodies in patients with severe immunosuppression, including patients with multiple myeloma, following COVID-19 vaccination.
Abstract 13775: Determinants and Prognostic Implications of Improved and Non-Improved Left Ventricular Ejection Fraction in Chronic Heart Failure
Authors: Peter Nordbeck, Dan Liu, kai hu
Journal: Circulation (2021)

Introduction: Clinical implications of improvement in left ventricular ejection fraction (LV EF) are not well investigated. Hypothesis: To evaluate determinants and prognostic value of longitudinal changes in ejection fraction among chronic heart failure (HF) patients with reduced EF (HFrEF, EF ≤40%) and to determine risk factors of adverse outcomes among HFrEF patients with or without improve EF Methods: 573 consecutive hospitalized HFrEF patients (aged 66±13years, male 75.6%) with baseline (BL) and follow-up (FUP) echocardiography examinations (interval at least ≥12 months) were included. Patients were divided into improved EF (iEF, ≥5% increase in FUP_EF, n=335) or non-improved EF (niEF, &lt;5% increase in FUP_EF, n=238). Primary endpoints included all-cause death, cardiovascular (CV) death, and CV rehospitalization. Results: Lower BL_EF (≤30%, OR 2.70, P&lt;0.001), smaller LV end-diastolic dimension (&lt;65mm, OR 2.62, P&lt;0.001), and absence of coronary artery disease (CAD, OR 1.73, P=0.006) independently associated with EF improvement in this cohort. During follow-up (median 27 months), overall mortality (20.3% vs. 38.2%), CV mortality (9.0% vs. 19.7%), CV rehospitalization rate (25.4% vs. 45.0%), and HF rehospitalization rate (8.4% vs. 20.6%) were all significantly lower in iEF group than in niEF group (all P&lt;0.001). After adjustment for age, sex, and other confounders associated with CV events, iEF remained independently associated with lower overall mortality (HR 0.50, P&lt;0.001), CV mortality (HR 0.43, P&lt;0.001), CV and HF rehospitalization (HR 0.44 and 0.34, P&lt;0.001). For HFrEF patients with iEF, elevated C-reaction protein and NT-proBNP levels were related to increased risk of CV events. For HFrEF patients with niEF, elevated NT-proBNP, reduced longitudinal systolic function, and enlarged RV were independently related to increased risk of CV events. Conclusions: Improvement in LV EF during follow-up is a powerful determinant of reduced overall mortality, CV mortality, and CV rehospitalization in HFrEF patients independent of age, sex and other identified risk factors.
Abstract P450: Single-cell Transcriptomic Profiling Of The Type-2 Diabetic Mouse Heart
Authors: Charles D Cohen, Miles J De Blasio, Gabriella E Farrugia, Malathi S Dona, Ian Hsu, Darnel Prakoso, Crisdion Krstevski, David M Nash, Mandy Li, Taylah L Gaynor, Minh Deo, Grant R Drummond, Rebecca H Ritchie, Alexander R Pinto
Journal: Circulation Research (2021)

Background: Diabetes is associated with a significantly elevated risk of heart failure. However, the precise cellular and molecular protagonists underpinning the development of heart failure in diabetes remains unclear. Moreover, very little is known, of how disparate non-myocyte populations of the heart contribute to diabetic cardiomyopathy. Methodology: To address this gap in knowledge, we conducted single-cell transcriptomic analysis of non-myocytes from heart ventricles of spontaneous type-2 diabetic ( db/db ) male mice. Findings were corroborated by flow cytometry, histology and computational analysis of publically available bulk RNA sequencing datasets from alternative diabetes models. Results: Single-cell transcriptomic analysis of db/db mouse hearts revealed a concerted diabetes-induced cellular response driving cardiac pathological remodelling. We identified diabetes-induced up-regulation of pathways contributing to known features of diabetic cardiomyopathy such as dysregulation of vascular homeostasis and lipid metabolism, as well as augmented inflammation, in cell specific contexts. We also identified unexpected characteristics in the diabetic heart, including impaired protein folding and cellular trafficking within lymphatic vessels. Using flow cytometry and histology, increase in inflammatory cells, such as Ly6C hi monocytes, shifts in macrophage phenotype, and increased abundances of fibroblasts and endocardial cells were confirmed. Finally, integration of single-cell transcriptomic data with publically available bulk-RNA sequencing datasets from alternative diabetes models revealed shared hallmarks of diabetic heart and disease context-dependent features. Conclusions: Together, this work offers a new perspective for understanding the cellular and molecular mediators of diabetes-induced cardiac pathology. Targeting these mediators may offer new therapeutic avenues to address the cardiac complications associated with diabetes.
Abstract 6932: Safety of Left Atrial Appendage Closure on Uninterrupted Warfarin Therapy
Authors: David Yoo, Spencer Gibson, Matthew J Price, Andrea Natale, Rodney Horton, Vivek Y Reddy, Shephal Doshi, David R Holmes, Saibal Kar, douglas gibson
Journal: Circulation (2021)

Introduction: Left atrial appendage closure (LAAC) device for stroke prevention is a safe and effective alternative to oral anticoagulation (OAC) in patients with atrial fibrillation (AF). The safety of performing LAAC on uninterrupted warfarin (UW) compared to interrupted warfarin (IW) is currently unknown. Hypothesis: Complication rates of performing LAAC on UW vs. IW will be similar. Methods: We reviewed the data from the second half of PROTECT-AF trial, PREVAIL trial, CAP and CAP2 registries. Patients were categorized to the UW group if INR on the day of the procedure was ≥2 and to the IW group if INR was &lt;2. Procedural complications within 7 days of LAAC were reviewed. An association between complications and AC strategy was analyzed. Results: Data from 1580 patients were reviewed and 294 patients (18.6%) received LAAC on UW. The UW group had a mean INR of 2.4±0.4 and IW group had a mean INR of 1.3±0.3. There were several differences in baseline characteristics: lower BMI in the UW group (28.6±5.3 vs 29.5±6.0, p=0.01), fewer patients with hypertension in the UW group (87.1% vs 91.1%, p=0.04), lower HAS-BLED score in the UW group (2.0±1.0 vs 2.1±1.0, p&lt;0.01), and more patients with persistent AF in the UW group (37.1% vs 26.4%, p&lt;0.01). Overall, there were no significant differences in total or individual complication rates between the two groups (UW 5.1% vs IW 6.1%, p=0.59). Although not statistically significant, lower event rates were noted in the UW group for the following: stroke (0% vs 0.3%, p&gt;0.99), pericardial effusion requiring intervention (1.7% vs 1.8%, p&gt;0.99), pseudoaneurysm (0% vs 0.4%, p=0.59), hematoma (0% vs 0.2%, p&gt;0.99), and device embolism (0% vs 0.2%, p=1.0). The UW group had statistically insignificant higher events rates of AV fistula (0.3% vs 0%, p=0.19) and major bleeding requiring transfusion (1% vs 0.5%, p=0.38). In addition, there was no significant difference in periprocedural ischemic stroke (0% vs 0.3%, p&gt;0.99). Conclusion: In this retrospective analysis, no significant difference was observed in procedural complication rates when performing LAAC on UW vs. IW. These results suggest that LAAC can be safely performed without interruption of OAC.
Abstract 13543: Impaired Stroke Volume Response During Exercise in Patients With Heart Failure With Preserved Ejection Fraction (HFpEF): The Role of Dynamic Starling Mechanisms
Authors: Seamus B Hughes, Denis J Wakeham, James P Macnamara, Bryce Balmain, Christopher Hearon, Tony Babb, Benjamin D Levine, Satyam Sarma
Journal: Circulation (2021)

Introduction: Impaired stroke volume (SV) response during exercise is common in HFpEF. The regulation of SV during low intensity exercise is dependent on end-diastolic volume (EDV) reserve from a compliant left ventricle (LV). The Dynamic Starling Mechanism (DSM) quantifies beat-by-beat modulation of SV by respiratory-mediated changes in LV filling pressure and provides insight into the relationship between changes in LV compliance and SV response during exercise. We hypothesized low SV reserve during exercise would track with greater impairments in DSM gain in HFpEF patients. Methods: 11 HFpEF patients (68 ± 6 years; 7 females) were studied at rest and during 20 Watts of upright cycling and separated into higher or lower SV reserve (direct Fick) groups based on median SV response (&gt; vs ≤ 20% increase). DSM was quantified by transfer function (input/output frequency) analyses of beat-by-beat changes in pulmonary artery diastolic pressure (PAD, right heart catheterization) and SV (modelflow from radial arterial line waveform). Due to the small group size, magnitude of differences (i.e. effect size) between conditions and groups is assessed via Hedges’ g . Results: HFpEF patients with low SV reserve had blunted increases in SV compared to higher SV group patients (Δ 2 vs 31 ml, g = -2.0; Table). Compared to higher SV reserve, the lower SV reserve group exhibited a moderately greater increase in the power spectral density (PSD) of PAD ( g = 0.4) and decrease in PSD-SV ( g = 0.5) from rest to 20W. While both groups decreased DSM gain from rest to exercise, the lower SV reserve group had a greater decline (Δ -1.37 vs -0.61 ml/mmHg, g = -1.2). Conclusion: Lower SV reserve in patients with HFpEF is associated with impaired DSM gain during exercise. The lower gain was a function of increases in PAD PSD and decreases in SV PSD suggesting lower LV compliance and lower EDV reserve during exercise. Impaired DSM may explain low SV response and contribute to exercise limitations in patients with HFpEF.
Standardizing the Diagnostic and Therapeutic Approach to Newly Diagnosed Children with ITP: An ITP Consortium of North America (ICON) Quality Improvement Initiative
Authors: Alexander W. Rankin, Sherif M. Badawy, Carolyn M. Bennett, Taylah Buissereth, Kristen Campbell, Hannah Elkus, Rachael F. Grace, Allison Remiker, Stacey Rifkin, Taizo A. Nakano
Journal: Blood (2021)
Abstract 10516: Identification of a PCSK9-LDLR Disruptor Macrocycle with <i>in vivo</i> Function
Authors: Margaret E Brousseau, Kevin B Clairmont, Glen Spraggon, Alec N Flyer, Andrei A Golosov, Philipp Grosche, JÃ©rÃ´me AndrÃ©, Shari Caplan, Guanjing Chen, Li Fan, Raphael Gattlen, Alexander Koch, Ian Lewis, Jingzhou Li, Eugene Liu, Danuta Lubicka, Andreas Marzinzik, Katsumasa Nakajima, David Nettleton, Johannes Ottl, Meihui Pan, Tajesh Patel, Stephanie Pickett, Jennifer Poirier, Patrick C Reid, Xavier Pelle, Vanitha Subramanian, Victoria Vera, Mei Xu, Lihua Yang, Qing Yang, jinghua yu, Guoming Zhu, Lauren G Monovich
Journal: Circulation (2021)

Elevated LDL-C is a major risk factor for atherosclerotic cardiovascular disease, the leading cause of death worldwide. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has pronounced effects on LDL-C levels via its modulation of hepatic LDL receptors (LDLR), the main pathway for cholesterol removal from the circulation. The epidermal growth factor precursor homology domain A (EGF-A) of the LDLR serves as a primary contact with PCSK9 via a flat interface, presenting a challenge for identifying small molecule PCSK9-LDLR disruptors. We employed an affinity-based screen of 10 13 in vitro -translated macrocyclic peptides to identify high affinity PCSK9 ligands that utilize a novel, induced-fit pocket and partially disrupt the PCSK9-LDLR interaction (Hit 1 - PCSK9-LDLR FRET, IC 50 2 nM, A max 41%). Structure-based design led to 13 PCSK9i , a molecule with enhanced in vitro function (PCSK9-LDLR FRET, IC 50 2 nM, A max 78%) and pharmacokinetic properties suitable for in vivo evaluation. To determine if 13 PCSK9i ’s functional activity in vitro would translate in vivo , C57BL/6 mice were dosed with vehicle or 13 PCSK9i via subcutaneous injection twice-daily for 3 days, and blood and liver were collected for the measurement of plasma total cholesterol (TC) and hepatic LDLR density. A PCSK9 antibody was included as a positive control. As illustrated in the figure, 13 PCSK9i increased hepatic LDLR density in a dose-dependent manner. Despite being 1/100 th its size, 13 PCSK9i (MW = 1.65 kDa) increased hepatic LDLR density on par with a PCSK9 antibody (MW = 144 kDa). Plasma TC levels were significantly reduced versus vehicle in all 13 PCSK9i dose groups, with similar reductions noted in the 13 PCSK9i 30 mg/kg and PCSK9 antibody groups (44% and 48%, respectively). In summary, 13 PCSK9i breaks new ground with its previously undescribed allosteric mechanism and, in turn, as the smallest molecule identified to date with in vivo PCSK9-LDLR disruptor function.
TAMI-21. TUMOR-ASSOCIATED MICROGLIA GUIDE GBM INFILTRATION VIA PLEXIN-B2
Authors: Sangjo Kang, Anirudh Sattiraju, Yuhuan Li, Shalaka Wahane, Theo Hanna, Roland Friedel, Hongyan Zou
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is the most common malignant primary brain tumor. The nature of invasiveness of GBM makes complete surgical resection difficult. However, how GBM cells achieve wide infiltration in the brain is poorly understood. Microglia, the resident immune cells in the brain can support GBM growth and invasion, but the underlying mechanisms remain elusive. Here, we show that microglia are activated in a wide field away from tumor boundaries, ahead of tumor cell infiltration. Invading GBM cells are in close contact with microglia, progressively aligned with one another in the direction of tumor invasion. Moreover, ECM is also aligned with the infiltrating tumor and microglia, which may serve as invasion tracks in the brain. Mechanistically, we demonstrate that microglia direct cellular alignment and ECM remodeling in the invasion tracks through an axon guidance receptor Plexin-B2. Myeloid-specific ablation of Plexin-B2 perturbs microglia and tumor cell alignment, microglia migration, ECM organization, and GBM invasiveness. Together, our data reveal a hitherto under-appreciated role of microglia in providing directional cues for GBM invasion through physical interaction and alignment of ECM and tumor cells, thus providing new insights and novel molecular targets in curbing GBM invasion.