tbuckley/cabot-search huggingface dataset:
Abstract 10988: Prevalence and Outcomes of Cardiac Amyloidosis in All-Comer Referrals for Bone Scintigraphy
Authors: Christian Nitsche, Katharina Mascherbauer, Tim Wollenweber, Matthias Koschutnik, Carolina Dona, Varius Dannenberg, Felix Hofer, Andreas Kammerlander, Tatjana Traub-Weidinger, Georg Goliasch, Christian Hengstenberg, Marcus Hacker, Julia MASCHERBAUER
Journal: Circulation (2021)

Introduction: The prevalence of cardiac amyloidosis (CA) in the general population as well as prognostic implications remain poorly understood. Hypothesis: We aimed to identify CA prevalence and outcomes in bone scintigraphy referrals. Methods: Between 2010 and 2020, consecutive all-comers undergoing 99mtechnetium-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) bone scintigraphy were included retrospectively. CA was defined as positive cardiac tracer uptake (Perugini grade-1: subclinical CA; grade-2/3: clinical CA). All-cause mortality, cardiovascular (CV) death and hospitalization for heart failure (HHF) served as endpoints. Results: 17387 scans from 11527 subjects (61±16 y/o, 63.0% female, 73.6% cancer) were analyzed. Prevalence of CA was 3.3% (n=376/11527; grade-1: 1.8%, grade-2/3: 1.5%), and was higher among cardiac vs. non-cardiac referrals (18.2% vs. 1.7%). In 4 individuals with &gt;1 scan, progression from subclinical to clinical CA was observed. Cardiac biopsy revealed underlying transthyretin CA in 3 grade-1 patients. After a median of 6 years, clinical event rates were: 29.4% mortality, 2.6% CV death, and 1.5% HHF, all independently predicted by CA. Overall, adverse outcomes were driven by clinical CA (clinical vs. no CA, mortality: adjusted hazard ratio [AHR] 1.46 [95% confidence interval 1.12-1.90]; CV death: AHR 2.34 [1.49-3.68]; HHF: AHR 2.25 [1.51-3.37]). In non-cancer patients, subclinical CA had equally increased mortality to clinical CA (log-rank, p &gt;0.05), presumably due to longer observation/life expectancy. Conclusions: CA was identified in a substantial number of consecutive DPD referrals and associated with adverse outcomes. Subclinical (grade-1) progressed to clinical (grade-2/3) CA at follow-up and both had similarly increased mortality among non-cancer patients. Thus, in grade-1, clarification of the underlying pathology using myocardial biopsy is indicated to enable timely targeted therapy.
Abstract P509: Novel Protein Kinase C Epsilon Inhibitor Attenuates Uncoupled Endothelial Nitric Oxide Synthase And Vascular Endothelial Dysfunction
Authors: Brogan Galbreath, Arjun Nair, John Ringe, Ian T Madison, Tameka C Dean, Alexandra Lopez, Qian Chen, Lindon Young
Journal: Circulation Research (2021)

Endothelial nitric oxide synthase (eNOS) uncoupling reduces nitric oxide (NO) production when tetrahydrobiopterin (BH 4 ) is oxidized to dihydrobiopterin (BH 2 ), resulting in endothelial dysfunction and leukocyte adherence. Renovascular damage following shockwave lithotripsy (SWL) may occur via the potentiation of this mechanism. We aim to modulate uncoupled eNOS activity with myristoylated protein kinase C epsilon inhibitor ( myr -PKCε–; N- myr -EAVSLKPT) and activator ( myr -PKCε+; N- myr -HDAPIGYD). We hypothesize that myr -PKCε– with uncoupled eNOS (i.e., bound to BH 2 ) should reduce leukocyte-endothelial interactions in postcapillary venules and H 2 O 2 levels after SWL. Myr -PKCε+ should promote similar effects when eNOS is coupled (i.e., bound to BH 4 ). Mesenteric venules of anesthetized male SD rats (300g) were superfused for 120 min with 100 μM BH 2 and test solutions (Krebs’ buffer, 10 μM myr -PKCε+, or 10 μM myr -PKCε–) with or without 100 μM BH 4 . Leukocyte activity was evaluated via intravital microscopy. In separate SD rats, SWL was performed on left kidneys (16 kV, 500 shocks at 60 shocks/min and at 120 shocks/min). Then, normal saline or test solution cocktail ( myr -PKCε+ [0.9 mg/kg]/ myr -PKCε- [0.8 mg/kg] with BH 2 [2mg/kg] or BH 4 [0.8 mg/kg]) was given i.v. NO or H 2 O 2 levels were measured with 100 μm microsensors in left renal veins at baseline, end of SWL, and 5-min intervals for 30 min post-SWL. Data were analyzed using ANOVA Student-Newman-Keuls test. BH 2 -induced leukocyte rolling, adherence, and transmigration were significantly increased by myr -PKCε+ ( n = 6) and attenuated with myr- PKCε– ( n = 5) compared to control (n=5) at 120 min (p&lt;0.01). Following SWL, all treatments except myr -PKCε+ with BH 2 significantly reduced H 2 O 2 ( n = 5, p &lt; .01) and increased NO levels ( n = 5, p &lt; .01) compared to control. NO and H 2 O 2 levels following administration of myr -PKCε+ with BH 2 were similar to SWL control. Results suggest that myr -PKCε– attenuates uncoupled eNOS activity and H 2 O 2 release in rat renal veins, after SWL. Promoting coupled eNOS activity with BH 4 yields similar results. Promoting eNOS coupling with BH 4 or inhibiting uncoupled eNOS with myr- PKCε– attenuates oxidative stress and endothelial dysfunction following SWL and BH 2 -induced inflammation.
Abstract 13816: Real-World Impella Complications in Acute Myocardial Infarction Complicated by Cardiogenic Shock: A Meta-Analysis
Authors: Monica L Tung, Connor O'Brien, Liviu Klein, Richard Cheng
Journal: Circulation (2021)

Introduction: Mechanical support devices such as the Impella are increasingly used to support patients with acute myocardial infarction complicated by cardiogenic shock (AMICS) with observational evidence suggesting earlier use improves survival. However, complications associated with Impella including significant bleeding, hemolysis, vascular injury, limb ischemia and stroke are recognized but poorly quantified in this population outside of a small randomized experience. Methods: We performed a systematic MEDLINE search to select studies where Impella devices were used in AMICS. Pooled estimates of complications and study heterogeneity were calculated. Results: We included ten studies published between 2014 and 2020 with a total of 1037 patients. The median duration of Impella support ranged from 24 hours to 4.6 days. Overall survival to discharge or 30 days was 50% (range 36 % - 66%). Bleeding requiring transfusion occurred in 19.6% (95% confidence interval [CI], 15.2% - 24.8%) and hemolysis in 12.0% (95% CI, 9.0 -15.9%). Both analyses had significant study heterogeneity. Less common were vascular complications requiring surgery in 6.3% (95% CI, 2.8 - 10.2%), bleeding requiring intervention occurred in 4.8% (95% CI, 3.3% - 6.8%), limb ischemia in 4.3% (95% CI, 2.7% - 6.6%) and stroke 2.8% (95% CI, 1.8-4.3%). Two studies did not find significant differences in complication rates comparing Impella use before or after PCI. Conclusions: Use of Impella in AMICS is associated with significant morbidity. Real-world complication rates are however reassuringly similar to rates in the randomized experience. With increasing early use of Impella devices in acute MI complicated by CS, clinicians should be aware of these risks to allow for implant optimization, appropriate patient selection, and surveillance for complications. Further investigations are needed to understand clinical correlates of these complication rates.
NIMG-54. RADIOMIC FEATURES FROM LESION HABITAT PREDICT RESPONSE TO COMBINATION OF NIVOLUMAB AND BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA: A FEASIBILITY STUDY
Authors: Ruchika Verma, Yasmeen Rauf, Ipsa Yadav, Volodymyr Statsevych, Jonathan Chen, Wendi Evanoff, Manmeet Ahluwalia, Pallavi Tiwari
Journal: Neuro-Oncology (2021)

Abstract PURPOSE The use of immunotherapy in glioblastoma management is under active investigation. Glioblastomas are “cold” tumors, meaning that they have inactivated or fewer tumor infiltrative lymphocytes in addition to substantial tumor necrosis, attributing to their poor response to immunotherapy. A significant challenge is the apriori identification of Glioblastoma patients who will respond favorably to immunotherapy. In this work, we evaluated the ability of computerized MRI-based quantitative features (radiomics) extracted from the lesion habitat (including enhancing lesion, necrosis, and peritumoral hyperintensities) to predict response and progression-free survival (PFS) in recurrent GBM patients treated with combination of Nivolumab and Bevacizumab. METHODS Immunotherapy response assessment in neuro-oncology (iRANO) criteria along with PFS were used to analyze n=50 patients enrolled in a randomized clinical trial where patients received Nivolumab with either standard or low dose Bevacizumab. These patients were assessed to see if they had complete response, partial response, stable disease (i.e. responders, n=31), or disease progression (i.e. non-responders, n=19). Lesion habitat constituting necrotic core, enhancing tumor, and edema were delineated by expert radiologist on Gd-T1w, T2w and FLAIR MRI scans. COLIAGE radiomic features from each of the delineated regions were selected using minimum redundancy maximum relevance (mRMR) via cross-validation, to segregate non-responder patients from responders. A multivariable cox proportional hazard model was used to predict survival (PFS). RESULTS CoLlAGe correlation, sum average, and sum variance features (capture local heterogeneity) from the lesion habitat, were found to segregate non-responder patients from responders with an accuracy of 86%, followed by 80% using features from peritumoral hyperintensities and 78% from enhancing tumor. In our survival analysis, C-index of 0.688 was obtained using features from the entire lesion habitat, followed by peritumoral hyperintensities (0.675) and enhancing tumor (0.656). CONCLUSION Radiomic features from the lesion habitat may predict response to combination of Nivolumab and Bevacizumab in recurrent Glioblastomas.
Abstract 11969: Endocardial Viability Ratio is Associated With Survival in Advanced Heart Failure Patients
Authors: Olivia Ondigi, Kenneth C Bilchick, Patrick Stafford, Christian Selinksi, Kara Harrison, Jay Jalenak, Jarred Strickling, Kajal P Shah, Olivia Blazek, Hunter Mwansa, Khadijah Breathett, Amber Johnson, Nishaki Mehta, Younghoon Kwon, Nishtha Sodhi, Sula Mazimba
Journal: Circulation (2021)

Introduction: Myocardial oxygen supply is an important determinant of cardiac function. The Endocardial Viability Ratio (EVR), a measure of myocardial oxygen supply-demand balance, is calculated as a ratio of the diastolic pressure time index [(diastolic blood pressure - left ventricular end diastolic pressure) x (60 sec/heart rate - 0.2 sec)] and tension time index [systolic pressure x 0.2 sec]. We hypothesized that low EVR would be associated with adverse events in patients with heart failure (HF). Methods: EVR was calculated in the invasive arm of the ESCAPE trial in patients with available discharge blood pressure, pulmonary arterial wedge pressure, and heart rate as the ratio of the diastolic pressure time index (a measure of coronary blood supply) and tension time index (a measure of myocardial oxygen demand). Kaplan-Meier analysis and Cox proportional hazards regression was used to assess associations with EVR and a composite death endpoint including cardiac transplantation and left ventricular assist device implantation. Results: Among 143 patients (56.9 ± 13.3 years, 30.1% female), the median EVR was 1.168 (IQR 0.923-1.398). Survival during 180 days of follow-up was worse in patients with EVR below the median (p=0.0004) (Figure panel 1A). Among the 10 patients with EVR &lt; 0.7, considered to represent subendocardial ischemia, 50% reached this endpoint within 100 days (p=0.01 versus remaining patients) (Figure 1B). An increase of 0.1 in EVR was associated with an 18% relative risk reduction for this endpoint (HR 0.82, 95% CI 0.74-0.91, p=0.0002), while an increase of 0.5 in EVR was associated with a 62% relative risk reduction (HR 0.38, 95% CI 0.22-0.64, p=0.002). Conclusion: Decreased EVR, a marker of myocardial oxygen supply, is associated with adverse events in advanced HF patients. Further studies on the prognostic utility of EVR in HF are needed.
Abstract 12149: Prognostic Benefit of Heart Rate Reduction of Hospitalized Heart Failure Patients is Different Between Atrial Fibrillation and Sinus Rhythm
Authors: Makoto Kishihara, Kentaro Jujo, Takuma Takada, Takuro Abe, Shota Shirotani, Ayano Yoshida, Shonosuke Watanabe, Takehiro Hata, Yuichiro Minami, Yutaka Terajima, Nobuhisa Hagiwara
Journal: Circulation (2021)

Introduction: Heart rate (HR) reduction is a key strategy for improving clinical prognosis of patients with heart failure (HF) regardless of presenting atrial fibrillation (AF) or sinus rhythm (SR). However, the prognostic impact of HR reduction during hospitalization is still unclear. Hypothesis: The degree of HR reduction during hospitalization between HF patients with AF and SR differently contributes to the prognosis after discharge. Methods: This observational study included 1,930 hospitalized HF patients who were discharged alive. After excluding patients who were implanted pacing devices, those presenting paroxysmal AF, and those with missing data of HR, 1,137 patients were ultimately analyzed. Of them, 456 patients presented AF and 681 presented SR at admission. Change of HR was defined as the difference between HR at admission and discharge. We evaluated the association between in-hospital HR change and the incidence of a composite of cardiovascular death after discharge and HF re-hospitalization in patients with AF and SR, respectively. Results: During the observation period (median 528 (IQR: 135-736) days), the composite endpoint developed in 169 (37%) and 187 (27%) patients with AF and SR, respectively. The ROC curves for the composite endpoint showed the cut-off values of HR reduction were 0 bpm and 28 bpm in patients with AF and SR, respectively. Kaplan-Meier analysis showed a significantly lower incidence of a composite endpoint in patients who achieved HR reduction greater than the cut-off value in both groups (log-rank test: p&lt;0.05). HR reduction greater than the cut-off value was still an independent predictor for a composite endpoint in patients with AF after adjusting age, sex, HR at admission and LVEF (hazard ratio: 0.65, 95% confidence interval: 0.45-0.96). However, this finding was not observed in patients with SR (hazard ratio: 0.81, 95% confidence interval: 0.50-1.33). Conclusions: The ideal HR reduction level during hospitalization was different between AF and SR. Target HR reduction in HF patients with AF could lead to better clinical outcomes, but the benefit is limited in patients with SR.
Abstract 9905: A Deep Neural Network Detects Elevated Right Ventricular Systolic Pressure Using Data Captured from a Digital Stethoscope
Authors: Ling Guo, Urvi Tiwari, Emileigh Lastowski, John S Chorba, Suleman Ilyas, Caroline Currie, Gaurav Choudhary, John Maidens, Adam Saltman
Journal: Circulation (2021)

Introduction: Pulmonary hypertension (PH) and elevated peak right ventricular systolic pressure (RVSP) are associated with poor outcomes in a number of cardiopulmonary diseases. PH often goes undiagnosed because right heart catheterization is invasive and expensive. RVSP measured by echocardiography has been used with some success as a non-invasive proxy, yet it is still expensive and operator-dependent, resulting in inadequate and/or delayed diagnosis of PH. We developed and evaluated an artificial intelligence (AI) tool to detect elevated RVSP, using phonocardiogram (PCG) recorded from digital stethoscopes. Methods: 6,062 15-second PCG recordings were taken using the Eko CORE and DUO digital stethoscopes from 797 patients with corresponding echocardiogram-measured RVSP. These, plus an additional 169,160 unlabelled PCG recordings with no corresponding echocardiogram, were used to train a deep convolutional neural network to identify an RVSP above 40mmHg. Mel spectrograms from the PCGs were randomly cropped into 5s segments and used to train the network. The networks were evaluated via 5-fold cross validation with the folds split by patient to prevent leakage between training and test sets. Results: Across the 5 cross validation folds, the model produced an average area under the ROC curve of 0.79 (range 0.76 - 0.85), sensitivity of 0.73 (range 0.67 - 0.80) and specificity of 0.74 (range 0.64 - 0.82) at detecting a peak RVSP &gt;= 40 mmHg. Incorporating patient age, gender and body mass index into the network did not improve performance. Conclusions: We demonstrated the ability of an AI tool to detect elevated peak RVSP using PCG. Use of a digital stethoscope with this tool has the potential to be a low-cost, rapid and minimally invasive screen for elevated RVSP in a point-of-care setting, to increase early detection of PH.
Abstract 13834: The Effect of Dapagliflozin on Serum Uric Acid in Heart Failure With Reduced Ejection Fraction: Insights From DAPA-HF
Authors: Kieran F Docherty, Paul WELSH, David Morrow, Pardeep S Jhund, Naveed Sattar, Ann Hammarstedt, Anna Maria Langkilde, Marc S Sabatine, John J McMurray
Journal: Circulation (2021)

Introduction: Elevated serum uric acid (sUA) levels are common in patients with heart failure and reduced ejection fraction (HFrEF). sUA, in part, reflects the use of diuretics, and higher sUA is associated with a higher risk of adverse outcomes in HFrEF. We examined the effect of dapagliflozin on sUA, and the efficacy of dapagliflozin according to baseline sUA, in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial. Methods: Patients in NYHA class II-IV with a LVEF ≤40%, and elevated plasma NT-proBNP were included in DAPA-HF. Key exclusions included hypotension, systolic BP &lt;95 mmHg, and eGFR &lt;30 ml/min/1.73m 2 . The primary outcome was a composite of worsening HF (hospitalization for HF or an urgent HF visit requiring iv therapy) or CV death. sUA was measured pre-randomization and at 52 weeks. The effect of dapagliflozin on sUA was assessed using a linear regression model adjusted for baseline value. The efficacy of dapagliflozin was assessed using baseline sUA as a continuous variable. Results: Of the 4744 randomized patients, 3119 (65.7%) had sUA measured at baseline, with a mean of 6.10±1.70 (median 5.9, IQR 4.9-7.1) mg/dL. The placebo-corrected change in sUA at 52 weeks was -0.83 mg/dL (95% CI -0.93, -0.74); p&lt;0.001.In adjusted models including diuretic use/dose, higher sUA was associated with an elevated risk of the primary endpoint; hazard ratio 1.09 (1.03-1.14) per 1mg/dL sUA; p=0.0015 Figure, Panel A .The benefit of dapagliflozin, compared with placebo, on the primary endpoint was consistent across the range of sUA studied ( Figure, Panel B ; P interaction=0.77). Conclusions: In DAPA-HF, higher sUA was associated with worse outcomes and dapagliflozin significantly reduced sUA. The efficacy of dapagliflozin on outcomes was consistent across the range of sUA studied.
Abstract 14496: The Role of ACE Inhibitors and Angiotensin Receptor Blockers in Cryoballoon Ablation Outcomes for Paroxysmal Atrial Fibrillation
Authors: Ibragim Al-seykal, Abhishek Bose, Parag A Chevli, Ajay K Mishra, Zeba Hashmath, Gregory Berberian, Jerzy Januszkiewicz, Qiying Dai, Douglas Laidlaw
Journal: Circulation (2021)

Background: Cryoballoon ablation (CBA) is recommended for patients with paroxysmal atrial fibrillation (AF) refractory to anti-arrhythmic drugs. However, only 70% of patients benefit from an initial CBA. There is a growing evidence that pretreatment with angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blocker (ARB) decreases recurrence of AF post ablation, particularly in non-paroxysmal AF undergoing radiofrequency ablation. The role of ACE-I and ARB in patients with paroxysmal AF in CBA remains unknown. We decided to investigate the role of ACE-I and ARB in preventing recurrence of atrial arrhythmias (AA) following CBA for paroxysmal AF. Methods: We followed 103 patients (Age 60.6 ± 9.1, 29% women) with paroxysmal AF undergoing CBA for one year post procedure. Recurrence was assessed by documented AA on EKG or any form of long-term cardiac rhythm monitoring. A multivariable cox proportional hazard model was used to assess if ACE-I or ARB treatment predicted risk of AA recurrence. Results: After a one year follow up, 19 (18.4%) participants developed recurrence of AA. Use of ACE-I or ARB therapy was noted in the study population. Patients on ACE-I/ARB had a greater prevalence of hypertension and coronary artery disease. On a multivariate model adjusted for baseline demographics and risk factors for AF, ACEI or ARB therapy did not prevent recurrence of AA following CBA (Table, p=0.72). Similarly, on Kaplan-Meier analysis pretreatment with ACE-I/ARB did not predict time to first recurrence of AA (Figure, p=0.2173). Conclusion: In our study population pre-ablation treatment with an ACE-I or an ARB had no influence on the recurrence of AA following CBA for paroxysmal AF.
DDRE-12. DETERMINATION OF TOTAL AND UNBOUND LEVELS OF A POTENT INHIBITOR OF FIBROBLAST GROWTH FACTOR RECEPTOR, INFIGRATINIB, IN HUMAN PLASMA, CEREBROSPINAL FLUID AND BRAIN TUMOR BY A VALIDATED LC-MS/MS ASSAY
Authors: Tigran Margaryan, Nader Sanai, Artak Tovmasyan
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Infigratinib is an orally available potent inhibitor of fibroblast growth factor receptor (FGFR) under investigation in a Phase 0 clinical trial for recurrent high-grade gliomas harboring oncogenic FGFR mutation or translocation (NCT04424966). Here, we report on our development and validation of an LC-MS/MS method for determination of total and unbound levels of infigratinib in human plasma, cerebrospinal fluid (CSF) and glioblastoma tissue. METHODS Infigratinib was extracted from human plasma, CSF and glioblastoma homogenate samples by protein precipitation with methanol. Unbound fractions of infigratinib in plasma and brain tissues were determined by equilibrium dialysis. Validation was performed using Sciex ExionLC UHPLC system coupled with Sciex QTRAP 6500+ MS/MS detector using positive electrospray ionization mode. The method was validated according to FDA guidelines and CAP/CLIA regulations. RESULTS The method was validated for 0.2-1000 nmol/L concentration range using plasma as matrix for all biospecimens. The analytical separation was optimized on Phenomenex Kinetex™ F5 column with total run time of 3.5 min using isocratic mode. Maximum coefficient of variation for intra- and inter-day precision was 12.7% and the accuracy was within 88.5-115.0% in all matrixes. The analyte is stable in plasma for at least 19 hours at room temperature (RT). Plasma stability at -20°C was demonstrated for at least 119 days. Stability of stock and working solutions was demonstrated for at least 15 hours (RT) and 60 days (2-8°C). The unbound fraction of infigratinib in pooled human plasma and brain were determined to be 0.01. CONCLUSIONS A sensitive and rapid bioanalytical method is successfully developed and validated to quantify total and unbound infigratinib levels in human plasma, CSF and glioblastoma tissue. The method is presently employed to evaluate plasma pharmacokinetics and CNS penetration of infigratinib in recurrent glioblastoma patients in an ongoing Phase 0 clinical trial.
The eyes have it: getting the gist of covid-19 transmission
Authors: Will Stahl-Timmins
Journal: BMJ (2021)

A new interactive graphic, published by <i>The BMJ</i>, is designed to help people to decide how best to protect themselves and others from covid-19. Will Stahl-Timmins explains why data visualisation can help us understand complex problems, and what inspired him and his co-authors to create this graphic