tbuckley/cabot-search huggingface dataset:
uPAR<sup>+</sup> extracellular vesicles: a robust biomarker of resistance to checkpoint inhibitor immunotherapy in metastatic melanoma patients
Authors: Letizia Porcelli, Michele Guida, Simona De Summa, Roberta Di Fonte, Ivana De Risi, Marianna Garofoli, Mariapia Caputo, Antonio Negri, Sabino Strippoli, Simona Serratì, Amalia Azzariti
Journal: Journal for ImmunoTherapy of Cancer (2021)

Emerging evidence has highlighted the importance of extracellular vesicle (EV)-based biomarkers of resistance to immunotherapy with checkpoint inhibitors in metastatic melanoma. Considering the tumor-promoting implications of urokinase-type plasminogen activator receptor (uPAR) signaling, this study aimed to assess uPAR expression in the plasma-derived EVs of patients with metastatic melanoma to determine its potential correlation with clinical outcomes.Blood samples from 71 patients with metastatic melanoma were collected before initiating immunotherapy. Tumor-derived and immune cell-derived EVs were isolated and analyzed to assess the relative percentage of uPAR+ EVs. The associations between uPAR and clinical outcomes, sex, BRAF status, baseline lactate dehydrogenase levels and number of metastatic sites were assessed.Responders had a significantly lower percentage of tumor-derived, dendritic cell (DC)-derived and CD8+ T cell-derived uPAR +EVs at baseline than non-responders. The Kaplan-Meier survival curves for the uPAR+EV quartiles indicated that higher levels of melanoma-derived uPAR+ EVs were strongly correlated with poorer progression-free survival (p<0.0001) and overall survival (p<0.0001). We also found a statistically significant correlation between lower levels of uPAR+ EVs from both CD8+ T cells and DCs and better survival.Our results indicate that higher levels of tumor-derived, DC-derived and CD8+ T cell-derived uPAR+ EVs in non-responders may represent a new biomarker of innate resistance to immunotherapy with checkpoint inhibitors. Moreover, uPAR+ EVs represent a new potential target for future therapeutic approaches.
Exercise for Frail, Elderly Patients with Acute Heart Failure — A Strong Step Forward
Authors: Stefan D. Anker, Andrew J.S. Coats
Journal: New England Journal of Medicine (2021)

Exercise rehabilitation has a long history in the management of chronic heart failure, with the first randomized trial of exercise training dating back to 19901 — and by the late 1990s, it had become an integral part of therapy.2 There is solid evidence from multiple trials and meta-analyses that exercise training improves exercise capacity and reduces symptoms in patients with stable heart failure. However, trial data showing a reduction in the risk of hospitalization or death in patients with heart failure who participated in exercise training are lacking, although the results from a large trial, HF-ACTION (Heart Failure: A Controlled . . .
Abstract 16660: Gender Disparities in the Presentation, Management and Outcomes of Patients With Acute Coronary Syndrome: Insights From the Acute Coronary Syndrome Quality Improvement in Kerala (ACS QUIK) Trial
Authors: Haitham Khraishah, Sun Young Jeong, barrak alahmad, Abdulhamied Alfaddagh, Njambi Mathenge, Mohamad B Kassab, Dhaval S KOLTE, Mazen Albaghdadi
Journal: Circulation (2020)

Introduction: Despite the increasing interest in sex differences in acute coronary syndrome (ACS) presentation, management, and outcomes in high-income countries, reports on such differences from low- and middle-income countries (LMICs) are limited. Limited resources in LMICs may worsen health disparities experienced by women and vulnerable populations. Methods: Using ACS QUIK trial database, we examined sex-differences in terms of baseline characteristics, management received, and relevant clinical outcomes of 21,374 patients presenting with ACS. The main outcomes were the rates of in-hospital and 30-day composite of death, reinfarction, stroke, and major bleeding. We fitted log Poisson multivariate random effects models to obtain the relative risks comparing females to males. We used random intercepts for different hospitals and centers as the clustering variable. Effect measure modification by baseline variables was examined by restricting the analysis to each category and comparing the effect estimates for females to males. Results: A total of 5,191 (24.3%) patients were women. Compared to men, women presenting with ACS were older (65±12 vs 58±12 years; p &lt; 0.001), more likely to have hypertension (61.2% vs 42.4%; p &lt; 0.001), and diabetes mellitus (53.5% vs 41.4%; p &lt; 0.001). After symptom onset, women tended to present later to the hospital (medians, 300 vs 238 mins; p &lt; 0.001) and had higher Killip class on presentation (17.8% vs 12.3%; p &lt; 0.001). Women presenting with STEMI were less likely to receive primary PCI (45.9% vs 49.8% of men, p &lt;0.001) and had longer median door-to-balloon times (medians, 90 vs 80 mins for men; p &lt;0.001). Compared to men, women were 53% more likely to experience in-hospital MACE (adjusted RR = 1.53; 95% CI, 1.32-1.77; p&lt;0.001), and 39% higher risk of 30-day MACE (adjusted RR = 1.39; 95% CI, 1.65-2.07, p &lt;0.001). Conclusion: In summary, our study confirms a higher CVD risk profile, delayed presentation, suboptimal medical care in women presenting with ACS in Kerala, India. Women were also found to have higher in-hospital and 30-day MACE, even after adjustment for potential confounders.
What should define a SARS-CoV-2 “breakthrough” infection?
Authors: John S. Schieffelin, Elizabeth B. Norton, Jay K. Kolls
Journal: Journal of Clinical Investigation (2021)

Recently, there have been several reports of SARS-CoV-2 "breakthrough" infections that have occurred in recipients of the FDA-approved SARS-CoV-2 vaccines (1).These reports have the potential to undermine public confidence in the efficacy of these vaccines.Moreover, the use of the term "breakthrough" infections implies that the virus broke through a protective barrier provided by the vaccine.But is this what happened in these cases?In most cases, the answer is no, and this answer lies in the fundamental understanding of the mucosal immune system throughout the respiratory tract: the upper respiratory tract and the lower respiratory tract.The current vaccines prevent COVID-19, by definition a lower respiratory tract illness, in greater than 90% of recipients (2-5).Recent studies of fully vaccinated individuals monitored by routine nasal testing have shown marked reductions, but not a complete absence, of SARS-CoV-2-positive tests (6-9).We believe it is a mistake to think that these vaccines will prevent nasal (upper airway) infection.This inference is based on the current routes of immunization.
Abstract P214: Ideal Cardiovascular Health And Progression Of Extra-coronary Calcification In The Multi-ethnic Study Of Atherosclerosis
Authors: Oluseye Ogunmoroti, Olatokunbo Osibogun, Lena Mathews, Olumuyiwa A Esuruoso, Chiadi E Ndumele, Victor Okunrintemi, Gregory L Burke, Roger S Blumenthal, Matthew J Budoff, Erin D Michos
Journal: Circulation (2021)

Background: Ideal cardiovascular health (CVH) is associated with a lower incidence of cardiovascular disease (CVD). Extra-coronary calcification (ECC) – measured at the aortic valve (AVC), mitral annulus (MAC), ascending thoracic aorta (ATAC) and descending thoracic aortic (DTAC) – is an indicator of systemic atherosclerosis. However, the association between ideal CVH and ECC is unknown. This study examined whether favorable CVH was associated with a lower risk of ECC. Methods: We analyzed data from 6,504 men and women aged 45-84 years from MESA, a multi-ethnic cohort free of CVD at baseline. Extra-coronary calcification [AVC, MAC, ATAC and DTAC] was measured by non-contrast cardiac CT scan at baseline and after an average of 2.4 years. Prevalent and incident ECC were defined as an Agatston score &gt;0. Each CVH metric (smoking, physical activity, body mass index, diet, blood pressure, total cholesterol and blood glucose) was scored 0-2 points, with 2 indicating “ideal”, 1 “intermediate” and 0 “poor”. The maximum CVH score attainable ranged from 0-14 points (inadequate score: 0-8; average: 9-10; optimal: 11-14). We used Poisson regression and linear mixed-effect models to examine the association between CVH and ECC adjusted for age, sex, race/ethnicity, education, income, health insurance and study site. Results: The mean (SD) age of participants was 62 (10) years, 53% were women, 39% White, 12% Chinese American, 26% Black and 22% Hispanic. Optimal and average CVH scores were associated with a lower prevalence and incidence of ECC as well as lower ECC extent at baseline compared to inadequate scores (Table). In addition, optimal and average CVH scores were associated with less ECC progression at 2 years although the associations were only significant for MAC and DTAC. Conclusion: In this multi-ethnic cohort, favorable CVH was associated with a lower risk of developing extra-coronary atherosclerosis. These findings underscore the importance of primordial prevention as an intervention to reduce the burden of CVD.
Abstract 16082: Machine Learning to Improve Left Ventricular Scar Quantification in Hypertrophic Cardiomyopathy Patients
Authors: Zeinab N Ghaziani, Jesse Sun, Raymond H Chan, Harry Rakowski, Martin S Maron, Ethan J Rowin, BO WANG, Wendy Tsang
Journal: Circulation (2020)

Introduction: Accurate and reproducible scar quantification of late gadolinium enhancement (LGE) images from cardiac magnetic resonance imaging (CMR) is important in risk stratifying hypertrophic cardiomyopathy (HCM) patients. Previous machine learning algorithms for CMR LGE quantification deployed three-dimensional convolutional neural network (CNN) architecture, which required image cropping and custom graphic processing units (GPUs) to function, thus limiting their general applicability. We aim to develop a deep two-dimensional (2D) CNN model that contours the left ventricle (LV) endo- and epicardial borders and quantifies LGE. Hypothesis: We hypothesize that a deep 2D CNN model, which uses commercially available GPUs, could be used to efficiently and accurately contour LV endo- and epicardial borders and quantify CMR LGE in HCM patients. Methods: We retrospectively studied 296 HCM patients (2423 images) from the University Health Network (Toronto, Canada) and Tufts Medical Center (Boston, USA). LGE images were manually segmented by an expert reader. Scar was defined as 5 standard deviations higher than the mean of the annotated normal region pixels. A 2D U-net CNN variant was used to train a model on 80% of the datasets. Testing was performed on the remaining 20%. We applied a 5-folds cross validation algorithm for training to improve model robustness. Model performance was assessed using the Dice Similarity Coefficient (DSC). Results: We were able to develop a deep learning model that could successfully perform both LV segmentation and scar quantification using a generally available GPU card. Our algorithm did not require image cropping and processed one image every 60 milliseconds. DSC scores averaged across the 5-folds was excellent at 0.89+0.22 for the endocardium and 0.81+0.17 for the epicardium, and good at 0.57+0.31 for scar. Conclusions: Using novel 2D CNN methods, we have successfully developed an automatic algorithm that rapidly provides LV endo- and epicardial contours and scar quantification on LGE CMR images that is superior to previously published studies. Unlike previous algorithms, our program does not require the use of custom CPUs or image cropping, potentially allowing it to be integrated into routine clinical practice.
Musculoskeletal manifestations of childhood cancer and differential diagnosis with juvenile idiopathic arthritis (ONCOREUM): a multicentre, cross-sectional study
Authors: Adele Civino, Giovanni Alighieri, Eleonora Prete, Anna Maria Caroleo, Silvia Magni-Manzoni, Luciana Vinti, Micol Romano, Nicola Santoro, Giovanni Filocamo, Tamara Belotti, Francesca Santarelli, Chiara Gorio, Francesca Ricci, Antonella Colombini, Serena Pastore, Simone Cesaro, Patrizia Barone, Federico Verzegnassi, Alma Nunzia Olivieri, Monica Ficara, Angela Miniaci, Giovanna Russo, Romina Gallizzi, Roberta Pericoli, Luciana Breda, Rossella Mura, Rosa Anna Podda, Daniela Onofrillo, Bianca Lattanzi, Elisa Tirtei, Maria Cristina Maggio, Raffaela De Santis, Rita Consolini, Annalisa Arlotta, Francesco La Torre, Chiara Mainardi, Maria Antonietta Pelagatti, Elisa Coassin, Ilaria Capolsini, Roberta Burnelli, Assunta Tornesello, Francesca Soscia, Alessandro De Fanti, Donato Rigante, Cristina Pizzato, Carmela De Fusco, Massimo Eraldo Abate, Andrea Roncadori, Elisa Rossi, Giulia Stabile, Andrea Biondi, Loredana Lepore, Valentino Conter, Roberto Rondelli, Andrea Pession, Angelo Ravelli
Journal: The Lancet Rheumatology (2021)
Abstract 14771: Obstructive Sleep Apnea is Associated With Cardiac Dysfunction in Children With Congenital Heart Disease
Authors: Daniel Combs, Vanessa Fernandez, brent j barber, Wayne J Morgan, Chiu-Hsieh Hsu, Jennifer Andrews, Sairam Parthasarathy MD, Scott E Klewer, Michael D Seckeler
Journal: Circulation (2020)

Introduction: Obstructive sleep apnea (OSA) is associated with cardiac dysfunction in children without congenital heart disease (CHD). Children with CHD are at increased risk for OSA and may be susceptible to further cardiovascular consequences due to OSA but the extent and nature of such cardiovascular effects of OSA are unknown. Methods: Children (6-17 years old) with corrected CHD without current cyanosis or Down syndrome were recruited from pediatric cardiology clinic. Home sleep tests were done to determine the presence and severity of OSA. OSA was defined as an obstructive apnea hypopnea index (oAHI) ≥1. Mild OSA was defined as an oAHI of ≥1 to &lt;5 and moderate OSA was defined as an oAHI of ≥5 to &lt;10. Standard clinically indicated echocardiograms were performed in clinic. Echocardiographic findings were compared between children with CHD with and without comorbid OSA using t-tests, Wilcoxon-sign rank tests as well as linear or logistic regression as appropriate. Results: Thirty-two children had sleep study and echocardiographic data available. OSA was present in 18 children (56%). OSA was mild in 89% and moderate in 11% of cases. There were no significant differences in age, body mass index, CHD severity, gender or ethnicity between children with and without OSA. Children with OSA had larger height-indexed right ventricular end-diastolic diameter (RVDi) compared to those without OSA (median 1.35, 95% CI 1.09, 1.56 vs. 1.21, 95% CI 1.01, 1.57; p=0.04). Children with moderate OSA had a reduced left ventricular shortening fraction compared to both those with mild OSA and no OSA (30.0 ± 6.1% vs. 38.7 ± 4.4%; p=0.009 and 39.2 ± 3.6%; p=0.007, respectively). Children with moderate OSA had increased left ventricular end-systolic diameter compared to those with mild OSA and no OSA (3.4 ± 0.4 cm vs. 2.5 ± 0.4; p=0.007 and 2.4 ± 0.5; p=0.001, respectively). Children with an RVDi above the median were seven times more likely to have OSA than those with an RVDi below the median (odds ratio 6.9.; 95% CI 1.3, 35; p=0.02). Conclusions: OSA is associated with changes in cardiac morphology and reduced contractility in children with CHD. Additionally, the presence of right ventricular dilation may suggest the need for OSA evaluation in children with CHD.
Impact of smoking on the development of idiopathic pulmonary fibrosis: results from a nationwide population-based cohort study
Authors: Won Bae, Chang-Hoon Lee, Jinwoo Lee, Young Whan Kim, Kyungdo Han, Sun Mi Choi
Journal: Thorax (2021)

Smoking has been considered an important risk factor for idiopathic pulmonary fibrosis (IPF) incidence. However, there are no population-based large-scale studies demonstrating the effects of smoking on the development of IPF. We aimed to evaluate the effect of smoking on IPF development using a nationwide population-based cohort.Using the Korean National Health Information Database, we enrolled individuals who had participated in the health check-up service between 2009 and 2012. Participants having a prior diagnosis of IPF were excluded. The history of smoking status and quantity was collected by a questionnaire. We identified all cases of incident IPF through 2016 on the basis of ICD-10 codes for IPF and medical claims. Cox proportional hazards models were used to calculate the adjusted HR (aHR) of the development of IPF.A total of 25 113 individuals (0.11%) with incident IPF were identified out of 23 242 836 participants registered in the database. The risk of IPF was significantly higher in current and former smokers than in never smokers, with an aHR of 1.66 (95% CI 1.61 to 1.72) and 1.42 (95% CI 1.37 to 1.48), respectively. Current smokers had a higher risk of IPF than former smokers (aHR 1.17, 95% CI 1.13 to 1.21). The risk of IPF development increased as the smoking intensity and duration increased.Smoking significantly increased the risk of IPF development. Current smokers had a higher risk of IPF than former smokers. A dose-response relationship was observed between smoking and the development of IPF.
Abstract 17390: Maternal and Fetal Cardiovascular Adaptations to Pregnancy and Outcomes in Mothers With Cardiac Disease - A Magnetic Resonance Imaging Study
Authors: Brahmdeep S Saini, Robin Ducas, Yamamura Kenichiro, Mike Seed, Rachel M Wald
Journal: Circulation (2020)

Introduction: Insufficient maternal cardiac output (CO) has been implicated in poor pregnancy outcomes in mothers with heart disease (HD). Simultaneous delineation of vascular flows in the mother and her fetus have not been reported but could contribute to our understanding of the mechanisms of adverse events in this susceptible population. Methods: Pregnant women with moderate or severe HD (n=22; age 32±5 years) were studied using magnetic resonance imaging (MRI) and were compared with healthy controls (n=21; 34±3 years). Each MRI study included maternal and fetal components during the third trimester of pregnancy (corresponding to peak CO) and six months postpartum (surrogate for baseline hemodynamics). Phase contrast (PC) imaging was used to quantify maternal and fetal vascular flows. Fetal vessel T1 and T2 oximetry was used for derivation of fetal oxygen delivery and consumption. Maternal cardiac index (CI) was calculated using CO and pre-pregnancy body surface area. In the HD group, an “adapter” to pregnancy was defined as a woman with peak pregnancy CI measurement which met or exceeded the mean CI in the control population. Maternal and fetal outcomes were recorded. Results: There was no antepartum differences in absolute CO or CI in HD versus controls (CO 7.2±1.5 versus 7.3±1.6 L/min, p=0.79; CI 4.0±0.7 versus 4.3±0.7 L/min/m 2 , p=0.28). The percent increase in CO and CI (antepartum minus postpartum) was greater in women with HD versus controls (CO 46±24% versus 27±16%, p=0.02; CI 51±28% versus 28±17%, p&lt;0.01). Fetal growth and oxygen delivery/consumption were similar between groups. Six adverse maternal cardiovascular events occurred in the HD group (heart failure n=2 and arrhythmia n=4) and there were none in the control group. There were no adverse fetal events in either group. There were 6 HD adapters (30%) and the adverse event rate was lower as compared with non-adapters (0% versus 38%, p=0.03). Conclusions: Maternal and fetal vascular flows can be characterized in pregnancy using MRI. Impaired adaptation to pregnancy in women with HD, as determined by magnitude of change in CO/CI, appears to be associated with adverse outcomes of pregnancy in the mother.
Association of Increased Prostate-Specific Antigen Levels After Treatment and Mortality in Men With Locally Advanced vs Localized Prostate Cancer
Authors: Martin T. King, Ming-Hui Chen, Laurence Collette, Anouk Neven, Michel Bolla, Anthony V. D’Amico
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Increased prostate-specific antigen (PSA) levels after treatment (PSA failure) may have different associations with outcomes for men with locally advanced vs localized prostate cancer. <h3>Objective</h3> To evaluate whether the association between PSA failure and death may be different in locally advanced vs localized prostate cancer. <h3>Design, Setting, and Participants</h3> This multicenter cohort study included patients from 2 randomized clinical trials. The Dana-Farber Cancer Institute (DFCI) 95-096 trial randomized 206 men with localized prostate cancer from December 1, 1995, to April 15, 2001, whereas the European Organisation for Research and Treatment of Cancer (EORTC) 22961 trial randomized 970 men with locally advanced prostate cancer from October 30, 1997, to May 1, 2002. Data were analyzed from January 1, 2020, to October 31, 2020. <h3>Interventions</h3> The DFCI 95-096 trial randomized men to 0 vs 6 months of androgen deprivation therapy (ADT) with external beam radiotherapy; the EORTC 22961 trial randomized men to 6 vs 36 months of ADT with external beam radiotherapy. <h3>Main Outcomes and Measures</h3> For each trial, the PSA doubling time (time to doubling of PSA levels) associated with PSA failure was evaluated. The risk of all-cause mortality associated with PSA failure (nadir plus 2 definition) was evaluated after adjustment of baseline covariates and treatment. <h3>Results</h3> This analysis included a total of 1173 men (206 from DFCI 95-096 and 967 with available tumor stage from EORTC 22961; median age, 70.0 [interquartile range (IQR), 65.0-74.0 years). For DFCI 95-096, 161 men died (30 [18.6%] due to prostate cancer) at a median follow-up of 18.2 (IQR, 17.3-18.8) years. Among the 108 men with PSA failure, the median PSA doubling time was 13.0 (IQR, 7.4-31.1) months. For EORTC 22961, 230 men died (75 [32.6%] due to prostate cancer) at a median follow-up of 6.4 (IQR, 6.3-6.6) years. Among 290 men who experienced PSA failure, the median PSA doubling time was 5.0 (IQR, 2.9-8.9) months. Compared with DFCI 95-096, PSA failure was associated with a higher risk of all-cause mortality in EORTC 22961 (adjusted hazard ratios, 3.98 [95% CI, 2.92-5.44];<i>P</i> &lt; .001 vs 1.51 [95% CI, 1.03-2.23];<i>P</i> = .04). <h3>Conclusions and Relevance</h3> The association of PSA failure with outcomes may differ between locally advanced and localized prostate cancer. This finding supports the study of treatment intensification with the use of novel antiandrogen agents in addition to ADT at the time of PSA failure after treatment for locally advanced disease. <h3>Trial Registration</h3> ClinicalTrials.gov Identifiers:NCT00116220andNCT00003026