tbuckley/cabot-search huggingface dataset:
Novel avenues to approach non-CPAP therapy and implement comprehensive obstructive sleep apnoea care
Authors: Jean-Louis Pépin, Peter Eastwood, Danny J. Eckert
Journal: European Respiratory Journal (2021)

Recent advances in obstructive sleep apnoea (OSA) pathophysiology and translational research have opened new lines of investigation for OSA treatment and management. Key goals of such investigations are to provide efficacious, alternative treatment and management pathways that are better tailored to individual risk profiles to move beyond the traditional continuous positive airway pressure (CPAP)-focused, “one size fits all” trial-and-error approach, which is too frequently inadequate for many patients. Identification of different clinical manifestations of OSA (clinical phenotypes) and underlying pathophysiological phenotypes (endotypes) that contribute to OSA have provided novel insights into underlying mechanisms and have underpinned these efforts. Indeed, this new knowledge has provided the framework for precision medicine for OSA to improve treatment success rates with existing non-CPAP therapies such as mandibular advancement devices and upper airway surgery, and newly developed therapies such as hypoglossal nerve stimulation and emerging therapies such as pharmacotherapies and combination therapy. Additionally, these concepts have provided insight into potential physiological barriers to CPAP adherence for certain patients. This review summarises the recent advances in OSA pathogenesis, non-CPAP treatment, clinical management approaches and highlights knowledge gaps for future research. OSA endotyping and clinical phenotyping, risk stratification and personalised treatment allocation approaches are rapidly evolving and will further benefit from the support of recent advances in e-health and artificial intelligence.
RADT-31. TREATMENT TRENDS AND SURVIVAL OUTCOMES IN ATYPICAL MENINGIOMA
Authors: Yusef Syed, Manali Rupji, Jeffrey Switchenko, Bree Eaton, Jeffrey Olson, Hoang Kimberly, David Bray, Hiu-Kuo Shu, Jim Zhong
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND WHO grade II (atypical) meningiomas are treated with surgical resection, often followed by adjuvant fractionated radiation therapy (FRT). The increased availability of frameless stereotactic radiosurgery (SRS) presents an opportunity to offer patients a high biological effective dose over fewer fractions. Here we study the patterns of care and outcomes of these two forms of adjuvant RT. METHODS Patients with atypical meningioma were abstracted from the National Cancer Database (NCDB). Descriptive statistics were reported, and differences between treatment groups were assessed using either a chi-square test or ANOVA. Patients were grouped by treatment type and Kaplan Meier (KM) analysis was performed to compare overall survival (OS) using a log rank test. Univariable (UVA) and multivariable (MVA) cox regression analyses were completed. RESULTS Of 10,015 cases diagnosed from 2004-2016, 7,153 received surgery alone, 2,059 received surgery and adjuvant FRT (S+RT), and 362 received adjuvant SRS (S+SRS). The use of adjuvant RT increased by 71.8% for S+RT and 97.8% for S+SRS. In 2004, 15.1% of 443 registered patients received S+RT and 2.26% received S+SRS, while in 2016 these figures were 26.0% and 4.47%, respectively, for the 1051 registered patients (p&amp;lt; 0.001 and 0.022, respectively). For the 8,636 patients with survival data there was no significant difference in median OS between S+RT and S+SRS (130 months vs. 125 months, log rank p=0.935). On UVA, S+RT conferred better survival compared to surgery alone (HR 0.81 [0.72-0.91], p&amp;lt; 0.001) while S+SRS trended towards better survival (HR 0.82 [0.64-1.06], p=0.124). On MVA, no significant OS benefit was seen with S+RT (HR 0.96 [0.85-1.08], p=0.491) or S+SRS (HR 0.90 [0.69-1.16], p=0.413) versus surgery alone. CONCLUSIONS While the use of adjuvant RT for atypical meningioma has increased substantially since 2004, OS is comparable between FRT and SRS. The data presented here support further prospective investigation of adjuvant SRS.
Abstract 12567: Reduced Myocardial Strain is Associated With Myocardial Inflammation and Fibrosis on Cardiovascular Magnetic Resonance Imaging in Collegiate Athletes Recovering From SARS-CoV-2 Infection
Authors: John Heyniger, Juliet Varghese, Preethi Chandrasekaran, Katarzyna Gil, Simon Lee, Marc Lee, Kan N Hor, Curt Daniels, Orlando P Simonetti, Saurabh Rajpal
Journal: Circulation (2021)

Introduction: Myocarditis is an important cause of sudden cardiac death in competitive athletes. There have been reports of myocardial inflammation on cardiovascular magnetic resonance (CMR) in athlete and non-athlete populations after SARS-CoV-2 infection; however, their clinical and functional significance is not known. We sought to investigate the relationship between left ventricular (LV) strain and other CMR markers suggestive of myocardial inflammation or fibrosis. Hypothesis: Reduced myocardial strain is associated with the presence of CMR abnormalities suggestive of inflammation, fibrosis, or necrosis in athletes recovering from SARS-CoV-2 infection. Methods: Collegiate athletes (N = 123) underwent a comprehensive CMR exam including strain encoded (SENC) imaging. We analyzed LV global longitudinal strain (GLS) across five groups defined by the presence or absence of late gadolinium enhancement (LGE), and T1 or T2 abnormalities. Myocarditis diagnosis on CMR required both abnormal T1 or LGE, and abnormal T2, in the same LV segment. Results: We enrolled 11 COVID negative control athletes (Group 1). Among COVID positive athletes, 42 had no abnormalities on CMR (Group 2), 31 had isolated right ventricular insertion point (RVIP) LGE (Group 3), 28 had LGE beyond RVIP (Group 4), and 11 athletes had myocarditis (Group 5). GLS was significantly lower in Groups 3, 4, and 5 compared with negative controls (p&lt;0.05, Figure 1). There was a deterioration in GLS as CMR abnormalities progressed from control athletes to those with LGE and myocarditis. There was no significant difference in LV ejection fraction between the 5 groups. Conclusions: In conclusion, SARS-CoV-2 infection in collegiate athletes leads to subtle abnormalities in cardiac function detected by GLS that correlate with abnormal mapping and LGE suggestive of myocardial inflammation and fibrosis. The clinical significance of these abnormalities remains to be determined.
Abstract 13735: Classic Pattern Dyssynchrony Score: A Predictor of Response to Cardiac Resynchronization Therapy in Pediatric and Congenital Heart Disease
Authors: Henry Chubb, Anne M Dubin, Leo Lopez, Berthold Klas, Michelle Kaplinski, Scott R Ceresnak, Kara Motonaga, William R Goodyer, Anthony Trela, Deb Hanisch, Doff B McElhinney, Mark K Friedberg
Journal: Circulation (2021)

Introduction: Cardiac resynchronization therapy (CRT) is associated with an improvement in survival in selected pediatric and congenital heart disease (CHD) patients. However, there is minimal data to guide the identification of CRT responders in these challenging subgroups, even though implant is more complex and entails a longer lifetime legacy of device-related complications. Hypothesis: Echocardiographic measures of dyssynchrony predict response to CRT in this patient population Methods: This single-center study included all CRT pediatric and/or CHD patients (implant date 2004-2018). Response to CRT was defined as change in systemic ventricle ejection fraction (SVEF) on an ordinal scale (worsened/no change/improved). Multiple established echo indices (conventional and strain-derived) were assessed prior to implant. In addition, a novel ‘CPD-Score’, using an automated assessment of the presence of each of the four Classic Pattern Dyssynchrony (CPD) criteria on strain imaging (septal flash, lateral stretch, early peak septal strain, late peak lateral strain), was created. (Figure) Results: Of 127 CRT recipients, 91 met inclusion criteria (age 11yr (IQR 3-22yr), baseline SVEF 36±15%). In 62 (68%), SVEF improved following CRT (15 (16%) no change, 14 (15%) deteriorated). The presence of a septal flash was the best conventional echo predictor of response (PPV 78%). Conventional, strict, CPD also had high PPV for CRT response (72%) but was identified in only 9 (10%) patients. ‘CPD-Score’ offered a more graded response and higher PPV. A score of ≥3 was observed in 21 patients with PPV 96% (CPD-Score≥2 in 48 patients, PPV 83%). On stepwise multivariate ordinal regression, CPD-Score was independently associated with response (p= 0.02). Conclusion: CRT in pediatric and CHD patients is associated with an improvement in SVEF for the majority of recipients. Those with multiple features of CPD (‘CPD-Score’) are most likely to have an improvement in EF following CRT.
Abstract 10878: New Bleeding Risk Prediction Model for Patients with Atrial Fibrillation on Direct Oral Anticoagulants
Authors: Yoshihiro Tanaka, Nicola Lancki, Sadiya Khan, Karlyn Martin, Rod S Passman
Journal: Circulation (2021)

Introduction: Although several risk scores exist to predict major bleeding events (MBEs) in patients with atrial fibrillation (AF) on anticoagulation therapy, most were derived from warfarin treated patients. Therefore, we sought to develop a new bleeding risk score specifically for AF patients on direct oral anticoagulants (DOAC). Hypothesis: A DOAC-specific risk prediction model will have good discrimination and calibration for 1-year and 3-year MBEs. Methods: AF patients aged ≥ 18 years on DOAC therapy who had at least 12-month follow-up between 2010 and 2017 were extracted from the Northwestern Medicine EHR. The primary endpoint was MBE defined by the International Society on Thrombosis and Hemostasis (ISTH) criteria. Seventy percent of patients were randomly assigned to a derivation cohort and the rest of 30% was used as an internal validation cohort. In the derivation cohort, all significant univariate predictors (p &amp;lt; 0.05) were incorporated into a multivariate Cox proportional hazard model. Harrel’s c-statistics was used for discrimination and Hosmer-Lemeshow test for calibration. Results: A total of 7,642 patients with AF on DOAC (Apixaban 43.9%, Rivaroxaban 36.4%, Edoxaban 0.1%, Dabigatran 19.5%) were analyzed (mean age, 69 ± 12 years: men, 59.5%: non-Hispanic White, 85.8%). During a median follow-up period of 3.3 years (interquartile range 2.0-5.0), 1,283 MBEs (922 in derivation cohort and 361 in validation cohort) were observed. Final model involved age, race, body mass index in addition to all components of CHA 2 DS 2 -Vasc score. Calibration plots at 1 year and 3 years looked good fit and Hosmer-Lemeshow test was not statistically significant. C-statistics of the new model at 1 year and 3 years were 0.70 (95% CI: 0.67 - 0.72) and 0.67 (95% CI: 0.65 - 0.69), both of which were higher than the reported c-statistics from HAS-BLED score. In the validation cohort, we observed the same significant differences in c-statistics at both years. Conclusions: A DOAC-specific risk prediction score had good model performance to quantify bleeding risk in patients with AF on DOAC.
Abstract 12772: Regulation of Blood Pressure by Smooth Muscle TRPV4 Channels Under Normal and Hypertensive Conditions
Authors: Yen Chen, Zdravka Daneva, Maniselvan Kuppusamy, Matteo Ottolini, Eliska Klimentova, Swapnil K Sonkusare
Journal: Circulation (2021)

Introduction: Recent studies suggest that transient receptor potential vanilloid 4 (TRPV4) channel is a functionally important Ca 2+ influx pathway in arterial smooth muscle cells (SMCs). Hypothesis: We hypothesized that SMC TRPV4 (TRPV4 SMC ) channels regulate blood pressure under normal conditions and in hypertension. Results: Radiotelemetric recordings showed lower blood pressures in the SMC-specific TRPV4 -/- (TRPV4 SMC -/- ) mice than the control mice. Phenylephrine (PE, α1 adrenergic receptor or α1AR agonist)-induced constriction was blunted in small mesenteric arteries (MAs) from TRPV4 SMC -/- mice, whereas intraluminal pressure-induced constriction was increased. These data demonstrated that TRPV4 SMC channels contribute to α1AR-induced vasoconstriction but oppose pressure-induced vasoconstriction. Both PE and intraluminal pressure increased the activity of elementary Ca 2+ influx signals through TRPV4 SMC channels (TRPV4 SMC sparklets). TRPV4 agonist GSK1016790A (30 nM) activated the currents through large-conductance, Ca 2+ -sensitive K + (BK) channels in SMCs, whereas phenylephrine had no effect on BK channel currents. These data implied the presence of two functionally distinct pools of TRPV4 SMC channels: 1) α1AR-activated, constrictor TRPV4 SMC channels; and 2) pressure-activated, dilator TRPV4 SMC channels. Next, direct STORM imaging demonstrated that ~30% TRPV4 SMC channels co-localize with α1ARs and ~10% TRPV4 SMC channels co-localize with BK channels. Importantly, only ~3% TRPV4 SMC channels co-localized with both α1ARs and BK channels, supporting the concept of spatially distinct constrictor and dilator TRPV4 SMC channels. Angiotensin II (Ang II, 7-14 days) infusion resulted in a lower increase in blood pressure in TRPV4 SMC -/- mice than the control mice, demonstrating a crucial role of TRPV4 SMC channels in blood pressure elevation in hypertension. Moreover, Ang II infusion in C57BL6 mice increased α1AR-TRPV4 SMC signaling; reduced pressure-activation of TRPV4 SMC channels; and reduced TRPV4 SMC -BK channel signaling. Conclusions: Our results show that increased constrictor TRPV4 SMC channel activity and reduced dilator TRPV4 SMC channel activity combine to elevate blood pressure in hypertension.
Abstract 12538: MICAL1 Constrains Cardiac Stress Responses and Protects Against Disease by Oxidizing CaMKII
Authors: Klitos Konstantinidis, Vassilios J Bezzerides, Lo Lai, Holly Isbell, An-Chi Wei, Yuejin Wu, Meera Viswanathan, Ian Blum, Jonathan Granger, Donghui Zhang, Danielle Heims-Waldron, Elizabeth Luczak, Kevin R Murphy, Daniel Gratz, Bruno Manta, Qiang Wang, Qinchuan Wang, Alex Kolodkin, Vadim Gladyshev, Thomas J Hund, William T Pu, Mark Wu, Anthony Cammarato, Mario Bianchet, Madeline Shea, Rodney Levine, Mark E Anderson
Journal: Circulation (2019)

Oxidant stress can contribute to health and disease. Here we show that invertebrates and vertebrates share a common stereospecific redox pathway that protects against pathological responses to stre...
Integrated Safety Analysis of Tagraxofusp, a CD123-Directed Targeted Therapy, in Patients with Hematologic Malignancies
Authors: Naveen Pemmaraju, Hagop Kantarjian, Kendra Sweet, Eunice S. Wang, Andrew A. Lane, Haris Ali, Anthony S. Stein, Abdulraheem Yacoub, David A. Rizzieri, Sumithira Vasu, Vikas Gupta, Sangmin Lee, Gary J. Schiller, James M. Foran, Minakshi S. Taparia, Todd L. Rosenblat, Roland B. Walter, Debra Sieminski, Madhu Anant, Mrinal M. Patnaik, Tariq I. Mughal, Marina Konopleva
Journal: Blood (2021)
Abstract 9756: An ECG-Based Machine Learning Model for Predicting New Onset Atrial Fibrillation is Superior to Age and Clinical Variables in Selecting a Population at High Stroke Risk
Authors: John Pfeifer, Sushravya Raghunath, Christopher Kelsey, Jeffrey Ruhl, Dustin Hartzel, Alvaro Ulloa Cerna, Linyuan Jing, David vanMaanen, Joseph Leader, Thomas Morland, Ruijun Chen, Christoph Griessenauer, Noah Zimmerman, Steven R Steinhubl, Brandon Fornwalt, Christopher M Haggerty
Journal: Circulation (2021)

Background: Several large trials have employed age or clinical features to select patients for atrial fibrillation (AF) screening to reduce strokes. We hypothesized that a deep neural network (DNN) model risk prediction based on ECG would be superior to age and clinical variables at selecting a population at high risk for AF and AF-related stroke. Methods: We retrospectively included all patients with an ECG at Geisinger without a prior history of AF. Incidence of AF and AF-related strokes were identified as outcomes within 1 and 3 years after the ECG, respectively. AF-related stroke was defined as a stroke where AF was diagnosed at the time of stroke or within a year after the stroke. We selected a high-risk cohort for AF screening based on five risk stratification methods - criteria from four clinical trials (mSToPS, STROKESTOP, GUARD-AF and SCREEN-AF) and the DNN model at the qualifying ECG. We simulated patient selection and evaluated outcomes for twenty 1-year periods between 2010-2014 centered around the ECG encounter. For the clinical trials, the patients were considered eligible if they met the criteria before or within the period unless they satisfied exclusion criteria at the time of ECG. Results: The DNN model achieved optimal sensitivity (65%), PPV (10%), NNS for AF (10) within this population compared with all other risk models with a NNS for AF-related stroke of 160. Total screening number, sensitivity, positive predictive value (PPV) and number needed to screen (NNS) to capture AF and AF-related stroke are summarized in Table 1. The number of additional screens for the DNN model was slightly higher for two of the other models (SCREEN-AF and STROKESTOP) but lower than the other two (mSToPS and GUARD-AF). Conclusions: A DNN ECG-based risk prediction model is superior to contemporary AF-screening criteria based on age alone or age and clinical features in selecting a population for additional screening due to high risk for future AF and potential AF-related strokes.
Abstract 6910: Psychosocial Impairments and Frailty, Cognitive Performance, and Quality of Life Among Older Adults With Atrial Fibrillation
Authors: Jordy Mehawej, Jane Saczynski, Mayra Tisminetzky, Hawa O Abu, Apurv Soni, Weijia Wang, Mathew Joanne, Eric Ding, Marc Gagnier, Loay Alrojolah, Robert Goldberg, David D McManus
Journal: Circulation (2021)

Introduction: Psychosocial impairments (i.e., depression or anxiety) and geriatric impairments are prevalent among older patients with atrial fibrillation (AF) and adversely impact their long-term outcomes. However, little is known about the association between symptoms of anxiety or depression and various impairments associated with older age. Hypothesis: We hypothesize that depression and anxiety would be associated with frailty, cognitive impairment, and low quality of life among older adults with AF. Methods: We analyzed data from the Systemic Assessment of Geriatric Elements-AF study. Participants with AF aged 65 years and older, with a CHA 2 DS 2 -VASc≥2, were recruited from multiple clinics in Georgia and Massachusetts. Patient Health Questionnaire-9 and the Generalized Anxiety Disorder-7 Scale were used to assess depression and anxiety symptoms, respectively. We used a GEE model to examine the association between depression and anxiety at baseline with our principal study outcomes over a 2-year follow-up period. Results: 972 participants (mean age 74 years; 48 % female; 87 % were non-Hispanic White) were included in this study. Participants who met the criteria for anxiety (29%) or depression (26%) at baseline, as compared to those without, were more likely to be frail ( OR = 2.20, 95% CI: 1.58-3.05; OR [OR] = 4.32, 95% CI: 3.16-5.90, respectively) and to have a lower AF related quality of life over 2 years ( OR= 3.21, 95% CI: 2.52-4.11; OR= 3.71, 95% CI: 2.94-4.69, respectively). However, there was no association between depression or anxiety and cognitive impairment. Conclusions: Anxiety and depression in older adults with AF were associated with increased risk of frailty and decreased AF related quality of life. As such, addressing mental health needs of older adults may improve their clinical outcomes and quality of life.
PATH-13. INTRAOPERATIVE EVALUATION OF IDH MUTATION STATUS AND TUMOR INVASION IN GLIOMA
Authors: Hannah Brown, Diogo Garcia, Rong Chen, Mark Jentoft, Erik Middlebrooks, Kaisorn Chaichana, Alfredo Quinones-Hinojosa, R Graham Cooks
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Intraoperative detection of residual tumor and isocitrate dehydrogenase (IDH) mutations can assist in maximizing surgical resection beyond contrast enhancing margins and guide intraoperative surgical decision making for glioma patients. We aimed to evaluate the use of desorption electrospray ionization-mass spectrometry (DESI-MS) for intraoperative assessment of IDH mutations and estimation of tumor cell percentage (TCP). METHODS This is a prospective study using intraoperative DESI-MS analysis of freshly obtained tissue samples to evaluate IDH mutations via 2-hydroxyglutarate (2-HG) intensity and TCP via measurement of N-acetylaspartic acid (NAA) intensity and characteristic lipid profiles. These IDH mutation and TCP estimates were subsequently validated by a senior neuropathologist. RESULTS A total of 247 biopsies from a 49-patient study were previously collected and analyzed at Indiana University. Assessment of TCP in 203 margin and core biopsies based on NAA intensity yielded sensitivity, specificity, and accuracy values of 91, 76, and 83%, whereas TCP assessment based on characteristic lipid profiles yielded 76, 85, and 81%, respectively. Assessment of IDH mutation status of 71 core biopsies yielded sensitivity, specificity, and accuracy values of 89, 100, and 94%. Further validation of the methodology is being performed in an ongoing collaboration with Mayo Clinic-Jacksonville, where we have collected 178 biopsies from 24 patients. Preliminary results of IDH mutation assessments indicate 100% sensitivity, specificity, and accuracy. DISCUSSION/CONCLUSION We present a novel system to allow intraoperative evaluation of IDH status and to guide surgical resection by TCP measurement from tissue biopsies. Prospectively, we propose to modify our DESI-MS system by placing a surgical material (e.g. cottonoid) along the surgical margin and transferring material from the blot to a microscope slide prior to DESI-MS analysis. This will allow the retention of the spatial distribution of diagnostic molecules while analyzing a wall of the surgical cavity without the need for biopsy.