tbuckley/cabot-search huggingface dataset:
CTNI-15. PHASE 0/I TRIAL OF MYCOPHENOLATE MOFETIL COMBINED WITH RADIATION TO OVERCOME GLIOBLASTOMA TREATMENT RESISTANCE BY TARGETING DE-NOVO PURINE METABOLISM: INTERIM REPORT
Authors: Yoshie Umemura, Yilun Sun, Larry Junck, Denise Leung, Michelle Kim, Wajd Al-Holou, Oren Sagher, Jason Heth, Matthew Schipper, Costas Lyssiotis, Bernard Marini, Theodore Lawrence, Daniel Wahl
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND De novo purine synthesis promotes glioblastoma growth and stemness, invasiveness, and resistance to chemoradiation. Mycophenolate mofetil (MMF) is an FDA-approved inhibitor of de novo purine synthesis that sensitizes glioblastoma to radiation and chemotherapy in mice. This Phase 0/I trial of MMF with Radiotherapy in Recurrent Glioblastoma (NCT04477200) aims to determine the maximum-tolerated dose of MMF that can be combined with radiation,and the extent to which the active metabolite of MMF accumulates in brain tumors and inhibits de novo purine synthesis. METHODS Key eligibility criteria are age ≥18, KPS score ≥60%, and recurrent glioblastoma or gliosarcoma with clinical indication for re-irradiation (phase I) or re-resection/biopsy (phase 0). Patients with tumors involving ≥3 lobes or leptomeningeal space or bevacizumab use within 8 weeks are excluded. MMF 500-2000mg PO BID is given one week pre-operatively in Phase 0 (N=8), and up to 2000mg PO BID (starting 1000mg) on TITE-CRM dose escalation on Phase 1 cohort (N=30). RESULTS Since 7/2020, three Phase 0 and six Phase I subjects have been enrolled. On the phase I cohort, 1500mg BID dose has been reached. Studyrelated toxicities have been limited to mainly grade 1-2 nausea and fatigue. No notable study related hematotoxicity have been noted. Additionally, mass spectrometry-based correlative measurements of the activity of de novo GTP synthesis are ongoing. CONCLUSION MMF has been well tolerated up to 1500mg BID combined with radiotherapy in recurrent glioblastoma patients in this interim analysis. An additional upfront glioblastoma cohort with MMF with standard of care will activate in 2021. These studies will determine the maximum tolerated dose of MMF in combination with radiation and chemotherapy and provide a preliminary efficacy estimate at that dose. Encouraging results would support a randomized clinical trial to determine efficacy of MMF combined with chemoradiation in glioblastoma, and to define potential biomarkers for effectiveness.
Oral Minocycline As Systemic Therapy for Uncomplicated Venous Access Device-Related Bloodstream Infection with Coagulase-Negative Staphylococci in Patients after Allogeneic Hematopoietic Cell Transplantation
Authors: Firas Bayoudh, Julie Descy, Corentin Fontaine, Frederic Baron, Evelyne Willems, Yves Beguin, Jean-Baptiste Giot, Sophie Servais
Journal: Blood (2021)
Time to Benefit of Bisphosphonate Therapy for the Prevention of Fractures Among Postmenopausal Women With Osteoporosis
Authors: William James Deardorff, Irena Cenzer, Brian Nguyen, Sei J. Lee
Journal: JAMA Internal Medicine (2021)

The clinical decision to initiate bisphosphonate therapy for the treatment of osteoporosis requires balancing shorter-term harms and burdens (eg, gastroesophageal irritation or severe musculoskeletal pain) with longer-term benefits in reducing potential fractures.
Abstract 6994: Impact of Urine Osmolality at Discharge on Prognosis in Heart Failure Patients
Authors: MOTOHIRO FUJITA, Noriko Kikuchi, Tsuyoshi Shiga, Tsuyoshi Suzuki, Nobuhisa Hagiwara
Journal: Circulation (2021)

Introduction: Urine osmolality (U-OSM) is determined by the balance of water and solutes, antidiuretic hormone, and renal function. U-OSM can be altered in heart failure (HF) patients, and is influenced by multiple factors, including volume status, diuretics, and so on. However, it is not known whether U-OSM is a predictive factor of prognosis among symptomatic HF patients. Hypothesis: The aim of the study is to clarify the impact of U-OSM at discharge according to baseline renal dysfunction on prognosis among symptomatic HF patients. Methods: This study is a sub-analysis from HIJ-HF-III, which is a single center registry that collected prospectively consecutive 1,408 HF patients hospitalized at Tokyo Women’s Medical University from 2015 to 2019. 745 HF patients who were discharged alive and had available data of U-OSM at discharge were included in this study. The primary endpoint is all cause death after discharge. Results: Mean age was 69 +/- 14.8 years old, 60.1 % of the patients were male. 36.3 % of the patients had renal dysfunction. Median U-OSM at discharge was 465 mOsm/l. During the median follow-up period of 20.1 months after discharge, 108 (14.5 %) patients were died. Kaplan-Meier survival analysis showed that low U-OSM at discharge was associated with high mortality among HF patients with renal dysfunction (p=0.049). On the other hand, there was not associated between U-OSM and mortality after discharge among HF patients without renal dysfunction (p=0.944). Multivariate logistic regression showed that low U-OSM at discharge was independently associated with increased the risk of death (hazard ratio [per 1 mOSM/l]: 1003, 95%CI 1.000-1.005, p=0.041) among HF patients with renal dysfunction. Conclusion: Among HF patients with renal dysfunction, low U-OSM at discharge was significantly associated with poor outcome after discharge.
NIMG-71. IDENTIFYING CLINICALLY APPLICABLE MACHINE LEARNING ALGORITHMS FOR GLIOMA SEGMENTATION USING A SYSTEMATIC LITERATURE REVIEW
Authors: Niklas Tillmanns, Avery Lum, W R Brim, Harry Subramanian, Ming Lin, Khaled Bousabarah, Ajay Malhotra, Jin cui, Alexandria Brackett, Sam Payabvash, Ichiro Ikuta, Michele Johnson, Bernd Turowski, Mariam Aboian
Journal: Neuro-Oncology (2021)

Abstract PURPOSE Nowadays Machine learning (ML) algorithms are often used for segmentation of gliomas, but which algorithms provide the most accurate method for implementation into clinical practice has not fully been identified. We performed a systematic review of the literature to characterize the methods used for glioma segmentation and their accuracy. METHODS In accordance to PRISMA, a literature review was performed on four databases, Ovid Embase, Ovid MEDLINE, Cochrane trials (CENTRAL) and Web of science core-collection first in October 2020 and in February 2021. Keywords and controlled vocabulary included artificial intelligence, machine learning, deep learning, radiomics, magnetic resonance imaging, glioma, and glioblastoma. Publications were screened in Covidence and the bias analysis was done in agreement with TRIPOD. RESULTS Sixty-six articles were used for data extraction. BRATS and TCIA datasets were used in 36.6% of all studies, with average number of patients being 141 (range: 1 to 622). ML methods represented 45.3% of studies, with deep learning used in 54.7%; Dice score for the tumor core ranged from 0.72 to 0.95. The most common algorithm used in the machine learning papers was support vector machines (SVM) and for deep learning papers, it was Convolutional Neural Networks (CNN). Preliminary TRIPOD analysis yielded an average score from 12 (range: 7-16) with the majority of papers demonstrating deficiencies in description of the ML algorithm, funding role, data acquisition and measures of model performance. CONCLUSION In the last years, many articles were published on segmentation of gliomas using machine learning, thus establishing this method for tumor segmentation with high accuracy. However, the major limitations for clinically applicable use of ML in glioma segmentation include more than one-third of publications use the same datasets, thus limiting generalizability, increase the likelihood of overfitting, show and lack of ML network description and standardization in accuracy reporting.
Abstract 10237: Activated Protein C Protects Neurons from Alzheimer’s Disease-Related Changes Through Reduction of Tau Hyperphosphorylation
Authors: Jiayuan Murphy, Van Le, Kayla Davitt, Cole Logan, Di Ren, Ji Li
Journal: Circulation (2021)

Introduction: Activated protein C (APC) is a blood serine protease that has been shown to have neuroprotective function via its downstream signaling cascade. However, there is no study has investigated how the lack of APC signaling is associated with Alzheimer’s disease (AD)-related neuronal changes. Hypothesis: Diminished APC signaling is related to AD-associated biomarkers and behavioral symptoms. APC ameliorates these symptoms via the activation of the protein kinase B (Akt) signaling pathway which inhibits glycogen synthase kinase 3β (GSK3β) and tau hyperphosphorylation. Methods: Immunofluorescence imaging and proteomic analysis were performed on EPCR R84A/R84A mice, which had blunted APC activity due to mutated endothelial protein C receptor (EPCR), for examining amyloid β (Aβ) deposition. A rodent model of AD, 5xFAD mice, were subjected to either one-time or chronic daily APC injection (100 μg/kg/d i.p.). Morris's water maze test was performed to assess spatial memory and learning. The tissue of the hippocampus and cortex were collected for transcriptomic and proteomic analysis. Results: EPCR R84A/R84A mice showed greater hippocampal and cortical deposition of Aβ comparing to EPCR WT/WT counterparts. This result indicates defective APC signaling might contribute to the development of Aβ accumulation and insoluble plaque formation. A one-time injection of APC significantly activated AKT through phosphorylating the Ser 473 site, as well as inhibited AKT’s downstream target, GSK3β, via phosphorylation at Ser 9 in both wild-type and 5 x FAD mice. Downregulation of GSK3β activity is associated with decreased tau phosphorylation at Ser 202 /Thr 205 but not Ser 396 , indicating a reduction in the hyperphosphorylated form of tau that is prone to neurofibrillary tangle formation. Additionally, chronic APC administration for 3 months was observed to attenuate the cognitive deficits seen in 5 x FAD mice. Conclusions: APC has a crucial neuroprotective role because dampened APC signaling is related to AD-associated neuronal changes. APC has the downstream effect of Akt activation, which in turn inhibits GSK3β and the hyperphosphorylation of tau, ameliorating both the histological and behavioral markers seen in AD.
Abstract 14290: Implementation of a Comprehensive STEMI Protocol Improves Key Process Metrics for Transfer STEMI Patients
Authors: Radoslav Zinoviev, Anirudh Kumar, Chetan Huded, Michael Johnson, Kathleen A Kravitz, Grant W Reed, Amar Krishnaswamy, Damon M Kralovic, Fredric M Hustey, Abigail S Brown, Samir R Kapadia, Umesh N Khot
Journal: Circulation (2021)

Introduction: Despite improvements in STEMI door-to-balloon time (D2BT), the majority of patients who present to US hospitals without PCI capability do not achieve the national goal D2BT of ≤ 120 minutes for transfer STEMI patients. We sought to determine the impact of a comprehensive STEMI protocol (CSP) on key process and outcome metrics in transfer STEMI patients. Methods: The CSP is a 4-step STEMI protocol aimed at minimizing STEMI care variability. The protocol streamlines STEMI care by (1) allowing catheterization lab activation by emergency physicians without cardiology consultation, (2) standardizing early administration of guideline-directed medical therapy (GDMT), (3) ensuring immediate transfer to a PCI-capable facility, and (4) implementing a radial artery-first approach (RAFA). We evaluated outcomes in 499 STEMI patients transferred to our hospital from January 1, 2011 to July 14, 2014 prior to implementation of CSP (control group) and 775 patients presenting from July 15, 2014 to July 15, 2019, after implementation of the CSP. Results: Compared to the control group, after implementation of CSP there was a significant increase in the number of STEMI patients transferred to our hospital who received GDMT (84.6% vs 93.9%, p&lt;0.001). There was a significant increase in the use of RAFA (19.0% vs 77.7%, p&lt;0.001). The median D2BT decreased from 114 minutes prior (IQR 94.0-146.0min, p&lt;0.001) to 97 minutes (IQR 82.0-115.0min) after CSP implementation, with substantially more patients reaching the target D2BT of 120 minutes (55.7% vs 80.1%, p&lt;0.001). There was a trend towards lower in-hospital mortality after CSP implementation (4.4% vs 2.8%, p=0.180) though the results were not powered to show statistical significance. Conclusion: The CSP significantly improved STEMI care key process metrics (GDMT, RAFA, and D2BT) with a trend to lower mortality for patients presenting with STEMI to outside facilities who are transferred to a CCF PCI-capable hospital.
Abstract 12810: Data-Driven Clusters of Cardiac Structure and Function and Association With Premature Cardiovascular Disease: The Coronary Artery Disease in Young Adults (CARDIA) Study
Authors: Michael C Wang, Lindsay R Pool, Norrina B Allen, Paul A Reyfman, Yuan Luo, Joao A Lima, Don M Lloyd-jones, Sadiya S Khan
Journal: Circulation (2021)

Introduction: Abnormal indices of cardiac structure and function likely cluster together. However, the clinical relevance of data-driven patterns of cardiac remodeling across a broad range of echocardiographic measures, particularly in mid-life, is not known. Hypothesis: Latent class analysis (LCA) will identify distinct clusters of cardiac structure and function based on echocardiographic indices in middle-aged adults that differ in risk of CVD. Methods: We included all CARDIA participants without CVD who underwent an echocardiogram. Continuous parameters were indexed to participant height (if appropriate), imputed with the SVDImpute algorithm (if missing), and filtered to remove pairwise correlations &gt;0.6. We applied LCA using a total of 31 echocardiographic indices (standardized to mean 0 and standard deviation 1) to identify distinct groups based on model convergence, the Bayesian Information Criterion, and class membership &gt;5%. We examined the association between groups and risk of premature CVD (coronary artery disease, stroke, or heart failure) with Cox regression adjusted for traditional risk factors. Results: Of 3,361 participants, mean (SD) age was 50.1 (3.6) years, 57% were female, and 46% were non-Hispanic Black. LCA identified 3 groups: (1) optimal cardiac mechanics; (2) impaired systolic function; and (3) impaired diastolic function ( FIGURE ). Over a median 8.9 years of follow-up, risk of CVD was higher in the impaired diastolic function group (unadjusted hazard ratio [HR] 4.08 [95% CI: 2.48, 6.71] and adjusted HR 1.95 [1.12, 3.40]) compared with the optimal group. The impaired systolic function group had a higher unadjusted risk of CVD (1.86 [1.10, 3.15], which attenuated after adjustment (1.36 [0.79, 2.36]). Conclusions: Unbiased, model-based clustering of cardiac structure and function in middle-aged adults identified distinct patterns of cardiac remodeling that were associated with risk of future CVD.
Clofarabine-Based Chemotherapy for <i>KMT2A</i>r Infantile Acute Lymphoblastic Leukemia
Authors: Tanja Andrea Gruber, Deqing Pei, John Kim Choi, Cheng Cheng, Elaine Coustan-Smith, Dario Campana, Hope Swanson, Jennifer L Pauley, Hiroto Inaba, Monika Metzger, Jeffrey E. Rubnitz, Raul C Ribeiro, Susana C. Raimondi, William E. Evans, Mary V. Relling, Ching-Hon Pui, Sima Jeha
Journal: Blood (2021)
Abstract 11822: Comparison of Outcome of Cardiopulmonary Resuscitation in COVID Positive versus COVID Negative Patients; a Tertiary Care Hospital Experience From Pakistan Cardiopulmonary Resuscitation in COVID Positive versus COVID Negative Patients
Authors: Amber Ahmed, madiha iqbal, MFAISAL Khan, Sana Hirani
Journal: Circulation (2021)

Introduction: The impact of Covid-19 on outcomes of In-hospital cardiac arrest IHCA remains unclear. Aims &amp; Methodology: We, conducted a retrospective cohort study to compare the characteristics and outcome of CPR in Covid positive V/s Covid negative patients, at our institute. Data were retrieved from a review of the medical records of all patients who underwent cardiac arrest during the pandemic period. Taking Covid-19 as the exposure variable, our sample population was divided into two cohorts. Results: Eighty patients who underwent CPR were included in the study with;40 patients in each group. The mean age was 61 in the positive group and 65 in the negative group. The male to female ratio was equal in the covid positive group but the male population was higher in the negative group. (77%). The most frequent comorbidities were the same (Diabetes, hypertension, and ischaemic heart disease) in both groups. All of the patients had ARDS in Covid positive group while septic shock was the commonest diagnosis (48.9%) in the negative group. In the positive group, 74% of patients were in high dependency unit (HDU) and 26% were in ICU. In the negative group,94% of patients were in HDU and 6% in ICU. The initial rhythm was Pulseless electrical activity (PEA) in 52% of the positive group and all of the patients (100%) in the negative group. Eight percent of covid positive patients had shockable rhythm while remaining had asystole. The median duration of CPR was 15 minutes in the positive group and 17 minutes in the negative group. Although the return of spontaneous circulation (ROSC) was achieved in 14% of patients in covid positive, none of them survived to discharge. In the negative group, 30% of patients achieved ROSC while survival to discharge was 15%. The odds of mortality were 6.88 [95% confidence interval (CI)0.789-60] times higher in COVID-19-positive patients, compared to negative patients. Conclusions: Covid-19 infection is associated with poor outcomes in IHCA compared to non-covid illnesses.
The Increased Use of Diagnostic Studies over Time in Acute Myelogenous Leukemia Patients
Authors: Chijioke Okereke, Ashley D Fox, Thuy Le, Sujith Abbagoni, Anand P Jillella, Locke J. Bryan, Tahsin Anwar, Mohammad A. H. Mian, Vamsi Kota
Journal: Blood (2021)
Abstract 12501: Admission Serum Chloride Concentrations and Mortality Outcomes in Heart Failure Patients
Authors: OLAYIWOLA AMORAN, Ankur Chaudhury, Harpreet Singh, Andrew Kohut
Journal: Circulation (2021)

Introduction: Acute decompensated CHF is associated with a number of electrolyte abnormalities. Hyponatremia has been well established as having a close association with mortality in CHF patients, however in the past decade several robust retrospective studies have raised the intriguing possibility that chloride levels may be as or more significant than sodium levels as a mechanistic player in the pathophysiology of CHF, and a potential target for future therapeutics. Hypothesis: Admission chloride is related to all-cause mortality in CHF patients, even when adjusted for LVEF. Methods: 96 patients admitted to the Hospital of the University of Pennsylvania between 1/1/2017 and 12/31/2019 with a diagnosis of acute decompensated CHF were selected. The relationship between admission chloride on first admission during which patient received IV diuretics and all-cause mortality was analyzed by univariate regression, with multivariate adjustment for LVEF. Results: Per our univariate Cox proportional hazards regression model, admission chloride was inversely related with all-cause mortality in our population of CHF patients (HR per unit change 0.925; 95% CI: 0.864-0.990; p&lt;0.05) indicating a ~7.5% relative improvement in survival per unit increase in chloride. After multivariable adjustment for LVEF, admission chloride remained independently inversely related with mortality (HR per unit change 0.923; 95% CI: 0.859-0.991, p&lt;0.05). After multivariable adjustment for admission sodium however, admission chloride lost its significance with mortality (HR per unit change 0.953; p=0.213). Conclusions: Our study confirms that chloride levels are an important predictor of all-cause mortality in CHF patients, independent of LVEF. Figure 1 visually illustrates the worsening of cumulative mortality in patients within the lowest chloride tertile, although our Kaplan Meier survival curves remained just outside the bounds of significance (p=0.052).
Abstract 14215: Mortality and Readmission Among Medicare Beneficiaries Hospitalized for Heart Failure Who Are Treatment Candidates for SGLT-2 Inhibitors
Authors: Muthiah Vaduganathan, Stephen J Greene, Shuaiqi Zhang, Karen Chiswell, Adam D Devore, Javed Butler, Paul A Heidenreich, Joanna Huang, Michelle M Kittleson, Karen E Joynt Maddox, James J McDermott, Anjali T Owens, Pamela Peterson, Scott Solomon, Orly Vardeny, Clyde W Yancy, Gregg C Fonarow
Journal: Circulation (2021)

Background: SGLT2i form the latest pillar in the management of HFrEF and appear effective across a range of patient profiles. There is increasing interest around initiation of SGLT2i during hospitalization, yet little is known about the putative benefits of this implementation strategy. Methods: We evaluated Medicare beneficiaries with HFrEF (≤40%) hospitalized at 228 sites in the GWTG-HF Registry in 2016 who had linked claims data for ≥1 year post-discharge. We identified those eligible for a SGLT2i under the FDA label for dapagliflozin (excluding eGFR&lt;30 mL/min per 1.73 m 2 , dialysis, or type 1 diabetes). We evaluated 1-year outcomes overall and among key subgroups (age≥75y, sex, race, hospital region, eGFR, diabetes status, triple therapy). Results: Among 7,767 patients hospitalized for HFrEF, 6,218 (80%) would be SGLT2i candidates (mean age 79±8y, 38% women, 12% Black). Among eligible candidates, discharge use of β-blockers, ACEi/ARB, MRA, ARNI, and triple therapy (ACEi/ARB/ARNI+β-blocker+MRA) was in 86%, 65%, 30%, 3%, and 21%, respectively. Treatment candidates faced a 1-year incidence [95% CI] of mortality and HF readmission of 38% [36-39%] and 32% [31-33%], respectively, and each exceeded 25% across all key subgroups. Among 1,301 beneficiaries eligible for already on triple therapy, 1-year incidence of mortality was 26% [24-28%] and 1-year HF readmission was 30% [27-32%]. Conclusions: Medicare beneficiaries eligible for SGLT2i after HF hospitalization, including those well-treated with other disease-modifying therapies, face high risks of mortality and HF readmission by 1 year. Whether these heightened risks can be modified with implementation of SGLT2i at time of a worsening HF event is the subject of ongoing clinical trials.