tbuckley/cabot-search huggingface dataset:
Abstract 255: National Institutes of Health Research Funding of the Top Science Gaps Recognized in the 2015 American Heart Association Emergency Cardiac Care Guidelines
Authors: Ryan A Coute, Ashish R Panchal, Timothy J Mader, Michael C Kurz
Journal: Circulation (2020)

Objective: A descriptive analysis of NIH funding of the top science gaps recognized in the 2015 AHA Emergency Cardiac Care cardiac arrest (CA) guidelines over a five-year period. Methods: A search within NIH RePORTER for the period of 2015 to 2019 was performed using the following terms: “cardiac arrest” or “cardiopulmonary resuscitation” or “heart arrest” or “circulatory arrest” or “pulseless electrical activity” or “ventricular fibrillation” or “resuscitation”. Grants were identified as CA research (yes/no) using predefined, published criteria. NIH funded CA abstracts were individually reviewed and categorized using the previously recognized ten most urgent science gaps in the 2015 AHA ECC CA guidelines published by Panchal et al. The data were analyzed descriptively. Results: The search yielded 1,518 NIH-funded grants over the study period, of which 172 (11.3%) were classified as individual CA grants. A total of 42 (24.4%) did not address a top 10 scientific gap. The remaining 130 grants addressed the following scientific gaps: optimization of post-CA care (78 grants, 45.3%), prediction of patients at risk of CA (12, 7%), developing tools for early neuroprognostication (7, 4.1%), hemodynamic monitoring/goal directed resuscitation (4, 2.3%), optimizing educational strategies for providers (4, 2.3%), optimal airway strategies (2, 1.2%), and understanding why bystanders fail to respond (1, 0.6%). Previously existing scientific networks or data centers accounted for 19 (11%) grants and 3 (1.7%) grants addressed both optimizing post-CA care and early neuroprognostication gaps. Recognized scientific gaps in dispatch-directed CPR, individualized resuscitation strategies, and novel technology for out-of-hospital CA identification and response did not receive specifically directed NIH grant funding. Conclusion: Additional research funding targeting critical knowledge gaps in the 2015 cardiac arrest guidelines is needed promote broader evidence-based guideline development. Current NIH funding is concentrated in a few areas leaving disparity among recognized high-yield scientific gaps in CA care.
Abstract 15229: Clinical Phenotype Differences in Outcomes and Responses of Spironolactone in Heart Failure With Preserved Ejection Fraction
Authors: Maeveen Riordan, David P Kao
Journal: Circulation (2020)

Introduction: Several clinical phenotypes have been described in patients with heart failure with preserved ejection fraction (HFpEF). This heterogeneity may explain why no therapies have improved outcomes in clinical trials of HFpEF patients. In a secondary analysis of TOPCAT, the authors discovered improved mortality in female HFpEF patients treated with spironolactone. The objective of this study was to determine if outcomes for spironolactone in women with HFpEF varied by female-specific phenotypes. Methods: Using 10 clinical variables, a latent class analysis (LCA) of 5196 female patients from 7 clinical trials (BEST, IPRESERVE, MOCHA, NEAT-HFpEF, RELAX, TOPCAT, and SOLVD) was used to identify phenotypes across the LVEF spectrum, which included 3 distinct phenotypes of HFpEF patients. A post-hoc analysis of TOPCAT was completed to analyze the outcomes of spironolactone versus placebo by female phenotype. The outcomes were cardiovascular (CV) mortality, heart failure (HF) hospitalizations, all-cause mortality, and CV hospitalizations. Results: Table 1 shows characteristics of 3 female HFpEF phenotypes: phenotype 1 “aging hypertensive”, phenotype 2 “younger hypertensive”, and phenotype 3 “obesity phenotype”. 887 female patients from the TOPCAT trial were analyzed according to these phenotypes. Of these, only phenotype 1 showed a benefit of spironolactone therapy compared to placebo with regards to the primary outcome of CV mortality and HF hospitalizations (20.8% vs 30.2%, p&lt;0.05) as well as the composite of all-cause mortality and CV hospitalizations (41.1% vs 51.3%, p&lt;0.05). Conclusion: Older, hypertensive women with HFpEF show a significant reduction in CV mortality and HF hospitalizations when treated with spironolactone vs. placebo, whereas other women did not. Prior studies show that this phenotype is often associated with a higher mortality, thus spironolactone may be particularly important in this patient population.
Peripheral blood non-canonical small non-coding RNAs as novel biomarkers in lung cancer
Authors: Wanjun Gu, Junchao Shi, Hui Liu, Xudong Zhang, Jin J. Zhou, Musheng Li, Dandan Zhou, Rui Li, Jingzhu Lv, Guoxia Wen, Shanshan Zhu, Ting Qi, Wei Li, Xiaojing Wang, Zhaohua Wang, Hua Zhu, Changcheng Zhou, Kenneth S. Knox, Ting Wang, Qi Chen, Zhongqing Qian, Tong Zhou
Journal: Molecular Cancer (2020)

Abstract One unmet challenge in lung cancer diagnosis is to accurately differentiate lung cancer from other lung diseases with similar clinical symptoms and radiological features, such as pulmonary tuberculosis (TB). To identify reliable biomarkers for lung cancer screening, we leverage the recently discovered non-canonical small non-coding RNAs (i.e., tRNA-derived small RNAs [tsRNAs], rRNA-derived small RNAs [rsRNAs], and YRNA-derived small RNAs [ysRNAs]) in human peripheral blood mononuclear cells and develop a molecular signature composed of distinct ts/rs/ysRNAs (TRY-RNA). Our TRY-RNA signature precisely discriminates between control, lung cancer, and pulmonary TB subjects in both the discovery and validation cohorts and outperforms microRNA-based biomarkers, which bears the diagnostic potential for lung cancer screening.
SVFX: a machine learning framework to quantify the pathogenicity of structural variants
Authors: Sushant Kumar, Arif Harmanci, Jagath Vytheeswaran, Mark B. Gerstein
Journal: Genome biology (2020)

Abstract There is a lack of approaches for identifying pathogenic genomic structural variants (SVs) although they play a crucial role in many diseases. We present a mechanism-agnostic machine learning-based workflow, called SVFX, to assign pathogenicity scores to somatic and germline SVs. In particular, we generate somatic and germline training models, which include genomic, epigenomic, and conservation-based features, for SV call sets in diseased and healthy individuals. We then apply SVFX to SVs in cancer and other diseases; SVFX achieves high accuracy in identifying pathogenic SVs. Predicted pathogenic SVs in cancer cohorts are enriched among known cancer genes and many cancer-related pathways.
Ras Homolog Family Member F, Filopodia Associated Promotes Hepatocellular Carcinoma Metastasis by Altering the Metabolic Status of Cancer Cells Through RAB3D
Authors: Shi Li, Yu Liu, Yifeng Bai, Min Chen, Donghui Cheng, Mengwan Wu, Jianling Xia
Journal: Hepatology (2020)

The mechanism by which tumor cells resist metabolic stress remains unclear, but many oncogenes are known to regulate this process. Accordingly, metabolic stress is closely associated with tumor metastasis. In this study, gene chip technology showed that Ras homolog family member F, filopodia associated (RHOF), a member of the Rho guanosine triphosphatase family, is an oncogene that is significantly related to hepatocellular carcinoma (HCC) metastasis; however, it has rarely been reported in tumors. Our aim was to determine the clinicopathological significance and role of RHOF in HCC progression and investigate the associated mechanisms.The results showed that compared to expression in adjacent noncancerous tissues, RHOF was frequently up-regulated in HCC tumor samples and elevated under conditions of glucose deprivation. RHOF expression was associated with tumor-node-metastasis stage, T grade, metastasis status, recurrence, and survival in HCC. RHOF also affected cell morphology and promoted migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cell lines. Analysis of the underlying mechanism showed that RHOF promoted the Warburg effect by up-regulating the expression and function of several glycolytic enzymes in HCC cells. This metabolic shift enhanced HCC cell migration and invasion. Specifically, RHOF exerted a tumor-promoting effect by directly interacting with AMP-activated protein kinase (AMPK) and increasing the phosphorylation of AMPK. This subsequently affected RAB3D mRNA stability and led to elevated RAB3D expression, thereby amplifying the Warburg effect and malignant biological behaviors of HCC cells.RHOF helps tumor cells resist metabolic stress through modulating the Warburg effect and plays a critical role in promoting HCC cell migration, invasion, and EMT, highlighting its important role in remodeling the metastatic microenvironment and regulating tumor metastasis. RHOF shows potential as a therapeutic target and prognostic biomarker for HCC.
THU0082 Induction of adjuvant arthritis in the male lewis rat: lipoidal amine exhibits an “all-or-nothing” threshold response distinct from the mycobacterial linear dose response
Authors: U Feige, C King, B Bolon
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Marked polyarthritis can be induced in male Lewis rats by injection of either heat-killed Mycobacterium tuberculosis (H37Ra, Difco) in paraffin oil (AdA) or lipoidal amine in complete Freund’s adjuvant (LA/CFA). <h3>Objectives</h3> The present study examined whether or not the disease severity in these two models is related to the dose of the inciting agent. <h3>Methods</h3> Adjuvant arthritis was induced in male Lewis rats (190 to 240 g) by administration of M. tuberculosis (AdA; 1.25, 2.5, 5, 10, 20 or 40 mg/ml) or lipoidal amine (LA/CFA; 4, 6.25, 12.5, 25, 50, 100, 200, or 400 mg/ml). The clinical evaluation included measurements of body weight and hind paw volume (by water plethysmography) on day 0 and then daily between days 8 to 16. At necropsy on day 16, inflammation (by histopathology) and bone integrity (bone mineral density [BMD] by DEXA; histopathology) were assessed in the tibiotarsal (hock) and femorotibial (knee) joints. <h3>Results</h3> Induction of AdA followed a typical dose-response curve for most parameters, including body weight, loss of BMD (hock and knee), inflammation (paw volume and histopathology), and bone erosion (histopathology). In contrast, LA/CFA exhibited an “all-or-nothing” response with a threshold for activity of 50 mg/ml. The severity of arthritis (measured both clinically and morphologically) was comparable at day 16 for AdA engendered by &gt; 1.25 mg/ml of mycobacteria and LA/CFA induced by &gt; 50 mg/ml. These data indicate that AdA and LA/CFA exhibit different dose-response patterns. <h3>Conclusion</h3> The practical implication of this finding is that AdA will be the better adjuvant arthritis model for investigating the biology and treatment of inflammatory joint disease over a range of lesion severities.
Abstract 269: The Design of an Adaptive Clinical Trial - The Extracorporeal Cardiopulmonary Resuscitation for Refractory Out of Hospital Cardiac Arrest (EROCA) Project
Authors: Juliana Tolles, Kelley Kidwell, Kristine Broglio, Todd Graves, William J Meurer, Roger J Lewis, Robert W Neumar
Journal: Circulation (2020)

Introduction: Extracorporeal cardiopulmonary resuscitation (ECPR) for out-of-hospital cardiac arrest (OHCA) is promising but unproven. We developed a concept for a randomized Bayesian adaptive clinical trial to define the interval after arrest during which patients derive benefit. Hypotheses: We hypothesized that the simulated design characteristics of the adaptive design would efficiently confirm or refute the existence of a therapeutic window for ECPR in a future trial. Methods: Through iterative simulation and design modification, we developed a Bayesian adaptive trial of ECPR for adults with OHCA. The goals of the trial design were to address the uncertainty surrounding the OHCA-to-ECPR interval within which clinical benefit might be preserved and the difference in prognosis between patients with non-shockable vs shockable rhythms. The treatment effect was defined as the mean 90-day utility-weighted Modified Rankin Scale (uwmRS) for each rhythm subgroup and estimated CA-to-ECPR interval. The trial adaptively lengthens or contracts the estimated CA-to-ECPR eligibility window depending on the probability of benefit from ECPR. We simulated trial performance under six potential ECPR efficacy scenarios. We compared the adaptive design to a fixed design. Results: The trial had 91-100% power to detect a benefit from ECPR for non-shockable rhythms and 69-98% power for shockable rhythms under the scenarios simulated (figure). The design had a high probability of identifying the maximum CA-to-ECPR interval within which ECPR produces a clinically significant benefit of 0.2 on the uwMRS. In null scenarios, the 97-99% of the simulated trials ended early declaring futility. Conclusions: The adaptive trial design helps to ensure the patient population most likely to benefit from treatment—as defined by rhythm subgroup and estimated CA-to-ECPR interval—are enrolled. The design also promotes early termination of the trial if continuation is likely to be futile.
Abstract 138: Socioeconomically Equitable Public Defibrillator Placement Using Mathematical Optimization
Authors: K.H. Benjamin Leung, Steven Brooks, Timothy Chan, Gareth Clegg
Journal: Circulation (2020)

Introduction: Mathematical optimization can be used to place automated external defibrillators (AEDs) in locations that maximize coverage of out-of-hospital cardiac arrests (OHCAs). However, the extent to which optimization strategies affect socioeconomically equitable distribution of AEDs is unknown. Methods: All suspected OHCAs and registered AEDs in Scotland between Jan. 2011 - Sept. 2017 with a recorded location were included and mapped across the quintiles of the Scottish Index of Multiple Deprivation (SIMD), a national measure of socioeconomic status. First, we maintained AEDs at current locations and modeled placing an equal number of additional AEDs to maximize “coverage” (i.e., AED located within 100 m) of suspected OHCAs. A second analysis determined optimal sites for relocating all existing AEDs to optimize coverage without additional AEDs. We computed the proportion of OHCAs covered in each SIMD quintile under each AED placement strategy. A Wilcoxon signed-rank test was used to test difference in coverage levels across all regions of Scotland. Results: We identified 49,692 suspected OHCAs and 1,532 AEDs. Existing AEDs covered 1,384 OHCAs (2.8%), with OHCA coverage peaking in quintile 3 (moderate deprivation), indicating a mismatch with the distribution of suspected OHCA. Adding an equal number of new AEDs in optimal locations covered 10,465 OHCAs (21.1%; P&lt;0.001). Optimal relocation of existing AEDs with no additional units covered 9,464 OHCAs (19.0%; P&lt;0.001). OHCA coverage under either optimization strategy peaked in quintile 1 (highest deprivation), aligning to the OHCA incidence distribution. Conclusion: Optimizing AED placement significantly increases OHCA coverage and better aligns coverage with OHCA incidence across SIMD quintiles, improving socioeconomic equity of OHCA coverage. Relocating existing AEDs could achieve similar coverage to doubling the number of devices.
Defining the Comprehensive Genomic Landscapes of Pancreatic Ductal Adenocarcinoma Using Real-World Endoscopic Aspiration Samples
Authors: Alexander Semaan, Vincent Bernard, Jaewon J. Lee, Justin W. Wong, Jonathan Huang, Daniel B. Swartzlander, Bret M. Stephens, Maria E. Monberg, Brian R. Weston, Manoop S. Bhutani, Kyle Chang, Paul A. Scheet, Anirban Maitra, Yasminka A. Jakubek, Paola A. Guerrero
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Most patients with pancreatic ductal adenocarcinoma (PDAC) present with surgically unresectable cancer. As a result, endoscopic ultrasound–guided fine-needle aspiration (EUS-FNA) is the most common biospecimen source available for diagnosis in treatment-naïve patients. Unfortunately, these limited samples are often not considered adequate for genomic analysis, precluding the opportunity for enrollment on precision medicine trials. Experimental Design: Applying an epithelial cell adhesion molecule (EpCAM)-enrichment strategy, we show the feasibility of using real-world EUS-FNA for in-depth, molecular-barcoded, whole-exome sequencing (WES) and somatic copy-number alteration (SCNA) analysis in 23 patients with PDAC. Results: Potentially actionable mutations were identified in &amp;gt;20% of patients. Further, an increased mutational burden and higher aneuploidy in WES data were associated with an adverse prognosis. To identify predictive biomarkers for first-line chemotherapy, we developed an SCNA-based complexity score that was associated with response to platinum-based regimens in this cohort. Conclusions: Collectively, these results emphasize the feasibility of real-world cytology samples for in-depth genomic characterization of PDAC and show the prognostic potential of SCNA for PDAC diagnosis.
Air Pollution, Cardiovascular Disease, and Dementia—Reply
Authors: Debora Rizzuto, Giulia Grande, Andrea Bellavia
Journal: JAMA Neurology (2020)

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Abstract 16721: A Meta-Analysis of Early versus Delayed Revascularization Among Patients With Non-st-segment Elevation Myocardial Infarction
Authors: Mohammed Faisaluddin, Samarthkumar J Thakkar, Ashish Kumar, Richard Alweis, Kirolos Barssoum, Yaqub Nadeem Mohammed, Harsh P Patel, Raj Patel, Rajkumar P Doshi, Shilpkumar Arora, SIDAKPAL S PANAICH
Journal: Circulation (2020)

Introduction: Several randomized control trials (RCTs) have compared early versus delayed coronary revascularization in non-ST-segment elevation myocardial infarction (NSTEMI) and have reported contradicting results. Hypothesis: We performed a meta-analysis of all the available RCTs to date to determine the best strategy in NSTEMI. Methods: We performed a comprehensive search of PubMed, EMBASE, and Cochrane databases for all RCTs comparing an early versus delayed revascularization in NSTEMI. The primary endpoint was all-cause mortality. The secondary endpoints were re-infarction and refractory ischemia. We used the Paule-Mandel (PM) estimator of Tau with Knapp-Hartung adjustment to calculate relative risk (RR) with a 95% confidence interval (CI). Results: Thirteen RCTs were included in the final analysis. The median time between randomization and angiography ranged from 0.5 to 14 h in the early group and 18.3 to 86.0 h in the delayed group. There was no difference in mortality (5.7% vs 6.6%; RR 0.90; 95% CI 0.78-1.04; p = 0.83) (PANEL A) as well as rate of re-infarction (6.7% vs. 7.7%; RR 0.83; 95% CI 0.10-6.71; p = &lt;0.001) (PANEL B) among both the strategy. However, early revascularization was associated with a reduction in refractory ischemia (4.8% vs 7.4%; RR 0.64; 95% CI 0.44-0.94; p=0.002) (PANEL C) Conclusions: Early revascularization for NSTEMI does not reduce the risk of mortality or re-infarction compared with delayed revascularization. Nonetheless, an early invasive approach does decrease the rate of refractory ischemia in NSTEMI.
Have large increases in fast track referrals improved bowel cancer outcomes in UK?
Authors: Michael Thompson, Daniel O’Leary, Iona Heath, Lynn Faulds Wood, Brian Ellis, Karen Flashman, Neil Smart, John Nicholls, Neil Mortensen, Paul Finan, Asha Senapati, Robert Steele, Peter Dawson, James Hill, Brendan Moran
Journal: BMJ (2020)

More precise risk stratification is required to enable timely diagnosis of bowel cancer while avoiding unnecessary investigation, argue Michael Thompson and colleagues UK Department of Health policies to improve survival from bowel cancer through GP referral guidelines and public awareness campaigns have increased urgent referrals to hospitals. This has led to an unsustainable demand for colonoscopy and CT colonography without evidence of significant clinical benefit. These policies could be improved by more precise stratification of the risk of having bowel cancer to achieve prompt, rather than earlier, diagnosis while avoiding over-referral and investigation of patients with transient symptoms from benign conditions. The first UK cancer plan was developed in 2000 to improve outcomes for patients. The plan introduced the concept of the "two week wait," from urgent GP referral to the first outpatient appointment. In 2000, the committee developing the referral criteria for bowel cancer1 advised that only those with symptoms persisting for 6 weeks should be referred. The 2005 National Institute for Health and Care Excellence ( NICE) review of the guidelines largely endorsed the referral criteria, which identified nine out of 10 bowel cancers (box 1) and had a 9-14% predictive value for cancer34 (table 1). Fast track clinics reduced time to diagnosis but not to treatment.34 Over the following nine years the number of referrals increased by 45% (table 1) while the predictive value for cancer decreased from 14% to 8%34567 (table 1). A review of several articles was carried out in 2001-04, with one study reporting a 14% predictive value for cancer and another, by 2009, before the introduction of the public awareness campaign, reporting a predictive value of 7.9%. Box 1 ### Seven typical characteristics of bowel cancer2 These characteristics identified over 92% of bowel cancers referred to outpatient departments. Adding two age thresholds: >40 … RETURN TO TEXT