tbuckley/cabot-search huggingface dataset:
Abstract 14859: Mesenchymal Stem Cells Rescue Patient-Specific Cardiomyocyte Viability and Function Following Doxorubicin Injury via Microvesicle Mediated Mitochondrial Transfer to Recapitulate Human Clinical Trial Results
Authors: Connor G OBrien, Mehmet O Ozen, Evgeniya Vaskova, Jihye Jung, Michelle Santoso, Liye Shi, Christine A Wahlquist, Zewen Jiang, Yunshin Jung, Gentaro Ikeda, Yitian Zeng, Robert Sinclair, Adrian Gee, Ronald M Witteles, Mark Mercola, Katrin Svensson, Utkan Demirci, Phillip C Yang
Journal: Circulation (2020)

Introduction: Anthracyclines are effective chemotherapeutic agents associated with cardiac toxicity. Anthracycline induced cardiomyopathy (AIC) carries a mortality of 20% at four years. Effective therapies for AIC have not been established. The NIH-sponsored Stem Cell Injection for Cancer Survivors (SENECA) Trial examined the role of allogeneic mesenchymal stem cells (MSC) to treat AIC. To predict the efficacy of MSC in the SENECA patients, we performed an in vitro clinical trial to study the restorative effects of MSC on patient-specific iPSC-derived cardiomyocytes (iCM) by assessing the effects in vitro following doxorubicin (dox) exposure. Hypothesis: MSC secretome will rescue SENECA Trial patient-specific iCM from dox injury. Methods and Results: We generated three SENECA patient-specific iPSC lines. In vitro iCM dox sensitivity was shown to be comparable to published values. iCM were cultured in 1μM dox for 24hrs, treated with MSC or MSC-secretome, and assessed for viability and apoptosis. Co-culture of MSC with iCM using a 1μm trans-well system improved iCM viability by 43% (p-value &lt; 0.005) and reduced apoptosis (p-value = 0.013). To better define the paracrine mechanism, MSC-secretome was divided into microvesicles &gt;200nm (MV) and exosomes &lt;200nm (Ex) using a novel filtration system. MV recapitulated the effect of co-culture, improving iCM viability by 87.8% (p-value = 0.006) and reducing apoptosis by 60% (p-value = 0.013). Treatment with Ex had no effect. MV restore contractility and calcium transients in the dox-injured iCM. MV were found to contain mitochondria (MT), which are taken up by iCM. Treated iCM demonstrate increased MT-copy number and augmented MT-biogenesis. Inhibition of MT function in MV attenuated therapeutic efficacy. We were unblinded to SENECA outcomes. In our cohort, the MSC-treated patient improved across all endpoints while placebo treated patients did not consistent with our in vitro findings. Conclusion: Allogeneic MSC attenuate apoptosis and restore contractility following dox injury in patient-specific iCM. MV and MT-transfer appear to be the putative mechanism. Our findings correlate with the SENECA results, demonstrating proof-of-concept that iPSC-derivatives can be used to predict trial outcomes.
Evaluating social and spatial inequalities of large scale rapid lateral flow SARS-CoV-2 antigen testing in COVID-19 management: An observational study of Liverpool, UK (November 2020 to January 2021)
Authors: Mark A. Green, Marta García-Fiñana, Ben Barr, Girvan Burnside, Christopher P. Cheyne, David Hughes, Matthew Ashton, Sally Sheard, Iain E. Buchan
Journal: The Lancet Regional Health - Europe (2021)

Large-scale asymptomatic testing of communities in Liverpool (UK) for SARS-CoV-2 was used as a public health tool for containing COVID-19. The aim of the study is to explore social and spatial inequalities in uptake and case-detection of rapid lateral flow SARS-CoV-2 antigen tests (LFTs) offered to people without symptoms of COVID-19.Linked pseudonymised records for asymptomatic residents in Liverpool who received a LFT for COVID-19 between 6th November 2020 to 31st January 2021 were accessed using the Combined Intelligence for Population Health Action resource. Bayesian Hierarchical Poisson Besag, York, and Mollié models were used to estimate ecological associations for uptake and positivity of testing.214 525 residents (43%) received a LFT identifying 5192 individuals as positive cases of COVID-19 (1.3% of tests were positive). Uptake was highest in November when there was military assistance. High uptake was observed again in the week preceding Christmas and was sustained into a national lockdown. Overall uptake were lower among males (e.g. 40% uptake over the whole period), Black Asian and other Minority Ethnic groups (e.g. 27% uptake for 'Mixed' ethnicity) and in the most deprived areas (e.g. 32% uptake in most deprived areas). These population groups were also more likely to have received positive tests for COVID-19. Models demonstrated that uptake and repeat testing were lower in areas of higher deprivation, areas located further from test sites and areas containing populations less confident in the using Internet technologies. Positive tests were spatially clustered in deprived areas.Large-scale voluntary asymptomatic community testing saw social, ethnic, digital and spatial inequalities in uptake. COVID-19 testing and support to isolate need to be more accessible to the vulnerable communities most impacted by the pandemic, including non-digital means of access.Department of Health and Social Care (UK) and Economic and Social Research Council.
A Systematic Review of Animal Models of NAFLD Finds High‐Fat, High‐Fructose Diets Most Closely Resemble Human NAFLD
Authors: Yu Ri Im, Harriet Hunter, Dana de Gracia Hahn, Amedine Duret, Qinrong Cheah, Jiawen Dong, Madison Fairey, Clarissa Hjalmarsson, Alice Li, Hong Kai Lim, Lorcán McKeown, Claudia‐Gabriela Mitrofan, Raunak Rao, Mrudula Utukuri, Ian A. Rowe, Jake P. Mann
Journal: Hepatology (2021)

Background and Aims Animal models of human disease are a key component of translational hepatology research, yet there is no consensus on which model is optimal for NAFLD. Approach and Results We generated a database of 3,920 rodent models of NAFLD. Study designs were highly heterogeneous, and therefore, few models had been cited more than once. Analysis of genetic models supported the current evidence for the role of adipose dysfunction and suggested a role for innate immunity in the progression of NAFLD. We identified that high‐fat, high‐fructose diets most closely recapitulate the human phenotype of NAFLD. There was substantial variability in the nomenclature of animal models: a consensus on terminology of specialist diets is needed. More broadly, this analysis demonstrates the variability in preclinical study design, which has wider implications for the reproducibility of in vivo experiments both in the field of hepatology and beyond. Conclusions This systematic analysis provides a framework for phenotypic assessment of NAFLD models and highlights the need for increased standardization and replication.
Abstract 17409: Improved Diagnosis of Coronary Artery Disease Using Cardiac CT Compared With Exercise Stress Testing in an Urban Public Hospital Patient Population
Authors: Johnny Wu, Ivan Rudenko, Chandana Shekar, Suraj Dahal, April Kinninger, Matthew J Budoff, Sion Roy
Journal: Circulation (2020)

Introduction: Heart disease remains the leading cause of death in the United States, with the disease burden particularly high in various racial and ethnic groups. In serving an underserved population comprised largely of Hispanic and African American individuals, it is crucial for an urban public hospital to diagnose heart disease in a resource-efficient and cost-effective manner. The greater positive predictive value of cardiac CT relative to exercise stress testing presents the opportunity for such hospitals to optimize resource utilization in identifying patients with coronary artery disease (CAD). Hypothesis: The positive predictive value of cardiac CT in diagnosing CAD is greater than that of exercise stress testing in the patient population served by an urban public hospital. Methods: Patients at Harbor-UCLA Medical Center (Torrance, California) were identified for inclusion in this observational study on the basis of a positive (i.e., abnormal) exercise stress test result or a positive cardiac CT result, during the period between January 2015 and September 2019. These patients were subsequently referred for invasive coronary artery angiography, with the diagnosis of obstructive CAD established by an indication for revascularization via percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Data were analyzed using a two-tailed Z-test for two proportions. Results: Seventy-six catheterization laboratory results were analyzed. Fifteen subjects with an abnormal exercise stress test result, out of a total of 41 (36.6%), had an indication for PCI or CABG. Twenty-five cardiac CT imaging subjects, out of a total of 35 (71.4%), had an indication for PCI or CABG. The proportion of positive cardiac CT results with an indication for PCI or CABG was significantly higher than the abnormal exercise stress test proportion (p=0.0024). Conclusions: Among urban public hospital patients who were referred for invasive coronary artery angiography, it was determined that cardiac CT provides a greater positive predictive value in the diagnosis of obstructive CAD than exercise stress testing. This result may help guide the optimal allocation of diagnostic resources in an urban public hospital.
Abstract 14819: Excess Epicardial Fat Volume is Associated With Increased Cardiovascular Structural and Functional Abnormalities in Menopausal Women Regardless of Body Weight: The Higher the Epicardial Fat Volume, the Higher the Abnormalities
Authors: Mahfouz EL SHAHAWY, Susan Tucker, Lillee Izadi, Antonella Sabatini
Journal: Circulation (2020)

Background: It has been reported that an increase in epicardial fat volume (EFV) has been associated with an increase in cardiovascular structural and functional abnormalities (CVSFA). Purpose: The purpose of this study is to assess whether a step-wise increase in EFV is associated with a proportional increase in CVSFA. Methods: We screened 2,756 asymptomatic subjects, ages 20-79, for CVD risk using the Early Cardiovascular Disease Risk Scoring System (ECVDRS), which consists of 10 tests; 7 are vascular and 3 are cardiac. The vascular tests are: large (C1) and small (C2) artery stiffness, blood pressure (BP) at rest and post-mild protocol exercise (PME), CIMT, abdominal aorta ultrasound, retinal photography, and microalbuminuria. The 3 cardiac tests are: Pro-BNP, ECG, and LV ultrasound. Additional tests are waist circumference, BMI, fasting blood sugar, lipid profile, and CRP. 596 out of the total subjects were asymptomatic, and out of these 220 (37%) underwent cardiac CT for coronary artery calcium scoring (CACS) and EFV determination using Siemens Somatom Definition Dual source CT scanner 64x2. 107 out of the 220 were females (48%). These females were divided into 5 groups based on their EFV: 24 with &lt; 69cm 3 ; 33 between 70cm 3 and 94cm 3 ; 16 between 95cm 3 and 119cm 3 ; 20 between 120cm 3 and 144cm 3 ; and 14 &gt;145cm 3 . Results: As noted in the table, a step-wise increase in EFV was associated with proportional increases in CVSFA, specifically CACS, resting BP, abnormal rise in BP-PME, CRP, and triglycerides. An increase in EFV was noticeably associated with an increase in resting blood BP by a 10mmHg difference between the group whose EFV &lt; 120cm 3 and those whose EFV is &gt; 120cm 3 . Conclusions: Based on our data, we feel that excess EFV appears to be the villain for most CVSFA. Accordingly, we urge all healthcare professionals that it is time to focus on early and accurate assessment of this significant risk marker, which is the culprit for many CVD risk factors. Early detect to protect.
Video-assisted skin-sparing breast-conserving surgery for breast cancer and immediate reconstruction with autologous tissue: Clinical outcomes
Authors: I. Fujiwara, H. Nakajima, N. Mizuta, K. Sakaguchi, Y. Hachimine
Journal: Journal of Clinical Oncology (2009)

e11580 Background: This study analyzed clinical results of video-assisted breast-conserving surgery for breast cancer. Methods: Video-assisted breast-conserving surgery is indicated for breast cancer that has not invaded the skin. A skin incision is made at an inconspicuous site. Skin-sparing partial mastectomy was performed endoscopically on 244 patients (stage I, n=94; stage II, n=150). Morbidity, curability and patient satisfaction were analyzed. Results: Skin necrosis was seen in 9 patients. Local recurrence was seen in 13 patients (mean postoperative interval, 65.3 months). Distant metastasis-free survival at 60 months was 93.6% for stage I and 90.5% for stage II. Overall survival was 95.7% for stage I and 96.9% for stage II. Satisfaction with surgery as investigated by questionnaire was “good” for 72.3% of patients. Conclusions: Video-assisted breast-conserving surgery showed no increases in local or distant recurrence and patient satisfaction was high. Video-assisted breast-conserving surgery appears useful for local treatment of breast cancer. No significant financial relationships to disclose.
Cell-free DNA copy number variations predict efficacy of immune checkpoint inhibitor-based therapy in hepatobiliary cancers
Authors: Xu Yang, Ying Hu, Keyan Yang, Dongxu Wang, Jianzhen Lin, Junyu Long, Fucun Xie, Jinzhu Mao, Jin Bian, Mei Guan, Jie Pan, Li Huo, Ke Hu, Xiaobo Yang, Yilei Mao, Xinting Sang, Jiao Zhang, Xi Wang, Henghui Zhang, Haitao Zhao
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background This study was designed to screen potential biomarkers in plasma cell-free DNA (cfDNA) for predicting the clinical outcome of immune checkpoint inhibitor (ICI)-based therapy in advanced hepatobiliary cancers. Methods Three cohorts including 187 patients with hepatobiliary cancers were recruited from clinical trials at the Peking Union Medical College Hospital. Forty-three patients received combination therapy of programmed cell death protein 1 (PD-1) inhibitor with lenvatinib (ICI cohort 1), 108 patients received ICI-based therapy (ICI cohort 2) and 36 patients received non-ICI therapy (non-ICI cohort). The plasma cfDNA and blood cell DNA mutation profiles were assessed to identify efficacy biomarkers by a cancer gene-targeted next-generation sequencing panel. Results Based on the copy number variations (CNVs) in plasma cfDNA, the CNV risk score model was constructed to predict survival by using the least absolute shrinkage and selection operator Cox regression methods. The results of the two independent ICI-based therapy cohorts showed that patients with lower CNV risk scores had longer overall survival (OS) and progression-free survival (PFS) than those with high CNV risk scores (log-rank p&lt;0.01). In the non-ICI cohort, the CNV risk score was not associated with PFS or OS. Furthermore, the results indicated that 53% of patients with low CNV risk scores achieved durable clinical benefit; in contrast, 88% of patients with high CNV risk scores could not benefit from combination therapy (p&lt;0.05). Conclusions The CNVs in plasma cfDNA could predict the clinical outcome of the combination therapy of PD-1 inhibitor with lenvatinib and other ICI-based therapies in hepatobiliary cancers.
Abstract 16588: Using Machine Learning to Improve Survival Prediction After Heart Transplantation
Authors: Brian Ayers, Toumas Sandhold, Igor Gosev, Sunil Prasad, Arman Kilic
Journal: Circulation (2020)

Introduction: Prior risk models for predicting survival after orthotopic heart transplantation (OHT) have displayed only modest discriminatory capability. With increasing interest in the application of machine learning (ML) to predictive analytics in clinical medicine, this study aimed to evaluate whether modern ML techniques could improve risk prediction in OHT. Methods: Data from the United Network for Organ Sharing registry was collected for all adult patients that underwent OHT from 2000 through 2019. The primary outcome was one-year post-transplant mortality. Dimensionality reduction and data re-sampling were employed during training. The final ensemble model was created from 100 different models of each algorithm: deep neural network, logistic regression, adaboost, and random forest. Discriminatory capability was assessed using area under receiver-operating-characteristic curve (AUROC), net reclassification index (NRI), and decision curve analysis (DCA). Results: Of the 33,657 study patients, 26,926 (80%) were randomly selected for the training set and 6,731 (20%) as a separate testing set. One-year mortality was balanced between cohorts (11.0% vs 11.3%). The optimal model performance was a final ensemble ML model. This model demonstrated an improved AUROC of 0.764 (95% CI, 0.745-0.782) in the testing set as compared to the other models (Figure). Additionally, the final model demonstrated an improvement of 72.9% ±3.8% (p&lt;0.001) in predictive performance as assessed by NRI compared to logistic regression. The DCA showed the final ensemble method improved risk prediction across the entire spectrum of predicted risk as compared to all other models (p&lt;0.001). Conclusions: An ensemble ML model was able to achieve greater predictive performance as compared to individual ML models as well as logistic regression for predicting survival after OHT. This analysis demonstrates the promise of ML techniques in risk prediction in OHT.
Putting the Microenvironment into the Immunotherapy Companion Diagnostic
Authors: Myrto Moutafi, David L. Rimm
Journal: Clinical Cancer Research (2021)

Abstract A post hoc analysis in advanced gastric cancer showed stronger association of programmed cell death-ligand 1 (PD-L1) with immunotherapy efficacy measured by combined positive score (CPS) compared with tumor cells (TC%). This finding suggests expression in immune cells in the tumor microenvironment increases the value of the companion diagnostic test. See related article by Lei et al., p. 3926
Abstract 15382: Variant Subtype and Regionality Aid Assessment of Pathogenicity in <i>Plakophillin-2</i> ( <i>PKP2</i> )
Authors: Annika Dries, Anna Kirillova, Chloe Reuter, Hana Zouk, Megan Hawley, Crystal Tichnell, Brittney Murray, Birgit Funke, John Garcia, Christopher M Haggerty, Cynthia James, Victoria Parikh
Journal: Circulation (2020)

Loss of function variants in PKP2 are associated with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), but little is known about the consequences of PKP2 missense variation. We hypothesized that truncating variants in PKP2 are more likely to be associated with cardiomyopathy than missense, and that the pathogenicity of PKP2 missense variants varies by gene region . We assembled genetic tests from probands with variants in PKP2 and ARVC-relevant diagnoses from industry partners (N=176) and evaluated the proportion of probands with truncating (N=98) and missense (N=78) variants in this disease-associated population vs. the general population (represented by gnomAD: N=97 truncating; N=12408 missense). Truncating variants were enriched in the disease-associated population (OR=160.7, p&lt;0.0001), while missense variants were not. To identify potential hotspots for pathogenic missense variation, we examined the proportion of probands with disease-associated vs. general population-associated missense variants within sliding windows across the length of the PKP2 transcript. We found 18 windows enriched for diseased probands with missense variants, one of which lies within a known functional domain (FDR=0.001, Figure 1). We then performed a variant-level analysis on independent publicly available databases of ARVC-associated variants (University Medical Center Groningen and ClinVar, N=44 vs. gnomAD, N=546), and found two of the same windows (FDR=0.2). Four out of six PKP2 missense variants listed as pathogenic in ClinVar fell within disease-associated windows. Truncating PKP2 variants are more likely to be associated with disease than missense variants. Examination of disease-associated regions of missense variation in PKP2 identified potential hotspots for pathogenicity. Future directions include further validation based on highly clinically adjudicated ARVC populations and in vitro examination of functional relevance of these domains.
Left Atrial Appendage Occlusion during Cardiac Surgery to Prevent Stroke
Authors: Richard P. Whitlock, Emilie P. Belley-Cote, Domenico Paparella, Jeff S. Healey, Katheryn Brady, Mukul Sharma, Wilko Reents, Petr Budera, Andony J. Baddour, Petr Fila, P.J. Devereaux, Alexander Bogachev-Prokophiev, Andreas Boening, Kevin H.T. Teoh, Georgios I. Tagarakis, Mark S. Slaughter, Alistair G. Royse, Shay McGuinness, Marco Alings, Prakash P. Punjabi, C. David Mazer, Richard J. Folkeringa, Andrea Colli, Álvaro Avezum, Juliet Nakamya, Kumar Balasubramanian, Jessica Vincent, Pierre Voisine, Andre Lamy, Salim Yusuf, Stuart J. Connolly
Journal: New England Journal of Medicine (2021)

Surgical occlusion of the left atrial appendage has been hypothesized to prevent ischemic stroke in patients with atrial fibrillation, but this has not been proved. The procedure can be performed during cardiac surgery undertaken for other reasons.
Abstract P118: Machine Learning Algorithm For Improving Classification Of Myocardial Infarction Across A Diverse Population Using US Veteran Electronic Health Record Data
Authors: Kelly Cho, Nicholas Link, Petra Schubert, Zeling He, Jacqueline P Honerlaw, Tianrun Cai, Ariela R Orkaby, Saadia Qazi, Vidisha Tanukonda, Jiehuan Sun, Kumar Dahal, Ashley Galloway, Lauren Costa, Yichi Zhang, David R Gagnon, Chuan Hong, Yuk-lam Ho, J. M Gaziano, Peter W Wilson, Tianxi Cai, Katherine P Liao
Journal: Circulation (2021)

Introduction: The majority of population-based studies of myocardial infarction (MI) rely on billing codes for classification. Classification algorithms employing machine learning (ML) increasingly used for phenotyping using electronic health record (EHR) data. Hypothesis: ML algorithms integrating billing and information from narrative notes extracted using natural language processing (NLP) can improve classification of MI compared to billing code algorithms. Improved classification will improve power to compare risk factors across population subgroups. Methods: Retrospective cohort study of nationwide Veterans Affairs (VA) EHR data. MI classified using 2 approaches: (1) published billing code algorithm, (2) published phenotyping pipeline incorporating NLP and ML. Results compared against gold standard chart review of MI outcomes in 308 Veterans. We also tested known association between high density lipoprotein cholesterol (HDL-C) and MI outcomes classified using the 2 approaches among Black and White Veterans, stratified by sex and race; prior study showed HDL-C less protective for Black compared to White individuals. Results: We studied 17,176,658 million Veterans, mean age 69 years, 94% male, 12% self-report Black, 71% White. The billing code algorithm classified MI at positive predictive value (PPV) 0.64 compared to the published ML approach, PPV 0.90; the latter classified a modestly higher percentage of non-White Veterans. Using ML algorithm for MI, we replicated a reduced protective effect of HDL-C in Black vs White male and female Veterans (Table); with the billing code algorithm no association was observed between low density lipoprotein cholesterol (LDL-C) or HDL-C with MI among Black female Veterans. Conclusions: Using nationwide VA data, application of an ML approach improved classification of MI particularly among non-White Veterans, resulting in improved power to study differences in association for MI risk factors among Black and White Veterans.