tbuckley/cabot-search huggingface dataset:
Abstract 10595: Health Related Quality of Life as Predictor of Outcomes in Heart Failure
Authors: Alfonso F Siu, Mingyuan Zhang, Peter Wolhfahrt, Jincheng Shen, Omar Wever-Pinzon, Kevin Shah, Craig H Selzman, Carlos Rodriguez-Correa, Rami Alharethi, Rachel Hess, Stavros G Drakos, Benjamin A Steinberg, Rashmee U Shah, James C Fang, John A Spertus, Abdallah G Kfoury, Tom Greene, Josef Stehlik
Journal: Circulation (2021)

Introduction: Accurate assessment of the risk of adverse outcomes can assist in the management of patients with heart failure (HF). Hypothesis: Health-related quality of life (HRQoL) can improve prediction of HF outcomes beyond that of the more traditional clinical disease characteristics. Methods: We included consecutive patients with HF with reduced ejection fraction (HFrEF) who were seen in the HF clinic and completed patient reported outcome assessment (PROs) as part of routine care. Elastic net and gradient boosting regression analysis were used to build predictive models for HF hospitalization, heart transplant, left ventricular assist device implantation or death (composite outcome), including a range of clinical variables and PRO results as covariates. Results: There were 1,165 patients with HFrEF (mean age 60.5±16.2, 65% male) with median follow-up time of 490 days. Addition of PROs to more traditional risk factors improved model performance, as analyzed by C-statistics. The gradient boosting regression was chosen as the final model based on superior prediction performance - c-statistic 0.733 and favorable stratification of patient risk - Figure 1A . The Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ) and PROMIS dimensions of Satisfaction with social roles and activities and Physical function were covariates with high variable importance measure in the model. The predictive value of PROs was also confirmed by determining freedom from the composite endpoint in the 20th, 50th and 80th percentiles of PRO strata, while assigning the remaining clinical variables a median value ( Figure 1B ). In this analysis, PROs discriminated outcomes independent of other clinical characteristics. Conclusions: HRQoL appears to significantly modify outcome in HFrEF. Routine assessment of PROs could help to more accurately assess risk of adverse outcomes and personalize informed treatment decisions.
Knockout of circRNAs by base editing back-splice sites of circularized exons
Authors: Xiang Gao, Xu-Kai Ma, Xiang Li, Guo-Wei Li, Chu-Xiao Liu, Jun Zhang, Ying Wang, Jia Wei, Jia Chen, Ling-Ling Chen, Li Yang
Journal: Genome biology (2022)

Abstract Many circular RNAs (circRNAs) are produced from back-splicing of exons of precursor mRNAs and are generally co-expressed with cognate linear RNAs. Methods for circRNA-specific knockout are lacking, largely due to sequence overlaps between forms. Here, we use base editors (BEs) for circRNA depletion. By targeting splice sites involved in both back-splicing and canonical splicing, BEs can repress circular and linear RNAs. Targeting sites predominantly for circRNA biogenesis, BEs could efficiently repress the production of circular but not linear RNAs. As hundreds of exons are predominantly back-spliced to produce circRNAs, this provides an efficient method to deplete circRNAs for functional study.
Abstract MP13: Serum Metabolomic Signatures Of Plant-based Diets And Incident Chronic Kidney Disease
Authors: Hyunju Kim, Bing Yu, Xin Li, Kari E Wong, Eric Boerwinkle, Sara B Seidelmann, Andrew S Levey, Eugene P Rhee, Josef Coresh, Casey M Rebholz
Journal: Circulation (2022)

Introduction: Greater adherence to plant-based diets is associated with a lower risk of incident chronic kidney disease (CKD). Metabolomics can help identify blood biomarkers of plant-based diets and understand the underlying mechanisms. Objectives: Using untargeted metabolomics, we aimed to identify metabolites associated with 4 plant-based diet indices (PDI) [overall PDI, provegetarian, healthful PDI, and unhealthful PDI] and incident CKD in 2 subgroups within the Atherosclerosis Risk in Communities Study. Methods: Participants (n 1 =1,762; n 2 =2,152) reported usual dietary intake using a food frequency questionnaire. We used linear regression models to examine the association between 4 PDIs and 374 individual metabolites. We used Cox regression models to evaluate associations between PDI-related metabolites and incident CKD. Estimates were meta-analyzed across 2 subgroups. We calculated C-statistics to assess whether metabolites improved the prediction of those in the highest quintile vs. lower 4 quintiles of PDIs, and whether PDI-related metabolites predicted incident CKD. Results: We identified 82 significant PDI-metabolite associations (overall PDI=27; provegetarian=17; healthful PDI=20; unhealthful PDI=18); 11 metabolites overlapped across the overall PDI, provegetarian, and healthful PDI. The addition of metabolites improved prediction of those in the highest quintile vs. lower 4 quintiles of PDIs compared to participant characteristics alone ( P -value ≤0.001 for all tests). Six PDI-related metabolites representing 2 pathways were significantly associated with incident CKD ( Table ) and improved prediction of incident CKD beyond traditional risk factors (difference in C-statistics for all 6 metabolites=0.005, P -value=0.006). Conclusions: In a community-based study of US adults, we identified metabolites that were related to plant-based diets that predicted incident CKD. These metabolites highlight pathways through which plant-based diets are associated with incident CKD.
Duration of Protection against Mild and Severe Disease by Covid-19 Vaccines
Authors: Nick Andrews, Elise Tessier, Julia Stowe, Charlotte Gower, Freja Kirsebom, Ruth Simmons, Eileen Gallagher, Simon Thelwall, Natalie Groves, Gavin Dabrera, Richard Myers, Colin N.J. Campbell, Gayatri Amirthalingam, Matt Edmunds, Maria Zambon, Kevin Brown, Susan Hopkins, Meera Chand, Shamez N. Ladhani, Mary Ramsay, Jamie Lopez Bernal
Journal: New England Journal of Medicine (2022)

Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), have been used since December 2020 in the United Kingdom. Real-world data have shown the vaccines to be highly effective against Covid-19 and related severe disease and death. Vaccine effectiveness may wane over time since the receipt of the second dose of the ChAdOx1-S (ChAdOx1 nCoV-19) and BNT162b2 vaccines.
Abstract 10124: Chronic Kidney Disease as Predictor for Length of Stay in Patients with New-Onset Atrial Fibrillation with Rapid Ventricular Response
Authors: Vahid Namdarizandi, Awfa Elabidin, Bassman Tappuni, Ali AlKhayru, Belal Kaseer, Leanne Pereira, Michael Fatuyi, Dominique Brandt, Kamal Shemisa
Journal: Circulation (2021)

Background: Atrial fibrillation with rapid ventricular response (AFib with RVR) is an arrhythmia caused by the atria of the heart beating chaotically and irregularly and is frequently associated with worse outcomes in chronic kidney disease (CKD). We sought to investigate the length of stay (LOS) in patients presenting at the emergency department with Afib with RVR and a history of CKD. Methods: Comorbidity, clinical outcomes and length of stay (LOS) were analyzed retrospectively in a cohort of 1638 patients presenting with new-onset of Afib with RVR at the emergency department from 2013 to 2018. Patients with a history of CKD vs. no history of CKD were compared using descriptive statistics, chi-square and Mann-Whitney tests. Results: The 343 patients admitted with a history of CKD had a median [IQR] glomerular filtration rate of 42 [29.4-51], were older 76(10.4) vs. 70.4(14) years of age, p&lt;.0001, were more likely to be African American 12.5% vs. 6.7% p=0.025,OR 1.99 [1.352-2.93] and had a higher median (IQR) CHA 2 DS 2 -VASc score of 5[4-6] vs. 4[2-5] (P&lt;.0001), and their median LOS was 4[2-6] vs.3[1-4] (Fig 1). Conclusion: CKD patients admitted with new-onset of Afib with RVR required additional care and longer LOS. Prevalence of other comorbidities is higher in this population, including heart failure and hypertension (most common), and thyroid disorder and COPD (least common).
15LO1 dictates glutathione redox changes in asthmatic airway epithelium to worsen type 2 inflammation
Authors: Tadao Nagasaki, Alexander J. Schuyler, Jinming Zhao, Svetlana N. Samovich, Kazuhiro Yamada, Yanhan Deng, Scott P. Ginebaugh, Stephanie A. Christenson, Prescott G. Woodruff, John V. Fahy, John B. Trudeau, Detcho Stoyanovsky, Anuradha Ray, Yulia Y. Tyurina, Valerian E. Kagan, Sally E. Wenzel
Journal: Journal of Clinical Investigation (2021)

Altered redox biology challenges all cells, with compensatory responses often determining a cell's fate. When 15 lipoxygenase 1 (15LO1), a lipid-peroxidizing enzyme abundant in asthmatic human airway epithelial cells (HAECs), binds phosphatidylethanolamine-binding protein 1 (PEBP1), hydroperoxy-phospholipids, which drive ferroptotic cell death, are generated. Peroxidases, including glutathione peroxidase 4 (GPX4), metabolize hydroperoxy-phospholipids to hydroxy derivatives to prevent ferroptotic death, but consume reduced glutathione (GSH). The cystine transporter SLC7A11 critically restores/maintains intracellular GSH. We hypothesized that high 15LO1, PEBP1, and GPX4 activity drives abnormal asthmatic redox biology, evidenced by lower bronchoalveolar lavage (BAL) fluid and intraepithelial cell GSH:oxidized GSH (GSSG) ratios, to enhance type 2 (T2) inflammatory responses. GSH, GSSG (enzymatic assays), 15LO1, GPX4, SLC7A11, and T2 biomarkers (Western blot and RNA-Seq) were measured in asthmatic and healthy control (HC) cells and fluids, with siRNA knockdown as appropriate. GSSG was higher and GSH:GSSG lower in asthmatic compared with HC BAL fluid, while intracellular GSH was lower in asthma. In vitro, a T2 cytokine (IL-13) induced 15LO1 generation of hydroperoxy-phospholipids, which lowered intracellular GSH and increased extracellular GSSG. Lowering GSH further by inhibiting SLC7A11 enhanced T2 inflammatory protein expression and ferroptosis. Ex vivo, redox imbalances corresponded to 15LO1 and SLC7A11 expression, T2 biomarkers, and worsened clinical outcomes. Thus, 15LO1 pathway–induced redox biology perturbations worsen T2 inflammation and asthma control, supporting 15LO1 as a therapeutic target.
Phase I Dose-Escalation Study of Venetoclax Plus BEAM Followed By Autologous Stem Cell Transplant (ASCT) for Chemoresistant or High-Risk Relapsed/Refractory Non-Hodgkin Lymphoma (NHL)
Authors: Joseph Maakaron, Qiuhong Zhao, Jayalakshmi Panicker Balakrishna, Marcin Puto, Wesley Ferguson, Sam Penza, Jonathan E Brammer, Kami J. Maddocks, Yvonne A. Efebera, Ayman Saad, Samantha Jaglowski, Basem M. William
Journal: Blood (2021)
Abstract P166: The Joint Secular Trends Of Sleep Quality And Diabetes Among The US Adults
Authors: Xuan Wang, Hao Ma, Shaveta Gupta, Yoriko Heianza, Vivian A Fonseca, Lu Qi
Journal: Circulation (2022)

Introduction: Despite the extensive efforts in controlling diabetes-related modifiable risk factors, two recent studies showed that the estimated prevalence of diabetes in the U.S. has still increased in the past two decades. The sleep quality has been related to the risk of diabetes. Hypothesis: We examined the secular trends of the overall sleep quality, and the joint trends in the prevalence of diabetes by the overall sleep quality among US adults from 2005 to 2018. Methods: A total of 17,046 participants aged 20 years or older, from seven cycles of National Health and Nutrition Examination Survey (NHANES) data between 2005 to 2018, were eligible for the study. A healthy sleep score was calculated based on sleep 7-8 hours, no trouble sleeping, no snoring, no nocturia and no excessive daytime sleepiness to represent an overall sleep quality. The trends in estimated prevalence of diabetes were examined in different sleep quality groups. Results: From 2005 to 2018, the overall sleep quality significantly declined among US adults ( P for trend&lt;0.001). Both the estimated age-standardized prevalence of diabetes and changing trend in prevalence of diabetes varied by the overall sleep quality groups. The highest prevalence of diabetes was consistently observed in the low sleep quality group in each cycle, in which a significantly increasing trend was also noted across cycles ( P for trend=0.004). In contrast, the lowest prevalence of diabetes was consistently observed in the high sleep quality group in each cycle, in which no increasing trend over time was observed ( P for trend=0.346). Such differential secular trends by sleep quality were more significant among Non-Hispanic Whites than other racial/ethnic minorities. Conclusions: The overall sleep quality decreased significantly between 2005-2018 in U.S. adults. The estimated prevalence of diabetes only increased in participants with low or medium overall sleep quality but remained stable in participants with high sleep quality.
Type I interferon transcriptional network regulates expression of coinhibitory receptors in human T cells
Authors: Tomokazu S. Sumida, Shai Dulberg, Jonas C. Schupp, Matthew R. Lincoln, Helen A. Stillwell, Pierre-Paul Axisa, Michela Comi, Avraham Unterman, Naftali Kaminski, Asaf Madi, Vijay K. Kuchroo, David A. Hafler
Journal: Nature Immunology (2022)
Precision Combination Therapies Based on Recurrent Oncogenic Coalterations
Authors: Xubin Li, Elisabeth K. Dowling, Gonghong Yan, Zeynep Dereli, Behnaz Bozorgui, Parisa Imanirad, Jacob H. Elnaggar, Augustin Luna, David G. Menter, Patrick G. Pilié, Timothy A. Yap, Scott Kopetz, Chris Sander, Anil Korkut
Journal: Cancer Discovery (2022)

Abstract Cancer cells depend on multiple driver alterations whose oncogenic effects can be suppressed by drug combinations. Here, we provide a comprehensive resource of precision combination therapies tailored to oncogenic coalterations that are recurrent across patient cohorts. To generate the resource, we developed Recurrent Features Leveraged for Combination Therapy (REFLECT), which integrates machine learning and cancer informatics algorithms. Using multiomic data, the method maps recurrent coalteration signatures in patient cohorts to combination therapies. We validated the REFLECT pipeline using data from patient-derived xenografts, in vitro drug screens, and a combination therapy clinical trial. These validations demonstrate that REFLECT-selected combination therapies have significantly improved efficacy, synergy, and survival outcomes. In patient cohorts with immunotherapy response markers, DNA repair aberrations, and HER2 activation, we have identified therapeutically actionable and recurrent coalteration signatures. REFLECT provides a resource and framework to design combination therapies tailored to tumor cohorts in data-driven clinical trials and preclinical studies. Significance: We developed the predictive bioinformatics platform REFLECT and a multiomics- based precision combination therapy resource. The REFLECT-selected therapies lead to significant improvements in efficacy and patient survival in preclinical and clinical settings. Use of REFLECT can optimize therapeutic benefit through selection of drug combinations tailored to molecular signatures of tumors. See related commentary by Pugh and Haibe-Kains, p. 1416. This article is highlighted in the In This Issue feature, p. 1397
Case 2-2022: A 70-Year-Old Man with a Recurrent Left Pleural Effusion
Authors: Peter C. Grayson, Cory A. Perugino, Vincent V. Dinculescu, Judith A. Ferry
Journal: New England Journal of Medicine (2022)

A 70-year-old man presented with a recurrent left pleural effusion. He had a history of polymyalgia rheumatica, relapsing polychondritis, scleritis, macrocytic anemia, and intermittent neutropenia, all of which had been refractory to multiple immunosuppressive agents. A diagnostic test was performed, and management decisions were made.
Abstract 004: Racial And Ethnic Differences In Cardiac Rehabilitation Participation: Effect Modification By Household Income
Authors: Joshua Garfein, Emily Guhl, Gretchen Swabe, Akira Sekikawa, Emma Barinas-Mitchell, Daniel E Forman, Jared W Magnani
Journal: Circulation (2022)

Introduction: Cardiac rehabilitation (CR) is associated with improved cardiovascular outcomes. Participation remains low, particularly in individuals of non-white race. It remains unclear how household income influences racial/ethnic differences in CR participation. We evaluated (1) differences in CR participation by race/ethnicity in a contemporary sample of insured US adults and (2) assessed how household income modifies associations between race/ethnicity and CR participation. Hypothesis: We hypothesized that individuals of non-white race/ethnicity would have lower participation than those of white race, but that the difference would be attenuated by higher annual household income. Methods: We identified 107,199 individuals with a CR-qualifying diagnosis between 1/1/2016 and 12/31/2018 in Optum’s de-identified Clinformatics® database. We evaluated associations between race/ethnicity and participation in CR, and assessed interaction between race/ethnicity and annual household income. Results: The mean±SD age of all participants was 70.4±11.6 years; 37.4% were female and 76.0% were white race. Overall, 28,443 (26.5%) attended ≥1 CR sessions. After adjustment, compared to white individuals, the odds of attending CR was 45% lower for Asian individuals [95% confidence interval (CI): 39%, 50%], 26% lower for Black individuals (95% CI: 22%, 30%), and 54% lower for Hispanic individuals (95% CI: 51%, 56%), all P &lt;0.0001. The time to CR attendance was also significantly longer for all non-white individuals. Associations between race/ethnicity and attendance at CR differed significantly across household income categories ( P , interaction=0.0005); however, non-white individuals were less likely to attend CR at all incomes. Conclusion: In a geographically and racially diverse cohort, participation in CR was low, especially among non-white candidates. Household income may impact the link between race/ethnicity and attendance at CR, but substantial racial and ethnic disparities exist across incomes.
Abstract 046: Remission Of Prediabetes In Middle-age And Risk Of Long-term Complications
Authors: Amelia S Wallace, Mary R Rooney, Justin Echouffo Tcheugui, Morgan Grams, Elizabeth Selvin
Journal: Circulation (2022)

Background: Prediabetes identifies people at high risk for diabetes and future cardiometabolic disease. It is unclear if remission of prediabetes is associated with better outcomes. Methods: We conducted a prospective cohort study of 7506 participants without diabetes who attended visit 2 (V2, 1990-1992) and visit 4 (V4, 1996-1998) of the Atherosclerosis Risk in Communities (ARIC) Study. We used Cox models to compare risk of mortality, incident diabetes, and cardiovascular and kidney disease over median 21.2 years of follow-up. Participants were classified by glycemia at V2 and V4 - stable normoglycemia: fasting glucose (FG) &lt;100mg/dL at both visits; remission of prediabetes: FG 100-125 mg/dL at V2 and FG &lt;100 mg/dL at V4; progression to prediabetes: FG &lt;100 mg/dL at V2 and FG 100-125 mg/dL at V4; and persistent prediabetes: FG 100-125 mg/dL at both visits. Analyses were adjusted for demographics and cardiometabolic risk factors. Results: There were 4064 (54%) participants (mean age: 56 years; 65% female; 12% black) with stable normoglycemia, 1149 (15%) participants (mean age: 57 years; 52% female; 18% black) with remission of prediabetes at V4, and 1511 (20%) participants (mean age: 57 years; 43% female; 20% black) with persistent prediabetes. As compared to participants with stable normoglycemia, participants with remission of prediabetes had higher risk of incident diabetes (HR 95%CI 1.71, 1.49-1.98), but no other outcomes. Participants with persistent prediabetes had increased risk of all outcomes, including mortality (HR 95%CI 1.13, 1.03-1.24), and incident diabetes (HR 95% CI 3.24, 2.88-3.65) ( Table ). Conclusions: Persistent prediabetes over 6 years in middle age was associated with increased risk of mortality and cardiometabolic disease as compared to stable normoglycemia. People with remission of prediabetes had increased risk of diabetes, but no increased risk of long-term clinical outcomes. Repeat measures of glycemia in middle age could improve risk-stratification for future cardiometabolic disease.
Neutralization of SARS-CoV-2 Variants in Transplant Recipients After Two and Three Doses of mRNA-1273 Vaccine
Authors: Deepali Kumar, Victor H. Ferreira, Victoria G. Hall, Queenie Hu, Reuben Samson, Terrance Ku, Matthew Ierullo, Beata Majchrzak-Kita, George Tomlinson, Anne-Claude Gingras, Atul Humar
Journal: Annals of Internal Medicine (2021)

COVID-19 is more severe in transplant recipients. Variants of concern have supplanted wild-type virus. In transplant recipients, data are limited on 2-dose or 3-dose vaccine immunogenicity against variant viruses.To assess neutralizing antibody responses against SARS-CoV-2 variants in transplant recipients after 2 and 3 vaccine doses.Secondary analysis of a randomized, double-blind, controlled trial of a third dose of mRNA-1273 vaccine versus placebo. (ClinicalTrials.gov: NCT04885907).Single-center transplant program.Organ transplant recipients.Third dose of mRNA-1273 vaccine versus placebo.Sera were analyzed for neutralization against wild-type virus and the Alpha, Beta, and Delta variants using a surrogate virus neutralization assay and a spike-pseudotyped lentivirus assay.A total of 117 transplant recipients were analyzed (60 in the mRNA-1273 group and 57 in the placebo group). Sera were obtained before and 4 to 6 weeks after the third dose. After 2 doses, the proportion of patients with positive neutralization for all 3 variants was small compared with wild-type virus. After the third dose of mRNA-1273 vaccine, the proportion with a positive neutralization response versus placebo was improved for all 3 variants as measured by both assays. Based on the pseudovirus neutralization assay against the Delta variant, 33 of 60 (55%) patients were positive in the mRNA-1273 group versus 10 of 57 (18%) in the placebo group (difference, 37 [95% CI, 19 to 53] percentage points). The differences were 36 (CI, 17 to 51) percentage points for the Alpha variant and 31 (CI, 15 to 46) percentage points for the Beta variant. In the mRNA-1273 group, lower neutralization values were observed for variants compared with wild-type virus, especially the Beta variant.There is no clear correlate of protection for neutralizing antibody. This was a secondary analysis.In organ transplant recipients, a third dose of mRNA vaccine increases neutralizing antibody response against SARS-CoV-2 variants compared with placebo.Ajmera Transplant Centre.