tbuckley/cabot-search huggingface dataset:
β‐blockers and ACE inhibitors are not a risk factor for severe systemic sting reactions and adverse events during venom immunotherapy
Authors: Gunter Johannes Sturm, Sereina Annik Herzog, Werner Aberer, Teresa Alfaya Arias, Darío Antolín‐Amérigo, Patrizia Bonadonna, Elisa Boni, Andrzej Bożek, Marta Chełmińska, Barbara Ernst, Nina Frelih, Radoslaw Gawlik, Asli Gelincik, Thomas Hawranek, Wolfram Hoetzenecker, Aránzazu Jiménez Blanco, Karolina Kita, Reşat Kendirlinan, Mitja Košnik, Karin Laipold, Roland Lang, Francesco Marchi, Marina Mauro, Marita Nittner‐Marszalska, Iwona Poziomkowska‐Gęsicka, Valerio Pravettoni, Donatella Preziosi, Oliviero Quercia, Norbert Reider, Marta Rosiek‐Biegus, Berta Ruiz‐Leon, Christoph Schrautzer, Pilar Serrano, Aytül Sin, Betül Ayşe Sin, Johanna Stoevesandt, Axel Trautmann, Martina Vachová, Lisa Arzt‐Gradwohl
Journal: Allergy (2021)

There is controversy whether taking β-blockers or ACE inhibitors (ACEI) is a risk factor for more severe systemic insect sting reactions (SSR) and whether it increases the number or severity of adverse events (AE) during venom immunotherapy (VIT).In this open, prospective, observational, multicenter trial, we recruited patients with a history of a SSR and indication for VIT. The primary objective of this study was to evaluate whether patients taking β-blockers or ACEI show more systemic AE during VIT compared to patients without such treatment.In total, 1,425 patients were enrolled and VIT was performed in 1,342 patients. Of all patients included, 388 (27.2%) took antihypertensive (AHT) drugs (10.4% took β-blockers, 11.9% ACEI, 5.0% β-blockers and ACEI). Only 5.6% of patients under AHT treatment experienced systemic AE during VIT as compared with 7.4% of patients without these drugs (OR: 0.74, 95% CI: 0.43-1.22, p = 0.25). The severity of the initial sting reaction was not affected by the intake of β-blockers or ACEI (OR: 1.14, 95% CI: 0.89-1.46, p = 0.29). In total, 210 (17.7%) patients were re-stung during VIT and 191 (91.0%) tolerated the sting without systemic symptoms. Of the 19 patients with VIT treatment failure, 4 took β-blockers, none an ACEI.This trial provides robust evidence that taking β-blockers or ACEI does neither increase the frequency of systemic AE during VIT nor aggravate SSR. Moreover, results suggest that these drugs do not impair effectiveness of VIT. (Funded by Medical University of Graz, Austria; Clinicaltrials.gov number, NCT04269629).
Abstract 14951: Maresin 1 Induces Cardiomyocyte Hypertrophy Through RORα/IGF-1/PI3K/Akt Pathway
Authors: Tri Wahyuni, Arisa Kobayashi, Shota Tanaka, Yoshiaki Miyake, Ayaha Yamamoto, Anton Bahtiar, Matsumoto Kotaro, Makiko Maeda, Masanori Obana, Yasushi Fujio
Journal: Circulation (2020)

Myocardial inflammation is a critical event for the onset and progression of the heart failure. Maresin 1 (MaR1) was originally identified as a macrophage lipid mediator that exhibits anti-inflammatory and pro-resolving activities. Though it is widely accepted that macrophages positively and negatively regulate myocardial inflammation through cytokines and growth factors, the biological functions of lipid mediators, such as MaR1, in cardiomyocytes remain to be addressed. This study explored the functional roles of MaR1 in cardiomyocytes. Neonatal rat cardiomyocytes (NRCMs) were stimulated with MaR1 for 48 hours. Immunofluorescent staining with anti-sarcomeric α-actinin antibody revealed that MaR1 (50 nM) induced a significant increase in cardiomyocyte surface area (1760.34±66.86μm 2 vs. 960.83±29.46μm 2 ). Quantitative RT-PCR analyses revealed that the treatment with MaR1 upregulated the expression of IGF-1 mRNA (2.9±0.6 folds), accompanied by the enhanced level of total and phosphorylated Akt. Interestingly, MaR1 did not influence the expression of BNP and skeletal actin significantly, suggesting that MaR1 induced physiological hypertrophy. Since MaR1 is a ligand of RORα, we examined the effects of RORα blockade (SR3335) and found that this compound inhibited the increase of cardiomyocyte surface area by abrogating MaR1-mediated activation of IGF-1/PI3K/Akt pathway. Importantly, treatment with wortmannin or NVP-AEW541, inhibitors for PI3K or IGF-1 receptor, respectively, suppressed MaR1-induced cardiomyocyte hypertrophy, indicating that IGF-1/PI3K/Akt pathway is essential for MaR1-induced hypertrophy. In conclusion, MaR1 is a novel lipid mediator that induces physiological cardiomyocyte hypertrophy by activating RORα/IGF-1/PI3K/Akt pathway. Thus, MaR1 could coordinate the resolving process and tissue recovery in myocardial inflammation.
Abstract PO-051: The splanchnic mesenchyme during fetal development is the major source of pancreatic cancer associated fibroblasts
Authors: Lu Han, Yongxia Wu, Sean Sweeney, Ulyss Roesner, Khushbu Patel, Melodie Parrish, Xuezhong Yu, Cynthia Timmers, Michael Ostrowski, Gustavo Leone
Journal: Cancer Research (2020)

Abstract In pancreatic ductal adenocarcinoma (PDAC), cancer associated fibroblasts (CAFs) play critical and complex roles in the tumor microenvironment. CAFs are also a major cell type in the desmoplastic stroma in PDAC and may account for half of the entire tumor tissue. Multiple subtypes of CAFs have been identified based on gene expressions, but the tissue origin(s) of CAF subtypes are unknown and genetic tools to robustly target them in vivo are lacking. Here we aimed to examine three potential tissue sources of CAFs: the pancreatic epithelium (through epithelium-to-mesenchyme transition), the bone marrow (through migration via the circulation), and the pancreatic mesenchyme or tissue resident fibroblasts (TRFs) in the normal pancreas (through proliferation). We utilized a genetically engineered mouse model of PDAC, where Kras and p53 mutations were engineered in the pancreatic epithelium using an Flp-Frt system. To determine whether the pancreatic epithelium gives rise to CAFs, we permanently labeled the pancreatic epithelium with a GFP reporter and traced their cell descendants by GFP expression. Despite robust GFP labeling of the epithelium, GFP expression was rarely identified in CAFs, suggesting little contribution of epithelium to the CAF pool. To determine whether the bone marrow gives rise to CAFs, we transplanted donor bone marrow carrying a ubiquitously expressed GFP reporter allele to GFP-negative recipient mice. We found that only a small proportion of pancreatic CAFs were tagged with GFP, suggesting a small proportion of CAFs have a bone marrow origin. Lastly, to determine whether the splanchnic mesenchyme during fetal development gives rise to CAFs, we used an inducible CreER-Loxp system to activate Tomato expression in the splanchnic mesenchyme during mid-gestation, and lineage traced their cell descendants. Tomato expression was identified in the majority of both pancreatic TRFs and CAFs, suggesting that they originate from the splanchnic mesenchyme. In summary, we found that TRFs are derived from the splanchnic mesenchyme during fetal development and they expand to contribute to the vast majority of CAFs in PDAC. The bone marrow contributes to a small proportion of CAFs, and the pancreatic epithelium contributes even less. This provides approaches to robustly target CAFs in vivo to further investigate their heterogeneity and function in PDAC. Citation Format: Lu Han, Yongxia Wu, Sean Sweeney, Ulyss Roesner, Khushbu Patel, Melodie Parrish, Xuezhong Yu, Cynthia Timmers, Michael Ostrowski, Gustavo Leone. The splanchnic mesenchyme during fetal development is the major source of pancreatic cancer associated fibroblasts [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-051.
Regression to the Mean Contributes to the Apparent Improvement in Glycemia 3.8 Years After Screening: The ELSA-Brasil Study
Authors: Maria Inês Schmidt, Paula Bracco, Scheine Canhada, Joanna M.N. Guimarães, Sandhi Maria Barreto, Dora Chor, Rosane Griep, John S. Yudkin, Bruce B. Duncan
Journal: Diabetes Care (2020)

OBJECTIVE Glycemic regression is common in real-world settings, but the contribution of regression to the mean (RTM) has been little investigated. We aimed to estimate glycemic regression before and after adjusting for RTM in a free-living cohort of adults with newly ascertained diabetes and intermediate hyperglycemia (IH). RESEARCH DESIGN AND METHODS The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) is a cohort study of 15,105 adults screened between 2008 and 2010 with standardized oral glucose tolerance test and HbA1c, repeated after 3.84 ± 0.42 years. After excluding those receiving medical treatment for diabetes, we calculated partial or complete regression before and after adjusting baseline values for RTM. RESULTS Regarding newly ascertained diabetes, partial or complete regression was seen in 49.4% (95% CI 45.2–53.7); after adjustment for RTM, in 20.2% (95% CI 12.1–28.3). Regarding IH, regression to normal levels was seen in 39.5% (95% CI 37.9–41.3) or in 23.7% (95% CI 22.6–24.3), depending on use of the World Health Organization (WHO) or the American Diabetes Association (ADA) definition, respectively; after adjustment, corresponding frequencies were 26.1% (95% CI 22.4–28.1) and 19.4% (95% CI 18.4–20.5). Adjustment for RTM reduced the number of cases detected at screening: 526 to 94 cases of diabetes, 3,118 to 1,986 cases of WHO-defined IH, and 6,182 to 5,711 cases of ADA-defined IH. Weight loss ≥2.6% was associated with greater regression from diabetes (relative risk 1.52, 95% CI 1.26–1.84) and IH (relative risk 1.30, 95% CI 1.17–1.45). CONCLUSIONS In this quasi–real-world setting, regression from diabetes at ∼4 years was common, less so for IH. Regression was frequently explained by RTM but, in part, also related to improved weight loss and homeostasis over the follow-up.
Abstract 14034: Sustaining and Spreading Success: Longer Term Outcomes and Spread of a Multi-Center Quality Improvement Project to Reduce Post-operative Chest Tube (CT) Duration (on Behalf of the Pediatric Acute Care Cardiology Collaborative and Pediatric Cardiac Critical Care Consortium)
Authors: Shreya S Sheth, Alaina Kipps, Nicolas L Madsen, Lara Khadr, Margaret Graupe, Ashlin Tignor, MAYTE FIGUEROA, Lawrence Greiten, Stephen Hart, Megan Jensen, Jennifer A Mauney, Taylor Morse, Madalsa Patel, Amelia St John, David Saudek, Katherine E Bates
Journal: Circulation (2020)

Introduction: Using a collaborative learning model, we previously showed reduced post-operative CT duration and length of stay (LOS) after 10 STS benchmark surgeries. Here we report sustained gains across the original 9 centers (labeled era 1) and spread of the project (era 2) to 9 new centers in the PAC 3 -PC 4 network. Methods: Data on patients undergoing surgeries was collected across the two eras. Each era consisted of a baseline phase (era 1: 6/2017-6/2018, era 2: 5/2019-8/2019) and an intervention phase (era 1: 7/2018-3/2020, era 2: 9/2019-3/2020). The primary outcome was post-operative CT duration in hours, with aim of 20% reduction in the intervention vs baseline phases. Balancing measures included rate of reinsertion and readmission for effusion. The collaborative learning model included monthly webinars with peer support, data transparency, and QI education. Statistical process control methods and traditional statistics were used to analyze CT duration and LOS over time. Results: Among 3656 patients at 18 centers, demographics were comparable across eras. Era 1 cohort (n=2779) sustained a 23.5% reduction in CT duration (median 88.9 vs 67.9 hours, p=&lt;.0001) and a 12.5% reduction in LOS days (median 8 vs 7, p=0.03). Era 2 cohort (n=877) showed a 6.95% reduction (median 68.3 vs 63.5 hours, p=0.03) in CT duration in the first 7 months of intervention phase. Across both eras, rates of reinsertion (1.77% vs 1.25%, p=0.48) and readmission for effusion did not change (1.26% vs 2.29%, p=1.00). Conclusions: In this multicenter prospective interventional cohort study, reductions in CT duration and LOS were sustained in 9 centers following a collaborative learning model, without adverse events. Nine new centers show promising early results, suggesting that this intervention can be spread successfully. With its use of phased spread, peer support, data transparency, and education, this project serves as a model for sustaining and spreading clinical quality improvement.
Premature Menopause, Clonal Hematopoiesis, and Coronary Artery Disease in Postmenopausal Women
Authors: Michael C. Honigberg, Seyedeh M. Zekavat, Abhishek Niroula, Gabriel K. Griffin, Alexander G. Bick, James P. Pirruccello, Tetsushi Nakao, Eric A. Whitsel, Leslie V. Farland, Cecelia Laurie, Charles Kooperberg, JoAnn E. Manson, Stacey Gabriel, Peter Libby, Alexander P. Reiner, Benjamin L. Ebert, Pradeep Natarajan
Journal: Circulation (2020)

Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown.We included postmenopausal women from the UK Biobank (n=11 495) aged 40 to 70 years with whole exome sequences and from the Women's Health Initiative (n=8111) aged 50 to 79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of any CHIP and CHIP with variant allele frequency >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes, and hormone therapy use. Secondary analyses considered natural versus surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease.The sample included 19 606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with versus without a history of premature menopause was 8.8% versus 5.5% (P<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: odds ratio, 1.36 [95% 1.10-1.68]; P=0.004; CHIP with variant allele frequency >0.1: odds ratio, 1.40 [95% CI, 1.10-1.79]; P=0.007). Associations were larger for natural premature menopause (all CHIP: odds ratio, 1.73 [95% CI, 1.23-2.44]; P=0.001; CHIP with variant allele frequency >0.1: odds ratio, 1.91 [95% CI, 1.30-2.80]; P<0.001) but smaller and nonsignificant for surgical premature menopause. In gene-specific analyses, only DNMT3A CHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (hazard ratio associated with all CHIP: 1.36 [95% CI, 1.07-1.73]; P=0.012; hazard ratio associated with CHIP with variant allele frequency >0.1: 1.48 [95% CI, 1.13-1.94]; P=0.005).Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease.
Abstract 336: Data-driven Classification of Arrest Location for Emergency Department Cardiac Arrests
Authors: Nancy Mikati, Clifton W Callaway, Patrick J Coppler, Jonathan Elmer
Journal: Circulation (2020)

Introduction: Out-of-hospital cardiac arrest (OHCA), in-hospital cardiac arrest (IHCA), and emergency department (ED) cardiac arrests differ in epidemiology, etiology, and outcomes. Resuscitation research is inconsistent in how ED arrests are classified. We used unsupervised learning to compare ED arrests to non-ED OHCA and to non-ED IHCA. Hypothesis: Clinical features of ED cardiac arrest patients who achieve return of spontaneous circulation (ROSC) are more similar to IHCA than to OHCA. Methods: We performed a retrospective study including all patients resuscitated from cardiac arrest who were treated at a single academic medical center from January 2010 to December 2019. We abstracted clinical information from our prospective registry, including the details of arrest location (ED arrests, OHCA, or IHCA); age; sex; initial arrest rhythm; number of doses of epinephrine, bicarbonate and shocks given during the arrest; duration of arrest; most advanced airway placed intra-arrest; number of rearrests; early post-arrest illness severity (Pittsburgh Cardiac Arrest Category: PCAC); and survival to hospital discharge. We used unsupervised learning (K-prototypes) to identify clusters within the OHCA and IHCA cohorts. We determined the number of subgroups using Scree plots. Finally, we assigned individual ED arrest patients the nearest OHCA or IHCA cluster based on the shortest Gower distance from that patient to the nearest cluster center. Results: We included 2,723 patients: 1,709 (63%) OHCA, 642 (23%) IHCA, and 372 (14%) ED arrests. We identified 3 clusters in the OHCA cohort, and 4 clusters in the IHCA cohort. Of the total ED arrest cases, 292 (78%) most closely resembled an IHCA cluster and 80 (22%) most closely resembled an OHCA cluster. The large majority (64%) of ED arrests that were closest to an IHCA cluster survived to hospital discharge; 50% of this subset were awake post-arrest (PCAC I), and 16% were deeply comatose (PCAC IV). In contrast, only 13% of ED arrests that were closest to an OHCA cluster survived to hospital discharge; 65% of this subset were deeply comatose (PCAC IV) and only 5% were awake post arrest (PCAC I). Conclusion: Among cardiac arrest patients with ROSC, the large majority of ED arrests resemble IHCA more than OHCA.
OP0019 Endogenous dna and arthritis
Authors: V Collins, S Hajizadeh, A Tarkowski
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Recent studies have shown that DNA, in addition to functioning as hereditary material, is able to activate the immune system. In particular, bacterial DNA displays <i>in vivo</i> and <i>in vitro</i> immunostimulatory properties. These properties have been attributed to certain unique properties of bacterial DNA including high content of unmethylated cytosines in CpG dinucleotides. Although eukaryotic nuclear DNA is not immunostimulatory, we have found that mitochondrial DNA (mtDNA), like bacterial DNA, can activate inflammation. <h3>Objectives</h3> The aims of our studies were to assess the arthritogenicity in mice of endogenous mtDNA sequences and to assess a potential role in human inflammatory disease. <h3>Methods</h3> Highly purified mtDNA as well as synthetically produced oligonucleotides were injected intra-articularly into murine knee joints. The development of arthritis was evaluated histopathologically. In addition, we analysed by PCR the synovial fluids (SF) of rheumatoid arthritis (RA) patients for the presence of free mtDNA. <h3>Results</h3> Intra-articular injection of mtDNA and fragments of the mitochondrial genome containing unmethylated CpG sequences gave rise to arthritis in mice. This inflammation was mediated by macrophages and their products, such as TNF-alpha. In contrast, T/B lymphocytes or granulocytes did not participate in the onset or progression of the disease. The SF of 40/54 RA patients tested contained extracellular, PCR-amplifiable mtDNA. <h3>Conclusion</h3> Our results indicate that endogenous mtDNA is pro-inflammatory and may participate in the induction and/or propagation of arthritis in man.
Abstract 16755: Personalized Virtual Cardiac Resynchronization Therapy Simulation Based on a 12-Lead ECG and CMR Predicts Electrical Activation Changes After Cardiac Resynchronization Therapy
Authors: Kenneth C Bilchick, Eric Lluch, Pim Oomen, Xu Gao, Jeffrey W Holmes, Christopher M Kramer, Tommaso Mansi
Journal: Circulation (2020)

Introduction: Simulating electrical remodeling after cardiac resynchronization therapy (CRT) based on individual patient characteristics could enhance the effectiveness of the procedure, help select optimal CRT candidates, and yield important prognostic data. Hypothesis: A Virtual CRT (V-CRT) simulation based on the 12-lead ECG and cardiac magnetic resonance (CMR) for evaluation of biventricular structure and extent of scar with late gadolinium enhancement (LGE) would predict changes in electrical activation after CRT. Methods: V-CRT uses cardiac geometry and scar (LGE) from CMR, a torso avatar from CMR scouts, and an electrophysiology model derived from the baseline ECG, the left ventricular (LV) pacing site, and programmed CRT pacing parameters. Ventricular activation times and the resulting QRS duration (QRSd) after CRT were estimated. The predicted QRS durations were then compared with the actual QRS durations after CRT pacing. Results: 20 CRT patients (age 67.3 ± 10.2 years, 30% female, 50% with LV scar) had a mean pre-CRT QRSd of 151 ± 12.8 ms. This predicted post-CRT QRSd depended significantly on the LV pacing site with a median maximum-minimum difference per patient over all possible pacing sites of 39.8 ms (IQR 32.5-44.2 ms). The post-CRT QRSd predicted by V-CRT based on the actual LV pacing site correlated well with the observed post-CRT QRS duration (r=0.51, p=0.02) (Figure). Predicted changes in the QRS duration were strongly associated with changes in LV activation times (r=0.74, p=0.0002), but not RV activation times (no correlation). Greater predicted reductions in LV activation times were more common in patients with greater LV end-diastolic volume indices (LVEDVIs) by CMR (r=-0.58, p=0.01). Conclusions: V-CRT effectively predicts changes in electrical activation after CRT. These findings have important implications for patient selection for CRT, prognosis after CRT, and CRT implementation strategies.