tbuckley/cabot-search huggingface dataset:
Abstract 11282: Meta-Analysis of Residential Portable Air Cleaner Use and Circulating Inflammatory Biomarkers
Authors: Sharine Wittkopp, Dalia Walzer, Lorna Thorpe, Tim Roberts, Yuhe Xia, Terry Gordon, Robert D Brook, George Thurston, Jonathan D Newman
Journal: Circulation (2021)

Introduction: Fine particulate matter air pollution (PM 2.5 ) exposure is associated with elevated circulating inflammatory biomarkers implicated in cardiovascular disease (CVD). Portable Air Cleaners (PAC)s reduce PM 2.5 exposure and may lower concentrations of inflammatory biomarkers. Methods: We performed a systematic review and meta-analysis of randomized crossover trials of in-home high efficiency particulate air (HEPA) PACs vs. sham control on changes in CRP, IL-6, and/or TNFα among adults with no smoking exposure using Medline, Embase, and Cochrane Central Register of Controlled Trials with the Ovid Platform, Inspec, Compendix, and Web of Science Core Collection. Two investigators (S.W, D.W.) independently screened and reviewed the studies. We used RevMan 5.3 to perform the meta-analysis. Results: Search results included 459 articles screened, 26 selected for full review, and 14 that met inclusion criteria, representing N=724 participants included in the meta-analysis. Ten studies reported CRP, 9 reported IL-6, and 5 reported TNFα. Based on WHO guidelines, 5 studies were in regions of extreme PM 2.5 exposure (&gt;35 μg/m 3 ), 3 were high (10-35 μg/m 3 ), 3 were low (&lt;10 μg/m 3 ), and 2 lacked baseline PM 2.5 . Median (± S.D.) duration of HEPA/sham use was 9 ± 6.6 days. Reductions in PM 2.5 ranged from 2.6 to 54.9 μg/m 3 (35-82%) and varied by baseline PM 2.5 , although reporting of baseline PM 2.5 was incomplete across trials. Compared to sham PAC use, active PACs were associated with a 7% lower CRP (95% CI -13%, 0%) and 12% lower IL-6 (-22%, -2%), P&lt;0.05 for both (Figure). Subgroup analyses demonstrated consistency of effect of PACs across levels of baseline PM 2.5 . Conclusions: Our data demonstrate that PAC use is associated with significant reductions in circulating CRP and IL-6, with a magnitude of effect similar to clinical trials of statins and IL-1β inhibition. Given the role of inflammation in CVD, PACs may be useful to reduce systemic inflammation and cardiovascular risk.
TMOD-31. AN ORGANOTYPIC TISSUE PLATFORM TO BRIDGE IN VITRO AND IN VIVO ASSAYS FOR BRAIN CANCER TREATMENT
Authors: Breanna Mann, Noah Bell, Denise Dunn, Scott Floyd, Shawn Hingtgen, Andrew Satterlee
Journal: Neuro-Oncology (2021)

Abstract Brain cancers remain one of the greatest medical challenges. The lack of experimentally tractable models that recapitulate brain structure/function represents a major impediment. Platforms that enable functional testing in high-fidelity models are urgently needed to accelerate the identification and translation of therapies to improve outcomes for patients suffering from brain cancer. In vitro assays are often too simple and artificial while in vivo studies can be time-intensive and complicated. Our live, organotypic brain slice platform can be used to seed and grow brain cancer cell lines, allowing us to bridge the existing gap in models. These tumors can rapidly establish within the brain slice microenvironment, and morphologic features of the tumor can be seen within a short period of time. The growth, migration, and treatment dynamics of tumors seen on the slices recapitulate what is observed in vivo yet is missed by in vitro models. Additionally, the brain slice platform allows for the dual seeding of different cell lines to simulate characteristics of heterogeneous tumors. Furthermore, live brain slices with embedded tumor can be generated from tumor-bearing mice. This method allows us to quantify tumor burden more effectively and allows for treatment and retreatment of the slices to understand treatment response and resistance that may occur in vivo. This brain slice platform lays the groundwork for a new clinically relevant preclinical model which provides physiologically relevant answers in a short amount of time leading to an acceleration of therapeutic translation.
Abstract 13283: Mitochondrial DNA Damage and Remodelling of Nucleoid Bodies in Pulmonary Artery Smooth Muscle Cells From Human Patients With Pulmonary Arterial Hypertension
Authors: Jenna A Rossi, Kimberly J Dunham-Snary, Jeffrey D Mewburn, Stephen L Archer
Journal: Circulation (2021)

Introduction: Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy characterized by pulmonary artery smooth muscle cell (PASMC) hyperproliferation. PAH-PASMC have mitochondrial defects, including increased fragmentation, and increased production of reactive oxygen species (ROS). Mitochondrial-derived ROS can cause DNA damage. Mitochondrial DNA (mtDNA) is surrounded by replication proteins which form nucleoid bodies (NB). Hypothesis: We hypothesize that mtDNA damage is increased and NB structure altered in human PAH PASMC. Methods &amp; Results: We profiled mtDNA and NB composition and integrity in control and PAH PASMC (n = 5/group). mtDNA content was assessed via confocal immunofluorescence of discrete extranuclear double-stranded DNA colocalized with mitochondria. Lower mtDNA content was observed in PAH PASMC vs control (1.8±0.2 vs 3.5±0.2 mtDNAs/μm 3 mitochondria, p&lt;0.0001). Reduced mtDNA in PAH vs control was validated by qPCR (0.69±0.07 vs 1.00±0.07 ng mtDNA/μg cellular protein, n=4-5, p=0.0182). siRNA targeting of Mitofusin2 (Mfn2) in normal PASMC to mimic the mitochondrial fragmentation of PAH, reduced total mtDNA compared to control (1.05±0.06 vs 3.5±0.2 mtDNA/μm 3 mitochondria, n=9, p&lt;0.0001), suggesting increased fission reduces mtDNA expression. Amplification of an 8.8kb mtDNA fragment, a measure of mtDNA damage, revealed increased damage in PAH vs control (14.3±3.9 vs 28.7±2.4 pg mtDNA, n=4, p=0.02). PAH PASMC exhibited higher expression of NB proteins vs control (n=5/measurement): TFAM (+96.7±23.3%, p=0.0032), SSBP (+63.4±14.4%, p=0.0023), and POLG (+59.0±24.0%, p=0.0397). These results were confirmed via immunoblotting for TFAM (+161.9±39.3%, n=4-5, p=0.0045) . Immunofluorescence verified increased TFAM in PAH PASMC vs control. Conclusions: We report a paradoxical upregulation of NB proteins despite reduced mtDNA content and elevated mtDNA damage in PAH. We speculate there is an unsuccessful compensatory attempt to restore mtDNA levels by increasing the expression of mtDNA’s replication apparatus in PAH PASMC.
Abstract 12993: Administration of Echogenic Immunoliposome-Targeted CD146 <sup>+</sup> Mesenchymal Stem Cells Reduces Hypercholesterolemia and Atherosclerosis
Authors: Yong-jian Geng, Melvin E Klegerman, Song Gao, Harnath S Shelat, David D McPherson
Journal: Circulation (2021)

Introduction and Hypothesis: Mesenchymal stem cells (MSC) have been used to treat atherosclerosis and diabetes in animal studies and clinical trials. We developed a nanotechnology in which MSC can be targeted with anti-CD146/ICAM bifunctional (BF) echogenic immunoliposomes (ELIP) for treatment of atherosclerosis. Here, we tested the hypothesis that BF-ELIP targeted MSC therapy is biologically safe and effective for preventing hypercholesterolemia and atheroma. Methods and Results: BF-ELIP with antibodies to the mesenchymal marker CD146 and the adhesion protein ICAM-1 were mixed with CD146 + MSC grown from adipose tissue of green fluorescence protein (GFP)-transgenic mice. The BF-ELIP/MSC mixtures or controls, such as non-immune ELIP (NE)/MSC mixtures, NE and MSC alone, were intravenously administered to C57BL/6J wild type (WT) and apolipoprotein-E deficient (ApoE -/- ) mice, which were age-/sex-matched. In a nearly 4 months followup, all the mice survived the ELIP/MSC injection without major adverse effects observed. No major difference in blood pressure was found between ELIP/MSC-treated and non-MSC controls. Total cholesterol and glucose were examined in blood samples collected from the animals. ApoE -/- mice developed significantly higher cholesterol (p&lt;0.05) but lower glucose (p&lt;0.05) levels than WT mice. The BF-ELIP targeted MSC injection reduced levels of total cholesterol and, to a lesser extent, glucose (p&lt;0.05). Non-invasive ultrasound confirmed enhancement of ELIP echogenicity and imaging of atheroma. Fluorescence microscopy illustrated GFP expression in the MSC mixtures and the arterial wall with atheroma. H&amp;E and Oil-Red O staining showed reduced plaque formation and lipid loading in the arterial wall of ApoE -/- but not WT mice with the MSC delivery. Conclusions: Administration of BF-ELIP targeted MSCs appears to be a safe, effective procedure, which may mitigate hypercholesterolemia and atherogenesis.
Civil disobedience is a last resort
Authors: Anthony MacKenzie-Gureje
Journal: BMJ (2021)

A worsening climate crisis evidently carries several associated negative health outcomes in given populations, including potential increased global mortality and displacement of populations.1 As doctors, we have beneficence and non-maleficence deeply and inexorably encoded into our profession, so I agree that we have a duty not just to raise awareness of climate change but to engage in processes and discussions that will mitigate its effects. …
A Retrospective Multicenter Case Study Evaluating the Characteristics, Management and Outcome of Acquired Amegakaryocytic Thrombocytopenia
Authors: Anais Roeser, Guillaume Moulis, Mikael Ebbo, Louis Terriou, Elsa Poullot, Bertrand Lioger, Marie Chilles, Hélène Labussière, Christelle Mausservey, Micheline Pha, Mathieu Puyade, Stephane Cheze, Nicolas Limal, Corinne Haioun, Marc Michel, Bertrand Godeau, Matthieu Mahevas
Journal: Blood (2021)
Abstract 10610: Schistosomiasis and Cardiovascular Disease in 1,000 HIV-Infected and Uninfected Tanzanian Adults: A Prospective Cohort Study
Authors: Justin Kingery, Brooke Bullington, Myung Hee Lee, Bernard Desdarius, Salama Fadhil, Godfrey Kisigo, Peter Shigella, Jennifer Downs, Robert Peck
Journal: Circulation (2021)

Background: Variations in immune phenotype are increasingly recognized as drivers of cardiovascular disease (CVD). For example, the inflammatory effect of HIV-infection is associated with a 2-fold higher risk of CVD. Conversely, schistosome infection induces an anti-inflammatory immune response, which may counter CVD pathways related to inflammation. Whether the immune regulatory effect of schistosome infection is sufficient to suppress the contrasting stimulatory effect of another disease such as HIV remains unknown and may provide critical insight into the immunologic basis of non-communicable diseases. Methods: In this prospective cohort study, we enrolled 1,000 HIV-infected and uninfected adults at a referral HIV clinic in a schistosome endemic area in Mwanza, Tanzania. Standardized history, echocardiography and serum were obtained. Blood pressure was monitored over two years. Regression models adjusted for age and sex were used to quantify associations. Results: We enrolled 503 schistosome infected and 497 uninfected adults with a median age of 36 [28- 43]. Schistosome infection was significantly associated with a lower prevalence of hypertension (39.6% vs 46.7%, p=0.016), myocardial diastolic dysfunction (8.1% vs 13.4%, p=0.015) and total-to-high density lipoprotein ratio (1.77 vs 1.82, p&lt;0.0001) as compared to uninfected participants. Additionally, schistosome-infection was associated with significantly improved change in blood pressure over time (0.67 vs 3.35 mmHg increase, p=0.005). When stratified by concurrent HIV-infection, schistosome infection was associated with lower prevalence of diastolic dysfunction and total-to-HDL ratio in HIV- infected adults but lower prevalence of hypertension in those without HIV-infection. Conclusions: We provide the first evidence that schistosome infection may directly impact cardiac function and slow the age-related increase in blood pressure over time. Further, associations between schistosome and CVD differ by HIV status, implying that immune mediated interactions may have important physiologic ramifications for CVD. The patterns of these interactions may provide insight into the immunologic mechanisms of cardiovascular diseases.
Abstract 9500: One-Year Safety and Effectiveness of Bivalirudin in Patients Undergoing Elective Percutaneous Coronary Intervention
Authors: Jiawen Li, Yuejin Yang, Jinqing Yuan, Xueyan Zhao
Journal: Circulation (2021)

Introduction: A lot of large studies (HORIZONS-AMI, BRIGHT, EUROMAX, etc.) have shown that bivalirudin in acute myocardial infarction patients undergoing primary percutaneous coronary intervention (PCI) could reduce the bleeding while prevent thrombosis. However, data on patients undergoing elective PCI are lacking which warrants research attention. Methods: 1152 patients undergoing elective PCI anticoagulated with bivalirudin and 10251 patients anticoagulated with UFH were performed propensity score matching at 1:2 ratio. Finally, 957 and 1713 patients were enrolled in bivalirudin and UFH group respectively. The safe endpoints were according to the Bleeding Academic Research Consortium (BARC). The effective endpoint was major adverse cardiac and cerebrovascular events (MACCE). Results: During one-year follow-up, multivariate Cox analysis showed bivalirudin group had a reduction in the risk of BARC 2, 3 or 5 bleeding (HR: 0.580, 95% CI: 0.340-0.989, P=0.045), but not in the risk of BARC 3 or 5 bleeding (P=0.214) compared with UFH with or without glycoprotein IIb/IIIa inhibitors (GPI) group. To further study, we also analyzed 254 (14.8%) patients with GPI in UFH group and then found the risk of BARC 2, 3 or 5 bleeding in bivalirudin group reduced (P=0.001). As for MACCE, there was no significant difference between bivalirudin group and UFH with or without GPI group (P=0.159). Moreover, there was also no significant difference in the risk of death, revascularization, intrastent thrombosis or stroke, but a reduction in the risk of MI between bivalirudin group and UFH with or without GPI group (P=0.002). Conclusions: In patients undergoing elective PCI, bivalirudin significantly reduced the risk of BARC 2, 3 or 5 bleeding, but not that of BARC 3 or 5 bleeding compared UFH with or without GPI. No significant difference in MACCE between two groups, while bivalirudin significantly reduced the risk of MI.
Abstract 9794: Factors Associated with Enhanced Low-Density Lipoprotein Cholesterol Lowering with Bempedoic Acid Among Patients Enrolled in Phase 3 Studies
Authors: Christie M Ballantyne, Harold E Bays, Jeremy Smart, Yang Zhang, Kausik K Ray
Journal: Circulation (2021)

Bempedoic acid (BA) inhibits ATP-citrate lyase in the cholesterol synthesis pathway. In phase 3 studies, 12 weeks of BA lowered low-density lipoprotein cholesterol (LDL-C) levels compared with placebo by a mean of 17.8% among patients primarily receiving moderate- to high-intensity statin and by 24.5% among statin intolerant patients who were receiving low-dose or no statin. Cholesterol guidelines (Grundy et al. J Am Coll Cardiol . 2019;73:e285) categorize statins according to percent LDL-C lowering: high-intensity (≥ 50%), moderate-intensity (30-49%), and low-intensity (&lt; 30%). We examined LDL-C lowering with BA similarly using pooled data from 4 phase 3 studies in patients on background maximally tolerated statins; 3488 (2321 BA, 1167 PBO) patients were included in the analysis. From baseline to week 12, BA lowered LDL-C levels comparable to that of a moderate- or high-intensity statin (≥ 30%) in 28.9% of patients; this degree of LDL-C lowering was observed in 50.9% of the patients not receiving background statin therapy (Table). A multivariate analysis showed that the absence of baseline statin use was associated with increased rates of achieving at least a 30% reduction in LDL-C with BA treatment (odds ratio [95% CI], 2.49 [1.94, 3.19; P &lt; .0001). Further, being female, a history of diabetes, baseline ezetimibe use, and a higher baseline hsCRP level were also associated with at least a 30% reduction in LDL-C levels ( P &lt; .01 for each). These findings suggest that 1) a significant proportion of patients initiating BA treatment may achieve LDL-C lowering comparable to moderate- or high-intensity statin therapy, especially among patients who cannot tolerate a statin, and 2) patients with hypercholesterolemia who are at higher risk for a cardiovascular event, including women and patients with a history of statin intolerance, diabetes, or higher baseline hsCRP levels, may also achieve enhanced LDL-C lowering with bempedoic acid.
NIMG-51. DEUTERIUM METABOLIC IMAGING OF BRAIN TUMOR IMMORTALITY USING 2H-PYRUVATE
Authors: Georgios Batsios, Céline Taglang, Meryssa Tran, Anne Marie Gillespie, Sabrina Ronen, Joseph Costello, Pavithra Viswanath
Journal: Neuro-Oncology (2021)

Abstract Telomere maintenance is essential for tumor immortality and sustained tumor proliferation. Most tumors, including high-grade glioblastomas and low-grade oligodendrogliomas achieve telomere maintenance via reactivation of the expression of telomerase reverse transcriptase (TERT), which is silenced in normal somatic cells. Due to this essential role, TERT is a therapeutic target and TERT inhibitors such as 6-thio-2’-deoxyguanosine are in clinical trials. Non-invasive methods of imaging TERT, therefore, have the potential to provide a readout of tumor proliferation and response to therapy. We previously showed that TERT expression is associated with elevated levels of NADH in gliomas. Since NADH is essential for the conversion of pyruvate to lactate, measuring pyruvate flux to lactate could be useful for imaging TERT expression. In this context, deuterium magnetic resonance spectroscopy (2H-MRS) recently emerged as a novel, clinically translatable method of monitoring metabolic fluxes. The goal of this study was to assess the potential of [U-2H]pyruvate for non-invasive imaging of TERT status in gliomas. Following intravenous injection of [U-2H]pyruvate, lactate production was significantly higher in mice bearing orthotopic oligodendroglioma (SF10417, BT88) or glioblastoma (GBM1, GBM6) tumors relative to tumor-free controls. 2D chemical shift imaging showed localization of lactate production to tumor vs. contralateral normal brain. Importantly, following treatment of mice bearing orthotopic GBM6 or BT88 tumors with the TERT inhibitor 6-thio-2’-deoxyguanosine, lactate production from [U-2H]pyruvate was significantly reduced at early timepoints when alterations in tumor volume could not be detected by anatomical imaging, pointing to the ability of [U-2H]pyruvate to report on pseudoprogression. Collectively, we have, for the first time, demonstrated the utility of [U-2H]pyruvate for metabolic imaging of brain tumor burden and treatment response in vivo. Importantly, since 2H-MRS can be implemented on clinical scanners, our results provide a novel, non-invasive method of integrating information regarding a fundamental tumor hallmark, i.e. TERT, into glioma patient management.
Abstract 12236: Population-Level Analyses of Alcohol Consumption as a Predictor of Acute Atrial Fibrillation Episodes
Authors: Sidney Aung, gregory nah, Eric Vittinghoff, Christopher Groh, Christina Fang, Gregory M Marcus
Journal: Circulation (2021)

Introduction: We conducted an instrumental variable analysis to test whether acute alcohol consumption leads to increased emergency department (ED) visits for AF at the level of the general population. Methods: We analyzed blood alcohol concentration measurements obtained from individuals using commercially available Bluetooth-enabled breathalyzer devices (BACtrack, San Francisco, CA) collected between January 1, 2014 and December 31, 2016 to identify dates associated with heightened alcohol consumption that corresponded to recurrent, nationally-recognized events. Outcomes included ED visits with AF (main analysis) or supraventricular tachycardia (SVT; as a negative control) in California between January 1, 2005 to December 30, 2015 using Office of Statewide Health Planning and Development data. A secondary analysis examining rates of new-onset AF was conducted. We utilized population denominators for age, sex, and race/ ethnicity in California from the US Census. Multivariable adjusted Poisson regression models were utilized to compare rates of AF during and 6 days following instrumental events compared to all other days of the year. Results: Using 1,269,054 breath alcohol measurements obtained from 36,158 individuals, we identified 8 recurring events associated with heightened alcohol consumption. After multivariable adjustment, excess alcohol consumption inferred from our instrumental variables was associated with 719 additional AF visits per 100,000 person-years (95% CI 189-1249, p = 0.008; Table ). The association between these events and new-onset AF exhibited a stronger effect (1,757 additional visits, 95% CI 945-2,569, p &lt; 0.001). A negative control analysis failed to exhibit significantly heightened rates of SVT during those same dates. Conclusion: These data suggest that acute alcohol consumption is associated with a higher risk for discrete AF episodes, as well as for new-onset (incident) AF, in the general population.
Abstract 9874: Cardiovascular Safety of Sleeve Gastrectomy vs. Roux-en-y Gastric Bypass Among Older Patients with Type 2 Diabetes
Authors: Karine Suissa, Sebastian Schneeweiss, Matthew Hutter, Seoyoung C Kim, Elisabetta Patorno
Journal: Circulation (2021)

Introduction: Surgical treatment for obesity, a major risk factor for diabetes and cardiovascular disease, may lead to important improvements in cardiovascular health. Sleeve gastrectomy (SG) procedures have gained popularity over Roux-en-Y gastric bypass (RYGB), though it is unclear which procedure results in improved cardiovascular outcomes. Our objective was to evaluate the comparative cardiovascular safety of SG vs. RYGB in older patients with type 2 diabetes (T2D). Methods: Using Medicare claims data, we identified a cohort of T2D patients ≥65 years that underwent a SG or RYGB procedure between 2010 and 2018. Patients undergoing a SG were propensity-score (PS) matched 1:1 to RYGB patients on the propensity score of receiving the procedure. The two co-primary outcomes were a major adverse cardiovascular event (MACE, a composite of stroke, myocardial infarction (MI) or all-cause mortality) and hospitalization for heart failure (HHF). Secondary outcomes were the individual components of MACE. Subjects were followed until the occurrence of an outcome, end of patient data or enrollment or death, whichever came first. We estimated the hazard ratios (HR) for each outcome, adjusting for demographics, comorbidities, medication use and healthcare utilization using PS matching. Results: A total of 5,514 patients undergoing SG were PS-matched to 5,514 undergoing RYGB and followed for a median of 2.3 years (IQR: 1.2, 3.9) after the procedures. Compared to RYGB, patients undergoing SG had a similar risk of MACE (rate 2.5 vs. 3.0 per 100 person-years (py); HR: 0.94; 95% CI: 0.82, 1.09) and of HHF (rate 12.2 vs. 10.9 per 100 py; HR: 1.01; 95%CI: 0.94, 1.09). For secondary outcomes, the risk of MI was higher for SG (rate 0.8 vs. 0.7 per 100 py; HR: 1.33, 95%CI: 1.02, 1.75), whereas SG was associated with a lower risk of all-cause mortality (rate 1.5 vs. 2.2 per 100 py; HR: 0.68; 95%CI: 0.57, 0.81). Conclusions: In older patients with T2D, SG was associated with a similar risk of MACE and HHF compared to RYBG. However, when we assessed the individual components of MACE separately, SG was associated with a higher risk of MI and a lower risk of death, compared with RYBG.
Clonal Hematopoiesis Is More Common in People Living with HIV and May be Associated with Increased Prevalence of Cardiovascular Disease
Authors: Sergiu Pasca, Shiyu Wang, Susan Langan, Aparna Pallavajjala, Lisa Haley, Christopher D Gocke, Wendy S Post, Matthew Budoff, Sabina Haberlen, Todd Brown, Joseph Margolick, Richard F. Ambinder, Lukasz P. Gondek
Journal: Blood (2021)