tbuckley/cabot-search huggingface dataset:
Abstract 10696: Cerebral Blood Flow and Vascular Function Are Impaired in Adults Who Report Adverse Childhood Events
Authors: Paula Rodriguez Miguelez, Jacob Looney, Marsha Blackburn, jeffrey thomas, Jennifer Pollock, Ryan A Harris
Journal: Circulation (2021)

Introduction: Adverse childhood events (ACEs), including abuse, neglect, or severe household dysfunctions, have been associated with the development of premature cardiovascular disease (CVD) during adulthood. Acute and intense emotional stress leads to structural changes in the brain that reduce cerebral blood flow, specifically in the medial prefrontal cortex (mPFC). In response, the body releases stress hormones and mediators that cause peripheral vascular dysfunction, a prognostic marker of CVD. Whether or not ACEs predispose adults to reductions in mPFC blood flow and associated peripheral vascular dysfunction has yet to be investigated. Hypothesis: This study sought to test the hypotheses that ACEs contribute to reductions in mPFC blood flow and associated peripheral vascular dysfunction. Methods: Fifty-three young adults (34 ± 3 yrs), with no evidence of overt CVD, were divided into a high (HiA) and no (NoA) ACE group based on their self-reported ACE questionnaire score: HiA: ACE score ≥ 4 (n=17) or NoA: ACE score = 0 (n=36). Near-infrared spectroscopy was utilized to assess blood flow (tHb), O 2 delivery (O 2 Hb), and O 2 consumption (HHb) in the mPFC. Peripheral vascular function was determined using the flow-mediated dilation (FMD) technique. Results: The HiA group had a significantly ( p =0.009) lower tHb compared to the NoA (56 ± 4 vs. 69 ± 3 μM, respectively). In addition, O 2 Hb and HHb were significantly ( p ≤0.04) reduced in the HiA when compared to the NoA. Likewise, FMD was significantly ( p =0.001) lower in HiA (6.3 ± 0.7%) compared to NoA (9.4 ± 0.5%). Significant associations were also identified between ACEs and tHb ( r = -0.574; p =0.001) and between tHb and FMD ( r =0.477; p =0.021). Conclusion: For the first time, we have documented that blood flow in mPFC is reduced and vascular function is impaired in adults who reported ACEs compared with adults who did not report ACEs. Notably, individuals exposed to a greater number of ACEs present with lower cerebral blood flow and higher CVD risk. Future studies are warranted to evaluate possible mechanisms underlying these dysfunctions as well as potential therapeutic interventions to reduce as well as to prevent the exacerbated CVD risk observed in individuals exposed to ACEs.
Abstract 11866: Cardiorespiratory Fitness and Mortality in Older Adults Age 60 to 90 Years
Authors: Tydus Thai, Karo Gyurjian, Bryant Hammershaimb, Derek Phan, Cheng Chen, Franz Schweis, Aiyu Chen, chengyi zheng, Ming Lee
Journal: Circulation (2021)

Introduction: With an aging population and advances in technology and surgical interventions, physicians are sometimes faced with difficult treatment decisions for older patients. Invasive treatment options may not be beneficial in older adults with limited survival. Chronological age alone does not fully reflect a patient’s prognosis and should not be the only factor used to guide treatment decisions. In this study, we assessed the association of cardiorespiratory fitness with all-cause mortality among adults age 60 to 90 years. Methods: This retrospective cohort study included patients age 60-90 years who underwent symptom-limited exercise treadmill testing at an integrated health system from 2011 to 2019. Patients were categorized into three age groups: 60-70 years, 70-80 years, and 80-90 years. Cardiovascular fitness was categorized into low fitness (&lt;5 METs), moderate fitness (5-10 METs), and high fitness (&gt;10 METs). Median follow-up was 3.5 years. Hazard ratios (HR) associated with exercise capacity were calculated using multivariable Cox regression models. Results: The study cohort included 40520 patients: 27021 (66.7%) age 60-70 years, 11638 (27.6%) age 70-80 years, and 1861 (4.6%) age 80-90 years. After treadmill testing, 3494 (8.6%) were categorized as low fitness, 21863 (54.0%) as moderate fitness, and 15163 (37.4%) as high fitness. Older age, female sex and presence of cardiovascular risk factors including hypertension, diabetes, and chronic kidney disease were associated with having low fitness. Low fitness and higher chronological age were independently associated with lower survival. Using the age 60-70 years group with high fitness as reference, the age 80-90 group with high fitness had better survival than their younger counterparts with low fitness (age 80-90 high fitness: HR 2.9, 95% CI 1.2-7.2; age 60-70 low fitness HR 4.3, 95% CI 3.1-5.9; age 70-80 low fitness HR 6.8, 95% CI 5.2-8.9). Conclusions: High cardiorespiratory fitness is a strong predictor of survival. When assessing a patient’s prognosis for long-term survival, chronological age alone should not be the only factor considered. Evaluation of cardiorespiratory fitness using treadmill testing may be useful for tailoring prognostic information.
BIOM-18. METHYLATION ANALYSIS TO REVEAL THE CELLULAR ORIGIN OF PROGNOSTIC CIRCULATING CELL-FREE DNA IN GLIOBLASTOMA
Authors: Jacob Till, Aseel Abdalla, Zhuoyang Wang, Wanding Zhou, S Ali Nabavizadeh, Zev Binder, Jasmin Hussain, Taylor Black, Stephanie Yee, Arati Desai, Stephen J Bagley, Erica Carpenter
Journal: Neuro-Oncology (2021)

Abstract We have previously demonstrated an independent association between high levels of plasma circulating cell-free DNA (ccfDNA) concentration and poor survival outcomes in patients with newly diagnosed glioblastoma. Given that somatic mutations are rarely detected in glioblastoma patient plasma, we reasoned that DNA shed by tumor (circulating tumor DNA, ctDNA) was not likely to be a driver of prognostic increases in ccfDNA. To investigate the tissue of origin for this prognostic ccfDNA, we analyzed the plasma ccfDNA methylation signatures of 23 patients with newly diagnosed glioblastoma using the Illumina Infinium EPIC array, a genome-wide DNA methylation technique covering over 850,000 CpG sites. Deconvolution of the ccfDNA methylation signatures based on published reference methylomes revealed an increased proportion of ccfDNA derived from granulocytes in glioblastoma specimens compared to healthy controls (p &amp;lt; 0.0001). Further, this granulocyte proportion was increased in patients with high ccfDNA levels (above median value) compared to patients with low ccfDNA (p = 0.0001). Granulocyte proportion correlated with ccfDNA concentration (Spearman r = 0.64, p = 0.001). The top two gene sets identified by differential methylation analysis followed by gene set enrichment analysis (methylGSA) between high- and low-ccfDNA specimens were “neutrophil activation involved in immune response” (GO:0002283, p = 3.4E-23) and “neutrophil degranulation” (GO:0043312, p = 3.4E-23). Additional analysis of ccfDNA fragment size identified larger fragments ( &amp;gt; 700 bp) as the major source of the prognostic signal (log-rank p = 0.002 for progression-free survival) compared to traditionally sized ccfDNA fragments (50-700 bp, log-rank p = 0.12). Taken together, these data suggest that granulocytes are the primary contributing source of prognostic ccfDNA in glioblastoma. Future studies are needed to determine the mechanism through which granulocyte-derived ccfDNA is associated with clinical outcomes in glioblastoma and to explore related therapeutic opportunities.
Abstract 13929: Do Tipsy Young People Develop More Atrial Fibrillation Than Sober Ones? - The Impact of Alcohol Burden on the Risk of Atrial Fibrillation: A Nationwide Population-Based Study
Authors: Minju Han, So-Ryoung Lee, Eue-keun Choi, Jaewook Chung, HuiJin Lee, JungMin Choi, Sang-Hyeon Park, Seung-woo Lee, Kyung-Do Han, Sunhwa Kim, Seil Oh, Gregory Lip
Journal: Circulation (2021)

Introduction: Alcohol is an adjustable risk factor for atrial fibrillation (AF), but its impact on the young population is unclear. We examined the effect of alcohol intake on the risk of AF in young Korean adults. Hypothesis: The alcohol intake will show positive relationship with the risk of AF. Methods: From the National Health Insurance Service database, we identified 1 537 836 people aged 20-39 without AF who underwent 4 serial annual health checkups during 2009-2012. At the first checkup, we sorted subjects into “No” and “Yes” groups, according to whether their weekly drinking exceeded 105g. They were also scored according to their usual weekly alcohol intake: “0” (n=507 463), “1” (&lt;105g/wk, n=639 651), “2” (105≤g&lt;210/wk, n=242 842), and “3” (210g≤/wk, n=147 880). We defined the alcohol burden as the number of times the subject answered he/she drank more than 105g of alcohol weekly, in the four checkups. Score of cumulative amounts of alcohol was computed by adding up one’s alcohol intake scores over the 4 years. The AF risk was estimated using Cox proportional hazards model. Results: During a median of 5.6±1.2 years, new AF was diagnosed in 3 066 (0.2%). “Yes” group showed a higher risk of AF compared to “No” group (adjusted hazard ratios (aHR) 1.15, 95% confidence interval (CI) 1.06-1.25, p ≤0.001, Panel A). The risk was also in a positive association with the first drinking scores: aHRs with 95% CIs of the “1”, “2”, and “3” groups compared to “0” group were 1.00 (0.91-1.10), 1.11 (0.99-1.24), and 1.21 (1.07-1.37), p =0.039 (Panel B). As 57.3% in alcohol burden 0 group, 13.2% in 1, 9.6% in 2, 9.4% in 3, and 10.0% in 4, aHRs of burden 1, 2, 3, and 4 compared to burden 0 were 1.14 (1.02-1.27), 1.03 (0.90-1.17), 1.15 (1.02-1.30), and 1.24 (1.11-1.39); p =0.001 (Panel C). The score of cumulative amounts of alcohol was in a positive relationship with the risk of AF ( p =0.003, Panel D). Conclusions: Cumulative alcohol burdens and amounts showed positive correlations with the risk of AF in young adults.
Abstract 10767: Therapeutic Effects of Clustered Human Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells for Chronic Hind Limb Ischemia
Authors: Junki Yokota, Takuji Kawamura, Keisuke Miyake, Akima Harada, Takashi Shibuya, Shigeru Miyagawa
Journal: Circulation (2021)

Introduction: Human induced pluripotent stem cell-derived mesenchymal stem cell (iPS-MSC) is a promising cell source of regeneration therapy for hind limb ischemia (HLI). To date, we have already demonstrated the clustered cell administration has better therapeutic effects for HLI than single-cell administration using autologous myoblast cells. In this study, we administered clustered iPS-MSCs into the chronic HLI mouse and evaluated the regeneration effect. Methods: Human iPS cells were cultured in a serum-free medium containing the transforming growth factor-β pathway inhibitor SB431542 for the differentiation to MSC in vitro . These iPS-MSCs were expanded to form cell patches (10 6 cells/sheet). These iPS-MSC patches were mechanically fragmented and were then administered into HLI mice as clustered cells (CC group, n=10). As control groups, non-clustered single iPS-MSC (SC, n=12) or Hanks’ balanced salt solution (HBSS, n=9) were administered. HLI was induced to the NOD/Shi-scid mouse by resecting the femoral artery and vein. The mice of which blood perfusion, being evaluated with Laser Doppler Perfusion Imaging (LDPI) at day 7, was under 40 % as compared with contralateral leg were included in the further study as the “chronic HLI model”. Serial change of LDPI and histological change of leg muscles were analyzed regarding angiogenesis and skeletal muscle regeneration. Results: Blood perfusion was significantly improved in CC (56.16±20.03%) as compared with HBSS (34.09±12.80%, P=0.0140) and SC (29.04±6.770%, P=0.0010) at day 14. Also, histological analysis showed the number of CD31 + endothelial cells is significantly larger in CC (353.6±59.97/mm 2 ) as compared with HBSS (126.2±22.85/mm 2 , P=0.0004) and SC (103.6±23.81/mm 2 , P=0.0001). The mean diameter of skeletal muscle cells is significantly larger in CC (42.28±4.113μm) as compared with SC (29.02±2.535μm, P=0.0001) and HBSS (29.61±3.103μm, P=0.0007). Conclusions: The clustered iPS-MSC significantly augmented angiogenesis and muscle regeneration in chronic HLI as compared with single-cell administration.
Abstract 10520: Emerging Cardiovascular Side Effects of Selective and Non-Selective Immunotherapies in Cancer Patients: 2021 Results from the Global WHO Database
Authors: Astha Prasai, Saraswati Pokharel, Umesh Sharma
Journal: Circulation (2021)

Introduction: Immune checkpoint inhibitors (ICIs), and adoptive cell transfer (ACT) - which involves collecting and using patient’s own immune cells to treat their cancer, are two rapidly emerging therapeutic modalities for various advanced stage cancers. Emerging cardiovascular side effects of ICIs and ACTs are currently being recognized. Objective: We analyzed the newly reported side-effect profiles of FDA-approved ICIs (anti-CTLA-4, anti-PD-1 and anti-PD-L1) and ACTs (also known as CAR-T therapy). Methods: We utilized the global data available in VigiBase®, World Health Organization’s global database for adverse drug reactions (ADRs), maintained by the Uppsala Monitoring Centre. We extracted information on reports of suspected ADRs, also called Individual Case Safety Reports (ICSRs). ICSRs of ICI and ACT therapy on cardiovascular system were extracted, and the side effect profile of the two groups of immunotherapies were systematically analyzed. Results: Based on the records obtained to-date, a total of 6,000 cardiovascular ADRs caused by ICIs (Ipilimumab, Nivolumab, Pembrolizumab, Cemiplimab, Atezolizumab, Avelumab and Durvalumab), and 500 ADRs by ACTs (Kymriah, Yescarta, Tecartus, Brevanzi and Abecma) have been reported. ICI therapies were predominantly associated with myocarditis (1098), cardiac failure (614), acute coronary syndrome (548) and pericarditis/pericardial effusion (516). ACT therapies were associated with tachyarrhythmia (263), cardiac arrest (44) and cardiorenal events (25). A propensity analysis demonstrated ICIs to be associated with autoimmunity-related ADRs, whereas ACTs were associated with acute cytokine release-related ADRs. Conclusions: Using a large-scale global WHO data platform, we have identified unique tendencies for cardiovascular ADRs resulting from non-selective (ICIs) and highly-selective (ACTs) immunotherapies for cancer: the former is associated with serious autoimmune effects, and the latter is associated with acute cytokine-release-related ADRs.
Assessing the role of qualitative factors in pandemic responses
Authors: Melisa Mei Jin Tan, Rachel Neill, Victoria Haldane, Anne-Sophie Jung, Chuan De Foo, See Mieng Tan, Pami Shrestha, Monica Verma, Mathias Bonk, Salma M Abdalla, Helena Legido-Quigley
Journal: BMJ (2021)

Melisa Tan and colleagues argue that assessments of national pandemic preparedness and response capacities should be extended to include social factors, leadership, and use of evidence The covid-19 pandemic has emphasised shortcomings in global systems for measuring the ability of countries to respond rapidly to emerging infectious disease threats. Existing monitoring and evaluation processes—including the Global Health Security Index, the Epidemic Preparedness Index, and the Joint External Evaluation—have highlighted a lack of preparedness across countries, particularly among low and middle income countries. Currently, these measurement frameworks emphasise structural aspects of the health system, including capacity, laboratory infrastructure, financing, surveillance, and emergency response operations, but fail to account for critical dimensions such as governance, cooperation, and collaboration, which are difficult to quantify.12 During the covid-19 pandemic these qualities have shaped the ability of countries to prepare proactively, respond promptly, and recover equitably while protecting the health and wellbeing of communities. Overlooking these considerations has biased existing frameworks towards high income countries, failed to account for socioeconomic inequalities, and underestimated the role of leadership and societal engagement in translating policy planning into implementation.12 The preparedness indicators therefore do not accurately reflect the ability of countries to respond to infectious hazards. After consulting experts on covid-19 working across academia, government, the private sector, and not-for-profit sector, and carrying out desk reviews (see supplementary data on bmj.com for details),1 and building on recent work that highlighted limitations of the Global Health Security Index, we outline six factors that have shaped national responses to covid-19 (box 1). Such "soft" factors must be incorporated into future national and global measurement frameworks to advance a holistic, equitable, and truly preventive approach to evaluating pandemic preparedness. Box 1 ### Essential components in shaping pandemic preparedness and responseRETURN TO TEXT
Abstract 14194: Dynamic Metabolite Profiles of Heart Failure and Central Hemodynamics
Authors: Carl Lejonberg, Anna Egerstedt, Olof Gidlöf, Tomasz Czuba, Gustav Smith
Journal: Circulation (2021)

Aim: Large-scale plasma metabolite profiling is garnering considerable interest for the discovery of therapeutic targets and facilitation of precision medicine across a range of conditions. Heart failure (HF) represents a particularly promising application of metabolite profiling for precision medicine. Here, we performed untargeted metabolite profiling of heart failure cases and healthy controls, and studied transplant dynamics and central hemodynamic correlates of identified metabolites. Methods and Results: Metabolite profiling was conducted with liquid chromatography-tandem mass spectrometry methods in two independent case-control samples: one sample with advanced HF patients undergoing right-heart catheterization (RHC, n=248) and healthy controls of matching age and sex (n=30), and one sample with HF outpatients (n=83) and controls from a population-based cohort (n=583). Metabolites associated with HF were identified based on multivariable-adjusted logistic regression models. In total, 93 of 1370 studied metabolites were significantly associated with HF in both cohorts with concordant directionality, after Bonferroni correction. A subset of the advanced HF patients underwent heart transplantation (n=28), after which a second sample was obtained at the routine 6 month follow up exam. In linear mixed-effects regression models, 17 metabolites (18%) returned significantly towards healthy control levels. Of these, 13 (76%) were associated with at least one of 14 central hemodynamic parameters. Most associations were with right atrial pressure (RAP, 10 metabolites), mixed venous oxygen saturation (12 metabolites) and left-ventricular stroke work index (9 metabolites). For example, vanillylmandelate, a catecholamine metabolite, was associated with stroke volume and cardiac index, while kynurenine, an immunomodulatory tryptophan metabolite mainly produced in the liver and previously associated with kidney function, was associated with higher left-sided (pulmonary arterial wedge pressure) and right sided (RAP) filling pressures. Conclusions: Here, we comprehensively identified metabolites associated with HF and describe the hemodynamic correlates and metabolite dynamics upon HF reversal by transplantation.
BRMP-02. Feasibility and evaluation of a novel language paradigm for intraoperative language testing
Authors: Katharina Rosengarth, Delin Pain, Frank Dodoo-Schitto, Katharina Hense, Teele Tamm, Christian Ott, Ralf Lürding, Elisabeth Bumes, Mark Greenlee, Karl-Michael Schebesch, Nils Ole Schmidt, Christian Doenitz
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Mapping language during direct cortical stimulation (DCS) in the stetting of awake craniotomy might be challenging without using more than one language paradigm. Applying several language tasks leads to increasing surgery times and to patient’s exhaustion. Additionally, a single language trial must be performed in less than 4 seconds to avoid DCS-induced seizures. Therefore, we aimed to design a single language paradigm which pictures highly relevant language functions and simultaneously restrains the assessment time of single language trials up to 4 seconds. METHOD The intraoperative language task comprised a combination of picture naming and verb generation. During DCS patients should generate correct sentences according to the language stimulus by not exceeding 4 seconds. To assess the intraoperative feasibility of the language task we included 30 healthy subjects in a pilot study to measure subjects’ speed of performing a single language task trial and to evaluate the language paradigm according to its language sensitivity by using the paradigm as a task for functional MRI. Intraoperatively, 21 patients with brain tumors in language associated brain areas were included. Patients received neuropsychological testing before and after surgery. RESULTS The pilot study showed in healthy subjects that by applying the novel paradigm during fMRI there is activation in a left accentuated network of inferior frontal and parietal regions and the superior and middle temporal gyrus (p&amp;lt;.05, FEW). It was feasible to conduct a single language trial of the novel paradigm in a time frame of 4s (performance speed 2.53 s; SD=.32s). Intraoperatively, tumor patients showed DCS-associated language errors while conducting the language task. Postoperatively, mild language but no other neuropsychological deteriorations compared to presurgical assessment were observed (p&amp;lt;.05). CONCLUSION We present a novel language paradigm which safely pictures and monitors highly relevant language functions and consequently can minimize postoperative language deficits.