tbuckley/cabot-search huggingface dataset:
Abstract 10286: Age-Specific Threshold for Cardiovascular Disease Risk Stratification and Treatment Decision-Making
Authors: Zhe Xu, Angela M Wood
Journal: Circulation (2021)

Introduction: Cardiovascular disease (CVD) preventative interventions are targeted at people with predicted CVD risk above pre-specified thresholds. However, younger people with high relative risks and who may benefit from intervention are often missed because their absolute risks are below the threshold. We aim to investigate the use of age- and sex-specific thresholds for CVD risk stratification for allocating statin therapy. Methods: We used primary care data from Clinical Practice Research Datalink in the UK on 1,642,498 people, aged 40-85 years and without prevalent CVD. We predicted each person’s 10-year CVD risk, using age- and sex-specific Cox models with conventional risk factors from past medical records. We compared the implications of initiating statins in people identified as being at high CVD risk from 3 strategies: a. predicted risk ≥ 10% (the recommended UK threshold); b. predicted risk ≥ 10% or above the age- and sex-specific 90 th percentile; c. predicted risk ≥ 7.5% for people aged 40-54 years, ≥ 10% for 55-69 years, and ≥ 15% for 70-85 years (an intermediate “pragmatic” approach). We calculated the C-statistic to assess the ability to discriminate high-risk people and the number needed to screen (NNS) to prevent one CVD event, assuming statin allocation reduced CVD risk by 25%. Results: Replacing the single threshold (strategy a) with age- and sex-specific thresholds (strategy b) significantly improved the discriminatory ability to identify high-risk men aged 40-45 years and high-risk women aged 40-60 years (Figure 1a). Similarly, the NNS reduced by 70% for men aged 40-45 years, and 89% for women aged 40-60 years (Figure 1b). Using pragmatic age-group thresholds (strategy c) also showed significant gains, although to a lesser degree, in discrimination and NNS for younger people. Conclusions: Our results suggest using age- and sex-specific thresholds can modestly enhance CVD risk stratification for allocation of statin therapy among younger people.
Restoring Dysfunctional Bone Marrow Endothelial Cell Alleviates Aplastic Anemia
Authors: Shu-Qian Tang, Wei-Li Yao, Hong-Yan Zhao, Qi Wen, Yuan-Yuan Zhang, Zhong-Shi Lyu, Tong Xing, Yu Wang, Lan-Ping Xu, Xiao-Hui Zhang, Xiao-Jun Huang, Yuan Kong
Journal: Blood (2021)
Development of a fluorescent multiplex assay for detection of MSI-High tumors.
Authors: Jeff W. Bacher, Regenia L. Smalley, Lawrence J. Burgart, Wael M. Abdel-Megid, Richard B. Halberg, Stephen N. Thibodeau
Journal: Cancer Research (2005)

441  Determining whether a tumor exhibits MSI is useful for identifying patients with HNPCC and sporadic gastrointestinal cancers with defective DNA mismatch repair (MMR), aids in establishing a clinical prognosis and response to chemotherapy. A panel of markers was suggested for MSI analysis by a NCI workshop in 1997, but this panel has limitations resulting from the inclusion of dinucleotide markers that are less sensitive and specific for detection of tumors with MMR deficiencies compared to other types of markers. This study demonstrates that mononucleotides are the most sensitive and specific markers for detection of tumors with defects in MMR and identifies an optimal panel of markers for detection of MSI-High tumors. A set of 266 mono-, di-, tetra- and penta-nucleotide repeat microsatellite markers were used to screen for MSI in colorectal tumors. The best markers for detection of MSI-H tumors were selected for a MSI Analysis System, which includes five mononucleotide markers: BAT-25, BAT-26, NR-21, NR-24 and MONO-27. In addition, two pentanucleotide markers were added to identify sample mix-ups and/or contamination. We classified 153 colorectal tumors using the new MSI Analysis System and compared the results to those obtained with a panel of 10 microsatellite markers combined with IHC analysis. We observed 99% concordance between the two methods with nearly 100% accuracy in detection of MSI-H tumors. Approximately 5% of the MSI-H tumors had normal levels of four MMR proteins and as a result would have been misclassified based solely on IHC analysis, emphasizing the importance of performing MSI testing. The new MSI Analysis System offers several distinct advantages over other methods of MSI testing in that it is extremely sensitive and specific, amenable to high-throughput analysis, meets the 2004 NCI guidelines on MSI testing and overcomes problems inherent to the original NCI marker panel. The use of a single multiplex fluorescent MSI assay reduces the time and costs involved in MSI testing while increasing reliability and accuracy and thus should facilitate widespread screening for MSI in tumors of patients with gastrointestinal cancers.
Dietary nitrate supplementation to enhance exercise capacity in hypoxic COPD: EDEN-OX, a double-blind, placebo-controlled, randomised cross-over study
Authors: Matthew J Pavitt, Adam Lewis, Sara C Buttery, Bernadette O Fernandez, Monika Mikus-Lelinska, Winston A S Banya, Martin Feelisch, Michael I Polkey, Nicholas S Hopkinson
Journal: Thorax (2021)

Dietary nitrate supplementation improves skeletal muscle oxygen utilisation and vascular endothelial function. We hypothesised that these effects might be sufficient to improve exercise performance in patients with COPD and hypoxia severe enough to require supplemental oxygen.We conducted a single-centre, double-blind, placebo-controlled, cross-over study, enrolling adults with COPD who were established users of long-term oxygen therapy. Participants performed an endurance shuttle walk test, using their prescribed oxygen, 3 hours after consuming either 140 mL of nitrate-rich beetroot juice (BRJ) (12.9 mmol nitrate) or placebo (nitrate-depleted BRJ). Treatment order was allocated (1:1) by computer-generated block randomisation.The primary outcome was endurance shuttle walk test time. The secondary outcomes included area under the curve to isotime for fingertip oxygen saturation and heart rate parameters during the test, blood pressure, and endothelial function assessed using flow-mediated dilatation. Plasma nitrate and nitrite levels as well as FENO were also measured.20 participants were recruited and all completed the study. Nitrate-rich BRJ supplementation prolonged exercise endurance time in all participants as compared with placebo: median (IQR) 194.6 (147.5-411.7) s vs 159.1 (121.9-298.5) s, estimated treatment effect 62 (33-106) s (p<0.0001). Supplementation also improved endothelial function: NR-BRJ group +4.1% (-1.1% to 14.8%) vs placebo BRJ group -5.0% (-10.6% to -0.6%) (p=0.0003).Acute dietary nitrate supplementation increases exercise endurance in patients with COPD who require supplemental oxygen. Trial registration number ISRCTN14888729.
Abstract 14162: Impact of Migraine Headaches on Stress Induced Takotsubo Cardiomyopathy
Authors: Jobin J Varghese, Omar Yacob, Hector Garcia-Garcia
Journal: Circulation (2021)

Introduction: Takotsubo cardiomyopathy (TTC) is an acute process, characterized by ventricular dysfunction, typically due to a neuro-cardiogenic mechanism. Although many stressors have previously been identified and can precipitate TTC, there have been no reports citing the association or effects of migraines attacks. Hypothesis: Migraines predispose a protective effect on TTC patients Methods: We conducted a US-wide analysis of TTC hospitalizations from 2013 to 2017 by querying the National Inpatient Sample database. Patients admitted with a principal diagnosis of TTC with a history of migraines were identified using the ICD-10 codes. TTC patients with migraines were then compared to TTC patients without migraines regarding mortality and acute inpatient complications (intubation, cardiac arrest, heart failure exacerbation, acute kidney injury). A logistic regression model was constructed to account for potential confounders. Results: A total of 172025 TTC patients were identified, of those patients, 3610 were found to have suffered from migraines. After accounting for potential confounders, TTC patients with a diagnosis of migraine were associated with a lower odds for mortality (OR: 0.388; [0.311-0.485]; p &lt;0.001) and acute complications (OR: 0.511 [0.471-0.554]); p &lt;0.001) compared to those without migraines. In terms of mortality, the presence of acute complications had the highest odds for mortality (7.830 [7.439-8.240]; p &lt;0.001), followed by cerebrovascular disease, cancer, and age. Depression, Diabetes, smoking, and obesity were associated with a decreased odds for mortality. Conclusions: TTC patients with migraines were associated with lower mortality and better inpatient outcomes.
Abstract 12506: Exploring the Absence of an Intervention: A Randomized, Placebo-Controlled, Triple Blind Study on Notoginseng Supplementation in A Population With Normal to Mild Hypertension and Hypercholesterolemia
Authors: Malkanthi Evans, Erin D Lewis, David C Crowley, Andy Zeng, Jing Struve, Najla Guthrie
Journal: Circulation (2021)

Introduction: The concept of a lack of intervention in a pre-disease population with hypercholesterolemia has not been previously reported. This study examined the concept of the effects of the absence of an intervention in the placebo group vs. supplementation of a special formulation of Panax Notoginseng (FNG) in relation to cardiovascular disease (CVD) risk markers and validated CVD-risk factor scores. Methods: Participants in this randomized, placebo-controlled, triple-blind study were supplemented with FNG or placebo for 12 weeks. Lipid profile, blood pressure (BP), and endothelial vasodilation parameters were assessed at baseline and weeks 4, 8 and 12 and safety assessed at screening and end of study. The participants in both groups followed the Therapeutic Lifestyle Change (TLC) diet during a 4-week run-in and throughout the study. The TLC diet for 4 weeks ensured all participants starting the study had similar baseline measurements and placebo effects were adequately addressed. Results: Participants in the placebo group had a non-significant 1.37% reduction in HDL-C at 8 and 12 weeks, as well, as an increase in systolic BP from baseline at week 12. Participants in the placebo had no change in estimated Framingham Heart Study 10-year risk for CVD, while the FNG group had a 0.1% reduction from baseline at week 12. A total of 67.5% of participants supplemented with FNG had improvements in at least two CVD risk factors (LDL-C, HDL-C and systolic BP) compared to 40.0% of those on placebo (p=0.007). In a post-hoc subgroup analysis of participants with baseline LDL-C &gt;3.5 mmol/L, 41.7% of participants in the FNG group had reductions in their systolic BP and LDL-C and improvements in HDL-C levels at week 12, compared to placebo where there were no improvements. Conclusions: The lack of an intervention in a population at risk of CVD, represented by the placebo group, resulted in a negative impact on cardiovascular risk factors and warrants further investigation on the importance of pre-emptive supplementation of notoginseng in populations with mild hypertension and hypercholesterolemia. This study supports a previously defined concept in nutritional interventions which described changing from proof of efficacy to that of probable harm in pre-disease populations.
Abstract 11453: Beyond Anatomy: Use of Sinus Propagation Mapping to Identify the Slow Pathway for Cryoablation in Pediatric Patients
Authors: William M Fogarty, Anna Kamp, Naomi J Kertesz, Rohan Kumthekar
Journal: Circulation (2021)

Introduction: Slow pathway (SP) modification via cryoablation is a common treatment of atrioventricular nodal reentrant tachycardia (AVNRT) in pediatric patients. Traditionally, SP modification was achieved by anatomical landmarks, ideal electrogram characteristics, or low voltage bridge mapping. Recently, sinus propagation mapping (SPM) is a tool that has been used to augment identification of the SP. We hypothesize that the use of SPM will decrease the total number of ablations performed and decrease the number of ablations until the SP was successfully modified without a significant increase in procedure time. Methods: We conducted a retrospective review of patients who underwent cryoablation for AVNRT from August 2016 through March 2021. There were no other technological or procedural changes during the study period besides the addition of SPM. We excluded patients greater than 21 years of age, the use of radiofrequency ablation, prior AVNRT ablation, additional pathways or arrhythmias, and those with congenital heart disease. Patients were divided into two groups: those who did and did not undergo SPM. Mann-Whitney U tests were utilized to compare significance between the two groups. Results: Out of 122 patients identified by IMPACT database query, 103 met inclusion criteria. Fifty-two patients (50.5%) had SPM completed during their procedures. Age, weight, and BSA were not statistically different between the groups. Ablation was acutely successful in all but two patients, both in the non-SPM group. The median number of ablations needed until successful SP modification was 2 in patients who underwent SPM, and 4 in the non-SPM group (p = 0.03). There was no significant difference between total number of ablations between groups. The median total procedural time was longer in the SPM group (152 vs 125 min, p = 0.01). There was no difference in clinical recurrence or complications between the two groups. Conclusions: Sinus propagation mapping can be utilized to further improve the successful treatment of AVNRT with cryotherapy by lowering the number of ablations needed until successful SP modification. However, the technique requires some additional time to collect sufficient data points to create the sinus map.
Assessing Cardiac Amyloidosis Subtypes by Unsupervised Phenotype Clustering Analysis
Authors: Louis Bonnefous, Mounira Kharoubi, Mélanie Bézard, Silvia Oghina, Fabien Le Bras, Elsa Poullot, Valérie Molinier-Frenkel, Pascale Fanen, Jean-François Deux, Vincent Audard, Emmanuel Itti, Thibaud Damy, Etienne Audureau
Journal: Journal of the American College of Cardiology (2021)

Cardiac amyloidosis (CA) is a set of amyloid diseases with usually predominant cardiac symptoms, including light-chain amyloidosis (AL), hereditary variant transthyretin amyloidosis (ATTRv), and wild-type transthyretin amyloidosis (ATTRwt). CA are characterized by high heterogeneity in phenotypes leading to diagnosis delay and worsened outcomes. The authors used clustering analysis to identify typical clinical profiles in a large population of patients with suspected CA. Data were collected from the French Referral Center for Cardiac Amyloidosis database (Hôpital Henri Mondor, Créteil), including 1,394 patients with suspected CA between 2010 and 2018: 345 (25%) had a diagnosis of AL, 263 (19%) ATTRv, 402 (29%) ATTRwt, and 384 (28%) no amyloidosis. Based on comprehensive clinicobiological phenotyping, unsupervised clustering analyses were performed by artificial neural network–based self-organizing maps to identify patient profiles (clusters) with similar characteristics, independent of the final diagnosis and prognosis. Mean age and left ventricular ejection fraction were 72 ± 13 years and 52% ± 13%, respectively. The authors identified 7 clusters of patients with contrasting profiles and prognosis. AL patients were distinctively located within a typical cluster; ATTRv patients were distributed across 4 clusters with varying clinical presentations, 1 of which overlapped with patients without amyloidosis; interestingly, ATTRwt patients spread across 3 distinct clusters with contrasting risk factors, biological profiles, and prognosis. Clustering analysis identified 7 clinical profiles with varying characteristics, prognosis, and associations with diagnosis. Especially in patients with ATTRwt, these results suggest key areas to improve amyloidosis diagnosis and stratify prognosis depending on associated risk factors.
Abstract 13932: Association Between Layer-Specific Global Longitudinal Strain and Cardiovascular Events After Coronary Artery Bypass Grafting
Authors: Filip Soeskov Davidovski, Mats H Lassen, Kristoffer G Skaarup, Morten Sengelov, soeren Lindberg, Flemming Olsen, Kirstine Ravnkilde, Thomas Fritz-Hansen, Sune H Pedersen, Allan Iversen, soeren galatius, Gunnar Gislason, Rasmus Mogelvang, Tor Biering-Sørensen
Journal: Circulation (2021)

Introduction: Sectionalized quantification of layer-specific global longitudinal strain (GLS) has recently become available with new technological advancements. We sought to investigate the prognostic value of layer-specific strain in patients undergoing coronary artery bypass grafting (CABG). Methods: This retrospective cohort study comprised patients undergoing isolated CABG between 2006 and 2011. The patients were followed through nation-wide registries for the composite endpoint of heart failure (HF) or cardiovascular death (CVD) (HF/CVD). Multivariable Cox regression models adjusted for clinical and echocardiographic baseline characteristics, as well as European System for Cardiac Operative Risk Evaluation II (EuroSCORE II) were used to assess the association between layer-specific GLS and the endpoint. Results: Of 641 patients included (mean age 67 years, 84% male), 62 experienced the composite of outcome (HF: n=30, CVD: n=38) during a median follow-up of 3.8 years. Patients who developed the outcome during follow-up had reduced layer-specific GLS in all layers (GLSendo: -14.3% vs. -16.3; GLSww: -12.2 vs. -13.9; GLSepi: -10.7 vs. -12.2). Additionally, all layer-specific GLS parameters were predictors of outcome in unadjusted models (GLSendo: HR=1.11 (1.05-1.17); GLSww: HR=1.13 (1.06-1.21); GLSepi: HR=1.15 (1.07-1.24), per 1% absolute decrease). The risk of the endpoint increased linearly with decreasing absolute GLS for all layers ( Figure 1 ). These findings were unchanged in multivariable models. Patients with reduced GLS in any layer had a higher risk of HF/CVD, however, the risk was highest for those with reduced epicardial GLS (HR=2.60 (1.46-4.66), p=0.001). Conclusions: Layer-specific GLS is an independent prognosticator of cardiovascular events after CABG. Reduced epicardial GLS poses the highest risk of HF/CVD.
Abstract 12771: HDAC Inhibition With Quisinostat Reduces Pulmonary Vascular Remodeling in Experimentally Induced Pulmonary Arterial Hypertension
Authors: Xiaoqing Sun, Quint Hagdorn, Diederik Van Der Feen, Eva L Peters, Ingrid Schalij, Kim A Schilders, Peter Dijke, anton vonk noordegraaf, Frances S De Man, Rolf M Berger, Marie Jose Goumans, Harm Bogaard, Kondababu Kurakula
Journal: Circulation (2021)

Introduction: Histone deacetylases (HDACs) expression and activity are increased in pulmonary arterial hypertension (PAH). Although inhibiting HDACs has been promoted as a treatment for PAH, results from preclinical studies were equivocal and raised concerns regarding safety. Quisinostat is a “second generation” HDAC inhibitor, which is highly potent against HDAC1 and elicits a prolonged pharmacodynamic response. Hypothesis: Quisinostat may exert therapeutic effects in experimentally-induced PAH. Methods: HDAC1 expression was measured in lungs and microvascular endothelial cells (MVECs) from control donors and PAH patients. HDAC activity, proliferation and inflammation were measured after quisinostat treatment of PAH MVECs. Chronic quisinostat treatment was tested in three PAH rat models: the Sugen + hypoxia (SuHx), the Monocrotaline shunt flow (MF) and pulmonary artery banding (PAB) model. Results: HDAC1 expression is increased in lungs of PAH patients. Quisinostat decreased proliferation and mitigated inflammatory cytokine expression in MVECs. Conditioned medium from quisinostat treated PAH MVECs inhibited the growth of healthy pulmonary artery smooth muscle cells. In vivo , quisinostat treatment reduced right ventricular (RV) systolic pressure, RV afterload and total pulmonary resistance in SuHx rats. Further analysis by histology revealed that quisinostat reduced pulmonary vascular remodeling in both SuHx and MF rat models by reducing proliferation and perivascular inflammation. The PAB rat model demonstrated that quisinostat had no independent effect on RV function or remodeling. Conclusions: Quisinostat can partly reverse RV afterload and pulmonary vascular remodeling in established experimental PAH and may be a promising intervention for PAH.
INNV-16. CNS-TAP TOOL RECOMMENDATIONS OF TARGETED ANTI-CANCER AGENTS COMPARED TO THOSE SELECTED BY A MULTIDISCIPLINARY TUMOR BOARD IN A MOLECULARLY-DRIVEN DIPG CLINICAL TRIAL (PNOC003)
Authors: Holly Roberts, Karthik Ravi, Allison Schepers, Bernard Marini, Cassie Kline, Sabine Mueller, Carl Koschmann, Andrea Franson
Journal: Neuro-Oncology (2021)

Abstract Genetic sequencing of diffuse intrinsic pontine gliomas (DIPG) has revealed genomic heterogeneity, sparking an interest in individualized and targeted treatment options for this particularly devastating disease. A feasibility study, PNOC003: Molecular Profiling for Individualized Treatment Plan for DIPG (NCT02274987), was completed within the Pacific Pediatric Neuro-Oncology Consortium. In this study, a multidisciplinary tumor board reviewed detailed molecular and genomic profiling of each participant’s tumor and made molecularly-targeted treatment recommendations. Separately, our team developed the Central Nervous System Targeted Agent Prediction (CNS-TAP) tool, which combines pre-clinical, clinical, and CNS penetration data with patient-specific genomic information to derive numeric scores for targeted anticancer agents, aimed to objectively evaluate these therapies for use in patients with CNS tumors. We hypothesized that highly-scored agents within CNS-TAP would overlap with the agents recommended by the tumor board in PNOC003. For each study participant, we used the genomic profiling report to identify actionable alterations and incorporated these data into CNS-TAP to identify the highest-scoring agents. We compared high-scoring agents within CNS-TAP with recommendations from the tumor board for each of the enrolled 28 participants. Overall, 93% of patients (26/28) had at least one agent recommended by both the tumor board and CNS-TAP. Additionally, 38% of all agents (36/95) recommended by the tumor board were also selected by CNS-TAP. We identified factors that likely contributed to the differences in therapy recommendations between these two methods: CNS-TAP requires additional clinician input to account for drug-drug interactions, includes only classically-defined anticancer agents, and cannot easily be updated in real-time as new data emerge. However, CNS-TAP provides an objective evaluation of targeted therapies, whereas tumor boards are inherently subjective. A prospective study incorporating both CNS-TAP and a molecular tumor board for targeted therapy selection in high-grade glioma is currently ongoing to further compare and objectively evaluate these methods.
Outcome of Human Umbilical Cord Blood Stem Cell Transplantation (CBT) for Acute Myeloid Leukemia in Patients Achieving First Complete Remission after One Versus Two Induction Courses: A Study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)
Authors: Arnon Nagler, Myriam Labopin, Jan J. Cornelissen, Edouard Forcade, Patrice Chevallier, Nathalie Fegueux, Jorge Sierra, Hélène Labussière-Wallet, Jennifer Byrne, Thomas Cluzeau, Didier Blaise, Frédéric Baron, Annalisa Ruggeri, Mohamad Mohty, Deborah Desmier
Journal: Blood (2021)
Tri-Specific CD19xCD20xCD22 VHH CAR-T Cells (LCAR-AIO) Eradicate Antigen-Heterogeneous B Cell Tumors, Enhance Expansion, and Prolong Persistence in Preclinical In Vivo Models
Authors: Zhe (joy) Zhou, Yue Han, Hong-Bo Pan, Cai-Jun Sang, Dong-Lin Shi, Chong Feng, Hui Xiao, Qiu-Chuan Zhuang, Ping-Yan Wang, Xiao-Hu (Frank) Fan
Journal: Blood (2021)