tbuckley/cabot-search huggingface dataset:
Abstract 13462: 6-minute Walk Test Variability May be Reduced by a Structured Training and Monitoring Program, Potentially Facilitating Detection of Treatment Effects
Authors: Judith A Hsia, Marc P Bonaca, Robin White, Victoria Anderson, William R Hiatt
Journal: Circulation (2020)

Background: The 6-minute walk test (6MWT) is well established for evaluation of functional exercise capacity in patients with conditions such as pulmonary hypertension, peripheral arterial disease and heart failure. Its popularity as an endpoint in heart failure trials has increased in parallel with health authority acceptance of the test as a measure of patients' function. Minimizing variability is key to the successful conduct and outcome of trials with 6MWT endpoints. We assessed the impact on walking distance variability of a structured training and monitoring program Methods: After systematically observing conduct of 6MWT worldwide, our core lab developed a multifaceted approach including inspection and standardization of the walking course, standardized training, review of the first 3 tests for each test administrator and random tests thereafter, standardized data collection methods, and assessment of intra-test inconsistencies with feedback. Variability of walking distance using this structured approach is descriptively compared with 6MWT data from the literature. Results: In a multicenter trial which used the structured program, the standard deviation (SD) of distance walked was 21.7% of the mean at baseline and 22.6% at Week 4 (Table). For comparison, we reviewed 2018-19 reports of 6MWT not utilizing this structured approach and identified 5 multicenter studies of patients with heart failure which reported mean and SD of distance walked (Table). Baseline distance walked ranged from 104 to 385 m (weighted mean 220.4 m); SD of distance walked ranged from 28% to 135% of distance walked (weighted mean 70.9%). Conclusion: Standardization of the 6MWT walking course, structured training of test administrators and monitoring of test quality may reduce test variability which could improve accuracy of treatment effect assessment and possibly require smaller sample sizes.
Abstract 13598: The G-protein BetaGamma Subunits Regulate Platelet Function
Authors: Ahmed Alarabi, Zubair Karim, Victoria Hinojos, Patricia A Lozano, Keziah Hernandez, Jean Montes Ramirez, Fadi T Khasawneh, Fatima Z Alshbool
Journal: Circulation (2020)

Platelet activation involves tightly regulated processes to ensure a proper hemostasis response, but when unbalanced, can lead to pathological consequences such as thrombus formation. G-protein coupled receptors (GPCRs) regulate platelet function by interacting with and mediating the response to various physiological agonists. To this end, an essential mediator of GPCR signaling is the G protein Gαβγ heterotrimers, in which the βγ subunits are central players in downstream signaling pathways. While much is known regarding the role of the Gα subunit in platelet function, that of the βγ remains poorly understood. Therefore, we investigated the role of Gβγ subunits in platelet function using a Gβγ (small molecule) inhibitor, namely gallein. We observed that gallein inhibits platelet aggregation and secretion in response to agonist stimulation, in both mouse and human platelets. Furthermore, gallein also exerted inhibitory effects on integrin αIIbβ3 activation and clot retraction. Finally, gallein’s inhibitory effects manifested in vivo , as documented by its ability to modulate physiological hemostasis and delay thrombus formation. Taken together, our findings demonstrate, for the first time, that Gβγ directly regulates GPCR-dependent platelet function, in vitro and in vivo . Moreover, these data highlight Gβγ as a novel therapeutic target for managing thrombotic disorders.
Exploratory study of the effectiveness of nebulised saline in children with neurodisability
Authors: Natalia Galaz Souza, Andrew Bush, Hui-Leng Tan
Journal: European Respiratory Journal (2020)

<b>The prescription of nebulised saline in children and young people with neurodisability was associated with improved respiratory outcomes and was favourably received by patients and their caregivers</b>https://bit.ly/3mSyzag
Abstract 17233: Clock Modulating Small Molecule SR9011 Enhances Cell Cycle Arrest in Pulmonary Arterial Hypertension
Authors: Yann Grobs, Marie-Claude Lampron, Geraldine Vitry, Mark Orcholski, Steeve Provencher, Olivier BOUCHERAT, Sebastien Bonnet, Roxane Paulin
Journal: Circulation (2020)

Background: Pulmonary arterial hypertension (PAH) is a rapidly progressing disease of the lung vasculature, characterized by the remodeling of small pulmonary arteries in which pulmonary arterial smooth muscle cells (PASMCs) exhibit a cancer-like phenotype, with uncontrolled replication, self-sustaining growth signals, evasion of growth suppressors and resistance to apoptosis. In healthy cells, cell division is controlled by the circadian clock resulting in timed mitosis and rhythmic DNA replication. This suggests that impaired circadian clock might be involved in the cell cycle disorders seen in PAH. Especially, impaired function of the nuclear receptor Rev-Erbα (a core clock protein) has been associated with circadian clock impairment and cell cycle disorders in cancer. Hypothesis: Rev-Erbα impairment is involved in PAH pathogenesis. Methods &amp; Results: We synchronized (Zeitgeber method using 50% horse serum for 2 hours) human PASMCs isolated from 4 PAH patients and 4 controls, and demonstrated a reduced (p=0.0192) (immunoblot) expression of Rev-Erbα 12 hours post synchronization in PAH-PASMCs compared to controls, associated with increased proliferation (Ki67 assay) and resistance to apoptosis (annexin V assay) (p&lt;0.05), which were reversed by the Rev-Erbα agonist SR9011 (10μM for 24h). RNAseq (n=4/group) demonstrated that most of the downregulated (2-fold cut-off) genes following SR9011 treatments were involved in cytokinesis, meiosis, mitotic processes, cell cycle progression, chromosome segregation and recombination (p&lt;0.05). In vivo , Rev-Erbα was also significantly decreased in male and female monocrotaline rats. SR9011 treatments (n=15/group) for 2 weeks (50mg/kg, i.p.) improved PA hemodynamics ( RVSP:47.80mmHg vs 75.29mmHg \mPAP:26.69mmHg vs 44.36mmHg, p&lt;0.0001); vascular remodeling, decreased proliferation(p=0.0001), increased apoptosis(p=0.0002)) and decreased RV hypertrophy (Fulton Index:0.3869 vs 0.5093 p=0.0006) compare to vehicle treated rats. These results were also repeated in the Fawn Hooded rats model. Conclusion: Our results suggest the involvement of Clock pathways in PAH etiology and thus open new avenue of investigation in PAH and new therapeutic options using clock-modulating small molecules.
Abstract 14040: Hospitalizations for Respiratory Syncytial Virus and Vaccine Preventable Infections Following Pediatric Heart Transplantation: A PHIS Database Analysis
Authors: Emily A Hayes, Stephen Hart, Charitha Gowda, Deipanjan Nandi
Journal: Circulation (2020)

Introduction: Despite improvements in pediatric heart transplant outcomes, respiratory syncytial virus (RSV) and vaccine preventable infections (R/VPI) are a major cause of morbidity and hospital resource use. The frequency and risk factors for hospitalizations due to R/VPI in heart transplant recipients are unknown. Methods: Patients ≤18 years who underwent heart transplantation at hospitals contributing to the Pediatric Health Information System database from 9/2003 to 12/2018 were identified. The transplant hospitalization and subsequent hospitalizations for R/VPI through 12/2018 were analyzed. Risk factors for R/VPI hospitalizations were evaluated using negative regression binomial models adjusted for potential demographic and clinical confounders. Total hospital costs were determined adjusted for 2018 US $. Results: Of 3,815 transplant recipients, 681 (17.9%) had a R/VPI hospitalization during 23,746 available person-years of follow-up after transplant. There were 984 R/VPIs diagnosed during 951 hospitalizations, and 440 (44.7%) occurred in the first year after transplant (Figure). The most common causes were RSV (n=380; 38.6%), influenza (n=265; 26.9%), and pneumococcus (n=105; 10.7%). In adjusted analyses, there was an increased risk of R/VPI hospitalization in patients requiring mechanical circulatory support prior to transplant, those who received induction with ≥ 2 immunosuppressive agents, and patients &lt;2 years old. The median length of stay for a R/VPI hospitalization was 4 days (interquartile range [IQR]: 2-8 days) with a median total cost of $11,081 (IQR: $6,215 - $24,322). Conclusions: Hospitalization for R/VPIs occurred frequently following pediatric heart transplantation and were associated with significant cost. Potential strategies to minimize R/VPI could include expanding vaccine use through accelerated immunization schedules in younger patients and routine monitoring of immunogenicity after vaccination.
Transferrin/transferrin receptor‐mediated drug delivery
Authors: Hongyan Li, Zhong Ming Qian
Journal: Medicinal Research Reviews (2002)

Abstract Since transferrin was discovered more than half a century ago, a considerable effort has been made towards understanding tranferrin‐mediated iron uptake. However, it was not until recently with the identification and characterization of several new genes related to iron homeostasis, such as the hemochromatosis protein HFE and the iron transporter DMT1, that our knowledge has been advanced dramatically. A major pathway for cellular iron uptake is through internalization of the complex of iron‐bound transferrin and the transferrin receptor, which is negatively modulated by HFE, a protein related to hereditary hemochromatosis. Iron is released from transferrin as the result of the acidic pH in endosome and then is transported to the cytosol by DMT1. The iron is then utilized as a cofactor by heme and ribonucleotide reductase or stored in ferritin. Apart from iron, many other metal ions of therapeutic and diagnostic interests can also bind to transferrin at the iron sites and their transferrin complexes can be recognized by many cells. Therefore, transferrin has been thought as a “delivery system” for many beneficial and harmful metal ions into the cells. Transferrin has also be widely applied as a targeting ligand in the active targeting of anticancer agents, proteins, and genes to primary proliferating malignant cells that overexpress transferrin receptors. This is achieved by conjugation of transferrin with drugs, proteins, hybride systems with marcomolecules and as liposomal‐coated systems. Conjugates of anticancer drugs with transferrin can significantly improve the selectivity and toxicity and overcome drug resistance, thereby leading to a better treatment. The coupling of DNA to transferrin via a polycation such as polylysine or via cationic liposomes can target and transfer of the extrogenous DNA particularly into proliferating cells through receptor‐mediated endocytosis. These kinds of non‐viral vectors are potential alternatives to viral vectors for gene therapy, if the transfection efficiency can be improved. Moreover, transferrin receptors have shown potentials in delivery of therapeutic drugs or genes into the brain across blood–brain barrier. © 2002 Wiley Periodicals, Inc. Med Res Rev, 22, No. 3, 225–250, 2002; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/med.10008
Abstract 351: Current Barriers for College Students to Perform Cardiopulmonary Resuscitation on Strangers and Family Members
Authors: Daniela Dluzynski, Trey Baird, Trevor Short, Rachel VanScoy, Ashish R Panchal
Journal: Circulation (2020)

Background: As opioid associated cardiac arrests increase on US college campuses, there is a need for students to learn and perform CPR. These arrests are respiratory in origin and require provision of compressions with rescue breathing (conventional CPR) over hands-only CPR. Unfortunately, only some college students will provide rescue breaths as mouth to mouth contact is a leading barrier to initiate CPR. The objective of this study was to evaluate the barriers of college students to performing conventional CPR on strangers and family members. Methods: Undergraduate students at The Ohio State University were recruited from Jan 2018 to Dec 2019 to participate in a survey. Respondents’ demographic data were collected, and they were asked about their attitudes concerning performing conventional CPR on strangers and family. This was followed by identifying their potential barriers to performing conventional CPR. Inclusion criteria were age &gt; 17 and missing &lt; 10% of survey data. Barriers were compared between respondents who were unlikely to perform CPR (unlikely) and those likely to perform CPR (likely). Descriptive statistics were calculated. Results: A total of 883 surveys were included in the analysis (response rate 74%). Of these respondents, 495 (56%) were likely to perform CPR on a stranger and 743 (84%) were likely to perform CPR on a family member. When performing CPR on a stranger, the barriers of fear of an incorrect method (unlikely: 81% vs likely: 61%, P&lt;0.001) and mouth to mouth contact (unlikely: 31% vs likely: 24%, p=0.03) were different between groups while facing legal risk and causing harm to the victim were not. In contrast, when performing CPR on a family member, there were no differences between groups except for the fear of applying an incorrect method, which persisted as a larger barrier for those unlikely to perform CPR (unlikely: 72% vs likely: 62%, p&lt;0.05). Conclusion: There are many barriers that influence college students’ intention to perform CPR. Surprisingly, the most significant barrier reported by both groups was fear of performing CPR incorrectly, while the fear of mouth-to-mouth contact was not as prevalent. Further evaluation is necessary in the post-COVID-19 era to understand the impact of increased fear of infectious diseases.
Convalescent plasma for COVID-19: male gender, older age and hospitalisation associated with high neutralising antibody levels, England, 22 April to 12 May 2020
Authors: Jennifer Mehew, Rachel Johnson, David Roberts, Heli Harvala
Journal: Eurosurveillance (2020)

We analysed factors associated with neutralising antibody levels in 330 convalescent plasma donors. Women and younger donors were more likely not to have measurable neutralising antibodies, while higher antibody levels were observed in men, in older donors and in those who had been hospitalised. These data will be of value in the timely recruitment of convalescent plasma donors most likely to have high levels of neutralising antibodies for ongoing studies investigating its effectiveness.
Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma
Authors: Lakshmi Nayak, Annette M. Molinaro, Katherine Peters, Jennifer L. Clarke, Justin T. Jordan, John de Groot, Leia Nghiemphu, Thomas Kaley, Howard Colman, Christine McCluskey, Sarah Gaffey, Timothy R. Smith, David J. Cote, Mariano Severgnini, Jennifer H. Yearley, Qing Zhao, Wendy M. Blumenschein, Dan G. Duda, Alona Muzikansky, Rakesh K. Jain, Patrick Y. Wen, David A. Reardon
Journal: Clinical Cancer Research (2020)

VEGF is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase II study of pembrolizumab alone or with bevacizumab in recurrent glioblastoma.Eighty bevacizumab-naïve patients with recurrent glioblastoma were randomized to pembrolizumab with bevacizumab (cohort A, n = 50) or pembrolizumab monotherapy (cohort B, n = 30). The primary endpoint was 6-month progression-free survival (PFS-6). Assessed biomarkers included evaluation of tumor programmed death-ligand 1 expression, tumor-infiltrating lymphocyte density, immune activation gene expression signature, and plasma cytokines. The neurologic assessment in neuro-oncology (NANO) scale was used to prospectively assess neurologic function.Pembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% [95% confidence interval (CI), 16.3-41.5], median overall survival (OS) was 8.8 months (95% CI, 7.7-14.2), objective response rate (ORR) was 20%, and median duration of response was 48 weeks. For cohort B, PFS-6 was 6.7% (95% CI, 1.7-25.4), median OS was 10.3 months (95% CI, 8.5-12.5), and ORR was 0%. Tumor immune markers were not associated with OS, but worsened OS correlated with baseline dexamethasone use and increased posttherapy plasma VEGF (cohort A) and mutant IDH1, unmethylated MGMT, and increased baseline PlGF and sVEGFR1 levels (cohort B). The NANO scale contributed to overall outcome assessment.Pembrolizumab was ineffective as monotherapy and with bevacizumab for recurrent glioblastoma. The infrequent radiographic responses to combinatorial therapy were durable. Tumor immune biomarkers did not predict outcome. Baseline dexamethasone use and tumor MGMT warrant further study as potential biomarkers in glioblastoma immunotherapy trials.
Abstract 14734: Characterisation and Prognostic Relevance of Left Ventricular Global Longitudinal Strain in Patients With Systemic Lupus Erythematosus
Authors: Shaun Khanna, James M Newman, Aditya Bhat, Henry H Chen, Gary Gan, Timothy C Tan
Journal: Circulation (2020)

Introduction: Systemic lupus erythematosus (SLE) is a chronic inflammatory disease modulated by pro-inflammatory cytokines, which may result in myocardial dysfunction. Mean global longitudinal strain (GLS) is proposed to be a more sensitive measure of cardiac function in comparison to standard two-dimensional measures of left ventricular (LV) systolic function. Quantification of subclinical cardiac function, with impairment of LV-GLS, right ventricular free wall strain (RV-FWS), left atrial strain (LAs), and its prognostic relevance in patients with SLE is undefined. Hypothesis: SLE patients have evidence of subclinical cardiac dysfunction and the presence of impaired LV-GLS in this population portends a poor prognosis. Methods: Consecutive patients admitted to our institution with known history of SLE (&gt; 1-year disease activity) were examined. Patients with pre-existing cardiac disease, LV ejection fraction (EF) &lt;50% and those without comprehensive transthoracic echocardiograms were excluded. Mean GLS was performed offline using vendor-independent software (TomTec v4.6) and compared to age-, gender- and risk factor- matched controls. SLE patients were followed for up for the composite outcome of all-cause death and major adverse cardiovascular events. Results: A total of 51 patients with SLE were compared to 51 matched controls. No significant differences in baseline demographics, medications and laboratory investigations was observed. Patients with SLE showed evidence of subclinical cardiac dysfunction with significantly lower LV-GLS (%) (-16.7±2.8 vs -21.3±2, p&lt;0.01), lower RV FWS (%) (-21.2±4.8 vs -28.8±4.7, p&lt;0.01) and LAs (%) (31.9±6.7 vs 35.5±6.1, p&lt;0.01) when compared to controls, despite normal LVEF, RV FAC and LAEF. On analysis of outcomes of SLE patients, a total of 11 (21.6%) patients suffered the composite end-point during a mean follow-up of 48 months. Of interest, LV-GLS was a predictor of the composite outcome on log-rank test and cox regression analysis (p&lt;0.01). Conclusions: Our results suggest that SLE patients display evidence of subclinical cardiac dysfunction via a reduction in LV GLS, RV-FWS and LAs. Impairment in LV-GLS is associated with adverse cardiovascular outcomes in this population.
Abstract 13843: Icd Therapy After the First Primary-Prevention Implantable Cardioverter-Defibrillator Battery Change-out
Authors: Benjamin H Buck, Eric Kellett, Rana Elgazzar, Chad Ward, Omar Kahaly, Jemina Osei, Prabhpreet Singh, Raul Weiss, Jaret Tyler, Muhammad Afzal, Ralph S Augostini, Steven J Kalbfleisch, John Hummel, Toshi Okabe, Emile G Daoud, Mahmoud Houmsse
Journal: Circulation (2020)

Background: Implantable cardioverter-defibrillator (ICD) therapy prevents sudden cardiac death in selected patients with heart failure. When a primary prevention ICD arrives at elective replacement interval (ERI), conventional management is to replace the device. However, the effectiveness of ICDs in patients with nonischemic and ischemic cardiomyopathy (NICM and ICM, respectively) whose left ventricular ejection fraction (LVEF) improved to ≥50% before replacement is unclear. Hypothesis: The therapeutic benefit of primary prevention ICD for NICM is attenuated by the recovery of LVEF at the time of ERI. Methods: Consecutive patients presenting for first time primary prevention ICD battery change-out at a single quaternary care center between 1/1/2008 and 6/27/2019 were included. The primary endpoint was the rate of ICD therapy (ICD discharge and anti-tachycardia pacing) according to LVEF recovery at ERI. Results: During the study period 6851 ICDs were placed, of which 310 underwent battery change-out, of whom 100 did not receive therapy from the first ICD, of whom 44 had NICM. The demographics of the NICM cohort are in the table. Following ERI, 0 (0%) with NICM and recovered LVEF had received ICD therapy, whereas 13 (30%) with persistently low LVEF had received therapy (p = 0.07). Furthermore, among patients without recovered LVEF, the NICM group had a lower rate of therapy (4, 12%) than the ICM group (12, 32%) (p=0.04). Conclusion: Rates of ICD therapy provided by primary prevention ICD after first battery change out trended towards a significantly lower rate in NICM patients with LVEF that recovered to ≥50% than those without LVEF recovery. No other patient demographic significantly predicted therapy-free survival but the analysis was limited by sample size. A prospective study with a larger cohort would be necessary to better estimate therapy-free survival.
Abstract 15442: Low Serum Levels of Insulin-like Growth Factor-1 Are Associated With Long-term Risk of Adverse Cardiovascular Events in Diabetic Patients Following Percutaneous Coronary Intervention
Authors: Yuichi Chikata, Hiroshi Iwata, Takehiro Funamizu, Katsutoshi Miyosawa, Shinichiro Doi, Hirohisa Endo, Hideki Wada, Ryo Naito, Hirokazu KONISHI, Manabu Ogita, Yoshiteru Kato, Iwao Okai, Tomotaka Dohi, Takatoshi Kasai, Kikuo Isoda, Shinya Okazaki, Katsumi MIYAUCHI
Journal: Circulation (2020)

Background: Insulin-like growth factor-1 (IGF-1) is a protein which plays protective roles against cardiovascular disorders, including the endothelial dysfunction and the instability of atherosclerotic plaque. However, prognostic implication of serum IGF-1 level has been rarely evaluated in diabetic patients with established coronary artery disease. Methods: This single center observational study involved consecutive 819 diabetic patients underwent percutaneous coronary intervention (PCI) since 2008 to 2018. In frozen-stocked (-80°C) serum, IGF-1 was measured by ELISA assay. Endpoints were set as cardiovascular (CV) death and the composite of CV death, myocardial infarction and ischemic stroke (3-point MACE). The median and the range of follow-up period was 4.0 and 0-10.4 years, respectively. Results: Participants were divided by the median of IGF-1 (75 ng/ml) (low (n=412) and high IGF-1 group (n=407)). Unadjusted Kaplan-Meier analyses with log-rank test showed the significantly higher incidences of CV death and 3P-MACE in low IGF-1 group ( Figures ). Moreover, multivariate Cox proportional hazard analysis adjusted by covariates including age, sex, PCI for acute coronary syndrome, multivessel disease, renal function (eGFR, ml/min/1.73m 2 ) and glycated hemoglobin (HbA1c, %) demonstrated that low IGF-1≤75 ng/ml was associated with substantially increased risk of CV death (Hazard Ratio (HR): 1.9, 95% confidence interval (95%CI): 1.1-3.6, p=0.03) and 3P-MACE (HR 1.7, 95%CI:1.0-2.7, p=0.04), respectively. Conclusion: Findings in this study suggest that serum IGF-1 levels are a useful and independent prognostic indicator in diabetic patients following PCI.