tbuckley/cabot-search huggingface dataset:
Sex-Specific Cardiovascular Risks of Cancer and Its Therapies
Authors: Nicholas S. Wilcox, Seth J. Rotz, McKay Mullen, Evelyn J. Song, Betty Ky Hamilton, Javid Moslehi, Saro H. Armenian, Joseph C. Wu, June-Wha Rhee, Bonnie Ky
Journal: Circulation Research (2022)

In both cardiovascular disease and cancer, there are established sex-based differences in prevalence and outcomes. Males and females may also differ in terms of risk of cardiotoxicity following cancer therapy, including heart failure, cardiomyopathy, atherosclerosis, thromboembolism, arrhythmias, and myocarditis. Here, we describe sex-based differences in the epidemiology and pathophysiology of cardiotoxicity associated with anthracyclines, hematopoietic stem cell transplant (HCT), hormone therapy and immune therapy. Relative to males, the risk of anthracycline-induced cardiotoxicity is higher in prepubertal females, lower in premenopausal females, and similar in postmenopausal females. For autologous hematopoietic cell transplant, several studies suggest an increased risk of late heart failure in female lymphoma patients, but sex-based differences have not been shown for allogeneic hematopoietic cell transplant. Hormone therapies including GnRH (gonadotropin-releasing hormone) modulators, androgen receptor antagonists, selective estrogen receptor modulators, and aromatase inhibitors are associated with cardiotoxicity, including arrhythmia and venous thromboembolism. However, sex-based differences have not yet been elucidated. Evaluation of sex differences in cardiotoxicity related to immune therapy is limited, in part, due to low participation of females in relevant clinical trials. However, some studies suggest that females are at increased risk of immune checkpoint inhibitor myocarditis, although this has not been consistently demonstrated. For each of the aforementioned cancer therapies, we consider sex-based differences according to cardiotoxicity management. We identify knowledge gaps to guide future mechanistic and prospective clinical studies. Furthering our understanding of sex-based differences in cancer therapy cardiotoxicity can advance the development of targeted preventive and therapeutic cardioprotective strategies.
Hearing Loss After Radiation and Chemotherapy for CNS and Head-and-Neck Tumors in Children
Authors: Dana Keilty, Mohammad Khandwala, Zhihui Amy Liu, Vicky Papaioannou, Eric Bouffet, David Hodgson, Ryan Yee, Sharon Cushing, Normand Laperriere, Sameera Ahmed, Donald Mabbott, Vijay Ramaswamy, Uri Tabori, Annie Huang, Ute Bartels, Derek S. Tsang
Journal: Journal of Clinical Oncology (2021)

Hearing loss (HL) is a serious secondary effect of treatment for CNS and head-and-neck tumors in children. The goal of this study was to evaluate incidence and risk factors for HL in patients with multiple ototoxic exposures.We evaluated 340 ears from 171 patients with CNS or head-and-neck tumors treated with radiation, with or without chemotherapy, who had longitudinal audiologic evaluation. International Society of Pediatric Oncology-Boston grades were assigned to 2,420 hearing assessments. Multivariable weighted ordinal logistic regression was fitted to evaluate the effect of clinicopathologic features on HL.Mean cochlea dose (odds ratio [OR] 1.04 per Gy, P < .001), time since radiotherapy (RT; OR 1.21 per year, P < .001), cisplatin dose (OR 1.48 per 100 mg/m2, P < .001), and carboplatin dose (OR 1.41 per 1,000 mg/m2, P = .002) were associated with increasing International Society of Pediatric Oncology-Boston grade of HL. There was no synergistic effect of RT and cisplatin (interaction term, P = .53) or RT and carboplatin (interaction term, P = .85). Cumulative incidence of high-frequency HL (> 4 kHz) was 50% or greater at 5 years after RT if mean cochlea dose was > 30 Gy, while incidence of HL across all frequencies continued to increase beyond 5 years after RT.Children treated with radiation and chemotherapy experience a high incidence of HL over time, with associations found between more severe HL and cisplatin or carboplatin dose as well as mean cochlea dose. Mean cochlea dose of ≤ 30 Gy is proposed as a goal to reduce the risk of HL; a lower threshold (20-25 Gy) may be considered in patients receiving platinum chemotherapy to reduce cumulative HL burden.
The Impact of Vaccination on Incidence and Outcomes of SARS-CoV-2 Infection in Patients with Kidney Failure in Scotland
Authors: Samira Bell, Jacqueline Campbell, Emilie Lambourg, Chrissie Watters, Martin O’Neil, Alison Almond, Katharine Buck, Edward J. Carr, Laura Clark, Zoe Cousland, Mark Findlay, Nicola Joss, Wendy Metcalfe, Michaela Petrie, Elaine Spalding, Jamie P. Traynor, Vinod Sanu, Peter Thomson, Shona Methven, Patrick B. Mark
Journal: Journal of the American Society of Nephrology (2022)

Patients with kidney failure requiring KRT are at high risk of complications and death following SARS-CoV-2 infection, with variable antibody responses to vaccination reported. We investigated the effects of COVID-19 vaccination on the incidence of infection, hospitalization, and death from COVID-19 infection.
Universal prediction of cell-cycle position using transfer learning
Authors: Shijie C. Zheng, Genevieve Stein-O’Brien, Jonathan J. Augustin, Jared Slosberg, Giovanni A. Carosso, Briana Winer, Gloria Shin, Hans T. Bjornsson, Loyal A. Goff, Kasper D. Hansen
Journal: Genome biology (2022)

Abstract Background The cell cycle is a highly conserved, continuous process which controls faithful replication and division of cells. Single-cell technologies have enabled increasingly precise measurements of the cell cycle both as a biological process of interest and as a possible confounding factor. Despite its importance and conservation, there is no universally applicable approach to infer position in the cell cycle with high-resolution from single-cell RNA-seq data. Results Here, we present tricycle, an R/Bioconductor package, to address this challenge by leveraging key features of the biology of the cell cycle, the mathematical properties of principal component analysis of periodic functions, and the use of transfer learning. We estimate a cell-cycle embedding using a fixed reference dataset and project new data into this reference embedding, an approach that overcomes key limitations of learning a dataset-dependent embedding. Tricycle then predicts a cell-specific position in the cell cycle based on the data projection. The accuracy of tricycle compares favorably to gold-standard experimental assays, which generally require specialized measurements in specifically constructed in vitro systems. Using internal controls which are available for any dataset, we show that tricycle predictions generalize to datasets with multiple cell types, across tissues, species, and even sequencing assays. Conclusions Tricycle generalizes across datasets and is highly scalable and applicable to atlas-level single-cell RNA-seq data.
Functional Precision Medicine: Putting Drugs on Patient Cancer Cells and Seeing What Happens
Authors: Anthony Letai
Journal: Cancer Discovery (2022)

Abstract Summary: For too long, assays exposing patient tumor cells to drugs to identify active therapies have been dismissed as ineffective. In this issue of Cancer Discovery, two groups independently demonstrate clinical utility of such functional precision medicine assays in hematologic malignancies. See related article by Kornauth et al., p. 372. See related article by Malani et al., p. 388.
Abstract 10228: Efficacy and Safety of Catheter Ablation in Patients with Atrial Fibrillation and Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta-Analysis
Authors: Muhammad U Siddiqui, Joey Junarta, Adnan Ahmed, Ahmed K Pasha, Rene Alvarez, Daniel R Frisch
Journal: Circulation (2021)

Background: Catheter ablation for atrial fibrillation is a proven alternative to pharmacologic rhythm control in patients with heart failure with reduced ejection fraction (HFrEF). Whether outcomes differ in patients with heart failure with preserved ejection fraction (HFpEF) is of interest. Methods: Medline, Scopus, and Cochrane Central Register of Controlled Trials were systematically searched to identify relevant studies. We extracted or calculated a risk ratio (RR) and 95% confidence intervals (CI) from each study. Primary outcomes of interest include atrial arrythmia recurrence and repeat ablation. Harm outcomes of interest include all-cause mortality, all-cause hospitalizations, cardiovascular hospitalizations, stroke/transient ischemic attack, and cardiac tamponade. Results: We included 7 observational studies comprising 2,525 patients with HFpEF who underwent catheter ablation for atrial fibrillation. There were no significant differences in primary and harm outcomes when comparing catheter ablation for atrial fibrillation in patients with HFpEF to patients with no heart failure. Similarly, there were no significant differences in outcomes when comparing catheter ablation for patients with HFpEF to HFrEF. The certainty in these estimates was low. Conclusions: Non-randomized studies suggest that catheter ablation for atrial fibrillation in patients with HFpEF is associated with similar arrythmia free survival and safety profile when compared to patients with HFrEF and without heart failure. This suggests that patients with AF and HFpEF may benefit equally from catheter ablation as those with AF and HFrEF.
Open-source automated insulin delivery: international consensus statement and practical guidance for health-care professionals
Authors: Katarina Braune, Rayhan A Lal, Lenka Petruželková, Gary Scheiner, Per Winterdijk, Signe Schmidt, Linda Raimond, Korey K Hood, Michael C Riddell, Timothy C Skinner, Klemens Raile, Sufyan Hussain
Journal: The Lancet Diabetes & Endocrinology (2021)
Unlocking the complexity of HIV and Mycobacterium tuberculosis coinfection
Authors: Eileen P. Scully, Bryan D. Bryson
Journal: Journal of Clinical Investigation (2021)

HIV and Mycobacterium tuberculosis (M. tuberculosis) coinfection increases the risk of active tuberculosis (aTB), but how HIV infection and medications contribute to drive risk remains unknown. In this issue of the JCI, Correa-Macedo and Fava et al. investigated alveolar macrophages (AMs) from people living with HIV (PLWH). To mimic the earliest event in tuberculosis (TB), the authors isolated AMs from broncheoalveolar lavage (BAL) of PLWH, healthy individuals, and healthy individuals taking antitretroviral therapy (ART) as preexposure prophylaxis (PrEP) to prevent HIV acquisition. These AMs were exposed to M. tuberculosis and epigenetic configuration, transcriptional responses, and cytokine production were assessed. M. tuberculosis–stimulated AMs from PLWH and from healthy individuals on PrEP showed blunted responses compared with healthy controls. While HIV infection is the major risk factor for TB, these findings suggest that ART may modulate AM responses and potentially contribute to residual risk of aTB in fully treated HIV.
Abstract 10999: Pod-Based E-liquids Induce Vascular Endothelial Cell Dysfunction
Authors: Sana Majid, Robert M Weisbrod, Jessica L Fetterman, Rachel J Keith, Rose M Robertson, Aruni Bhatnagar, Daniel J Conklin, Naomi Hamburg
Journal: Circulation (2021)

Introduction: Pod-based e-cigarettes including JUUL represent the most commonly used product type and more efficiently deliver nicotine; however, their cardiovascular effects are poorly understood. Methods: We evaluated endothelial function (cell viability by TUNEL and nitric oxide bioavailability using DAF-2DA) in human aortic endothelial cells (HAECs) exposed for 90 minutes to one of four JUUL pod flavors (Menthol, Mint, Mango and Virginia Tobacco) or constituents propylene glycol (PG)/vegetable glycerol (VG) at 30:70 ratio with and without nicotine salt, as well as their heated particle fractions separated with a mini-MOUDI impactor. In healthy young adults, we assessed endothelial cell function in nonusers of tobacco products, pod users and combustible cigarette users for eNOS activation. Results: We observed significant increases in cell death with JUUL e-liquid flavors across 0.0001-1% dilutions. PG/VG vehicle alone and with nicotine salt induced cell death to similar levels as the JUUL e-liquids. All JUUL e-liquids at 0.0001% dilution impaired A23187-stimulated nitric oxide production. Exposure to particle fractions of JUUL e-liquids at 0.001% dilution also reduced A23187-stimulated nitric oxide production. Endothelial cells from pod users showed reduced eNOS activation compared with nonusers and similar to reduced levels in combustible cigarette users (figure). Conclusions: Our data suggest endothelial toxicity of pod-based e-liquids and their constituents, including in young adult users.
Persistent Opioid Use After Cardiac Implantable Electronic Device Procedures
Authors: Timothy M. Markman, Chase R. Brown, Lin Yang, Gustavo S. Guandalini, Matthew C. Hyman, Jeffrey S. Arkles, Pasquale Santangeli, Robert D. Schaller, Gregory E. Supple, Rajat Deo, Saman Nazarian, Sanjay Dixit, David J. Callans, Andrew E. Epstein, Francis E. Marchlinski, Peter W. Groeneveld, David S. Frankel
Journal: Circulation (2021)

Prescription opioids are a major contributor to the ongoing epidemic of persistent opioid use (POU). The incidence of POU among opioid-naïve patients after cardiac implantable electronic device (CIED) procedures is unknown.This retrospective cohort study used data from a national administrative claims database from 2004 to 2018 of patients undergoing CIED procedures. Adult patients were included if they were opioid-naïve during the 180-day period before the procedure and did not undergo another procedure with anesthesia in the next 180 days. POU was defined by filling an additional opioid prescription >30 days after the CIED procedure.Of the 143 400 patients who met the inclusion criteria, 15 316 (11%) filled an opioid prescription within 14 days of surgery. Among these patients, POU occurred in 1901 (12.4%) patients 30 to 180 days after surgery. The likelihood of developing POU was increased for patients who had a history of drug abuse (odds ratio, 1.52; P=0.005), preoperative muscle relaxant (odds ratio, 1.52; P<0.001) or benzodiazepine (odds ratio, 1.23; P=0.001) use, or opioid use in the previous 5 years (OR, 1.76; P<0.0001). POU did not differ after subcutaneous implantable cardioverter defibrillator or other CIED procedures (11.1 versus 12.4%; P=0.5). In a sensitivity analysis excluding high-risk patients who were discharged to a facility or who had a history of drug abuse or previous opioid, benzodiazepine, or muscle relaxant use, 8.9% of the remaining cohort had POU. Patients prescribed >135 mg of oral morphine equivalents had a significantly increased risk of POU.POU is common after CIED procedures, and 12% of patients continued to use opioids >30 days after surgery. Higher initially prescribed oral morphine equivalent doses were associated with developing POU.
Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies
Authors: Steven M. Horwitz, James M. Foran, Michael Maris, Jennifer Kimberly Lue, Ahmed Sawas, Craig Okada, Tatyana A. Feldman, Lubomir Sokol, Matthew Mei, Ian W. Flinn, Diego Villa, Mary-Elizabeth M. Percival, Deepa Jagadeesh, Kerry J. Savage, Oleg Akilov, Catherine S. Diefenbach, Youn H. Kim, Gloria H. Y. Lin, Tina Catalano, Penka S. Petrova, Bob Uger, Naomi Molloy, Kathleen Large, Ingmar Bruns, Stephen M. Ansell
Journal: Blood (2021)
Warm Season and Emergency Department Visits to U.S. Children’s Hospitals
Authors: Aaron S. Bernstein, Shengzhi Sun, Kate R. Weinberger, Keith R. Spangler, Perry E. Sheffield, Gregory A. Wellenius
Journal: Environmental Health Perspectives (2022)

Extreme heat exposures are increasing with climate change. Health effects are well documented in adults, but the risks to children are not well characterized.
Abstract EP28: SO CLOSE YET SO FAR : HOW WELL ARE WE DOING WITH GDMT FOR HEART FAILURE WITH REDUCED EJECTION FRACTION - A COMMUNITY HOSPITAL ANALYSIS
Authors: Kriti Lnu, Resha khanal, Yijin Wert, Roberto Hodara
Journal: Circulation (2022)

Background: The use of maximum tolerated doses of guideline directed medical therapy (GDMT) for patient with heart failure with reduced ejection fraction (HFrEF) has been suboptimal in routine clinical practice. In particular, the rate of adoption of the angiotensin receptor blocker-neprilysin inhibitor (ARNI) has lagged. In this study, we aim to evaluate the use of optimal GDMT and the effect of ARNI on heart failure related re-admission (HFRR) in a real life setting from a single center community hospital. Method: Retrospective chart review was conducted in patients who were admitted to our hospital system for HFrEF between December 2019-January 2021. Data was collected for patient demographics, comorbidities, admission and discharge medications, length of stay and rate of 30-day HFRR. Results: 357 patients were included in the analysis. 92.7% were discharged on beta blockers, 50% were discharged on ACE-I/ARB, 6.4% were discharged on ARNI and 47.75% were discharged on MRAs. The target doses of each were only achieved in 7.3%, 27%, 100% and &lt;1% respectively. 43% patients were not discharged on either ACE-I/ARB/ARNI. Patients discharged on ARNI had numerically lower rates of chronic kidney disease &gt; stage 3, and lower BNP levels than those discharged on ACE-I/ARB. HFRR was lower in patient discharged on ARNI vs ACE-I/ARB (4.17% vs 16%), although this was not statistically significant due to low sample volume (p = 0.20). Conclusion: Our study shows that the rate of adoption of GDMT, especially ARNI, in hospitalized HFrEF patients in clinical practice lags significantly behind from that reported in clinical trials. Although there was no statistical significance achieved in comparison due to small sample size, we see a trend of decreased heart failure readmission in patients discharged on ARNI. The wide gap of adoption of GDMT in the real world remains a challenge, and adversely impacts patient outcomes.
Abstract P134: Venous Thromboembolism Mortality And Trends In U.S. Adults 65+: 2011-2018
Authors: Katherine Giorgio, Richard Maclehose, Rob Walker, Faye L Norby, Diego Adrianzen-Herrera, Alvaro Alonso, Neil Zakai, Pamela L Lutsey
Journal: Circulation (2022)

Introduction: Venous thromboembolism (VTE) afflicts approximately 1 million Americans annually. Over the past decade there has been a movement towards outpatient management of uncomplicated acute events and use of oral anticoagulant agents for treatment. The purpose of this study was to update the estimated rates and trends of VTE-related mortality in older adults in the U.S. Methods: Medicare 20% sample claims data from 2011 to 2018 were used to create a cohort of beneficiaries with a VTE event using validated ICD codes. All-cause mortality, identified by National Death Index linkage, was assessed at 30 days and 1 year after VTE for each year over the full study period. Subgroup analyses were conducted by age, sex, race, and cancer-related VTE. Estimates were standardized for age, sex, and/or race, where appropriate. Results: The study included 113,826 VTE patients, mean age 77 years (SD=8), and were 61% (n=69,338) female. The cohort was 84% (n=95,976) non-Hispanic White, 11% (n=12,051) non-Hispanic Black, and 5% (n=5,799) other/unknown, and 34% (n=38,252) VTE events were cancer-related. Overall, 30-day and 1-year mortality was 2.5% (2,857 of 113,141) and 19.6% (19,621 of 100,035) (Table). Mortality rates increased with age and were slightly higher in men and in non-White patients. Cancer-related VTE was associated with greater 30-day (4.7% vs. 1.5%) and 1-year mortality (32.9% vs. 12.9%) than non-cancer VTE. Mortality rates remained steady over the study period in most subgroups. Mortality following cancer-related VTE appeared to decrease steadily over time for both 30-day (from 5.4% in 2011 to 4.4% in 2018) and 1-year mortality (from 36.3% in 2011 to 31.6% in 2017). Conclusions: Among contemporary VTE patients aged 65 and older, the risk of mortality is 2.5% at 30 days and 19.6% at 1 year. Despite notable changes to VTE management, all-cause mortality in Medicare beneficiaries with VTE was largely unchanged from 2011 to 2018, except for decreasing mortality following cancer-related VTE.
Abstract 11076: Cardiac AKAP12 Overexpression Reduces Cyclic Amp Accumulation in the Vicinity of β <sub>2</sub> Ar
Authors: Hanan Qasim, Arfaxad Reyes Alcaraz, Bradley K McConnell
Journal: Circulation (2021)

Introduction: In Heart Failure (HF), signaling downstream the β 2- Adrenergic Receptor (β 2 AR) is critical. Sympathetic stimulation of β 2 AR triggers Protein Kinase A (PKA) dependent phosphorylation of proteins that regulate cardiac function. Cyclic adenosine monophosphate (cAMP) accumulation in the vicinity of β 2 AR is crucial for PKA stimulation. cAMP levels are regulated in part by phosphodiesterases (PDEs). A Kinase Anchoring Protein 12 (AKAP12) has been reported to directly bind β 2 AR, PKA, and PDE4. Previously, we reported that cardiac overexpression of AKAP12 (oxAKAP12) in both male and female mice reduced left ventricular ejection fraction (EF) and fractional shortening (FS) significantly after 14-days of chronic Isoproterenol treatment when compared to control groups. Hypothesis: AKAP12 overexpression progresses HF development by reducing local cAMP levels in the vicinity of β 2 AR. Methods: AC16 cells (Human ventricular cell lines) were grouped into [1] control group or [2] cells stably transfected to overexpress human AKAP12 (oxAKAP12). cAMP accumulation in real-time downstream the β 2 AR was detected for 60 minutes in live cells using the luciferase-based biosensor (GloSensor) post-treatment with 10μM Epinephrine (EPI). Additionally, cells were pre-treated for 2 hours with either 10μM Rolipram (selective PDE4 inhibitor) or 0.1mM IBMX (non-selective PDE inhibitor) followed by 10μM EPI treatment. Results: oxAKAP12 cells (expressing AKAP12 protein 3 folds higher than controls) had significantly lower maximum cAMP accumulation post-EPI treatment downstream the β 2 AR (2.06 ± 0.32) compared to controls (9.04 ± 0.73), [p=0.0001]. Rolipram pretreatment increased cAMP levels in the oxAKAP12 group to (3.75± 0.72), however, the control group was still significantly higher (9.63 ± 0.95), [p=0.0032]. IBMX pretreatment increased cAMP levels in the oxAKAP12 group to (6.94 ± 1.55) which wasn’t significantly different from the control group (9.75 ± 2.52), [p=0.4152]. Conclusions: Cardiac overexpression of AKAP12 significantly reduces cAMP levels downstream of the β 2 AR. Potentially through scaffolding other PDEs aside from PDE4.