tbuckley/cabot-search huggingface dataset:
Abstract 15613: Evaluating the Heart Failure With Preserved Ejection Fraction (HFpEF) Phenotype Amongst Persons Living With HIV; a Miami Health System Analysis
Authors: Jelani Grant, Bertrand Ebner, Louis Vincent, Quentin Loyd, Alexis Powell, Catherine Boulanger, Barry E Hurwitz, claudia Martinez
Journal: Circulation (2020)

Introduction: Current evidence suggests a 1 to 2-fold increased risk of heart failure among persons living with HIV (PWH), with possible underlying mechanisms including increased vascular stiffness, chronic inflammation and myocardial toxicity. This study evaluated the prevalence of HFpEF and differences in cardiovascular complications in PWH with and without HFpEF. Methods: Participants included 257 of 965 PWH at our Special Immunology Clinic at the Jackson Memorial and University of Miami Hospitals from 2017-19. Demographic, clinical, and laboratory information, were obtained from retrospective review of the electronic health records. HFpEF was confirmed by clinical and echocardiography findings, from which H2FpEF score was derived. Patients with an EF &lt;50% were excluded. Results: The prevalence of HFpEF was 0.7%, while the mean H2FpEF score was 3.3±1.4. Thus, on average the cohort had an intermediate probability of HFpEF. When comparing persons with compared with those without HFpEF, mean age (56.4 vs. 52.0 years) and proportion of women (57.1 vs.45.0%) did not significantly differ. Similarly, groups did not differ on mean CD4 count (665 vs. 568 cells/uL, p=0.40), % with undetectable Viral Load (85.7% vs. 71.6%, p=0.41), or antiretroviral therapy use (100.0% vs. 92.8%, p=0.46). Of note, the prevalence of coronary artery disease (CAD) (14.3% vs. 1.6%, p=0.009), myocardial infarction (28.6 vs. 1.8%, p&lt;0.001), abnormal stress testing (14.3% vs. 0.8%, p=0.001), PCI (14.3% vs. 0.9%, p=0.001), type II diabetes (57.1% vs. 16.0%, p=0.003), HbA1C (8.0±2.9% vs. 5.9±1.4%, p=0.004) and chronic kidney disease (57.1% vs. 10.2%, p&lt;0.001) were higher in PWH with HFpEF. Of note, the groups had comparable mean EF (55.0 vs. 56.0%, p=0.66), diastolic dysfunction (33.3% vs. 41.9%, p=0.68), left ventricular (LV) hypertrophy (28.6% vs. 20.9%, p=0.62) and LV mass index (86.4±30.8 vs. 79.1±23.2 g/m2, p=0.34). Conclusions: The overall prevalence was similar to that reported in persons 45 years of age or more in the general population. Risk markers for atherosclerotic disease were significantly higher in PWH with HFpEF. HIV disease severity did not appear to be associated with HFpEF prevalence. Further studies evaluating the pathophysiology of HFpEF in PWH are needed.
Abstract 016: Association Of Fat Mass, Lean Mass, And Waist Circumference With Risk Of Heart Failure Among Community Dwelling Adults
Authors: Ambarish Pandey, Matthew W Segar, Ian J Neeland, Kershaw Patel
Journal: Circulation (2021)

Introduction: Higher body mass index and obesity are associated with a higher risk of diabetes and heart failure (HF) development. However, the contribution of measures of body composition such as fat mass (FM), lean mass (LM), and central adiposity (waist circumference, WC) towards the risk of HF, and if these relationships are modified by diabetes status (DM) is unknown. Methods: Adults from visit 5 of the Atherosclerosis Risk in Communities Study without prevalent HF were included. FM and LM were measured using bioelectric impedance. Multivariable adjusted Cox proportional hazards models were created to evaluate the associations of FM, LM, and WC with the risk of HF after adjustment for potential confounders ( see Fig legend ). Multiplicative interaction testing and stratified analysis by DM status were performed using adjusted Cox models and restricted cubic splines to evaluate whether the association of body composition parameters and risk of HF were modified by DM status. Results: The present study included 5,555 participants (58.3% women, 79.3% white). Over a median follow-up of 4.6 years, there were 254 HF events (4.6%). In the overall cohort, higher LM was significantly associated with higher risk of HF (aHR [95% CI] per 1 SD higher LM: 1.34 [1.13-1.60]) with no interaction by DM status. However, the associations of FM and WC with risk of HF were modified by DM status (p-interaction: FM*diabetes = 0.03, WC*diabetes = 0.008). Higher FM and WC were each significantly associated with higher risk of HF in adults with DM (aHR [95% CI] per 1-SD higher FM: 1.23 [1.01-1.49], per 1SD higher WC: 1.57 [1.31 - 1.89]) but not among those without DM at baseline (aHR [95% CI] FM: 0.99 [0.80 - 1.23], WC: 1.06 [0.87 - 1.30]) ( Figure ). Conclusions: Higher LM was significantly associated with a higher risk of HF irrespective of diabetes status. In contrast, the association of FM and WC with the risk of HF was modified by the presence of DM such that higher FM and WC were associated with a higher risk of HF among adults with DM but not those without DM.
Abstract MP41: Rates Of Acute Myocardial Infarction Around The Covid-19 Pandemic And Comparable Time Periods In 2019 In An Integrated Healthcare Delivery System
Authors: Matthew T Mefford, Ran Liu, Lei Qian, Teresa N Harrison, Steven J Jacobsen, JaeJin An, Mingsum Lee, Nigel Gupta, Chileshe N Price, Paul Muntner, Kristi Reynolds
Journal: Circulation (2021)

Background: Stay at home orders and fear of acquiring COVID-19 may have led to an avoidance of care for medical emergencies including acute myocardial infarction (AMI). We sought to examine rates of confirmed AMI cases between January 1-June 30, 2019 and 2020. Methods: We identified Kaiser Permanente Southern California members ≥ 18 years old with a hospitalization or emergency department visit for AMI, defined by ICD-10 primary diagnosis codes. Rates of AMI per 100,000 member-weeks were calculated for pre-pandemic and pandemic periods of January 1-March 3, 2020 and March 20-June 30, 2020, respectively, and in the same periods of 2019 overall and for ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI), separately. March 4-19, 2020 was considered a washout period given the gradual rollout of stay-at-home orders. Rate ratios (RR) and 95% confidence intervals (CI) were calculated comparing pre-pandemic and pandemic periods of 2020 to 2019 using Poisson regression. Results: The mean age of patients presenting with AMI during the 2020 (n=3,029) and 2019 (n=3,518) periods was 69 years, and a majority of events occurred among men (62%) and whites (47%). Rates of AMI in the pre-pandemic period of 2020 and same period in 2019 were 4.23 and 4.45 per 100,000 member weeks, respectively. During the pandemic period of 2020 and the same period in 2019, rates were 3.04 and 3.85 per 100,000 member-weeks, respectively. (Figure) There was no evidence rates of AMI were different during the pre-pandemic period of 2020 compared to the same period in 2019 (RR 0.95, 95% CI 0.88, 1.03). In contrast, rates of AMI were lower during the pandemic period of 2020 compared to the same period of 2019 (RR 0.79, 95% CI 0.74, 0.85), and among NSTEMI (RR 0.80, 95% CI 0.74, 0.86) and STEMI (0.74, 95% CI 0.66, 0.84) cases. Conclusion: AMI rates were lower during the COVID-19 pandemic compared to the year prior. Public health messaging is important to ensure people seek care for medical emergencies.
A systematic review of transdiagnostic risk and protective factors for general and specific psychopathology in young people
Authors: Samantha J. Lynch, Matthew Sunderland, Nicola C. Newton, Cath Chapman
Journal: Clinical Psychology Review (2021)

A large body of research has emerged over the last decade examining empirical models of general and specific psychopathology, which take into account comorbidity among psychiatric disorders and enable investigation of risk and protective factors that are common across disorders. This systematic review presents findings from studies of empirical models of psychopathology and transdiagnostic risk and protective factors for psychopathology among young people (10-24 years). PsycInfo, Medline and EMBASE were searched from inception to November 2020, and 41 studies were identified that examined at least one risk or protective factor in relation to broad, empirically derived, psychopathology outcomes. Results revealed several biological (executive functioning deficits, earlier pubertal timing, genetic risk for ADHD and schizophrenia, reduced gray matter volume), socio-environmental (stressful life events, maternal depression) and psychological (low effortful control, high neuroticism, negative affectivity) transdiagnostic risk factors for broad psychopathology outcomes, including general psychopathology, internalising and externalising. Methodological complexities are discussed and recommendations for future studies of empirical models of psychopathology are presented. These results contribute to a growing body of support for transdiagnostic approaches to prevention and intervention for psychiatric disorders and highlight several promising avenues for future research.
Treatment of opioid use disorder in primary care
Authors: Megan Buresh, Robert Stern, Darius Rastegar
Journal: BMJ (2021)

Abstract Opioid use disorder (OUD) is a common, treatable chronic disease that can be effectively managed in primary care settings. Untreated OUD is associated with considerable morbidity and mortality—notably, overdose, infectious complications of injecting drug use, and profoundly diminished quality of life. Withdrawal management and medication tapers are ineffective and are associated with increased rates of relapse and death. Pharmacotherapy is the evidence based mainstay of OUD treatment, and many studies support its integration into primary care settings. Evidence is strongest for the opioid agonists buprenorphine and methadone, which randomized controlled trials have shown to decrease illicit opioid use and mortality. Discontinuation of opioid agonist therapy is associated with increased rates of relapse and mortality. Less evidence is available for the opioid antagonist extended release naltrexone, with a meta-analysis of randomized controlled trials showing decreased illicit opioid use but no effect on mortality. Treating OUD in primary care settings is cost effective, improves outcomes for both OUD and other medical comorbidities, and is highly acceptable to patients. Evidence on whether behavioral interventions improve outcomes for patients receiving pharmacotherapy is mixed, with guidelines promoting voluntary engagement in psychosocial supports, including counseling. Further work is needed to promote the integration of OUD treatment into primary care and to overcome regulatory barriers to integrating methadone into primary care treatment in the US.
13P Comparison study of different programmed death-ligand 1 (PD-L1) assays, readers and scoring methods in triple-negative breast cancer (TNBC)
Authors: A. Noske, D-C. Wagner, K. Schwamborn, S. Foersch, K. Steiger, M. Kiechle, S. Karapetyan, D. Oettler, A. Hapfelmeier, W. Roth, W. Weichert
Journal: Annals of Oncology (2021)
Lenalidomide and dexamethasone with or without clarithromycin in patients with multiple myeloma ineligible for autologous transplant: a randomized trial
Authors: Noemi Puig, Miguel T. Hernández, Laura Rosiñol, Esther González, Felipe de Arriba, Albert Oriol, Verónica González-Calle, Fernando Escalante, Javier de la Rubia, Mercedes Gironella, Rafael Ríos, Ricarda García-Sánchez, José M. Arguiñano, Adrián Alegre, Jesús Martín, Norma. C. Gutiérrez, María J. Calasanz, María L. Martín, María del Carmen Couto, María Casanova, Mario Arnao, Ernesto Pérez-Persona, Sebastián Garzón, Marta S. González, Guillermo Martín-Sánchez, Enrique M. Ocio, Morton Coleman, Cristina Encinas, Ana M. Vale, Ana I. Teruel, María Cortés-Rodríguez, Bruno Paiva, M. Teresa Cedena, Jesús F. San-Miguel, Juan J. Lahuerta, Joan Bladé, Ruben Niesvizky, María-Victoria Mateos
Journal: Blood Cancer Journal (2021)

Abstract Although case-control analyses have suggested an additive value with the association of clarithromycin to continuous lenalidomide and dexamethasone (Rd), there are not phase III trials confirming these results. In this phase III trial, 286 patients with MM ineligible for ASCT received Rd with or without clarithromycin until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). With a median follow-up of 19 months (range, 0–54), no significant differences in the median PFS were observed between the two arms (C-Rd 23 months, Rd 29 months; HR 0.783, p = 0.14), despite a higher rate of complete response (CR) or better in the C-Rd group (22.6% vs 14.4%, p = 0.048). The most common G3–4 adverse events were neutropenia [12% vs 19%] and infections [30% vs 25%], similar between the two arms; however, the percentage of toxic deaths was higher in the C-Rd group (36/50 [72%] vs 22/40 [55%], p = 0.09). The addition of clarithromycin to Rd in untreated transplant ineligible MM patients does not improve PFS despite increasing the ≥CR rate due to the higher number of toxic deaths in the C-Rd arm. Side effects related to overexposure to steroids due to its delayed clearance induced by clarithromycin in this elderly population could explain these results. The trial was registered in clinicaltrials.gov with the name GEM-CLARIDEX: Ld vs BiRd and with the following identifier NCT02575144. The full trial protocol can be accessed from ClinicalTrials.gov. This study received financial support from BMS/Celgene.
Abstract 071: Ten-year Change In Tv Viewing Is Associated With Concurrent Change In Pericardial Adipose Tissue In Middle-aged Adults: The Coronary Artery Risk Development In Young Adults (CARDIA) Study
Authors: Minsuk Oh, Kelley Pettee Gabriel, David R Jacobs, James G Terry, Jingzhong Ding, John J Carr, Jennifer G Robinson, Wei Bao, Kara M Whitaker
Journal: Circulation (2021)

Introduction: Pericardial adipose tissue (PAT), an ectopic adipose depot surrounding the coronary arteries, is a pathogenic risk factor for cardiometabolic disease; however, the association of sedentary behavior with PAT is poorly understood. We examined the longitudinal association of 10-year change in TV viewing with concurrent change in PAT. Hypothesis: Increased h/day of TV viewing over 10 years are associated with larger mean increases in PAT during the same 10-year period. Methods: Middle-aged adults (N=1659, mean age=40.4, 912 females, 733 blacks) from the Coronary Artery Risk Development in Young Adults (CARDIA) Study at the exam years 15 (2000-2001) and 25 (2010-2011) were included. Both TV viewing (h/day) and the volume of PAT (mL) were measured at Years 15 and 25 using the CARDIA physical activity questionnaire and computed tomography, respectively. Covariates measured at year 15 included PAT, sociodemographic factors, cardiovascular disease risk factors, diet quality, TV viewing, moderate-to-vigorous intensity physical activity (MVPA), inflammatory cytokines, and waist circumference. Multivariable linear regression was used to estimate 10-year change in PAT across increasing tertiles (≤ -1, &gt; -1 to &lt; 1, ≥ 1 h/day) of 10-year changes in TV viewing. Results: On average, TV viewing and PAT increased between the two exam years by 0.2 h/day (8.7% increase, mean: 2.3 → 2.5 h/day) and 11.8 mL (25.9% increase, mean: 45.6 → 57.4 mL), respectively (all p &lt; 0.01). In the fully adjusted model including MVPA and other major confounders, the highest tertile of 10-year change in TV viewing was associated with greater change in PAT (β = 2.97 mL, p &lt; 0.01) when compared with the lowest tertile (see Figure 1 ), while mean PAT change was intermediate in the middle tertile. Conclusions: A greater 10-year increase in TV viewing is associated with a greater concurrent increase in PAT, independent of MVPA and other important confounders. Reducing TV viewing time may be associated with less PAT accumulation with age.
100P Efficacy of enobosarm, a selective androgen receptor (AR) targeting agent, in patients with metastatic AR+/ER+ breast cancer resistant to estrogen receptor targeted agents and CDK 4/6 inhibitor in a phase II clinical study
Authors: C. Palmieri, H. Linden, S. Birrell, E. Lim, L.S. Schwartzberg, H.S. Rugo, P. Cobb, K. Jain, C. Vogel, J. O'Shaughnessy, S.R.D. Johnston, R.H. Getzenberg, K.G. Barnette, M. Steiner, A.M. Brufsky, B. Overmoyer
Journal: Annals of Oncology (2021)
Hyperthermia Selectively Destabilizes Oncogenic Fusion Proteins
Authors: Yasen Maimaitiyiming, Qian Qian Wang, Chang Yang, Yasumitsu Ogra, Yinjun Lou, Clayton A. Smith, Liaqat Hussain, Yi Ming Shao, Jiebo Lin, Jinfeng Liu, Lingfang Wang, Yong Zhu, Haiyan Lou, Yuan Huang, Xiaoxia Li, Kao-Jung Chang, Hao Chen, Hongyan Li, Ying Huang, Eric Tse, Jie Sun, Na Bu, Shih-Hwa Chiou, Yan Fang Zhang, Hao Ying Hua, Li Ya Ma, Ping Huang, Ming Hua Ge, Feng-Lin Cao, Xiaodong Cheng, Hongzhe Sun, Jin Zhou, Vasilis Vasliou, Pengfei Xu, Jie Jin, Mikael Bjorklund, Hong-Hu Zhu, Chih-Hung Hsu, Hua Naranmandura
Journal: Blood Cancer Discovery (2021)

The PML/RARα fusion protein is the oncogenic driver in acute promyelocytic leukemia (APL). Although most APL cases are cured by PML/RARα-targeting therapy, relapse and resistance can occur due to drug-resistant mutations. Here we report that thermal stress destabilizes the PML/RARα protein, including clinically identified drug-resistant mutants. AML1/ETO and TEL/AML1 oncofusions show similar heat shock susceptibility. Mechanistically, mild hyperthermia stimulates aggregation of PML/RARα in complex with nuclear receptor corepressors leading to ubiquitin-mediated degradation via the SIAH2 E3 ligase. Hyperthermia and arsenic therapy destabilize PML/RARα via distinct mechanisms and are synergistic in primary patient samples and in vivo, including three refractory APL cases. Collectively, our results suggest that by taking advantage of a biophysical vulnerability of PML/RARα, thermal therapy may improve prognosis in drug-resistant or otherwise refractory APL. These findings serve as a paradigm for therapeutic targeting of fusion oncoprotein-associated cancers by hyperthermia.Hyperthermia destabilizes oncofusion proteins including PML/RARα and acts synergistically with standard arsenic therapy in relapsed and refractory APL. The results open up the possibility that heat shock sensitivity may be an easily targetable vulnerability of oncofusion-driven cancers.See related commentary by Wu et al., p. 300.
Abstract P172: Endothelial Function In The Early Years After Delivery: Effect Of Adverse Pregnancy Outcomes And Activity Behaviors
Authors: Abbi D Lane-Cordova, Erin O'Connor, Janet M Catov, Bo Fernhall, Jihong Liu, Sara Wilcox
Journal: Circulation (2021)

Introduction: Adverse pregnancy outcomes (APOs) are independently associated with cardiovascular disease (CVD). Endothelial dysfunction may indicate early CVD and can be influenced by physical activity (PA) and sedentary behavior (SED). Hypothesis: We hypothesized women with a past APO would have worse endothelial function versus controls and that mid-pregnancy and current PA would be directly related while SED would be inversely related to endothelial function in the years soon after delivery. Methods: We used venous occlusion plethysmography to measure baseline forearm blood flow, reactive hyperemia, and vascular conductance (forearm blood flow/mean arterial pressure) in a case control study of 53 women 6 mo to 3 yrs after a singleton birth; 26% with past APO, 21% African American, mean age=33±1 yrs, mean BMI=27.4±0.9 kg/m 2 . Current and mid-pregnancy leisure time PA and weekday SED were assessed with validated questionnaires. We evaluated differences in endothelial function by APO exposure with t-tests and relations of endothelial function with PA and SED with Spearman correlations. Results: Baseline forearm blood flow (APO: 1.6±0.2; non-APO: 1.8±0.1 ml*min -1 *100 ml -1 tissue, p=0.3) and reactive hyperemia (APO: 13.2±2; non-APO: 11.4±1 ml*min -1 *100 ml -1 , p=0.8) were similar between groups. Vascular conductance was non-significantly lower in women with a past APO: 1.7x10 -2 versus 2.1x10 -2 ml*min -1 *100 ml -1 mmHg -1 in women without a past APO, p&lt;0.10. Vascular conductance was related to current and mid-pregnancy SED (figure) but not PA (r=0.2 and r=0.06, p&gt;0.05 for mid-pregnancy and current PA). Associations of mid-pregnancy and current SED with vascular conductance after delivery persisted after adjustment for age and BMI. Conclusions: Forearm vascular conductance tended to be lower soon after delivery in women with an APO. Mid-pregnancy and current SED were inversely related to forearm vascular conductance and may represent targets for interventions aimed at improving endothelial function after delivery.
Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency
Authors: Donald B. Kohn, Claire Booth, Kit L. Shaw, Jinhua Xu-Bayford, Elizabeth Garabedian, Valentina Trevisan, Denise A. Carbonaro-Sarracino, Kajal Soni, Dayna Terrazas, Katie Snell, Alan Ikeda, Diego Leon-Rico, Theodore B. Moore, Karen F. Buckland, Ami J. Shah, Kimberly C. Gilmour, Satiro De Oliveira, Christine Rivat, Gay M. Crooks, Natalia Izotova, John Tse, Stuart Adams, Sally Shupien, Hilory Ricketts, Alejandra Davila, Chilenwa Uzowuru, Amalia Icreverzi, Provaboti Barman, Beatriz Campo Fernandez, Roger P. Hollis, Maritess Coronel, Allen Yu, Krista M. Chun, Christian E. Casas, Ruixue Zhang, Serena Arduini, Frances Lynn, Mahesh Kudari, Andrea Spezzi, Marco Zahn, Rene Heimke, Ivan Labik, Roberta Parrott, Rebecca H. Buckley, Lilith Reeves, Kenneth Cornetta, Robert Sokolic, Michael Hershfield, Manfred Schmidt, Fabio Candotti, Harry L. Malech, Adrian J. Thrasher, H. Bobby Gaspar
Journal: New England Journal of Medicine (2021)

Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency.
Cellular and transcriptomic analyses reveal two-staged chloroplast biogenesis underpinning photosynthesis build-up in the wheat leaf
Authors: Naresh Loudya, Priyanka Mishra, Kotaro Takahagi, Yukiko Uehara-Yamaguchi, Komaki Inoue, Laszlo Bogre, Keiichi Mochida, Enrique López-Juez
Journal: Genome biology (2021)

Abstract Background The developmental gradient in monocot leaves has been exploited to uncover leaf developmental gene expression programs and chloroplast biogenesis processes. However, the relationship between the two is barely understood, which limits the value of transcriptome data to understand the process of chloroplast development. Results Taking advantage of the developmental gradient in the bread wheat leaf, we provide a simultaneous quantitative analysis for the development of mesophyll cells and of chloroplasts as a cellular compartment. This allows us to generate the first biologically-informed gene expression map of this leaf, with the entire developmental gradient from meristematic to fully differentiated cells captured. We show that the first phase of plastid development begins with organelle proliferation, which extends well beyond cell proliferation, and continues with the establishment and then the build-up of the plastid genetic machinery. The second phase is marked by the development of photosynthetic chloroplasts which occupy the available cellular space. Using a network reconstruction algorithm, we predict that known chloroplast gene expression regulators are differentially involved across those developmental stages. Conclusions Our analysis generates both the first wheat leaf transcriptional map and one of the most comprehensive descriptions to date of the developmental history of chloroplasts in higher plants. It reveals functionally distinct plastid and chloroplast development stages, identifies processes occurring in each of them, and highlights our very limited knowledge of the earliest drivers of plastid biogenesis, while providing a basis for their future identification.