tbuckley/cabot-search huggingface dataset:
PML is involved in DNA-damage response and maintaining genome stability.
Authors: Zhi-Xiang Xu, Rui-Xun Zhao, Zhao-Mei Mu, Michael D. Story, Kun-Sang Chang
Journal: Cancer Research (2004)

2286  The tumor suppressor gene PML is consistently disrupted by the t(15;17) in acute promyelocytic leukemia (APL). Disruption of PML function in APL is believed to involve in the pathogenesis of the disease. A role of PML in regulation of gene expression and apoptosis has been well documented. Recent studies demonstrated that PML colocalizes in vivo with several enzymes involve in DNA repair in response to DNA damage. Our study shows that stable overexpression of PML significantly increased survival of cells exposed to ionizing radiation (IR). Inducible expression of PML reduces the number of cells positive for IR-induced BrdU ssDNA foci. Higher number of ssDNA foci was found in PML deficient cells. These results suggest that PML may play a role in mediating DNA strand break repair in response to IR. The ability of PML-deficient cells in repairing damaged DNA after IR exposure was determined by pulse-field gel electrophoresis. This study demonstrates a reduced DNA repair efficiency in the absence of PML. Our study further shows that inducible expression of PML significantly increased the expression of TopBP1 and Rad51. Pulse-chase labeling experiments demonstrated that PML overexpression substantially increases the stability of these proteins. Adenovirus mediated re-expression of PML in PML−/− MEF substantially increased TopBP1 and Rad51 expression, demonstrated a mechanism of PML-dependent expression of these two DNA-damage response proteins. Inhibition of PML expression by small interference (si)RNA significantly reduced the expression of TopBP1, Rad51, BLM and Rad9 proteins. In PML-deficient NB4 cells, Rad51, BLM, Rad9, and other DNA-damage response proteins are unable to form IR-induced foci. ATRA-induced reorganization of PML nuclear bodies (NBs) is associated with the reappearance of IR-induced foci. This study supports a role of PML in IR-induced DNA-damage response. We hypothesize that PML plays a role in organizing and stabilizing the DNA repair enzymes complex and increase the efficiency of DNA repair by homologous recombination. Our study further shows a substantial increased in the incidence of tetraploid chromosomes in PML−/− MEF and in 293T cells treated with PML specific siRNA. This study supports a role of PML in maintaining genome stability. Furthermore, a significant increase in centrosome amplification was found in PML deficient cells supporting a role of PML in genome stability.
Bedside Electrical Impedance Tomography Unveils Respiratory “Chimera” in COVID-19
Authors: Caio C. A. Morais, Bijan Safaee Fakhr, Roberta R. De Santis Santiago, Raffaele Di Fenza, Eizo Marutani, Stefano Gianni, Riccardo Pinciroli, Robert M. Kacmarek, Lorenzo Berra
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
Abstract 16063: Demographic Differences in the Burden of Heart Failure Attributable to Obesity-Associated Metabolic Risk Factors: The Atherosclerosis in Communities (ARIC) Study
Authors: Robert Okyere, Roberta Florido, Sui Zhang, Justin Echouffo-Tcheugui, Carine Hamo, Erin D Michos, VIJAY NAMBI, Wendy S Post, Gary Gerstenblith, Roger S Blumenthal, Christie M Ballantyne, Josef Coresh, Elizabeth Selvin, Chiadi E Ndumele
Journal: Circulation (2020)

Background: The development of metabolic syndrome (MetS) and diabetes among those with obesity varies by age, sex, race and socioeconomic status (SES) and is associated with increased heart failure (HF) risk. There are limited data about whether the HF burden related to these metabolic risk factors differs across demographic groups. Hypothesis: There is significant variation in the proportion of HF events attributable to obesity-associated metabolic risk factors across demographic groups. Methods: We studied 10,133 white and black participants at ARIC Visit 4 (1996-98) without baseline HF. Age was categorized as &lt; or ≥65 yrs and SES categorized as low, medium or high based on education, income, and area deprivation index. MetS was defined by AHA/NHLBI criteria. HF follow-up was through 2018. Individuals with obesity (BMI ≥30kg/m 2 ) were grouped as: no MetS or diabetes, MetS alone, or both MetS and diabetes (highest metabolic risk). Across demographic strata, we assessed: metabolic risk group prevalences; hazard ratios (HRs) for HF associated with each metabolic risk group (Cox regression); and the population attributable risk (PAR) for HF associated with metabolic risk factors in those with obesity. Results: Those with age ≥65, male sex, black race and low SES were more likely to be in the highest metabolic risk group ( Table ). Over 20 years (N= 2,194 events), compared to normal weight without MetS or diabetes, the highest metabolic risk was associated with 3-5 fold higher HF risk in all subgroups. Stronger HF associations were seen for those &lt; vs ≥65 years (p interaction &lt;0.001) and for women vs men (p interaction 0.03). The PAR for obesity-associated metabolic risk factors varied by race (39 vs 32% for blacks vs whites) and SES (40 vs 28% for low vs high SES). Conclusion: There are important demographic differences in the burden of HF related to metabolic risk factors. Addressing disparities in the HF impact of metabolic risk factors is critical to efforts to improve health equity.
A validated pediatric disease risk index for allogeneic hematopoietic cell transplantation
Authors: Muna Qayed, Kwang Woo Ahn, Carrie L. Kitko, Mariam H. Johnson, Nirali N. Shah, Christopher Dvorak, Karin Mellgren, Brian D. Friend, Michael R. Verneris, Wing Leung, Jacek Toporski, John Levine, Joseph Chewning, Alan Wayne, Urvi Kapoor, Brandon Triplett, Kirk R. Schultz, Gregory A. Yanik, Mary Eapen
Journal: Blood (2020)

Abstract A disease risk index (DRI) that was developed for adults with hematologic malignancy who were undergoing hematopoietic cell transplantation is also being used to stratify children and adolescents by disease risk. Therefore, to develop and validate a DRI that can be used to stratify those with AML and ALL by their disease risk, we analyzed 2569 patients aged &amp;lt;18 years with acute myeloid (AML; n = 1224) or lymphoblastic (ALL; n = 1345) leukemia who underwent hematopoietic cell transplantation. Training and validation subsets for each disease were generated randomly with 1:1 assignment to the subsets, and separate prognostic models were derived for each disease. For AML, 4 risk groups were identified based on age, cytogenetic risk, and disease status, including minimal residual disease status at transplantation. The 5-year leukemia-free survival for low (0 points), intermediate (2, 3, 5), high (7, 8), and very high (&amp;gt;8) risk groups was 78%, 53%, 40%, and 25%, respectively (P &amp;lt; .0001). For ALL, 3 risk groups were identified based on age and disease status, including minimal residual disease status at transplantation. The 5-year leukemia-free survival for low (0 points), intermediate (2-4), and high (≥5) risk groups was 68%, 51%, and 33%, respectively (P &amp;lt; .0001). We confirmed that the risk groups could be applied to overall survival, with 5-year survival ranging from 80% to 33% and 73% to 42% for AML and ALL, respectively (P &amp;lt; .0001). This validated pediatric DRI, which includes age and residual disease status, can be used to facilitate prognostication and stratification of children with AML and ALL for allogeneic transplantation.
Evaluation of a Patient-Centered Fall-Prevention Tool Kit to Reduce Falls and Injuries
Authors: Patricia C. Dykes, Zoe Burns, Jason Adelman, James Benneyan, Michael Bogaisky, Eileen Carter, Awatef Ergai, Mary Ellen Lindros, Stuart R. Lipsitz, Maureen Scanlan, Shimon Shaykevich, David Westfall Bates
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Falls represent a leading cause of preventable injury in hospitals and a frequently reported serious adverse event. Hospitalization is associated with an increased risk for falls and serious injuries including hip fractures, subdural hematomas, or even death. Multifactorial strategies have been shown to reduce falls in acute care hospitals, but evidence for fall-related injury prevention in hospitals is lacking. <h3>Objective</h3> To assess whether a fall-prevention tool kit that engages patients and families in the fall-prevention process throughout hospitalization is associated with reduced falls and injurious falls. <h3>Design, Setting, and Participants</h3> This nonrandomized controlled trial using stepped wedge design was conducted between November 1, 2015, and October 31, 2018, in 14 medical units within 3 academic medical centers in Boston and New York City. All adult inpatients hospitalized in participating units were included in the analysis. <h3>Interventions</h3> A nurse-led fall-prevention tool kit linking evidence-based preventive interventions to patient-specific fall risk factors and designed to integrate continuous patient and family engagement in the fall-prevention process. <h3>Main Outcomes and Measures</h3> The primary outcome was the rate of patient falls per 1000 patient-days in targeted units during the study period. The secondary outcome was the rate of falls with injury per 1000 patient-days. <h3>Results</h3> During the interrupted time series, 37 231 patients were evaluated, including 17 948 before the intervention (mean [SD] age, 60.56 [18.30] years; 9723 [54.17%] women) and 19 283 after the intervention (mean [SD] age, 60.92 [18.10] years; 10 325 [53.54%] women). There was an overall adjusted 15% reduction in falls after implementation of the fall-prevention tool kit compared with before implementation (2.92 vs 2.49 falls per 1000 patient-days [95% CI, 2.06-3.00 falls per 1000 patient-days]; adjusted rate ratio 0.85; 95% CI, 0.75-0.96;<i>P</i> = .01) and an adjusted 34% reduction in injurious falls (0.73 vs 0.48 injurious falls per 1000 patient-days [95% CI, 0.34-0.70 injurious falls per 1000 patient-days]; adjusted rate ratio, 0.66; 95% CI, 0.53-0.88;<i>P</i> = .003). <h3>Conclusions and Relevance</h3> In this nonrandomized controlled trial, implementation of a fall-prevention tool kit was associated with a significant reduction in falls and related injuries. A patient–care team partnership appears to be beneficial for prevention of falls and fall-related injuries. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02969343
Abstract 16337: A Risk Score That Predicts Recurrence of Neurally Mediated Syncope Using Electrocardiographic and Vectorcardiographic Parameters
Authors: Calina-Patricia Tentea, Roxana Chiorescu, Sorin Crisan, Sorin Pop, Jeremy N Ruskin, Dan Blendea
Journal: Circulation (2020)

Introduction: We have previously demonstrated that isolated very low QRS voltage (VLV defined as ≤0.3mV) in the frontal leads on the electrocardiogram (ECG; Figure A), as well as flat QRS loops in the frontal plane on ECG-derived vectorcardiograms (VCG; Figure B) predict recurrence of neurally mediated syncope (NMS). This phenomenon is possibly related to a specific ventricular geometry and activation pattern. Hypothesis: The aim of this study was to attempt to incorporate these novel ECG and VCG risk factors for recurrence of syncope into a prognostic risk score. Methods: We included 215 patients (age 48±20years), with NMS and a median of 3 syncopal episodes. The patients were followed for a median of 10 months (IQR 4-20). To weigh the relative importance of the prognostic risk factors identified in multivariate Cox regression analysis we attributed a score of 1 point for HR 1.5-1.99, 2 points for HR 2.0-2.49, and 3 points for HR ≥ 2.5. The total risk score, was divided into three categories: low risk (0-2), intermediate risk (3-5) and high risk (≥6). Results: The multivariate analysis identified history of ≥ 2 syncopal events (HR 3.85, 95%CI 1.62-9.14), left ventricular end-diastolic diameter of &lt; 39mm by echocardiography (HR 1.94, 95%CI 1.00-3.82), isolated VLV QRS in frontal leads (HR 2.60, 95%CI 1.37-4.86) and flat QRS VCG loops in frontal plane (HR 2.23, 95%CI 1.24-3.99) as independent predictors for NMS recurrence (all P &lt; 0.05). The actuarial total syncope recurrence rate at 1 year was 54.6% (95%CI 38.2-72.6) in the high-risk score category, 25.3% (95%CI 16.8-37.1) in the intermediate risk category, and 6.2% (95%CI 2.2-16.2) in the low-risk category (log rank test P&lt;0.0001; Figure C). The ROC curve showed an AUC of 0.77 for the predictive value of the total risk score. Conclusions: The risk of recurrence of NMS could be stratified using a risk score that incorporates novel ECG and VCG parameters in addition to more established clinical and echocardiographic variables.
Abstract 13760: Intensive versus Standard Blood Pressure Control in Patients With Peripheral Artery Disease: The Systolic Blood Pressure Intervention Trial (SPRINT)
Authors: Johanna Frary, Christina Byrne, Muthiah Vaduganathan, Tor Biering-srensen, Michael H Olsen, Deepak L Bhatt, Manan Pareek
Journal: Circulation (2020)

Background: High blood pressure (BP) is the strongest modifiable risk factor for cardiovascular (CV) disease and is highly prevalent among individuals with peripheral artery disease (PAD). Purpose: To assess the efficacy and safety of intensive versus standard BP control in patients with PAD, and to assess if the presence of PAD modified treatment effect. Methods: SPRINT was a randomized, controlled, open-label trial in which individuals aged ≥50 years, at high CV risk, and with a systolic BP 130-180 mmHg were randomized to intensive (systolic BP target &lt;120mmHg) or standard BP control (systolic BP target 135-139 mmHg). The primary outcome was the composite of acute coronary syndromes, stroke, heart failure, or CV death. Safety outcomes included serious adverse events, such as hypotension, syncope, electrolyte abnormalities, acute kidney injury or failure, or injurious falls. We assessed the risk of events in patients with PAD versus those without and assessed the efficacy and safety of intensive BP in patients with PAD. Subgroup heterogeneity was evaluated using interaction analyses. Results: Of 9361 participants, 503 (5.3%) had baseline PAD (intensive group 250 (5.3%) versus standard group 253 (5.4%); P=0.90). Median follow-up duration was 3.2 years (range 0-4.6 years). PAD was independently associated with a higher risk of both the primary outcome (hazard ratio (HR) 1.61, 95% confidence interval (CI): 1.23-2.12; P&lt;0.001) and composite serious adverse events (HR 1.49, 95% CI: 1.32-1.69; P&lt;0.001). The presence of PAD did not modify the efficacy and safety of intensive versus standard BP control (P≥0.05). However, due to the higher baseline risk in PAD patients, the absolute risk reduction of the primary outcome with intensive treatment was larger compared with patients without PAD (1.8% versus 1.6%), as was the risk of death from any cause (2.3% versus 1.1%) (Figure) . Conclusion: Intensive BP control reduced CV events and death in patients with hypertension and PAD.
Abstract 16026: Invasive Hemodynamic Assessment of Patients With Heart Failure With Preserved Ejection Fraction With Anemia and Iron Deficiency
Authors: Anna Subramaniam, Yogesh Reddy, Masaru Obokata, Barry A Borlaug
Journal: Circulation (2020)

Introduction: Anemia is associated with increased mortality, cardiovascular events, and decreased quality of life in patients with heart failure with preserved ejection fraction (HFpEF). Iron deficiency may contribute to disease severity independent of effects on red cell mass. The hemodynamic consequences of anemia and iron deficiency in HFpEF remain unclear. Methods: We analyzed a cohort of 313 consecutive subjects with HFpEF diagnosed by invasive hemodynamic assessment, and compared echocardiographic and hemodynamic characteristics of anemic versus non-anemic subjects. Anemia was defined as hemoglobin &lt;13 g/dL in men and &lt;12 g/dL in women. Iron deficiency was defined as ferritin &lt;100 ug/L. Results: Compared to patients without anemia, HFpEF patients with anemia displayed higher NT-proBNP, elevated pulmonary artery (PA) pressures at rest and at peak exercise, and lower oxygen consumption at peak exercise (Table). There was no difference in pulmonary capillary wedge pressure (PCWP). Patients with iron deficiency were more likely to be women. At rest, patients with iron deficiency displayed lower left ventricular (LV) mass, higher resting SVRI and lower cardiac index (CI), but there were not significant differences with exercise. Conclusions: Anemia in HFpEF is associated with greater evidence of congestion and more severe pulmonary hypertension, contributing to reduced exercise capacity. Iron deficiency in HFpEF is more common in women and associated with lower cardiac output at rest, but hemodynamics are otherwise similar. Further study is required to understand the mechanisms by which anemia and iron deficiency influence cardiac function and outcomes in HFpEF.
Allergens TRP a swITCH to Initiate Type 2 Immunity
Authors: Charlotte E. Cheadle, Drew A. Glencross, Catherine M. Hawrylowicz
Journal: Immunity (2020)

<h2>Summary</h2> Allergens induce type-2 immunity, but unresolved questions remain about initiation of this response. In this issue, Perner et al. propose that cutaneous activation of TRPV1<sup>+</sup> sensory neurons by protease allergens stimulates release of substance P to induce migration of Th2-skewing CD301b<sup>+</sup> DC to draining lymph nodes.
Abstract 13777: Coexisting Metabolic Syndrome Inhibits Myocardial Mitophagy in Renovascular Hypertensive Pigs, Aggravating Cardiac Injury and Dysfunction
Authors: Arash Aghajani Nargesi, Mohamed C Farah, Xiang-yang Zhu, Lei Zhang, Hui Tang, Kyra L Jordan, Ishran M Saadiq, Amir Lerman, Lilach O Lerman, Alfonso Eirin
Journal: Circulation (2020)

Introduction: Subjects with renovascular hypertension (RVH) often manifest with metabolic syndrome (MetS), increasing risk for heart failure, yet the mechanisms underlying cardiac injury remain unknown. Reduced mitophagy and accumulation of impaired mitochondria have been linked to progression of heart failure. Hypothesis: We hypothesized that superimposition of MetS on RVH in swine inhibits myocardial mitophagy, aggravating mitochondrial damage, cardiac injury and dysfunction. Methods: Pigs were studied after 16 weeks of RVH (renal artery stenosis) with or without diet-induced MetS, and Lean controls (n=6 each). Cardiac function was assessed in vivo (multidetector-CT), and cardiac mitochondrial structure, function, mitophagy, and myocardial fibrosis ex vivo. Results: MetS groups developed obesity, whereas RVH groups developed hypertension (Table). Mitochondrial matrix density and ATP production were lower and H2O2 production higher in both RVH groups vs. Lean and MetS (Fig. AB). However, MetS+RVH failed to activate mitophagy and downregulate myocardial expression of mitophagy-related microRNAs achieved by Lean+RVH (Fig. CD). Myocardial expression of the mitophagy marker PTEN-induced kinase (PINK)-1 inversely correlated with myocardial fibrosis (R 2 =0.195, p=0.031). Cardiac fibrosis, hypertrophy, and diastolic dysfunction (decreased E/A ratio) were greater in MetS+RVH vs. Lean+RVH (Table, Fig. E). Conclusions: MetS aggravates myocardial mitochondrial damage and dysfunction in swine RVH. MetS+RVH failed to activate mitophagy, resulting in greater cardiac remodeling, fibrosis, and diastolic dysfunction. Mitochondrial injury and impaired mitophagy may constitute important mechanisms and potential therapeutic targets to ameliorate cardiac structural damage and dysfunction in patients with coexisting MetS and RVH.
A Pregnant Woman With Shortness of Breath
Authors: Sarah Chuzi, Patrick Eucalitto, Lynn M. Yee
Journal: JAMA Cardiology (2020)

A 40-year-old woman with a history of vitral valve endocarditis is pregnant and presents with mild exertional dyspnea, a right ventricular heave, and elevated jugular venous pulsation. What would you do next?
Abstract 15485: Hematological Changes and Coagulation Dysfunction in 633 Patients With Covid-19
Authors: Mo Yang, Huixia Deng, Liang Li, Yafang Tan, Jieyu Ye, Qiang Li
Journal: Circulation (2020)

Introduction: A previously unknown coronavirus was discovered from patients with pneumonia. The disease caused by this virus was named as coronavirus disease 2019 (COVID-19). In addition to pulmonary manifestations, hematological changes such as lymphopenia, thrombocytopenia, and coagulation dysfunction can also be found in COVID-19 patients, and the mechanism is still unclear. Methods: A total of 633 COVID-19 patients from Wuhan hospital of China were retrospectively analyzed. Clinical case data of all patients were collected, including gender, age, chronic underlying diseases, outcome, and blood laboratory test results. The hematological features of COVID-19 patients and the factors affecting their outcome were analyzed. Results: The median age was 62 years ( IQR; 51.0-70.0) and 330 (52%) were men. Lymphopenia ( lymphocyte count, 1.0 х10 9 / L [IQR, 0.7-1.4]) occurred in 317/607 patients (52%), prolonged prothrombin time (13.8 seconds [IQR, 13.1-15.1]) in 289/486 patients (59%), increased D-Dimer level (0.7 mg/L[IQR,0.2-2.9]) in 230/411 patients (57%) and increased C-reactive protein levels (10.7 mg/L [IQR, 2.2-49.7]) in 217/426 patients (51%). Compared with the survival patients, death patients have higher white blood cell count (11.7 х 10 9 /L [IQR, 8.4 to 15.6]), neutrophil count (10.8 х 10 9 /L [IQR, 7.8 to 13.9]), neutrophil count/lymphocyte count (20.5 [IQR, 12.4-34.2]), activated partial thromboplastin time (36.8 seconds [IQR, 31.3-42.3]), prothrombin time (17.1 seconds [IQR, 14.7 to 19.7]), D-Dimer level (4.6 mg/L [IQR, 1.0 to 7.8]), C-reactive protein level (111.8 mg/L (IQR, 53.1 to 196.6), and low lymphocyte count (0.5 х 10 9 /L [IQR, 0.3 to 0.7]). The results of logistic multivariate regression analysis showed that age, neutrophil count, prothrombin time, and C-reactive protein were risk factors for patients with COVID-19. Conclusions: Hematological changes are common in patients with COVID-19. The early stage of the disease is mainly characterized by lymphopenia, and the late stage may be characterized by more severe lymphopenia, even neutrophils elevation, elevated C-reactive protein, and severe coagulation disorder. The pathogenesis may be mediated by a direct viral infection and/or indirect immunopathology.