tbuckley/cabot-search huggingface dataset:
Abstract 15254: Baseline Fragmented QRS Increases the Risk of Major Arrhythmic Events in Hypertrophic Cardiomyopathy: Systematic Review and Meta-Analysis
Authors: Pattara Rattanawong, Tanawan Riangwiwat, Chanavuth Kanitsoraphan, Pakawat Chongsathidkiet, Napatt Kanjanahattakij, Wasawat Vutthikraivit, Eugene H Chung
Journal: Circulation (2017)

Introduction: Fragmented QRS reflects disturbances in the myocardium predisposing the heart to ventricular tachyarrhythmias. Recent studies suggest that fragmented QRS (fQRS) is associated with worse major arrhythmic events in hypertrophic cardiomyopathy (HCM). However, a systematic review and meta-analysis of the literature has not been done. We assessed the association between fQRS and major arrhythmic events in hypertrophic cardiomyopathy by a systematic review of the literature and a meta-analysis. Hypothesis: Baseline fQRS is a predictor of major arrhythmic events in HCM. Methods: We comprehensively searched the databases of MEDLINE and EMBASE from inception to May 2017. Included studies were published prospective or retrospective cohort studies that compared major arrhythmic events (sustained ventricular tachycardia, sudden cardiac arrest, or sudden cardiac death) in HCM with fQRS versus non-fQRS. Data from each study were combined using the random-effects, generic inverse variance method of DerSimo...
Potential New Horizons for the Prevention of Cerebrovascular Diseases and Dementia
Authors: Leonardo Pantoni
Journal: JAMA Neurology (2019)

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CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer
Authors: Laura M. McLane, Mohamed S. Abdel-Hakeem, E. John Wherry
Journal: Annual Review of Immunology (2019)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, metabolic dysregulation, poor memory recall and homeostatic self-renewal, and distinct transcriptional and epigenetic programs. The ability to reinvigorate Tex cells through inhibitory receptor blockade, such as αPD-1, highlights the therapeutic potential of targeting this population. Emerging insights into the mechanisms of exhaustion are informing immunotherapies for cancer and chronic infections. However, like other immune cells, Tex cells are heterogeneous and include progenitor and terminal subsets with unique characteristics and responses to checkpoint blockade. Here, we review our current understanding of Tex cell biology, including the developmental paths, transcriptional and epigenetic features, and cell intrinsic and extrinsic factors contributing to exhaustion and how this knowledge may inform therapeutic targeting of Tex cells in chronic infections, autoimmunity, and cancer.
Abstract P278: Potential Value of Long-term Intensive BP Treatment in 40-year Patients: A Computer Simulation Study
Authors: Anusorn Thanataveerat, Ciaran N Kohli-Lynch, Eric Vittinghoff, Mark J Pletcher, Andrew E Moran
Journal: Circulation (2017)

Introduction: Intensive blood pressure (BP) goals are considered for high cardiovascular disease (CVD) risk adults ≥50 years old; the long-term value of intensive BP goals in younger high CVD risk patients has not been studied. Objectives: We used individual patient computer simulations to assess the incremental value of intensive BP goals in high CVD risk patients as young as 40 years. Methods: Six age/sex cohorts of 100,000 individuals were assembled by sampling NHANES surveys 1999-2010. BP and other risk factor trajectories were projected from ages 60 to 69, 50 to 69, and 40 to 69 years based on Framingham Offspring Cohort analyses. One BP treatment scenario simulated treating BP &lt;140/90 mmHg in all patients ≥140/90; a second scenario added to the first a goal &lt;BP 130/90 mmHg in patients with systolic BP ≥130 and 10-year CVD risk ≥10%. Costs included added treatment and side-effect costs and avoided CVD costs. Incremental cost-effectiveness ratios (ICERs) assessed changes in costs and quality-adjusted life years due to adding intensive BP goals in each cohort. Results: Intensive goals were generally cost-effective in high-risk CVD risk patients (Table). Treating 40-year old cohorts was the highest value strategy. This was because of large life-year gains when events are prevented early in life and because hypertensive 40 year-olds “age into” much higher BPs and CVD risk over time. To illustrate the latter, mean untreated systolic BPs at age 60 were 152, 148, and 146 mmHg, and mean 10-year CVD risk scores were 17%, 15% and 13% for 40-, 50- and 60-year-old male cohorts, respectively. Conclusion: Intensive BP goals were projected to be cost-effective over a 30-year time horizon in high-risk hypertensive patients as young as 40 years old.
Global Case-Fatality Rates in Pediatric Severe Sepsis and Septic Shock
Authors: Bobby Tan, Judith Ju-Ming Wong, Rehena Sultana, Janine Cynthia Jia Wen Koh, Mark Jit, Yee Hui Mok, Jan Hau Lee
Journal: JAMA Pediatrics (2019)

The global patterns and distribution of case-fatality rates (CFRs) in pediatric severe sepsis and septic shock remain poorly described.We performed a systematic review and meta-analysis of studies of children with severe sepsis and septic shock to elucidate the patterns of CFRs in developing and developed countries over time. We also described factors associated with CFRs.We searched PubMed, Web of Science, Excerpta Medica database, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Cochrane Central systematically for randomized clinical trials and prospective observational studies from earliest publication until January 2017, using the keywords "pediatric," "sepsis," "septic shock," and "mortality."Studies involving children with severe sepsis and septic shock that reported CFRs were included. Retrospective studies and studies including only neonates were excluded.We conducted our systematic review and meta-analysis in close accordance to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled case-fatality estimates were obtained using random-effects meta-analysis. The associations of study period, study design, sepsis severity, age, and continents in which studies occurred were assessed with meta-regression.Meta-analyses to provide pooled estimates of CFR of pediatric severe sepsis and septic shock over time.Ninety-four studies that included 7561 patients were included. Pooled CFRs were higher in developing countries (31.7% [95% CI, 27.3%-36.4%]) than in developed countries (19.3% [95% CI, 16.4%-22.7%]; P < .001). Meta-analysis of CFRs also showed significant heterogeneity across studies. Continents that include mainly developing countries reported higher CFRs (adjusted odds ratios: Africa, 7.89 [95% CI, 6.02-10.32]; P < .001; Asia, 3.81 [95% CI, 3.60-4.03]; P < .001; South America, 2.91 [95% CI, 2.71-3.12]; P < .001) than North America. Septic shock was associated with higher CFRs than severe sepsis (adjusted odds ratios, 1.47 [95% CI, 1.41-1.54]). Younger age was also a risk factor (adjusted odds ratio, 0.95 [95% CI, 0.94-0.96] per year of increase in age). Earlier study eras were associated with higher CFRs (adjusted odds ratios for 1991-2000, 1.24 [95% CI, 1.13-1.37]; P < .001) compared with 2011 to 2016. Time-trend analysis showed higher CFRs over time in developing countries than developed countries.Despite the declining trend of pediatric severe sepsis and septic shock CFRs, the disparity between developing and developed countries persists. Further characterizations of vulnerable populations and collaborations between developed and developing countries are warranted to reduce the burden of pediatric sepsis globally.
Abstract 21312: Lactate Dehydrogenase A Affects Neutrophil Transcellular Extravasation by Upregulating Invadopodia Signaling
Authors: Chanchal Sur Chowdhury, Elizabeth Wareham, Juying Xu, Sachin Kumar, Ashwini Hinge, Marie Dominique Filippi
Journal: Circulation (2017)

During inflammation, such as ischemia reperfusion injury or atherosclerosis, excessive neutrophil infiltration drives pathogenesis. Yet, the relationship between neutrophil transmigration and inflammation is ill-defined. Neutrophils migrate through endothelial cells (EC) via para (between EC) and transcellular (through an EC, TCM) mechanisms. During TCM, neutrophils interact with EC via invadopodia-like structures to form a ‘pore’ into EC membrane, thus facilitating neutrophil migration through EC body. We recently reported that deficiency in Rap1b, a member of RasGTPase superfamily, enhanced neutrophil recruitment to inflamed lungs and susceptibility to endotoxin shock. Rap1b-/- neutrophils exhibit increased TCM, invadopodia-like formation and metalloproteinase (MMP) release, suggesting mode of migration may influence inflammation outcome. Here, we used Rap1b-/- neutrophils to further investigate the link between neutrophil migration and inflammation. Using mass spectrometry, we found 2-fold increase in glycolytic enzymes hexokinase1, LDHA and PGK1, in Rap1b-/- protrusions compared to WT. Immunofluorescent staining and western blotting confirmed this observation. Inhibition of LDHA with a specific inhibitor FX11, inhibited Rap1b-/- invadopodia protrusions, MMP release and TCM. We then tested effects of LDHA inhibition on neutrophil transendothelial migration in vivo. Rap1b-/- and WT neutrophils were tagged with cell tracker dyes and transferred to recipient mice, treated with FX11 or DMSO control. Ear microvasculature was stimulated with FMLP and labeled with PECAM antibody to visualize EC junctions. More Rap1b-/- cells migrated out of vessels compared to WT cells at the same vascular environment. FX11 treatment significantly abrogated this increase. This suggests that LDHA and enhanced glycolytic metabolism play critical roles during transmigration in vivo perhaps by changing neutrophil migratory behavior and inflammation outcome. Since lactate, the glycolytic byproduct, induces milieu acidification and acidity play a major role in ischemic damage to the heart, our findings may be important for our understanding of cardiovascular injury and for the development of approaches for effective treatment.
Abstract P012: Three Biological Age Estimates May Capture Distinct Aspects of Aging
Authors: Joanne M Murabito, Qiang Zhao, Daniel Levy, Emelia J Benjamin, Martin G Larson, Kathryn L Lunetta
Journal: Circulation (2017)

Background: Biological age ( BA ) may reflect an individual’s aging process better than chronological age ( CA ). The objective of our study was to construct BA measures from different types of biomarkers and test their associations with mortality and age-related disease in a community-based sample. Methods: We selected 6 clinical predictors that capture pulmonary, vascular, atherosclerosis, insulin sensitivity, inflammatory, and kidney domains of aging, and 9 inflammatory biomarkers measured in Framingham Heart Study Offspring cohort participants at exams 7 (1998-2001, N=3539, mean age 62±10) and 8 (2005-2008, N=3021, mean age 67±9). We used the Klemera-Doubal method to calculate a clinical variable BA and an inflammatory marker BA. We computed BA using DNA methylation (DNAm) data at exam 8 using Horvath’s method. For each of the measures we computed the difference ( ΔAge ) between BA and CA and modeled the effects of ΔAge after accounting for CA. We followed participants through 2014 for all-cause mortality (N=713), cardiovascular disease (CVD, N=412), coronary heart disease (CHD, N=223), stroke (N=129), and cancer (N=509). Results: Inflammatory and clinical ΔAge were correlated (=0.35, =0.33, for exams 7 and 8 respectively), and also across exams (inflammatory ΔAge exam 7 vs 8: =0.61; clinical ΔAge: =0.76). DNAm ΔAge was not significantly correlated with exam 8 inflammatory or clinical ΔAge. After adjusting for CA and sex, larger inflammatory and clinical ΔAge, corresponding to older BA than CA, was associated with significantly increased hazards of all-cause mortality, CVD, and CHD (Table). The clinical and inflammatory ΔAge were significant (p&lt;0.05) in models containing both measures. DNAm ΔAge was associated with increased hazards of all-cause mortality, CVD, cancer, and stroke, and remained significant in a model for mortality that also included inflammatory ΔAge (p&lt;0.05). Conclusions: Our findings suggest the three BA measures may be complementary in predicting risk for age-related disease.
Long-Term Evaluation of Efficacy and Safety of Ofatumumab Added to Fludarabine &amp; Cyclophosphamide in Subjects with Relapsed Chronic Lymphocytic Leukemia: Final Analysis of Complement 2 Trial
Authors: Sebastian Grosicki, Ewa Lech-Maranda, K Govind Babu, Justyna Rybka, Elena Litvinskaya, Javier Loscertales, Irina Kryachok, Janusz Kłoczko, Grygoriy Rekhtman, Wojciech Homenda, Jerzy Blonski, Tommaso Stefanelli, Ghislaine Vincent, Hiya Banerjee, Tadeusz Robak
Journal: Blood (2018)
Pooled safety analysis of high-specific-activity I-131 MIBG in iobenguane scan positive cancer patients.
Authors: Camilo Jimenez, Ravinder K. Grewal, Gregory Ravizzini, Bennett B Chin, Miguel H Pampaloni, Katherine K. Matthay, Jessica Donato Jensen, Tess Lin, Stuart Apfel, Theresa White, Nancy Stambler, Vincent A. DiPippo, Syed Mahmood, Vivien Wong, Daniel Pryma
Journal: Journal of Clinical Oncology (2019)

388 Background: Iobenguane scan positive cancers include pheochromocytoma and paraganglioma (PPGL), neuroblastoma, and gastroenteropancreatic neuroendocrine tumors. A pooled analysis was conducted to assess the safety profile of high-specific-activity I-131 metaiodobenzylguanidine (HSA I-131 MIBG [AZEDRA]) in PPGL and neuroblastoma. Methods: Safety data were pooled from four clinical studies with 118 subjects who received HSA I-131 MIBG. Adverse events (AEs) were described by age, gender, race, number of HSA I-131 MIBG doses, temporal association of AEs within 12 weeks after therapeutic dose 1, vital signs, laboratory values, hematological events of Grade 3/4 or serious AEs, and changes in mean hematology values over a period of 12 months. Results: Out of 118 subjects, mean age was 47.0 ± 18.9 years (range 3-76); 57.6% were males and 74.6% were white. A total of 102 (86.4%) subjects had at least one AE assessed as treatment-related. The incidences of most AEs were similar among both genders and all racial groups. The most common toxicities associated with HSA I-131 MIBG were gastrointestinal disorders, with nausea the most prevalent. The incidences of nausea and salivary gland pain showed decreasing trends with age while dyspnea, asthenia, and peripheral edema showed increasing trends. The second most common toxicities were hematologic. Following each therapeutic dose, mean hemoglobin, leukocytes, neutrophils, and platelets decreased. Most hematological AEs resolved within 12 weeks, and recovery to pre-therapeutic dose values was apparent 6 months after each therapeutic dose. After therapeutic dose 1, higher percentages of subjects experienced AEs in the first 2 weeks, and the incidence decreased beyond 6 weeks. No notable changes were observed in clinical chemistry tests. The incidence of Grade 3/4 AEs was similar following each therapeutic dose. Conclusions: HSA I-131 MIBG was safe and well-tolerated among subjects with iobenguane scan positive cancers. No trends were discerned between baseline characteristics and AEs. Hematology results reflected toxicity profile expected in a population of subjects administered a radiopharmaceutical. Clinical trial information: Pooled Safety.
Abstract 2287: Diastolic Dysfunction is Common in Asymptomatic HIV Patients
Authors: Priscilla Hsue, Husam Farah, Ann F Bolger, Swapna Palav, Samira Y Ahmed, Amanda Schnell, Steven G Deeks, Jeffrey N Martin, Prashant Bhave, Rebecca Cogswell, David D Waters
Journal: Circulation (2007)

Background: The mechanism by which HIV infection increases cardiac events remains unclear. The purpose of this study was to determine the prevalence of systolic and diastolic dysfunction in a contemporary group of asymptomatic HIV patients. Methods: We performed echocardiography in 196 HIV-infected adults and 52 uninfected controls. Left ventricular ejection fraction (EF), left ventricular mass indexed to the body surface area, and diastolic function were assessed according to the American Society of Echocardiography standards. Results: The average age was 47 ± 8 years and 85% were male. Of the HIV patients, 26% had hypertension, 35% were cigarette smokers, and 38% used IV drugs. The median duration of HIV infection was 15 years (IQR 11–18), 82% were on antiretroviral therapy, and 63% had an undetectable viral load. As shown in the table, LV mass index was higher in HIV patients, EF was similar in both groups, and nine (4.6%) of the HIV patients had evidence of LV systolic dysfunction (defined as an EF<50...
MAPK4 overexpression promotes tumor progression via noncanonical activation of AKT/mTOR signaling
Authors: Wei Wang, Tao Shen, Bingning Dong, Chad J. Creighton, Yanling Meng, Wolong Zhou, Qing Shi, Hao Zhou, Yinjie Zhang, David D. Moore, Feng Yang
Journal: Journal of Clinical Investigation (2019)

MAPK4 is an atypical MAPK. Currently, little is known about its physiological function and involvement in diseases, including cancer. A comprehensive analysis of 8887 gene expression profiles in The Cancer Genome Atlas (TCGA) revealed that MAPK4 overexpression correlates with decreased overall survival, with particularly marked survival effects in patients with lung adenocarcinoma, bladder cancer, low-grade glioma, and thyroid carcinoma. Interestingly, human tumor MAPK4 overexpression also correlated with phosphorylation of AKT, 4E-BP1, and p70S6K, independent of the loss of PTEN or mutation of PIK3CA. This led us to examine whether MAPK4 activates the key metabolic, prosurvival, and proliferative kinase AKT and mTORC1 signaling, independent of the canonical PI3K pathway. We found that MAPK4 activated AKT via a novel, concerted mechanism independent of PI3K. Mechanistically, MAPK4 directly bound and activated AKT by phosphorylation of the activation loop at threonine 308. It also activated mTORC2 to phosphorylate AKT at serine 473 for full activation. MAPK4 overexpression induced oncogenic outcomes, including transforming prostate epithelial cells into anchorage-independent growth, and MAPK4 knockdown inhibited cancer cell proliferation, anchorage-independent growth, and xenograft growth. We concluded that MAPK4 can promote cancer by activating the AKT/mTOR signaling pathway and that targeting MAPK4 may provide a novel therapeutic approach for cancer.
Health minister says women harmed by mesh should sue their surgeons
Authors: Jacqui Wise
Journal: BMJ (2019)

A health minister has called on women to sue their surgeons for clinical negligence if they have experienced complications from mesh treatment.

Speaking in an adjournment debate about medical devices, Jackie Doyle-Price said that she did not want to pre-empt what will come out of the Cumberlege review, which is due to report later this year.1 But she said, “It is becoming clear that mesh was deployed far too insensibly—far too many women were given this treatment, often at comparatively young ages, given that this was going to stay in their body for a long time.”

She said that the conversations that had taken place between women who were having this treatment and their surgeons were “utterly inadequate.”

Doyle-Price told the House of Commons, “I say to those women who have …
Retinopathy Outcomes With Empagliflozin Versus Placebo in the EMPA-REG OUTCOME Trial
Authors: Silvio E. Inzucchi, Christoph Wanner, Uwe Hehnke, Isabella Zwiener, Stefan Kaspers, Douglas Clark, Jyothis T. George, Bernard Zinman
Journal: Diabetes Care (2019)

Sodium–glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce cardiovascular (CV) events in CV outcome trials in patients with type 2 diabetes and CV disease. In BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME), the SGLT2 inhibitor empagliflozin reduced the risk of 3-point major adverse CV events (3P-MACE; composite of CV death, nonfatal myocardial infarction, or nonfatal stroke) by 14% versus placebo, driven primarily by a 38% reduction in the risk of CV death (1). Empagliflozin also reduced the risk of a prespecified microvascular outcome (composite of time to first initiation of retinal photocoagulation, vitreous hemorrhage, diabetes-related blindness, or incident/worsening nephropathy) by 38% versus placebo, driven by a reduction in kidney outcomes (2). Similarly, in Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6), the glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide reduced the risk of 3P-MACE versus placebo (hazard ratio [HR] 0.74 [95% CI 0.58, 0.95]; P < 0.001), but was associated with a 76% increase in the risk of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) (1.49 vs. 0.86 events/100 patient-years, respectively; HR 1.76 [95% CI 1.11, 2.78]; P = 0.02]) (3). The reason for the increased risk of retinopathy in SUSTAIN-6 is unknown but has been hypothesized to be a consequence of rapid glucose lowering (4). In Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER), the GLP-1 RA liraglutide reduced the risk of 3P-MACE versus placebo …
AraC-Daunorubicin-Etoposide (ADE) Response Prediction in Pediatric AML Patients Using a Computational Biology Modeling (CBM) Based Precision Medicine Workflow
Authors: Christopher R. Cogle, Taher Abbasi, Neeraj Kumar Singh, Mohammed Sauban, Rahul K Raman, Robinson Vidva, Anuj Tyagi, Anay Ashok Talawdekar, Arko Das, Steven M. Kornblau, Fieke W Hoff, Terzah M. Horton, Shireen Vali
Journal: Blood (2018)
Large Scale Culture and Differentiation of Erythroblasts from PBMC and iPSC
Authors: Maria Claessen, Eszter Varga, Steven Heshusius, Esther Heideveld, Martin Hansen, Anna Visser, Marijke Thiel-Valkhof, Erica Sellink, Patrick Burger, Sacha Zeerleder, Marie Jose Kersten, Emile van den Akker, Marieke von Lindern
Journal: Blood (2018)
Abstract 16637: Increased Bleeding Associated With CYP3A4 and P-gp Interacting Medications in Patients Managed on Rivaroxaban
Authors: Joseph A Goble, Kiumars Zolfaghari, Stephanie Yu, Paul J Godley, Laurel A Copeland, Gregory J Dehmer, Jeffrey B Michel
Journal: Circulation (2017)

Introduction: Rivaroxaban has been identified as a substrate of the cytochrome P450 (CYP) 3A4 enzyme and the P-glycoprotein (P-gp) system. Concomitant interacting medications (CIM) that affect thes...