bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex-Based Differences in Presentation, Treatment, and Complications Among Older Adults Hospitalized for Acute Myocardial Infarction
Authors: Nanna Michael G. , Hajduk Alexandra M. , Krumholz Harlan M. , Murphy Terrence E. , Dreyer Rachel P. , Alexander Karen P. , Geda Mary , Tsang Sui , Welty Francine K. , Safdar Basmah , Lakshminarayan Dharshan K. , Chaudhry Sarwat I. , Dodson John A. 
Published: October 2019

Background:
Studies of sex-based differences in older adults with acute myocardial infarction (AMI) have yielded mixed results. We, therefore, sought to evaluate sex-based differences in presentation characteristics, treatments, functional impairments, and in-hospital complications in a large, well-characterized population of older adults (≥75 years) hospitalized with AMI.

Methods and Results:

We analyzed data from participants enrolled in SILVER-AMI (Comprehensive Evaluation of Risk Factors in Older Patients With Acute Myocardial Infarction)—a prospective observational study consisting of 3041 older patients (44% women) hospitalized for AMI. Participants were stratified by AMI subtype (ST-segment–elevation myocardial infarction [STEMI] and non-STEMI [NSTEMI]) and subsequently evaluated for sex-based differences in clinical presentation, functional impairments, management, and in-hospital complications. Among the study sample, women were slightly older than men (NSTEMI: 82.1 versus 81.3,
P
<0.001; STEMI: 82.2 versus 80.6,
P
<0.001) and had lower rates of prior coronary disease. Women in the NSTEMI subgroup presented less frequently with chest pain as their primary symptom. Age-associated functional impairments at baseline were more common in women in both AMI subgroups (cognitive impairment, NSTEMI: 20.6% versus 14.3%,
P
<0.001; STEMI: 20.6% versus 12.4%,
P
=0.001; activities of daily living disability, NSTEMI: 19.7% versus 11.4%,
P
<0.001; STEMI: 14.8% versus 6.4%,
P
<0.001; impaired functional mobility, NSTEMI: 44.5% versus 30.7%,
P
<0.001; STEMI: 39.4% versus 22.0%,
P
<0.001). Women with AMI had lower rates of obstructive coronary disease (NSTEMI:
P
<0.001; STEMI:
P
=0.02), driven by lower rates of 3-vessel or left main disease than men (STEMI: 38.8% versus 58.7%; STEMI: 24.3% versus 32.1%), and underwent revascularization less commonly (NSTEMI: 55.6% versus 63.6%,
P
<0.001; STEMI: 87.3% versus 93.3%,
P
=0.01). Rates of bleeding were higher among women with STEMI (26.2% versus 15.6%,
P
<0.001) but not NSTEMI (17.8% versus 15.7%,
P
=0.21). Women had a higher frequency of bleeding following percutaneous coronary intervention with both NSTEMI (11.0% versus 7.8%,
P
=0.04) and STEMI (22.6% versus 14.8%,
P
=0.02).

Conclusions:
Among older adults hospitalized with AMI, women had a higher prevalence of age-related functional impairments and, among the STEMI subgroup, a higher incidence of overall bleeding events, which was driven by higher rates of nonmajor bleeding events and bleeding following percutaneous coronary intervention. These differences may have important implications for in-hospital and posthospitalization needs.
Frailty, Acute Organ Dysfunction, and Increased Disability After Hospitalization in Older Adults Who Survive Critical Illness: A Prospective Cohort Study
Authors: Hope Aluko A. , Law Jammie , Nair Rahul , Kim Mimi , Verghese Joe , Gong Michelle Ng 
Published: October 2019

Purpose: We aimed to describe the association between prehospital frailty (PHF), acute organ dysfunction (AOD), and posthospital disability (PHD) outcome in older adults admitted to the intensive care unit (ICU). Methods: In a prospective observational cohort study, we assessed PHF using the Clinical Frailty Scale (CFS) and assessed the level of AOD using Sequential Organ Failure Assessment (SOFA) scores on ICU day 1. We assessed Activities of Daily Living disability levels through to 6 months after discharge and used generalized estimating equations (log link and negative binomial family) to determine the independent association of PHF and AOD with PHD. Results: Of the 302 patients enrolled, 221 (73.1%) survived the hospitalization. Prehospital frailty was associated with PHD (adjusted incident rate ratio [aIRR] 95% confidence interval [95% CI] per unit increase in CFS 1.38 [1.15-1.67], P = .001). Total day 1 SOFA score was weakly associated with PHD, (aIRR [95% CI] 1.05 [1.00-1.10], P = .037) while day 1 SOFA neurologic score was strongly associated with PHD (aIRR [95% CI] 1.42 [1.24-1.62] per unit increase in SOFA neurologic score, P < .001), and these effects were independent of PHF and other premorbid factors. Conclusions: Both PHF and early acute brain dysfunction are important factors associated with increasing PHD in older adults who survive critical illness.
Incorporating mpMRI biopsy data into established pre-RP nomograms: potential impact of an increasingly common clinical scenario
Authors: Leong Joon Yau , Herrera-Caceres Jaime O. , Goldberg Hanan , Tham Elwin , Teplitsky Seth , Gomella Leonard G. , Fleshner Neil E. , Lallas Costas D. , Trabulsi Edouard J. , Chandrasekar Thenappan 
Published: October 2019

Background: We examine the practical application of multiparametric MRI (mpMRI) prostate biopsy data using established pre-RP nomograms and its potential implications on RP intraoperative decision-making. We hypothesize that current nomograms are suboptimal in predicting outcomes with mpMRI targeted biopsy (TBx) data. Materials and methods: Patients who underwent mpMRI-based TBx prior to RP were assessed using the MSKCC and Briganti nomograms with the following iterations: (1) Targeted (T) (targeted only), (2) Targeted and Systematic (TS) and (3) Targeted Augmented (TA) (targeted core data; assumed negative systematic cores for 12 total cores). Nomogram outcomes, lymph node involvement (LNI), extracapsular extension (ECE), organ-confined disease (OCD), seminal vesicle invasion (SVI), were compared across iterations. Clinically significant impact on management was defined as a change in LNI risk above or below 2% (Δ2) or 5% (Δ5). Results: A total of 217 men met inclusion criteria. Overall, the TA iteration had more conservative nomogram outcomes than the T. Moreover, TA better predicted RP pathology for all four outcomes when compared with the T. In the entire cohort, Δ2 and Δ5 were 16.6–25.8% and 20.3–39.2%, respectively. In the subset of 190 patients with targeted and systematic cores, TA was a better approximation of TS outcomes than T in 71% (MSKCC) and 82% (Briganti) of patients. Conclusion: In established pre-RP nomograms, mpMRI-based TBx often yield variable and discordant results when compared with systematic biopsies. Future nomograms must better incorporate mpMRI TBx core data. In the interim, augmenting TBx data may serve to bridge the gap.
Treatment Patterns and Clinical Outcomes for Central Retinal Vein Occlusion in the Antivascular Endothelial Growth Factor Era
Authors: Stallworth Jeannette Y. , Thomas Akshay S. , Constantine Ryan , Stinnett Sandra S. , Fekrat Sharon 
Published: October 2019

Purpose: This article describes treatment patterns and visual outcomes for central retinal vein occlusion (CRVO) in the antivascular endothelial growth factor (anti-VEGF) era. Methods: A retrospective cohort study of eyes diagnosed with CRVO between 2009 and 2016 was conducted. Treatment history and visual acuity (VA) measurements were abstracted from medical records and analyzed. Results: A total of 476 eyes of 476 patients (median age 67 years, median follow-up 25.4 months) were included. Optical coherence tomography was obtained in 93.9% and fluorescein angiography in 80% of cases on presentation. Mean VA at presentation and final visit was 20/60 and 20/94, respectively, for eyes with nonischemic CRVO, whereas that of ischemic cases remained worse than 20/800 at final follow-up. Intravitreal bevacizumab was the most common first treatment (42.2%). Intravitreal steroid was the first treatment in 3.6% and ultimately administered in 11.3% of eyes. In the first year, an average of 5.2 ± 3.6 and 2.2 ± 3.4 anti-VEGF injections were given in treatment-naive and nontreatment-naive eyes, respectively. Conclusions: In our real-world cohort, anti-VEGF injection burden and frequency are lower than in published clinical trials. Visual outcomes in both ischemic and nonischemic eyes with CRVO are poorer than expected and worse than those recorded in controlled trial settings.
The occurrence of wakefieldite, a rare earth element vanadate, in the rhyolitic Joe Lott Tuff, Utah, USA
Authors: Bagiński Bogusław , Macdonald Ray , Belkin Harvey E. , Kotowski Jakub , Jokubauskas Petras , Marciniak-Maliszewska Beata 
Published: October 2019

AbstractThe high-silica rhyolitic Joe Lott Tuff was erupted at 19.2 ± 0.4 Ma from the Mount Belknap caldera, SW Utah. Certain units in the tuff contain two species of wakefieldite, the Nd- and Y-dominant types. They occur in disseminated streaks and patches in association with rhodochrosite, calcite, Fe oxide, cerite-(Ce), and a Mn silicate (caryopilite?), thought to have been deposited from hydrothermal fluids. The wakefieldites contain the highest levels of As (≤15.34 wt.% As2O5) and P (≤5.7 wt.% P2O5) yet recorded in this mineral, indicating significant solid solution towards chernovite-(Y) and xenotime-(Y). Thorium levels are also unusually high (≤14.2 wt.% ThO2). The source of the hydrothermal fluid(s) is unknown but might be related to uranium mineralisation in the region, in that As, V and U are commonly associated in such deposits.
Chromatin State and Immunotherapy
Authors: Haining W. Nicholas 
Published: October 2019

Abstract
The functional impairment of T cell-mediated immunity within the tumor microenvironment (TME) is a defining feature of many cancers. Checkpoint blockade therapy seeks to reinvigorate T cell responses by targeting inhibitory receptors such as PD-1, which are upregulated by dysfunctional TILs. However, the fundamental mechanisms underlying T cell dysfunction in the TME remain poorly understood, as are the mechanisms by which checkpoint blockade overcomes this dysfunction. Initial studies of dysfunctional CD8+ T cells in both human and mouse tumors suggested that they share features of T cell exhaustion, including co-inhibitory receptor upregulation and defects in cytokine production. However, more recent studies have suggested that TIL dysfunction is a unique state that is distinct from T cell exhaustion. Here we show that anti-PD-1 therapy acts on a specific subpopulation of CD8+ tumor-infiltrating lymphocytes (TILs) in melanoma mouse models as well as patients with melanoma. We find that dysfunctional CD8+ TILs possess canonical epigenetic and transcriptional features of T cell exhaustion, mirroring those seen in chronic viral infection. Similar to chronic viral infection, exhausted CD8+ TILs contain a subpopulation of "stem-like exhausted" T cells that have a distinct regulatory state. Stem-like exhausted TILs also have critical functional attributes that are not shared by the majority "terminally exhausted" TILs: they retain more polyfunctionality, persist following transfer into tumor-bearing mice, and differentiate to repopulate terminally exhausted TILs in the TME. As a result, stem-like exhausted CD8+ TILs are better able to control tumor growth than terminally exhausted cells. Stem-like exhausted, but not terminally exhausted, CD8+ TILs can respond to anti-PD-1 therapy without reversion of their exhausted epigenetic state. CD8+ T cells with a stem-like exhausted phenotype can be found in human melanoma samples and patients with a higher fraction of this subpopulation in their tumors have a significantly longer duration of response to combination checkpoint blockade therapy. Responsiveness to checkpoint blockade is therefore restricted to a subpopulation of exhausted TILs that retain specific functional properties which enable them to control tumors. Approaches to expand stem-like exhausted CD8+ T cells in the tumor microenvironment may be an important component of improving checkpoint blockade response.

Disclosures
Haining: Rheos Medicines: Consultancy; Iomx Therapeutics: Consultancy; Third Rock Ventures: Consultancy; Roche: Research Funding; Calico: Research Funding; Novartis: Research Funding; Tango Therapeutics: Consultancy, Equity Ownership.
Endothelium-Derived Microparticles: Functions and Clinical Relevance
Authors: Fish Jason 
Published: October 2019

Abstract
Extracellular vesicles (EVs) are receiving increased attention as circulating biomarkers of disease. Since they are produced by cells of the cardiovascular system, their contents (including lipids, proteins and microRNAs) can be measured to provide information about the relative health or dysfunction of the cardiovascular system. We recently demonstrated that healthy endothelium can package anti-inflammatory microRNAs into secreted EVs. The transfer of EV-encapsulated microRNAs can suppress monocyte activation through the targeting of genes encoding inflammatory signaling components in the recipient cell. The microRNA content of EVs therefore serve not only as a biomarker but can functionally contribute to cell-cell communication in the cardiovascular system to affect vascular health and disease. We have developed a methodology for high-throughput profiling of microRNAs in human plasma EV samples and will present data elucidating microRNA biomarkers in the setting of co-morbidities that elevate cardiovascular risk. In these settings, we are identifying predictive biomarkers of cardiovascular disease and are determining the functional importance of EVs to disease progression.

Disclosures
No relevant conflicts of interest to declare.
Extracellular Vesicle microRNA: A Biomarker for Vascular Dysfunction in Pregnancy?
Authors: Laurent Louise 
Published: October 2019

Abstract
Placental dysfunction, including preeclampsia and fetal growth restriction, is a leading contributor to maternal and fetal morbidity and mortality. Development of effective prevention and treatment strategies has been limited by lack of identification of at-risk pregnancies. We performed small RNA sequencing of maternal serum microRNAs (miRNAs) to discover and independently verify biomarkers differentially expressed in patients who later developed preeclampsia. In this study, maternal serum was collected between 17-28 weeks gestation in two cohorts: The high-risk UCSD Placenta Study (19 cases, 29 controls); and the Sera Prognostics PAPR Study (54 cases, 110 controls). Samples were divided into Discovery (2/3) and Verification sets (1/3). Cases and controls were matched for gestational age (GA) at blood draw. miRNAs were isolated and sequenced to yield miRNA counts. Individual miRNAs and pairwise ratios (reversals) were tested in blinded verification. Biomarker discovery and verification were performed on the entire GA range and for 3 GA windows: 170/7 - 215/7 (Early); 195/7 - 244/7 (Middle); and 222/7 - 280/7 (Late) weeks. In Discovery, best performing miRNAs and reversals were selected for each GA window. Performance was then confirmed in blinded Verification (Table 2). 7/50 Early GA reversals had significant AUCs (mean Discovery AUC 0.78, mean Verification AUC 0.79). 21/50 Late GA reversals had significant AUCs (mean Discovery AUC 0.71, mean Verification AUC 0.68). Of biological importance, verified reversals contained a high proportion of miRNAs that were strongly expressed in placenta and/or encoded in the chr14q32 and chr19q13 miRNA clusters. miR-155-5p, present in 21 verified reversals, has been reported to mediate repression of eNOS by TNFα, which is a regulatory interaction associated with preeclampsia. We identified and verified differentially abundant miRNAs in maternal serum at 17-28 weeks GA in pregnancies that later developed signs and symptoms of preeclampsia compared to pregnancies with uncomplicated outcomes. Our findings suggest that maternal serum miRNAs may be useful as biomarkers for prediction of placental dysfunction and warrant validation in large independent cohorts.

Disclosures
No relevant conflicts of interest to declare.
Chronic Innate Immune Signaling in Myelodysplasia
Authors: Starczynowski Daniel T. 
Published: October 2019

Abstract
Chronic inflammatory diseases associated with activated innate immune signaling pathways often precede Myelodysplastic Syndromes (MDS), thus a role for chronic innate immune signaling in hematopoietic cells is suspected in the development of MDS. The innate immune system recognizes pathogens and host cellular by-products by pattern recognition receptors (PRR). Among the first PRRs to be identified were the Toll-like receptors (TLRs), which consist of 10 human members. Upon binding to ligand, TLRs recruit intracellular adaptors, kinases, and effector molecules which results in pathway activation. Chronic TLR signaling impairs HSC function, creates an inflammatory environment, and alters normal hematopoiesis, which suggests a causal role in MDS. Despite growing evidence linking dysregulation of innate immune signaling in MDS, how sustained activation of innate immune signaling downstream of various receptor families contributes to MDS remains an open question. This talk will highlight the recent evidence that implicates a cell-intrinsic role of innate immune pathway activation in MDS HSC and environmental inflammatory factors that are involved in the pathogenesis of MDS.

Disclosures
No relevant conflicts of interest to declare.
T Cell Metabolism and Memory
Authors: Rathmell Jeffrey C 
Published: October 2019

Abstract
Lymphocyte activation leads to rapid proliferation and differentiation and we have shown that CD4 T cell subsets are metabolically distinct. These specific metabolic programs may allow new understanding and approaches to manipulate immunity. Using metabolic network analysis of metabolomics and proteomics we defined several metabolic nodes differentially utilized by CD4 T cell subsets, including glutamine metabolism. By genetically deleting the glucose transporter Glut1 or the glutaminolysis enzyme, Glutaminase (GLS), we have shown that glycolysis and glutaminolysis are both used by activated T cells. All effector T cells require glycolysis, but we found that Th17 cells preferentially require GLS while Th1 cells are actively impaired by this enzyme. Thus, inhibition of GLS both reduces Th17 responses and promotes differentiation of Th1 cells and can lead to signs of T cell exhaustion. We show that GLS-deficiency can protect against Th17-mediated inflammatory models and also can augment effector function of Th1 CAR-T cells against B cell targets. Understanding mechanisms that regulate T cell metabolism may provide new tools to modulate immunity the balance of T cell effector populations to both suppress inflammation or promote effector function.

Disclosures
Rathmell: Calithera: Research Funding.
Analysis of Elderly Patients with Chronic Myeloid Leukemia
Authors: Kelkitli Engin , Goker Hakan , Turgut Mehmet , Atay Memis Hilmi 
Published: October 2019

Abstract
Aims
We aimed to evaluate in clinical results >65 years with chronic myeloid leukemia (CML).
Methods
191 CML patients treated with imatinib frontline were evaluated retrospectively. 56 patients who aged >65 years were included our study. The clinical characteristics and treatment outcomes of these patients were evaluated.
Results
A total of 56 patients (24 [57.1%] men, 32 [42.9%] women) were evaluated retrospectively. The median age of the patients was 72 years (range 66-92years). Of the patients, 56 (98.2%) were in the chronic phase and one (1.8%) were in the accelerated phase when diagnosed. All of patients (100%) were receiving imatinib as the first-line therapy.
Imatinib treatment induced 51 (91.8%) complete hematological responses at 3 months, 29 (51.8 %) complete cytogenetic responses at 6 months and 37 (66.6%) major molecular responses at 12months.
As a result, nilotinib and dasatinib were used in 28 (50%) patients as second-line therapy because of intolerance 5 (8.9%), primary and soconder unresponsiveness 14 (25%), 9 (16.1%) respectively. Second-line Tyrosine kinase inhibitors (TKI) induced 23 complete hematological responses (82.1%) at 3 months, and 20 major molecular responses (71.4%) at 12 months. Fifty-two of 56 patients (92.9%) are still alive. The 5 year median overall survival and progression free survival rates were 92% and 85% respectively.
Conclusion
The prognosis of CML patients has changed with Tyrosine kinase inhibitors (TKI). In our study, we found that the response rate and survival rates elderly patients were similar to the younger patients in the literature.

Disclosures
No relevant conflicts of interest to declare.
Normal and Aberrant NKL-Code in B-Cell Development and Lymphoma
Authors: Nagel Stefan , Roderick MacLeod A.F. , Meyer Corinna , Kaufmann Maren , Drexler Hans G. 
Published: October 2019

Abstract
Homeobox genes encode transcription factors which regulate basic processes in development and cell differentiation. Several members of the NKL subclass are deregulated in T-cell progenitors and support leukemogenesis. We have recently described particular expression patterns of nine NKL homeobox genes in early hematopoiesis and T-cell development. Here, we screened NKL homeobox gene activities in normal B-cell development and extended the NKL-code to include this lymphoid lineage. Analysis of public expression profiling datasets revealed that HHEX and NKX6-3 were the only members differentially active in naïve B-cells, germinal center B-cells, plasma cells and memory B-cells. Subsequent examination of different types of B-cell malignancies showed both aberrant overexpression of NKL-code members and ectopic activation of subclass members physiologically silent in lymphopoiesis including BARX2, DLX1, EMX2, NKX2-1, NKX2-2 and NKX3-2. Based on these findings we performed detailed studies of the B-cell specific NKL homeobox gene NKX6-3 which showed enhanced activity in patient subsets of follicular lymphoma, mantle cell lymphoma and diffuse large B-cell lymphoma (DLBCL), and in three DLBCL cell lines to serve as in vitro models. While excluding genomic and chromosomal rearrangements at the locus of NKX6-3 (8p11) promoter studies demonstrated that B-cell factors MYB and PAX5 activated NKX6-3 transcription. Furthermore, aberrant BMP7/SMAD1-signalling and deregulated expression of chromatin complex components AUTS2 and PCGF5 promoted NKX6-3 activation. Finally, NKL homeobox genes HHEX, HLX, MSX1 and NKX6-3 were expressed in B-cell progenitors and generated a regulatory gene network in cell lines which we propose may provide physiological support for NKL-code formation in early B-cell development. Together, we identified an NKL-code in B-cell development whose violation may deregulate differentiation and promote malignant transformation.

Disclosures
No relevant conflicts of interest to declare.