bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Successful Model for Adult Emergency Medicine Protocol Implementation for Sickle Cell Disease
Authors: Desai Payal C. , Delatore Luca , Hanes Deborah , Rettig Amy , Gill Miranda , Walsh Jason , Graham Emily , Adkins Eric 
Published: October 2019

Abstract

Introduction: Sickle Cell Disease (SCD) affects approximately 1 in 350 African American newborn infants each year in the United States and 70,000-100,000 people in the United States. Vaso-occlusive pain crisis is the most common complication that results in patients seeking emergency care for sickle cell disease. In the US in 2006, an estimated 232,381 emergency department (ED) visits were related to sickle cell disease, which resulted in approximately $356 million of ED health care costs and $2.6 billion of combined ED and inpatient costs. Initial pediatric data suggests that time to opiate initiation effectively decreased the total ED length of stay, and total intravenous opiates. While adult ED protocols have been implemented, results on time to first opiate as well as health care utilization has been variable.
Methods: A multidisciplinary quality improvement group was formed to improve emergency room department care delivery for patients with sickle cell disease. The existing NIH 2014 sickle cell guideline and Tanabe protocol was modified to include individualized pain plans (Figure 1). The primary goal was defined as average time to first opiate of < 60 minutes. The secondary goal was to improve long term health care utilization as measures by length of ED stay and readmission rates for patients with sickle cell disease. The data was compared to a year prior to protocol implementation given the seasonal variations observed in patient admissions and encounter volumes. For reporting, those patients that require a toxicology screen prior to opiate administration were excluded from the data analysis.
Results: There were a total of 352 encounters from 102 unique patients that occurred time of protocol initiation (January 2015-June 2015). The average time to first opiate in January 2014 was 170 min and June 2014 was 166min. After protocol implementation, the average time to first opiate in January 2015 was 123 min and June 2015 62 min (Figure 2). The readmission rate compared to May and June 2014 was decreased by 43% and 20% in May and June 2015, respectively. The average length of ED stay decreased from 9.4 hrs in June 2014 to 5.0 hrs in June 2015 (Figure 3).
Conclusion: With a collaborative multi-disciplinary approach, successful ED protocol implementation is feasible. The collaboration can lead to better patient care with improvement in time to analgesia. The model may also contribute to reduction in health care utilization.
Figure 1. ED Pain Protocol Algorithm Figure 1. ED Pain Protocol Algorithm Figure 2. Time to First Opiate (mins) Figure 2. Time to First Opiate (mins) Figure 3. Length of Stay in the Emergency Department (Hrs) Figure 3. Length of Stay in the Emergency Department (Hrs)

Disclosures
Desai: Pfizer: Consultancy.
Metabolomic Profiling Identifies Hypoxia-Induced Imbalanced Lands' Cycle Promotes Sickling and Disease Progression
Authors: Wu Hongyu , Bogdanov Mikhail , Zhang Yujin , Sun Kaiqi , Song Anren , Liu Hong , Adebiyi Morayo G, , Alexander Danny C. , Milburn Michael V. , Idowu Modupe , Juneja Harinder S. , Xia Yang 
Published: October 2019

Abstract
Sickle cell disease (SCD) is a prevalent hemolytic genetic disorder with high morbidity and mortality affecting millions of individuals worldwide. Although it is well accepted that deoxygenation and polymerization of sickle hemoglobin (HbS) are initial triggers for sickling, it has been known for more than three decades that abnormal membrane lipid organization and composition are found in sickle erythrocyte. Early studies showed some lipids are altered in sickle erythrocytes, however, no studies have identified overall membrane lipid alteration and functional role of those altered specific lipids in SCD. Using unbiased metabolomic profiling, we found that lysophospholipids (LPLs), particularly lysophosphocholines (LysoPCs), were significantly elevated inside erythrocytes of mice with SCD due to imbalanced Lands' cycle. Lands' cycle containing two concerted enzymes: phospholipases A2 (PLA2s) and lysophospholipid acyltransferases (LPLATs) was initially discovered in 1958. However, its function and cellular regulation in membrane homeostasis in SCD remain unrecognized prior to our metabolomics screening. Here, we demonstrated that enhancing imbalanced Lands' cycle promotes a process of sickling and disease progression in mice by inducing LysoPC content inside erythrocytes. Significantly, correcting impaired Lands' cycle reduced LysoPC levels within erythrocytes and attenuated sickling and disease progression in mice. Mechanistically, we revealed that hypoxia-mediated MEK/ERK activation underlies imbalanced Lands' cycle by preferentially inducing activity of PLA2 but not LPCAT1 in mouse sickle erythrocytes. Additionally, the detrimental role of impaired Lands' cycle-induced LysoPC production in sickling via MEK/ERK-dependent activation of PLA2 in SCD patients mirrors our mouse finding. Overall, our studies have identified a pathological role of imbalanced Lands' cycle in SCD, revealed molecular basis regulating Lands' cycle and immediately provided novel therapeutic possibilities for the disease.

Disclosures
No relevant conflicts of interest to declare.
Barth Syndrome: An Under-Recognized Cause of Chronic Neutropenia
Authors: Steward Colin G. , Groves Sarah J. , Taylor Carolyn L. , Maisenbacher Melissa K. , Versluys Birgitta , Newbury-Ecob Ruth , Ozsahin Hulya , Hamilton Leo , Damin Michaela K. , Bowen Valerie M. , McCurdy Katherine R. , Mackey Michael C. , Bolyard Audrey Anna , Dale David C. 
Published: October 2019

Abstract

Barth syndrome is an X-linked disease characterized by defective remodeling of phospholipid side chains in mitochondrial membranes. Major features include neutropenia, fetal or childhood onset dilated cardiomyopathy, motor delay and proximal myopathy, feeding problems and constitutional growth delay. Improved diagnostic testing, recognition of the wide disease phenotype and a worldwide patient/family support network have recently facilitated much more rapid ascertainment, now with at least 186 living males diagnosed worldwide. We provide a comprehensive survey of neutropenia seen in Barth syndrome and its management based on the study of 90 patients. Neutropenia (i.e. at least one count less than 1.5 x 109/L) was detected in 74 of 90 (82%) patients; 28 of 90 (31%) patients had a mean neutrophil count less than 1.5 x 109/L; 13 of 90 (14%) had a mean count less than 0.5 x 109/L. Neutropenia may be the sole presenting feature in Barth syndrome. Importantly, it can take on any form: intermittent and unpredictable, chronically severe or cyclical, thus mimicking other diseases. Eighty-seven patients had reported monocyte data. Monocytosis was seen in 65 of 87 (75%) patients with at least one monocyte count greater than 1.0 x 109/L and 23 of 87 (26%) had at least one monocyte count greater than 3.0 x 109/L.
Some patients who were neutropenic and had a bone marrow evaluation showed myelocyte arrest. Neutropenic Barth patients are highly responsive to granulocyte colony-stimulating factor, although dosing can be challenging because of innate variations in their neutrophil counts. Clinical improvement with reduced signs and symptoms of infections is the usual response to this treatment. Barth syndrome should be considered in any male with neutropenia accompanied by any of the characteristic features of Barth syndrome and in those with idiopathic neutropenia.

Disclosures
Dale: Amgen: Consultancy, Honoraria, Research Funding.
Erythropoietin Mediated Increase in Monocyte-Derived Liver Macrophages; A Role for Kupffer Cells?
Authors: Gilboa Dafna , Haim-Ohana Yasmin , Ben-Califa Nathali , Deshet-Unger Naamit , Bab-Hiram Sahar , Gassmann Max , Mittelman Moshe , Neumann Drorit 
Published: October 2019

Abstract
Erythropoietin (EPO) is the major hormone that drives mammalian erythropoiesis, via its surface receptor, EPO-R. It is mainly used for treating anemia associated with chronic renal failure and certain malignancies, although this latter indication is currently disputed. EPO-Rs were also found in non-erythroid cells, including dendritic cells and bone marrow macrophages (Lifshitz, 2008; 2010). Here we addressed the effect of EPO on hepatic-macrophages, namely resident liver macrophages (Kupffer cells) and liver monocyte-derived macrophages (MFs). Utilizing the rat Kupffer cell line (RKC-2) we demonstrate that these cells express EPO-R transcripts and cell surface EPO-R, as detected by our novel EPO-R antibody (GM1012; Maxwell 2015). EPO treatment of the RKC-2 cells led to a 1.5±0.06 fold increase (p<0.05) in EPO-R mRNA levels and a 2±0.01 fold decrease (p<0.01) in surface EPO-R levels. Stimulation of the cells with EPO induced a 15%±0.06 (p=0.01) increase in transcript levels of CCL-2 (a chemo attractant for monocytes) and a 15%±0.6 (p<0.05) increase in the levels of the secreted chemokine. EPO treatment also enhanced cellular activity of the RKC-2 cells as manifested in a 50%±0.13 (p<0.01) increase in cell migration, an increase in phagocytosis of microbeads (40%±0.08, p<0.01) and of E.coli (13%±0.05, p<0.01).
Finally, in vivo experiments in which C57BL/6 mice were injected 3 times a week with 180U recombinant Human EPO (rHuEPO), demonstrated an EPO-induced selective increase in MFs (19.5%±0.01, p=0.05), but not in Kupffer cells. Elevated CCL-2 in sera of EPO-injected mice (2.1 fold increase, p<0.01) supports a mechanism by which EPO stimulates Kupffer cells to increase secretion of CCL-2, which in turn enhances recruitment of monocytes to the liver and their subsequent differentiation into MFs.
The present study points to a new as hitherto unexplored action of EPO on two separate liver macrophage populations (Kupffer cells and MFs) which play crucial and distinct roles in liver homeostasis and immunity as well as in liver pathologies. EPO selective actions on liver macrophages thus call for future studies on the effects of this hormone on inflammation in the liver with a therapeutic goal to enhance liver immunity.

Disclosures
Mittelman: Celgene: Research Funding, Speakers Bureau; GlaxoSmithKline: Research Funding; Johnson & Johnson: Research Funding, Speakers Bureau; Novartis Pharmaceuticals Corporation: Research Funding; Roche: Research Funding; Amgen: Research Funding.
Staged Interventions to Improve Quality and Reduce Cost of Care in Patients with Suspected Heparin-Induced Thrombocytopenia
Authors: Samuelson Bethany T , Holmes Meredith , White Andrew , Glynn Emily , Martin Daniel B , Garcia David , Kelly Janet , Wittkowsky Ann Kathryn 
Published: October 2019

Abstract
Background
Heparin induced thrombocytopenia (HIT) is a rare but often considered diagnosis that requires treatment, in the form of costly parenteral anticoagulants, while awaiting the results of confirmatory testing. We hypothesized that improving the accuracy and consistency with which a patient's risk of HIT was determined, through the use of Computer-based Provider Order Entry (CPOE) interventions, would lead to decreased cost of care.
Methods
This study was conducted out of two affiliated US academic medical centers with a shared electronic medical record (EMR). A series of staged interventions, including provider and pharmacist education, real-time alerts and a CPOE based decision support tool were implemented as part of a multidisciplinary quality improvement project between January 1, 2013 and December 31, 2013. All inpatients ³18 years of age who underwent laboratory testing for HIT and/or were started on bivailrudin therapy for suspected HIT between January 1, 2012 and December 31, 2014 were included. For the purposes of our study, we defined the pre-intervention period as January 1 through December 31, 2012 and the post-intervention period as January 1 through December 31, 2014. The primary outcome was mean monthly bivalirudin expenditure at each institution. The secondary outcomes were number of HIT enzyme-linked immunosorbent assay (ELISA) and serotonin release assay (SRA) tests sent per month.
Results
We observed a statistically significant reduction in mean monthly bivalirudin expenditures from $64,178 to $17,704 (p = 0.0002) at one of the included centers and a decrease that approached significance from $28,275 to $16,708 (p = 0.100) at the other. Statistically significant reductions were also noted in mean monthly ELISA testing rates from 38.1 to 19.8 (p=0.01) and mean monthly SRA testing rates from 9.4 to 3.1 (p=0.0001) across both centers.
Discussion
Our findings suggest that the use of a computer-based order entry intervention, as part of a multidisciplinary quality improvement effort, can effectively reduce cost and decrease rates of lab testing in the management of heparin-induced thrombocytopenia. Such interventions are relatively low cost and of low complexity in institutions with established order entry systems and have the potential for a lasting impact on cost and quality of care.

Disclosures
No relevant conflicts of interest to declare.
Protein S As a Potential Treatment for FIX-Derived Deep Vein Thrombosis
Authors: Pilli Vijaya Satish Sekhar , Plautz Willium , Majumder Rinku , Simioni Paolo 
Published: October 2019

Abstract
Background: Every year, 0.1-0.2% of the USA population experiences deep vein thrombosis (DVT). Two causes of DVT are increased Factor IX (FIX) levels and hyperactivating mutations in FIX (FIX Padua variant- R338L and Malmo variant T148A). In principle, inhibition of activated FIX (FIXa) should alleviate DVT. Previous in vitro studies demonstrated that the anticoagulant Protein S (PS) inhibits the intrinsic pathway mediated by wild type FIXa, making PS an attractive candidate to treat DVT.
Aims: To establish Protein S as a remedy for FIX-mediated DVT/Padua/Malmo
Methods: Anisotropy, clotting assays, thrombin generation assays, co-localization, co-immunoprecipitation, and bleeding assays.
Results: We further explored the physiological relevance of the PS-FIXa interaction and PS-mediated inhibition of FIXa by ex vivo (co-immunoprecipitation) and in vivo (co-localization) studies. Because PS can inhibit FIXa in vivo, we used competitive, direct anisotropy assays and co-immunoprecipitation assays to measure the efficiency PS and hyperactive FIXa (R338L) interaction. Interestingly, the results demonstrated that FIXa R338L has lost its affinity towards PS compared with wild type FIXa. The same finding was obtained by ex vivo thrombin generation assays and FXa generation assays supplemented with various concentrations of PS. Thus, to be inhibited, hyperactive FIX requires a greater amount of PS compared with wild type FIXa. We are further confirming this finding with mouse models.
Conclusion: Addition of PS to plasma inhibits both wild type and R338L FIXa and extends clotting time. Previous studies showed that the addition of PS has no significant negative effects. Thus, we conclude that PS supplementation potentially constitutes a novel and effective treatment for FIX-mediated DVT.

Disclosures
No relevant conflicts of interest to declare.
Donor-Derived B Cells Produce Potent AML-Specific Antibodies That Recognize Novel Tumor-Specific Antigens and Mediate Graft-Versus-Leukemia Immunity
Authors: Gillissen Marijn Aletta , Kedde Martijn , Yasuda Etsuko , Levie Sophie E. , Bakker Arjen Q. , Claassen Yvonne B. , Bohne Martino , Speijer Dave , Picavet Daisy I. , Stap Jan , van Oers Marinus H. J. , Beaumont Tim , van Helden Pauline M. , Spits Hergen , Hazenberg Mette D. 
Published: October 2019

Abstract
Unleashing the tumor-specific immune response by immunotherapies such as checkpoint inhibitors or allogeneic stem cell transplantation can result in long lasting tumor regression. While the role of T cells in such graft versus leukemia (GvL) immune responses has been established, the contribution of B cells to GvL responses is less clear. Using SEREX and other techniques, the presence of antibodies directed against established tumor antigens following allogeneic hematopoietic stem cell transplantation (HSCT) has been demonstrated. The function of these antibodies remains to be established though. Here we tested the hypothesis that B cells contribute to GvL.
We selected three patients with high-risk AML who mounted potent GvL responses after allogeneic HSCT. Of these patients we established antibody-producing clonal B cell lines following transduction of memory B cells from the peripheral blood of these patients with Bcl-6 and Bcl-xL and screened those for producing antibodies specifically binding to surface antigens on AML cell lines and AML blasts. A number of antibodies were identified that recognized primary AML blasts isolated from newly diagnosed AML patients, but did not bind to healthy bone marrow, peripheral blood mononuclear cells or tissues such as liver, skin and colon. Target identification analyses revealed two novel, AML-specific surface proteins as primary targets of these antibodies. These newly identified AML-specific antigens are widely expressed on different types of AML, including blasts of the last 17 AML patients that entered our clinic of whom diagnosis material was made available for this project.
Strikingly, antibody binding to one of these targets induced direct cell death of cultured AML cell lines and of primary AML blasts. Cytotoxicity of the antibodies was rapid, occurred both at 37o C and 4o C and could be prevented by Cytochalasin D, an actin polymerization inhibitor that stabilizes the cytoskeleton. This, in combination with the observation that cell death could not be prevented by apoptosis inhibitors indicated that the tumor cells were killed through a necrotic pathway like oncosis. Other antibodies induced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent-cytotoxicity (CDC).
Together these data indicate that tumor selective antibodies are elicited following allogeneic HSCT in AML patients with a strong GvL response. The direct and indirect cytotoxic activities against tumor cells of these antibodies suggest that they contribute to the GvL response.

Disclosures
No relevant conflicts of interest to declare.
Impact of Bone Marrow Plasmacytosis on Outcome in Patients with AL Amyloidosis Following Autologous Stem Cell Transplant
Authors: Hwa Yi L. , Kumar Shaji K. , Lacy Martha Q. , Gertz Morie A. , Buadi Francis , Rajkumar S. Vincent , Go Ronald S. , Leung Nelson , Kapoor Prashant , Dingli David , Russell Stephen J. , Lust John A. , Hayman Suzanne R. , Kourelis Taxiarchis , Dispenzieri Angela 
Published: October 2019

Abstract
Background: Previous studies have demonstrated inferior overall survival (OS) among patients with AL amyloidosis who have bone marrow plasmacytosis (BMPC) >10%. It is well recognized that AL patients who achieve the deepest hematologic responses have superior organ response and OS rate.
Methods: We designed a study to determine if BMPC% affects CR rate post ASCT and whether pre-transplant induction therapy improves response rate and OS among patients with a higher baseline BMPC burden.
Results: Among 415 AL patients who underwent ASCT at Mayo Clinic, Rochester within 12 months of diagnosis, 116 (28%) had BMPC>10% at diagnosis. The median age was 57.2 years. The median follow up for surviving patients was 67.3 months. There was no statistically significant difference in age, gender, time from diagnosis to transplant, or use of attenuated conditioning regimen between groups with high (>10%) and low (≤ 10%) bone marrow involvement. The high BMPC group tended to receive more induction chemotherapy before ASCT, and presented with greater value of albumin, beta-2 microglobulin and difference in serum free light chain (dFLC). A higher CR rate was observed in low BMPC group (44.6% versus 26.7%, p=0.0013). In patients with high BMPC, a higher CR rate (33.9% versus 17.7%, p<0.05) was seen in those who received pre-ASCT induction therapy compared with no induction therapy. Among 3 groups of patients who had: no pre-ASCT therapy; steroid only as induction; and induction chemotherapy, the 5-year OS rates were 50.5%, 40% & 67.5%, respectively, p<0.03.
Conclusions: Lower bone marrow burden at diagnosis yielded a deeper response following ASCT. Compared to no therapy, patients who were treated with steroid only pre-ASCT had an inferior OS, but other induction regimens appeared to improve survival. These data would support the concept that using induction therapy prior to ASCT conditioning among patients with higher tumor burden may be of value.
Figure 1. In BMPC > 10% at diagnosis, OS comparison between induction therapies pre-ASCT Figure 1. In BMPC > 10% at diagnosis, OS comparison between induction therapies pre-ASCT Figure 2. Figure 2. Figure 3. Figure 3.

Disclosures
Kumar: Celgene: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Sanofi: Research Funding; AbbVie: Research Funding; Millenium/Takeda: Research Funding; Onyx: Research Funding; Skyline, Noxxon: Honoraria; Janssen: Research Funding. Gertz:Celgene: Honoraria; millenium: Consultancy, Honoraria; Onyx: Honoraria; Novartis: Honoraria; Smith Kline: Honoraria.