bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Marijuana Smoking Among Adult Sickle Cell Patients on Trends in Sickle Cell Crisis Hospitalizations and Acute Chest Syndrome: A Nationwide Inpatient Assessment
Authors: Sama Shashank , Tandon Varun , Kethireddy Nikhila , Boddu Prajwal 
Published: November 2019

PURPOSE
Pain for sickle cell patients occurs on a daily basis, but this becomes magnified during a sickle cell crisis (SCC). The mainstay of treatment during hospitalization is intravenous fluids and opiates however this can be a nidus for an opiate addiction long term, especially in the ongoing opiate epidemic. Marijuana has been used in a variety of chronic pain disorders including those from cancer. It is known that within the sickle cell population, smoking tobacco increases the risk of acute chest syndrome. Marijuana use or its derivatives used to treat pain has not been studied on a large scale within the sickle cell population. We propose the question of whether marijuana use affects SCC admissions as well as acute chest syndrome (ACS).
METHODS
The National Inpatient Sample (NIS) dataset was queried from 2005 to 2014 to identify the primary diagnosis of SCC with the International Classification of Disease (ICD) Code 282.42, 282.62, 282.64 and 282.69, as has been done in the literature. We then identified those with marijuana use, excluding those used in the past and not currently with the ICD code 304.30, 304.31 and 304.32. Additionally we identified those with ACS with the ICD code of 517.3. We then used multivariate analysis along with Chi-square for non-continuous variables using the statistical software SAS.
RESULTS
Between the years of 2005 and the 2014, there were a total of 798,313 hospitalizations for sickle cell crisis in the United States. Around 0.08 % of these patients had marijuana use. When stratified by race marijuana use was predominantly documented among African Americans (95.2%) followed by Hispanics (3.8%). Length of stay was statistically the same among marijuana users at 4.65 vs 5.28 days without use (p = 0.11) when compared to non-users. Total charges at the end of hospitalization were also the same at $23134.2 vs $24662.7 (p=0.60) with marijuana users and non-users respectively. Marijuana patients did that lower proportions of ACS at 5.46% vs 8.48% without (p= 0.004) and a relative risk of 0.64. Proportion of death was the same with marijuana users of 0% and non-users 0.28% (p=0.16). The age at admission was higher at 30.77 when compared to 27.25 among non-users (p=0.0009).
CONCLUSIONS:
Marijuana use was associated with lower instances of ACS with a relative risk of 0.64. Additionally patients presented on average 3 years later than non-users. The fact that mortality, length of stay and total charges were the same amongst the two groups may indicate that during a crisis, the disease process is the same, however outside of having a crisis, marijuana use may help with pain control given later presentation.
CLINICAL IMPLICATIONS:
Further research should be done to look at marijuana use as an alternative to pain control for sickle cell patients in the community setting.

Disclosures
No relevant conflicts of interest to declare.
Glycolytic Biomarkers Predictive of Transformation in Patients with Follicular Lymphoma
Authors: Monrad Ida , Madsen Charlotte , Lauridsen Kristina , Honoré Bent , Plesner Trine Lindhardt , Hamilton-Dutoit Stephen , d'Amore Francesco , Ludvigsen Maja 
Published: November 2019

Introduction
Follicular lymphoma (FL) is an indolent lymphoma derived from germinal center B cells, covering approximately 20% of all lymphomas. The malignancy is generally considered an incurable condition, hence with a median survival time exceeding 10 years. A portion of patients experience early progression or histological transformation (HT) to a more aggressive lymphoma, typically diffuse large B cell lymphoma which occurs in up to 45% of FL patients, reducing the median survival after transformation to 1-2 years. Early detection of reliable predictors of HT would allow pre-emptive therapeutic intervention strategies and aim at improved survival for patients with transformed FL. In this study, we focus on the two glycolytic enzymes, Aldolase A and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Both proteins have previously been found to be upregulated at diagnosis in various solid cancers and associated with poor survival. In addition to its glycolytic effects, GAPDH has been recognized for its non-glycolytic effects including regulation of DNA replication and repair, RNA nuclear export and apoptosis.
Aim
The aim of this study was to identify biomarkers predictive of HT in patients with FL, by investigating the correlation between intratumoral aldolase A and GAPDH expression levels with the risk of transformation in pre-therapeutic tumor samples from FL patients.
Materials and Methods
Immunohistochemical aldolase A and GAPDH expression levels were quantified using digital image analysis in pre-therapeutic tumor tissue from FL patients at time of diagnosis for patients without (n=51) or with (n=41) subsequent HT, as well as in sequential samples at time of transformation (n=41). Staining intensities were assessed as area fractions (AFs) of the stained area normalized to the region of interest on whole biopsy sections.
Results
At time of initial FL diagnosis, FL patients with subsequent transformation had significantly higher levels of aldolase A and GAPDH expression compared to patients with no subsequent transformation, (p<0.001 and p=0.005). High levels of aldolase A expression (75th percentile cut-off), were found to be associated with a significantly shorter transformation free survival (TFS) (p=0.015) and progression free survival (PFS) (p=0.001). Furthermore, high levels of GAPDH expression were found to be associated with a significantly shorter TFS (p<0.001), PFS (p=0.034) as well as overall survival (OS) (p=0.018).
Conclusion
These results suggest that at time of initial FL diagnosis, aldolase A expression and GAPDH expression, maybe as indicators of high metabolic turnover, may be predictive of the patient's risk of subsequent histological transformation.

Disclosures
No relevant conflicts of interest to declare.
Increased Mutagenesis during Fetal Hematopoietic Development in Down Syndrome
Authors: Hasaart Karlijn , Manders Freek , Chuva de Sousa Lopes Susana , Van Boxtel Ruben 
Published: November 2019

Children with Down syndrome are predisposed to leukemia during the first years of their life. 5-10% of newborns with Down syndrome are born with transient myeloproliferative disorder (TMD), which often spontaneously disappears. The majority of these patients achieves complete remission. However, in 20-30% of all TMD patients the disease progress in acute megakaryoblastic leukemia. In addition, they have a 20 fold higher risk of developing B-lymphocyte acute leukemia (B-ALL). Leukemic development in Down syndrome is initiated during fetal development. However, it is unclear why fetuses with a trisomy of chromosome 21 have an increased risk of developing leukemia.
Previously, we have developed a method to study somatic mutations in single cells using clonal cultures. Here, we applied this method to human fetal hematopoietic stem and progenitor cells (HSPCs) from liver and bone marrow of Down syndrome human fetuses and control fetuses with two copies of chromosome 21 (D21). In addition, we characterized somatic mutation accumulation in not affected small intestine stem cells. Subsequently, we performed in depth mutational analyses to characterize active processes using mutational signatures in fetal stem cells, which potentially can drive leukemic development during early life. Recently, we have shown that that healthy adult HSPCs gradually accumulate somatic mutations in a linear fashion with an annual mutation rate of 14.2 base substitutions per year. Whereas the somatic mutation rate is significantly higher during fetal development. Subsequently, in Down syndrome fetuses the overall somatic mutation rate of fetal stem cells is significantly increased compared to D21 fetal stem cells (P-value: 0,024). We performed phylogenetic analysis to study relatedness of the cells and observed an higher somatic mutation rate in the first cell divisions. This elevated mutation rate can be explained by increased contribution of mutational process signature 1 and 5, which are already present in fetal stem cells. Therefore, Down syndrome fetal stem cells show enhanced activity or increased sensitivity to mutational processes that are normally active during development. The same mutational signatures are present in TMD blast cells, indicating that these processes can cause cancer driver mutations and subsequently contribute to leukemic development. Interestingly, some Down syndrome fetal stem cells showed very high mutation numbers that could partly be attributed to mutational signature 18, which likely reflect oxidative-stress induced mutagenesis. These findings, show increased mutagenesis in Down syndrome during fetal development in hematopoietic stem cells and small intestine stem cells. This increased mutagenesis can potentially explain why children with Down syndrome have an increased risk of developing leukemia in early life.

Disclosures
No relevant conflicts of interest to declare.
Analysis of the Safety Profiles of Anticoagulants Using the EMA Pharmacovigilance Database
Authors: Elalamy Ismail 
Published: November 2019

Introduction
Anticoagulants are widely used in the treatment of cancer-associated-thrombosis (CAT). Low molecular weight heparin (LMWH) has been the standard of care for years. However, recent data reported the use of direct oral anticoagulant (DOAC) in CAT patients with a higher rate of bleeding and more specifically a higher risk a gastrointestinal (GI) bleeding. The objective of this analysis is to investigate about the GI bleeding data in cancer and non-cancer patients.
Method
The public European database of suspected adverse drug reaction reports were checked in April 2019 for all the reports concerning DOACs and LMWHs available in Europe. These reports are submitted electronically by national medicines regulatory authorities and by pharmaceutical companies that hold marketing authorizations. A patients receiving an anticancer drug was considered as a cancer patients. All data from all patients regarding the GI haemorrhage.
Results
A total of 216 540 cases were found in the database. Gender (female: 46.5%, male: 45.6%, N/A: 7.9%). Most of the patients were > 65 years (63.8%). 32 591 cases for a LMWH and 183 949 for a DOAC. Among all, 2080 received an anticancer drug and 79 783 did not received an anticancer drug. Data about co-mediation were missing for all other cases. GI haemorrhages were common in both cancer (10.3%) and non-cancer patients (16.0%) receiving anticoagulants (Table 1).
Conclusion
GI haemorrhages were common in both cancer and non-cancer patients receiving anticoagulants, suggesting that GI haemorrhages may not only be linked to GI cancer. Furthermore, these data could suggest that patients receiving LMWH were less exposed to GI haemorrhages.
Table 1. GI bleeding in patients with anticoagulants.
Table 1

Disclosures
Elalamy: Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; LEO Pharma: Honoraria, Research Funding; Aspen: Honoraria, Research Funding; Bayer Healthcare: Honoraria, Research Funding.
The Vasculopathy in the Bone Marrow Microenvironment of Humanized Sickle Cell Mice Is Reversible By Blood Transfusion
Authors: Park Shin-Young , Mattè Alessandro , Jung Yookyung , Ryu Jina , Anand Wilson , Han Eun Young Anna , Liu Min , Carbone Carmine , Melisi Davide , Nagasawa Takashi , Lin Charles , Silberstein Leslie E. , De Franceschi Lucia 
Published: November 2019

Sickle cell disease (SCD) is a monogenic red cell disorder with high morbidity and mortality due to significant end-organ disease. Here we investigated for the first time the impact of SCD on the bone marrow (BM) vascular niche, which is critical for hematopoiesis. In SCD mice, we find a disorganized and structurally abnormal BM vasculature with highly tortuous arterioles and fragmented sinusoidal vessels, the latter filled with aggregates of sickle erythroid and myeloid cells. By in vivo imaging, sickle and control red blood cells exhibit significantly slow intravascular flow speeds in sickle cell BM but not in control BM. These abnormalities lead to increased ROS production in expanded erythroblast populations, and to up-regulation in the BM of HIF-1a and key growth factors required to support angiogenesis, e.g. VEGF-A, Ang1, Ang2. Moreover, increased levels of VCAM-1, a marker for vascular dysfunction, are detected. SCD also impacts the BM perivascular niche, i.e. the number of CXCL12-abundant reticular cells, is markedly decreased, and is associated with mobilization of hematopoietic stem/progenitor cells as well as mature leukocytes to the periphery. Strikingly, the distorted vascular network is completely reversed by blood transfusion, which highlights the plasticity of the BM vascular niche. Thus, we provide molecular and cellular features of the pathologic BM microenvironment, which suggest that the local hypoxia-induced angiogenic network combined with inflammatory vascular dysfunction is responsible for the vasculopathy. In addition, the findings may serve to develop new biomarkers and therapeutic targets of BM end-organ damage.
Figure

Disclosures
No relevant conflicts of interest to declare.
Correction of Iron Deficiency in Hospitalized Heart Failure Patients Does Not Improve Patient Outcomes
Authors: Mistry Ronak , Kohut Andrew , Locantore-Ford Patricia 
Published: November 2019

Background:
Heart failure (HF) is a chronic medical condition that affects approximately 1-2% of the world's population and greater than 10% of those age 65 and older. Among patients with HF, iron deficiency (ID), defined as ferritin <100 ng/ml or transferrin saturation (TSat) <20% with ferritin 100-300 ng/ml, has an estimated prevalence of 30-50%, often without concomitant anemia. Thus, ID in HF is often underdiagnosed unless actively sought after. ID in HF has been shown to be an independent contributor of increased mortality, hospitalization and early readmission compared to HF patients without ID or HF patients with anemia without ID. A large trial, namely IRONOUT, illustrated the superiority of intravenous iron (IVFe) over oral iron supplements for HF patients who were identified as iron deficient. The FAIR-HF and CONFIRM-HF trials showed improved functional outcomes and quality of life in HF patients treated with IVFe and that these benefits were conferred even 1 year after treatment. However, these trials focus on iron store correction in patients with chronic heart failure patients. Little data are available regarding the correction of ID in patients who are admitted to hospitals for HF exacerbations.
Methods:
We performed a retrospective analysis of hospital records of patients admitted with HF as a primary or secondary diagnosis to a city-based large academic teaching health system between April 1, 2014 and April 1, 2017. Thereafter, we identified those patients who had sufficient iron studies (hemoglobin, iron, ferritin, transferrin, TSat) during their hospitalization to diagnose ID, as per the criteria above. Patients with ID were then stratified into those that did and did not receive IVFe. Patient charts were evaluated to two primary endpoints, namely one-year readmissions for HF and patient mortality.
Results:
In total, 390 patients had sufficient iron studies performed to assess ID status, of which 279 met criteria for ID (71.5%). Eighty-four of the 279 patients received IVFe. Amongst patients that received IVFe, 38 patients were readmitted for HF (45.2%) and 6 patient deaths occurred within 1 year (7.14%). Amongst the remaining 195 patients who did not receive IVFe, 93 were readmitted for HF (47.69%) and 15 patient deaths occurred within 1 year (7.69%).
Conclusion:
These data suggest that despite clinical benefit in patient functional outcomes and overall quality of life in chronic heart failure patients treated with IVFe, treatment of ID in acute HF patients does not result in a reduction in admissions for HF or improvements in patient mortality.

Disclosures
No relevant conflicts of interest to declare.
Genotypic and Alelicas Frequencies of the ABO and Rh Systems in the State of Rio Grande Do Norte, Northeast of Brazil
Authors: Morais Linduarte Varela , Paiva Aldair Sousa , Sales Valéria SF , Cavalcanti Geraldo Barroso 
Published: November 2019

Objective: To determine the immunophenotyping of a population of blood donors, intended to build a database for transfusion medicine. 2) To make available to patients with chronic diseases that are systematically dependent on blood transfusions as compatible as possible in ABH, Rh (DCcEe) and Kell 1 antigen systems. Method: A cross-sectional study was carried out on 11,664 blood donors for the ABH system typing and of these, 1255 blood donors were selected randomly for the determination of blood group antigens of the Rh system and Kell antigen. Blood centrifugation methods, centrifuge hemolysis tube test and indirect Coombs test were used for blood typing. The results obtained were compared by the Chi-square test. A level of statistical significance of p ≤ 0.05 was considered. Results: Antigenic frequencies for the ABH system found: the frequency found for the blood group O 48.8%, the frequency found for the blood group A 35.4%; the frequency found for the blood group B 10.6% and the frequency found for the blood group AB 3.2%. In the Rh-Hr system the most frequent antigens found: e 94.5%, D 88.9%; c 80.6; C 56.4%; E 26.3%. For the Kell antigen, the frequency found was 6.7%. The most frequent phenotypes found were DCcee 23.3%; ddccee 18.1%, DCCee 16.7%; Dccee 11.0%; DCcEe 10.2% and DccEe 8.8%. The lowest frequency was found: DCcEE 0.64% and ddCcEe 0.08% Conclusion: The antigenic and phenotypic frequencies found show the great importance and necessity of the immunophenotyping of these antigens of blood groups in order to transfuse them, making them as compatible as possible, thus reducing the risk of alloimmunization. Due to the great miscegenation of our population, we find different frequencies in each region, making initiatives in this regard more relevant.

Disclosures
No relevant conflicts of interest to declare.
β2-m - a Trigger for NLRP3 Inflammasome Activation within Macrophages Promoting Multiple Myeloma Cell Proliferation
Authors: Hofbauer Daniel , Mougiakakos Dimitrios , Büttner-Herold Maike , Neumann Frank , Nolting Jens , Bisht Savita , Zeiser Robert , Hamarsheh Shaima'A , Ricagno Stefano , Zaiss Mario , Eberhardt Martin , Boettcher Martin , Bitterer Katrin , Mackensen Andreas , Bruns Heiko 
Published: November 2019

Multiple myeloma (MM) is closely dependent on cross-talk between malignant plasma cells and cellular components of the inflammatory bone marrow milieu, which promotes disease progression, bone destruction and immune-impairment. However, the molecular mechanisms initiating this inflammatory microenvironment remain poorly defined. Beta-2-microglobulin (β2M) accumulates during MM and represents an established prognostic biomarker, but little is known regarding its immunoregulatory potential. Here, we found that β2m triggers an enhanced caspase-1 dependent release of mature IL-1β (15.8 ± 4.5 ng/ml) and IL-18 (5.8 ± 2.1 ng/ml) by macrophages in a NLRP3 dependent way. Activation of the NLRP3 inflammasome was initiated, after phagocytosis of β2m and subsequent lysosomal rupture due to amyloid fibril formation in lysosomes, in a process which partially involved lysosomal protease cathepsin B. β2m mediated NLRP3 inflammasome activation also occurs in tumor-associated macrophages (TAMs) of MM patients leading to the release of IL-1β and IL-18 towards MM cells. Moreover, TAMs in a murine MM model (5TMM) displayed an active NLRP3 inflammasome as well. Treatment of 5TMM mice with MCC950, a selective NLRP3 inhibitor, reduced tumor progression and thus attenuated the severity of MM. Our findings shed new light on β2m as macrophagic NLRP3 inflammasome activator which contributes to MM cell progression, and open a potential novel avenue for therapies of this severe malignancy.
Figure

Disclosures
Bruns: Morphosys AG: Research Funding.
Smooth Muscle Cytochrome b5 Reductase 3 Deficiency Accelerates Pulmonary Hypertension Development in Sickle Cell Mice
Authors: Wood Katherine , Durgin Brittany , Schmidt Heidi M , Hahn Scott , Baust Jeffrey , Bachman Tim , Vitturi Dario A. , Ghosh Samit , Ofori-Acquah Solomon Fiifi , Mora Ana , Gladwin Mark T , Straub Adam 
Published: November 2019

Pulmonary and systemic vasculopathy are significant risk factors for early morbidity and death in patients with sickle cell disease (SCD). An underlying mechanism of SCD vasculopathy is vascular smooth muscle (VSM) nitric oxide (NO) resistance, which is mediated by NO scavenging reactions with plasma hemoglobin and reactive oxygen species that can oxidize soluble guanylyl cyclase (sGC), the NO receptor. Prior studies show that cytochrome b5 reductase 3 (CYB5R3), known as methemoglobin reductase in erythrocytes, functions in VSM as an sGC heme iron reductase critical for reducing and sensitizing sGC to NO and generating cGMP for vasodilation. Therefore, we hypothesized that VSM CYB5R3 deficiency accelerates development of pulmonary hypertension (PH) in SCD. Bone marrow transplant was used to create SCD chimeric mice with background smooth muscle cell (SMC) specific tamoxifen-inducible Cyb5r3 knockout (SMC R3 KO) and wild-type (WT) control.Three weeks after completing tamoxifen treatment, we observed 60% knockdown of pulmonary arterial SMC CYB5R3, 5-6 mmHg elevated right ventricular maximum systolic pressure (RVmaxSP) and biventricular hypertrophy in SS chimeras with SMC R3 KO (SS/R3KD) relative to wild-type (SS/R3WT). Right ventricular (RV) contractility, heart rate, hematological parameters and cell-free hemoglobin were similar between groups. When identically generated SS/R3 chimeras were studied 12-weeks after completing tamoxifen treatment, RVmaxSP in SS/R3KD had not increased further, but RV hypertrophy relative to SS/R3WT persisted. These are the first studies to establish involvement of SMC CYB5R3 in SCD-associated development of PH, which can exist in mice by 5 weeks of SMC CYB5R3 protein deficiency.

Disclosures
Vitturi: Complexa Inc: Consultancy. Ofori-Acquah:Shire Human Genetic Therapies Inc: Other: Financial Relationship. Gladwin:Globin Solutions, Inc: Patents & Royalties: Provisional patents for the use of recombinant neuroglobin and heme-based molecules as antidotes for CO poisoning; Bayer Pharmaceuticals: Other: Co-investigator; United Therapeutics: Patents & Royalties: Co-inventor on an NIH government patent for the use of nitrite salts in cardiovascular diseases . Straub:Bayer Pharmaceuticals: Research Funding.