bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frequency of Venous Thromboembolism in 6513 Patients with COVID-19: A Retrospective Study
Authors: Crowther Mark , Garcia David A. , Hill Jason , Savage Bryan , Peress Shira , Chang Kevin , Deitelzweig Steven 
Published: November 2020

Background: Patients infected with coronavirus 2 (SARS-CoV-2) appear to be at increased risk for venous thromboembolism (VTE), especially if they become critically ill with coronavirus disease 2019 (COVID-19). Some centers have reported very high rates of thrombosis despite anticoagulant prophylaxis.
Methods: The electronic health record (EHR) of a New Orleans-based health system was searched for all patients with PCR-confirmed SARS-CoV-2 infection who were either admitted to hospital or treated and discharged from an emergency department between March 1 and May 1, 2020. From this cohort, patients with confirmed VTE (either during or after their hospital encounter) were identified by administrative query of the EHR.
Results: Between March 1, 2020 and May 1, 2020, 6,153 patients with COVID-19 were identified; 2,748 of these patients were admitted, while 3,405 received care exclusively through the emergency department. Data on patient outcomes were determined up until and including May 21, 2020. In total, 637 patients required mechanical ventilation and 206 required renal replacement therapy. Within the hospitalized cohort, the overall mortality rate was 24.5% and VTE occurred in 86 patients (3.1%). In the 637 patients who required mechanical ventilation at some point during their hospital stay, 45 developed VTE (7.2%). After a median follow-up of 14.6 days, VTE had been diagnosed in 3 of the 2,075 admitted who were discharged alive (0.14%).
Conclusions: Among 6,153 patients with COVID-19 who were hospitalized or treated in emergency departments, we did not find evidence of unusually high VTE risk. Pending further evidence from prospective, controlled trials, our findings support a traditional approach to primary VTE prevention in patients with COVID-19.

Disclosures
Crowther: Precision Biologicals: Membership on an entity's Board of Directors or advisory committees; Hemostais Reference Laboratories: Honoraria; Pfizer: Speakers Bureau; CSL Behring: Speakers Bureau; Alnylam: Divested equity in a private or publicly-traded company in the past 24 months; Servier Canada: Membership on an entity's Board of Directors or advisory committees; Diagnostica Stago: Speakers Bureau; Asahi Kasei: Membership on an entity's Board of Directors or advisory committees.
Epidemiological and Survival Analysis of Primary Intestinal Non-Hodgkin's Lymphoma Patients from SEER Database
Authors: Singh Vinit , Agrawal Pooja , Gupta Varsha , Prakash Amulya , Du Doantrang T. 
Published: November 2020

Introduction: Gastrointestinal tract is the most common site of extranodal non-Hodgkin's lymphoma (EN-NHL). Most of the data published so far has been on the gastric NHL and very limited data is available on primary intestinal - Non-Hodgkin's Lymphoma (PI-NHL). Here, we are presenting the epidemiological and survival data for PI-NHL from the SEER 21 database.
Methods: Data for all the EN-NHL and Intestinal NHL are collected for the period 2000-2015 from the SEER 21 database based on the WHO ICD-O3 classification. PI-NHL data has been extracted from EN- NHL and intestinal datasets and then cross-matched for accuracy of the desired patient subset selection. A total of 9,290 PI-NHL cases common to both the lists were selected and used for analysis. Patients with incomplete staging and survival data were excluded from the survival analysis. Survival analysis variables include gender (male or female), ethnicity (white or non-white), early age of onset (≤ 50 years), late age of onset (&gt;50 years), location (small or large intestine), the staging of the tumor as early-stage (stage 1 and stage 2) or late-stage tumors (stage 3 and stage 4), and history of prior malignancy (first primary tumor or second/later primary tumor). Survival analysis is done using a cox-proportional hazard regression model.
Results: The percentage of PI-NHL of all the intestinal cancers and extranodal non-Hodgkin's lymphoma is 1.42% (1.40 - 1.45, 95% CI) and 10.52% (10.32 - 10.72, 95% CI) respectively. The demographic and clinical characteristics of the patients are described in Figure 1. In the survival analysis (Figure 2), the risk of overall mortality is higher in the late-onset cancers (HR - 1.16, 1.08 -1.24, P-value&lt;0.001), non-white population (HR- 1.13, 1.05 - 1.22, P-value 0.002) and second or later primary tumors (HR - 1.10, 1.01 - 1.20, P-Value - 0.036). Gender, site, and stage are not significantly related to mortality but the trend towards higher mortality is seen in the late-stage tumor (HR - 1.04, 0.97 - 1.12, P-Value - 0.29).
Conclusion: PL-NHL is a rare type of intestinal malignancy. Our study showed that the risk of overall mortality is higher in late-onset cancer, non-white population, and in second or later primary tumors. Gender, site, and stage are not significantly related to mortality. The analysis was done for overall survival and this may have affected the outcome of the survival variables. Therefore, a survival analysis of cause-specific mortality data will give a more elaborate picture of the relationship between the mortality data and these variables.

Disclosures
No relevant conflicts of interest to declare.
Sickle Cell Disease Model Mice Lacking 2,3-Dpg Show Reduced RBC Sickling and Improvements in Markers of Hemolytic Anemia
Authors: Knee Kelly M. , Barakat Amey , Tomlinson Lindsay , Ramaiah Lila , Wenzel Zane , Kapinos Brendon , Ahn Youngwook , Lintner Nathanael G. , Field S. Denise , Jasuja Reema , Pettersen Betty A. 
Published: November 2020

Sickle cell disease (SCD) is a severe genetic disorder caused by a mutation in hemoglobin (b6Glu-Val), which allows the mutant hemoglobin to assemble into long polymers when deoxygenated. Over time, these polymers build up and deform red blood cells, leading to hemolytic anemia, vaso-occlusion, and end organ damage. A number of recent therapies for SCD have focused on modulating the mutant hemoglobin directly, however, reduction or elimination of 2,3-DPG to reduce Hb S polymerization and RBC sickling has recently been proposed as a therapeutic strategy for SCD. Current clinical studies focus on activation of pyruvate kinase to reduce 2,3-DPG, however, direct targeting of the enzyme which produces 2,3-DPG; Bisphosphoglycerate Mutase (BPGM) may also be possible.
In this study we evaluate the impact of elimination of 2,3-DPG on SCD pathology by complete knockout of BPGM in Townes model mice. Animals with complete knockout of BPGM (BPGM -/-) have no detectable 2,3-DPG, while animals that are heterozygous for BPGM (BPGM -/+) have 2,3-DPG levels comparable to Townes mice. Western Blot analysis confirms that BPGM -/- animals completely lack BPGM, while BPGM -/+ animals have BPGM levels that are nearly equivalent to Townes mice. As expected from the lack of 2,3-DPG, BPGM -/- animals have increased oxygen affinity, observed as a 39% decrease in p50 relative to Townes mice.
Complete elimination of 2,3-DPG has significant effects on markers of hemolytic anemia in BPGM -/- mice. Mice lacking 2,3-DPG have a 60% increase in hemoglobin (3.7 g/dL), a 53% increase in red blood cell count, and a 29% increase in hematocrit relative to Townes mice. The BPGM -/- mice also have a 57% decrease in reticulocytes, and a 61% decrease in spleen weight relative to Townes animals, consistent with decreased extramedullary hematopoiesis. Consistent with the reduction in hemolysis, BPGM -/- animals had a 59% reduction in red blood cell sickling under robust hypoxic conditions. BPGM -/+ animals had hemoglobin, RBC, and hematocrit levels that were similar to Townes animals, and a similar degree of RBC sickling to Townes mice. Liver phenotype was similar across all variants, with areas of random necrosis observed in BPGM -/-, BPGM -/+ and Townes mice. Higher percentages of microcytic and/or hyperchromic RBCs were observed in BPGM -/- animals relative to BPGM -/+ or Townes animals.
These results suggest that modulation of 2,3-DPG has a positive effect on RBC sickling and hemolytic anemia, which may have therapeutic benefits for SCD patients. However, the lack of improvement in organ damage suggests that modulation of 2,3-DPG alone may not be sufficient for complete elimination of SCD phenotypes, and further investigation of this therapeutic avenue may be necessary.

Disclosures
No relevant conflicts of interest to declare.
Bclw Overexpression Predicts Aggressive Disease in B-Cell Lymphomas
Authors: McBride Amanda , Adams Clare M , Mitra Ramkrishna , Eischen Christine M 
Published: November 2020

B-cell lymphomas encompass a phenotypically and genetically heterogenous subgroup within hematologic malignancies. Despite this heterogeneity, the ability to evade apoptosis is a unifying feature across B-cell lymphomas, and alterations within the Bcl-2 family of apoptosis regulatory proteins is a key mechanism for this evasion. While overexpression of the anti-apoptotic Bcl-2 family member BCL2 has been widely described in multiple B-cell lymphomas, altered expression of other anti-apoptotic proteins within this family, including BCLX, MCL1, A1 and, in particular, BCLW has been under-investigated. This is highlighted by clinical trials of the BCL2 inhibitor, venetoclax, which found poor single agent activity in B-cell lymphomas that were thought to be highly BCL2-dependent. Therefore, we investigated the contributions of anti-apoptotic Bcl-2 proteins in B-cell lymphomas. Analysis of gene expression profiling datasets of patient samples of major B-cell lymphoma subtypes as compared to normal B-cells demonstrated differential overexpression of anti-apoptotic Bcl-2 proteins, with BCL2, BCLX and BCLW being significantly overexpressed in multiple B-cell lymphoma subtypes. Focusing on aggressive B-cell lymphoma subtypes, BCLW was consistently overexpressed across all major B-cell lymphoma subtypes. Notably, BCLW overexpression was maintained in high grade follicular lymphoma compared to low grade, whereas BCL2 levels decreased as grade increased. These findings indicate that BCLW overexpression is selected for in more aggressive B-cell lymphoma subtypes. BCLW overexpression in aggressive B-cell lymphoma cell lines conferred resistance to the non-specific BH3 mimetic navitoclax as well as to venetoclax. Further, analysis of diffuse large B-cell lymphoma (DLBCL) cell lines demonstrated that the combination of high BCLW/low BCL2 in GCB DLBCL and high BCLW/moderate BCL2 in non-GCB DLBCL is also associated with decreased navitoclax sensitivity, suggesting that high BCLW may confer treatment resistance. In accordance with this, analysis of patient outcomes in DLBCL demonstrates that patients exhibiting high BCLW levels with low BCL2 levels have poorer survival than those with low BCLW. Moreover, Cox regression analysis showed BCLW was an independent determinant of overall survival in DLBCL. Together, our results indicate that BCLW predicts for more aggressive disease in B-cell lymphomas and increased resistance to therapy.

Disclosures
Eischen: AbbVie Inc.:Research Funding.
COVID-19 in Relation to Hematological Events (Thrombosis/Bleeding) and Mortality in Inpatient Setting
Authors: Gadde Saikrishna , Manjunath Nikhil , Badari Ambuga , Cole John T. , Saeed Rula 
Published: November 2020

COVID-19 is a newly diagnosed entity that has been identified for about 6 months. With the US now being the prevalent nation affected, we aimed to identify factors that were relevant to survival and hematological events in COVID patients. Our group had primarily been assessing COVID-19 confirmed patients as per PCR at Ochsner Medical Center in Louisiana; we primarily studied patients who were admitted between January 2020 to May 2020. Our main events that are currently being studied include factors such as mortality, length of stay, and bleeding or thrombotic events. Secondary endpoints included factors such as influence on blood type and also amount of transfusions required by these patients.
Our overall analysis of 1773 patients yielded a number of 60 patients who were able to identify as having an active cancer diagnosis. This disproportionate number of patients may be related to factors such as reluctance to visit the hospital among cancer patients, a phenomenon noted similarly in Cardiology where the number of admissions for cardiac causes had declined suddenly during this pandemic timeline. Our half of our population was African American and included an even proportion of males and females. The age range of patients was between 35-93 years old.
The most common malignancies that were noted to co-occur with COVID-19 in our population seemed to be lung, prostate, and hematological malignancies. Although final analyses regarding mortality are to be completed, the proportion of patients who had died with a diagnosis of cancer was around 50% per collection of our current data. Twenty three out of 60 (38%) patients required blood transfusions. In comparison to other reports which had reported bleeding events and thrombotic events, our report had revealed a much less rate of bleeding events (5/60) and thrombotic events (5/60). We plan to repeat our analysis to assess for any confounders in identifying these events, as noted, since some earlier literature had reported between ¼ to ⅔ of patients having a thrombotic event.
Our analysis also looks at other descriptive variables such as use of anticoagulant and antiplatelet agents, absolute counts of neutrophils and lymphocytes, platelets, and coagulation markers. Also, our assessment includes a study in assessment of any delays noted in chemotherapy dates for these patients. Analysis of assessment of bleeding, thrombosis, and mortality for the entire patient group is currently in process.

Disclosures
No relevant conflicts of interest to declare.
A Novel Assay Using Enzyme Capture - ELISA for Accurate Determination of Factor XIII Activity
Authors: Waller Amanda P. , Durda Michael A. , Franz Kennedy , Abdelghani Eman , Kerlin Bryce A. 
Published: November 2020

Background: The currently available, clinically approved factor XIII (fXIII) activity assays rely on indirect measurement of activated fXIII transglutaminase activity by detecting "ammonia-release" during an intermediate step of the reaction. Unfortunately, this assay is also sensitive to fXIII-independent ammonia-producing reactions that may take place physiologically in plasma, rendering it prone to overestimate fXIII activity, especially when levels are &lt;10% (0.1 IU/mL). High quality quantitative fXIII activity assays are required for the accurate and timely diagnosis of fXIII deficiency. fXIII circulates in complex with fibrinogen, and activated fXIII retards fibrinolysis by incorporating α2-antiplasmin (α2AP), a potent antifibrinolytic, into the forming clot via intermolecular α2AP:fibrin crosslinks. We have thus developed a new fXIII transglutaminase activity assay that directly measures α2-AP incorporation onto captured fibrin(ogen):fXIII complexes. We hypothesized that this novel assay has high sensitivity in detecting FXIII activity, especially at the low end of the dynamic range (&lt;10%; &lt;0.01 IU/mL).
Methods: A standard curve was established by diluting known concentrations of recombinant factor XIII-A (rFXIII-A; Tretten) into (1) fXIII-A congenitally deficient and (2) fXIII immunodepleted plasma to determine if our assay is able to detect variable fXIII concentrations from 1 to 200% (0.01 - 2 IU/mL).
Results: We demonstrated that α2-AP incorporation is dependent upon rfXIII-A concentration in the starting sample and was linear from 1-12% (0.01 - 0.12 IU/mL; Figure). Further expansion of the standard curve to include all concentrations within the normal physiologic range demonstrated that the assay remains strongly linear from 1-20% (0.01 - 0.2 IU/mL; R2 0.966). Moderate linearity (R2 0.908) extended to 50% (0.5 IU/mL). The curve plateaued between 50%-200% (0.5 IU/mL- 2 IU/mL). Thus, the dynamic range of the Enzyme Capture-ELISA is expected within 1-50% (0.01 - 0.5 IU/mL).
Conclusion: We conclude that Enzyme Capture-ELISA is a promising novel method for accurate detection of FXIII activity and is expected to improve sensitivity at low levels (&lt;20%; &lt;0.02 IU/mL), which are most clinically relevant. Further experiments are needed to refine the upper limit of assay linearity and thereby refine the dynamic range of the assay. With further optimization and validation, the EC-ELISA method may provide an improved diagnostic assay.

Disclosures
No relevant conflicts of interest to declare.
Diagnostic Utility of Targeted Next Generation Sequencing in Patients with Vascular Anomalies
Authors: Eng Whitney , Dilek Sophie , Ward Abigail , Kozakewich Harry PW , Al-Ibraheemi Alyaa , Janeway Katherine , Adams Denise M , Church Alanna 
Published: November 2020

Background: Vascular anomalies are diverse entities and can range in severity from self-limiting to life-threatening. Diagnosis and care of these patients is challenging due to overlapping clinical and histologic features. Recently, it has been established that many vascular anomalies arise from somatic mutations in cancer genes (PIK3CA, AKT, NRAS). Use of cancer genomics in patients with vascular anomalies may establish a genetic diagnosis and expand use of targeted medical therapies. We evaluated the utility of targeted next generation sequencing for vascular anomalies patients at a single pediatric center.
Methods: Using OncoPanel, a hybrid-capture and massively parallel sequencing assay that surveys DNA sequences of 447 genes implicated in cancer, we analyzed genetic variants in lesional tissue from vascular anomalies patients evaluated at Boston Children's Hospital between 5/2/2017 and 3/23/2020.
Results: A total of 276 patients were consented and sequenced under the Dana Farber Cancer Institute Profile protocols DFCI 11-104 (n= 68) and DFCI 17-000 (n= 208). Clinical diagnoses prior to testing were varied and 11 patients (7%) had an unknown diagnosis. Tissue was analyzed for 138 patients. Targeted sequencing resulted in diagnostically significant alterations in 80 of 138 (57%) of patients and therapeutically significant alterations in 58 of 138 (42%) patients. To date, 18 patients in our cohort have been treated with medical therapy informed by their genetic diagnosis. Several more await enrollment on clinical trials. For patients with diagnoses previously categorized as unknown (n=11), sequencing led to identification of a genetic variant in 6 patients (54%). Additionally, 8/138 patients had variants requiring further evaluation for potential germline involvement.
Discussion: Next generation sequencing in vascular anomalies patients identified actionable variants in a large proportion of the patients in our cohort. The mTOR inhibitor sirolimus has been used to treat a variety of vascular anomalies, but not all patients respond to this treatment. Targeted therapies based on specific genotypes hold promise as clinical trials in vascular anomalies are emerging. Additionally, sequencing in this cohort identified several variants suggesting a germline cancer predisposition requiring follow-up. Use of next generation sequencing has clinical utility and increased use of this testing may improve diagnosis, prognosis, and treatment for patients with vascular anomalies.

Disclosures
Adams: Novartis: Consultancy; Venthura: Consultancy.

OffLabel Disclosure:
Sirolimus is used off-label for the treatment of vascular anomalies.
An Improved Animal Model of Multiple Myeloma Bone Disease
Authors: Mehdi Syed , Zangari Maurizio , Yong Donghoon 
Published: November 2020

Multiple myeloma (MM) is a plasma cell malignancy that represents an accumulation of terminally differentiated monoclonal plasma cells (PCs) in the bone marrow (BM), accompanied by increased osteoclasts and decreased osteoblasts in areas adjacent to myeloma cells, leading to MM associated bone disease (MMBD). Osteolytic bone disease is one of the defining features of MM. During the disease, over 90% of patients are developing MMBD. Many of MM animal models have been developed and enable us to interrogate the mechanisms of MM tumorigenesis. Most MMBD models were derived by intratibial injection of myeloma cells. In these models, osteolysis occurs locally at the site where myeloma cells were injected. Mouse myeloma cells, 5TGM1 transplanting C57BL/KaLwRij mouse via the tail vein develops and shows MMBD features close to human MMBD. Even in this model, the MMBD levels on each mouse are widely varied. Lack of appropriate in vivo MMBD model hampers our understanding of the disease and developing therapy. We try to establish a murine model for MMBD to study its pathophysiology and test a novel treatment.
1x106 luciferase-expressing 5TGM1 (5TGM1-Luc) cells were injected into 8-12 week old NOD SCID gamma mouse (NSG) and C57BL/KaLwRij mouse via the tail vein. Myeloma progression was weekly assessed by in vivo bioluminescence (BL) imaging using IVIS-200 (Perkin Elmer). Mice were sacrificed when they showed endpoint signals such as significant weight loss, hindlimb paralysis, etc.. At postmortem, the micro-computer tomography (micro-CT) was performed for bone histo-morphometric analyses using micro CT400, Scano medical, Inc.
The median survival was 56 days in NSG, while 42 days in C57BL/KaLwRij. In vivo BL image analysis showed that myeloma slowly develops in NSG mouse in comparison to C57BL/KaLwRij mouse. Histomorphic analyses found that severe osteolytic lesions occur at the lumbar spine in NSG mouse compared to C57BL/KaLwRij mouse, but no significant difference at the femur of both strains. At the lumbar spine, trabecular thickness (p &lt; 0.0004) and trabecular space (p &lt; 0.0014) were significantly increased in NSG mouse compared to C57BL/KaLwRij mouse. On the contrary, trabecular number (p &lt; 0.0002) and bone volume density (p &lt; 0.0005) were significantly decreased in NSG mouse compared to C57BL/KaLwRij mouse.
In conclusion, we found that the systemic 5TGM1 injected NSG mouse slowly progresses myeloma and develops more severe MMBD than C57BL/KaLwRij model. This model will serve a better MMBD model to evaluate the therapeutic effects of MMBD targeted drugs.

Disclosures
No relevant conflicts of interest to declare.