bluuebunny/crossref_metadata_2025_split huggingface dataset:
Audit of red blood cell transfusion in patients with acute leukemia at a tertiary care university hospital
Authors: Jaime‐Pérez José Carlos , García‐Salas Gerardo , Áncer‐Rodríguez Jesús , Gómez‐Almaguer David 
Published: February 2020

BACKGROUNDRed blood cell (RBC) transfusion support is essential in patients with acute leukemia (AL). A restrictive RBC transfusion approach is assumed to be safe for most individuals with AL. The aim of this audit was to assess RBC transfusion appropriateness in AL patients at an academic center.STUDY DESIGN AND METHODSRBC transfusions in acute lymphoblastic leukemia and acute myeloid leukemia patients of all ages between January 1, 2013, and March 31, 2019, were analyzed for adherence to evidence‐based criteria. Transfusion appropriateness was compared among ordering specialties, patient locations, and hematologic diagnoses. Pretransfusion hemoglobin was compared between categories. Overtransfusion rates were also analyzed. Descriptive statistics and categorical and numerical tests were employed to determine statistical significance.RESULTSA total of 510 RBC transfusions were received by 133 AL patients in the departments of internal medicine, hematology, and pediatrics. Overall, 84.5% were appropriate according to established criteria. Internal medicine was the ordering department with the highest rate of appropriateness (88.1%). The outpatient clinic was the location with the highest adherence (85.9%), whereas the intensive care unit had the lowest (70%; p = 0.03). The reasons for most appropriate and inappropriate transfusions were asymptomatic anemia with a hemoglobin below (60.6%) or above (69.6%) 7 g/dL in patients without cardiac disease, respectively. Overtransfusion was present in 22% of episodes.CONCLUSIONRBC transfusion in AL patients reflected good adherence to guidelines. However, continuing education in transfusion medicine and prospective chart auditing are needed to improve adherence to established guidelines.
A Stabilizing Control Algorithm for Asynchronous Parallel Quadratic Programing via Dual Decomposition
Authors: Lee Kooktae 
Published: February 2020

Abstract
This paper proposes a control algorithm for stable implementation of asynchronous parallel quadratic programing (PQP) through a dual decomposition technique. In general, distributed and parallel optimization requires synchronization of data at each iteration step due to the interdependency of data. The synchronization latency may incur a large amount of waiting time caused by an idle process during computation. We aim to mitigate this synchronization penalty in PQP problems by implementing asynchronous updates of the dual variable. The price to pay for adopting asynchronous computing algorithms is the unpredictability of the solution, resulting in a tradeoff between speedup and accuracy. In the worst case, the state of interest may become unstable owing to the stochastic behavior of asynchrony. The stability condition of asynchronous PQP problems is investigated by employing the switched system framework. A formal algorithm is provided to ensure the asymptotic stability of dual variables. Furthermore, it is shown that the implementation of the proposed algorithm guarantees the uniqueness of optimal solutions, irrespective of asynchronous behavior. To verify the validity of the proposed methods, simulation results are presented.
Control-Oriented Modeling and Repetitive Control in In-Layer and Cross-Layer Thermal Interactions in Selective Laser Sintering
Authors: Wang Dan , Jiang Tianyu , Chen Xu 
Published: February 2020

Abstract
Although laser-based additive manufacturing (AM) has enabled unprecedented fabrication of complex parts directly from digital models, broader adoption of the technology remains challenged by insufficient reliability and in-process variations. In pursuit of assuring quality in the selective laser sintering (SLS) AM, this paper builds a modeling and control framework of the key thermodynamic interactions between the laser source and the materials to be processed. First, we develop a three-dimensional finite element simulation to understand the important features of the melt pool evolution for designing sensing and feedback algorithms. We explore how the temperature field is affected by hatch spacing and thermal properties that are temperature-dependent. Based on high-performance computer simulation and experimentation, we then validate the existence and effect of periodic disturbances induced by the repetitive in- and cross-layer thermomechanical interactions. From there, we identify the system model from the laser power to the melt pool width and build a repetitive control algorithm to greatly attenuate variations of the melt pool geometry.
A Study of Improving the Formability of the Commercial Pure Titanium Foils
Authors: Zhu Jiaqi , Nunnally Alex , Gau Jenn-Terng , Xu Siguang 
Published: February 2020

Abstract
In order to obtain the optimum forming process for commercial pure titanium grade 2 foils, a series of tensile tests and micro scale limited dome height (µ-LDH) tests at four temperatures, and meso scale limited dome height tests (meso-LDH) with three punch speeds were conducted on the as-received foils with a thickness of 75 µm. The effects of temperature, geometry, and high-velocity impact were investigated to understand their influences on the formability of the foils. It has been found in the tensile tests that the formability can be improved by elevating temperatures; this has been validated by the µ-LDH tests. Based on forming limit diagrams (FLDs) of the meso-LDH specimens, the high-velocity impact forming process results in not only much better formability but also more uniform thickness distributions than the quasi-static. By analyzing the fractographical scanning electron microscope (SEM) pictures of the meso-LDH specimens, it has been proven that the formability of the foils by using high-velocity impact process is superior to the conventional process. Furthermore, high-velocity impact causes forming limit curve (FLC) to shift in the upper right direction on the right-hand side of FLD. Therefore, it is suggested forming the foils by using high-velocity impact forming process at the elevated temperature for obtaining a better formability and more uniform thickness distribution. It is also recommended to make the radius of the LDH hemisphere punch close to the smallest feature of the designed products for obtaining more accurate FLCs.
Data-driven discovery of changes in clinical code usage over time: a case-study on changes in cardiovascular disease recording in two English electronic health records databases (2001–2015)
Authors: Rockenschaub Patrick , Nguyen Vincent , Aldridge Robert W , Acosta Dionisio , García-Gómez Juan Miguel , Sáez Carlos 
Published: February 2020

ObjectivesTo demonstrate how data-driven variability methods can be used to identify changes in disease recording in two English electronic health records databases between 2001 and 2015.DesignRepeated cross-sectional analysis that applied data-driven temporal variability methods to assess month-by-month changes in routinely collected medical data. A measure of difference between months was calculated based on joint distributions of age, gender, socioeconomic status and recorded cardiovascular diseases. Distances between months were used to identify temporal trends in data recording.Setting400 English primary care practices from the Clinical Practice Research Datalink (CPRD GOLD) and 451 hospital providers from the Hospital Episode Statistics (HES).Main outcomesThe proportion of patients (CPRD GOLD) and hospital admissions (HES) with a recorded cardiovascular disease (CPRD GOLD: coronary heart disease, heart failure, peripheral arterial disease, stroke; HES: International Classification of Disease codes I20-I69/G45).ResultsBoth databases showed gradual changes in cardiovascular disease recording between 2001 and 2008. The recorded prevalence of included cardiovascular diseases in CPRD GOLD increased by 47%–62%, which partially reversed after 2008. For hospital records in HES, there was a relative decrease in angina pectoris (−34.4%) and unspecified stroke (−42.3%) over the same time period, with a concomitant increase in chronic coronary heart disease (+14.3%). Multiple abrupt changes in the use of myocardial infarction codes in hospital were found in March/April 2010, 2012 and 2014, possibly linked to updates of clinical coding guidelines.ConclusionsIdentified temporal variability could be related to potentially non-medical causes such as updated coding guidelines. These artificial changes may introduce temporal correlation among diagnoses inferred from routine data, violating the assumptions of frequently used statistical methods. Temporal variability measures provide an objective and robust technique to identify, and subsequently account for, those changes in electronic health records studies without any prior knowledge of the data collection process.
Phase II study of pembrolizumab and capecitabine for triple negative and hormone receptor-positive, HER2−negative endocrine-refractory metastatic breast cancer
Authors: Shah Ami N , Flaum Lisa , Helenowski Irene , Santa-Maria Cesar A , Jain Sarika , Rademaker Alfred , Nelson Valerie , Tsarwhas Dean , Cristofanilli Massimo , Gradishar William 
Published: February 2020

BackgroundResponse rates to single agent immune checkpoint blockade in unselected pretreated HER2−negative metastatic breast cancer (MBC) are low. However, they may be augmented when combined with chemotherapy.MethodsWe conducted a single-arm, phase II study of patients with triple negative (TN) or hormone receptor-positive endocrine-refractory (HR+) MBC who were candidates for capecitabine. Patients were treated with pembrolizumab 200 mg intravenously day 1 and capecitabine 1000 mg/m2by mouth twice daily on days 1–14 of a 21-day cycle. The primary end point was median progression-free survival (mPFS) compared with historic controls and secondary end points were overall response rate (ORR), safety and tolerability. The study had 80% power to detect a 2-month improvement in mPFS with the addition of pembrolizumab over historic controls treated with capecitabine alone.ResultsThirty patients, 16 TN and 14 HR+ MBC, were enrolled from 2017 to 2018. Patients had a median age of 51 years and received a median of 1 (range 0–6) prior lines of therapy for MBC. Of 29 evaluable patients, the mPFS was 4.0 (95% CI 2.0 to 6.4) months and was not significantly longer than historic controls of 3 months. The median overall survival was 15.4 (95% CI 8.2 to 20.3) months. The ORR was 14% (n=4), stable disease (SD) was 41% (n=12) and clinical benefit rate (CBR=partial response+SD>6 months) was 28% (n=8). The ORR and CBR were not significantly different between disease subtypes (ORR 13% and 14%, CBR 25% and 29% for TN and HR+, respectively). The 1-year PFS rate was 20.7% and three patients have ongoing responses. The most common adverse events were low grade and consistent with those seen in MBC patients receiving capecitabine, including hand-foot syndrome, gastrointestinal symptoms, fatigue and cytopenias. Toxicities at least possibly from pembrolizumab included grade 3 or 4 liver test abnormalities (7%), rash (7%) and diarrhea (3%), as well as grade 5 hepatic failure in a patient with liver metastases.ConclusionsCompared with historical controls, pembrolizumab with capecitabine did not improve PFS in this biomarker unselected, pretreated cohort. However, some patients had prolonged disease control.Trial registration numberNCT03044730.
Clinical use of 4D flow MRI for quantification of aortic regurgitation
Authors: Alvarez Ana , Martinez Vicente , Pizarro Gonzalo , Recio Manuel , Cabrera Jose Ángel 
Published: February 2020

ObjectiveThe main objective of the present study was to compare the use of four-dimensional (4D) flow MRI with the habitual sequence (two-dimensional phase-contrast (2DPC) MRI) for the assessment of aortic regurgitation (AR) in the clinical routine.MethodsThis was a retrospective, observational cohort study of patients with varying grades of AR. For the purposes of the present study, we selected all the cases with a regurgitant fraction (RF)>5% as determined by 2DPC MRI (n=34). In all cases, both sequences (2DPC and 4D flow MRI) were acquired in a single session to ensure comparability. We compared the results of the two techniques by evaluating forward flow, regurgitant flow and regurgitation fraction. Then, the patients were divided into subgroups to determine if these factors had any influence on the measurements: aortic diameter (≤ vs >38 mm), valve anatomy (tricuspid vs bicuspid/quadricuspid), stenosis (gradient ≥15 vs <15) and region of interest location (aortic valve vs sinotubular junction).ResultsNo statistically significant differences were observed between the two techniques with Pearson’s correlation coefficients (r) of forward flow (r=0.826/p value<0001), regurgitant flow (r=0.866/p value<0001) and RF (r=0.761/p value<0001).ConclusionsThe findings of this study confirm the value of 4D flow MRI for grading AR in clinical practice with an excellent correlation with the standard technique (2DPC MRI).
Epstein–Barr Virus miRNA BART2-5p Promotes Metastasis of Nasopharyngeal Carcinoma by Suppressing RND3
Authors: Jiang Chen , Li Lei , Xiang Yan-Qun , Lung Maria Li , Zeng Tingting , Lu Jiabin , Tsao Sai Wah , Zeng Mu-Sheng , Yun Jing-Ping , Kwong Dora L.W. , Guan Xin-Yuan 
Published: February 2020

Abstract

Nasopharyngeal carcinoma is an Epstein–Barr virus (EBV)-related malignancy. Recently, we found that the EBV-encoded miRNA BART2-5p was increased in the serum of patients with preclinical nasopharyngeal carcinoma and that the copy number positively correlated with disease progression. In this study, we established its role in nasopharyngeal carcinoma progression and explored underlying mechanisms and clinical significance. BART2-5p was an independent unfavorable prognostic factor for progression-free survival and its circulating abundance positively associated with distant metastasis. Ectopic expression of BART2-5p promoted migration and invasion of EBV-negative nasopharyngeal carcinoma cells, whereas genetic downregulation of BART2-5p in EBV-positive nasopharyngeal carcinoma cells decreased aggressiveness. Mechanistically, BART2-5p targeted RND3, a negative regulator of Rho signaling. Downregulation of RND3 phenocopied the effect of BART2-5p and reconstitution of RND3 rescued the phenotype. By suppressing RND3, BART2-5p activated Rho signaling to enhance cell motility. These findings suggest a novel role for EBV miRNA BART2-5p in promoting nasopharyngeal carcinoma metastasis and its potential value as a prognostic indicator or therapeutic target.

Significance:
This study shows that EBV-encoded BART2-5p miRNA suppresses expression of the RND3 Rho family GTPase, consequently promoting ROCK signaling, cell motility, and metastatic behavior of NPC cells.
Yf-H-2015005, a New CXCR4 Antagonist, in the Mobilization of Hematopoietic Stem Cells in Patients with Non-Hodgkin Lymphoma: A Randomized-Controlled Phase 3 Study
Authors: Liu Weiping , Li Yufu , Wang Quanshun , Ding Kaiyang , Su Hang , Shuang Yue-rong , Gao Sujun , Jing Hongmei , Chai Ye , Zou Dehui , Liu Hui , Wang Chunling , LIU Lihong , Zhang Yicheng , Lin Jinying , Zhu Haiyan , Shang Meixia , Yan Xiaoyan , Yao Chen , Chang Fengyuan , Zhu Jun , Song Yuqing 
Published: February 2020

Background:
Autologous hematopoietic stem cell transplantation (AHSCT) is an important therapy for non-Hodgkin's lymphoma (NHL). This study evaluated the safety and efficacy of YF-H-2015005, a new CXCR4 antagonist, when used to mobilize hematopoietic stem cells in patients with NHL eligible for treatment with AHSCT.
Methods:
This phase III, multicenter, randomized (1:1), double-blind, placebo-controlled study enrolled patients (age range, 18 to 65 years) with NHL, and who were in their first or second complete or partial remission. The patients received granulocyte colony-stimulating factor (G-CSF, 10 mg/kg/day) each morning for up to 8 days. Treatment with YF-H-2015005 (0.24 mg/kg/day) or placebo was initialed during the evening of the fourth day of G-CSF administration, and then continued for up to 4 days. Starting on day 5, apheresis was performed for 9 to 10 hours after each dose of YF-H-2015005 or until ≥ 5 × 106 CD34+ cells/kg had been collected. The primary endpoint was the percentage of patients who collected ≥ 5 × 106 CD34+ cells/kg during the course of 4 or fewer apheresis days. The secondary endpoints were the percentage of patients who collected ≥ 2 × 106 CD34+ cells/kg during the course of 4 or fewer apheresis days, the number of apheresis days required to reach ≥ 2 × 106 CD34+ cells/kg, the number of apheresis days required to reach ≥ 5 × 106 CD34+ cells/kg, and patient safety.
Results:
A total of 101 patients with NHL were randomly assigned to the YF-H-2015005 group (n = 51or placebo group (n = 50), respectively. The percentage of patients who met the primary endpoint was 57% (29/51) in the YF-H-2015005 group and 12% (6/50) in the placebo group (P &lt; 0.001). A larger proportion of patients in the YF-H-2015005 group (86%) achieved the secondary endpoint of collecting ≥ 2 × 106 CD34+ cells/kg in 4 or fewer apheresis days when compared with the placebo group (38%, P &lt; 0.001). Patients in the YF-H-2015005 group required shorter time periods to collect ≥ 2 × 106 CD34+ cells/kg (1 days vs. 4 days) and ≥ 5 × 106 CD34+ cells/kg (3 days vs. not reached). Treatment-related adverse event were observed in 37 patients (20 in the YF-H-2015005 group and 17 in the placebo group). The most common adverse events in the YF-H-2015005 group were diarrhea (14%), hyperhidrosis(6%), elevated alkaline phosphatase (6%). No serious treatment-related adverse event occurred.
Conclusions:
The combination of YF-H-2015005 and G-CSF was a tolerable regimen for use in rapidly mobilizing and collecting CD34+ cells for transplantation in patients with NHL.

Disclosures
Zhu: Mundipharma: Research Funding.
Hematopoietic Stem Cell Function in β-Thalassemia Is Impaired and Is Rescued By Targeting the Bone Marrow Niche
Authors: Aprile Annamaria , Gulino Alessandro , Villa Isabella , Beretta Stefano , Merelli Ivan , Rubinacci Alessandro , Ponzoni Maurilio , Marktel Sarah , Tripodo Claudio , Lidonnici Maria Rosa , Ferrari Giuliana 
Published: February 2020

Hematopoietic stem cells (HSC) are regulated by signals from the bone marrow (BM) niche and little is known about their fate in altered hematological conditions associated to non-malignant diseases. In β-thalassemia ineffective erythropoiesis and secondary alterations, as abnormal regulation of bone metabolism, iron overload and hormonal factors, induce changes in the BM homeostasis with a potential impact on HSC-niche interaction. We addressed these unexplored issues in the murine disease model and in patients' cells.
We investigated hematopoiesis in thalassemic Hbbth3/+ (th3) mutant mice and we found lower frequency, reduced quiescence and reconstituting potential of HSC. th3 HSC have impaired self-renewal, which is rescued upon transplantation in a normal BM, proving an active role of the niche microenvironment. Both stromal and hematopoietic components of the BM niche are altered in th3 mice. Consistently with the common finding of osteoporosis in patients, we found reduced bone deposition with decreased levels of parathyroid hormone (PTH), which is a key regulator of bone metabolism but also of HSC activity. Low PTH negatively affects bone deposition and expression of the Notch-ligand Jag1 by th3 mesenchymal and osteolineage cells, thus reducing the activation of Notch1 in HSC and consequently impairing their function. In vivo activation of PTH signaling through the reestablished Jag1-Notch1 pathway restores the functional pool of th3 HSC by correcting HSC-niche crosstalk.
In addition to the stromal component of the BM, hematopoietic cells with a key role in regulating the fate of HSC, such as megakaryocytes (Mk), were found defective in maturation, possibly due to reduced circulating levels of thrombopoietin (TPO). We are currently investigating the molecular causes of dysmegakaryopoiesis and the Mk-HSC interaction in thalassemic mice.
Strikingly, reduced HSC quiescence was confirmed in samples from patients affected by β-thalassemia, along with impaired stromal niche and megakaryopoiesis, thus highlighting the clinical relevance of our findings. Further investigation will unravel the multiple molecular mechanisms that affect in trans HSC functions in the complexity of the stressed thalassemic BM microenvironment. Our results uncover a defect of HSC in β-thalassemia, induced by an altered BM niche and provide new relevant insight for improving transplantation and gene therapy approaches.

Disclosures
No relevant conflicts of interest to declare.
Hemopexin Replacement Therapy Protects Sickle Cell Disease Mice from Acute Kidney Injury
Authors: Ghosh Samit , Orikogbo Oluwaseun , Hazra Rimi , Flage Bethany , Crosby Danielle , Ofori-Acquah Solomon Fiifi 
Published: February 2020

Acute kidney injury (AKI) is a major clinical concern during episodes of acute chest syndrome and vaso-occlusive crisis in sickle cell disease (SCD). AKI increases the risk of chronic kidney disease (CKD) and end stage renal disease (ESRD). We previously showed that alpha-1-microglobulin (A1M), a low affinity heme-binding protein that carries heme for renal clearance is elevated in patients and mice with homozygous SCD (SS). Hemopexin (Hx), which primarily scavenges circulating heme to the liver, is exhausted in SCD. In this study, we explored the idea that acquired Hx deficiency in SCD is a risk factor for AKI development in SCD. We studied mice with a global knockout of Hx with no detectable plasma Hx at baseline. Plasma A1M was significantly elevated in the Hx-/-mice compared to control (Hx+/+) mice (n=5; p&lt;0.01). We then transplanted whole bone marrow cells from SS mice into Hx+/+and Hx-/-mice to create bone marrow chimeric SSHx+/+and SSHx-/-mice with SCD phenotype. The chimeras had elevated plasma A1M compared to recipient littermates (Hx+/+and Hx-/-) and low baseline glomerular filtration rate (GFR). Modest elevation of circulating heme with infusion of hemin (20 μmoles/kg bw) worsened GFR and caused severe AKI. Next, to determine whether hemin induced AKI is attenuated by elevation of circulating Hx, we infused SS mice with purified Hx, and control SS mice with either purified A1M or vehicle immediately prior to the hemin challenge. We observed improved GFR in the Hx-treated SS mice, while vehicle and A1M-treated mice suffered 23% and 39% loss of GFR respectively compared to their baseline. In agreement with the GFR data, the levels of several AKI diagnostic markers, plasma creatinine (plasma Cr), urinary albumin-creatinine ratio (uACR) and kidney injury molecule (uKIM-1) were elevated significantly in vehicle and A1M treated mice following hemin challenge. In Hx-treated mice, these biomarkers remained unaltered. Importantly, Hx infusions re-directed excess heme in SS mice to the liver, while A1M infusion significantly increased total heme content in the kidneys. Two-way ANOVA analysis of GFR (p&lt;0.01) and plasma Cr (p&lt;0.001) revealed significant exacerbation of kidney injury in A1M treated SS mice compared to vehicle treated mice. Histopathology of renal tissue showed considerable tissue damage in vehicle and A1M infused SS mice, while Hx treated SS mice kidneys appeared relatively normal. This study provides genetic evidence that hemopexin deficiency promotes AKI development in SCD, and we provide proof-of-principle for hemopexin replacement therapy to treat AKI in SCD.

Disclosures
Ofori-Acquah: Shire Human Genetic Therapies Inc: Other: Financial Relationship.