bluuebunny/crossref_metadata_2025 huggingface dataset:
Serumspiegel von MicroRNA-371a-3p (M371-Test) als neuer Biomarker für testikuläre Keimzelltumoren: Ergebnisse einer prospektiven Multicenterstudie
Authors: Dieckmann Klaus-Peter , Radtke Arlo , Geczi Lajos
Published: February 2021

Zielsetzung: Die Ergebnisse früherer Studien deuteten darauf hin, dass die Serumspiegel der microRNA (miR)-371a-3p (so genannter M371-Test) eine sehr viel höhere Sensitivität und Spezifität aufweisen als die klassischen Tumormarker für testikuläre Keimzelltumoren (germ cell tumors, GCTs) und sowohl für Seminome als auch für Nichtseminome anwendbar sind. Unser Ziel war es, den Nutzen dieses Tests als neuen Biomarker für GCTs zu bestätigen. Patienten und Methoden: Im Rahmen einer prospektiven Multicenter-Studie wurden die Serumspiegel von miRNA-371a-3p (miR-Spiegel) in Serumproben von 616 Patienten mit testikulären GCTs und 258 männlichen Kontrollen mittels quantitativer Polymerase-Kettenreaktion untersucht. Die GCT-Patientenpopulation umfasste 359 Patienten mit Seminom und 257 mit einem Nichtseminom; 371 hatten eine Erkrankung im klinischen Stadium I, 201 hatten eine systemische Erkrankung und 46 ein Rezidiv. Bei 424 Patienten erfolgten paarige Messungen vor und nach der Orchiektomie und bei 118 Patienten mit systemischer Erkrankung wurden serielle Messungen während der Behandlung durchgeführt. Die miR-Spiegel wurden mit denen von β-HCG (humanes Choriongonadotropin), α-Fetoprotein und Laktatdehydrogenase verglichen. Ergebnisse: Bei der GCT-Primärdiagnose betrug die Sensitivität des M371-Tests 90,1 %, die Spezifität 94,0 %, die Fläche unter der Kurve 0,966 in der Receiver-Operating-Characteristic-Analyse und der positive prädiktive Wert 97,2 %. Die Sensitivität von α-Fetoprotein, humanem β-Choriongonadotropin und Laktatdehydrogenase lag bei Seminomen bei weniger als 50 % und bei Nichtseminomen geringfügig höher. Es bestand eine signifikante Assoziation zwischen den miR-Spiegeln und dem klinischen Stadium, der Größe des Primärtumors und dem Ansprechen auf die Behandlung. Bei Rezidiven waren erhöhte miR-Spiegel zu beobachten, die anschließend bei einer Remission auf den Normalwert abfielen. Teratome exprimierten keine miR-371a-3p. Schlussfolgerung: Mit einer Sensitivität und Spezifität von mehr als 90 % schneidet der M371-Test besser ab als die klassischen GCT-Tumormarker. Alle histologischen Subgruppen mit Ausnahme des Teratoms exprimieren diesen Tumormarker. Nach weiterer Validierung könnte der Test für den klinischen Einsatz in Betracht kommen.
Star-rating evaluation model for rating the energy-efficiency level of android google play apps
Authors: Mahmoud Almasri Abdullah , Borges Gouveia Luis
Published: February 2021

The tremendous increase in smartphone usage is accompanied by an increase in the need for more energy. This preoperational relationship between modern technology and energy generates energy-greedy apps, and therefore power-hungry end users. With many apps falling under the same category in an app store, these apps usually share similar functionality. Because developers follow different design and development schools, each app has its energy-consumption habits. Since apps share similar features, an end-user with limited access to recharging resources would prefer an energy-friendly app rather than a popular energy-greedy app. However, app stores do not indicate the energy behavior of the apps they offer, which causes users to randomly choose apps without understanding their energy-consumption behavior. A review of the relevant literature was provided covering various energy-saving techniques. The results gave an initial impression about the popularity of the usage of two power-saving modes where the average usage of these modes did not exceed 31% among the total 443 Android users. To address this issue, we propose a star-rating evaluation model (SREM), an approach that generates a tentative energy rating label for each app. The model was tested on 7 open-source apps to act as a primary evaluation sample. To that end, SREM adapts current energy-aware refactoring tools to demonstrate the level of energy consumption of an app and presents it in a star-rating schema similar to the Ecolabels used on electrical home appliances. As per our results, SREM helped in saving 35% of smartphone energy.
Electrochemical batteries for smart grid applications
Authors: Salkuti Surender Reddy
Published: February 2021

This paper presents a comprehensive review of current trends in battery energy storage systems, focusing on electrochemical storage technologies for Smart Grid applications. Some of the batteries that are in focus for improvement include Lithium-ion, metal-air, Sodium-based batteries and flow batteries. A descriptive review of these batteries and their sub-types are explained along with their suitable applications. An overview of different types and classification of storage systems has been presented in this paper. It also presents an extensive review on different electrochemical batteries, such as lead-acid battery, lithium-based, nickel-based batteries and sodium-based and flow batteries for the purpose of using in electric vehicles in future trends. This paper is going to explore each of the available storage techniques out there based on various characteristics including cost, impact, maintenance, advantages, disadvantages, and protection and potentially make a recommendation regarding an optimal storage technique.
Novel hybrid framework for image compression for supportive hardware design of boosting compression
Authors: D. R. Premachand , Eranna U.
Published: February 2021

Performing the image compression over the resource constrained hardware is quite a challenging task. Although, there has been various approaches being carried out towards image compression considering the hardware aspect of it, but still there are problems associated with the memory acceleration associated with the entire operation that downgrade the performance of the hardware device. Therefore, the proposed approach presents a cost effective image compression mechanism which offers lossless compression using a unique combination of the non-linear filtering, segmentation, contour detection, followed by the optimization. The compression mechanism adapts analytical approach for significant image compression. The execution of the compression mechanism yields faster response time, reduced mean square error, improved signal quality and significant compression ratio performance.
An artificial immune system algorithm for solving the uncapacitated single allocation p-Hub median problem
Authors: Grine Fatima Zahraa , Kamach Oulaid , Khatab Abdelhakim , Sefiani Naoufal
Published: February 2021

The present paper deals with a variant of hub location problems (HLP): the uncapacitated single allocation p-Hub median problem (USApHMP). This problem consists to jointly locate hub facilities and to allocate demand nodes to these selected facilities. The objective function is to minimize the routing of demands between any origin and destination pair of nodes. This problem is known to be NP-hard. Based on the artificial immune systems (AIS) framework, this paper develops a new approach to efficiently solve the USApHMP. The proposed approach is in the form of a clonal selection algorithm (CSA) that uses appropriate encoding schemes of solutions and maintains their feasibility. Comprehensive experiments and comparison of the proposed approach with other existing heuristics are conducted on benchmark from civil aeronautics board, Australian post, PlanetLab and Urand data sets. The results obtained allow to demonstrate the validity and the effectiveness of our approach. In terms of solution quality, the results obtained outperform the best-known solutions in the literature.
desenvolvimento da autonomia discente nas aulas de italiano como língua adicional
Authors: Vieira Daniela Aparecida
Published: February 2021

Segundo Freire (1996), Mezzadri (2003) e Kumaravadivelu (2006), um dos principais escopos do processo de ensino-aprendizagem é promover a autonomia dos alunos. Diante disso, este artigo tem como objetivo apresentar reflexões, de caráter teórico e prático, sobre a importância do desenvolvimento da autonomia discente nas aulas de italiano como língua adicional. No que concerne aos aspectos teóricos, serão tratadas algumas definições de autonomia em âmbito didático-pedagógico. Em seguida, serão abordadas as noções de língua estrangeira, segunda língua e língua adicional, procurando-se explicar por que, neste texto, optou-se pelo último termo. Quanto aos aspectos práticos, serão mostrados alguns dados de um estudo de caso realizado no primeiro semestre de 2015 em uma sala de aula do Italiano no Campus, curso de extensão da Faculdade de Filosofia, Letras e Ciências Humanas da Universidade de São Paulo. A análise dos dados, realizada à luz dos postulados teóricos tratados neste artigo, parece indicar que, durante as aulas, os estudantes puderam construir conhecimentos na e sobre a língua italiana e, ao mesmo tempo, refletir sobre o seu próprio processo de aprendizagem linguística, o que provavelmente contribuiu para os discentes se tornarem mais autônomos.
pluralidade linguístico-cultural do italiano e o silêncio dos materiais didáticos
Authors: Landulfo Cristiane , Caramori Alessandra Paola , Viana Adriane
Published: February 2021

O italiano é convencionalmente difundido como língua nacional da Itália. No entanto, em outros países, esse idioma também tem o status de língua oficial, segunda língua e língua nacional. Partindo dessa premissa, o presente artigo tem o propósito de refletir sobre o que chamamos de pluralidade linguístico-cultural do italiano, bem como apresentar dados de uma pesquisa cujo objetivo foi verificar se e como os materiais didáticos de língua italiana mais utilizados pelos professores brasileiros que responderam ao nosso questionário contemplam essa pluralidade. O corpus deste estudo foi analisado sob o enfoque qualitativo-interpretativista. Os resultados demonstraram um total apagamento dos outros países.
Guias turísticos colaborativos e Pbworks: o caso de “Viaggiare in Italia”
Authors: Elia Antonella
Published: February 2021

Este artigo apresentará uma reflexão sobre as peculiaridades da linguagem do turismo e dos guias turísticos que, mesmo em sua recente evolução digital, continuam a representar um dos gêneros textuais mais conhecidos e populares do setor. Na segunda parte do artigo será apresentado o projeto "Viaggiare in Italia", uma experiência de escrita colaborativa realizada pelos alunos do terceiro ano do Departamento de Língua e Literatura Italiana da Faculdade de Letras da Universidade de Istambul. A experimentação, que utilizou a plataforma wiki PBworks, teve como objetivo prioritário contribuir para o desenvolvimento de uma consciência pragmática sobre as peculiaridades da linguagem do turismo. O projeto buscou atingir seus objetivos por meio de uma abordagem proativa, que envolveu ativamente os alunos por meio da produção de um mini-guia multimídia colaborativo sobre cidades italianas.
Familial Evaluation in Idiopathic Ventricular Fibrillation
Authors: Mellor Greg J. , Blom Lennart J. , Groeneveld Sanne A. , Winkel Bo G. , Ensam Bode , Bargehr Johannes , van Rees Bianca , Scrocco Chiara , Krapels Ingrid P.C. , Volders Paul G.A. , Tfelt-Hansen Jacob , Krahn Andrew D. , Hassink Rutger J. , Behr Elijah R.
Published: February 2021

Background:

Familial cascade screening is well established in patients with heritable cardiac disease and in cases of sudden arrhythmic death syndrome. The clinical benefit of family screening in idiopathic ventricular fibrillation (IVF) is unknown.

Methods:

Patients with IVF were identified from national and institutional registries. All underwent systematic and comprehensive clinical evaluation to exclude identifiable causes of cardiac arrest with a minimum requirement of ECG, cardiac (echocardiogram or magnetic resonance imaging) and coronary imaging, exercise ECG, and sodium channel blocker provocation. Additional investigations including genetic testing were performed at the physician’s discretion. First-degree relatives who were assessed with at least a 12-lead ECG were included in the final cohort. Results of additional investigations, performed at the physician’s discretion, were also recorded. Results were coded as normal, abnormal, or minor findings.

Results:

We identified 201 first-degree relatives of 96 IVF patients. In addition to a 12-lead ECG, echocardiography was performed in 159 (79%) and ≥1 additional investigation in 162 (80%) relatives. An inherited arrhythmia syndrome was diagnosed in 5 (3%) individuals from 4 (4%) families. Two relatives hosted the
DPP6
risk haplotype identified in a single proband, one of whom received a primary prevention implantable cardioverter defibrillator. In 3 separate families, an asymptomatic parent of the IVF proband developed a type 1 Brugada ECG pattern during sodium channel blocker provocation. All were managed with lifestyle measures only. The early repolarization (ER) ECG pattern was present in 16% probands and was more common in relatives in those families than those where the proband did not have early repolarization (25% versus 8%,
P
=0.04).

Conclusions:

The yield of family screening in relatives of IVF probands is low when the proband is comprehensively investigated. The significance of J wave syndromes in relatives and the role for systematic sodium channel blocker provocation are, however, uncertain and require further research.
Ongoing Risk of Ventricular Arrhythmias and All-Cause Mortality at Implantable Cardioverter Defibrillator Generator Change
Authors: Yuyun Matthew F. , Erqou Sebhat A. , Peralta Adelqui O. , Hoffmeister Peter S. , Yarmohammadi Hirad , Echouffo-Tcheugui Justin B. , Martin David T. , Joseph Jacob , Singh Jagmeet P.
Published: February 2021

Background:

Uncertainty still surrounds implantable cardioverter defibrillator (ICD) generator change at time of elective replacement indicator, in primary prevention patients with improved left ventricular ejection fraction (LVEF) beyond guideline recommendations or without prior appropriate ICD therapies.

Methods:

We conducted a meta-analysis of studies assessing the risk of appropriate ICD therapies and all-cause mortality after generator change in patients with improved LVEF>35% versus unimproved LVEF≤35% or patients without versus with prior appropriate ICD therapies during the life of their first ICD generator. A systematic electronic search of PubMed, EMBASE, and Cochrane Library databases until December 31, 2019 was performed. Estimates were combined using random-effects model meta-analyses.

Results:

In 15 studies that included 29 730 patients, 25.3% had LVEF improvement >35% at time of generator change. The pooled annual incidence of appropriate ICD therapies was significantly lower in those with improved LVEF, compared with patients with unimproved LVEF: 4.6% versus 10.7%; risk ratio, 0.50 (95% CI, 0.36–0.68),
P
<0.0001. The pooled rate of all-cause mortality was 6.6% versus 10.9% per year, risk ratio of 0.65 (95% CI, 0.62–0.69),
P
<0.0001. Risk of inappropriate shock was comparable between the 2 groups (
P
=0.750). In 8 studies (N=27 209), the pooled incidence of ventricular arrhythmia was significantly lower in patients without prior ICD therapies (3.9% per annum), compared with those with prior ICD therapies (12.5 % per annum), risk ratio of 0.37 (95% CI, 0.33–0.41),
P
<0.001.

Conclusions:

There was significant reduction in risk of ventricular arrhythmias and mortality in patients with improved versus unimproved LVEF or those who received versus those who did not receive appropriate ICD therapies during the life of their first ICD generator. However, we found a substantial residual outcome risk in these groups of patients.
Furosemide for Accelerated Recovery of Blood Pressure Postpartum in Women with a Hypertensive Disorder of Pregnancy
Authors: Lopes Perdigao Joana , Lewey Jennifer , Hirshberg Adi , Koelper Nathanael , Srinivas Sindhu K. , Elovitz Michal A. , Levine Lisa D.
Published: February 2021

Persistent postpartum hypertension is a significant cause of maternal morbidity. Our objective was to study the effect of furosemide on postpartum blood pressure recovery in women with hypertensive disorders of pregnancy. We performed a randomized, double-blind, placebo-controlled trial of a 5-day course of 20 mg oral furosemide versus placebo in women with gestational hypertension and preeclampsia with/without severe features from June 2018 to October 2019. Primary outcomes were persistent hypertension at 7 days postpartum (using generalized linear models to calculate adjusted relative risk) and days to resolution of hypertension (Kaplan-Meier curves), stratified by severe/nonsevere hypertensive disease. Secondary outcomes included readmissions and need for additional hypertensive medication.We randomized 384 women (192 per group). Baseline characteristics were similar except cesarean delivery rate was higher in the furosemide group (29% versus 20%;
P
=0.04). In women randomized to furosemide, there was a 60% reduction in the prevalence of persistently elevated blood pressure at 7 days when controlling for cesarean (adjusted relative risk, 0.40 [95% CI, 0.20–0.81]). The magnitude of reduction was greater in women with nonsevere disease (adjusted relative risk, 0.26 [95% CI, 0.10–0.67]). Number of days to blood pressure resolution was significantly shorter among women with nonsevere disease randomized to furosemide (8.5 versus 10.5;
P
=0.001). There were no significant differences in readmissions or need for additional antihypertensive medication postpartum between groups. In this double-blinded randomized trial, a short course of postpartum furosemide significantly improved blood pressure control in women with hypertensive disorders of pregnancy, mostly among women without severe disease.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT035556761.
Dietary Carbohydrate Intake and New-Onset Hypertension: A Nationwide Cohort Study in China
Authors: Li Qinqin , Liu Chengzhang , Zhang Shaojie , Li Rui , Zhang Yuanyuan , He Panpan , Zhang Zhuxian , Liu Mengyi , Zhou Chun , Ye Ziliang , Wu Qimeng , Li Huan , Qin Xianhui
Published: February 2021

The association between carbohydrate intake and the risk of hypertension remains uncertain. We aimed to evaluate the prospective relations of the amount and type of carbohydrate intake with new-onset hypertension. A total of 12 177 adults who were free of hypertension at baseline from the China Health and Nutrition Survey were included. Dietary intake was measured by 3 consecutive 24-hour dietary recalls combined with a household food inventory. The study outcome was new-onset hypertension, defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg or diagnosed by physician or under antihypertensive treatment during the follow-up. A total of 4269 subjects developed hypertension during 95 157 person-years of follow-up. Overall, there was a U-shaped association between the percentage energy consumed from total carbohydrate (mean, 56.7%; SD, 10.7) and new-onset hypertension (
P
for nonlinearity <0.001), with the lowest risk observed at 50% to 55% carbohydrate intake. The increased risks were mainly found in those with lower intake of high-quality carbohydrate (mean, 6.4%; SD, 5.6) or higher intake of low-quality carbohydrate (mean, 47.0%; SD, 13.0). Moreover, there was an inverse association between the plant-based low-carbohydrate scores for low-quality carbohydrate and new-onset hypertension. However, there was a U-shaped association between the animal-based low-carbohydrate scores for low-quality carbohydrate and new-onset hypertension (
P
for nonlinearity <0.001). In summary, both high and low percentages of carbohydrate diets were associated with increased risk of new-onset hypertension, with minimal risk at 50% to 55% carbohydrate intake. Our findings support the intake of high-quality carbohydrate, and the substitution of plant-based products for low-quality carbohydrate for prevention of hypertension.
Illuminating the Development of Precontractual Liability
Authors: Vandenberghe Ann-Sophie , Kovac Mitja
Published: February 2021

By using the tools of comparative law & economics, this article aims to shed a light on the development of precontractual liability. Precontractual liability sensu stricto is about the question to what extent one can be held liable for cost incurred by the other party preliminary to, or during precontractual negotiations, when negotiations fail. Comparative legal analysis has observed that the requirements for establishing a successful claim for precontractual liability are very similar at common law and at civil law despite the very different starting positions from which each legal system’s rules have developed. By finding correspondence between what comparative law has found and what is expected under an efficient legal system, this study provides empirical evidence for the efficiency hypothesis of law.
Response of Monsoon Rainfall to Changes in the Latitude of the Equatorward Coastline of a Zonally Symmetric Continent
Authors: Hui Katrina L. , Bordoni Simona
Published: February 2021

Recent studies have shown that the rapid onset of the monsoon can be interpreted as a switch in the tropical circulation, which can occur even in the absence of land–sea contrast, from a dynamical regime controlled by eddy momentum fluxes to a monsoon regime more directly controlled by energetic constraints. Here we investigate how one aspect of continental geometry, that is, the position of the equatorward coastal boundary, influences such transitions. Experiments are conducted with an aquaplanet model with a slab ocean, in which different zonally symmetric continents are prescribed in the Northern Hemisphere poleward from southern boundaries at various latitudes, with “land” having a mixed layer depth two orders of magnitude smaller than ocean. For continents extending to tropical latitudes, the simulated monsoon features a rapid migration of the convergence zone over the continent, similar to what is seen in observed monsoons. For continents with more poleward southern boundaries, the main precipitation zone remains over the ocean, moving gradually into the summer hemisphere. We show that the absence of land at tropical latitudes prevents the rapid displacement into the subtropics of the maximum in lower-level moist static energy and, with it, the establishment of an overturning circulation with a subtropical convergence zone that can transition rapidly into an angular momentum–conserving monsoon regime.
Anomalous insertion of the anterior horn of the medial meniscus combined with anterior horn hypertrophy and a synovial cyst: case report and literature review
Authors: Chen Peng , Huang Pengzhou , Ren Yuxiang , Jiang Guanwei , Zhang Wentao , Zhang Xintao
Published: February 2021

Objective

To gain a greater understanding of anomalous insertions of the anterior horn of the medial meniscus through evaluation of a rare case and a review of the existing literature on medial meniscus malformations.

Methods

This report describes a 26-year-old man with an anomalous insertion of the anterior horn of the medial meniscus combined with symptomatic hypertrophy of the anterior horn and a synovial cyst. We also conducted a review of the existing literature on medial meniscus malformations using five major scholarly literature databases and search engines.

Results

The literature review revealed that the incidence of anomalous insertions of the anterior horn of the medial meniscus is 0.5% to 2.8%. Not all patients undergo surgical excision; some are only symptomatically treated. In our patient, the arthroscopic view was consistent with the imaging characteristics. No special operation was performed to treat the anomalous insertion. At the 18-month follow-up, the patient had no symptom recurrence and had returned to practicing sports.

Conclusion

The pain during hyperextension in our patient was caused by a cyst and anterior horn hypertrophy. If the symptoms in such cases are not caused by the anomalous insertion, no special treatment is needed.
Inpatient Hypercoagulable Work-up in a Community Teaching Hospital: A Preventable Cost with No Added Benefit
Authors: Ackula Haritha , Patil Shekhar , Maradana Sandhya , Syed Masood Pasha , Siddiqui Ahmad Daniyal
Published: February 2021

Background: Thrombophilia testing in hospitalized patients is often inaccurate and rarely clinically useful especially in acute settings. Testing for inherited thrombophilia is often done in the setting of recurrent unprovoked venous thromboembolism (VTE). Several prospective studies have shown that heritable thrombophilia status is not statistically associated with recurrent VTE. Additionally, such testing may be confounded by ongoing disease or treatment. The cost per thrombophilia panel testing range anywhere between $1100 to $2400 based on estimation of charges billed by a large commercial laboratory. We aim to identify patterns and costs involved in inpatient thrombophilia testing in a community teaching hospital.

Methods: The study was conducted as a part of our quality improvement initiative in a community teaching hospital. We performed a retrospective chart review of patients above the age of 18 years who had a clinically and radiologically confirmed diagnosis of venous thromboembolism during the year of 2016 and performed descriptive analysis. Institutional IRB was obtained and data was collected by reviewing the electronic medical records .

Results: A total of 395 patients with the diagnosis of VTE were included (mean age 68.5, 54.2% female). At least one thrombophilia test was ordered in 66 of the 395 patients (16.7%). Around 38 (9.6%) patients were already on anticoagulation for atrial fibrillation/flutter, deep venous thrombosis (DVT) and pulmonary embolism (PE) among whom 5/38 (13.2%) patients underwent thrombophilia testing. Number of patients with a prior history of DVT or PE or both were 67/395(20%). Out of these, 26/67 (38.8%) patients were on anticoagulation and 14/67 (20.9%)patients underwent thrombophilia testing during their hospital stay. Only 11/395 (2.8%) patients had a family history of DVT/PE among whom 4 were tested. The approximate cost of the testing was $132,000 considering roughly $2000 per test on an average for a total of 66 tests.

Discussion: Thrombophilia testing in hospitalized patients adds little if at all any value to their acute management. However, it does add a significant unnecessary avoidable cost to the hospital. Although inpatient thrombophilia testing is not supported by current guidelines for inherited thrombophilia evaluation, the testing is often done in hospitalized patients with recurrent thromboembolism. Learning the pattern of thrombophilia testing in hospitalized patients will help us implement measures to prevent unnecessary testing and the significant costs associated with it.

Conclusion: With the increasing emphasis on value-based health care, thrombophilia testing should be considered only if it affects overall patient management and preferably in an outpatient setting with appropriate indications.

Disclosures

No relevant conflicts of interest to declare.
Intensity of End of Life Care for Hematologic Malignancy Patients in Western Washington, United States and Alberta, Canada
Authors: Khaki Ali Raza , Xu Yuan , Chennupati Shasank R , Ramsey Scott D , Fedorenko Catherine , Shankaran Veena , Cowan Andrew J. , Cheung Winson Y
Published: February 2021

Background: Aggressive care at the end of life (EOL) leads to unnecessary suffering and healthcare costs for patients with cancer. We have previously shown that among patients with solid tumor malignancies, EOL utilization of chemotherapy, intensive care unit (ICU) admissions and >1 emergency department (ED) visits are higher in Washington State vs Alberta (AB). In this study, we use cancer registry and claims data to compare EOL care among patients with hematological malignancies between western Washington (WW) and AB.

Methods: Adult patients with hematological malignancies diagnosed between 2007 and 2017 who died before December 31, 2018 were identified from regional population-based cancer registries in WW and AB. Data sources were 1) WW Cancer Surveillance System (a regional SEER registry) with data from 13 counties linked to enrollment files and claims from four regional insurers and 2) Canada National Ambulatory Care Reporting System, Discharge Abstracts Database, and chemotherapy records from AB Health Services. Proportions of patients receiving chemotherapy, ICU admission, or >1 ED visit in the last 30 days of life (DOL) in WW and AB were determined among all patients and those ≥65 years and compared using two sample z-test with two-tailed hypothesis (α=0.006 after Bonferroni correction).

Results: 7859 AB and 3767 WW patients met study inclusion criteria. Median age was 76 (IQR 66-83) and 79 (IQR 71-86) for AB and WW, respectively; 78% and 85% were over age 65, 33% and 59% with ≥2 Charlson Comorbidity Score. Cancer distribution was 33% (AB) and 54% (WW) non-Hodgkin lymphoma, 14% (AB) and 20% (WW) myeloma and 27% (AB) and 19% (AB) leukemia. Table 1 shows utilization of chemotherapy, >1 ED visits and ICU admissions in AB and WW for all patients and Table 2 in those ≥65 years. More patients in WW vs AB were treated with chemotherapy (21% WW vs 7% AB) and admitted to ICU (34% WW vs 9% AB) in the last 30 DOL, whereas multiple ED visits were more similar between WW and AB (17% vs 19%, respectively). Similarly, among patients ≥65 years, chemotherapy use and ICU admissions were higher in WW. The same was true for patients in the last 60 and 90 DOL.

Conclusions: Similar to what was noted in solid tumor patients, intensity of healthcare use at EOL is greater in WW vs AB for patients with hematological malignancies. However, ≥1 ED visits were similar between populations. Further work is needed to understand drivers of high intensity healthcare use and identify interventions to minimize low value care at EOL.

Disclosures

Khaki: Merck: Other: share/stockholder; Pfizer: Other: share/stockholder. Ramsey:AstraZeneca: Other: Personal Fees. Cowan:Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Research Funding.
Increasing Doses of Anticoagulation Are Associated with Improved Survival in Hospitalized COVID-19 Patients
Authors: Ionescu Filip , Nair Girish B , Petrescu Ioana , Konde Anish S , Zimmer Markie Sue , Anusim Nwabundo , Jindal Vishal , Gaikazian Susanna , Anderson Joseph , Stender Michael , Huben Marianne Terese , Jaiyesimi Ishmael
Published: February 2021

Background: Hypercoagulability may contribute to COVID-19 pathogenicity. Evidence comparing clinical outcomes among patients with COVID-19 receiving therapeutic compared to prophylactic dose anticoagulation is limited. We evaluated whether therapeutic anticoagulation (tAC) is associated with improved survival compared to prophylactic (pAC) and no anticoagulation (AC) in hospitalized COVID-19 patients.

Methods: This was a retrospective, multi-center cohort study of consecutive COVID-19 patients admitted between March 13th, 2020 and May 5th, 2020 to eight hospitals within a large academic system in Southeast Michigan, USA. Participants were assigned to three groups based on whether they received no AC, pAC throughout most of their hospitalization, or at least 3 days of tAC. Major bleeding was defined as transfusion of five or more units of packed red blood cells within 48 hours regardless of hemoglobin level, hemoglobin < 7g/dL and any red blood cell transfusion or a diagnosis code for major bleeding during the hospitalization or radiological evidence of intracranial hemorrhage

Results: A total of 3480 patients were included (mean age, 64.5 years [17.0]; 51.5% female; 52.1% black and 40.6% white). 18.5% (n=642) were treated in the intensive care unit (ICU). 60.9% received pAC (n=2121), 28.7% received at least 3 days of tAC (n=998), and 10.4% (n=361) did not receive AC. Propensity score (PS) weighted Kaplan-Meier plot demonstrated a statistical difference in the 25-day survival probability in the tAC group compared to the pAC group (57.5% vs 50.7%, Figure). In a PS weighted multivariate proportional hazards model adjusting for age, body mass index and ICU status, AC was associated with a reduced risk of death at both prophylactic (hazard ratio [HR] 0.35 [95% confidence interval {CI} 0.22-0.54]) and therapeutic doses (HR 0.14 [95% CI 0.05-0.23]) compared to no AC. Major bleeding occurred more frequently among tAC patients (81 [8.1%]) compared to those who received no AC (20 [5.5%]) or pAC (46 [2.2%]).

Conclusions : Higher doses of AC are associated with lower mortality in hospitalized COVID-19 patients. The lowest hazard ratio was observed in ICU patients, but risk was also significantly lower in non-ICU hospitalized patients. Bleeding occurred more frequently with higher doses of anticoagulation. Ongoing randomized trials are warranted to prospectively evaluate efficacy and risk of tAC in patients with COVID-19.

Figure

Disclosures

No relevant conflicts of interest to declare.
Role of Hypercoagulable Studies in Cryptogenic Stroke: A Retrospective Study
Authors: Prakash Amulya , Korem Sindhuja , Inkollu Sindhura , Gandhi Haresh , Iqbal Farrukh , Abaskhroun Peter , Pernia Julio , Rojas Juan , Singh Vinit , Du Doantrang T.
Published: February 2021

Introduction:

Hypercoagulable states are recognized, although uncommon, etiology of ischemic stroke especially in young adults under the age of 40 and children. Currently, there are no specific guidelines related to screening patients for inherited thrombophilia who are diagnosed with ischemic stroke without any identifiable risk factors. Typically, patients to be screened for thrombophilia will have prior unexplained thromboembolic events. We evaluated the association between thrombophilia and cryptogenic stroke and the role of serologic and genetic testing to establish the diagnosis.

Material and methods:

We performed a retrospective study through a review of EHR of patients diagnosed with ischemic stroke at our hospital between 2015- 2019 with laboratory testing for thrombophilia. The primary outcome was to identify any positive association between thrombophilia and cryptogenic stroke. The secondary outcome was to identify any change in clinical management based on thrombophilia testing results.

Results:

Among 35 patients included, who had an average age of 58.5 years ± 16.37 years with 36.6% under the age of 55 and 63.3% above the age of 55. Sex distribution was 40% female and 60%, male. Of 35 patients who had thrombophilia studies ordered, 9 patients had at least one positive thrombophilia test identified but none of them had any resultant change in management. 2 patients had protein C deficiency, 3 patients had protein S deficiency and 4 patients had antithrombin III deficiency, however, they were measured during the acute phase and were not repeated as an outpatient. None of the patients were found to have any Factor V and PT gene G20210A gene mutation. Lupus anticoagulant, antiphospholipid antibodies, homocysteine level were not uniformly tested.

Conclusion:

Only 8% of all patients who had thrombophilia testing had at least one positive study with no change in clinical management. We concluded that there is a poor correlation between inherited thrombophilia and cryptogenic stroke. The majority of our patients who had worked up done were above the age of 55 years who didn't display any symptom of thrombophilia previously. It raises a question of reflexive and inappropriate testing in the absence of clear guidelines for thrombophilia workup in the setting of cryptogenic stroke.

Disclosures

No relevant conflicts of interest to declare.
Obesity-Driven Acceleration of Acute Promyelocytic Leukemia Development in Mice with Inserted PML-RARa
Authors: Kincaid John W.R. , Ribeiro Susan Pereira , Sanchez Gabriela , Hill-Baskin Anne , Berger Nathan A.
Published: February 2021

While a number of solid tumors are identified as obesity-associated cancers, multiple myeloma and acute promyelocytic leukemia (APL) are the only hematologic malignancies included in this category. APL is a highly treatable form of AML characterized by maturation arrest at the promyelocyte stage, and frequent cures with combined ATRA and Arsenic Trioxide therapy. APL is initiated by a chromosomal translocation that causes the fusion of thePMLandRARAgenes, leading to the production of PML-RARA protein. To determine if obesity accelerates the development of APL, we used a genetically-engineered knock-in model in which human PML-RARA cDNA was inserted into the 5' untranslated region of the murine cathepsin G gene (Ctsg), which targets expression to early myeloid progenitor cells. This knock-in transgene was extensively backcrossed (>20 generations) into the C57BL/6J (B6) genetic background, which has been consistently shown to render mice susceptible to diet-induced obesity.Ctsg-PML-RARA mice developed on the B6 background generate a lethal APL-like leukemia with a latency of 8-12 months, and a penetrance of about 60%, as cooperating mutations occur and cause clinical disease.

We placed cohorts of B6.Ctsg-PML-RARA heterozygous (mCG+/PR) and wild-type (WT) mice, genotyped by PCR, on high-fat (HFD) [57% coconut oil fat] and low-fat (LFD) [10% coconut oil fat] diets, collecting peripheral blood via the retro- orbital sinus at 30 day intervals and performing automated blood counts to observe temporal associations in disease development. HFD feeding significantly accelerated the development of APL in mCG+/PR mice, leading to anemia, thrombocytopenia, leukocytosis of the granulocyte series, and splenomegaly. Survival rate reduction demonstrated sexual-dimorphism, with male HFD-fed mCG+/PR mice displaying a median leukemia-free survival time of 211 days compared to 266 days in the female HFD-fed mCG+/PR cohort. In contrast, LFD-fed mCG+/PR male mice showed a median survival time of 318 days, whereas none of LFD-fed mCG+/PR female group nor any of the WT groups on HFD or LFD have reached median survival as of 325 days. Moreover, no signs of leukemia were observed in either HFD- and LFD-fed WT groups, indicating that adiposity alone had no leukemogenic effect. These studies clearly demonstrate that obesity accelerates leukemogenesis in theCtsg-PML-RARA mouse model of acute promyelocytic leukemia.

High density flow cytometry will be applied in the bone marrow of the different groups to evaluate the modulation of multiple hematopoietic cell lineages and cell surface markers.

Disclosures

No relevant conflicts of interest to declare.
Prdm16 Is a Critical Regulator of Adult Long-Term Hematopoietic Stem Cell Quiescence
Authors: Gudmundsson Kristbjorn Orri , Du Yang , Nguyen Nhu , Oakley Kevin , Han Yufen , Gudmundsdottir Bjorg , Liu Pentao , Tessarollo Lino , Jenkins Nancy , Copeland Neal
Published: February 2021

Regulation of quiescence is critical for the maintenance of adult hematopoietic stem cells (HSCs). PRDM16 encodes a zinc-finger transcription factor homologous to MECOM and was first cloned from chromosome translocations in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients. Disruption of Prdm16 during mouse embryonic development has been shown to cause a profound loss of fetal liver HSCs; however, the underlying mechanisms and the function of Prdm16 in adult HSCs remain unclear. Using a novel Prdm16 conditional knockout mouse model, we show that Prdm16 deletion in adult mouse hematopoietic system have a less severe effect on HSCs, causing a gradual decline in adult HSC numbers and a concomitant increase in the multipotent progenitor (MPP) compartment. Prdm16 deletion in the hematopoietic system following transplantation produced the same phenotype indicating that the defect is intrinsic to adult HSCs. This HSC loss was also exacerbated by stress induced by 5-FU injections. Annexin V staining showed no difference in apoptosis between wild type and knockout adult long-term HSCs (LT-HSCs). In contrast, BrdU analysis revealed that loss of Prdm16 significantly increases cycling of LT-HSCs with majority of the cells found in the S to G2/M phase. Consistently, RNA-seq analysis of mouse LT-HSCs with and without Prdm16 deletion showed that Prdm16 loss induced a significant decrease in the expression of several known cell cycle regulators of HSCs. Two such genes were further identified as direct targets of Prdm16. Our results suggest that Prdm16 preserves the function of adult LT-HSCs by promoting their quiescence.

Disclosures

No relevant conflicts of interest to declare.
Single-Cell Transcriptome of Early Hematopoiesis Guides Arterial Endothelium-Promoted Functional T Cell Generation from Human Pluripotent Stem Cells
Authors: Shen Jun , Xu Yingxi , Zhang Shuo , Lyu Shuzhen , Wang Zack , Wang Min , Li Xin , Cheng Tao
Published: February 2021

Human pluripotent stem cells (hPSCs) provide a powerful platform for generating functional hematopoietic cells for blood disease modeling and therapeutic testing. However, the quantity and quality of hPSC-derived blood cells remain to be improved. Here, by performing extensive single-cell transcriptomic analyses to map fate choices and gene expression programs during hematopoietic differentiation of hPSCs, we construct the first hematopoietic landscape of hPSCs at the single-cell level and identify strategies to promote hematopoietic progenitor (HP) generation from hPSCs with functional T cell potential.

By focusing specifically on cell populations and molecular events involved in endothelial-to-hematopoietic transition (EHT), we compared the difference of early hematopoiesis between hPSCs and human embryos (Yang Zeng et al. Cell Research. 2019) and found aerobic metabolism was dysregulated during in-vitro-directed differentiation. The decreased oxygen metabolism program was further deciphered as a key molecular event occurred during the EHT. Providing hypoxia at the stage of EHT enhanced hematopoietic differentiation of hPSCs via specifying arterial programs, including arterial hemogenic endothelium (AHE) and arterial endothelium cells (AE).

To further determine the effect of AE on hematopoietic development, we isolated AE, venous endothelium and mesenchymal cells identified in our single-cell transcriptomic analyses and cocultured them with AHE respectively for HP generation. AE were finally validated as a critical regulator of definitive HP specification with more T cell potential. T cells generated from AE-primed HPs (AE-T) were highly functional and exhibited polyfunctional production of interferon (IFN)-γ, tumor necrosis factor alpha (TNF-α), and IL-2 in response to phorbol 12-myristate 13-acetate (PMA) and ionomycin. To further evaluate the function of AE-T, we engineered T cells with CD19-CAR. The in vitro cytotoxicity of CAR-engineered AE-T was performed both in CD19+ cell lines (Nalm-6 and Raji) and human primary B-ALL samples. The efficacy of CAR-engineered AE-T in vivo was evaluated in a mouse xenograft model inoculated intravenously with luciferase-expressing Nalm-6 cells. Similar to CD19 CAR-transduced peripheral blood T cells, the AE-T potently inhibited tumor growth both in vitro and in vivo.

Collectively, our study provides benchmark datasets to understand the origins of human hematopoiesis and presents an advance for guiding the generation of functional T cells in vitro for clinical applications.

Disclosures

No relevant conflicts of interest to declare.
Anti-Acute Monocytic Leukemia Activities of Selenium Nanoparticles Embedded in Nanotube Consisted of Triple-Helix β-D-Glucan
Authors: Chen Yanling , Lv Fengzhi , Luo Ziyi , Zhang Dongdong , Zhou Fuling
Published: February 2021

Acute monocytic leukemia (AML-M5) is a subtype of acute myeloid leukemia (AML) which has the characteristics of high degree of malignancy, prone to extramedullary infiltration, poor efficacy of conventional chemotherapy, easy recurrence, etc. Besides, chemotherapy has large side effects and high cost. Therefore, it is urgent to find natural, non-toxic and cheap drugs for the treatment of AML-M5.

Polysaccharide is a class of natural macromolecular substances with biological activities such as immune regulation, anti-tumor, anti-oxidation, anti-virus, and hypoglycemic activity. Selenium is a component of human erythrocyte glutathione peroxidase, it participates in the metabolism of peroxide and iodine in the body, regulates the level of iodine and free radicals in the organism, and can enhance the body's ability to prevent and resist diseases. LNT-Se has the activity of SeNPs and the physiological function of polysaccharide.Due to the self-assembly behavior of rigid triple helix β-glucan (LNT) extracted from Lentinus edodes in aqueous solution, Selenium nanoparticles (SeNPs) could be encapsulated in the cavities of hollow nanotubes consisted of LNT to form stable complexes (LNT-Se) with high dispersity and biocompatibility. It could significantly improve the safety, biocompatibility and anti-tumor activity of SeNPs, and had powerful applications in the field of nanomaterials.

In this study, we found that LNT-Se could inhibit the proliferation of AML-M5 cell lines such as THP-1, Molm-13, MV-4-11 and greatly promote the apoptosis of AML-M5 cell lines and M5 patient cells, and obviously block cells in the G2/M phase. It had little toxicity to normal cell lines, hematopoietic stem cells (HSC) and healthy human peripheral blood mononuclear cells (PBMC). Besides, we used a novel optofluidics chips wth diffused total internal reflection (TIR) method to capture single Molm-13 GFP + cell, and at the same time detected the signal intensity changes of GFP at different drug concentrations. At the single-cell level, We also observed the swelling, lysis and fluorescence intensity of the cells after treatment.

Therefore, it's a promising drug for the treatment of AML-M5. These findings indicate that LNT-Se inhibit theproliferation of leukemia cell and it can be a natural inducer for therapy of AML.

Disclosures

No relevant conflicts of interest to declare.