bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of tire slip losses on the energy demand and fuel consumption of a light-duty vehicle
Authors: d’Ambrosio Stefano , Vitolo Roberto
Published: November 2021

The contribution of the tire-road slip of traction wheels to the total resistance opposing the motion of a light-duty commercial vehicle has been investigated through the simulation of several homologation and custom driving cycles. The calculation of the contribution of the tire slip losses was based on the estimation of the longitudinal tire slip, by means of Pacejka’s MF5.2 tire model. In this work, the computational steps required to evaluate this contribution were implemented in a previously developed fuel consumption simulation tool. Simulations were performed under several vehicle loading conditions and tire inflation pressures on traction and non-traction wheels, and considering different tire-road adherence conditions, in order to obtain a characterization of the tire slip losses over a wide range of working conditions. An analysis of the results shows that, although the contribution of tire slip losses to the total vehicle energy demand and fuel consumption may be relevant – especially under low-load, low adherence conditions – the sensitivity of the average on-cycle vehicle energy/fuel consumption to changes in the tire inflation pressure is only affected slightly by tire slip losses. Therefore, tire slip losses can be neglected in practice, when the aim of a simulation is to optimize the tire pressure to achieve average vehicle working conditions over a driving cycle.
Causal simulation experiments: Lessons from bias amplification
Authors: Stokes Tyrel , Steele Russell , Shrier Ian
Published: November 2021

Recent theoretical work in causal inference has explored an important class of variables which, when conditioned on, may further amplify existing unmeasured confounding bias (bias amplification). Despite this theoretical work, existing simulations of bias amplification in clinical settings have suggested bias amplification may not be as important in many practical cases as suggested in the theoretical literature. We resolve this tension by using tools from the semi-parametric regression literature leading to a general characterization in terms of the geometry of OLS estimators which allows us to extend current results to a larger class of DAGs, functional forms, and distributional assumptions. We further use these results to understand the limitations of current simulation approaches and to propose a new framework for performing causal simulation experiments to compare estimators. We then evaluate the challenges and benefits of extending this simulation approach to the context of a real clinical data set with a binary treatment, laying the groundwork for a principled approach to sensitivity analysis for bias amplification in the presence of unmeasured confounding.
Unpacking the Role of Feedback in Virtual Team Effectiveness
Authors: Handke Lisa , Klonek Florian , O’Neill Thomas A. , Kerschreiter Rudolf
Published: November 2021

Feedback is a cornerstone of human development. Not surprisingly, it plays a vital role in team development. However, the literature examining the specific role of feedback in virtual team effectiveness remains scattered. To improve our understanding of feedback in virtual teams, we identified 59 studies that examine how different feedback characteristics (content, source, and level) impact virtual team effectiveness. Our findings suggest that virtual teams benefit particularly from feedback that (a) combines performance-related information with information on team processes and/or psychological states, (b) stems from an objective source, and (c) targets the team as a whole. By integrating the existing knowledge, we point researchers in the direction of the most pressing research needs, as well as the practices that are most likely to pay off when designing feedback interventions in virtual teams.
Integrating Validity Evidence to Revise a Child Abuse Knowledge Test for Early Childhood Education Providers: A Mixed Methods Approach
Authors: Panlilio Carlomagno C. , Famularo Lisa , Masters Jessica , Dore Sarah , Verdiglione Nicole , Yang Chengwu , Lehman Erik , Hamm Robert M. , Fiene Richard , Bard David , Kapp Karl M. , Levi Benjamin H.
Published: November 2021

Knowledge tests used to evaluate child protection training program effectiveness for early childhood education providers may suffer from threats to construct validity given the contextual variability inherent within state-specific regulations around mandated reporting requirements. Unfortunately, guidance on instrument revision that accounts for such state-specific mandated reporting requirements is lacking across research on evaluation practices. This study, therefore, explored how collection and integration of validity evidence using a mixed methods framework can guide the instrument revision process to arrive at a more valid program outcome measure.
High Strength Wastewater Reclamation Capacity of Vetiver Grass in Tropics: The Case of Ethiopia
Authors: Aregu Mekonnen Birhanie , Soboksa Negasa Eshete , Kanno Girum Gebremeskel
Published: November 2021

It is generally accepted that industrial wastewater like tannery effluent is high strength wastewater. The aim of this study was to examine the capacity of Vetiver grass for the treatment of high strength wastewater in a constructed wetland. Two constructed wetland beds were designed and one of them was not planted used as a control group. The grass was planted with 20 cm by 20 cm distance from each seedling. The biometric characteristics of Vetiver grass was evaluated by taking randomly selected clusters of the grass. The concentration of chromium in the extract of parts of the grass was determined by atomic absorption spectrophotometer. The Chromium bioaccumulation and Translocation factor was estimated. Composite samples before and after treatment of 4 different hydraulic retention time was collected. The physiochemical analysis of the wastewater has been carried out. The constructed wetland bed with Vetiver grass performed that, BOD, COD, NH4-N, NO3-N, TN, PO4-P, and TP were reduced at the retention time of 9 days by 91.9%, 96.3%, 62%, 86%, 88.7%, 96.3%, and 92.2% respectively. Chromium was also reduced by 97% at retention time of both 7 and 9 days over the planted bed. The bed with plant performs significantly better than without plant at P-value <.01. Therefore, Vetiver grass has a capacity to reclaim high strength industrial wastewater in tropical areas.
Handwashing Practice and Its Predictors Among Mothers of Children Aged 0 to 23 Months in South Ethiopia: Community Based Cross-Sectional Study
Authors: Mekonen Temesgen , Admasie Amha , Leka Yakob Lencha , Darota Damene , Feleke Fentaw Wassie
Published: November 2021

Background:

Maternal handwashing practice is an important measure to prevent the spreading of childhood disease. Handwashing is still being practiced to a very low extent especially at critical times since the global prevalence of handwashing with soap was estimated at 19% by a systematic review after compiling 42 studies all over the world.

Objective:

To assess the handwashing practice and its predictors among mothers of children aged 0 to 23 months in Mareka District, south Ethiopia, 2020.

Method:

A community-based cross-sectional study was conducted with a multistage sampling technique on 520 women having children aged 0 to 23 months in Mareka District. Data were collected by using interviewer-administered pre-tested structured questionnaires. Data were checked for completeness and entered into Epi data entry 4.6.2. The data were exported into SPSS version 22 for analysis with multivariate logistic regression analysis at P < .05.

Result:

Mothers wash their hands with soap and water after visiting the latrine (27.1%), after cleaning the child’s bottom (28.5%), before cooking (6.2%), before eating (6.9%), and before feeding the child (21.2%). The most important predictors were water availability near the handwashing location with an adjusted odds ratio (AOR) 5.26 (95% CI 1.99-13.69) and soap availability near the handwashing location with AOR 0.40 (95% CI 0.18-0.89) for good handwashing practice.

Conclusion:

The handwashing practice at critical times was low. The presences of water and soap near the handwashing location were the most important predictors. It is necessary to increase the provision of both water and soap near the handwashing location for improving handwashing with soap and water at key times.
Social influence bias in ratings: A field experiment in the hospitality sector
Authors: Cicognani Simona , Figini Paolo , Magnani Marco
Published: November 2021

We investigate the empirical phenomenon of rating bubbles, that is, the presence of a disproportionate number of extremely positive ratings in user-generated content websites. We test whether customers are influenced by prior ratings when evaluating their stay at a hotel through a field experiment that exogenously manipulates information disclosure. Results show the presence of (asymmetric) social influence bias (SIB): access to information on prior ratings that are above the average positively influences the consumers’ rating of the hotel. In contrast, information on ratings that are below the average does not affect reviewers. Furthermore, customers who have never been to the hotel before the intervention are more susceptible to prior ratings than customers who have repeatedly been to the hotel before. Finally, customers who are not used to writing online reviews are more prone to SIB than customers who frequently write online reviews. Our findings suggest that online rating systems should be adjusted to mitigate this bias, especially as these platforms become more relevant and widespread in the hospitality sector.
A bottom-up method for remixing narratives for virtual heritage experiences
Authors: Basaraba Nicole
Published: November 2021

Considering the impacts COVID-19 has had on travel and many economies, developing virtual experiences that are well-received by different publics has become even more prominent. This paper shows how a multimodal discourse analysis can be used to as a bottom-up approach to identifying narrative themes that can be used in virtual experiences for cultural heritage sites. A case study on 11 UNESCO World Heritage Australian Convict Sites shows how diverse sources of user-generated content, tourism marketing materials and historical information can be analysed and then remixed into a virtual tour of the sites in the form of an interactive web documentary (iDoc). Although this case study involved a total of seven narrative development phases, this paper focuses on two phases, namely how the user model and content model were determined. These models were later used to develop the resulting iDoc prototype. The user model focused on the prospective audience of cultural heritage tourists, and a content model of narrative themes for the iDoc was developed through a multimodal discourse analysis. This bottom-up approach of analysing existing cultural data allows for the discovery of the prospective audiences’ interests as well as narrative themes that can be included in virtual heritage experiences. It also provides a new creative methodology that can prevent issues that may arise with top-down narratives that focus too heavily on one institutional perspective or national narrative and lack direct engagement with or understanding of today’s publics.
Is eliciting dependency worth the effort? A study for the multivariate Poisson-Gamma probability model
Authors: Schwarzenegger Rafael , Quigley John , Walls Lesley
Published: November 2021

We examine whether it is worthwhile eliciting subjective judgements to account for dependency in a multivariate Poisson-Gamma probability model. The challenge of estimating reliability during product design motivated the choice of model class. For the multivariate Poisson-Gamma model we adopt an empirical Bayes methodology to present an estimator with improved accuracy. A simulation study investigates the estimation error of this estimator for different degrees of dependency and examines the impact of dependency being mis-specified when assessed by subjective judgement. Our theoretical and simulation findings give analysts insights about the value of eliciting dependency.
Examining conspiracy beliefs and COVID-19 in four countries: The role of disgust towards the political system and implications for prosocial behavior
Authors: Moon Chanki , Travaglino Giovanni A.
Published: November 2021

Since late 2019, the coronavirus SARS-COV-2 responsible for the COVID-19 disease has continued to spread across different regions of the world. As a result, governments have been implementing measures for controlling the disease which rely on people's cooperation. In this research, we considered predictors and implications of people's beliefs that they “haven’t been told the ‘whole story’ about COVID-19.” Specifically, we examined the role of disgust towards the political system in predicting conspiratorial tendencies across four countries, in Europe (Italy and the UK), North America (the USA), and Asia (South Korea). In addition, we investigated the implications of conspiratorial beliefs for individuals’ intentions to engage in prosocial cooperative behavior. In line with the idea that feelings of disgust towards the political system may indicate that people perceive the system as violating core norms, results showed that disgust was associated with stronger conspiratorial tendencies. Individuals’ conspiratorial tendencies were in turn associated with lower intentions to help others during the pandemic. Results were broadly consistent across the countries tested. Directions for future research are discussed.
Spatial distribution, prevalence, and determinants of unintended pregnancy among youth (15–24) in Ethiopia: Further analysis of Ethiopia Demographic and Health Survey
Authors: Kebede Sewnet Adem , Tusa Biruk Shalmeno , Weldesenbet Adisu Birhanu
Published: November 2021

Objectives:

This study aimed to determine the spatial distribution, prevalence, and determinant factors of unintended pregnancy among youth in Ethiopia.

Methods:

Using the Ethiopian Demographic and Health Survey 2016, a total of 2446 pregnant women aged 15–24 in the last 5 years, including current pregnancy, were included in the study. The unintended pregnancy data were spatially visualized using coordinates for each respondent in the survey using ArcGIS 10.3. The Bernoulli model was used to identify the presence of purely spatial unintended pregnancy cluster using SaTScan software. Logistic regression analysis was fitted to determine factors associated with unintended pregnancy among youth.

Results:

Unintended pregnancy among youth had spatial variation across the country. Among youth, 20.5% (confidence interval: (19.0, 22.2)) of pregnancies were estimated to be unintended. Spatial scan statistics identified 72 primary clusters (log-likelihood ratio of 37.6, at p < 0.001) which were located in Addis Ababa, southern part of Amhara, northwest of Oromia and northeast of Southern Nations, Nationalities and Peoples Region. Age, region, marital status, occupation, sex of household head, and number of household members were the determinant factors of unintended pregnancy among youth in Ethiopia.

Conclusion:

The distribution of unintended pregnancy among youth in Ethiopia was nonrandom. Unintended pregnancy prevention strategies among youth need to be targeted on the identified factors. Hence, we recommend creating awareness on sexual and reproductive health rights with special priority to the identified hotspot areas (Amhara, Addis Ababa, Gambella, Northern part of Southern Nations, Nationalities and Peoples Region, and northwest of Oromia region) to reduce unintended pregnancy.
Entrepreneurial Intention in Higher Vocational Education: An Empirically-Based Model With Implications for the Entrepreneurial Community
Authors: Li Zheng , Islam A. Y. M. Atiquil
Published: November 2021

This study explores how entrepreneurship education and government policies influence the entrepreneurial intention of students receiving higher vocational education. It employs an empirically-based model that tests the effects of perceived entrepreneurial education and perceived entrepreneurial policy on entrepreneurial self-efficacy and entrepreneurial intention. This study also analyzes the moderating effect of gender. The model was constructed based on the Theory of Reasoned Action. A total sample of 462 Chinese students from public and private higher vocational colleges were randomly selected to participate in this study, and their responses were analyzed using structural equation modeling. The results of the research model showed that perceived entrepreneurial education and policy had positive direct influences on entrepreneurial self-efficacy and intention, respectively. Subsequently, students’ entrepreneurial self-efficacy had a direct influence on their entrepreneurial intention. On the other hand, perceived entrepreneurial education and policy had multiple indirect influences on entrepreneurial intention mediated by entrepreneurial self-efficacy in higher vocational education. The findings also showed that gender did not significantly moderate the above direct and indirect causal relationships among the dimensions of the research model. Some implications for building better entrepreneurial community are provided. These include enabling students to obtain knowledge that is closely related to practice and to perceive the value of entrepreneurship education by creating participatory projects and teaching methods, issuing policies that college students care most about, proactively informing students about policy content in a clear and concise way, and fully considering the side effects of government policies and the compatibility among different kinds of policies.
Multi-angle and nonuniform ground motions on cable-stayed bridges
Authors: Efthymiou Eleftheria , Camara Alfredo
Published: November 2021

The definition of the spatial variability of the ground motion (SVGM) is a complex and multi-parametric problem. Its effect on the seismic response of cable-stayed bridges is important, yet not entirely understood to date. This work examines the effect of the SVGM on the seismic response of cable-stayed bridges by means of the time delay of the ground motion at different supports, the loss of coherency of the seismic waves, and the incidence angle of the seismic waves. The focus herein is the effect of the SVGM on cable-stayed bridges with various configurations in terms of their length and of design parameters such as the pylon shape and the pylon–cable system configuration. The aim of this article is to provide general conclusions that are applicable to a wide range of canonical cable-stayed bridges and to contribute to the ongoing effort to interpret and predict the effect of the SVGM in long structures. This work shows that the effect of the SVGM on the seismic response of cable-stayed bridges varies depending on the pylon shape, height, and section dimensions; on the cable-system configuration; and on the response quantity of interest. Furthermore, the earthquake incidence angle defines whether the SVGM is important to the seismic response of the cable-stayed bridges. It is also confirmed that the SVGM excites vibration modes of the bridges that do not contribute to their seismic response when identical support motion is considered.
Dose of Deferasirox Correlates with Effects but Is Different in Low-Risk Myelodysplastic Syndrome and Aplastic Anemia
Authors: Zhang Ruoxi , Wang Zhao , Han Bing
Published: November 2021

Backgrou n d : Patients with low-risk myelodysplastic syndrome (MDS) and aplastic anemia (AA) often need transfusions, which may accelerate the iron overload. The aim of this study was to evaluate the efficacy, safety and dose-effect relation of deferasirox (DFX) for patients with low-risk MDS and AA who were refractory to regular treatment in the real-world setting.

M ethods: This was a retrospective study. Patients with low-risk MDS or AA who failed to standard treatments and were transfusion-dependent were enrolled. DFX was given as the only treatment apart from transfusion. Patients were recorded for their medical history, laboratory tests, nuclear magnetic resonance (MRI), echocardiography and calculated for their overall survival (OS). Dose-effect relations of DFX were evaluated after the first 6 months. Total annual exposure of DFX was calculated after 12 months, expressed as accumulated exposure time at dose of 20mg/kg/d.

R esults: Of the 112 patients finally enrolled, 61 (54.5%) were low-risk MDS and 51 (45.5%) were AA. The median age was 56 (10, 89) years and 52.7% patients were males. The minimum dose of DFX for significant SF decrease was 20 mg/kg/d at 6 months; and the minimum accumulation of DFX had to reach 9 months at 20 mg/kg/d to maintain the efficacy at the time of 12 months for patients with low-risk MDS (p＜0.050). Different from MDS, the minimum dose for significant SF decrease was 10 mg/kg/d at 6 months; and the minimum accumulation had to reach 3 months at 20 mg/kg/d to maintain the efficacy at the time of 12 months for patients with AA (p＜0.050). Meanwhile, with same dose of exposure, significant improvements in hematological parameters were also observed in AA, but no dose-effect relations were found in MDS. 62.3% MDS and 51.0% AA patients stopped transfusion in the next 6 months. Erythroid responders had lower SF than non-responders after 12 months of DFX, both for MDS and AA (p＜0.05). Lower alanine aminotransferase (ALT) and aspartate aminotransferase (AST) compared with baseline after 12 months of DFX were observed and longer exposure time correlated with lower ALT (p＜0.050). No significant changes in cardiac function, however. Similar side effects were found in MDS and AA, with gastrointestinal disorders and elevated serum creatinine the most common. Higher dose and longer exposure time of DFX correlated with longer overall survival, both for patients with MDS and AA (p＜0.050).

Conclusion: Although dose of DFX varies greatly in different individuals, a significant decrease in SF and an improvement of hematologic parameters, organ functions, or even overall survival can be achieved if the accumulate dose reaches a certain level. In that case, patients with low-risk MDS need higher dose than those with AA.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
PKM2 Inhibition Enhances the Sensitivity of Doxorubicin in ABC Diffuse Large B-Cell Lymphoma Cells
Authors: Zhan Minglang , Wei Xiaolei , Huang Weimin , Wei Yongqiang , Feng Ru
Published: November 2021

Background: Pyruvate kinase muscle isoenzyme 2 (PKM2) is a key enzyme in aerobic glycolysis and thought to contribute to cancer cell metabolic reprogramming and regulating the reactive oxygen species (ROS). Doxorubicin has been showed to induced activated-B cell types diffuse large B-cell lymphoma (ABC-DLBCL) cells death by ROS accumulation. Our purpose was to evaluate whether PKM2 inhibition could enhance the sensitivity of doxorubicin in ABC-DLBCL.

Methods: MTT assay was used to evaluate the proliferation of 2 ABC-DLBCL cell lines by treated with PKM2 inhibitor, PKM2 shRNA and doxorubicin. Apoptosis were detected by FCM after staining with Annexin V/SYTOX Green. Western Blot was used to evaluated the expression of PARP, Mcl1, Bcl2, Bax, Bim, p38 and JNK in ABC-DLBCL cells treated with PKM2 inhibition, PKM2 shRNA and doxorubicin.

Results: PKM2 expression was found in both U2932 and SuDHL2 cell lines. Both PKM2 inhibitor and doxorubicin could inhibit the proliferation and induce apoptosis in ABC-DLBCL cell lines. PKM2 inhibitor could enhance the doxorubicin-induced apoptosis. ShRNA was used to knock down the PKM2 expression in ABC-DLBCL cell lines and PKM2 KD cell lines were more sensitive to doxorubicin. PKM2 inhibition could increase the expression of cleaved PARP, Bax, Bim, p38 and JNK as well as decrease Mcl1 and Bcl2 expression

Conclusions: PKM2 inhibition could sensitize ABC-DLBCL cell lines to the cytotoxic effects of doxorubicin.

Key words: PKM2, Doxorubicin, Diffuse large B cell lymphoma

Disclosures

No relevant conflicts of interest to declare.
Triple Post-Transplant Cyclophosphamide (PTCY) Based Gvhd Prophylaxis for HLA Matched or HLA Haploidentical Transplants
Authors: Galli Eugenio , Metafuni Elisabetta , Giammarco Sabrina , Limongiello Maria Assunta , Innocenti Idanna , Autore Francesco , Laurenti Luca , Chiusolo Patrizia , Sorà Federica , Bacigalupo Andrea , Sica Simona
Published: November 2021

We report a retrospective analysis of 198 consecutive allogeneic stem cell transplant (HSCT) recipients, who received post transplant cyclophosphamide (PTCY), cyclosporine and mycophenolate mofetile as g raft-versus-host-disease (GVHD) prophylaxis. The donor was either HLA matched (n=78) (siblings -32- or unrelated -46) , or a haploidentical relative (HAPLO) (n=120). End points of the study were acute and chronic GVHD, transplant related mortality (TRM), relapse, disease free survival (DFS) and graft versus host and relapse free survival (GRFS). The two groups were comparable except for an older age (49 vs 56 years) in the haplo-HLA group. The diagnosis was mainly acute leukemia (57%), myelofibrosis (21%) or lymphoma (12%). Conditioning was myeloablative in 77% and 73% respectively (p=0.57).

Acute GVHD grade II-IV developed in 10% of the HLA matched transplants vs 27% in the HAPLO group (p=0.005). The latter also had more moderate-to-severe cGVHD (4% vs 23%, p<0.001). The cumulative incidence of transplant related mortality (TRM) at 1 year for the HLA matched vs HAPLO patients, was 10% vs 21% (p=0.04) (Fig.1) , with age over 60 years being the major negative predictor in multivariate analysis.

Relapse at 1 year was 24% for HLA matched vs 10% for HAPLO transplants (p=0.051) (Fig.1).

Disease free survival (DFS) at 1 year was 65% and 68% in matched and HAPLO patients, respectively (p=0.85) (Fig.1) and GRFS 55% vs 49% (p=0.18). In multivariate analysis, age over 60 years was the strongest predictor of DFS and GRFS (HR 1.73, p=0.03 and HR 1,65, p= 0.02).

In conclusion: when using the same triple PTCY based GVHD prophylaxis, HLA matched grafts are associated with significantly less acute and chronic GvHD, if compared with HAPLO grafts. There is a trend for reduced TRM at 1 year, especially in chronic myelo-lymphoproliferative disorders, and a trend for increased relapse, resulting in identical disease free survival.

Figure 1 Figure 1.

Disclosures

Laurenti: Gilead: Honoraria; Roche: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; BeiGene: Honoraria. Sica: Pfizer: Honoraria.
CD43 Expression Is an Adverse Prognostic Factor in Newly Diagnosed Multiple Myeloma
Authors: Ning Xueqin , Wei Yongqiang , Wei Xiaolei , Feng Ru , Chen Bingyuan , Yi Zhengshan , Zheng Zhongxin
Published: November 2021

CD43 expression is an adverse prognostic factor in newly diagnosed multiple myeloma

Introduction

CD43 is an abundant, heavily-glycosylated, cell surface protein expressed on bone marrow hematopoietic stem cells and most white blood cells. Previous studies have found that CD43 also expressed in some types of lymphoma cells and associated with adverse outcomes. However, the prognosis value of CD43 expression in multiple myeloma (MM) remain unknown.

Patients and Methods

A total of 109 MM patients, newly diagnosed in Nanfang Hospital of Southern Medical University from January 2017 to December 2019, were included in the study. CD43 was detected by flow cytometre as follows: 2 ml of heparin anticoagulated bone marrow was collected from the patients at the time of diagnosis，1×10 6 cells were detected, and a gate was set for identifying abnormal plasma cells characterized by CD138 expression and CD38. CD43 positive was defined as more than 20% of the plasma cells expressed CD43.

Results

A total of 109 patients with newly diagnosed MM were enrolled in the study, including 77 patients (70.6%) for CD43 positive and 32 patients (29.4%) for CD43 negative . The median age was 58 years, and the male-female ratio was 1.7:1. Patients in the CD43 positive group were more likely to have international staging system (ISS) stage III (67.5% VS 46.9%, P= 0.044), hemoglobin < 85g/L (64.9% VS 37.5%, P= 0.008), 13q deletion (31.4% VS 10.4%), and higher percentage of bone marrow monoclonal plasma cells detected by flow cytometry (5.5% VS 1.4%, P=0.003).

Most patients enrolled in the study received bortezomib-based treatment. The very good partial response (VGPR) or better rate after 4 induction cycles was significantly lower in the CD43 positive group than CD43 negative group (35.1% VS 56.3%, P=0.041), and the overall response rate (ORR) in the CD43 positive group was lower than that in CD43 negative group (75.3% VS 84.4%, P=0.299), but no significantly difference.

The median follow-up time was 22 months. Patients with CD43 positive had significantly lower PFS (median PFS 24 months VS not reached, P =0.012), and OS (median OS not reached, P = 0.023) than those with CD43 negative. Multivariate analysis indicated that CD43 positive expression was an independent poor risk factor for PFS (HR 2.517 95%CI 1.178-5.376, P = 0.017) and OS (HR 3.664 95%CI 1.100-12.075, P = 0.034).

Conclusion

Our study showed that CD43 expression was an adverse prognosis for multiple myeloma.

Disclosures

No relevant conflicts of interest to declare.
A Transgenic Mouse Model of Cardiac AL Amyloidosis
Authors: Martinez-Rivas Gemma , Ayala Maria , Bender Sebastien , Roussel Murielle , Jaccard Arnaud , Bridoux Frank , Sirac Christophe
Published: November 2021

Background: AL amyloidosis is the most frequent type of amyloidosis caused by the deposition in tissues of fibrillar aggregates composed of an abnormal immunoglobulin (Ig) light chain (LC) and leading to organ dysfunction. The most frequent and severe forms involve kidney and heart. Research on this disease suffers from the lack of reliable animal models, that could allow a better understanding of the disease and the design of new therapeutic strategies. In the present study, we aimed at reproducing AL amyloidosis in a mouse model.

Methods: We developed an original transgenic approach using an insertion of a human pathogenic LC gene in the endogenous mouse kappa locus, such as the LC is produced by the naturally Ig producing B and plasma cells. Then, to avoid the association of human LCs with endogenous murine HCs, we backcrossed this strain with the DH-LMP2A mice, characterized by a high number of plasma cells devoid of endogenous HC. This strategy leads to a production of the human free LC similar or higher than in patients and proved efficient to reproduce in mice several monoclonal gammopathies of clinical significance (MGCS) (Fig.1A).

Results: Despite strong LC production (Fig.1B), mice did not naturally develop AL amyloidosis. In vitro, the full length LC was resistant to amyloid formation at physiological conditions but the variable domain (IGLV6) showed high propensity to form fibrils. A single injection of amyloid fibrils and/or seeds, obtained from the variable domain (VL) of the human LC gene, led to amyloid deposits starting at 1 month post-injection, especially in the heart, spleen, liver and, to a lesser extent, in the kidney (Fig.1C). We confirmed that the deposits contain the full-length human LCs, which elongate VL fibrils in vivo (Fig.1D).

Conclusions: This is, to our knowledge, the first transgenic mouse model of AL amyloidosis closely reproducing human lesions, especially in heart. Further studies are needed to better understand the early biochemical events leading to AL amyloidosis in vivo, but this model already shows that a partial degradation of the LC is likely required to initiate amyloid fibrils and that once seeded, the full length LC can elongate these fibrils. This mouse model opens new perspectives to better understand the toxicity of amyloid LC, their involvements in different biological processes and organ dysfunction and of course, to test new therapeutic approaches.

Figure 1 Figure 1.

Disclosures

Roussel: Takeda: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; BMS: Honoraria; Amgen: Consultancy. Jaccard: Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Abbvie: Honoraria. Bridoux: Janssen: Consultancy; AstraZeneca: Consultancy, Speakers Bureau. Sirac: Attralus, Inc: Patents & Royalties, Research Funding.
Dynamic Assessment of Measurable Residual Disease in Favorable-Risk Acute Myeloid Leukemia in First Remission, Treatment, and Outcomes
Authors: Yu Sijian , Liu Qifa
Published: November 2021

Purpose:We aimed to investigate outcomes of different post-remission treatment (PRT) choices based on dynamic measurable residual disease (MRD) in favorable-risk AML (FR-AML).

Methods: Four hundred and three younger patients with FR-AML in first complete remission (CR1) were enrolled in this registry-based cohort study, including 173 who received chemotherapy (CMT), 92 autologous stem cell transplantation (auto-SCT), and 138 allogeneic SCT (allo-SCT). Subgroup analyses were performed based on dynamic MRD after the first, second, and third courses of chemotherapy. The primary endpoint was the 5-year overall survival (OS).

Results: For patients with negative MRD after 1 course of chemotherapy, comparable OS was observed among the CMT, auto-SCT and allo-SCT groups (p=.284). But CMT had better graft-versus-host-disease-free, relapse-free survival (GRFS) than allo-SCT (p=.027). For patients with negative MRD after 2 courses of chemotherapy, comparable OS was also observed among the three groups (p=.967). However, CMT and auto-SCT had better GRFS than allo-SCT (p=.045; p=.020, respectively). For patients with negative MRD after 3 courses of chemotherapy, allo-SCT had better disease-free-survival than CMT (p=.011). However, OS was comparable among the three groups (p=.177). For patients with persistently positive MRD after 3 courses of chemotherapy or recurrent MRD, allo-SCT had better OS than CMT and auto-SCT (p=.012; p=.046, respectively).

Conclusions: Dynamic MRD might improve therapy stratification and optimize PRT selection for FR-AML in CR1. CMT might be preferable for patients with negative MRD within 3 cycles of chemotherapy while allo-SCT for patients with persistently positive MRD after 3 cycles of chemotherapy and recurrent MRD.

Disclosures

No relevant conflicts of interest to declare.
Thromboembolic Complications in a Pediatric Patient Population: Treatment with Direct Oral Anticoagulants. Monitoring of Treatment Efficiency with D-Dimer Levels and Safety Profile By Thromboelastogram
Authors: Ameri Afshin , Anderson Courtney M , Smith Joetta H , Patel Julisa
Published: November 2021

Direct oral anticoagulants (DOAC) such as the thrombin inhibitor Dabigatran and the coagulation factor Xa inhibitors Apixaban and Rivaroxaban have been in clinical use for the past 5-6 years. Familiarity with their use in the general pediatric population with thrombosis secondary to inflammatory disorders and rheumatologic disease is currently not as prevalent due to the widespread more conventional anticoagulation practice with the fractionated heparins in particular Lovenox. In this report we would like to summarize our experience in a pediatric patient population ranging from 3- 17 years with thrombotic disease. Of 55 patients with various thrombotic events 16 patients were treated with DOAC. There were 5 patients who had underlying inflammatory disease including COVID. Thrombotic complications included arterial as well as venous thrombotic events. All patients had elevated D-Dimer levels ranging from 360-4000 mcg/ml on diagnosis and normalized with successful anticoagulation. All patients had resolution of thrombosis. Thrombelastogram (TEG) were obtained on isolated patients during therapy and were useful to balance anticoagulation to prevent hemorrhagic complications.

In conclusion, DOAC are a safe and effective alternative to LMW Heparin in pediatric patients with arterial or venous thrombosis. Monitoring should include determination of D-Dimer levels for efficacy of treatment and TEG in cases with arterial disease where bleeding may be a secondary complication of therapy.

Disclosures

No relevant conflicts of interest to declare.
Hemogen/BRG1 Cooperativity Is Required for Erythrocyte Maturation and Hemoglobin Production during Mammalian Erythropoiesis
Authors: Guo Xiang
Published: November 2021

Hemogen, also known as EDAG, is a hematopoietic tissue-specific gene that regulates the proliferation and differentiation of hematopoietic cells. However, the mechanism underlying hemogen function in erythropoiesis is unclear. We found that depletion of hemogen in human CD34 + erythroid progenitor cells and HUDEP2 cells significantly reduced the expression of genes associated with heme and hemoglobin synthesis, supporting a positive role of hemogen in erythroid maturation. In human K562 cells, hemogen antagonized the occupancy of co-repressors NuRD complex and facilitated LDB1 complex-mediated chromatin looping. Hemogen recruited SWI/SNF complex ATPase BRG1 as a co-activator to regulate nucleosome accessibility and H3K27ac enrichment for promoter and enhancer activity. To ask if hemogen/BRG1 cooperativity is conserved in mammalian systems, we generated hemogen KO/KI mice and investigated hemogen/BRG1 function in murine erythropoiesis. Loss of hemogen in E12.5-E16.5 impeded erythroid differentiation through reducing the production of mature erythroblasts. ChIP-seq in WT and hemogen KO animal revealed BRG1 is largely dependent on hemogen to occupy chromatin at erythroid gene promoters and enhancers. In summary, hemogen/BRG1 interaction in mammals is essential for erythroid maturation and hemoglobin production through its active role in promoter and enhancer activity and chromatin organization.

Disclosures

No relevant conflicts of interest to declare.
Definitive Hematopoietic Stem Cells Minimally Contribute to Embryonic Hematopoiesis
Authors: Ulloa Bianca A , Habbsa Samima S , Potts Kathryn S , Lewis Alana , McKinstry Mia , Payne Sara , Flores Julio , Nizhnik Anastasia , Feliz Norberto Maria , Mosimann Christian , Bowman Teresa V.
Published: November 2021

Definitive hematopoietic stem cells (HSCs) emerge in the embryo and sustain major adult hematopoietic lineages. Although their functional potential is detected by transplant, nascent HSC contribution during development is both unknown and difficult to address due to the overlapping emergence of HSC-independent progenitors-cells that lack the multipotency and/or longevity of HSCs but express many of the same markers. Using sorted hematopoietic stem and progenitor cells from zebrafish embryos, we performed single cell RNA sequencing to decipher HSC and HSC-independent progenitor heterogeneity during the time frame of their emergence and initial maturation. After batch correction and dimensional reduction, we identified seven distinct populations that are inferred from RNA velocity analysis to originate from pre-hemogenic endothelium and develop into three main differentiation trajectories. We also determined that HSCs can be distinguished from HSC-independent progenitors based on the temporal regulation and differential activity of the draculin (drl) promoter that was previously shown to mark adult-contributing HSCs. From these studies, we found that the drl promoter is active in HSCs and HSC-independent progenitors at 1-day post-fertilization (dpf) but becomes highly expressed primarily in HSCs by 2 dpf. We applied a drl:cre-ER T2 tamoxifen-inducible Cre-loxP lineage-tracing approach to selectively lineage trace HSCs starting at 2 dpf and track their myeloid and lymphoid contribution during larval development and adulthood. We determined that HSC-independent progenitors primarily contribute to developmental lymphomyelopoiesis with minimal HSC contribution until after 7 dpf. Consistent with this result, we demonstrated that although HSCs robustly regenerated after hematopoietic injury using a novel inducible larval HSC injury model, their depletion had almost no impact on lymphoid and myeloid cell numbers up to 7 dpf. These findings suggest that HSCs are not entirely dormant during development and that there exists an uncoupling of HSC self-renewal and differentiation in development. In conclusion, we determine that it is the HSC-independent progenitors, and not HSCs, that sustain embryonic and early larval lymphomyelopoiesis. Acquiring a greater understanding regarding developmental differences in progenitor and HSC specification and maturation will inform and improve the generation of functional HSCs from renewable pluripotent stem cells.

Disclosures

No relevant conflicts of interest to declare.
Chimerism of Blood T-Cells and Leukemia Lineage Cells Following Myeloablative Hematopoietic Cell Transplantation Is a Risk Factor for Relapse and Chronic Graft-Versus-Host Disease
Authors: Khanolkar Rutvij A. , Dharmani-Khan Poonam , Khan Faisal M , Storek Jan
Published: November 2021

Background: Mixed chimerism of blood leukemia lineage cells has been reported to be highly predictive of relapse (Mattsson J et al. Leukemia 2001), but the utility of T-cell chimerism is controversial.

Methods: Chimerism of T-cells (CD3 +) and leukemic lineage cells (CD13 +/CD33 + for myeloid malignancies and CD19 + for B-lymphoid malignancies) was measured in the peripheral blood for 600 hematopoietic cell transplant (HCT) recipients at 3-months post-transplant. Conditioning was myeloablative (fludarabine+busulfan+4GyTBI) and GVHD prophylaxis was with ATG+CsA+MTX.

Results: Mixed (<95% donor) chimerism was present in 6% of patients in the leukemic lineage and 16% of patients in T-cells. Compared to patients with complete chimerism (≥95%), mixed chimerism predicted a significantly greater incidence of relapse (52% vs. 27%, P=0.044), and surprisingly, also a greater incidence of cGVHD (43% vs. 23%, P=0.028). Patients with mixed leukemic lineage chimerism also had poorer cGRFS (7% vs. 39%, P<0.001) and OS (29% vs. 55%, P<0.001). Mixed T-cell chimerism predicted a significantly greater incidence of relapse (46% vs. 24%, P<0.001) and lower cGVHD incidence (9% vs. 31%), with no difference in cGRFS or OS. The sensitivity/specificity/positive predictive value (PPV)/negative predictive value (NPV) of mixed leukemic lineage and T-cell chimerism for relapse were 65%/55%/35%/81% and 66%/57%/60%/79%, respectively. Sensitivity/specificity/PPV/NPV was similarly poor for cGVHD. In patients with complete leukemic lineage chimerism at 3-months, a ≥5% drop in donor chimerism at any future timepoint had sensitivity/specificity/PPV/NPV of 82%/79%/79%/82% for subsequent relapse.

Conclusion: In the setting of myeloablative conditioning and ATG-based GVHD prophylaxis, mixed chimerism at 3-months post-transplant is a risk factor for subsequent relapse. However, the utility of these measurements in guiding medical interventions may be limited by insufficient predictive values. Nevertheless, patients with mixed chimerism may be candidates for more intensive surveillance.

Disclosures

Storek: Atara Biotherapeutics: Other: Site PI, Research Funding.
Risk of Venous Thromboembolism in Hospitalized Patients with Acute Ischemic Stroke Versus Other Neurological Conditions
Authors: Dhanesha Nirav , Garg Aayushi , Shaban Amir , Samaniego Edgar , Chauhan Anil K , Leira Enrique
Published: November 2021

Background

The mechanism of increased risk of venous thromboembolism (VTE) after acute ischemic stroke (AIS) is unclear. In this study, we aimed to evaluate the risk of VTE in hospitalizations due to AIS as compared to those due to non-vascular neurological conditions. We also aimed to assess any potential association between VTE risk and the use of intravenous thrombolysis (rtPA) among hospitalizations with AIS.

Methods

In this case-control study, data were obtained from the Nationwide Inpatient Sample 2016-2018. Propensity score matching was used to adjust for the baseline differences between the groups. Logistic regression analysis was used to compare the risk of VTE.

Results

We identified 1,541,685 hospitalizations due to AIS and 1,453,520 hospitalizations due to non-vascular neurological diagnoses that served as controls. After propensity score matching, 640,560 cases with AIS and corresponding well-matched controls were obtained. Hospitalizations due to AIS had higher odds of VTE as compared to the controls [odds ratio (OR) 1.50, 95% confidence interval (CI) 1.40-1.60, P<0.001]. Among hospitalizations with AIS, 184,065 (11.9%) got rtPA. The odds of VTE were lower among the AIS hospitalizations that received rtPA as compared to those that did not (OR 0.89, 95% CI 0.79-0.99, P0.035).

Conclusion

Hospitalizations due to AIS have a higher risk of VTE as compared to the non-vascular neurological controls. Among AIS cases, the risk of VTE is lower among patients treated with rtPA. These epidemiological findings support the hypothesis that the risk of VTE after AIS might be partly mediated by an intrinsic pro-coagulant state.

Disclosures

No relevant conflicts of interest to declare.
Idiopathic Erythrocytosis: Vascular Complications
Authors: Malas Abdullah , Bufalino Shams , Hancock Christie , Bitran Jacob D.
Published: November 2021

Idiopathic Erythrocytosis (IE) is a diagnosis of exclusion once primary and secondary causes have been eliminated; yet IE remains an enigmatic disorder. Published series from decades ago (Modan & Modan J. Hematol [1968] 14:375; Pearson & Wetherly-Mein, Clin.Lab Hematol. [1974] 1:189) have reported high rates of vascular complications (46%) and advise phlebotomy to keep the hematocrit to less than 45%. A More recent series (McMullin B.J. Hematol. [2005] 130:174) advise no need for phlebotomy in patients with no co-morbidities such as vascular disease, diabetes, or hypertension. In an attempt to determine some practice guidelines, we undertook a retrospective analysis of patients identified with IE within our practice and to quantify the rates of vascular complications, if any.

From January 1, 2016 to December 31. 2020 99 patients were referred because of erythrocytosis. Twenty of these 99 patients had polycythemia rubra vera and 77 had secondary erythrocytosis ( 64 males, 13 females, median age 61 years). Of these 77 patients with secondary erythrocytosis, 40 had obstructive sleep apnea, 10 men abused testosterone, and 1 patient each was either post splenectomy or post kidney transplant, 1 patient had a renal cell carcinoma, and 1 patient had familial erythrocytosis. Twenty patients were identified as having IE and all 20 did not have a JAK2 mutation. There 13 males and 7 females with a median age of 63 years (range 31-76). The median hemoglobin was 17.2 gm/dl and the median hematocrit was 51.2 (range 15.0 to 18.4 and 49% to 55% respectively). The median erythropoietin level was 9.9 mu/ml (range 5-38.5). Two of the 20 patients underwent therapeutic phlebotomy and developed no vascular complications. Eighteen patients were simply followed with phlebotomy despite having comorbidities of hypertension, increased BMI, type II diabetes, and none developed vascular complications. IE remain an enigmatic disorder that requires uniform diagnostic criteria as well as uniform practice guidelines; however, given our retrospective review, we do not believe that therapeutic phlebotomy is justified.

Disclosures

No relevant conflicts of interest to declare.