bluuebunny/crossref_metadata_2025 huggingface dataset:
Coaction Between Physical Activity and Fruit and Vegetable Intake in Racially Diverse, Obese Adults
Authors: Heredia Natalia I. , Fernandez Maria E. , van den Berg Alexandra E. , Durand Casey P. , Kohl Harold W. , Reininger Belinda M. , Hwang Kevin O. , McNeill Lorna H.
Published: November 2019

Purpose:

There is minimal understanding of the potential for coaction, defined as action on one behavior increasing the likelihood of taking action on another behavior, between physical activity (PA) and fruit and vegetable (FV) intake. The purpose of this study was to assess the bidirectional coaction between FV intake and PA, as well as self-efficacy for these behaviors, in a racially diverse sample of obese adults.

Design:

This is a secondary analysis using data collected from the Path to Health study, a randomized controlled trial. ClinicalTrials.gov Identifier: NCT03674229.

Sample:

Obese adults who completed baseline and 6-month follow-up assessments.

Measures:

For this study, data on FV intake, leisure time PA, and 7-day accelerometer data were analyzed at baseline and 6-month follow-up.

Analysis:

We interchanged modeling the FV intake and PA change variables as the independent and dependent variables. We conducted multiple imputation and both linear and multinomial regression.

Results:

The sample (n = 168) was 59% female and mainly split between white (42%) and African American (42%). Change in self-efficacy for PA was predictive of change in self-efficacy for FV intake and vice versa. When compared with participants with no change in FV intake, someone with a positive change in FV intake was more likely to have a positive change in self-reported PA (adjusted risk ratio [RR] = 6.72, 95% confidence interval [CI] = 1.69-26.68). Likewise, when compared with no change, participants with a positive change in self-reported PA were more likely to report a positive change in FV intake (adjusted RR = 6.79, 95% CI = 1.70-27.17).

Conclusion:

Findings suggest coaction between self-efficacy for FV intake and PA as well as between FV intake and PA. Coaction could be capitalized on to more effectively promote both energy-balance behaviors.
Challenges and a Super Power: How Medical Students Understand and Would Improve Health in Neoliberal Times
Authors: Sointu Eeva
Published: November 2019

Even though much research underscores the significance of social inequalities in illness, the health consequences of inequity tend to occupy a marginal position in medical education. Drawing on qualitative interviews with third and fourth year medical students, this paper explores how future doctors understand and would improve health in the United States. While participants with background in public health and policy understand that social inequalities shape health and access to care, many others emphasize individual behaviour and motivation as central to ill health. Emphasizing health behaviour aligns with biomedical understandings of disease, and also captures the hold of neoliberal values over ideas of health and illness. Focus on health behaviour also provides a means of ignoring the racist roots of enduring inequity that underlies much ill health. Making inequity more visible in medical education and practice necessitates recognizing the sway of neoliberal thought over common-sense ideas of health and illness.
How to Change the Weight of Rare Events in Decisions From Experience
Authors: Hotaling Jared M. , Jarvstad Andreas , Donkin Chris , Newell Ben R.
Published: November 2019

When people make risky choices, two kinds of information are crucial: outcome values and outcome probabilities. Here, we demonstrate that the juncture at which value and probability information is provided has a fundamental effect on choice. Across four experiments involving 489 participants, we compared two decision-making scenarios: one in which value information was revealed during sampling ( standard) and one in which value information was revealed after sampling ( value ignorance). On average, participants made riskier choices when value information was provided after sampling. Moreover, parameter estimates from a hierarchical Bayesian implementation of cumulative-prospect theory suggested that participants overweighted rare events when value information was absent during sampling but did not overweight such events in the standard condition. This suggests that the impact of rare events on choice relies crucially on the timing of probability and value integration. We provide paths toward mechanistic explanations of our results based on frameworks that assume different underlying cognitive architectures.
Parental involvement in Spanish schools: The role of Parents’ Associations (AMPAs)
Authors: Álvarez-Álvarez Carmen
Published: November 2019

The involvement of families in Spanish schools is a legally recognised right, a social demand, an educational need and a permanent challenge. However, there are limited opportunities for families to become engaged with schools in Spain. Their primary avenues for involvement are Parents’ Associations ( Asociaciones de Madres y Padres de Alumnos, known as AMPAs), but there has been little research on them to date. This article describes a qualitative study carried out in collaboration with 36 AMPAs from Spanish state schools, aimed at understanding how their members describe, interpret and assess their current situation. The findings showed that AMPAs foster activities to galvanise schools, but that they demanded increased decision-making powers, additional training and support in managing the association. It can be concluded that AMPAs are a means of promoting significant parental involvement, which merits further study and a wider social dissemination.
Acceptance of illness mediate the effects of health literacy on self-management behaviour
Authors: Qiu Chen , Zhang Xiaonan , Zang Xiaoying , Zhao Yue
Published: November 2019

Background:

Self-management is crucial for blood pressure control and subsequent disease prevention. Health literacy and acceptance of illness may contribute to self-management behaviour; in addition, acceptance of illness may mediate the effects of health literacy on self-management behaviour among patients with hypertension.

Objective:

The aims of the research were to examine whether health literacy and acceptance of illness were associated with both pharmacological and non-pharmacological management behaviour and examine the possible mediating effects of the acceptance of illness in patients with hypertension.

Methods:

Hierarchical regression analysis was conducted to analyse the relationships between health literacy, acceptance of illness, pharmacological and non-pharmacological management behaviours. Mediation effects were examined by the PROCESS macro.

Results:

This was a cross-sectional study. A total of 478 hypertensive patients completed measures of health literacy, acceptance of illness, self-management, social support, depression, physical function and demographic and clinical characteristics. Functional, communicative, critical health literacy and acceptance of illness showed positive associations to pharmacological and non-pharmacological management behaviour. Acceptance of illness mediated the relationships between three types of health literacy, pharmacological and non-pharmacological management but the effects size and pathway differed. In detail, functional health literacy influenced pharmacological and non-pharmacological management behaviour mainly by indirect effects mediated by the acceptance of illness, but communicative and critical health literacy influenced pharmacological and non-pharmacological management behaviour mainly by direct effects.

Conclusions:

Acceptance of illness mediated the relationships between three types of health literacy and self-management. Health literacy and acceptance of illness should be addressed when taking measures to improve patients’ self-management behaviour.
Natural Language Processing (NLP) in Qualitative Public Health Research: A Proof of Concept Study
Authors: Leeson William , Resnick Adam , Alexander Daniel , Rovers John
Published: November 2019

Qualitative data-analysis methods provide thick, rich descriptions of subjects’ thoughts, feelings, and lived experiences but may be time-consuming, labor-intensive, or prone to bias. Natural language processing (NLP) is a machine learning technique from computer science that uses algorithms to analyze textual data. NLP allows processing of large amounts of data almost instantaneously. As researchers become conversant with NLP, it is becoming more frequently employed outside of computer science and shows promise as a tool to analyze qualitative data in public health. This is a proof of concept paper to evaluate the potential of NLP to analyze qualitative data. Specifically, we ask if NLP can support conventional qualitative analysis, and if so, what its role is. We compared a qualitative method of open coding with two forms of NLP, Topic Modeling, and Word2Vec to analyze transcripts from interviews conducted in rural Belize querying men about their health needs. All three methods returned a series of terms that captured ideas and concepts in subjects’ responses to interview questions. Open coding returned 5–10 words or short phrases for each question. Topic Modeling returned a series of word-probability pairs that quantified how well a word captured the topic of a response. Word2Vec returned a list of words for each interview question ordered by which words were predicted to best capture the meaning of the passage. For most interview questions, all three methods returned conceptually similar results. NLP may be a useful adjunct to qualitative analysis. NLP may be performed after data have undergone open coding as a check on the accuracy of the codes. Alternatively, researchers can perform NLP prior to open coding and use the results to guide their creation of their codebook.
Disturbance rejection of a class of discrete-time multi-agent systems with pinning control
Authors: Zhu Qiuguo , Wu Jun , Xiong Rong
Published: November 2019

For discrete-time multi-agent systems with random switching nonlinear linking and exogenous disturbances, the disturbance rejection problem is studied and a sufficient condition is presented using the Lyapunov function. In an example of five agents with pinning control, the condition is adopted to optimize disturbance rejection. A numerical simulation shows that the optimization is effective.
Structural and mechanical properties of ternary MgCaSi phase: A study by density functional theory
Authors: Wu Rui , Wang Ya-Ping , Yang Yan , Luo Dong-Ming , Meng Hong , Ma Li , Tang Bi-Yu
Published: November 2019

The structural, elastic, and electronic properties of multi-performance ternary phase MgCaSi have been investigated by density functional theory. The present results show that MgCaSi is thermodynamically and mechanically stable. The derived elastic constants indicate that the c axis is the easiest to compress, followed by the a and b axes. The bulk, shear, and Young’s moduli of MgCaSi are higher than these of the mother phase Ca2Si, demonstrating that the hardness of MgCaSi has been favorably improved. The higher Debye temperature of MgCaSi also indicates stronger interatomic interactions and better thermal conductivity. Although MgCaSi exhibits less brittleness based on Pugh’s empirical formula, Poisson’s ratio, and the Cauchy pressure, orthorhombic MgCaSi possesses lower anisotropy than Ca2Si based on several criteria. To reveal the bonding nature of MgCaSi, the electronic structures are further investigated. It is found that the strong Si−Si bond plays a significant role for structural stability and elastic properties.
Sublumbar grass awns in two cats: ultrasonographic features and ultrasound-guided retrieval
Authors: Della Santa Daniele , Mannucci Tommaso , Busoni Giulia , Citi Simonetta
Published: November 2019

Case series summary

Two adult cats were evaluated because of recurrent abscesses of the right lateral thoracoabdominal wall. The abscesses receded with antibiotics but relapsed shortly after therapy interruption. Ultrasonography identified fluid-filled lesions containing linear, hyperechoic material with distal acoustic shadowing in the sublumbar region of both cats. Ultrasound-guided retrieval of grass awns was performed in both cases, which resulted in complete clinical resolution.

Relevance and novel information

While sublumbar abscesses in dogs are a relatively common disease, their occurrence in cats is much less common. To our knowledge, this is the first report describing the ultrasonographic features of sublumbar abscessation induced by foreign bodies and their ultrasound-guided retrieval in cats.
High-Frequency Sensorineural Hearing Loss Alters Cue-Weighting Strategies for Discriminating Stop Consonants in Noise
Authors: Varnet Léo , Langlet Chloé , Lorenzi Christian , Lazard Diane S. , Micheyl Christophe
Published: November 2019

There is increasing evidence that hearing-impaired (HI) individuals do not use the same listening strategies as normal-hearing (NH) individuals, even when wearing optimally fitted hearing aids. In this perspective, better characterization of individual perceptual strategies is an important step toward designing more effective speech-processing algorithms. Here, we describe two complementary approaches for (a) revealing the acoustic cues used by a participant in a /d/-/g/ categorization task in noise and (b) measuring the relative contributions of these cues to decision. These two approaches involve natural speech recordings altered by the addition of a “bump noise.” The bumps were narrowband bursts of noise localized on the spectrotemporal locations of the acoustic cues, allowing the experimenter to manipulate the consonant percept. The cue-weighting strategies were estimated for three groups of participants: 17 NH listeners, 18 HI listeners with high-frequency loss, and 15 HI listeners with flat loss. HI participants were provided with individual frequency-dependent amplification to compensate for their hearing loss. Although all listeners relied more heavily on the high-frequency cue than on the low-frequency cue, an important variability was observed in the individual weights, mostly explained by differences in internal noise. Individuals with high-frequency loss relied slightly less heavily on the high-frequency cue relative to the low-frequency cue, compared with NH individuals, suggesting a possible influence of supra-threshold deficits on cue-weighting strategies. Altogether, these results suggest a need for individually tailored speech-in-noise processing in hearing aids, if more effective speech discriminability in noise is to be achieved.
Becoming White Teachers: Symbolic Interactions and Racializing the Raceless Norm in Predominantly Black Schools
Authors: Bell Marcus
Published: November 2019

Under the banner of critical whiteness studies, scholars from across the disciplinary spectrum have spent the past several decades investigating whiteness and white racial identity, both in the United States and abroad. Of the numerous findings, perhaps none is more pervasive than that of white racelessness: the idea that whites do not see themselves in racial terms but instead think of themselves as just normal. This article complicates white racelessness by examining whiteness that is spatially situated as the racial minority. Using an inductive interview method, the author interviews 32 white teachers who currently work in urban, predominantly black schools. Despite previous socialization as the invisible norm, white teachers were effectively racialized by repeated and continuous symbolic interactions with black students and their families. Through a multistep and mutually reinforcing process, teachers went from thinking of themselves as the invisible, raceless norm to seeing themselves as the hypervisible, racial other. Findings also show that white teachers devised ways to navigate their personal racial identities, all while trying to remain effective teachers to nonwhite students. The experiential loss of white privilege is also discussed.
A Case of Melanoma-Associated Retinopathy, Uveitis, and Optic Neuritis Associated With Pembrolizumab, Managed With Topical, Intravitreal, and Intravenous Steroids
Authors: Xie Kate , Kong Christina , Mehta Mitul C.
Published: November 2019

Purpose:

We report a case of advanced metastatic cutaneous melanoma with melanoma-associated retinopathy and pembrolizumab-related panuveitis and optic neuritis.

Methods:

The patient’s condition was managed by systemic, topical, and intravitreal corticosteroids without discontinuing pembrolizumab.

Results:

After initiation of systemic and topical steroid treatment, optic nerve edema improved. He developed chronic uveitis with cystoid macular edema with improvement in symptoms with intravitreal dexamethasone implants. The patient demonstrated a decrease in all metastatic lesions and improvement in melanoma-associated retinopathy.

Conclusions:

The new checkpoint inhibitor class including pembrolizumab shows promise as a therapy for advanced metastatic melanoma in patients resistant to all other forms of chemotherapy. In general, immune-related adverse effects are responsive to steroid therapy. The trend for treatment of posterior uveitis due to pembrolizumab is to discontinue pembrolizumab. Our case suggests that even severe cases of uveitis may be sufficiently ameliorated by concurrent systemic, intravitreal, and topical therapy to allow continuation of treatment.
Structure and Function of ATP-Dependent Chromatin Remodeling Complexes in Human Cancer
Authors: Kadoch Cigall
Published: November 2019

Dr. Cigall Kadoch will discuss how recent exome-and genome-wide sequencing studies in human cancers have unmasked a striking frequency of mutations in the genes encoding subunits of the mammalian SWI/SNF (mSWI/SNF) family of ATP-dependent chromatin remodeling complexes. Her laboratory uses biochemistry, structural biology, systems biology, and genomics-based approaches to define the mechanisms of chromatin and gene regulation carried out by the mSWI/SNF family of chromatin regulators. Specifically, they have studied rare, genetically well-defined pediatric cancers including synovial sarcoma, Ewing sarcoma, malignant rhabdoid tumor and others, all of which involve mSWI/SNF complex perturbations as critical drivers of their oncogenic programs. These studies have informed the diverse mechanisms underlying mSWI/SNF complex targeting and function in a wide array of cancers (including hematologic cancers) and developmental disorders and have provided new foundations for therapeutic development.

Disclosures

Kadoch: Foghorn Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
Mapping Stem Cell Dependencies in Cancer Heterogeneity and Therapy Resistance
Authors: Reya Tannishtha
Published: November 2019

Our research focuses on the signals that control stem cell self-renewal and how these signals are hijacked in cancer. Using a series of genetic models, we have studied how classic developmental signaling pathways play key roles in hematopoietic stem cell growth and regeneration and are dysregulated during leukemia development. Through this work we have identified Hedgehog and Wnt signaling, and more recently the cell fate determinant Musashi, as critical players in driving progression of hematologic malignancies and as targets for therapy. To search for new regulators of myeloid leukemia, we have carried out a focused screen of surface molecules that may enable leukemia cells to receive supportive cues from the microenvironment. This screen identified key new adhesion signals that are critical to leukemia growth, drug resistance and dissemination. Using high resolution in vivo imaging we have mapped how these mediate the interactions that leukemia cells make within their microenvironment. To complement this focused screen, we have also carried out a genome wide CRISPR screen to more generally define the biological determinants of myeloid leukemia establishment and propagation. This screen identified a large number of new genes and programs critically required for leukemia, including those essential for chromatin remodeling and spliceosomal assembly. Among these, RNA binding proteins (RBPs) in general, and the chromatin binding sub-family of RBPs in particular, emerged as key new dependencies of myeloid leukemia. The talk will focus in part on these new regulators.

Disclosures

No relevant conflicts of interest to declare.
Paracrine Bone Morphogenetic Protein Signaling in Iron Homeostasis
Authors: Babitt Jodie L.
Published: November 2019

Iron is an essential nutrient that is required not only for hemoglobin production in red blood cells, but also as a co-factor of many other proteins that perform fundamental cellular processes. However, excess iron can generate free oxygen radicals that can be toxic. Cells and organisms have therefore evolved mechanisms to tightly control iron levels. Systemic iron homeostasis is governed by the iron hormone hepcidin that binds and degrades the iron exporter ferroportin to limit iron absorption from dietary sources and iron release from iron-recycling macrophages and hepatocyte stores. The key source of hepcidin that controls systemic iron homeostasis is the liver. Hepcidin production by the liver is coordinated by several signals that communicate the body's iron needs. Increases in serum and tissue iron induce hepcidin production, whereas iron deficiency suppresses hepcidin production, as feedback mechanisms to maintain steady state iron levels. Inflammation induces hepcidin to limit iron availability to infectious organisms that also require iron to grow and proliferate. Increases in erythropoietic drive suppress hepcidin production to increase iron availability for red blood cell production. The bone morphogenetic protein (BMP) signaling pathway is the central signal transduction pathway that controls hepcidin production in the liver. Activation of BMP signaling by iron loading or suppression of BMP signaling by iron deficiency or erythropoietic drive are key mechanisms by which these signals control hepcidin transcription. Iron loading increases production of BMP6 and BMP2 ligands by liver endothelial cells. Endothelial-derived BMP6 and BMP2 have paracrine actions on BMP receptors and the co-receptor hemojuvelin on hepatocytes to phosphorylate SMAD transcription factors, which translocate to the nucleus to regulate hepcidin transcription. Erythropoietic drive increases the production of erythroferrone by erythrocyte precursors. Erythroferrone is secreted into the circulation where it binds BMP ligands to prevent their interaction with cell surface receptors, thereby inhibiting hepcidin transcription. This talk will focus on recent insights into the molecular mechanisms by whch paracrine BMP signaling in the liver coordinates hepcidin production to regulate systemic iron homeostasis.

Disclosures

Babitt: Ferrumax Pharmaceuticals, Inc: Equity Ownership, Patents & Royalties; Keryx BIopharmaceuticals, Inc (now part of Akebia Therapeutics): Consultancy; Disc Medicine: Consultancy.
Proteostasis and Myeloid Stem Cell Production
Authors: Signer Robert
Published: November 2019

Hematopoietic stem cells (HSCs) regenerate blood cells lost to turnover, injury and disease. Defects in HSC maintenance, such as those that occur during aging, lead to anemia, impaired immunity, and bone marrow failure. Over- or ectopic activation of HSC self-renewal programs leads to hematopoietic neoplasms. Thus, defects in HSC maintenance can lead to diverse malignant and non-malignant hematopoietic disorders. We recently discovered that HSCs have lower rates of protein synthesis than other blood cells. Low protein synthesis is necessary for HSCs, as genetic changes that increase protein synthesis impair HSC function. Importantly, this does not simply reflect HSC quiescence, as dividing HSCs also have lower rates of protein synthesis as compared to dividing restricted progenitors. However, why stem cells depend on low protein synthesis and how increases in protein synthesis impair stem cell function remain largely unknown. Translation is a key cog in both the gene expression and protein homeostasis (proteostasis) networks, and thus influences both the content and the quality of the proteome. We have now determined that low protein synthesis within HSCs is associated with elevated proteome quality in vivo. HSCs contain less ubiquitylated and unfolded proteins as compared to restricted myeloid progenitors, and modest increases in protein synthesis cause an accumulation of misfolded/unfolded proteins within HSCs. Thus, HSCs depend upon low protein synthesis to maintain proteome quality. To test how translational control of proteome quality affects stem cell function, we examined Aarssti/sti mice that harbor a mutation in the alanyl-tRNA synthetase, which causes a tRNA editing defect that increases amino acid misincorporation errors during translation. Aarssti/sti mice exhibit reduced HSC numbers and significantly diminished serial reconstituting activity in vivo, but do not exhibit defects within restricted progenitors. Surprisingly, a modest accumulation of misfolded/unfolded proteins does not induce significant activation of the unfolded protein response within HSCs, but instead overwhelms the capacity of the proteasome, which promotes the stabilization and increased abundance of c-Myc. Conditional deletion of a single copy of Myc is sufficient to significantly rescue serial reconstitution defects in Aarssti/sti HSCs. HSCs are thus dependent on low protein synthesis to maintain proteome quality and homeostasis to preserve their self-renewal activity in vivo.

Disclosures

No relevant conflicts of interest to declare.
Metabolic Control and Systems Immunology in Blood Cell Development
Authors: Chi Hongbo
Published: November 2019

Coordination of metabolic programs with cell fate decisions is a fundamental determinant of hematopoietic cell development and function. Hematopoietic cells at different developmental and activation stages exhibit distinct metabolic signatures. Emerging evidence further highlights the interplay between cell signaling and metabolic programming in these processes. We found that myelopoiesis, including the differentiation of monocytes, macrophages and dendritic cells (DCs), required mechanistic target of rapamycin complex 1 (mTORC1) signaling and anabolic metabolism. Loss of mTORC1 impaired myelopoiesis under steady state and dampened innate immune responses against Listeria monocytogenes infection. Stimulation of hematopoietic progenitors with macrophage colony-stimulating factor (M-CSF) resulted in mTORC1-dependent anabolic metabolism, which in turn promoted expression of M-CSF receptor and transcription factors PU.1 and IRF8, thereby constituting a feed-forward loop for myelopoiesis. Mechanistically, mTORC1 engaged glucose metabolism and initiated a transcriptional program involving glycolysis and sterol biosynthesis after M-CSF stimulation. Integrative metabolomic and genomic profiling further identified one-carbon metabolism as a central node in mTORC1-dependent myelopoiesis. Moreover, we found that differentiation of DCs from bone marrow precursors was associated with dynamic regulation of mTORC1 signaling and cell metabolism. Either reduced or excessive mTORC1 activity was detrimental to DC development, associated with impaired regulation of cell metabolism. Interestingly, in contrast to the obligatory role of mTORC1 in monocyte and DC development, mTORC2 function was dispensable in these processes. Our results demonstrate that the interplay between mTORC1 signaling and bioenergetic and biosynthetic activities constitutes key metabolic checkpoints to orchestrate myelopoiesis. We are currently applying systems immunology approaches to explore metabolic signaling in myelopoiesis.

Disclosures

No relevant conflicts of interest to declare.
Understanding the Mechanisms Driving Genomic Instability in Adult T-Cell Leukemia/Lymphoma
Authors: Madireddy Advaitha , Barreto-Galvez Angelica , Ye B. Hilda
Published: November 2019

Adult T-cell Leukemia/Lymphoma (ATLL) is a T-cell malignancy that results from infection by the retrovirus, human T cell lymphotropic virus-1 (HTLV-1). ATLL is endemic to Japan, the Caribbean regions and Latin America. Despite the rare occurrence of the disease, ATLL is a very aggressive malignancy with limited treatment options. Recent studies show that the ATLL patients diagnosed in North America (NA-ATLL), who are largely from the Caribbean region, have extremely poor prognosis as compared to the Japanese ATLL (J-ATLL) patients. A better understanding of the molecular pathogenesis of NA-ATLL is critical to identifying effective treatment measures for these patients. It has been previously shown that genomic instability including extensive chromosomal variations can be frequently found in ATLLs. However, the underlying mechanisms leading to this instability are unclear. Analysis of the mechanism of HTLV-1 action has revealed that the virus, in addition to hijacking the host cell machinery, disrupts DNA repair mechanisms and cell division processes. While the disruption of repair mechanisms could be held accountable for the accumulation of damage in ATLL cells, the precise nature of this disruption has not been fully understood. In proliferating cells, damage to the DNA occurs or is primarily recognized during DNA replication. This indicates that defective DNA replication could be an important factor driving genomic instability in ATLL cells. Possible involvement of replicative defects in the etiology of ATLL is further strengthened by the fact that genomic instability in ATLL cells has been shown to occur at difficult to replicate genomic regions referred to as common fragile sites. Here, using a powerful locus specific approach called the single molecule analysis of replicated DNA (SMARD), we show that perturbed DNA replication is an inherent component of disease manifestation in ATLL patients. Furthermore, our preliminary findings suggest that these changes in DNA replication can be largely attributed to the EP300 inactivating mutations often found among NA-ATLL patients. This study will help elucidate the molecular mechanisms contributing to the marked chemo-resistant feature of NA-ATLL patients, as compared to J-ATLL patients. In addition to increasing our understanding of the mechanisms contributing to ATLL in general, the results from this study may inform new and mechanism-based treatment paradigms that target the replicative defects of this unique disease.

Disclosures

No relevant conflicts of interest to declare.
The Effects of Text Messaging for Promoting the Retention of the First-Time Blood Donors, a Randomized Controlled Study (TEXT study)
Authors: Pongsananurak Chontara , Norasetthada Lalita , Tantiworawit Adisak , Rattarittamrong Ekarat , Rattanathammethee Thanawat , Sriwichai Maitree , Leetrakool Nipapan , Piriyakhuntorn Pokpong , Hantrakool Sasinee , Chai-Adisaksopha Chatree
Published: November 2019

Introduction

Recruiting blood donors remains a challenging process to ensure sufficient blood product supplies. There were several interventions implemented in order to promote the retention of first-time donors, including short messaging service (SMS). However, the efficacy of SMS for promoting the retention of blood donation has never been demonstrated in a randomized controlled trial. Here, we report the interim analysis of the TEXT study.

Methods

This is a single center, randomized- controlled trial. We enrolled participants 18 years of age or older who were first-time blood donors and who were able to read and understand text messages. Participants were excluded if the purposes of blood donation were as follows, autologous donation, apheresis or blood letting. Participants were also excluded if they had no cell phone number or lived temporarily in the area. Participants were randomized within 24 hours followed the blood donation in a 1:1 ratio (text group vs control group). Only participants who were allocated in the "text group'' would receive a computer-generated text message once his/her blood product was dispatched from the transfusion service. The content of text message was "We would like to inform you that your blood has been used for patients on DD.MM.YYYY. Because of your blood donation, patients' lives will be saved." The primary outcome of the study was the rate of returning for the second donation at 6 months. Odds ratio (OR) and 95% confidence interval (CI) for retention rate was calculated based-on a modified intention-to-treat analysis.

Results

In a modified intention-to-treat analysis, there were 867 participants allocated to the text group and 864 participants to the control group (Figure 1). Mean age was 26.1 (standard deviation, SD 9.2) and 26.2 (SD 9.4) years, respectively. The primary outcome occurred in 120 of 867 (13.8%) in the text group and 89 of 864 (10.3%) in the control group, OR 1.40 (95%CI 1.04 to 1.87, P-value=0.02). Number needed to treat was 29. Figure 2 demonstrates the Kaplan-Meier curves of participants who returned for the second blood donation comparing between text and control groups. The median time for returning was 119 days (interquartile range, 95.5-150.5) in text group and 119 days (interquartile range, 98-148) in control group. Subgroup analysis does not show significant interactions between participants' characteristics and outcome.

Conclusion

Among first-time blood donors, text messaging after blood product being dispatched is a simple, inexpensive and effective intervention to increase the retention rate for second donation at 6 months duration.

Disclosures

No relevant conflicts of interest to declare.
Glycosylationof Immunoglobulins Determine Bone Loss in Multiple Myeloma
Authors: Westhrin Marita , Kovcic Vlado , Bondt Albert , Holst Stephanie , Zhang Zejian , Sundan Anders , Slørdahl Tobias S. , Waage Anders , Wuhrer Manfred , Standal Therese
Published: November 2019

About 80% of patients with multiple myeloma develop a severe osteolytic bone disease causing pain and fractures. The myeloma cells secrete immunoglobulins and the presence of monoclonal immunoglobulins in serum is a hallmark of the disease. Immunoglobulins play a role in bone loss, but have not been linked with the bone disease in multiple myeloma.

In this work, we isolated immunoglobulins from serum of myeloma patients using protein G coupled magnetic beads and columns. We found that immunoglobulins from patients with bone disease (n=16) promoted osteoclast differentiation when added to human monocyte-derived pre-osteoclasts (p=0.006). We next fractionated the immunoglobulin samples by size-exclusion chromatography and found that the "osteoclast promoting activity" was in the high-molecular weight fractions, suggesting that they are in complexes. Since extent of complex formation may be determined by glycosylation, we examined whether there is a difference in immunoglobulin glycosylation between healthy controls and patients, and whether it changes during disease progression. To this end we analysed IgG glycosylation in serum samples from patients (n=72) and age and sex matched controls (n=51). These analyses showed that patient IgG was less galactosylated (p=0.02) and less sialylated (p=0.04) compared with control IgG. Moreover, patients with bone disease (n=43) had significantly less galactose on IgG compared with patients without bone disease (p=0.02, n=33). Supporting this data, we found that galactosidase treatment of immunoglobulins from patients without bone disease induced osteoclastogenesis (p=0.03), whereas addition of galactose to immunoglobulins of patients with bone disease removed their pro-osteoclastogenic effect (p=0.01). Further, the glycosyltransferases ST6GAL1 and B4GALT11, which add sialic acid and galactose to the sugar chain, respectively, are less expressed in plasma cells obtained from patients with bone disease (n=137) compared with those without (n=36, p<0.002, p<0.001, GSE755). Importantly, we observed a significant reduction of IgG glycosylation (p=0.02, n=8) in serum samples obtained from individual patients before and after the onset of bone disease.

Taken together, our data support that immunoglobulins promote bone loss in multiple myeloma.

Disclosures

No relevant conflicts of interest to declare.
"Identification of Mechanisms By Which Mesenchymal Stem/Stromal Cells Contribute to Acute Myeloid Leukemia"
Authors: Aldreiwish Allolo , Muradia Gauri , Gagne Remi , Beal Marc , Yauk Carole , Allan David S. , Diaz de la Guardia Rafael , Menendez Pablo , Rosu-Myles Michael , Lavoie Jessie .R.
Published: November 2019

Acute myeloid leukemia (AML) is a blood malignancy resulting in abnormal hematopoiesis that is reported to be associated with alterations in the bone marrow microenvironment (BME). Current treatments for this heterogeneous disease, which target the leukemic cells but not the BME, are largely unsuccessful for the majority of AML subtypes. By better understanding the mechanisms by which the BME contributes to leukemogenesis, it may be possible to introduce more effective treatments for AML.

Mesenchymal stem cells (MSCs) are an essential component of the BME that have been shown to support normal hematopoiesis. Therefore, MSCs may have several roles in the alteration of the BME, leukemogenesis, and AML relapse and can provide an excellent model for studying the BME in vitro. While some studies have characterized AML-derived MSCs (AML-MSCs), their exact role in the disease remains unclear. Our RNAseq analysis of AML-MSCs (n=30), and healthy donor MSCs (HD-MSCs) (n=8) identified that, among 7655 genes, 21 genes were significantly differentially expressed in AML-MSCs. Through in silico analysis of this gene set, genes of interest were identified as having the potential to directly alter the BME and affect AML pathogenesis through BMP/TGF-β pathways.

Current work is focusing on investigation of the effects of selected genes with biological relevance on MSCs intrinsic and extrinsic functional properties. This study will improve our understanding of the role of MSCs in AML BME and help in the discovery of new therapeutic targets.

Disclosures

No relevant conflicts of interest to declare.
A Review of Inappropriate D-Dimer Ordering at a Canadian Tertiary Care Centre
Authors: Oliver Monika , Karkhaneh Mohammad , Karathra Jacqueline , Goubran Mariam , Wu Cynthia M.
Published: November 2019

Introduction

The D-dimer has been validated for use in the diagnosis of venous thromboembolism (VTE). The high sensitivity of the assay allows for safe exclusion of VTE in patients with low pre-test probability. Pre-test probability scores such as the Wells score for Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) have been established to help guide physicians on when to order a D-dimer in patients with suspected VTE.

We sought to explore the landscape of D-dimer ordering at our institution and what clinical circumstances trigger D-dimer ordering.

Methods

We conducted a retrospective chart review of 237 patients in whom a D-dimer has been ordered over a 3-month period from January to March 2018 at the University of Alberta Hospital, Edmonton, Canada. Charts were reviewed for the following parameters: Specialty of ordering physician, apparent indication for ordering, patient risk factors for VTE and evidence of pre-test probability calculation. If no pre-test probability was recorded, we retrospectively calculated Wells DVT or PE scores depending on the apparent indication. We then reviewed subsequent investigations thought to be influenced by interpretation of the D-dimer. These included ventilation/perfusion scans (V/Q scan), ultrasound Doppler studies and Computerized Tomography pulmonary angiography (CTPA).

Results

Of the 237 charts reviewed, 84.4% of D-dimers were ordered in the Emergency Department while only 14.3% were drawn on admitted patients. Sixty-nine percent of the patients were identified as having at least one risk factor for the development of VTE with prolonged hospitalization (5.5%) and personal history of VTE (4.2%) being the most common. Indication for ordering was suspected VTE in 76.3% of patients while the indications was unclear in 12.7% of patients. An initial pre-test probability score was recorded for only 3 patients. Of the D-dimers ordered, 47.7% were above the upper limit of normal (≥ 0.50 mg/L) and considered a positive test. Forty five CTPAs and 27 V/Q scans were performed with only 4 (1.69%) and 6 (2.53%) confirming the presence of pulmonary emboli, respectively. Doppler ultrasounds were performed on 18 patients (7.6%) with only one confirming a DVT.

Conclusions

Our data shows that the majority of physicians at our institution fail to utilize pre-test probability tools prior to ordering a D-dimer. This leads to unnecessary costs, overuse of imaging studies and results in low rates of positive scans.

Disclosures

Wu: Bayer: Other: Local PI for trial ; BMS-Pfizer: Other: Local PI for trial ; Daiichi-Sankyo: Other: Local PI for trial .
Increased Thromboxane in Patients with Polycythemia Vera and Thrombosis: Evidence for Aspirin-Unsuppressible Platelet Activation In Vivo
Authors: Cacciola Rossella Rosari , Gentilini Cacciola Elio , Vecchio Veronica , Cacciola Emma
Published: November 2019

Polycyhemia vera (PV) is a myeloproliferative neoplasm characterized by increased thromboxane (TX) production and thrombotic risk. It is reported that serum TXB2 concentrations in PV patients are twofold higher than healthy controls and that low-dose aspirin (ASA) therapy reduces the risk of major vascular events by 50 to 60%. To evaluate this unusual size of the effect of ASA we have studied platelet count, hematocrit (HCT), β-thromboglobulin (β-TG) and platelet factor 4 (PF4), as markers of platelet activation, TXB2, as primary indicator of platelet activation, the platelet function activity (PFA), as indicator of ASA platelet sensitivity, and the clotting time (CT), as parameter of thrombin formation. We studied 60 patients (38 men, 22 women; mean age 51 years, range 32-70) with PV according to WHO criteria. The mean duration of disease was 12 years. All patients were on ASA 100 mg once daily. All patients were on phlebotomy. None had inherited or acquired thrombotic risk factors. Of 60 patients, 30 had thrombosis (20 men, 10 women) and 30 had no thrombosis. Of 30 with thrombosis, 15 developed nonfatal myocardial infarction (10 men, 5 women) defined by chest pain of typical intensity and duration and ST-segment elevation in any limb lead on electrocardiography, 10 had nonfatal stroke (8 men, 2 women) confirmed with the use of magnetic resonance imaging, and 5 (2 men , 3 women) had deep venous thrombosis confirmed by ultrasonography. Platelet count and HCT were measured by automated analyzer. β-TG and PF4 were determined by ELISA. TXB2 was measured by radioimmunoassay technique. ASA platelet sensitivity was measured by Platelet Function Analyzer (PFA-100). CT was measured by thromboelastometry. The mean platelet count was 430±170x109/L. The mean HCT value was 42±3%. The patients with thrombosis had high β-TG, PF4 and TXB2 (110±45 IU/ml, 45±21 IU/ml, and 1.700±1.990 nmol/L, respectively), shortened C/EPI closure time (T, unit: s, n.v. 84-160 s) (55±10 s) and shortened CT (CT, unit: s. n.v. 100-240 s) (45±20 s) whereas the patients without thrombosis had normal β-TG, PF4 and TXB2 (20±11 IU/ml, 6±2 IU/ml, and 800±280 nmpl/L, respectively), prolonged C/EPI closure time (249±40 s) and normal CT (110±20 s). These findings might suggest that in PV patients and thrombotic complications might need a platelet-selective dosage of ASA.

Disclosures

No relevant conflicts of interest to declare.
Evolution of Clinically Relevant Subclones during Chemotherapy Treatment of ALL As Determined By Single-Cell DNA and RNA Sequencing
Authors: Albertí Servera Llucia , Demeyer Sofie , Govaerts Inge , Gielen Olga , Segers Heidi , Uyttebroeck Anne , Boeckx Nancy , Maertens Johan A. , De Keersmaecker Kim , Cools Jan
Published: November 2019

Acute lymphoblastic leukemia (ALL), which is the most common cancer in children, shows extensive genetic intra-tumoral heterogeneity. This heterogeneity might be the underlying reason for an incomplete response to treatment and for the development of relapse. In order to envision the clinical implementation of a refined risk-category strategy based on ALL subclonal composition, it is essential to first generate a reference single-cell map and accumulate evidence on how the subclonal composition affects the response to treatment. For that, we performed large-scale and integrative single-cell genome and transcriptome profiling of pediatric samples at diagnosis, during drug treatment and in case of relapse. We used the 10x Genomics platform for single-cell RNA-sequencing analysis (around 4000 cells per sample) and the Tapestri Platform (Mission Bio) for targeted single-cell DNA-sequencing (around 5000 cells per sample) of the most mutated genomic regions in ALL. For the later, we developed a custom panel that covers 305 ALL mutational hotspots across 110 genes.

We have determined a reference single-cell map of the cellular (based on the gene expression profile) and the clonal composition (based on the co-occurrence of mutations at each individual cell) for pediatric ALL at diagnosis (8 T-ALL and 10 B-ALL patients). We have also reconstructed the tumor phylogeny highlighting the order of mutational acquisition and the most likely pattern of evolution. Moreover, we have studied how T-ALL evolves during drug treatment at single-cell resolution in 4 patients, unraveling which are the most sensitive clones to the therapy, which are the most resistant ones and when relapse clones originated. Single-cell RNA-sequencing also provided information on how normal hematopoiesis recovers during chemotherapy treatment.

The results show that ALL is typically composed by a major clone and 5-10 smaller clones that have different sensitivities to the therapy. We have been able to detect minor clones (<1% of the cells) at diagnosis that are clinically relevant. These very rare clones are either not responding to the therapy (present at minimal residual disease) or form the relapsed leukemia. These findings could have clinical implications for improved risk-stratification methods based on individualized patient's molecular profiles.

Disclosures

Maertens: Gilead Sciences: Other: Grants, personal fees and non-financial support; Cidara: Other: Personal fees and non-financial support; Amplyx: Other: Personal fees and non-financial support; F2G: Other: Personal fees and non-financial support; Merck: Other: Personal fees and non-financial support; Pfizer: Other: Grant and personal fees; Astellas Pharma: Other: Personal fees and non-financial support.