bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitigating Violence Against First Responder Teams: Results and Ideas From the Hackmanathon
Authors: Allen Joseph A. , Taylor Jennifer , Murray Regan M. , Kilcullen Molly , Cushenbery Lily , Gevers Josette , Larson Lindsay , Ioku Tomohiro , Maupin Cynthia , Perry Samantha , Park Semin , Rosen Michael , Fry Trevor , McLeod Poppy , Harris Alexa , Fosler Kaitlin
Published: October 2019

First responders are on the front line of patient care and service, but research has shown that they are also on the front line of exposure to violence. Currently, there is a lack of evidence-based interventions that prepare first responders to handle violence on the job. With the increase in emergency medical services (EMS) call volume and reports of at least 57% of the EMS responders having experienced workplace violence, there is a need to develop scientifically systematic solutions to improve emergency responder safety. Using an adapted version of the hackathon method, academic scholars and practitioner conference attendees at the Interdisciplinary Network for Group Research (INGRoup) Conference were deployed into three multidisciplinary teams to analyze the issue and develop specific solutions. These solutions offer unique interventions to improve first responder safety.
The Detailed Assessment of Posttraumatic Stress–Second Edition (DAPS-2): Initial Psychometric Evaluation in an MTurk-Recruited, Trauma-Exposed Community Sample
Authors: Petri Jessica M. , Weathers Frank W. , Witte Tracy K. , Silverstein Madison W.
Published: October 2019

The Detailed Assessment of Posttraumatic Stress (DAPS; Briere, 2001) is a comprehensive questionnaire that assesses posttraumatic stress disorder (PTSD) diagnostic criteria as well as peritraumatic responses and associated problems such as dissociation, suicidality, and substance abuse. DAPS scores have demonstrated excellent reliability, validity, and clinical utility, performing as well or better than leading PTSD questionnaires. The present study was an initial psychometric evaluation of the unreleased DAPS (DAPS-2), revised for Diagnostic and Statistical Manual of Mental Disorders–Fifth edition ( DSM-5), in an MTurk-recruited mixed trauma sample ( N = 367). DAPS-2 PTSD scale and associated features scales demonstrated high internal consistency and strong convergent and discriminant validity. In confirmatory factor analyses, the DSM-5 four-factor model of PTSD provided adequate fit, but the leading seven-factor model provided superior fit. These results indicate the DAPS-2 is a psychometrically sound measure of DSM-5 PTSD symptoms.
Bilingual effects on cognitive shifting and prefrontal activations in young children
Authors: Moriguchi Yusuke , Lertladaluck Kanda
Published: October 2019

Aims and objectives:

Bilingual children constantly experience spontaneous switching between languages in everyday settings, and some researchers suggest that this experience leads to an advantage in task performance during executive function tasks. Neural processing during executive function tasks remains largely unknown, especially in young bilingual children.

Methodology:

Using functional near-infrared spectroscopy, this study examined whether young children who attended an immersion second-language program demonstrated enhanced cognitive shifting and lateral prefrontal activation.

Data and analysis:

We recruited children ( N = 24) who attended an international nursery school, and examined whether their performance on cognitive shifting, and whether the oxygenated hemoglobin changes in the prefrontal regions during the task, were correlated with the children’s second-language verbal age and the length of time the children had been speaking the second language.

Findings:

Results revealed that the verbal age of the second language and the length of time speaking it were significantly correlated with behavioral performances of cognitive shifting tasks. However, they were not correlated with the activations in the lateral prefrontal regions.

Originality:

We examined the neural correlates of bilingual effects on cognitive shifting and prefrontal activations in young children.

Implications:

The results suggest that second-language experience may not be directly related to neural processing in the lateral prefrontal cortex, at least in young children.
Finally, Some Neurophysiologic Good News—Favorable Prognosis in Coma
Authors: Husain Aatif M.
Published: October 2019

[Box: see text]
Readability and Understandability Analysis of Online Materials Related to Abdominal Aortic Aneurysm Repair
Authors: Scott Benjamin B. , Johnson Anna Rose , Doval Andres F. , Tran Bao N. , Lee Bernard T.
Published: October 2019

Background:

Patients commonly use online materials as a source of health information. Since poor health literacy has been shown to correlate with negative outcomes, it is recommended that patient-directed materials be written at a sixth-grade reading level. This study evaluates the readability and understandability of commonly accessed online materials pertaining to both endovascular and open repair of abdominal aortic aneurysm.

Methods:

Searches for “endovascular repair abdominal aortic aneurysm” and “open repair abdominal aortic aneurysm” were performed on both Google and Bing, and the top 10 websites from each search engine were identified. Relevant websites (total N = 28, endovascular n = 15, open n = 15, and 2 redundant sites) with patient-directed content were analyzed. Readability was assessed using 9 established methods, and understandability was assessed using the Patient Education Materials Assessment Tool scoring system.

Results:

The average reading grade level for all sites was 12.8. Endovascular sites averaged a reading grade level of 13.6 with a range from 11.5 to 15.6. Open-repair websites had a grade-level average of 12.1 with a range from 9.9 to 14.1. Readability was found to be inversely related to understandability, with a Pearson correlation coefficient of −0.551 ( P = .003). No website was written at or below the recommended sixth-grade reading level.

Conclusions:

Patient-directed online health information pertaining to open and endovascular repair of abdominal aortic aneurysm exceeds the recommended sixth-grade reading level. Increasing complexity of health literature correlates with poor understandability. Modifications such as shorter sentences, fewer words with more than 6 letters, and increasing usage of clear visual aids can increase readability and understandability.
Democracy both young and old: Finland, Sweden and the interwar crisis of democracy
Authors: Kurunmäki Jussi
Published: October 2019

It is often pointed out in the literature of democratisation and the breakdown of democracy that old democracies have been able to stand against the threat of totalitarian and extremist political doctrines better than young ones. This observation has usually been based on the existence of solid political institutions, certain class structures, and the legitimacy of a political system. The focus of this article is on the rhetorical role that the division between ‘old’ and ‘young’ or ‘new’ democracies played during the interwar crisis of democracy. By focusing on the cases of Finland and Sweden, which have been described as a young democracy and an old democracy respectively in the literature on democratisation, the study directs attention to the ways in which the age of democracy has been produced in order to defend democratic institutions against totalitarian doctrines and practices. The article thus contributes to the conceptual history of democracy and helps explaining why Finland managed to maintain its democratic political institutions as one of the few new independent states that were born during and just after the First World War.
A new heuristics for the event ordering in binary decision diagram applied in fault tree analysis
Authors: Banov Reni , Šimić Zdenko , Grgić Davor
Published: October 2019

Fault tree is a common approach in probabilistic risk assessment of complex engineering systems. Since their introduction, binary decision diagrams proved to be a valuable tool for complete quantification of hard fault tree models. As is known, the size of the binary decision diagram representation is mainly determined by the quality of the selected fault tree event ordering scheme. Finding the optimal event ordering for binary decision diagram representation is a computationally intractable problem, for which reason heuristic approaches are applied to find reasonable good ordering schemes. The existing method for finding optimal ordering schemes related to special types of fan-in 2 read-once formulas is employed in our research to develop a new heuristic for fault tree. Various fault tree simplification methods are used for the sake of reducing fault tree model discrepancy from fan-in 2 read-once formulas. The reduced fault tree is traversed in a depth-first manner, as for every gate, the best ordering scheme is chosen from selected sets of input permutations. The quality of the final event ordering scheme is compared to orderings produced with depth-first left most heuristic on a set of fault tree models addressed in the literature as well as on a set of our hard models. Our method proves to be a useful heuristic for finding good static event ordering, and it compares favourably to the known heuristic based on a depth-first left most assignment approach.
Reliability of thermocautery-assisted circumcision: retrospective analysis of circumcision performed voluntarily in countries of low socioeconomic status
Authors: Cakiroglu Basri , Gozukucuk Ali , Arda Ersan , Tas Tuncay
Published: October 2019

Objective:

The objective of this study was to evaluate the reliability of thermocautery-assisted circumcision performed voluntarily in patients of poor countries.

Material and methods:

Between 2016 and 2019, 32,000 children aged 7 days to 17 years were circumcised in multiple countries. The patients’ urological examinations were done before the administration of local anaesthesia. Patients revealed to have undescended testicle, inguinal hernia, hypospadias, varicocele, penile rotation anomaly, epispadias and infection were not circumcised. All procedures were performed under local anaesthesia by using thermocautery. Afterwards, mucosa and skin were sutured using absorbable suture and the circumcised penis was dressed. Patients were instructed to remove the dressing after 3 days.

Results:

Bleeding, requiring surgical intervention and drug reactions were not observed. The most observed complication was mucosal oedema, which occurred in approximately one-quarter of patients (26%, 8320/32,000) and continued for 3–5 days after the surgery. The most serious complication was a trapped penis, which occurred in 25 patients (0.078%). In six (0.018%) cases, meatal stenosis developed. Wound infection developed in only 10 (0.03%) cases, through the formation of an aseptic environment. Penile adhesion was seen in 35 cases (0.1%) and improved with anti-inflammatory treatment without any surgical intervention.

Conclusion:

Thermocautery-assisted circumcision can be used as an effective, safe and useful technique with few complications and rapid healing rates.
Prognostic value of PD-L1 expression for surgically treated localized renal cell carcinoma: implications for risk stratification and adjuvant therapies
Authors: Chipollini Juan , da Costa Walter Henriques , Werneck da Cunha Isabela , de Almeida e Paula Felipe , Guilherme O. Salles Paulo , Azizi Mounsif , Spiess Philippe E. , Abreu Diego , Zequi Stênio de Cássio
Published: October 2019

Background:

We aimed to evaluate the prognostic role of programmed-death receptor ligand (PD-L1) in a multinational cohort of patients with localized renal cell carcinoma (RCC).

Methods:

Formalin-fixed paraffin-embedded blocks of 1017 patients from the Latin American Renal Cancer Group were analyzed. Tissue microarrays were immunostained for PD-L1 using a commercially available monoclonal antibody. Expression of PD-L1 in ⩾5% tumor cells was considered positive. PD-1 expression in immune cells was also assessed. All cases were reviewed twice based on antibody expression and compared with a positive control. Cox proportional hazard regression models were used to identify predictors of recurrence-free survival (RFS) and overall survival (OS).

Results:

A total of 738 cases with complete follow up met criteria. Median age was 57 [interquartile range (IQR): 49–64] years, and median follow up was 34 (IQR: 15–62.9) months. Median tumor size was 5 cm (IQR: 3.0–7.5 cm). Approximately 8.2% and 7.6% of tumors were PD-L1 and programmed cell-death 1 (PD-1) positive, respectively. PD-L1 and PD-1 positivity were significantly associated with higher tumor stage (both p < 0.001), and presence of tumor necrosis and lymphovascular multivariable analyses; PD-L1 positivity was found as a predictor of worse RFS [hazard ratio (HR) = 2.08, p = 0.05] and OS (HR = 2.61, p = 0.02).

Conclusions:

PD-L1 positivity was significantly associated with worse outcomes for patients with localized RCC at intermediate follow up. This marker may help stratify patients for stricter surveillance after surgical treatment and provide a basis for checkpoint-inhibitor therapy in the adjuvant setting.
Detection of Insulin Pump Malfunctioning to Improve Safety in Artificial Pancreas Using Unsupervised Algorithms
Authors: Meneghetti Lorenzo , Susto Gian Antonio , Del Favero Simone
Published: October 2019

Background:

Recent development of automated closed-loop (CL) insulin delivery systems, the so-called artificial pancreas (AP), improved the quality of type 1 diabetes (T1D) therapy. As new technologies emerge, patients put increasing trust in their therapeutic devices; therefore, it becomes increasingly important to detect malfunctioning affecting such devices. In this work, we explore a new paradigm to detect insulin pump faults (IPFs) that use unsupervised anomaly detection.

Methods:

We generated CL data corrupted with IPFs using the latest version of the T1D Padova/UVA simulator. From the data, we extracted several features capable to describe the patient dynamics and making more apparent suspicious data portions. Then, a feature selection is performed to determine the optimal feature set. Finally, the performance of several popular unsupervised anomaly detection algorithms is analyzed and compared on the identified optimal feature set.

Results:

Using the identified optimal configuration, the best performance is obtained by the Histogram-Based Outlier Score (HBOS) algorithm, which detected 87% of the IPF with only 0.08 false positives per day on average. Isolation forest is the best algorithm that offers more conservative performances, detection of 85% of the faults but only 0.06 false positives per day on average.

Conclusion:

Unsupervised anomaly detection algorithms can be used effectively to detect IPFs and improve the safety of the AP. Future studies will be dedicated to test the presented method inside dedicated clinical trials.
Microbiota and Neutrophil Development
Authors: Frenette Paul S.
Published: October 2019

Microbiota, Neutrophil Development, and Sickle Cell Disease Pathogenesis

Paul S. Frenette

RuthL. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, New York, USA

Real-time intravital microscopy analyses in humanized models of sickle cell disease (SCD) have uncovered a critical role for neutrophils in mediating vaso-occlusive episodes. Peripheral blood neutrophils are recruited in inflamed venules via the interactions of the selectin adhesion molecules (E- and P-selectin) with their ligands. These molecules mediate neutrophil rolling on the vessel wall allowing interactions with chemokines and integrins which lead to firm leukocyte adhesion. Firmly adherent neutrophils are functionally heterogenous. For example, only a subset of adherent neutrophils is capable of capturing free-flowing red blood cells (RBCs). The interactions between RBCs and adherent neutrophils lead to reductions of blood flow and promote vaso-occlusion. Recent studies show that neutrophil heterogeneity is dictated at least in part by the leukocyte's age. Older neutrophils that have spent more time in the circulation exhibit increased pro-inflammatory properties (e.g. adhesion, neutrophil extracellular trap formation, capacity to capture RBCs). The aging of neutrophils is regulated by the microbiota in that it is delayed in mice treated with broad-spectrum antibiotics. Wild-type mice kept in the germfree environment show lower aged neutrophil counts. SCD children (<5 years old) taking prophylactic Penicillin V have lower aged neutrophil counts than those off Penicillin V. Antibiotics also reduce chronic organ damage in SCD mice. Psychogenic stress is often reported by SCD patients as a trigger for vaso-occlusive episodes. We have recently tested the mechanisms of psychogenic stress on SCD vaso-occlusion and will present unpublished data linking signals from the brain regulating gut microbiota, hematopoiesis, and the innate immune response.

Disclosures

Frenette: Cygnal Therapeutics: Equity Ownership; GlaxoSmithKline: Consultancy, Research Funding; Ironwood Pharmaceuticals: Research Funding; Pfizer: Consultancy; Magenta Therapeutics: Consultancy.
Autoimmune Markers in Children with Chronic Immune Thrombocytopenia
Authors: Tahtakesen Güçer Tuba Nur , Aycicek Ali , Aydogan Gonul , Salcioglu Zafer , Yilmaz Ebru , Bayram Cengiz , Ozdemir Gul Nihal Nihal
Published: October 2019

Introduction: Chronic immune thrombocytopenia (ITP) is defined as isolated thrombocytopenia lasting longer than 12 months. Rheumatologic diseases, immunodeficiencies and thyroid diseases may coexist with chronic ITP due to possible immune dysregulation.

Aim: To evaluate the accompanying autoimmune diseases in children with chronic ITP.

Materials-Methods: A total of 154 children with chronic ITP (F /M: 1) diagnosed between 1995 and 2018 were included. Patients were evaluated with immunoglobulin levels, ANA, anti dsDNA, C3, C4, anti TPO, anti TG, T4, TSH, tissue transglutaminase IgA and Ig G.

Results: Of the 154 patients, 79 were female (51.3%) and 75 were male (48.7%). Mean age of the patients was 13.6 ± 5.8 years, mean age of diagnosis was 7 years ± 4. None of the patients had severe infections requiring hospitalisation. None of the patients had symptoms or findings of an autoimmune disorder. Of 154, two had low IgA levels (<7 mg / dL) and they were diagnosed as IgA deficiency. IgM and IgG levels were normal in all. C3 level was low in four patients (3%) and C4 level was low in one patient (0.7%). ANA was positive in 16 (12%) of the patients and anti-dsDNA was positive in four patients (0,3%). In three patients, Anti-dsDNA positivity was accompanied with ANA positivity and in one patient, C3 was low. These patients were followed up by pediatric rheumatology clinic. Twenty two patients had elevated anti TPO (15.5%) and 18 patients had elevated anti TG (12.7%) levels. Majority of patients with high thyroid autoantibodies were female (67.5%). Out of 129 patients evaluated by thyroid tests including fT4, TSH, AntiTPO and AntiTG, 29 (% 22,4) were diagnosed as Hashimoto thyroiditis. Thyroid hormone replacement was started in one patient . Of 93 patients evaluated with anti-tissue transglutaminases, 7 were found to have at least one positive TTG IgA or IgG. Two of these patients underwent endoscopy, but no evidence of celiac disease was found. In total, the number of patients with at least onepositive autoimmune marker was 54 (35%).

Discussion and Conclusion: Chronic ITP is known to accompany autoimmune diseases. Autoimmune diseases in patients with ITP may occur at any time in 10 years of diagnosis. Further studies for the detection of subclinical autoimmune conditions should be performed with a profit- loss account. Antibodies may be positive even when there is no clinical findings of the diseases. Further follow-up is needed to understand the clinical significance of autoimmune markers in chronic ITP.

Disclosures

No relevant conflicts of interest to declare.
Survival Improvement of Patients with Chronic Lymphocytic Leukemia (CLL) in Routine Care 1995 - 2017
Authors: Weide Rudolf , Feiten Stefan , Chakupurakal Geothy , Friesenhahn Vera , Kleboth Kristina , Köppler Hubert , Lutschkin Julia , Thomalla Jörg , van Roye Christoph , Heymanns Jochen
Published: October 2019

Introduction: Treatment options, progression free survival (PFS) and overall survival (OS) for patients with CLL have improved during the last 20 years in randomized controlled trials (RCT). Due to necessary inclusion- and exclusion criteria results from RCT are difficult to translate into routine care. We asked the question whether improved treatment options found in RCT are applied in routine care and whether they lead to a prolongation of survival.

Methods: All patients with CLL treated in a hematology-oncology group practice in Germany between 1995-2017 were documented retrospectively concerning diagnosis, treatment and survival in a database and analyzed statistically using SPSS.

Results: 724 outpatients with a median age of 67 (35-92) were analyzed. 427 (59%) were male, 297 (41%) were female. At diagnosis 556 (77%) were in Binet stage A, 91 (13%) stage B, 36 (5%) stage C and for 41 patients (6%) the stage couldn't be retrieved, mostly due to external diagnosis. The Charlson age adjusted comorbidity index (aaCCI) was distributed as follows: aaCCI ≤ 3 (19%), aaCCI 4 (27%), aaCCI 5 (24%) and aaCCI > 5 (31%). 56% received treatment during the evaluation period. Treatment consisted of bendamustine containing protocols in 69%, rituximab containing protocols in 66%, chlorambucil containing protocols in 53% and fludarabine containing protocols in 39%. 4% received obinutuzumab containing regimens, 9% ibrutinib and 3% idelalisib + rituximab. 10 patients (3%) had an allogeneic transplantation. Patients received a median of 2 lines of therapy (1-13). OS according to Binet stage was A 13.9 years (0.1-37.4), B 9.2 years (1.4-29.3) and C 7.9 years (0.5-19.4) respectively. OS was strongly correlated to the aaCCI: aaCCI 2-3 23.7 years (2.3-37.4), aaCCI 4 14.2 years (0.7-29.3), aaCCI 5 9.7 years (0.1-19.5) and aaCCI > 5 7.2 years (0.1-18.9). Median OS from the start of therapy improved over time: 1995-2001: 5.8 years (1.3-23.4), 2002-2008: 6.1 years (0.1-16.0+) and 2009-2017 median not reached (0.1-9.2+).

Conclusions: Survival of patients with CLL has improved in routine care during the last 20 years most likely due to improved treatment options. Survival was strongly related to disease stage, comorbidities and whether therapy included an anti-CD20-monoclonal antibody.

Disclosures

No relevant conflicts of interest to declare.
Risk-Adapted Anti-Mould Prophylaxis Improves Supportive Care in Childhood Leukemia Patients
Authors: Crazzolara Roman , Hutter Julia , Fritz Josef , Salvador Christina , Lass-Flörl Cornelia , Kropshofer Gabriele
Published: October 2019

BACKGROUND: Prophylaxis of invasive fungal infections in children treated for malignant hematologic disease has traditionally been based on the widespread use of fluconazole. With the awareness of increasing rates of invasive mould infections, new agents have been developed and offered to patients at highest risk.

METHODS: We compared the tolerance and outcome of different antifungal prophylaxis in 198 childhood patients treated for acute myeloid and lymphoblastic leukemia in a pediatric cancer center. Until 2011 antifungal prophylaxis with fluconazole was offered to all patients, resulting in 15.2-19.4% of invasive mould infections. As the burden of fungal infections was restricted to high risk patients only (i.e. acute myeloid leukemia, leukemia relapse, high risk acute lymphoblastic leukemia and patients after stem cell transplant) and no infection with candida was registered, antifungal prophylaxis was replaced with liposomal amphotericin and offered to this particular patient group.

RESULTS: Liposomal amphotericin was well tolerated; there was no occurrence of infusion-related reaction and/or glomerular-associated nephrotoxicity. The development of vincristine-induced neurotoxicity was significantly reduced, as stool frequency was increased up to 38% in patients treated with liposomal amphotericin (p = 0.024). Importantly, there was a marked shift in the percentage of patients with severe constipation (15.5% versus 4.2%, fluconazole versus liposomal amphotericin respectively, p = 0.010). Notably, with limitation of prophylactic treatment to high risk patients a major group of patients did not receive any antifungal prophylaxis (48.81%) and most importantly, the occurrence of invasive fungal infection was completely prevented (p = 0.021). In comparison, 10 patients in the fluconazole group developed proven invasive pulmonary infections. Of these, 6 patients developed disseminated disease, and 4 patients died. Aspergillus was isolated in 40% and rhizopus in 30% of biopsy specimens.

CONCLUSION: Polyene prophylaxis offers effective antifungal activity with improved tolerability compared to older agents. The potential impact of this treatment should be included in current prophylaxis guidelines of antileukemic treatment.

Disclosures

No relevant conflicts of interest to declare.
Clinical Course of Primary Immune Thrombocytopenia with Positive Antiphospholipid Antibodies
Authors: Cruz Ana Clara , Saraiva Sabrina , Colella Marina Pereira , Yamaguti Hayakawa Gabriela G , De Paula Erich Vinicius , Bizzacchi Joyce Maria Annichino , Orsi Fernanda Andrade
Published: October 2019

Introduction: Antiphospholipid (aPL) antibodies are commonly detected in patients with primary immune thrombocytopenic purpura (ITP) and whether the presence of these antibodies affect the prognosis of the disease is not known yet. Nevertheless, knowledge on the role of aPL in primary ITP would contribute to the management of the disease.

Aim: Our primary aim was to evaluate if aPL antibodies are associated with either persistence or chronic primary ITP. We also aimed to evaluate the association of aPL antibodies with platelet counts and any bleeding event during the follow-up.

Methods: This is a retrospective cohort study that took place in the Hematology Center of the University of Campinas. We collected data on patients with primary ITP diagnosed between January 2008 and January 2016. Lupus anticoagulant (LAC), IgG/IgM anticardiolipin and antibeta2glycoprotein1 (aB2GP1) assays were performed at diagnosis, and repeated within 12 weeks when positive. We compared the baseline characteristics of patients with and without aPL using chi-square test, when variables were categorical, or independent t-test when variables were continuous. We used logistic regression and linear regression to examine the association between aPL and binary and continuous outcomes respectively. Cox regression was used to evaluate the cumulative risk of bleeding. Analysis were adjusted for age and sex.

Results: One hundred ninety-six patients were included and the median follow up time was 41 months. Forty-nine patients (21%) were positive for aPL (29 LAC, 20 aB2GP-1, 25 anticardiolipin IgM ou IgG, and 4 triple-positive). Baseline characteristics were similar between groups. Positivity for aPL was not associated with the risk of either persistent (OR=1,5 95%CI= 0.8; 3.0) or chronic ITP (OR=1,2 95%CI= 0.6;2.4). Mean platelet counts at 3 months was 123 x 103 (SD 111 x 103) U/mL in aPL negative patients and 103 x 103 (SD 117 x 103) U/mL in aPL positive patients (mean difference -18 x103 [95%CI= -55 to 18 x103]). Mean platelet counts at 12 months was 127 x 103 U/mL in aPL negative patients and 117 x 103 U/mL in aPL positive patients (mean difference -10 x103 [95%CI= -50 to 29 x103]). aPL positivity was not associated with bleeding events (HR= 1.3 95%CI=0.9; 1.8).

Conclusion: Our results demonstrated that the presence of aPL does not influence the clinical course of primary ITP. This suggests that the investigation of aPL may not be useful for the management of primary ITP.

Disclosures

De Paula: Hematology and Transfusion Medicine Center, University of Campinas: Employment.
Chemoresistant Colorectal Cancer (CRC) Cells Show Increased Invasive Potential Which Is Part Is Mediated By VEGF-Signaling and Can be Attenuated By VEGF-Directed Agents
Authors: Sandrine Thouroude , Van Dreden Patrick , Gerotziafas Grigorios T. , Larsen Annette
Published: October 2019

Introduction. Cancer mortality is principally associated with the presence of drug-resistant, invasive subpopulations of tumor cells. However, the functional and mechanistic interactions between the two phenotypes are incompletely understood. Colorectal cancer (CRC) cells produce the vast majority of VEGF in the cancer environment and display endogenous VEGFR1/VEGF signaling which is believed to promoted survival under stress.

Methods. Migration and invasion was determined by the transwell assay (Boyden Chamber). For the tube formation assay, CRC cells were seeded onto 3D matrigels and incubated at 37° for 24 hr monitored by videomicroscopy. Determination of VEGF ligands was carried out by ELISA.

Results. We here characterize a panel of 4 isogenic CRC cell lines comprised of the parental HCT-116 cells and three independently derived sublines resistant to 5-fluorouracil, oxaliplatin and SN-38. Resistant cells secreted 3-7 fold more VEGF, while the HCT-116/5-FU cells also secreted 2 times more PlGF, compared to the parental cells. VEGF signaling is known to promote CRC cell migration and invasion. In agreement, resistant cells showed 6-11 fold increased migration, whereas the invasive capacity had increased 6-15 fold. Aflibercept inhibits all three VEGFR1 ligands (VEGF-A, VEGF-B and PlGF) on CRC cells accordingly, addition of aflibercept resulted in a significant decrease in both migration and invasion. Two of the three resistant cell lines were able to do vascular/vasculogenic mimicry by forming capillary-like cellular networks which could be significantly attenuated by aflibercept.

Conclusions.Taken together, our results indicate that acquired resistance to genotoxic agents may be accompanied by an increased invasive potential mediated, in part, by VEGF signaling that can be attenuated by aflibercept.

Disclosures

No relevant conflicts of interest to declare.
Outcomes in the Secondary Prevention of Cerebral Venous Thrombosis in Cancer Only Population
Authors: Abelhad Nadia Isabel
Published: October 2019

BACKGROUND AND PURPOSE:

There are scant data on the outcomes of cerebral venous thrombosis (CVT) in the cancer only population. Current anticoagulation guidelines exist for the general population but the effect of these strategies in cancer subgroups are not known. We examined the clinical outcomes such as recanalization, thrombosis recurrence and major bleeding during cerebral venous thrombosis treatment in an exclusively cancer population.

METHODS:

A retrospective cohort study of cancer only patients with cerebral venous thrombosis identified through an institutional data warehouse at MD Anderson Cancer Center between January 2002 and June 2017. Patients with other indications for long term anticoagulation, chronic cerebrovascular thrombosis or less than 12 month follow up were excluded from the primary analysis. The primary end point was thrombus recanalization. Secondary end points were major bleeding and recurrence of cerebral or venous thrombosis. Demographic data, cancer diagnosis and cancer-therapy was also obtained at the time of initial CVT for further analysis. Chi-square test or Fisher exact test were used to assess the association between categorical variables.

RESULTS:

The population comprised predominantly male adults (55.6%) with median age 54.5 years, IQR [41.5 to 62.4]. The underlying malignancies were non-hematologic in 64.4% of cases. Anticoagulation was used in the treatment of 73.3% of cases, predominantly low molecular weight heparin (LMWH), and a median duration of 7.9 months, IQR [3.1 to 30.8]. Partial and complete recanalization were achieved in 33.3% and 17.8% of cases, respectively. The CVT recurrence rate at 12 months was 15.6% and 31% of patients suffered major bleeding. Most of the major bleeding events (71.1%) occurred outside the brain. Anticoagulation therapy with LWMH showed a trend to a higher rate of thrombus recanalization (p=0.196) without an increment in the overall bleeding events. We observed a lower rate of major bleeding events in patients treated with LWMH when compared with oral anticoagulation (5/14 versus 18/31, respectively; p=0.049).

CONCLUSIONS:

Our findings suggest that LMWH might represent an effective and safe strategy for the management of CVT in cancer patients. The findings are consistent with results from large randomized trials for outcomes of cancer associated venous thrombosis in other anatomical locations. The impact of thrombus recanalization in recurrent thrombosis and bleeding outcomes deserves further exploration. Limitations to our study are the retrospective and non-randomized design for the adjudication of treatment agents.

Disclosures

No relevant conflicts of interest to declare.
A Novel Role for PIEZO1 in Calcium Homeostasis during Erythropoiesis
Authors: Aglialoro Francesca , Yagci Nurcan , von Lindern Marieke , van Wijk Richard , van den Akker Emile
Published: October 2019

In erythrocytes, the mechanosensitive ion transporter PIEZO1 is crucial to maintain cellular volume homeostasis during circulation. Gain of function mutations in the PIEZO1 gene lead to prolonged Ca2+ influx resulting in hereditary xerocytosis (HX). This rare disorder of erythrocyte hydration is characterized by dehydration caused by increased Gardos channel activation. HX patients display a mild to moderate degree of hemolysis, which is generally compensated by an increased reticulocyte count. In addition to its function in erythrocytes we found that PIEZO1 RNA is also expressed at the proerythroblast stage suggesting a role during erythropoiesis. We therefore hypothesize that disturbed Ca2+ homeostasis due to inappropriate PIEZO1 channel function leads to defects in erythroid differentiation.

Primary erythroblasts were cultured from peripheral blood mononuclear cells from an HX patient, heterozygous for the previously reported c.6262C>G p.Arg2088Gly mutation in PIEZO1 (Glogowska, 2017 Blood 130(16): 1845-1856). Primary erythroblasts displayed a twofold decreased proliferation compared to healthy controls. Incubating erythroblasts from a healthy control with the PIEZO1 agonist Yoda1 led to a dose dependent decrease in erythroblast proliferation, thereby recapitulating the patient's phenotype. In addition, Yoda1 treatment was accompanied with increased cell death and reduced enucleation. In HX patient's erythroblasts basal Ca2+ levels were higher compared to control cells. In agreement with this, Yoda1-induced PIEZO1 activation led to a dose dependent Ca2+ influx. Yoda1 caused Erk1/2 and SAPK/JNK phosphorylation as well as NFATc2 dephosphorylation, suggesting that PIEZO1 triggers calcium-dependent signal transduction, possibly via calcineurin activation. Indeed, Yoda1-induced NFATc2 dephosphorylation was blocked and SAPK/JNK phosphorylation was inhibited upon pre-incubation of erythroblasts with the calcineurin inhibitor FK506.

In conclusion, we found that PIEZO1 has a role in regulating Ca2+ homeostasis during erythropoiesis possibly through activation of calcineurin. Inappropriate PIEZO1 channel activation in erythroid cells results in cell death and proliferation/differentiation defects. This novel feature adds to the complexity of the phenotypic expression of HX.

Disclosures

van Wijk: RR Mechatronics: Research Funding; Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Trends of Palliative Care Utilization in Acute Myeloid Leukemia in the United States
Authors: Tella Sri Harsha , Kommalapati Anuhya , Bennett Charles L. , Goyal Gaurav
Published: October 2019

Background: Early integration of Palliative Care (PC) have shown to improve survival in some solid malignancies such as lung and colon cancers. In this study we sought to analyze the PC utilization in acute myeloid leukemia (AML) patients.

Methods: Using the National Cancer Data Base (NCDB) Participant User File, we extracted patient-level data of patients with AML reported between 2004 to 2015.Patients who received pain management and/or other palliative procedures were considered as PC utilizers. After excluding the cases with acute promyelocytic leukemia t (15, 17) (given its excellent prognosis), we classified the AML into three groups- AML with genetic abnormalities, therapy related AML and AML with dysplasia. Other co-variates included in the analysis were age, sex, race, origin, Charlson-Deyo comorbidity score, insurance status, household income, educational status, facility type (academic vs non-academic) and year of diagnosis. Multivariate logistic regression was performed to identify the predictors of palliative care utilization. Statistical analysis was done using PC SPSS v24.0.

Results: Of 102,778 patients, 3.4% (n=3504) received PC as initial treatment. PC utilization increased significantly from 2004-2006 to 2013-2015 (2.5% vs 3.9%, p < 0.001). Individuals of non-Hispanic origin (as compared to that of Hispanics) are more likely to receive PC as compared to that of non-Hispanics. (3.5 vs 1.8%, p<0.001). The patterns of PC utilization at non-academic centers were much higher than that of academic centers (4.4% vs 2.9%, p<0.001). As compared to that of AML, not otherwise specified subtype (3.3%), therapy-related AML (4%) and AML with dysplasia (4.3%) had higher rates of PC utilization, whereas individuals with AML with genetic abnormalities have lesser rates of PC utilization (1.9%) (p<0.001, all comparisons). Significant predictors of PC on multivariable regression are listed in the Table and forest plot.

Conclusions: We noticed a differential utilization of palliative care based on the histological subtype of AML. The lesser utilization of PC in AML with certain genetic abnormalities may be attributed to their better overall survival outcomes. Though we noticed an increased trend in PC utilization over the past decade, the overall PC utilization in AML is markedly low and plagued by origin and socio-economic status.

Disclosures

No relevant conflicts of interest to declare.
Development of Novel Nanobiosensor for Direct Measurement of the Oral Anticoagulant Agent: Dabigatran Etexilate
Authors: Al Johani Maher M , Chinnappana Raja , Eissaa Shimaa , Owaidah Tarek , Cialla-Mayc Dana , Poppc Jürgen , Zourob Mohammed
Published: October 2019

Dabigatran Etexilate is a new oral anticoagulant increasingly used for number of blood thrombosis conditions, prevention of strokes and systemic emboli among patients with atrial fibrillation. It provides safe and adequate anticoagulation for prevention and treatment of thrombus in several clinical settings. However, anticoagulation therapy can be associated with an increased risk of bleeding. There is a lack of specific laboratory tests to determine the level of this drug in blood. This is considered the most important obstacles of using this medication, particularly for patients with trauma, drug toxicity, in urgent need for surgical interventions or uncontrolled bleeding.The goal of this research project is to obtain and characterize DNA aptamers for Dabigatran Etexilate and to evaluate potential applications of these aptamers to develop low cost, sensitive, selective and user-friendly biosensors. In this work, we performed Systematic evolution of ligands by exponential enrichment (SELEX) to select specific DNA aptamers against dabigatran etexilate. Following multiple rounds of selection and enrichment with a randomized 60-mer DNA library, specific DNA aptamers for dabigatran were selected. We investigated the affinity and specificity of generated aptamers to the drug showing dissociation constants (Kd) ranging from 46.8- 208 nM. A preliminary application of one of the selected aptamers in an electrochemical nano-biosensor was successfully performed and showed high sensitivity and selectivity. This work represents novel work and clinically available. With further improvement of the assay and optimization, these aptamers are useful in developing Dabigatran Etexilate detection and analytical applications and with unique potentials of clinical uses in the near future.

Disclosures

No relevant conflicts of interest to declare.
Mean Corpuscular Volume (MCV) and Mean Corpuscular Hemoglobin (MCH) Determinations in Newborns with Beta Thalassemia
Authors: Bierman Kaitlin , Maurer Harold M. , Harper James
Published: October 2019

Newborns with alpha thalassemia trait have microcytic red blood cells (RBCs) used as a diagnostic screening tool at birth. Infants with beta thalassemia present with microcytosis sometime during the first year of life; however, whether microcytosis is present in newborns is unknown. In this study, we determined the MCV and MCH values in newborn infants, who have beta0 thalassemia major, intermedia, and minor by performing a retrospective study, with IRB approval.

189 eligible patients seen by the hematology/oncology group of 10 physicians at Children's Hospital Medical Center (CHMC) and UNMC were reviewed. Patients were identified by International Classification Codes-10 (56.1, 56.3, 57.3, 57.4). Of the 189 eligible patients with beta thalassemia major, intermedia, minor, and sickle cell trait (used as controls), there were 28 evaluable and 161 non-evaluable patients. The non-evaluable patients had either the wrong diagnosis (coexisting alpha thalassemia trait) (68) or no laboratory data within the newborn period or up to 6 months of age (93). A second control group used were normal complete blood count (CBC) values by age from the Pathology Laboratory at CHMC. Of the 28 evaluable infants, 5 had beta0 thalassemia major, 2 had sickle-beta+ thalassemia (regarded as intermedia for this study), 7 had beta thalassemia minor, and 14 had sickle cell trait. The diagnosis in each of the 28 infants was confirmed by newborn screening for a hemoglobinopathy and hemoglobin electrophoresis sometime after birth. The MCV, MCH, mean corpuscular hemoglobin concentration (MCHC), hemoglobin (hgb), hematocrit (hct), and red blood cell count (RBC) were taken on evaluable patients within the newborn period through 6 months of age and de-identified using the Safe Harbor Method.

MCV and MCH were found to be reduced in newborns with beta0 thalassemia and sickle-beta+ thalassemia. However, infants with beta thalassemia minor had normal MCV and MCH values. The MCHC, RBC, hgb, and hct were comparable to controls and within normal limits. By 3-4 months of age, in the infants with beta thalassemia major or intermedia, the MCV and MCH fell to clinically characteristic levels when compared to controls, and plateaued through 6 months of age. MCV and MCH values for infants with beta thalassemia minor, 0-6 months of age, were incomplete to be able to draw a similar conclusion.

The proposed mechanism for microcytosis in major and intermedia is an imbalance between alpha and beta globin chain synthesis, which is not apparent in newborns with minor.

In conclusion, the MCV and MCH can be used to screen for beta0 thalassemia major and intermedia in newborns. Although the data are discriminating despite the small numbers, a prospective study should confirm these findings.

Figure. Figure.

Disclosures

No relevant conflicts of interest to declare.
Computational Modeling and Microfluidics Reveal Characteristic Patterns of Regulation of Clot Structure and Mechanics By Tissue Factor Localization
Authors: Mitrophanov Alexander Y. , Govindarajan Vijay , Zhu Shu , Diamond Scott L. , Reifman Jaques
Published: October 2019

The growth of a blood clot is initiated by tissue factor (TF) exposure and is expected to depend on TF localization (i.e., its level and spatial distribution). We sought to understand how the structural and mechanical properties of clots under flow are shaped by simultaneously varying the surface density of TF and its area of exposure. We used a microfluidic device harboring thrombogenic surfaces that differed in length and TF surface density. We perfused human whole blood through this device and continually measured platelet deposition, thrombin formation, and fibrin accumulation by means of fluorescence microscopy. Using our recently developed, detailed mathematical model of spatial clot growth under flow, we performed computational simulations to gain insights into the connection between the structure of a clot and its mechanical properties, such as resistance to blood flow and flow axial velocity.

We detected a non-additive, synergistic influence of the thrombogenic surface length and TF surface density on bulk thrombin and fibrin generation. We found that thrombogenic surface length and TF density controlled not only bulk accumulation, but also the occlusivity of the deposited platelet mass, as well as clot resistance to flow. The extent of this control depended on the blood flow velocity. An increase in the TF surface density resulted in condition-dependent differential acceleration of platelet deposition, thrombin formation, and fibrin accumulation. The viscous resistance of the clot was characterized by spatial variations and was higher in the inner clot region. Notably, despite variations in the intraclot structure, variations in the intraclot flow velocity were minor compared to the abrupt decrease in flow velocity at the boundary of the platelet deposition domain.

Our analysis revealed characteristic patterns that describe how the shape, size, internal structure, and viscous resistance of a clot depend on the surface density of TF and its area of exposure. Taken together, our results suggest that the structure and mechanics of a growing clot are correlated, but can differ in their regulation by the distinct aspects of TF localization. These findings provide new insights into how initiating signals can temporally and spatially affect thrombus growth under flow.

DISCLAIMER: The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army or of the U.S. Department of Defense. This abstract has been approved for public release with unlimited distribution.

Disclosures

No relevant conflicts of interest to declare.
Favorable Overall Survival in Refractory Diffuse Large B-Cell Lymphoma When Responded to High-Dose Etoposide Mobilization Chemotherapy Followed By Autologous Peripheral Blood Stem Cell Transplantation
Authors: CAI Yu , Wang Chun , Song Xianmin , Wan Liping , Li Su , Yang Jun , Jiang Jieling
Published: October 2019

Objective: To evaluate the strategy of using high-dose etoposide mobilization followed by autologous peripheral blood stem cell transplantation (APBSCT) in patients with diffuse large B-cell lymphoma (DLBCL) refractory to Rituximab-based chemotherapy.

Methods: Forty patients with refractory DLBCL were treated with high-dose etoposide for stem cell mobilization. All patients were in progressive disease (PD) prior to mobilization, and underwent high dose chemotherapy followed by autologous peripheral blood stem cell transplantation (APBSCT).

Results: Successful PBSC mobilization was achieved in all patients. Twenty-three patients (57.5%) showed clinical response to high-dose etoposide. After APBSCT, 17 patients (42.5%) achieved CR. The 2-year progression-free (PFS) and overall survival (OS) rate were higher in patients responded to high dose etoposide (64.1% and 77.7%) compared to those without response (11.8% and 11.8%; P<0.001 for both). The response to high dose etoposide mobilization therapy was an independent prognostic factor for CR achievement, PFS and OS after APBSCT.

Conclusion: High-dose etoposide mobilization chemotherapy followed by APBSCT could rescue a proportion of patients with refractory diffuse large B-cell lymphoma who responded to etoposide mobilization regimen.

Disclosures

No relevant conflicts of interest to declare.