bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.