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Wearable technology has a history in sleep research dating back to the 1970s. Because modern wearable technology is relatively cheap and widely used by the general population, this represents an opportunity to leverage wearable devices to advance sleep medicine and research. However, there is a lack of published validation studies designed to quantify device performance against accepted gold standards, especially across different populations. Recommendations for conducting performance assessments and using wearable devices are now published with the goal of standardizing wearable device implementation and advancing the field.

SummarySystemic lupus erythematosus (SLE) is an autoimmune condition developing thrombocytopenia in about 10-15% of cases, however, mechanisms leading to low platelet count were not deeply investigated in this illness. Here we studied possible causes of thrombocytopenia, including different mechanisms of platelet clearance and impairment in platelet production. Twenty-five SLE patients with and without thrombocytopenia were included. Platelet apoptosis, assessed by measurement of loss of mitochondrial membrane potential, active caspase 3 and phosphatidylserine exposure, was found to increase in thrombocytopenic patients. Plasma from 67% SLE patients (thrombocytopenic and non-thrombocytopenic) induced loss of sialic acid (Ricinus communis agglutinin I and/or Peanut agglutinin binding) from normal platelet glycoproteins. Concerning platelet production, SLE plasma increased megakaryopoiesis (evaluated using normal human cord blood CD34+ hematopoietic progenitors), but inhibited thrombopoiesis (proplatelet count). Anti-platelet autoantibody depletion from SLE plasma reverted this inhibition. Overall, abnormalities were more frequently observed in thrombocytopenic than non-thrombocytopenic SLE patients and in those with active disease (SLEDAI≥5). In conclusion, platelet clearance due to apoptosis and desialylation, and impaired platelet production mainly due to inhibition of thrombopoiesis, could be relevant mechanisms leading to thrombocytopenia in SLE. These findings could provide a rational basis for the choice of proper therapies to correct platelet counts in these patients.[Figure: see text].

OBJECTIVE The adverse health effects of short sleep duration (i.e., six or fewer hours per night) are well established, including an increased risk of cardiovascular disease (CVD) and related mortality. However, there is heterogeneity in perceived sleep need among habitual short sleepers (HSS), with a sizable minority reporting no sleep-related daytime dysfunction. It has not been determined whether health risk associated with short sleep duration is consistent across individuals with and without reported dysfunction. The current study examined self-rated health (SRH), previously demonstrated to predict CVD risk, and objective CVD risk among HSS with and without reported dysfunction in the National Health and Nutrition Examination Surveys (NHANES). METHOD Participants were adults age 40-79 in the 2005-2006 and 2007-2008 NHANES cycles. Assessments included the single item SRH (poor to excellent), self-reported average sleep duration, and self-reported daytime sleep-related dysfunction. Ten-year atherosclerotic CVD and high lifetime CVD risk (≥39%) were calculated using previously validated algorithms. RESULTS HSS with no reported dysfunction rated their overall health significantly better than those with reported dysfunction; however, the "no dysfunction" HSS group evidenced modestly, though significantly, higher 10-year CVD risk compared with their dysfunction-reporting counterparts. High lifetime CVD risk, including younger adults age 20-39, was slightly higher for persons not reporting dysfunction, with the exception of short sleepers at the highest level of dysfunction who had the highest prevalence of high lifetime risk. CONCLUSIONS Findings suggest that the absence of perceived sleep-related dysfunction does not confer lower CVD risk, despite higher SRH. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

O útero materno permite ao feto repouso e sono profundo, sendo que imerso nesta estrutura, o feto já registra algumas experiências, as quais permitem que tenham lembranças deste período após o nascimento. O objetivo do estudo foi descrever o comportamento do recém-nascido, internado Unidade de Terapia Intensiva Neonatal (UTIN), quando exposto ao som uterino. Trata-se de um estudo quase-experimental, com 7 Recém-Nascidos (RNs) de 29 a 38 semanas, internados nesta unidade, no período de setembro a outubro de 2019. Os participantes foram expostos ao som uterino por 15 minutos ininterruptos dentro da incubadora, com Leq abaixo de 60,0 dBA. Como elementos do estudo foram avaliadas a Frequência Respiratória, Frequência Cardíaca, Saturação de Oxigênio. Também foi utilizado a escala da dor no recém-nascido e no lactente - Neonatal Infant Pain Scale (NIPS), além da avaliação dos estados de sono e vigília adaptada de Brazelton, antes e após a exposição do som uterino. Resultados: Identificou-se que após a exposição ao som uterino os RNs apresentaram redução da Frequência Respiratória (FR) e Frequência Cardíaca (FC). A escala da dor apresentou significância estatística p

Magnetoelastic resonant platforms are gaining attention in different sensing applications due mainly to their wireless detecting capacity. In that way, the improvement of the main parameters of those devices turns out to be essential in the development of advanced functional magnetoelastic resonators. In our attempt to improve such systems, we concluded that modified geometries of the resonant platforms can be a good alternative to achieve higher mass sensitivities. In this work, a novel high sensitive rhombus shaped magnetoelastic resonant platform design has been proposed. The obtained mass sensitivities have been both experimentally and theoretically compared with the classical rectangular sensors case. The results of these novel sensor geometry performance show an increase on the resonance frequency value by a factor of 1.53 with respect to the traditional rectangular one and, as a first consequence, an improvement of more than a 60 % in the mass sensitivity value. Besides, a multiple detection system based on a combination of both magnetoelastic platform geometries has been developed. The obtained results are very promising in the goal of achieving improved and novel multiple detection systems.

This investigatory study sought to explore the range and variation of well-being initiatives on a select cross-section of college campuses across the United States and in Canada. This whitepaper seeks to highlight innovative practices that may inspire institutions to consider new ways of promoting well-being for both students and employees. In this whitepaper, we report findings from 10 participating higher education institutions across three major categories: student-serving programs, employee-serving programs, and hybrid programs. The qualitative data collected from key stakeholder interviews and focus groups were analyzed for trends between and across institutions. Importantly, the results of this study are intended to be hypothesis-generating as opposed to hypothesis-testing. In an effort to describe the state of the field with respect to both common and innovative practices the findings have generated additional questions for further research. Several themes emerged from this study: (1) Campuses have not adopted a universally-accepted definition of well-being; (2) While many institutions are using iterations of the wellness wheel and its various dimensions (e.g. physical, emotional, intellectual, social, spiritual, financial) to guide their efforts, there is not a dominant model for structuring or measuring well-being initiatives on campus; (3) There appears to be a systematic shift from use of the term "wellness" to "well-being"; (4) While many institutions are still utilizing traditional health education practices, there appears to be a movement toward more systemic, environmental approaches to well- being, including structural, organizational, and financial strategies, in addition to a range of policy initiatives; (5) There is a range of engagement in well-being initiatives, with significant variance based on institutional philosophy; and (6) Many institutions are designing well-being initiatives that address health disparities-particularly among underrepresented or marginalized populations.

Objective Obstructive sleep apnea (OSA), a serious respiratory disorder, confers increased risk of cardiovascular disease and mortality. Adherence to the standard and effective treatment, continuous positive airway pressure (CPAP), is often poor. Personal relationships can influence adherence, but some forms of partner involvement (e.g., support, encouragement) have positive effects on CPAP adherence, whereas others (e.g., criticism, blame) are counterproductive. In the former, constructive partner efforts may enhance a patient's sense of autonomy, an important foundation for self-care. The present study examined how patients' perceptions of autonomy support from an intimate partner predict adherence to CPAP, and whether it is an independent predictor, relative to generally positive partner behavior (i.e., partner responsiveness) and partner negativity (i.e., negative social control). Method Ninety-two married or cohabiting OSA patients (mean age 49.7 years) completed measures of perceived partner autonomy support, responsiveness, and negative social control at Days 14 and 60 of CPAP treatment. Objective daily CPAP machine adherence data were collected for 60 days. Results Perceived partner autonomy support predicted more minutes of CPAP used per night and increasing CPAP use over time. These effects were independent of the significant adverse effects of partner negative social control and the more limited beneficial effects of partner responsiveness. Conclusion The study findings establish perceived partner autonomy support as an interpersonal predictor of adherence that is independent of negative social control and perceived partner responsiveness, and may inform psychosocial interventions for CPAP adherence and more general couple approaches to chronic illness management. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

to determine the frequency of major somatic mutations in the JAK2, MPL and CALR genes in the genomeof patients with Ph-negative myeloproliferative neoplasms that occur in individuals who have been exposed to ionizing radiation as a result of the Chornobyl accident.Molecular genetic analysis of genomic DNA samples isolated from blood was performed in90 patients with Ph-negative myeloproliferative neoplasia (MPN) with a history of radiation exposure and 191patients with spontaneous MPN utilizing allele-specific polymerase chain reaction (PCR).The presence of major mutations in the genes JAK2, CALR and MPL was revealed in patients with MPN witha history of radiation exposure with a frequency 58.9 % (53 of 90), 12.2 % (11 of 90), and 0 % respectively, and without exposure with frequency 75.4 % (144 of 191), 3.1 % (6 out of 191) and 1.6 % (3 out of 191) respectively.Mutations JAK2 V617F in patients with spontaneous MPN were observed in each clinical form: polycythemia vera (PV),essential thrombocythemia (ET) and primary myelofibrosis (PMF). CALR mutations were detected exclusively inpatients with PMF and ET, significantly more often in groups with a radiation exposure history (18.9 % and 33.3 %,vs. 4.2 % and 6.5 %) than without one. At the same time, the occurence of MPL mutations was determined only inpatients with spontaneous MPN in 1.6 % of casees. Triple negative mutation status of genes JAK2, MPL and CALR prevailed in the group of patients with MPN with a history of radiation exposure and was 27.8 %, against 16.2 % inpatients without radiation exposure (p = 0.05).Genomic research of patients with Ph-negative MPN revealed features of molecular genetic damage inthose patients who were exposed to IR as a result of the Chornobyl accident and those with spontaneous MPN. Thedata obtained by determining of JAK2, MPL and CALR genes mutational status in the genome of patients with MPN isnecessary to expand the understanding of the mechanism of leukogenesis, especially caused by radiation.Meta: vyznachyty chastotu osnovnykh somatychnykh mutatsiĭ geniv JAK2, MPL ta CALR u genomi khvorykh na Ph-negatyvnimiieloproliferatyvni neoplaziï, shcho vynykaiut' v osib, iaki zaznaly diï ionizuiuchoï radiatsiï vnaslidok avariï na ChAES.Materialy i metody. Provedeno molekuliarno-genetychnyĭ analiz zrazkiv genomnoï DNK, vydilenykh z krovi 90khvorykh na Ph-negatyvni miieloproliferatyvni neoplaziï (MPN) z radiatsiieiu v anamnezi i 191 khvorogo na spontanniMPN metodom alel'-spetsyfichnoï polimeraznoï lantsiugovoï reaktsiï.Rezul'taty. Vyiavleno naiavnist' osnovnykh mutatsiĭ v genakh JAK2, MPL i CALR u khvorykh na MPN z radiatsiĭnym anamnezom z chastotoiu 58,9 % (53 iz 90), 12,2 % (11 z 90), ta 0 % vidpovidno, ta bez takogo – 75,4 % (144 zi 191), 3,1%(6 zi 191) ta 1,6% (3 zi 191) vidpovidno. Mutatsiï JAK2 V617F u khvorykh na spontanni MPN sposterigalysia v kozhniĭnozologichniĭ formi: spravzhniĭ politsytemiï (SP), esentsial'niĭ trombotsytemiï (ET) i pervynnomu miielofibrozi(PMF). Mutatsiï CALR vyiavlialysia vykliuchno u khvorykh na PMF ta ET, dostovirno chastishe u grupakh z radiatsiĭnymanamnezom (18,9 %, ta 33,3 %, proty 4,2 % ta 6,5 %), nizh bez takogo. Vodnochas chastota mutatsiĭ MPL vyznachenatil'ky u khvorykh na spontanni MPN – u 1,6 %. Potriĭno negatyvnyĭ mutatsiĭnyĭ status geniv JAK2, MPL ta CALR prevaliuvav u grupi khvorykh na MPN z radiatsiĭnym anamnezom i skladav 27,8 %, proty 16,2 %, bez takogo (r = 0,05).Vysnovky. Doslidzhennia genomu khvorykh na Ph-negatyvni MPN vyiavyly osoblyvosti molekuliarno-genetychnykhposhkodzhen' u tykh khvorykh, iaki zaznaly vplyvu ionizuiuchoï radiatsiï vnaslidok avariï na ChAES i tykh, khto zakhvorivspontanno. Otrymani dani mutatsiĭnogo statusu geniv JAK2, MPL ta CALR v genomi khvorykh na MPN ie neobkhidnymy dliarozshyrennia uiavlen' shchodo mekhanizmu leĭkogenezu, osoblyvo sprychynenogo radiatsiieiu.

The discovery and characterization of novel parasite antigens to improve the diagnosis of Trypanosoma cruzi by serological methods and for accurate and rapid follow-up of treatment efficiency are still needed. TcTASV is a T. cruzi-specific multigene family, whose products are expressed on the parasite stages present in the vertebrate host. In a previous work, a mix of antigens from subfamilies TcTASV-A and TcTASV-C (Mix A + C) was sensitive and specific to identify dogs with active infection of high epidemiological relevance. Here, TcTASV-A and TcTASV-C were assayed separately as well as together (Mix A + C) in an ELISA format on human samples. The Mix A + C presented moderate sensitivity (78%) but high diagnostic accuracy with a 100% of specificity, evaluated on healthy, leishmaniasic, and Strongyloides stercoralis infected patients. Moreover, antibody levels of pediatric patients showed-2 years posttreatment-diminished reactivity against the Mix A + C (P < 0.0001), pointing TcTASV antigens as promising tools for treatment follow-up. Fil: Floridia Yapur, Noelia Aldana del Rosario. Universidad Nacional de Salta. Facultad de Ciencias Naturales; Argentina. Universidad Nacional de Salta. Sede Regional Orán. Instituto de Investigación de Enfermedades Tropicales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta; Argentina Fil: Monje Rumi, Maria Mercedes. Universidad Nacional de Salta. Facultad de Ciencias Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentina Fil: Ragone, Paula Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentina Fil: Lauthier, Juan José. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentina Fil: Tomasini, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentina Fil: D'Amato, Anahí Alberti. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentina Fil: Diosque, Patricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentina Fil: Cimino, Rubén Oscar. Universidad Nacional de Salta. Sede Regional Orán. Instituto de Investigación de Enfermedades Tropicales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta; Argentina Fil: Gil, José Fernando. Universidad Nacional de Salta. Sede Regional Orán. Instituto de Investigación de Enfermedades Tropicales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Investigaciones en Energía no Convencional. Universidad Nacional de Salta. Facultad de Ciencias Exactas. Departamento de Física. Instituto de Investigaciones en Energía no Convencional; Argentina Fil: Sanchez, Daniel Oscar. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; Argentina Fil: Nasser, Julio Rubén. Universidad Nacional de Salta. Facultad de Ciencias Naturales; Argentina Fil: Tekiel, Valeria Sonia. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; Argentina

Purpose Evaluate current recommendation for the use of noninvasive ventilation (Bi-level positive airway pressure- BiPAP modality) in hypoxemic acute respiratory failure, excluding chronic obstructive pulmonary disease. Methods Electronic searches in MEDLINE, Web of Science, Clinical Trials, and The Cochrane Central Register of Controlled Clinical Trials. We searched for randomized controlled trials comparing BiPAP to a control group in patients with hypoxemic acute respiratory failure. Endotracheal intubation and death were the assessed outcomes. Results Of the 563 studies found, nine met the inclusion criteria for this systematic review. The pooled RR (95% CI) for intubation in patients with acute pulmonary edema (APE)/community acquired pneumonia (CAP) and in immunosuppressed patients (cancer and transplants) were 0.61 (0.39–0.84) and 0.77 (0.60–0.93), respectively. For Intensive Care Units (ICU) mortality, the RR (95% CI) in patients with APE/CAP was 0.51 (0.22–0.79). The heterogeneity was low in all comparisons. Conclusions NIV showed a significant protective effect for intubation in immunosuppressed patients (cancer and transplants) and in patients with APE/CAP. However, the benefits of NIV for other etiologies are not clear and more trials are needed to prove these effects.

BACKGROUND Merkel cell carcinoma (MCC) is a rare but aggressive primary cutaneous carcinoma with high mortality rates. The present study intends to delineate the epidemiological profile of patients with MCC seen at the Clinics Hospital of the Medical School at the University of Sao Paulo, Brazil, and its association with Merkel cell polyomavirus (MCPyV). METHODS This is a retrospective study. A search was performed in the hospital's medical index for all cases of MCC from January 1994 to December 2012. Among patients with MCC, the available tumoral skin specimens were analyzed with two different techniques of polymerase chain reaction (PCR) (conventional and real-time) for detection of MCPyV DNA. Additionally, paraffin-embedded samples of patients with non-MCC skin cancers were also analyzed. Analyses suitable for categorical data (i.e., x² of Fisher) were used to compare the proportion of patients in each group. RESULTS Nineteen patients with MCC and 20 patients with non-MCC skin cancers entered the study. All MCC samples available (13) tested positive for the presence of MCPyV DNA; however, in the non-MCC skin cancer samples, the MCPyV DNA was detected in 4 of 20 samples (20%). MCPyV DNA detection rate was higher in patients with MCC than in the other group, and its analysis was statistically significant (P

Objective Multiple embryos have been transferred to compensate for low implantation rates, which in turn, increase the likelihood of multiple pregnancies. Despite the publication of clinical guidelines and a reduction in the number of embryos transferred, double embryo transfer still is the most common practice. There is no clear evidence of who should receive the single embryo transfer (SET), and it is more commonly indicated for patients of good prognosis. However, it is not clear how much the presence of other infertility factors can affect the SET prognosis. The aim of this study was to evaluate differences in clinical pregnancy rates (CPR) of frozen-thawed SET cycles for women presenting with different infertility factors. Methods Retrospective cohort study evaluating 305 frozen-thawed SET cycles performed in the last 10 years in a private IVF center. We included patients undergoing ovarian stimulation cycles, using ejaculated sperm and a frozen-thawed ET. Embryos were routinely vitrified and warmed up, and the blastocysts were transferred after endometrium preparation. The cycles were categorized according to the infertility factor classified by the Society for Assisted Reproductive Technologies (SART) as anatomic female factor (n=55), endocrine female factor (n=26), endometriosis (n=37), male factor (n=60), ovarian insufficiency (n=26), unexplained (n=24), multiple factors (n=45) and other (n=32). CPR were compared between the groups and the multivariate analysis was performed to evaluate the association of each infertility factor and the CPR, adjusted for confounders. Results The women varied in age from 18 to 44 years (35.9±3.8), presented Body Mass Index of 22.4±3.1kg/m2, baseline serum FSH of 7.4±8.3 IU/ml, and had a mean of 11.0±8.4 MII oocytes recovered and 6.4±5.3 embryos cryopreserved. The CPR, according to infertility factors were: anatomic female factor (25.9%), endocrine female factor (30.8%), endometriosis (27.8%), male factor (20.7%), ovarian insufficiency (21.7%), unexplained (9.5%), multiple factors (17.1%) and other (20.7%). Multivariate analysis did not show significant association of infertility factors and CPR adjusted for confounders. Conclusions Patients presenting different infertility factors seem to have a satisfactory CPR for a SET cycle, except those with unexplained infertility. This is a preliminary outcome and the number of patients by category is small; in addition, the retrospective characteristics of the study are its limitations. Overall, our findings suggest that patients presenting any infertility factor, except unexplained infertility, are suitable to receive a SET with satisfactory outcomes.

Several works have shown different aspects of the use of the plant Moringa oleifera. However, few review studies bring an approach to its use in food preparation, specifying its role as a functional food and its use as a natural additive, focusing on food biochemistry and including sensory acceptance and safety. Composed by multiple bioactive substances, Moringa oleifera has the potential to be used as a food additive, mainly as a preservative with the potential to prevent lipid oxidation and other unwanted chemical reactions that lead to product deterioration. Furthermore, it can improve the physicochemical characteristics of food, increasing its quality and shelf life. It also promotes nutritional improvement, elevating protein, mineral, and vitamin levels. Despite this, the sensorial characteristics of this plant result in a low consumer acceptance of the fortified products, which is a problem for the food industry. Apart from inconclusive works, some data involving Moringa’s safety are contradictory, resulting in its commercialization prohibition in Brazil in 2019. This review focused on important data about Moringa use to contribute to the literature and to the food industry, describing information about this medicinal plant effects on food products.

The gray platelet syndrome (GPS) is a rare platelet disorder, characterized by impaired alpha-granule biogenesis in megakaryocytes and platelets due to NBEAL2 mutations. Typical clinical features include macrothrombocytopenia, bleeding and elevated vitamin B12 levels, while bone marrow fibrosis and splenomegaly may develop during disease progression. Recently, the involvement of other blood lineages has been highlighted, revealing the role of NBEAL2 outside the megakaryocyte-platelet axis. Low leukocyte counts, decreased neutrophil granulation and impaired neutrophil extracellular trap formation represent prominent findings in GPS patients, reflecting deranged innate immunity and associated with an increased susceptibility to infection. In addition, low numbers and impaired degranulation of NK cells have been demonstrated in animal models. Autoimmune diseases involving different organs and a spectrum of autoantibodies are present in a substantial proportion of GPS patients, expanding the syndromic spectrum of this disorder and pointing to dysregulation of the adaptive immune response. Low-grade inflammation, as evidenced by elevation of liver-derived acute-phase reactants, is another previously unrecognized feature of GPS which may contribute to disease manifestations. This review will focus on the mechanisms underlying the pathogenesis of blood cell abnormalities in human GPS patients and NBEAL2-null animal models, providing insight into the effects of NBEAL2 in hemostasis, inflammation and immunity.

Summary Colon cancer remains the third most common cause of cancer in the US, and the third most common cause of cancer death. Worldwide, colon cancer is the second most common cause of cancer and cancer deaths. At least 25% of patients still present with metastatic disease, and at least 25-30% will develop metastatic colon cancer in the course of their disease. While chemotherapy and surgery remain the mainstay of treatment, understanding the fundamental cellular niche and mechanical properties that result in metastases would facilitate both prevention and cure. Advances in biomaterials, novel 3D primary human cells, modelling using microfluidics and the ability to alter the physical environment, now offers a unique opportunity to develop and test impactful treatment., Graphical Abstract, Bioengineering; Cancer; Disease

Familial platelet disorder with predisposition to acute myelogenous leukemia (FPD/AML) is an autosomal dominant condition characterized by abnormal platelet number and function and 30-60% risk of hematologic malignancies, including myelodysplastic syndrome, acute myelogenous leukemia and T-cell lymphoblastic leukemia.1 It is caused by heterozygous germline muta- tions in the gene encoding the transcription factor RUNX1, which is essential in the emergence of definitive hematopoiesis and plays a key role in the lymphoid and megakaryocyte lineages.1,2 RUNX1 mutations predispose to leukemia by inducing genomic instability which favors the acquisition of secondary somatic mutations.3 Thrombocytopenia is mild to moderate with normal- sized platelets and most patients display a platelet func- tion defect with impaired platelet aggregation and dense- granule deficiency.1 However, the platelet phenotype is heterogeneous4 and even normal platelet count and func- tion have been reported in rare carriers of RUNX1 muta- tions,5 highlighting that the diagnosis may be overlooked. Dysregulated expression of RUNX1-targets in platelets, including downregulation of the α2 subunit (GPIa) of col- lagen receptor α2b16 or persistent myosin 10 (MYH10) expression,7 have been proposed as screening tools to guide diagnosis, although it is at present unknown whether all FPD/AML patients harbor these defects. Therefore, molecular screening is still required to ade- quately identify RUNX1 mutation carriers.We report the finding of genetic mosaicism in a patient belonging to a well-characterized FPD/AML pedigree and describe the relationship between molecular and clinical features over a 12-year follow-up. Fil: Glembotsky, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Marin Oyarzún, Cecilia Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: de Luca, Geraldine. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Marzac, Christophe. Inserm; Francia Fil: Auger, Nathalie. Inserm; Francia Fil: Goette, Nora Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Marta, Rosana Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Raslova, Hana. Inserm; Francia Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina

The infection by COVID-19 is a serious global public health problem. An efficient way to improve this disease's clinical management would be to characterize patients at higher risk of progressing to critically severe infection using prognostic biomarkers. The telomere length could be used for this purpose. Telomeres are responsible for controlling the number of maximum cell divisions. The telomere length is a biomarker of aging and several diseases. We aimed to compare leukocyte telomere length (LTL) between patients without COVID-19 and patients with different clinical severity of the infection. Were included 53 patients who underwent SARS-CoV-2 PCR divided in four groups. The first group was composed by patients with a negative diagnosis for COVID-19 (n = 12). The other three groups consisted of patients with a confirmed diagnosis of COVID-19 divided according to the severity of the disease: mild (n = 15), moderate (n = 17) and severe (n = 9). The LTL was determined by Q-PCR. The severe group had the shortest LTL, followed by the moderate group. The negative and mild groups showed no differences. There is an increase of patients with hypertension (p = 0.0099) and diabetes (p = 0.0067) in moderate and severe groups. Severe group was composed by older patients in comparison with the other three groups (p = 0.0083). Regarding sex, there was no significant difference between groups (p = 0.6279). In an ordinal regression model, only LTL and diabetes were significantly associated with disease severity. Shorter telomere length was significantly associated with the severity of COVID-19 infection, which can be useful as a biomarker or to better understand the SARS-CoV-2 pathophysiology., Highlights ● Telomere length is a biomarker in several diseases, including infections. ● Experimental report that associated leukocyte telomere length with severity of SARS-CoV-2. ● Leukocyte telomere length could be used to stratify patients with a greater risk of severe illness.

Contents Acknowledgments vii Notes on Contributors ix Introduction: Translation and Anthropology Paula G. Rubel and Abraham Rosman 1 Part I: General Problems of Translation 1 Lyotard and Wittengenstein and the Question of Translation Aram A. Yengoyan 25 2 Translation and Belief Ascription: Fundamental Barriers Todd Jones 45 3 Translation, Transduction, Transformation: Skating "Glossando" on Thin Semiotic Ice Michael Silverstein 75 Part II Specific Applications 4 The Unspeakable in pursuit of the Ineffable: Representations of Untranslatability in Ethnographic Discourse Michael Herzfeld 109 5 Translating Folk Theories of Translation Deborah Kapchan 135 6 Second Language, National Language, Modern Language and Post-Colonial Dilemmas of Voice Webb Keane 153 7 Notes on Transliteration Brinkley Messick 177 8 The Ethnographer as Pontifex Benson Saler 197 9 Text Translation as Prelude for Soul Translation Alan F. Segal 213 10 Structural Impediments to Translation in Art Wyatt MacGaffey 249 11 Are Kinship Terminologies and Kinship Concepts Translatable? Abraham Rosman and Paula G. Rubel 269 Index 285

Essential thrombocythemia (ET) is comprised among chronic myeloproliferative neoplasms (MPN) and is caused by driver mutations in JAK2, CALR and MPL, which lead to megakaryocyte proliferation and prominent thrombocytosis. Thrombosis remains the main cause of morbidity in ET and is driven by the interplay between blood cells, the endothelium, the clotting cascade and host-derived inflammatory mediators. Platelet activation plays a key role in the thrombotic predisposition, although the underlying mechanisms remain poorly defined. In addition to their role in hemostasis, platelets participate in innate immunity and inflammation owing to the expression of toll-like receptors (TLR), which recognize inflammatory signals, triggering platelet functional responses. Considering the impact of inflammation on ET procoagulant state, we assessed the contribution of TLR2 and TLR4 to platelet hemostatic and inflammatory properties in ET patients, by using Pam3CSK4 and lipopolysaccharide (LPS) as specific TLR2 and TLR4 ligands, respectively. TLR2 ligation induced increased surface translocation of α-granule-derived P-selectin and CD40L, which mediate platelet interaction with leukocytes and endothelial cells, respectively, and higher levels of dense granule-derived CD63 in patients, whereas PAC-1 binding was not increased and LPS had no effect on these platelet responses. Platelet-neutrophil aggregate formation was elevated in ET at baseline and after stimulation of both TLR2 and TLR4. In addition, ET patients displayed higher TLR2- and TLR4-triggered platelet secretion of the chemokine RANTES (CCL5), whereas von Willebrand factor release was not enhanced, revealing a differential releasate pattern for α-granule-stored inflammatory molecules. TLR-mediated hyperresponsiveness contrasted with impaired or preserved responses to classic platelet hemostatic agonists, such as TRAP-6 and thrombin. TLR2 and TLR4 expression on the platelet surface was normal, whereas phosphorylation of downstream effector ERK1/2 was higher in patients at baseline and after incubation with Pam3CSK4, which may partly explain the enhanced TLR2 response. In conclusion, exacerbated response to TLR stimulation may promote platelet activation in ET, boosting platelet/leukocyte/endothelial interactions and secretion of inflammatory mediators, overall reinforcing the thromboinflammatory state. These findings highlight the role of platelets as inflammatory sentinels in MPN prothrombotic scenario and provide additional evidence for the close intertwining between thrombosis and inflammation in this setting. Fil: Marin Oyarzún, Cecilia Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Glembotsky, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Goette, Nora Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Lev, Paola Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: de Luca, Geraldine. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Baroni Pietto, Maria Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Moiraghi, Beatriz. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina Fil: Castro Ríos, Miguel A.. Consultorios Hematológicos; Argentina Fil: Vicente, Angeles. Hospital Alemán; Argentina Fil: Marta, Rosana Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Schattner, Mirta Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina

Chromosome 6q24-related transient neonatal diabetes mellitus is characterized by intrauterine growth restriction and low birth weight, with neonatal hyperglycemia resolving by 18 months and an increased risk for type 2 diabetes in adulthood. Molecularly, it is caused by overexpression of the 6q24 imprinted chromosomal region due to a duplication, uniparental disomy, or abnormal methylation. Conventional testing for this condition analyzes methylation patterns at the 6q24 locus but does not evaluate for the presence of other surrounding chromosomal abnormalities. We report a female with a history of neonatal hyperglycemia due to a paternally inherited duplication at chromosomal location 6q24. She subsequently presented to the pediatric genetics clinic at 15 months of age with developmental delay and abnormal balance. Microarray analysis identified a larger 14 Mb chromosomal duplication from 6q24 to 6q25.2, consistent with a diagnosis of duplication 6q syndrome. This case highlights the clinical importance of pursuing further genetic evaluation in patients diagnosed with chromosome 6q24-related neonatal hyperglycemia via targeted methylation-specific multiplex ligation-dependent probe amplification analysis identifying a duplication in this region. Early identification and intervention can improve developmental outcomes for patients with larger chromosome 6q duplications.

Major surgery is associated with an increased risk of venous thromboembolism, thus the application of mechanical or pharmacologic prophylaxis is recommended. The incidence of venous thromboembolism in patients with inherited platelet disorders undergoing surgical procedures is unknown and no information on the current use and safety of thromboprophylaxis, particularly of low-molecular-weight-heparin in these patients is available. Here we explored the approach to thromboprophylaxis and thrombotic outcomes in inherited platelet disorders patients undergoing surgery at venous thromboembolism-risk participating in the multicenter SPATA study. We evaluated 210 surgical procedures carried out in 155 patients with well-defined forms of inherited platelet disorders (venous thromboembolism-risk: 31% high, 28.6% intermediate, 25.2% low, 15.2% very low). The use of thromboprophylaxis was low (23.3% of procedures), with higher prevalence in orthopedic and gynecological surgeries, and was related to venous thromboembolism-risk. The most frequently employed thromboprophylaxis was mechanical and appeared to be effective, as no patients developed thrombosis, including patients belonging to the highest venous thromboembolism-risk classes. Low-molecular-weight-heparin use was low (10.5%) and it did not influence the incidence of post-surgical bleeding or of antihemorrhagic prohemostatic interventions. Two thromboembolic events were registered, both occurring after high venous thromboembolism-risk procedures in patients who did not receive thromboprophylaxis (4.7%). Our findings suggest that venous thromboembolism incidence is low in patients with inherited platelet disorders undergoing surgery at venous thromboembolism-risk and that it is predicted by the Caprini score. Mechanical thromboprophylaxis may be of benefit in patients with inherited platelet disorders undergoing invasive procedures at venous thromboembolism-risk and low-molecular-weight-heparin should be considered for major surgery. Fil: Paciullo, Francesco. Università di Perugia; Italia Fil: Bury, Loredana. Università di Perugia; Italia Fil: Noris, Patrizia. Universita Degli Studi Di Pavia; Italia Fil: Falcinelli, Emanuela. Università di Perugia; Italia Fil: Melazzini, Federica. Universita Degli Studi Di Pavia.; Italia Fil: Orsini, Sara. Università di Perugia; Italia Fil: Zaninetti, Carlo. Universita Degli Studi Di Pavia.; Italia Fil: Abdul Kadir, Rezan. Haemophilia Centre And Haemostasis Unit, Royal Free Fou; Reino Unido Fil: Obeng Tuudah, Deborah. Haemophilia Centre And Haemostasis Unit, Royal Free Fou; Reino Unido Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Glembotsky, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Fabris, Fabrizio. Università di Padova; Italia Fil: Rivera, Jose. Universidad de Murcia; España Fil: Lozano, Maria Luisa. Universidad de Murcia; España Fil: Butta, Nora. Hospital Universitario la Paz; España Fil: Favier, Remi. French Reference Centre For Inherited Platelet Disorder; Francia Fil: Cid, Ana Rosa. Hospital Universitario y Politecnico la Fe; España Fil: Fouassier, Marc. French Reference Centre For Inherited Platelet Disorder; Francia Fil: Podda, Gian Marco. Università degli Studi di Milano; Italia Fil: Santoro, Cristina. Università degli studi di Roma "La Sapienza"; Italia Fil: Grandone, Elvira. Casa Sollievo Della Sofferenza,s.giovanni Rotondo; Italia Fil: Henskens, Yvonne. Maastricht University Medical Centre; Países Bajos Fil: Nurden, Paquita. French Reference Centre For Inherited Platelet Disorder; Francia Fil: Zieger, Barbara. Albert Ludwigs University of Freiburg; Alemania Fil: Cuker, Adam. University of Pennsylvania; Estados Unidos Fil: Devreese, Katrien. University of Ghent; Bélgica Fil: Tosetto, Alberto. Hospital San Bortolo; Italia Fil: De Candia, Erica. Istituto Nazionale di Ricovero e Cura a Carattere Scientifico "Saverio de Bellis"; Italia Fil: Dupuis, Arnaud. French Reference Centre For Inherited Platelet Disorder; Francia Fil: Miyazaki, Koji. Kitasato University School Of Medicine; Japón Fil: Othman, Maha. Queens University; Canadá Fil: Gresele, Paolo. Università di Perugia; Italia

Background. Polycythemia vera (PV) patients are treated with periodic therapeutic phlebotomy (TP) alone or in combination with either hydroxyurea (HU), ruxolitinib (RUX) or interferon (IFN) to maintain hematocrit (HCT) levels below 45% as per NCCN guidelines. Since patients are seen periodically, PV patients may spend significant time with HCT levels above 45%, thereby increasing their risk of thrombosis [Marchioli NEJM 2013]. PV is associated with systemic symptoms with fatigue. These fatigue-related symptoms are found to be the most prevalent and severe as reported in an international survey among PV patients [Scherber Cancer 2016]. Symptomatic iron deficiency represents an unaddressed clinical challenge to PV patients as most PV patients have iron deficiency at diagnosis due to increased iron utilization [Ginzburg Leukemia 2018]. The iron deficiency worsens after repeated TP. We have demonstrated in a phase 2 study that rusfertide (PTG-300) has a good tolerability profile and achieves HCT control in PV patients with improvement in iron deficiency. Methods. This is a Phase 3, multicenter, global, randomized trial that compares the efficacy and safety of rusfertide compared to placebo when added on to current therapy for PV (Figure 1). The study population is PV subjects who require frequent phlebotomies to control their hematocrit with or without concurrent therapy. This is a three-part study in subjects with polycythemia vera: - Part 1a: randomized, double-blind, placebo-controlled, add-on parallel-group period for 32 weeks. Subjects will be stratified by their ongoing PV treatment and randomized 1:1 to rusfertide or placebo added-on to their ongoing PV treatment. - Part 1b: open-label treatment phase during which all subjects who complete Part 1a successfully will receive rusfertide for 20 weeks (Week 32 through Week 52). - Part 2: Long term extension (LTE) phase during which all subjects who complete Part 1b will continue to receive rusfertide for 32 weeks (Week 52 to Week 84). Inclusion Criteria: Approximately 250 subjects will be randomized. Eligibility criteria include PV diagnosis (by 2016 WHO criteria) and frequent phlebotomies with or without concurrent cytoreductive therapy to maintain HCT below 45% in the 6 months prior to enrollment in Part 1. Eligible subjects will continue to receive their therapy at screening for PV (phlebotomy alone (TP) or cytoreductive therapy + TP) and must have a hematocrit The "add on" design allows subjects to receive standard cytoreductive therapy to control WBC and/or platelets and to receive rusfertide/placebo. The dose of cytoreductive therapy in Part 1a and Part 1b may be decreased for safety but may not be increased for efficacy including control of hematocrit, elevated platelets and/or WBC. Primary endpoint: Proportion of subjects achieving a response starting at Week 20 through Week 32 (inclusive) who receive rusfertide compared to placebo. A response is defined as absence of phlebotomy eligibility defined as either: 1. a confirmed hematocrit ≥45% and that is at least 3% higher than the baseline hematocrit (value immediately prior to randomization at Week 0); confirmation required within 1 to 7 days, or 2. a hematocrit ≥48%. Key words: Hepcidin, Hematocrit, Rusfertide, PTG-300, Polycythemia Vera, PV, Therapeutic Phlebotomy Figure 1 Figure 1. Disclosures Verstovsek: Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; PharmaEssentia: Research Funding; Protagonist Therapeutics: Research Funding; CTI BioPharma: Research Funding; Ital Pharma: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; Celgene: Consultancy, Research Funding; Promedior: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Kuykendall: Pharmaessentia: Honoraria; Protagonist: Consultancy, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria; Abbvie: Honoraria; Incyte: Consultancy; Blueprint: Honoraria. Hoffman: AbbVie Inc.: Other: Data Safety Monitoring Board, Research Funding; Novartis: Other: Data Safety Monitoring Board, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Kartos Therapeutics, Inc.: Research Funding. Pemmaraju: Incyte: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; MustangBio: Consultancy, Other; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; DAVA Oncology: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Protagonist Therapeutics, Inc.: Consultancy; Roche Diagnostics: Consultancy; LFB Biotechnologies: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Samus: Other, Research Funding; Sager Strong Foundation: Other; Aptitude Health: Consultancy; Affymetrix: Consultancy, Research Funding; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Valone: Protagonist Therapeutics: Consultancy, Current equity holder in publicly-traded company. Modi: Protagonist Therapeutics: Current Employment. Khanna: Protagonist: Current Employment, Current equity holder in publicly-traded company. O'Connor: Protagonist Therapeutics: Current Employment. Gupta: Protagonist Therapeutics: Current Employment. Kiladjian: Taiho Oncology, Inc.: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

Introduction: Immunotherapy for AML holds promise in overcoming chemotherapy resistance and in preserving immunologic memory necessary for durable remissions.A bispecific T-cell engaging antibody targeting CD3 and CD123 (CD123-CODV-TCE) has been shown to stimulate T cells to target CD123-expressing leukemic cells in vitroand in mouse models 1. While the short-term immune stimulation mediated by the CD123TCE has the potential to result in clinical response, long-term disease control will require the development of immune memory. We have developed a personalized cancer vaccine in which patient's dendritic cells are fused with autologous leukemia cells resulting in presentation of a wide range of antigens to the immune system. Here, we describe a novel combination of CD123TCE with a DC/AML fusion vaccine ex vivo and in a xenograft murine model. We hypothesized that the CD123TCE will direct the vaccine-educated T cells to not only more effectively eradicate target leukemia cells but also evoke a repertoire of memory T cells and long-term response. Methods/Results: AML cells expressing CD123 were isolated from bone marrow mononuclear cells (BMMCs) from AML patients (n=3). DCs were generated from autologous adherent peripheral blood mononuclear cells (PBMCs) obtained at the time of disease remission as previously described 2,3. Concurrently, CD3+ T cells were isolated from the non-adherent fraction of PBMCs using magnetic bead separation. Fusion cells were generated by co-culturing the DC and tumor cells at a ratio of 3:1 in the presence of polyethylene glycol (PEG). Vaccine educated T cells were then generated by co-culture of T cells with the autologous fusion cells at a ratio of 10:1 for 5-7 days followed by T cell expansion via CD3/CD28 ligation. The capacity of the vaccine-educated T cells to target autologous leukemia cells with the addition of CD123TCE was assessed. The results demonstrated a statistically significant increase in Granzyme B activity in the target AML cells following co-culture with vaccine-educated T cells and the addition of the CD123TCE, compared to T cells + isotype control (n=3). Furthermore, vaccine stimulation in combination with CD123TCE led to a robust increase in induction of tumor specific activated T cells as detected by CD137 expression and intracellular IFN-γ production after co-culture of vaccine-educated T cells with autologous tumor cells in the presence of CD123TCE. The addition of CD123TCE to vaccine-educated T cells resulted in mean 25.4% and 9.6% intracellular IFN-γ expression for CD8 and CD4 T cells, respectively, compared to 8.5 and 3.1% IFN-γ expression following the addition of isotype control (n=3). Next, we examined the efficacy of the combined treatment with vaccine-educated T cells and CD123TCE in-vivo, in two independent xenograft experiments. NSG mice were irradiated with 300rads and challenged with 1x10 6 patient-derived CD123+ tumor cells via retro-orbital injections. After detection of human AML engraftment in the PB on day 76, the mice were inoculated IV with 1X10 6 resting, or ex vivo fusion vaccine educated autologous T cells IV. Subsequently, cohorts of mice were treated with CD123TCE or an appropriate isotype control every 3 days IP. A significant decrease in human leukemia burden was detected in the peripheral blood, spleen and bone marrows of analyzed animals after treatment with vaccine educated T cells and isotype control, or resting T cells and CD123TCE, compared to untreated mice (n=5). Strikingly, no detectable AML was found in peripheral blood, spleens and bone marrows of mice treated with vaccine educated T cells in combination with TCE (n=5). Of note, treatment with vaccine educated T cells led to an expansion of human CD3+ T cells in tissues obtained from the analyzed animals. These human T cells persisted in mice treated with the CD123TCE with a two-fold increase in tumor-specific CD8+ T cells, as assessed by intracellular IFN-γ secretion following ex vivo stimulation with autologous tumor lysate. Conclusions: We demonstrated that the combination of DC/AML fusion vaccine and CD123TCE led to increase in tumor specific T cell immunity, both ex-vivo and in a xenograft murine model when compared to uneducated T cells with CD123TCE or educated T cells with isotype control molecule. Most significantly, the combination treatment was shown to eradicate AML in this model with all animals remaining disease-free several months post inoculation. Disclosures Stroopinsky: The Blackstone Group: Consultancy. Nahas: Kite Pharma: Current Employment. Fraenkel: Sanofi: Current Employment. Yildirim: Sanofi: Current Employment. Bonnevaux: Sanofi: Current Employment. Guerif: Sanofi: Current Employment. Kufe: Genus Oncology: Current equity holder in publicly-traded company; Canbas: Consultancy; REATA: Consultancy, Current equity holder in publicly-traded company; Hillstream BioPharma: Current equity holder in publicly-traded company. Rosenblatt: Parexel: Consultancy; Wolters Kluwer Health: Consultancy, Patents & Royalties; Bristol-Myers Squibb: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imaging Endpoints: Consultancy; Attivare Therapeutics: Consultancy. Avigan: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Aviv MedTech Ltd: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Parexcel: Consultancy; Takeda: Consultancy; Sanofi: Consultancy.

Immune thrombocytopenia (ITP) is characterized by itsheterogeneity among patients with regard to both clinicalfeatures and response to treatment. Although there isstill much to investigate, this heterogeneity could be thereflection of multiple mechanisms contributing to thrombocytopenia,affecting individual patients in variable proportions.These mechanisms include increased platelet clearanceby autoantibodies targeting main platelet glycoproteins(GPs) (IIbIIIa, IbIX and IaIIa) and impaired megakaryopoiesis(McMillan et al, 2004). Recently, we reported thatITP plasma samples inhibit proplatelet (PP) formation bynormal megakaryocytes (MKs) (Lev et al, 2014), demonstratingthat thrombopoiesis, the key step of platelet production,is altered, a finding further confirmed by others(Iraqi et al, 2015). In agreement with these experimentaldata, studies on platelet kinetics show inadequate plateletproduction according to the degree of thrombocytopenia(Ballem et al, 1987). Fil: Grodzielski, Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Di Buduo, Christian A.. Universidad de Pavía; Italia. Fundacion San Matteo; Italia Fil: Goette, Nora Paula. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Lev, Paola Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Soprano, Paolo M.. Universidad de Pavía; Italia. Fundacion San Matteo; Italia Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Balduini, Alessandra. Universidad de Pavía; Italia. Fundacion San Matteo; Italia. Tufts Univwersity Medford; Estados Unidos Fil: Marta, Rosana Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina

In the field of veterinary anatomy, most of the specimens used in practical sessions are perfused with fixatives. Thus, they can be used for a longer time(,) reducing the number of animals for educational purposes. Formalin is the most commonly used fixative, consisting of a 37% formaldehyde solution. However, formaldehyde is a powerful irritant of the eyes and airways and is considered carcinogenic, causing nasopharyngeal cancer in exposed workers and professionals. In the present study, we explored an alternative method to avoid the use of formaldehyde in specimens used for gross anatomy practical sessions. We propose an inexpensive, non‐toxic fixative that is available worldwide, such as sea salt. This method consists of a continuous perfusion of saturated salt solution for a period of 6–8 h, enabling drainage of the solution to avoid a weight increase of the specimen, and allowing salt to be retained in the tissue. The method is based on recirculation of the saturated salt solution instead of maceration. Perfused specimens retained their natural consistency and joint mobility, with no blood, resembling a piece of meat from the slaughterhouse. They could be used immediately without a maceration period, or stored in the fridge until use and then kept in a bath of saturated salt solution for future conservation. In the case of the former, no refrigeration was needed. The specimens did not have an irritating or offensive smell, and could be used for long sessions (several hours per day) and stored for long periods. However, the blood vessels used for perfusion determine the results: a less invasive approach (through common carotid arteries) gave good preservation of the musculoskeletal system, whereas more invasive access to cannulate the abdominal aorta and vena cava caudalis was required to achieve better preservation of the viscera. In conclusion, we propose that perfusion followed by immersion in a saturated salt solution is a good alternative method for the preservation of specimens used in the practical teaching of gross veterinary anatomy. It is a very simple and inexpensive technique, and is much healthier for users than traditional formalin. Moreover, specimens can be preserved for prolonged periods, and maintain a similar appearance and consistency to fresh material.

Despite the evidence indicating that decision aids (DA) improve informed treatment decision making for prostate cancer (PCa), physicians do not routinely recommend DAs to their patients. We conducted semi-structured interviews with urologists (n = 11), radiation oncologists (n = 12) and primary care physicians (n = 10) about their methods of educating low-risk PCa patients regarding the treatment decision, their concerns about recommending DAs, and the essential content and format considerations that need to be addressed. Physicians stressed the need for providing comprehensive patient education before the treatment decision is made and expressed concern about the current unevaluated information available on the Internet. They made recommendations for a DA that is brief, applicable to diverse populations, and that fully discloses all treatment options (including active surveillance) and their potential side effects. Echoing previous studies showing that low-risk PCa patients are making rapid and potentially uninformed treatment decisions, these results highlight the importance of providing patient education early in the decision-making process. This need may be fulfilled by a treatment DA, should physicians systematically recommend DAs to their patients. Physicians’ recommendations for the inclusion of particular content and presentation methods will be important for designing a high quality DA that will be used in clinical practice.

Impaired iron homeostasis and the suppressive effects of proinflammatory cytokines on erythropoiesis, together with alterations of the erythrocyte membrane that impair its survival, cause anemia of inflammation. Recent epidemiologic studies have connected inflammatory anemia with critical illness, obesity, aging, kidney failure, cancer, chronic infection, and autoimmune disease. The proinflammatory cytokine, interleukin-6, the iron regulatory hormone, hepcidin, and the iron exporter, ferroportin, interact to cause iron sequestration in the setting of inflammation. Although severe anemia is associated with adverse outcomes in critical illness, experimental models suggest that iron sequestration is part of a natural defense against pathogens.

Equid alphaherpesvirus 1 (EHV-1) is an important pathogen of horses, associated with respiratory, neurological disease and abortions. As vaccination is not always effective, anti-herpetic therapy may represent an alternative to prevent the losses caused by the infection. We herein investigated the activity of ganciclovir (GCV), an anti-herpetic human drug, in rabbits experimentally infected with EHV-1. Thirty-days-old New Zealand rabbits were allocated in three groups (6 animals each) and submitted to different treatments: G1 (non-infected controls), G2 (inoculated with EHV-1) - 107 TCID50 intranasally - IN) and G3 (inoculated IN with EHV-1 and treated with GCV - 5mg/kg/day for 7 days) and monitored thereafter. All animals of G2 developed systemic signs (moderate to severe apathy, anorexia), ocular discharge and respiratory signs (serous to mucopurulent nasal discharge), including mild to severe respiratory distress. Viremia was detected in all rabbits of G2 for up to 11 days (mean duration = 6.5 days). One animal died after severe respiratory distress and neurological signs (bruxism, opistotonus). In addition, these animals gained less weight than the control (G1) and GCV-treated rabbits (G3) from days 4 to 14pi (p

Mechanisms leading to low platelet count in immune thrombocytopenia (ITP) involves both decreased production and increased destruction of platelet. However, the contribution of these pathologic mechanisms to clinical outcome of individual patients is uncertain. Here we evaluated diferent pathogenic mechanisms including in vitro megakaryopoiesis, platelet/megakaryocyte (MK) desialylation and MK apoptosis, and compared these efects with thrombopoyesis and platelet apoptosis in the same cohort of ITP patients. Normal umbilical cord blood-CD34+ cells, mature MK derived cells or platelets were incubated with plasma from ITP patients. Despite inhibition of thrombopoiesis previously observed, megakaryopoiesis was normal or even increased. Plasma from ITP patients afected the sialylation pattern of control platelets and this efect occurred concomitantly with apoptosis in 35% ITP samples. However, none of these abnormalities were observed in control MKs incubated with ITP plasma. Addition of mononuclear cells as immune efectors did not lead to phosphatidylserine exposure in MK, ruling out an antibody-mediated cytotoxic efect. These results suggest that both desialylation and apoptosis may be relevant mechanisms leading to platelet destruction although, they do not interfere with MK function. Analysis of these thrombocytopenic factors in individual patients showed no specifc distribution pattern. However, the presence of circulating antiplatelet autoantibodies was associated with higher incidence of abnormalities. In conclusion, the causes of thrombocytopenia are multifactorial and may occur together, providing a rational basis for the use of combination therapies targeting concomitant ITP mechanisms in patients with refractory disease. Fil: Grodzielski, Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Goette, Nora Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Glembotsky, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Baroni Pietto, Maria Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Mendez Huergo, Santiago Patricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Pierdominici, Marta S.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina Fil: Montero, Verónica S.. Centro de Educaciones Médicas e Investigación Clínica "Norberto Quirno"; Argentina Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Molinas, Felisa Concepción. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Lev, Paola Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Marta, Rosana Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina

Efficient and economical delivery of pharmaceuticals to patients is critical for effective therapy. Here we describe a multiorgan (lung, liver and breast cancer) microphysiological system (“Body-on-a-Chip”) designed to mimic both inhalation therapy and/or intravenous therapy using curcumin as a model drug. This system is “pumpless” and self-contained using a rocker platform for fluid (blood surrogate) bidirectional recirculation. Our lung chamber is constructed to maintain an air-liquid interface and contained a “breathable” component that was designed to mimic breathing by simulating gas exchange, contraction and expansion of the “lung” using a reciprocating pump. Three cell lines were used: A549 for the lung, HepG2 C3A for the liver, and MDA MB231 for breast cancer. All cell lines were maintained with high viability (>85%) in the device for at least 48 hours. Curcumin is used to treat breast cancer and this allowed us to compare inhalation delivery versus intravenous delivery of the drug in terms of effectiveness and potentially toxicity. Inhalation therapy could be potentially applied at home by the patient while intravenous therapy would need to be applied in a clinical setting. Inhalation therapy would be more economical and allow more frequent dosing with a potentially lower level of drug. For 24 hour exposure to 2.5 and 25 μM curcumin in the flow device the effect on lung and liver viability was small to insignificant, while there was a significant decrease in viability of the breast cancer (to 69% at 2.5 μM and 51% at 25 μM). Intravenous delivery also selectively decreased breast cancer viability (to 88% at 2.5 μM and 79% at 25 μM) but was less effective than inhalation therapy. The response in the static device controls was significantly reduced from that with recirculation demonstrating the effect of flow. These results demonstrate for the first time the feasibility of constructing a multiorgan microphysiological system with recirculating flow that incorporates a “breathable” lung module that maintains an air-liquid interface.

Background AF is reported in up to 20% of patients with Chagas, a prevalent disease in Latin-America. PV isolation (PVI) in the cornerstone of AF ablation. However, in Chagas cardiopathy (ChC), microvascular and autonomic abnormalities, atrial fibrosis and sinoatrial dysfunction are possible mechanisms of AF. Therefore, the results of PVI may be different in this subgroup. Objectives To describe long-term results of AF ablation in pts with Chagas versus non-Chagas disease (ChC x NonCh) and evaluate risk factors for post-ablation recurrence. Methods This is a prospective, single-center study that included pts with nonvalvular AF who underwent PVI between 2013 and 2016. All procedures were guided by eletroanatomic mapping and intracardiac echocardiogram. Categorical variables were analyzed using chi-square test and numerical variables with t-student test. Binary logistic regression was performed to identify independent predictors of recurrence of any sustained atrial tachyarrhythmias. Results Ablation was performed in 160 pts (54±15 yo, 59% male): 42 pts with ChC (26%, 62±8 yo) and 118 NonChC (74%, 53±15 yo; p At multivariate analysis, long-term persistent AF, hypertension and Chagas disease (HR= 2.21, 3.36 and 3.16, respectively) were independent predictors of recurrence. Conclusions Chagas disease is an independent predictor of recurrence after PVI. Further studies should address which strategy is more appropriate to this group of patients.

Acoustic wave based sensors have a major impact in the detection of low concentration of biological and chemical agents. Magnetoelastic resonator platforms are particularly interesting due to their low cost and wireless detection process. However, efforts in improving their performance are still focused only in the reduction of the size. In the present study, a new way to increase the sensitivity of magnetoelastic sensor platforms is proposed. This work demonstrates, both theoretically and experimentally, that the mass load sensitivity can be improved by tailoring sensor geometry and mass load position. Triangular and arched triangular shapes have been tested and compared with the traditional rectangular ones. It has been observed an increase in the mass sensitivity of more than 400% in Metglas (R) 2826MB magnetoelastic sensor by using new sensor platform geometries. Even higher sensitivities have been obtained by doing partial coatings on the sensor edge/tip instead of the traditional complete uniform coating. New geometries present an increase up to 6400% in partial coatings. The obtained results clearly show the key role of magnetoelastic resonator platforms geometries in the increase of mass load sensitivity and their importance in the draw of future labor-free and wireless sensors for low mass detection systems. This work was financially supported by the "Ministerio de Economia, Industria y Competitividad" (MAT2016-76739R(AEI/FEDER, UE)) and by the "Gobierno Vasco", under projects IT-630-13 (Basque University Research System Groups), ACTIMAT KK-2018/00099 and muF4 KK-2017/00089 (Elkartek Program). A.C. Lopes thanks to MSCA-IF-2015 (Marie Sklodowska Curie Actions) of the European Union's Horizon 2020 Programme for the received funds under grant agreement no [701852].

Childhood trauma is associated with poor health outcomes in adulthood. Mechanisms for these associations are not well understood because past studies have focused predominantly on populations that have already developed physical and mental health problems. The present study examined the association between childhood trauma and stress-related vulnerability factors in a healthy adult sample (n = 79; 68% female, mean age = 27.5, SD = 6.5). Emotion regulation difficulties were examined as a potential mediator. Participants completed baseline laboratory assessments of reported childhood trauma, emotion regulation difficulties, prior month sleep quality, baseline impedance cardiography and behavioural tests of executive functioning (EF) and a three-day experience sampling assessment protocol that included sleep diary, reported and objective pre-sleep arousal, daily hassles and reported EF difficulties. Reported history of childhood abuse was significantly associated with difficulties in emotion regulation, self-report and objective pre-sleep arousal, diary-assessed sleep quality, daily hassles and reported EF difficulties. Reported history of childhood neglect was associated with greater pre-sleep arousal and poorer EF-behavioural control. Emotion regulation difficulties mediated the relationship between childhood abuse and reported pre-sleep arousal, daily hassles and reported EF difficulties. In conclusion, history of childhood trauma is associated with a variety of stress-related vulnerability factors in healthy adults that may be viable early intervention targets.

Chronic myeloproliferative neoplasms (MPN) are stem cell disorders driven by mutations in JAK2, CALR, or MPL genes and characterized by myeloid proliferation and increased blood cell counts. They encompass three closely related conditions, including essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Elevated levels of cytokines released by clonal and non-clonal cells generate a chronic proinflammatory state that contributes to disease pathogenesis. Thrombosis represents the most common cause of morbidity and mortality in MPN, although paradoxically, patients may also present with a bleeding diathesis. The mechanisms leading to thrombosis are complex and multiple and include increased blood cells together with qualitative abnormalities of red cells, leukocytes, and platelets that favor a prothrombotic activated phenotype. The functional interplay between blood cells, the clotting cascade, and dysfunctional endothelium contributes to hypercoagulability and this process is perpetuated by the effect of inflammatory cytokines. In addition to their well-known function in hemostasis, platelets contribute to innate immunity and inflammation and play a key role in MPN thromboinflammatory state. In vivo platelet activation leads to platelet aggregate formation and exposure of adhesion molecules which favor their interaction with activated neutrophils and monocytes leading to circulating platelet-leukocyte heterotypic aggregates. Platelets are recruited to the activated endothelium further enhancing the reciprocal activation of both cell types. Crosstalk between activated cells drives cytokine production, further fuelling the self-reinforcing thromboinflammatory loop. In addition, MPN platelets provide a procoagulant scaffold which triggers the coagulation cascade and platelet-derived microparticles amplify this response. Markers of platelet, leukocyte, endothelial and coagulation activation are increased in MPN patients although prospective studies are required to determine the potential value of these parameters for identifying patients at increased thrombotic risk. Thrombosis remains the main complication of MPN patients, with a high risk of recurrence despite adequate cytoreductive and antithrombotic treatment. Deeper insight into the mechanism favoring thrombosis development in this setting may lead to novel therapeutic approaches for MPN thrombosis. Considering the critical role of inflammation in the vascular risk, concomitant targeting of inflammatory pathways could potentially impact on primary or secondary prevention strategies. Fil: Marin Oyarzún, Cecilia Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina

Study Objectives Much of what we assume about the effects of short sleep duration on neural reward processing derives from total sleep deprivation studies. Although total sleep deprivation appears rare, habitual short sleep is common: 30% of working US adults report habitually sleeping ≤ 6 hours/night. It remains largely unknown whether habitual short sleepers exhibit similar reward processing brain activation patterns to those observed following total sleep deprivation in prior studies. Therefore, our aim was to test objectively reward processing brain activation patterns associated with self-reported habitual short sleep duration in a large sample. Methods Nine hundred and fifty-two adult participants from the Human Connectome Project database were grouped on reported habitual short (≤6 hours) vs. medium-length (7–9 hours) sleep duration using the Pittsburgh Sleep Quality Index (PSQI). Reward processing brain activation was examined using a gambling task during functional magnetic resonance imaging (fMRI). Subject-level covariates for age, sex, continuous sleep duration, daytime dysfunction, and PSQI total score are provided as supplemental analyses. Results Brain activation patterns revealed expected reward processing-related activation for age and sex. However, activation for sleep duration, dysfunction, and PSQI score did not correspond to those evident in previous total sleep deprivation studies. Conclusions Self-reported short sleep duration, perceived sleep-related dysfunction, and sleep quality via PSQI do not appear to be meaningfully associated with activation in well-described regions of the human neurobiological reward circuit. As these findings are counter to prior results using experimental sleep deprivation, future work focused on more direct comparisons between self-reported sleep variables and experimental sleep deprivation appears warranted.

Myeloproliferative neoplasms (MPNs) driver mutations are usually found in JAK2, MPL, and CALR genes; however, 10%-15% of cases are triple negative (TN). A previous study showed lower rate of JAK2 V617F in primary myelofibrosis patients exposed to low doses of ionizing radiation (IR) from Chernobyl accident. To examine distinct driver mutations, we enrolled 281 Ukrainian IR-exposed and unexposed MPN patients. Genomic DNA was obtained from peripheral blood leukocytes. JAK2 V617F, MPL W515, types 1- and 2-like CALR mutations were identified by Sanger Sequencing and real time polymerase chain reaction. Chromosomal alterations were assessed by oligo-SNP microarray platform. Additional genetic variants were identified by whole exome and targeted sequencing. Statistical significance was evaluated by Fisher's exact test and Wilcoxon's rank sum test (R, version 3.4.2). IR-exposed MPN patients exhibited a different genetic profile vs unexposed: lower rate of JAK2 V617F (58.4% vs 75.4%, P =.0077), higher rate of type 1-like CALR mutation (12.2% vs 3.1%, P =.0056), higher rate of TN cases (27.8% vs 16.2%, P =.0366), higher rate of potentially pathogenic sequence variants (mean numbers: 4.8 vs 3.1, P =.0242). Furthermore, we identified several potential drivers specific to IR-exposed TN MPN patients: ATM p.S1691R with copy-neutral loss of heterozygosity at 11q; EZH2 p.D659G at 7q and SUZ12 p.V71 M at 17q with copy number loss. Thus, IR-exposed MPN patients represent a group with distinct genomic characteristics worthy of further study., United States. Army Research Office. Institute for Collaborative Biotechnologies (Grant W9111NF-09–001)

Plant diseases are considered one of the main factors influencing food production and to minimize losses in production, it is essential that crop diseases have a fast detection and recognition. Nowadays, recent studies use deep learning techniques to diagnose plant diseases in an attempt to solve the main problem: a fast, low-cost and efficient methodology to diagnose plant diseases. In this work, we propose the use of classical convolutional neural network (CNN) models trained from scratch and a Multichannel CNN (M-CNN) approach to train and evaluate the PlantVillage dataset, containing several plant diseases and more than 54,000 images (divided into 38 diseases classes with 14 plant species). In both proposed approaches, our results achieved better accuracies than the state-of-the-art, with faster convergence and without the use of transfer learning techniques. Our multichannel approach also demonstrates that the three versions of the dataset (colored, grayscaled and segmented) can contribute to improve accuracy, adding relevant information to the proposed artificial neural network.

Brain connectivity analysis via complex networks has been widely applied to elucidate functional aspects related to brain diseases, such as Alzheimer and Parkinson, and, more recently, to investigations concerning the functional organization of brain regions under motor imagery in brain computer interfaces (BCIs). Therefore, this work seeks to investigate the classification performance of steady-state visually evoked potential (SSVEP) brain-computer interfaces based on functional connectivity. Two different approaches were chosen for extracting functional connectivity and estimating the adjacency matrix from SSVEP-EEG signals: classical Pearson correlation and a new proposal based on Space-Time recurrence counting. These strategies were followed by graph feature evaluation (clustering coefficient, degree, betweenness and eigenvalue centralities), feature selection via Davies-Bouldin index and classification using a least squares classifier for 15 subjects in a 4-command SSVEP-BCI system. For comparison, we also employed a classical spectral feature extraction approach based on the fast Fourier transform (FFT). It was observed that it is possible to separate the classes with a mean accuracy of 0.56 for Pearson and 0.61 for the STR framework, with the clustering coefficient and the eigenvector centrality being the best attributes for these scenarios, respectively. Nonetheless, classical FFT-based feature extraction obtained the best decoding performance.

We examined the identification of trauma exposure and post-traumatic stress disorder (PTSD) in help-seeking urban children (N=157) presenting for care in community mental health clinics. Children and their parents completed a standard intake assessment conducted by a community clinician followed by a structured trauma-focused assessment conducted by a study clinician. Clinicians provided ratings of child functional impairment, parents reported on internalizing/externalizing problems, and children provided self-reports of PTSD symptom severity. Although community clinicians were mandated by clinic policy to ask about exposure to physical abuse, sexual abuse, and witnessed domestic violence, they identified exposure to these at significantly lower rates than study clinicians. Rates of PTSD based on community clinician diagnosis (1.9%) were also much lower than rates obtained by study clinicians (19.1%). A review of clinical charts one year after intake revealed no change in PTSD diagnosis rate following additional clinical contacts. Clinician-rated impairment, parent-rated emotional/behavioral problems, and child-rated PTSD symptom severity measures provided support for the validity of trauma exposure and PTSD as identified by study clinicians. Trauma exposure and PTSD diagnosis among help-seeking urban youth appear to be under-identified by community clinicians, which may compromise clinicians’ ability to respond to environmental risks and provide appropriate evidence-based treatments.

The use of CD3/target bispecific molecules has great therapeutic potential in oncology. This potential, however, is diminished due to serious on-target drug-related toxicities, restricting the development of bispecific T cell engagers to targets that have limited expression in normal tissues. Conditionally Active Biologic (CAB) technology is a proprietary platform that generates antibodies which have no or very little binding to the target antigen in healthy tissue (normal physiological conditions), but have strong binding in the context of diseased tissues (tumor microenvironment) based on the glycolytic tumor metabolism (including Warburg effect). Using our CAB technology, we have developed CD3/target bispecific antibodies that bind to recombinant CD3 and to CD3 expressing cells under in vitro tumor microenvironment conditions, but not in physiologic conditions (CAB CD3). CAB CD3 bispecific antibodies were generated against various well-established tumor associated antigens (TAA), including EpCAM, B7-H3, HER-2 and EGFR. All of these molecules play important roles in cancer biology and are attractive targets for the development of therapeutic bispecific antibodies. In addition, we have also developed CAB TAA / CAB CD3 bispecific antibodies. In vitro and in vivo efficacy data as well as toxicology studies in non-human primates for CAB-T cell engagers will be presented. Our data demonstrates that CAB bispecific antibodies are efficacious in vivo and have lower toxicity comparing to non-CAB bispecific antibodies. The CAB technology will allow the generation of a new class of T-cell engagers with increased safety margin and therapeutic index in the clinic. Citation Format: Ana Paula G. Cugnetti, Haizhen Liu, Jing Wang, Charles Xing, Christina Wheeler, Matthew Lucas, Cathy Chang, Gerhard Frey, William J. Boyle, Jay M. Short. Novel conditionally active bispecific T cell engagers targeting solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5698.

Conditionally Active Biologics (CAB) technology is a proprietary platform that selects antibodies binding to target antigens in the context of diseased tissues, but not normal tissues, taking advantage of the unique conditions in the tumor microenvironment. Using our CAB technology, we have developed CAB ADCs to various well-established tumor associated antigens (TAA), including Nectin-4, Her2 and CD46. Each of these molecules play an important role in cancer biology and are attractive targets for the development of therapeutic antibodies. These targets, however, are expressed on many normal tissues and have been implicated in a wide range of biological processes; therefore, limiting the use of traditional ADCs as cancer therapy. Using CAB technology, we have developed conditionally active ADCs that have no or very little binding to the target antigen in healthy tissue (normal physiological conditions), but have strong binding in the context of diseased tissues (tumor microenvironment) based on the glycolytic tumor metabolism (including Warburg effect). In vitro and in vivo efficacy data demonstrating the abilities of CAB ADCs to induce cytotoxicity of human target-expressing tumor cell lines, and to inhibit tumor growth in human tumor xenograft models will be presented. In conclusion, our data is consistent with our previous work on EpCAM, our clinical stage AXL and ROR2 CAB ADCs, and suggests that conditionally active ADCs generated using the CAB technology will provide a new generation of biologics with increased safety margin and therapeutic index in the clinic. Citation Format: Jing Wang, Charles Xing, Haizhen Liu, Ana Paula G. Cugnetti, Christina Wheeler, Matthew Lucas, Gerhard Frey, Cathy Chang, William J. Boyle, Jay M. Short. Conditionally active biologics (CAB): A novel class of molecules targeting solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4560.

This work presents a classification performance comparison between different frameworks for functional connectivity evaluation and complex network feature extraction aiming to distinguish motor imagery classes in electroencephalography (EEG)-based brain-computer interfaces (BCIs). The analysis was performed in two online datasets: (1) a classical benchmark-the BCI competition IV dataset 2a-allowing a comparison with a representative set of strategies previously employed in this BCI paradigm and (2) a statistically representative dataset for signal processing technique comparisons over 52 subjects. Besides exploring three classical similarity measures-Pearson correlation, Spearman correlation, and mean phase coherence-this work also proposes a recurrence-based alternative for estimating EEG brain functional connectivity, which takes into account the recurrence density between pairwise electrodes over a time window. These strategies were followed by graph feature evaluation considering clustering coefficient, degree, betweenness centrality, and eigenvector centrality. The features were selected by Fisher's discriminating ratio and classification was performed by a least squares classifier in agreement with classical and online BCI processing strategies. The results revealed that the recurrence-based approach for functional connectivity evaluation was significantly better than the other frameworks, which is probably associated with the use of higher order statistics underlying the electrode joint probability estimation and a higher capability of capturing nonlinear inter-relations. There were no significant differences in performance among the evaluated graph features, but the eigenvector centrality was the best feature regarding processing time. Finally, the best ranked graph-based attributes were found in classical EEG motor cortex positions for the subjects with best performances, relating functional organization and motor activity. Graphical Abstract Evaluating functional connectivity based on Space-Time Recurrence Counting for motor imagery classification in brain-computer interfaces. Recurrences are evaluated between electrodes over a time window, and, after a density threshold, the electrodes adjacency matrix is stablish, leading to a graph. Graph-based topological measures are used for motor imagery classification.

Chronic hepatitis C virus (HCV) is widely prevalent in the Virginia Department of Corrections (DOC). However, sustained virologic response (SVR) with all oral direct-acting antiviral (DAA) therapy is unknown. HCV treatment was provided through telemedicine following guidelines of the American Association for the Study of Liver Diseases and Infectious Diseases Society of America. SVR12 in the DOC was compared in two control groups: privately insured and indigent patients receiving care in HCV treatment clinics by the same providers during the same time period. Of 220 DOC patients, 180 were started on therapy (158 genotype [GT] 1, 15 GT2, and 10 GT3). SVR12 data on GT1 patients who received ledipasvir/sofosbuvir with or without ribavirin (RBV) were 96%, similar to our indigent (95%) and private clinic (93%) patients despite differences in age, gender, treatment experience, FIB-4, and use of RBV. Multiple logistic regression of GT1 patients identified lower FIB-4 ( p = .008) and treatment clinic ( p = .01) as independent predictors of SVR12. HCV treatment in the DOC by telemedicine with DAA is not only feasible but has a very high SVR12 similar to published trials.

Background: The Minnesota Stroke System was launched in 2013 to organize and recognize hospitals able to deliver acute stroke treatment. The goal of the system is to increase access to acute stroke treatment and improve outcomes for stroke patients. The Minnesota Department of Health designates Acute Stroke Ready Hospitals (ASRHs) according to ten criteria corresponding to the 2013 Brain Attack Coalition recommendations. This analysis explores whether implementation of the Minnesota Stroke System and the corresponding adoption of standards by ASRHs corresponded to an increase in intravenous (IV) alteplase utilization among rural Minnesota hospitals between 2012 and 2017. Methods: Stroke patient care data were submitted by hospitals into the Minnesota Stroke Registry. Rural Minnesota hospitals were grouped into three categories: early adopters that became designated between 2014-2015; late adopters (designated between 2016-2017); and never-designated hospitals. Trends in IV alteplase use from 2012 to 2017 were examined in each group. Results: Among 103 rural Minnesota hospitals, 21 never received designation, 21 were designated in 2016-2017, and 61 were designated between 2014-2015. Treatment of stroke patients with IV alteplase among all rural hospitals increased in Minnesota between 2012 and 2017 from 12.9% to 15.9% (p Conclusions: Trends in treatment with IV alteplase was highest among early adopting ASRHs. Sustained increases in treatment rates among early adopters suggests that similar increases may be seen in late-adopting ASRHs in the future. This analysis suggests that the implementation of a statewide system of care, namely adoption of standards and hospital designation, is a driver for sustained increases in treatment rates.

Background: The Minnesota Stroke System is comprised of hospitals able to deliver state-of-the-art stroke treatment. The system is designed to increase access to acute stroke treatment and improve outcomes for stroke patients. Between 2011 and 2013, the Minnesota Department of Health convened health care providers and stroke patient advocates to plan and create the components of a statewide stroke system for Minnesota. To launch the system, the Minnesota legislature gave MDH statutory authorization to designate Acute Stroke Ready Hospitals (ASRHs) and recognize Primary and Comprehensive Stroke Centers certified by national accreditation bodies. The ASRHs meet ten criteria corresponding to the 2013 Brain Attack Coalition recommendations. Analysis: Stroke patient data are reported to the Minnesota Stroke Registry by hospital-based abstractors. Data are combined for 2012-2013, 2014-2015, and 2016-2017. Performance metric statistics were calculated using SAS (Cary, NC). The resident population living within 30 minutes of designated hospitals was calculated from 2010 US Census Bureau data using ArcGIS 10.3 Network Analyst. Results: From 2012 to 2017, the number of designated ASRHs increased from zero to 89, out of 111 eligible hospitals. The percentage of residents living within 30 minutes of any designated facility increased from 60% to 90%. The percentage of all stroke patients whose computed tomography image was initiated within 25 minutes of arrival increased from 34.2% to 42.9%. Intravenous thrombolytic therapy increased from 8.8% to 11% of all ischemic stroke patients. Median door-to-imaging time decreased from 40 to 33 minutes. Median door-to-needle time decreased from 56 to 53 minutes. 28.7% of patients in 2012-2013 who received IV tPA were treated within 4.5 hours of time last known well, increasing to 35.6% in 2016-2017. Conclusions: The Minnesota Stroke System has successfully catalyzed and supported significant improvements in acute stroke treatment in Minnesota.