Immune recognition and processing of blood coagulation factor VIII by antigen-presenting cells

Hemophilia A is an X chromosome-linked bleeding disorder caused by a reduction or com­plete absence of coagulation factor VIII (FVIII). The bleeding tendency in patients suffering from hemophilia A can be treated by regular intravenous administrations of FVIII. A severe complication that occurs in approximately 30% of hemophilia A patients is the recognition of administered FVIII as “non-self” by the recipients’ immune system, leading to the formation of FVIII-neutralizing antibodies. The initial steps in the formation of these antibodies are recognition and uptake of the administered FVIII by antigen-presenting cells, which is followed by presentation of FVIII fragments to the immune system on MHC class II complexes. In this thesis the mechanism of FVIII endocytosis and presentation on MHC class II by antigen-presenting cells was investigated. The thesis describes that the uptake of FVIII by antigen-presenting cells can be inhibited by shielding or modifying certain amino acids in the C1 domain of FVIII. A FVIII variant was constructed that is less immunogenic. Administration of this FVIII variant to hemophilic mice led to significantly less antibody formation than administration of normal FVIII. Additionally, it was shown that recognition of FVIII by antigen-presenting cells leads to donor-dependent differences in the presentation of FVIII fragments on MHC class II. The results described in this thesis contribute to the development of alternative treatments for hemophilia A patients resulting in less formation of antibodies against FVIII

Human Newborn Monocytes Demonstrate Distinct BCG-Induced Primary and Trained Innate Cytokine Production and Metabolic Activation In Vitro

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Immune recognition and processing of blood coagulation factor VIII by antigen-presenting cells

Hemophilia A is an X chromosome-linked bleeding disorder caused by a reduction or com­plete absence of coagulation factor VIII (FVIII). The bleeding tendency in patients suffering from hemophilia A can be treated by regular intravenous administrations of FVIII. A severe complication that occurs in approximately 30% of hemophilia A patients is the recognition of administered FVIII as “non-self” by the recipients’ immune system, leading to the formation of FVIII-neutralizing antibodies. The initial steps in the formation of these antibodies are recognition and uptake of the administered FVIII by antigen-presenting cells, which is followed by presentation of FVIII fragments to the immune system on MHC class II complexes. In this thesis the mechanism of FVIII endocytosis and presentation on MHC class II by antigen-presenting cells was investigated. The thesis describes that the uptake of FVIII by antigen-presenting cells can be inhibited by shielding or modifying certain amino acids in the C1 domain of FVIII. A FVIII variant was constructed that is less immunogenic. Administration of this FVIII variant to hemophilic mice led to significantly less antibody formation than administration of normal FVIII. Additionally, it was shown that recognition of FVIII by antigen-presenting cells leads to donor-dependent differences in the presentation of FVIII fragments on MHC class II. The results described in this thesis contribute to the development of alternative treatments for hemophilia A patients resulting in less formation of antibodies against FVIII

Cyclic AMP in human preterm infant blood is associated with increased TLR-mediated production of acute-phase and anti-inflammatory cytokines in vitro

Background Preterm infants are at high risk of infection and have distinct pathogen recognition responses. Suggested mechanisms include soluble mediators that enhance cellular levels of cAMP. The aim of this study was to assess the relationship between blood cAMP concentrations and TLR-mediated cytokine production in infants during the first month of life. Methods Cord and serial peripheral blood samples (days of life 1–28) were obtained from a cohort of very preterm (<30 weeks’ gestational age) and term human infants. Whole-blood concentrations of cAMP and FSL-1 and LPS in vitro stimulated cytokine concentrations were measured by ELISA and multiplex bead assay. Results cAMP concentrations were higher in cord than in peripheral blood, higher in cord blood of female preterm infants, and lower at Days 1 and 7 in infants exposed to chorioamnionitis, even after adjusting for leukocyte counts. TLR2 and TLR4-mediated TNF-α, IL-1β, IL-6, IL-12p70, and IL-10 production in vitro increased over the first month of life in preterm infants and were positively correlated with leukocyte-adjusted cAMP levels and reduced by exposure to chorioamnionitis. Conclusions The ontogeny of blood cAMP concentrations and associations with chorioamnionitis and TLR-mediated production of cytokines suggest that this secondary messenger helps shape distinct neonatal pathogen responses in early life

Fundamental Elements of an Urban UTM

Urban airspace environments present exciting new opportunities for delivering drone services to an increasingly large global market, including: information gathering; package delivery; air-taxi services. A key challenge is how to model airspace environments over densely populated urban spaces, coupled with the design and development of scalable traffic management systems that may need to handle potentially hundreds to thousands of drone movements per hour. This paper explores the background to Urban unmanned traffic management (UTM), examining highlevel initiatives, such as the USA’s Unmanned Air Traffic (UTM) systems and Europe’s U-Space services, as well as a number of contemporary research activities in this area. The main body of the paper describes the initial research outputs of the U-Flyte R&D group, based at Maynooth University in Ireland, who have focused on developing an integrated approach to airspace modelling and traffic management platforms for operating large drone fleets over urban environments. This work proposes pragmatic and innovative approaches to expedite the roll-out of these much-needed urban UTM solutions. These approaches include the certification of drones for urban operation, the adoption of a collaborative and democratic approach to designing urban airspace, the development of a scalable traffic management and the replacement of direct human involvement in operating drones and coordinating drone traffic with machines. The key fundamental elements of airspace architecture and traffic management for busy drone operations in urban environments are described together with initial UTM performance results from simulation studies

Resolved versus confirmed ARDS after 24&#160;h: insights from the LUNG SAFE study

Purpose: To evaluate patients with resolved versus confirmed ARDS, identify subgroups with substantial mortality risk, and to determine the utility of day 2 ARDS reclassification. Methods: Our primary objective, in this secondary LUNG SAFE analysis, was to compare outcome in patients with resolved versus confirmed ARDS after 24\ua0h. Secondary objectives included identifying factors associated with ARDS persistence and mortality, and the utility of day 2 ARDS reclassification. Results: Of 2377 patients fulfilling the ARDS definition on the first day of ARDS (day 1) and receiving invasive mechanical ventilation, 503 (24%) no longer fulfilled the ARDS definition the next day, 52% of whom initially had moderate or severe ARDS. Higher tidal volume on day 1 of ARDS was associated with confirmed ARDS [OR 1.07 (CI 1.01\u20131.13), P = 0.035]. Hospital mortality was 38% overall, ranging from 31% in resolved ARDS to 41% in confirmed ARDS, and 57% in confirmed severe ARDS at day 2. In both\ua0resolved and confirmed\ua0ARDS, age, non-respiratory SOFA score, lower PEEP and P/F ratio, higher peak pressure and respiratory rate were each\ua0associated with mortality. In confirmed ARDS, pH and the presence of immunosuppression or neoplasm were also associated\ua0with mortality. The increase in area under the receiver operating curve for ARDS reclassification on day 2 was marginal. Conclusions: ARDS, whether resolved or confirmed at day 2, has a high mortality rate. ARDS reclassification at day 2 has limited predictive value for mortality. The substantial mortality risk in severe confirmed ARDS suggests that complex interventions might best be tested in this population. Trial Registration: ClinicalTrials.gov NCT02010073. \ua9 2018, Springer-Verlag GmbH Germany, part of Springer Nature and ESICM

Search for multimessenger sources of gravitational waves and high-energy neutrinos with Advanced LIGO during its first observing run, ANTARES, and IceCube

Astrophysical sources of gravitational waves, such as binary neutron star and black hole mergers or core-collapse supernovae, can drive relativistic outflows, giving rise to non-thermal high-energy emission. High-energy neutrinos are signatures of such outflows. The detection of gravitational waves and high-energy neutrinos from common sources could help establish the connection between the dynamics of the progenitor and the properties of the outflow. We searched for associated emission of gravitational waves and high-energy neutrinos from astrophysical transients with minimal assumptions using data from Advanced LIGO from its first observing run O1, and data from the Antares and IceCube neutrino observatories from the same time period. We focused on candidate events whose astrophysical origins could not be determined from a single messenger. We found no significant coincident candidate, which we used to constrain the rate density of astrophysical sources dependent on their gravitational-wave and neutrino emission processes

Death in hospital following ICU discharge : insights from the LUNG SAFE study

Altres ajuts: Italian Ministry of University and Research (MIUR)-Department of Excellence project PREMIA (PREcision MedIcine Approach: bringing biomarker research to clinic); Science Foundation Ireland Future Research Leaders Award; European Society of Intensive Care Medicine (ESICM), Brussels; St Michael's Hospital, Toronto; University of Milan-Bicocca, Monza, Italy.Background: To determine the frequency of, and factors associated with, death in hospital following ICU discharge to the ward. Methods: The Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE study was an international, multicenter, prospective cohort study of patients with severe respiratory failure, conducted across 459 ICUs from 50 countries globally. This study aimed to understand the frequency and factors associated with death in hospital in patients who survived their ICU stay. We examined outcomes in the subpopulation discharged with no limitations of life sustaining treatments ('treatment limitations'), and the subpopulations with treatment limitations. Results: 2186 (94%) patients with no treatment limitations discharged from ICU survived, while 142 (6%) died in hospital. 118 (61%) of patients with treatment limitations survived while 77 (39%) patients died in hospital. Patients without treatment limitations that died in hospital after ICU discharge were older, more likely to have COPD, immunocompromise or chronic renal failure, less likely to have trauma as a risk factor for ARDS. Patients that died post ICU discharge were less likely to receive neuromuscular blockade, or to receive any adjunctive measure, and had a higher pre- ICU discharge non-pulmonary SOFA score. A similar pattern was seen in patients with treatment limitations that died in hospital following ICU discharge. Conclusions: A significant proportion of patients die in hospital following discharge from ICU, with higher mortality in patients with limitations of life-sustaining treatments in place. Non-survivors had higher systemic illness severity scores at ICU discharge than survivors. Trial Registration: ClinicalTrials.gov NCT02010073