D:A4.1 Socio-economic impact assessment

The executive summary ends with six concise recommendations for facilitating more accountability for data management in cloud ecosystems: 1. Provide a stronger legal base for and enforcement of data protection and accountable behavior; 2. Facilitate independent auditing of responsible data stewardship; 3. Increase public awareness of the need for accountability; 4. Balance existing information asymmetries via partnerships; 5. Focus on larger enterprises working in the public sector first, as these can serve as an example for other types of businesses; 6. Demonstrate how A4Cloud tools and mechanisms can be turned into a business model in order to encourage greater uptake and use

Dexamethasone in children mechanically ventilated for lower Respiratory tract infection caused by respiratory syncytial Virus: a randomised controlled trial.

Objective:To determine the efficacy of dexamethasone in the treatment of mechanically ventilated children with respiratory syncytial virus–severe lower respiratory tract infection.Design:International, multicenter, randomized, double-blind, placebo-controlled trial.Setting:Twelve pediatric intensive care units.Subjects:Children (200 mm Hg and/or mean arterial pressure ≤10 cm H 2 O) and a noninferiority approach in those with severe oxygen abnormalities (PaO 2 /Fio 2 ≤200 mm Hg and mean arterial pressure >10 cm H 2 O). Primary outcome was the duration of mechanical ventilation. In the subgroup with mild oxygenation abnormalities, 45 of the 89 included patients received dexamethasone and 44 placebo; in the subgroup with severe oxygenation abnormalities, 28 of the 56 included patients received dexamethasone and 28 placebo. Baseline characteristics in both treatment arms were similar for both subgroups. After the third interim analysis, the trial was stopped early for futility taking the slow enrollment into account. At that time, the median duration (interquartile range) of mechanical ventilation was 137 (91–195) hrs in the dexamethasone- and 139 (117–188) hrs in the placebo-treated patients in the subgroup with mild oxygenation abnormalities ( p = .6). In the subgroup with severe oxygenation abnormalities, it was 171 (136–212) hrs in the dexamethasone- and 170 (125–201) hrs in the placebo-treated patients ( p = .6).Conclusion:In this prematurely ended trial in children mechanically ventilated for severe respiratory syncytial virus–lower respiratory tract infection, we found no evidence of a beneficial effect of dexamethasone in children with mild oxygenation abnormalities. Neither was evidence found that dexamethasone may prolong mechanical ventilation in those with severe oxygenation abnormalities.0info:eu-repo/semantics/publishe

The Time-Dependent Vehicle Routing Problem with Time Windows and Road-Network Information

International audienc

A branch-and-price Algorithm for the Vehicle Routing Problem with Time Windows on a road network

International audienc

Immunotherapy with subcutaneous immunogenic autologous tumor lysate increases murine glioblastoma survival

Immunotherapeutic strategies for glioblastoma, the most frequent malignant primary brain tumor, aim to improve its disastrous consequences. On top of the standard treatment, one strategy uses T cell activation by autologous dendritic cells (DC) ex vivo loaded with tumor lysate to attack remaining cancer cells. Wondering whether 'targeting' in vivo DCs could replace these ex vivo ones, immunogenic autologous tumor lysate was used to treat glioma-inoculated mice in the absence of ex vivo loaded DCs. Potential immune mechanisms were studied in two orthotopic, immunocompetent murine glioma models. Pre-tumoral subcutaneous lysate treatment resulted in a survival benefit comparable to subcutaneous DC therapy. Focussing on the immune response, glioma T cell infiltration was observed in parallel with decreased amounts of regulatory T cells. Moreover, these results were accompanied by the presence of strong tumor-specific immunological memory, shown by complete survival of a second glioblastoma tumor, inoculated 100 days after the first one. Finally, in combination with temozolomide, survival of established glioma in mice could be increased. Our results show the potential of immunogenic autologous tumor lysate used to treat murine glioblastoma, which will be worthwhile to study in clinical trials as it has potential as a cost-efficient adjuvant treatment strategy for gliomas.status: publishe

Immunotherapy with subcutaneous immunogenic autologous tumor lysate increases murine glioblastoma survival

Abstract Immunotherapeutic strategies for glioblastoma, the most frequent malignant primary brain tumor, aim to improve its disastrous consequences. On top of the standard treatment, one strategy uses T cell activation by autologous dendritic cells (DC) ex vivo loaded with tumor lysate to attack remaining cancer cells. Wondering whether ‘targeting’ in vivo DCs could replace these ex vivo ones, immunogenic autologous tumor lysate was used to treat glioma-inoculated mice in the absence of ex vivo loaded DCs. Potential immune mechanisms were studied in two orthotopic, immunocompetent murine glioma models. Pre-tumoral subcutaneous lysate treatment resulted in a survival benefit comparable to subcutaneous DC therapy. Focussing on the immune response, glioma T cell infiltration was observed in parallel with decreased amounts of regulatory T cells. Moreover, these results were accompanied by the presence of strong tumor-specific immunological memory, shown by complete survival of a second glioblastoma tumor, inoculated 100 days after the first one. Finally, in combination with temozolomide, survival of established glioma in mice could be increased. Our results show the potential of immunogenic autologous tumor lysate used to treat murine glioblastoma, which will be worthwhile to study in clinical trials as it has potential as a cost-efficient adjuvant treatment strategy for gliomas

Clinical-Grade Human Multipotent Adult Progenitor Cells Block CD8+ Cytotoxic T Lymphocytes

: MultiStem cells are clinical-grade multipotent adult bone marrow-derived progenitor cells (MAPCs), with extensive replication potential and broader differentiation capacity compared with mesenchymal stem cells. Human MAPCs suppress T-cell proliferation induced by alloantigens and mutually interact with allogeneic natural killer cells. In this study, the interaction between MultiStem and CD8(+) cytotoxic T lymphocytes (CTLs) was addressed for the first time. In an in vitro setting, the immunogenicity of MultiStem, the susceptibility of MultiStem toward CTL-mediated lysis, and its effects on CTL function were investigated. MultiStem was nonimmunogenic for alloreactive CTL induction and was-even after major histocompatibility complex class I upregulation-insensitive to alloantigen-specific CTL-mediated lysis. Furthermore, MultiStem reduced CTL proliferation and significantly decreased perforin expression during the T-cell activation phase. As a consequence, MultiStem dose-dependently impaired the induction of CTL function. These effects of MultiStem were mediated predominantly through contact-dependent mechanisms. Moreover, MultiStem cells considerably influenced the expression of T-cell activation markers CD25, CD69, and human leukocyte antigen-DR. The MultiStem-induced CD8(-)CD69(+) T-cell population displayed a suppressive effect on the induction of CTL function during a subsequent mixed-lymphocyte culture. Finally, the killer activity of activated antigen-specific CTLs during their cytolytic effector phase was also diminished in the presence of MultiStem. This study confirms that these clinical-grade MAPCs are an immune-modulating population that inhibits CTL activation and effector responses and are, consequently, a highly valuable cell population for adoptive immunosuppressive therapy in diseases where damage is induced by CTLs.status: publishe

Histamine and T helper cytokine–driven epithelial barrier dysfunction in allergic rhinitis

Background Allergic rhinitis (AR) is characterized by mucosal inflammation, driven by activated immune cells. Mast cells and TH2 cells might decrease epithelial barrier integrity in AR, maintaining a leaky epithelial barrier. Objective We sought to investigate the role of histamine and TH2 cells in driving epithelial barrier dysfunction in AR. Methods Air-liquid interface cultures of primary nasal epithelial cells were used to measure transepithelial electrical resistance, paracellular flux of fluorescein isothiocyanate-dextran 4 kDa, and mRNA expression of tight junctions. Nasal secretions were collected from healthy control subjects, AR patients, and idiopathic rhinitis patients and were tested in vitro. In addition, the effect of activated TH1 and TH2 cells, mast cells, and neurons was tested in vitro. The effect of IL-4, IL-13, IFN-γ, and TNF-α on mucosal permeability was tested in vivo. Results Histamine as well as nasal secretions of AR but not idiopathic rhinitis patients rapidly decreased epithelial barrier integrity in vitro. Pretreatment with histamine receptor-1 antagonist, azelastine prevented the early effect of nasal secretions of AR patients on epithelial integrity. Supernatant of activated TH1 and TH2 cells impaired epithelial integrity, while treatment with anti-TNF-α or anti-IL-4Rα monoclonal antibodies restored the TH1- and TH2-induced epithelial barrier dysfunction, respectively. IL-4, IFN-γ, and TNF-α enhanced mucosal permeability in mice. Antagonizing IL-4 prevented mucosal barrier disruption and tight junction downregulation in a mouse model of house dust mite allergic airway inflammation. Conclusions Our data indicate a key role for allergic inflammatory mediators in modulating nasal epithelial barrier integrity in the pathophysiology in AR

Increasing burden of viral bronchiolitis in the pediatric intensive care unit:an observational study

Purpose: Viral bronchiolitis is a major cause of pediatric intensive care unit (PICU) admission. Insight in the trends of bronchiolitis-associated PICU admissions is limited, but imperative for future PICU resource and capacity planning. Materials and methods: We retrospectively studied trends in PICU admissions for bronchiolitis in six European sites, including three full national registries, between 2000 and 2019 and calculated population-based estimates per 100,000 children where appropriate. Information concerning risk factors for severe disease and use of invasive mechanical ventilation was also collected when available. Results: In total, there were 15,606 PICU admissions for bronchiolitis. We observed an increase in the annual number, rate and estimates per 100,000 children of PICU admissions for bronchiolitis at all sites over the last two decades, while the proportion of patients at high risk for severe disease remained relatively stable. Conclusions: The international increased burden of bronchiolitis for the PICU is concerning, and warrants further international attention and investigation.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Increasing burden of viral bronchiolitis in the pediatric intensive care unit; an observational study

Purpose: Viral bronchiolitis is a major cause of pediatric intensive care unit (PICU) admission. Insight in the trends of bronchiolitis-associated PICU admissions is limited, but imperative for future PICU resource and capacity planning. Materials and methods: We retrospectively studied trends in PICU admissions for bronchiolitis in six European sites, including three full national registries, between 2000 and 2019 and calculated population-based estimates per 100,000 children where appropriate. Information concerning risk factors for severe disease and use of invasive mechanical ventilation was also collected when available. Results: In total, there were 15,606 PICU admissions for bronchiolitis. We observed an increase in the annual number, rate and estimates per 100,000 children of PICU admissions for bronchiolitis at all sites over the last two decades, while the proportion of patients at high risk for severe disease remained relatively stable. Conclusions: The international increased burden of bronchiolitis for the PICU is concerning, and warrants further international attention and investigation