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1. Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations

Author

Kumar, Vikrant, Pouw, Richard B, Autio, Matias I, Sagmeister, Manfred G, Phua, Zai Yang, Borghini, Lisa, Wright, Victoria J, Hoggart, Clive, Pan, Bangfen, Tan, Antson Kiat Yee, Binder, Alexander, Brouwer, Mieke C, Pinnock, Ellie, De Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van Der Flier, Michiel, Reiter, Karl, Nöthen, Markus M, Hoffmann, Per, EUCLIDS consortium, Schlapbach, Luregn J, Bellos, Evangelos, Anderson, Suzanne, Secka, Fatou, Martinón-Torres, Federico, Salas, Antonio, Fink, Colin, Carrol, Enitan D, Pollard, Andrew J, Coin, Lachlan J, Zenz, Werner, Wouters, Diana, Ang, Lay Teng, Hibberd, Martin L, Levin, Michael, Kuijpers, Taco W, Davila, Sonia, consortium, EUCLIDS, Pediatrics, Paediatric Infectious Diseases / Rheumatology / Immunology, Landsteiner Laboratory, and ARD - Amsterdam Reproduction and Development

Subjects
CFHR3, Genotype, Meningococcal disease, infectious disease, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Complement, in-depth sequencing, Blood Proteins, Complement System Proteins, Neisseria meningitidis, factor H, QR, Meningococcal Infections, Factor H-related protein, genotyping, Complement Factor H, Genetics, Humans, CFH, Genetic Predisposition to Disease, Genetics (clinical), RC
Abstract

Neisseria meningitidis protects itself from complement-mediated killing by binding complement factor H (FH). Previous studies associated susceptibility to meningococcal disease (MD) with variation in CFH, but the causal variants and underlying mechanism remained unknown. Here we attempted to define the association more accurately by sequencing the CFH-CFHR locus and imputing missing genotypes in previously obtained GWAS datasets of MD-affected individuals of European ancestry and matched controls. We identified a CFHR3 SNP that provides protection from MD (rs75703017, p value = 1.1 × 10−16) by decreasing the concentration of FH in the blood (p value = 1.4 × 10−11). We subsequently used dual-luciferase studies and CRISPR gene editing to establish that deletion of rs75703017 increased FH expression in hepatocyte by preventing promotor inhibition. Our data suggest that reduced concentrations of FH in the blood confer protection from MD; with reduced access to FH, N. meningitidis is less able to shield itself from complement-mediated killing.

Published
2022

2. Febrile illness in high-risk children: a prospective, international observational study

Author

van der Velden, Fabian J. S., de Vries, Gabriella, Martin, Alexander, Lim, Emma, von Both, Ulrich, Kolberg, Laura, Carrol, Enitan D., Khanijau, Aakash, Herberg, Jethro A., De, Tisham, Galassini, Rachel, Kuijpers, Taco W., Martinón-Torres, Federico, Rivero-Calle, Irene, Vermont, Clementien L., Hagedoorn, Nienke N., Pokorn, Marko, Pollard, Andrew J., Schlapbach, Luregn J., Tsolia, Maria, Elefhteriou, Irini, Yeung, Shunmay, Zavadska, Dace, Fink, Colin, Voice, Marie, Zenz, Werner, Kohlmaier, Benno, Agyeman, Philipp K. A., Usuf, Effua, Secka, Fatou, de Groot, Ronald, Levin, Michael, van der Flier, Michiel, Emonts, Marieke, Cunnington, Aubrey, Herberg, Jethro, Kaforou, Myrsini, Wright, Victoria, Baumard, Lucas, Bellos, Evangelos, D’Souza, Giselle, Habgood-Coote, Dominic, Hamilton, Shea, Hoggart, Clive, Hourmat, Sara, Jackson, Heather, Maconochie, Ian, Menikou, Stephanie, Lin, Naomi, Nichols, Samuel, Nijman, Ruud, Powell, Oliver, Pena Paz, Ivonne, Shah, Priyen, Shen, Ching-Fen, Vito, Ortensia, Wilson, Clare, Abdulla, Amina, Ali, Ladan, Darnell, Sarah, Jorgensen, Rikke, Mustafa, Sobia, Persand, Salina, Stevens, Molly M., Kim, Nayoung, Kim, Eunjung, Fidler, Katy, Dudley, Julia, Richmond, Vivien, Tavliavini, Emma, Liu, Ching-Chuan, Wang, Shih-Min, Salas, Antonio, Álvez González, Fernando, Balo Farto, Cristina, Barral-Arca, Ruth, Barreiro Castro, María, Bello, Xabier, García, Mirian Ben, Carnota, Sandra, Cebey-López, Miriam, Curras-Tuala, María José, Durán Suárez, Carlos, García Vicente, Luisa, Gómez-Carballa, Alberto, Gómez Rial, Jose, Leboráns Iglesias, Pilar, Martinón-Torres, Nazareth, Martinón Sánchez, José María, Mosquera Pérez, Belén, Pardo-Seco, Jacobo, Rodríguez, Lidia Piñeiro, Pischedda, Sara, Vázquez, Sara Rey, Rivero Calle, Irene, Rodríguez-Tenreiro, Carmen, Redondo-Collazo, Lorenzo, Sadiki Ora, Miguel, Serén Fernández, Sonia, Serén Trasorras, Cristina, Vilas Iglesias, Marisol, Balode, Anda, Bārzdiņa, Arta, Deksne, Dārta, Gardovska, Dace, Grāvele, Dagne, Grope, Ilze, Meiere, Anija, Nokalna, Ieva, Pavāre, Jana, Pučuka, Zanda, Selecka, Katrīna, Rudzāte, Aleksandra, Svile, Dace, Urbāne, Urzula Nora, Bojang, Kalifa, Zaman, Syed M. A., Anderson, Suzanne, RocaIsatou Sarr, Anna, Saidykhan, Momodou, Darboe, Saffiatou, Ceesay, Samba, D’alessandro, Umberto, Moll, Henriëtte A., Vermont, Clementien L, Borensztajn, Dorine M., Tan, Chantal, Zachariasse, Joany, Dik, W, Agyeman, Philipp KA, Berger, Christoph, Giannoni, Eric, Stocker, Martin, Posfay-Barbe, Klara M, Heininger, Ulrich, Bernhard-Stirnemann, Sara, Niederer-Loher, Anita, Kahlert, Christian R., Natalucci, Giancarlo, Relly, Christa, Riedel, Thomas, Aebi, Christoph, Schlapbach, Luregn J, Carrol, Enitan D, Cocklin, Elizabeth, Jennings, Rebecca, Johnston, Joanne, Leigh, Simon, Lewis-Burke, Nadia, Newall, Karen, Romaine, Sam, Eleftheriou, Irini, Tambouratzi, Maria, Marmarinos, Antonis, Xagorari, Marietta, Syggelou, Kelly, Calvo-Bado, Leo, Schweintzger, Nina A., Sagmeister, Manfred G., Kohlfürst, Daniela S., Zurl, Christoph, Binder, Alexander, Hösele, Susanne, Leitner, Manuel, Pölz, Lena, Rajic, Glorija, Bauchinger, Sebastian, Baumgart, Hinrich, Benesch, Martin, Ceolotto, Astrid, Eber, Ernst, Gallistl, Siegfried, Gores, Gunther, Haidl, Harald, Hauer, Almuthe, Hude, Christa, Keldorfer, Markus, Krenn, Larissa, Pilch, Heidemarie, Pfleger, Andreas, Pfurtscheller, Klaus, Nordberg, Gudrun, Niedrist, Tobias, Rödl, Siegfried, Skrabl-Baumgartner, Andrea, Sperl, Matthias, Stampfer, Laura, Strenger, Volker, Till, Holger, Trobisch, Andreas, Löffler, Sabine, Dewez, Juan Emmanuel, Hibberd, Martin, Bath, David, Miners, Alec, Fitchett, Elizabeth, de Jonge, Marien I., van Aerde, Koen, Alkema, Wynand, van den Broek, Bryan, Gloerich, Jolein, van Gool, Alain J., Henriet, Stefanie, Huijnen, Martijn, Philipsen, Ria, Willems, Esther, Gerrits, G.P.J.M., van Leur, M., Heidema, J., de Haan, L., Miedema, C.J., Neeleman, C., Obihara, C.C., Tramper-Stranders, G.A., Kandasamy, Rama, Paulus, Stéphane, Carter, Michael J., O’Connor, Daniel, Bibi, Sagida, Kelly, Dominic F., Gurung, Meeru, Thorson, Stephen, Ansari, Imran, Murdoch, David R., Shrestha, Shrijana, Oliver, Zoe, Valentine, Lucille, Allen, Karen, Bell, Kathryn, Chan, Adora, Crulley, Stephen, Devine, Kirsty, Fabian, Daniel, King, Sharon, McAlinden, Paul, McDonald, Sam, McDonnell, Anne, Pickering, Ailsa, Thomson, Evelyn, Wood, Amanda, Wallia, Diane, Woodsford, Phil, Baxter, Frances, Bell, Ashley, Rhodes, Mathew, Agbeko, Rachel, Mackerness, Christine, Baas, Bryan, Kloosterhuis, Lieke, Oosthoek, Wilma, Arif, Tasnim, Bennet, Joshua, Collings, Kalvin, van der Giessen, Ilona, Martin, Alex, Rashid, Aqeela, Rowlands, Emily, van der Velden, Fabian, Soon, Joshua, Martin, Mike, Mistry, Ravi, Zwerenz, Manuela, Buschbeck, Judith, Bidlingmaier, Christoph, Binder, Vera, Danhauser, Katharina, Haas, Nikolaus, Griese, Matthias, Feuchtinger, Tobias, Keil, Julia, Kappler, Matthias, Lurz, Eberhard, Muench, Georg, Reiter, Karl, Schoen, Carola, Mallet, François, Brengel-Pesce, Karen, Pachot, Alexandre, Mommert, Marine, Kolnik, Mojca, Vincek, Katarina, Srovin, Tina Plankar, Bahovec, Natalija, Prunk, Petra, Osterman, Veronika, Avramoska, Tanja, Kuijpers, Taco, Jongerius, Ilse, van den Berg, J. M., Schonenberg, D., Barendregt, A. M., Pajkrt, D., van der Kuip, M., van Furth, A. M., Sprenkeler, Evelien, Zandstra, Judith, van Mierlo, G., Geissler, J., consortium, PERFORM, Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Infectious diseases, ARD - Amsterdam Reproduction and Development, and Pediatrics

Subjects
All institutes and research themes of the Radboud University Medical Center, Fever, SDG 3 - Good Health and Well-being, Antibiotics, Paediatric, Pediatrics, Perinatology and Child Health, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], 610 Medicine & health, Infection, 610 Medizin und Gesundheit, Immunocompromised
Abstract

To assess and describe the aetiology and management of febrile illness in children with primary or acquired immunodeficiency at high risk of serious bacterial infection, as seen in emergency departments in tertiary hospitals. Prospective data on demographics, presenting features, investigations, microbiology, management, and outcome of patients within the ‘Biomarker Validation in HR patients’ database in PERFORM, were analysed. Immunocompromised children (N = 492); 94.3% proven/presumed bacterial (N = 164), 66.1% proven/presumed viral (N = 84), and 93.2% unknown bacterial or viral infections (N = 177). Mortality was 1.9% (N = 11) and 87.1% made full recovery (N = 522). Conclusion: The aetiology of febrile illness in immunocompromised children is diverse. In one-third of cases, no cause for the fever will be identified. Justification for standard intravenous antibiotic treatment for every febrile immunocompromised child is debatable, yet effective. Better clinical decision-making tools and new biomarkers are needed for this population. What is Known:• Immunosuppressed children are at high risk for morbidity and mortality of serious bacterial and viral infection, but often present with fever as only clinical symptom.• Current diagnostic measures in this group are not specific to rule out bacterial infection, and positivity rates of microbiological cultures are low. What is New:• Febrile illness and infectious complications remain a significant cause of mortality and morbidity in HR children, yet management is effective.• The aetiology of febrile illness in immunocompromised children is diverse, and development of pathways for early discharge or cessation of intravenous antibiotics is debatable, and requires better clinical decision-making tools and biomarkers.

Published
2022

3. An Innovative Software Platform for Efficient Energy, Environmental and Cost Planning in Buildings Retrofitting

Author

Seitaridis, Andreas, Mamounakis, Ioannis, Tagkoulis, Nikolas, Iliadis, Petros, Bellos, Evangelos, Papalexis, Christos, Sougakis, Vasileios, and Nikolopoulos, Nikos

Subjects
Sustainability assessment, Life cycle, Energy modeling and simulation
Abstract

Building stock renovation is a major challenge towards a sustainableenergy transition. In this context, there is a need for accurate and holistic assessmentof retrofitting solutions.While Life Cycle Assessment (LCA) and Life CycleCosting (LCC) methods are typically used to quantify the outcomes of a retrofitsolution, these methods are highly dependent on accurate data, which is oftennot available in the design phase. The work presented in this paper demonstratesa building renovation assessment platform that follows a holistic approach andenables rapid but accurate consideration of several renovation scenarios. Theinnovation lies in the integration of two specialized tools, namely VERIFY andINTEMA.building, for lifecycle and energetic calculations, respectively. The integrationoffers a solution for the case in which no operational data are available. After the detailed presentation of the platform, the architecture and the offeredfunctionality, a building renovation problem is considered as a demo case. A typicallow-efficiency Greek building is examined while interventions are assumed,such as insulation of external wall, replacement of glazing surfaces, as well asheat pump and photovoltaic installation. Results showcase a significant reductionin lifetime CO2 emissions and primary energy of around 785 tons and 700 MWh,respectively. At the same time, the economic viability is ensured with estimatedsavings of 225 ke during project lifecycle.

Published
2022
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4. Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations

Author

Kumar, Vikrant, Pouw, Richard B, Autio, Matias I, Sagmeister, Manfred G, Phua, Zai Yang, Borghini, Lisa, Wright, Victoria J, Hoggart, Clive, Pan, Bangfen, Tan, Antson Kiat Yee, Binder, Alexander, Brouwer, Mieke C, Pinnock, Ellie, De Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van Der Flier, Michiel, Reiter, Karl, Nöthen, Markus M, Hoffmann, Per, EUCLIDS consortium, Schlapbach, Luregn J, Bellos, Evangelos, Anderson, Suzanne, Secka, Fatou, Martinón-Torres, Federico, Salas, Antonio, Fink, Colin, Carrol, Enitan D, Pollard, Andrew J, et al, and University of Zurich

Subjects
2716 Genetics (clinical), 1311 Genetics, 10036 Medical Clinic, 610 Medicine & health
Published
2022
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5. sj-doc-1-pie-10.1177_09544089221093975 - Supplemental material for Experimental investigation of a two-phase closed thermosyphon with Al2O3/R134a nanorefrigerant

Author

Anand, R.S., Jawahar, C.P., Brusly Solomon, A., Bellos, Evangelos, and Ajay Vasanth, X.

Subjects
FOS: Materials engineering, FOS: Other engineering and technologies, 91299 Materials Engineering not elsewhere classified, 99999 Engineering not elsewhere classified
Abstract

Supplemental material, sj-doc-1-pie-10.1177_09544089221093975 for Experimental investigation of a two-phase closed thermosyphon with Al2O3/R134a nanorefrigerant by R.S. Anand, C.P. Jawahar, A. Brusly Solomon, Evangelos Bellos and X. Ajay Vasanth in Proceedings of the Institution of Mechanical Engineers, Part E: Journal of Process Mechanical Engineering

Published
2022
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6. SARS-CoV-2-related MIS-C:A key to the viral and genetic causes of Kawasaki disease?

Author

Sancho-Shimizu, Vanessa, Brodin, Petter, Cobat, Aurélie, Biggs, Catherine M., Toubiana, Julie, Lucas, Carrie L., Henrickson, Sarah E., Belot, Alexandre, Haddad, Elie, Beland, Kathie, Pujol, Aurora, Schlüter, Agatha, Planas-Serra, Laura, Aguilera-Albesa, Sergio, Valencia-Ramos, Juan, Rodríguez-Palmero, Agustí, Gut, Marta, Rivière, Jacques G., Colobran, Roger, Soler-Palacin, Pere, Rodriguez-Gallego, Carlos, Perez De Diego, Rebeca, Flores, Carlos, Alsina, Laia, Blazquez-Gamero, Daniel, Jordan, Iolanda, Keles, Sevgi, Emiroglu, Melike, Akcan, Ozge Metin, Alkan, Gulsum, Aytekin, Selma Erol, Gul, Yahya, Tüter Öz, Şadiye Kübra, Bozdemir, Sefika Elmas, Bayhan, Gulsum Iclal, Yüksek, Saliha Kanık, Parlakay, Aslınur Özkaya, Gülhan, Belgin, Yahşi, Aysun, Kilic, Ahmet Osman, Karbuz, Adem, Erdeniz, Emine Hafize, Özkan, Esra Akyüz, Orbak, Zerrin, Aydemir, Şehnaz, Celik, Jale Bengi, Kandemir, Bahar, Aytekin, Gökhan, Kapakli, Hasan, Yarar, Volkan, Yosunkaya, Alper, Vatansev, Hulya, Aytekin, Caner, Torun, Selda Hancerli, Nepesov, Serdar, Coskuner, Taner, Sözeri, Betül, Demirkol, Yasemin Kendir, Kasapcopur, Ozgur, Yıldız, Mehmet, Sevketoglu, Esra, Hatipoğlu, Nevin, Özçelik, Tayfun, Yesilbas, Osman, Gayretli Aydin, Zeynep Gökçe, Sediva, Anna, Klocperk, Adam, Bloomfield, Marketa, Meyts, Isabelle, Delafontaine, Selket, Haerynck, Filomeen, Hoste, Levi, Shahrooei, Mohammad, Marque, Laura, Neves, João Farela, Novelli, Giuseppe, Novelli, Antonio, Aiuti, Alessandro, Casari, Giorgio, Bousfiha, Amed Aziz, Almuhsen, Saleh Zaid, Sobh, Ali, Gagro, Alenka, Bajolle, Fanny, Bonnet, Damien, Lebon, Pierre, Lei, Weite, Lee, Danyel, Seeleuthner, Yoann, Zhang, Peng, Maglorius, Majistor, Philippot, Quentin, Pelham, Simon, Bastard, Paul, Zhang, Qian, Jouanguy, Emmanuelle, Puel, Anne, Herberg, Jethro, Kuijpers, Taco W, Bellos, Evangelos, Kaforou, Myrsini, Menikou, Stephanie, Pan-Hammarström, Qiang, Hammarström, Lennart, Abolhassani, Hassan, Bryceson, Yenan, Condino-Neto, Antonio, Prando, Carolina, Bando, Silvia Yumi, Cavalcanti, Andre, Fellay, Jacques, Blanchard-Hohner, Giradine, Mansouri, Davood, Mahmoudi, Shima, Boyarchuk, Oksana, Volokha, Alla, Bondarenko, Anastasiia, Stepanovskiy, Yuriy, Mogensen, Trine, van de Beek, Diederik, Andreakos, Evangelos, Papadaki, Maria, Abou Tayoun, Ahmad, Halwani, Rabih, Al-Mulla, Fahd, Franco, José Luis, Lau, Yu-Lung, Kwan, Mike, Imai, Kohsuke, Okada, Satoshi, Bolze, Alexandre, Butte, Manish J., Hsieh, Elena, Drolet, Beth A, Arkin, Lisa, Itan, Yuval, Maniatis, Tom, Arditi, Moshe, Cooper, Megan, Schmitt, Erica, Chakravorty, Samya, Anderson, Mark S., Su, Helen C., Notarangelo, Luigi D., MIS-C@CHGE, [missing], Tangye, Stuart G., Milner, Joshua D., Levin, Michael, Abel, Laurent, Bogunovic, Dusan, Casanova, Jean-Laurent, Zhang, Shen-Ying, Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Département de Pédiatrie et maladies infectieuses [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, Institut Pasteur [Paris] (IP), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Funded by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (R01AI088364 to J.-L. Casanova and S.-Y. Zhang, R01AI148963, R01AI151029, and R01AI150300 to D. Bogunovic, K08AI135091 to S.E. Henrickson, R21AI144315-02S1 to C.L. Lucas), the National Center for Advancing Translational Sciences, National Institutes of Health Clinical and Translational Science Award program (UL1 TR001866), the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (UM1HG006504 and U24HG008956), Institut National de la Santé et de la Recherche Médicale and Université de Paris, the French National Research Agency (ANR) Résilience-Covid-19 grant GenMIS-C, the ANR 'Investments for the Future' program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the ANR project AABIFNCOV (ANR-20-CO11-0001), the French Foundation for Medical Research (EQU201903007798), the French Foundation for Medical Research and ANR GENCOVID project, the ANRSCOV05 project, the Square Foundation, Grandir - Fonds de solidarité pour l’enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, UK Research and Innovation Future Leader’s Fellowship (MR/S032304/1), the NIHR Imperial Biomedical Research Centre at Imperial College Healthcare NHS Trust (70931), the Burroughs Wellcome Fund Career Awards for Medical Scientists, the Clinical Immunology Society, the American Academy of Allergy Asthma and Immunology, the Michael Smith Foundation for Health Research, the National Health and Medical Research Council of Australia, and the University of New South Wales Sydney COVID Rapid Response Initiative (to S.G. Tangye)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), Imperial College BRC, Imperial College Healthcare NHS Trust- BRC Funding, and UKRI Future Leader's Fellowship

Subjects
0301 basic medicine, viruses, Systemic Inflammatory Response Syndrome/epidemiology, Genome-wide association study, CHILDREN, COVID-19 (Malaltia), Pathogenesis, 0302 clinical medicine, hemic and lymphatic diseases, INFECTION, Medicine and Health Sciences, Immunology and Allergy, 030212 general & internal medicine, skin and connective tissue diseases, Child, 11 Medical and Health Sciences, COVID-19/epidemiology, Pediatria, Malaltia de Kawasaki, Systemic Inflammatory Response Syndrome, Settore MED/03, Inflammation Mediators/blood, Perspective, Cytokines, SHOCK, medicine.symptom, Inflammation Mediators, Lymphohistiocytosis, Hemophagocytic/genetics, congenital, hereditary, and neonatal diseases and abnormalities, HUMAN CORONAVIRUS NL63, SUSCEPTIBILITY LOCI, MULTISYSTEM INFLAMMATORY SYNDROME, Inflammation/etiology, Immunology, Innate Immunity and Inflammation, Inflammation, Biology, Mucocutaneous Lymph Node Syndrome, Cytokines/blood, Models, Biological, Lymphohistiocytosis, Hemophagocytic, SARS-CoV-2/immunology, 03 medical and health sciences, Immune system, Immunity, CORONARY ANEURYSMS, medicine, otorhinolaryngologic diseases, Immunodeficiency, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Pandemics, SARS-CoV-2, Mucocutaneous Lymph Node Syndrome/epidemiology, COVID-19, biochemical phenomena, metabolism, and nutrition, medicine.disease, Systemic inflammatory response syndrome, 030104 developmental biology, Etiology, Kawasaki disease, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, PIMS-TS, Biomarkers, Human Disease Genetics, Genètica, Biomarkers/blood, Genome-Wide Association Study
Abstract

SARS-CoV-2 is the trigger of MIS-C, which suggests that other viruses may trigger different forms of Kawasaki disease. The discovery of inborn errors of immunity underlying MIS-C would facilitate that of inborn errors of immunity to viruses underlying Kawasaki disease., Multisystem inflammatory syndrome in children (MIS-C) emerged in April 2020 in communities with high COVID-19 rates. This new condition is heterogenous but resembles Kawasaki disease (KD), a well-known but poorly understood and clinically heterogenous pediatric inflammatory condition for which weak associations have been found with a myriad of viral illnesses. Epidemiological data clearly indicate that SARS-CoV-2 is the trigger for MIS-C, which typically occurs about 1 mo after infection. These findings support the hypothesis of viral triggers for the various forms of classic KD. We further suggest that rare inborn errors of immunity (IEIs) altering the immune response to SARS-CoV-2 may underlie the pathogenesis of MIS-C in some children. The discovery of monogenic IEIs underlying MIS-C would shed light on its pathogenesis, paving the way for a new genetic approach to classic KD, revisited as a heterogeneous collection of IEIs to viruses.

Published
2021

7. Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Author

Borghini, Lisa, Png, Eileen, Binder, Alexander, Wright, Victoria J, Pinnock, Ellie, de Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van der Flier, Michiel, Schlapbach, Luregn J, Anderson, Suzanne, Secka, Fatou, Salas, Antonio, Fink, Colin, Carrol, Enitan D, Pollard, Andrew J, Coin, Lachlan J, Kuijpers, Taco W, Martinon-Torres, Federico, Zenz, Werner, Levin, Michael, Hibberd, Martin L, Davila, Sonia, Gormley, Stuart, Hamilton, Shea, Herberg, Jethro, Hourmat, Bernardo, Hoggart, Clive, Kaforou, Myrsini, Sancho-Shimizu, Vanessa, Abdulla, Amina, Agapow, Paul, Bartlett, Maeve, Bellos, Evangelos, Eleftherohorinou, Hariklia, Galassini, Rachel, Inwald, David, Mashbat, Meg, Menikou, Stefanie, Mustafa, Sobia, Nadel, Simon, Rahman, Rahmeen, Thakker, Clare, Bokhandi, S, Power, Sue, Barham, Heather, Pathan, N, Ridout, Jenna, White, Deborah, Thurston, Sarah, Faust, S, Patel, S, McCorkell, Jenni, Davies, P, Cratev, Lindsey, Navarra, Helen, Carter, Stephanie, Ramaiah, R, Patel, Rekha, Tuffrey, Catherine, Gribbin, Andrew, McCready, Sharon, Peters, Mark, Hardy, Katie, Standing, Fran, O'Neill, Lauren, Abelake, Eugenia, Deep, Akash, Nsirim, Eniola, Willis, Louise, Young, Zoe, Royad, C, White, Sonia, Fortune, PM, Hudnott, Phil, Alvez Gonzalez, Fernando, Barral-Arca, Ruth, Cebey-Lopez, Miriam, Jose Curras-Tuala, Maria, Garcia, Natalia, Garcia Vicente, Luisa, Gomez-Carballa, Alberto, Gomez Rial, Jose, Grela Beiroa, Andrea, Justicia Grande, Antonio, Leborans Iglesias, Pilar, Martinez Santos, Alba Elena, Martinon-Torres, Nazareth, Martinon Sanchez, Jose Maria, Mosquera Perez, Belen, Obando Pacheco, Pablo, Pardo-Seco, Jacobo, Pischedda, Sara, Rivero Calle, Irene, Rodriguez-Tenreiro, Carmen, Redondo-Collazo, Lorenzo, Seren Fernandez, Sonia, Porto Silva, Maria del Sol, Vega, Ana, Beatriz Reyes, Susana, Leon Leon, Maria Cruz, Navarro Mingorance, Alvaro, Gabaldo Barrios, Xavier, Onate Vergara, Eider, Concha Torre, Andres, Vivanco, Ana, Fernandez, Reyes, Gimenez Sanchez, Francisco, Sanchez Forte, Miguel, Rojo, Pablo, Ruiz Contreras, J, Palacios, Alba, Navarro, Marisa, Alvarez Alvarez, Cristina, Jose Lozano, Maria, Carreras, Eduardo, Brio Sanagustin, Sonia, Neth, Olaf, Martinez Padilla, Ma del Carmen, Prieto Tato, Luis Manuel, Guillen, Sara, Fernandez Silveira, Laura, Moreno, David, van Furth, AM Tutu, van der Flier, M, Boeddha, NP, Driessen, GJA, Pajkrt, D, Sanders, EAM, van de Beek, D, van der Ende, A, Philipsen, HLA, Adeel, AOA, Breukels, MA, Brinkman, DMC, de Korte, CCMM, de Vries, E, de Waal, WJ, Dekkers, R, Dings-Lammertink, A, Doedens, RA, Donker, AE, Dousma, M, Faber, TE, Gerrits, GPJM, Gerver, JAM, Heidema, J, Homan-van der Veen, J, Jacobs, MAM, Jansen, NJG, Kawczynski, P, Klucovska, K, Kneyber, MCJ, Koopman-Keemink, Y, Langenhorst, VJ, Leusink, J, Loza, BF, Merth, IT, Miedema, CJ, Neeleman, C, Noordzij, JG, Obihara, CC, van Overbeek-van Gils, ALT, Poortman, GH, Potgieter, ST, Potjewijd, J, Rosias, PPR, Sprong, T, ten Tussher, GW, Thio, BJ, Tramper-Stranders, GA, van Deuren, M, van der Meer, H, van Kuppevelt, AJM, van Wermeskerken, AM, Verwijs, WA, Wolfs, TFW, Agyeman, Philipp, Aebi, Christoph, Berger, Christoph, Giannoni, Eric, Stocker, Martin, Posfay-Barbe, Klara M, Heininger, Ulrich, Bernhard-Stirnemann, Sara, Niederer-Loher, Anita, Kahlert, Christian, Hasters, Paul, Relly, Christa, Baer, Walter, Paulus, Stephane, Frederick, Hannah, Jennings, Rebecca, Johnston, Joanne, Kenwright, Rhian, Agbeko, Rachel, Bojang, Kalifa, Sarr, Isatou, Kebbeh, Ngane, Sey, Gibbi, Saidykhan, Momodou, Cole, Fatoumatta, Thomas, Gilleh, Antonio, Martin, Walcher, Wolfgang, Geishofer, Gotho, Klobassa, Daniela, Martin, Mueller, Pfurtscheller, Klaus, Reiter, Karl, Roedl, Siegfried, Zobel, Gerfried, Zoehrer, Bettina, Toepke, Baerbel, Fucik, Peter, Gabriel, Markwart, Penzien, Johann M, Diab, Gedeon, Miething, Robert, Deeg, KH, Hammer, Jurg, Varnholt, Verena, Schmidt, Andreas, Bindl, Lutz, Sillaber, Ursula, Huemer, Christian, Meier, Primrose, Simic-Schleicher, G, Markart, Markus, Pfau, Eberhard, Broede, Hans, Ausserer, Bernd, Kalhoff, Hermann, Arpe, Volker, Schweitzer-Krantz, Susanne, Kasper, Johannes-Martin, Loranth, Kathrin, Bittrich, Hans J, Simma, Burkhard, Klinge, Jens, Fedlmaier, Michael, Weigand, Nicola, Herting, Egbert, Grube, Regina, Fusch, Christoph, Gruber, Alois, Schimmel, Ulf, Knaufer-Schiefer, Suzanne, Laessig, Wolfgang, Hennenberger, Axel, von der Wense, Axel, Tillmann, Roland, Schwarick, Juergen, Sitzmann, Friedrich C, Streif, Werner, Mueller, Herbert, Kurnik, Peter, Groneck, Peter, Weiss, Ute, Groeblacher-Roth, Helene, Bensch, Juergen, Moser, Reinhard, Schwarz, Rudolf, Lenz, Kurt, Hofmann, Thomas, Goepel, Wolfgang, Schulz, Dietrich, Berger, Thomas, Hauser, Erwin, Foerster, Kai Martin, Peters, Jochen, Nicolai, T Homas, Kumlien, Bjoern, Beckmann, Regina, Seitz, Christiane, Hueseman, D, Schuermann, Roland, Ta, Van Hop, Weikmann, Eckart, Evert, W, Hautz, Juergen, Seidenberg, Juergen, Wocko, Lucia, Luigs, Petra, Reiter, Hans-Ludwig, Quietzach, J, Koenig, Michael, Herrmann, Johanna, Mitter, Horst, Seidler, Ekkehard, Maak, Bernhard, Sperl, Wolfgang, Zwiauer, Karl, Meissl, Manfred, Koch, Reinhard, Cremer, Manfred, Breuer, HA, Goerke, W, Nossal, Robert, Pernice, Walter, Brangenberg, Ralf, Salzer, Hans R, Koch, Hartmut, Schaller, Gerhard, Paky, Franz, Strasser, Friedrich, Eitelberger, Franz, Sontheimer, D, Lischka, Andreas, Kronberger, Martina, Dilch, Alfred, Scheibenpflug, Christian, Bruckner, Robert, Mahler, Klaus, Runge, Klaus, Kunze, Wolfgang, Schermann, Peter, Consortium, EUCLIDS, European Commission, Meningitis Research Foundation, National Institute for Health Research (UK), Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne Hospitals NHS Foundation Trust, Instituto de Salud Carlos III, Xunta de Galicia, Wyeth Farma, Fundación Instituto de Investigación Sanitaria de Santiago de Compostela, Novartis, Swiss National Science Foundation, Swiss Society of Intensive Care Medicine, Gottfried und Julia Bangerter-Rhyner-Stiftung, Vinetum and Borer Foundation, Foundation for the Health of Children and Adolescents, Austrian National Bank, University of Zurich, Borghini, Lisa, Universidade de Santiago de Compostela. Departamento de Ciencias Forenses, Anatomía Patolóxica, Xinecoloxía e Obstetricia, e Pediatría, Png, Eileen [0000-0001-5586-6395], Wright, Victoria J [0000-0001-7826-1516], Schlapbach, Luregn J [0000-0003-2281-2598], Salas, Antonio [0000-0002-2336-702X], Martinon-Torres, Federico [0000-0002-9023-581X], Apollo - University of Cambridge Repository, ARD - Amsterdam Reproduction and Development, AII - Infectious diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Neurology, ANS - Neuroinfection & -inflammation, Medical Microbiology and Infection Prevention, Pediatrics, Public Health, Posfay Barbe, Klara, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), APH - Aging & Later Life, Amsterdam Reproduction & Development (AR&D), and Pediatric surgery

Subjects
0301 basic medicine, Candidate gene, Hypopharyngeal Neoplasms / microbiology, Meningococcal Infections / microbiology, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], MathematicsofComputing_GENERAL, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], lcsh:Medicine, Neisseria meningitidis, Regulatory Sequences, Nucleic Acid, Cohort Studies, 0302 clinical medicine, ComputingMethodologies_SYMBOLICANDALGEBRAICMANIPULATION, Hypopharyngeal Neoplasms / pathology, BINDING, Tumor Cells, Cultured, lcsh:Science, Genetics, Multidisciplinary, ddc:618, Cultured, TheoryofComputation_GENERAL, High-Throughput Nucleotide Sequencing, Genomics, Phenotype, 3. Good health, ddc, Tumor Cells, Multidisciplinary Sciences, GENOME, Science & Technology - Other Topics, Neisseria meningitidis / isolation & purification, Single-nucleotide polymorphism, 610 Medicine & health, KAPPA-B, Biology, Hypopharyngeal Neoplasms / genetics, Polymorphism, Single Nucleotide, Article, Meningococcal Infections / epidemiology, 03 medical and health sciences, SEQUENCE VARIATION, Genetic predisposition, Journal Article, Humans, Meningitis, Meningococcal Infections / genetics, Genetic Predisposition to Disease, Nucleic Acid, Polymorphism, General, Gene, Genotyping, Neisseria meningitidis / genetics, Genetic Association Studies, Genetic association, Genetic association study, 1000 Multidisciplinary, Science & Technology, Hypopharyngeal Neoplasms, genetic variants, meningococcal disease, lcsh:R, Single Nucleotide, EUCLIDS consortium, Gene regulation, Meningococcal Infections, 030104 developmental biology, 10036 Medical Clinic, Case-Control Studies, lcsh:Q, Software_PROGRAMMINGLANGUAGES, Regulatory Sequences, 030217 neurology & neurosurgery
Abstract

EUCLIDS consortium., Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA – a NF-kB subunit, master regulator of the response to infection – under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes., This work has been partially funded by the European Seventh Framework Programme for Research and Technological Development (FP7) under EUCLIDS Grant Agreement No. 279185. The UK meningococcal cohort was established with support from Meningitis Research Foundation through grants to Imperial College London. The Research from Newcastle partners was supported by the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The ESIGEM Research group activities were supported by grants from Instituto de Salud Carlos III (Proyecto de Investigación en Salud, Acción Estratégica en Salud: proyecto GePEM PI16/01478) (A.S.); Consellería de Sanidade, Xunta de Galicia (RHI07/2-intensificación actividad investigadora, PS09749 and 10PXIB918184PR), Instituto de Salud Carlos III (Intensificación de la actividad investigadora 2007–2016), Convenio de colaboración de investigación (Wyeth España-Fundación IDICHUS 2007–2011), Convenio de colaboración de investigación (Novartis España-Fundación IDICHUS 2010–2011), Fondo de Investigación Sanitaria (FIS; PI070069/PI1000540) del plan nacional de I + D + I and ‘fondos FEDER’ (F.M.T.). The Swiss Pediatric Sepsis study was funded by grants from the Swiss National Science Foundation (342730_153158/1), the Swiss Society of Intensive Care, the Bangerter Foundation, the Vinetum and Borer Foundation, and the Foundation for the Health of Children and Adolescents. The Western Europe Meningococcal Study was supported by grants no 8842, 10112 and 12710 of the Oesterreichische Nationalbank (Austria), grants A3-16.K-8/2008-11 and A3-16.K-8/2006–9 of the Department for Science and Research of the Styrian federal government (Austria) and the non for profit association ‘In Vita’, Graz (Austria).

Published
2019

8. Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Author

Wang, Xinzhu, Nijman, Ruud, Camuzeaux, Stephane, Sands, Caroline, Jackson, Heather, Kaforou, Myrsini, Emonts, Marieke, Herberg, Jethro A, Maconochie, Ian, Carrol, Enitan D, Paulus, Stephane C, Zenz, Werner, Van der Flier, Michiel, de Groot, Ronald, Martinon-Torres, Federico, Schlapbach, Luregn J, Pollard, Andrew J, Fink, Colin, Kuijpers, Taco T, Anderson, Suzanne, Lewis, Matthew R, Levin, Michael, McClure, Myra, Gormley, Stuart, Hamilton, Shea, Hourmat, Bernardo, Hoggart, Clive, Sancho-Shimizu, Vanessa, Wright, Victoria, Abdulla, Amina, Agapow, Paul, Bartlett, Maeve, Bellos, Evangelos, Eleftherohorinou, Hariklia, Galassini, Rachel, Inwald, David, Mashbat, Meg, Menikou, Stefanie, Mustafa, Sobia, Nadel, Simon, Rahman, Rahmeen, Thakker, Clare, Coin, Lachlan MJ, Bokhand, S, Power, Sue, Barham, Heather, Pathan, N, Ridout, Jenna, White, Deborah, Thurston, Sarah, Faust, S, Patel, S, McCorkell, Jenni, Davies, P, Crate, Lindsey, Navarra, Helen, Carter, Stephanie, Ramaiah, R, Patel, Rekha, Tuffrey, Catherine, Gribbin, Andrew, McCready, Sharon, Peters, Mark, Hardy, Katie, Standing, Fran, O'Neill, Lauren, Abelake, Eugenia, Deep, Akash, Nsirim, Eniola, Willis, Louise, Young, Zoe, Royad, C, White, Sonia, Fortune, PM, Hudnott, Phil, Alvez Gonzalez, Fernando, Barral-Arca, Ruth, Cebey-Lopez, Miriam, Jose Curras-Tuala, Maria, Garcia, Natalia, Garcia Vicente, Luisa, Gomez-Carballa, Alberto, Gomez Rial, Jose, Grela Beiroa, Andrea, Justicia Grande, Antonio, Leborans Iglesias, Pilar, Martinez Santos, Alba Elena, MartinonTorres, Nazareth, Martinon Sanchez, Jose Maria, Morillo Gutierrez, Beatriz, Mosquera Perez, Belen, Obando Pacheco, Pablo, Pardo-Seco, Jacobo, Pischedda, Sara, RiveroCalle, Irene, Rodriguez-Tenreiro, Carmen, Redondo-Collazo, Lorenzo, Salas Ellacuriagal, Antonio, Seren Fernandez, Sonia, Porto Silva, Maria del Sol, Vega, Ana, Vilanova Trillo, Lucia, Salas, Antonio, Beatriz Reyes, Susana, Leon Leon, Maria Cruz, Navarro Mingorance, Alvaro, Gabaldo Barrios, Xavier, Onate Vergara, Eider, Concha Torre, Andres, Vivanco, Ana, Fernandez, Reyes, Gimenez Sanchez, Francisco, Sanchez Forte, Miguel, Rojo, Pablo, Ruiz Contreras, J, Palacios, Alba, Epalza Ibarrondo, Cristina, Fernandez Cooke, Elizabeth, Navarro, Marisa, Alvarez Alvarez, Cristina, Jose Lozano, Maria, Carreras, Eduardo, Brio Sanagustin, Sonia, Neth, Olaf, Martinez Padilla, Ma del Carmen, Prieto Tato, Luis Manuel, Guillen, Sara, Fernandez Silveira, Laura, Moreno, David, van Furth, AM Tutu, Boeddha, NP, Driessen, GJA, Emonts, M, Hazelzet, JA, Pajkrt, D, Sanders, EAM, van de Beek, D, van der Ende, A, Philipsen, HLA, Adeel, AOA, Breukels, MA, Brinkman, DMC, de Korte, CCMM, de Vries, E, de Waal, WJ, Dekkers, R, Dings-Lammertink, A, Doedens, RA, Donker, AE, Dousma, M, Faber, TE, Gerrits, GPJM, Gerver, JAM, Heidema, J, Homan-van der Veen, J, Jacobs, MAM, Jansen, NJG, Kawczynski, P, Klucovska, K, Kneyber, MCJ, Koopman-Keemink, Y, Langenhorst, VJ, Leusink, J, Loza, BF, Merth, IT, Miedema, CJ, Neeleman, C, Noordzij, JG, Obihara, CC, van Overbeek-van Gils, ALT, Poortman, GH, Potgieter, ST, Potjewijd, J, Rosias, PPR, Sprong, T, ten Tussher, GW, Thio, BJ, Tramper-Stranders, GA, van Deuren, M, van der Meer, H, van Kuppevelt, AJM, van Wermeskerken, AM, Verwijs, WA, Wolfs, TFW, Agyeman, Philipp, Aebi, Christoph, Berger, Christoph, Giannoni, Eric, Stocker, Martin, Posfay-Barbe, Klara M, Heininger, Ulrich, Bernhard-Stirnemann, Sara, Niederer-Loher, Anita, Kahlert, Christian, Hasters, Paul, Relly, Christa, Baer, Walter, Frederick, Hannah, Jennings, Rebecca, Johnston, Joanne, Kenwright, Rhian, Pinnock, Elli, Agbeko, Rachel, Secka, Fatou, Bojang, Kalifa, Sarr, Isatou, Kebbeh, Ngange, Sey, Gibbi, Momodou, Saidy Khan, Cole, Fatoumata, Thomas, Gilleh, Antonio, Martin, Klobassa, Daniela S, Binder, Alexander, Schweintzger, Nina A, Sagmeister, Manfred, Baumgart, Hinrich, Baumgartner, Markus, Behrends, Uta, Biebl, Ariane, Birnbacher, Robert, Blanke, Jan-Gerd, Boelke, Carsten, Breuling, Kai, Brunner, Juergen, Buller, Maria, Dahlem, Peter, Dietrich, Beate, Eber, Ernst, Elias, Johannes, Emhofer, Josef, Etschmaier, Rosa, Farr, Sebastian, Girtler, Ylenia, Grigorow, Irina, Heimann, Konrad, Ihm, Ulrike, Jaros, Zdenek, Kalhoff, Hermann, Kaulfersch, Wilhelm, Kemen, Christoph, Klocker, Nina, Koester, Bernhard, Kohlmaier, Benno, Komini, Eleni, Kramer, Lydia, Neubert, Antje, Ortner, Daniel, Pescollderungg, Lydia, Pfurtscheller, Klaus, Reiter, Karl, Ristic, Goran, Roedl, Siegfried, Sellner, Andrea, Sonnleitner, Astrid, Sperl, Matthias, Stelzl, Wolfgang, Till, Holger, Trobisch, Andreas, Vierzig, Anne, Vogel, Ulrich, Weingarten, Christina, Welke, Stefanie, Wimmer, Andreas, Wintergerst, Uwe, Wueller, Daniel, Zaunschirm, Andrew, Ziuraite, Ieva, Zukovskaja, Veslava, Consortium, EUCLIDS, Sands, Caroline [0000-0002-3749-7941], Jackson, Heather [0000-0002-1054-9983], Kaforou, Myrsini [0000-0001-9878-4007], Paulus, Stephane C [0000-0002-0703-9114], Martinon-Torres, Federico [0000-0002-9023-581X], Apollo - University of Cambridge Repository, Pediatric surgery, AII - Infectious diseases, Internal medicine, Pathology, Psychiatry, Amsterdam Reproduction & Development (AR&D), Posfay Barbe, Klara, European Commission, National Institute for Health Research (UK), NIHR Biomedical Research Centre (UK), Medical Research Council (UK), Wellcome Trust, Pediatrics, Public Health, Paediatric Infectious Diseases / Rheumatology / Immunology, Amsterdam Neuroscience - Neuroinfection & -inflammation, Neurology, Medical Microbiology and Infection Prevention, and Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE)

Subjects
Male, 0301 basic medicine, ACCURACY, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], MENINGITIS, Antibiotics, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], MathematicsofComputing_GENERAL, lcsh:Medicine, 0601 Biochemistry and Cell Biology, chemistry.chemical_compound, 0302 clinical medicine, ComputingMethodologies_SYMBOLICANDALGEBRAICMANIPULATION, Blood plasma, 030212 general & internal medicine, Child, lcsh:Science, ddc:618, Multidisciplinary, music.instrument, TheoryofComputation_GENERAL, Bacterial Infections, Lipidome, ddc, Sphingomyelins, 3. Good health, Cholesterol, Virus Diseases, Child, Preschool, Female, Adolescent, medicine.drug_class, Bilirubin, Inositol Phosphates, 0299 Other Physical Sciences, 610 Medicine & health, DIAGNOSIS, Fever of Unknown Origin, Article, Virus, Diagnosis, Differential, 03 medical and health sciences, Lactosylceramide, Journal Article, medicine, Metabolomics, Humans, General, music, business.industry, lcsh:R, Infant, Lysophosphatidylcholines, Diagnostic markers, Omics, EUCLIDS consortium, 030104 developmental biology, chemistry, Immunology, lcsh:Q, Software_PROGRAMMINGLANGUAGES, business, ddc:600, Biomarkers
Abstract

EUCLIDS consortium., Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The ‘omics’ approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics., This work was partially supported by the European Seventh Framework Programme for Research and Technological Development (FP7) under EUCLIDS Grant Agreement no. 279185. ICED: The Research was supported by the National Institute for Health Research Biomedical Research Centre based at Imperial College. This work was further supported by the Medical Research Council and National Institute for Health Research [grant number MC_PC_12025] through funding for the MRC-NIHR National Phenome Centre, infrastructure support was provided by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at Imperial NHS Healthcare Trust. MK acknowledges funding from the Wellcome Trust (Sir Henry Wellcome Fellowship grant 206508/Z/17/Z).

Published
2019

9. The Impact of Insulation Layer in Various Solar Heating Systems: An Energetic and Financial Evaluation

Author

Christos Tzivanidis, Ioannis Alexopoulos, Kimon A. Antonopoulos, Bellos Evangelos, and G. Mitsopoulos

Subjects
Engineering, Heating system, Insulation layer, business.industry, Underfloor heating, Financial evaluation, Mechanical engineering, Structural engineering, TRNSYS, business, Solar energy, Fan coil unit
Abstract

Solar energy utilization in buildings is vital because of the increasing demand of energy for heating and cooling. Also, improvements in building structure are needed in order to decrease the heating and cooling demand. In this study, the impact of insulation layer thickness in the solar coverage of two solar heating systems is analyzed energetically and financially. The examined building is a typical Greek Building located in Athens with area 100m2. The first heating system combines flat plate collectors with a fan coil system, while the other is an underfloor heating system coupled with flat plate collectors. An auxiliary heater is located in both systems in order to supply extra energy when it is needed. The final results show that 6cm of insulation lead to minimum cost and fan coil system is the less expensive solution. TRNSYS 16 is the simulation tool of the study and gives many features to the users for solar applications in buildings.

Published
2015

10. cnvCapSeq: detecting copy number variation in long-range targeted resequencing data

Author

Bellos, Evangelos, Kumar, Vikrant, Lin, Clarabelle, Maggi, Jordi, Phua, Zai Yang, Cheng, Ching-Yu, Cheung, Chui Ming Gemmy, Hibberd, Martin L, Wong, Tien Yin, Coin, Lachlan JM, and Davila, Sonia

Abstract

Targeted resequencing technologies have allowed for efficient and cost-effective detection of genomic variants in specific regions of interest. Although capture sequencing has been primarily used for investigating single nucleotide variants and indels, it has the potential to elucidate a broader spectrum of genetic variation, including copy number variants (CNVs). Various methods exist for detecting CNV in whole-genome and exome sequencing datasets. However, no algorithms have been specifically designed for contiguous target sequencing, despite its increasing importance in clinical and research applications. We have developed cnvCapSeq, a novel method for accurate and sensitive CNV discovery and genotyping in long-range targeted resequencing. cnvCapSeq was benchmarked using a simulated contiguous capture sequencing dataset comprising 21 genomic loci of various lengths. cnvCapSeq was shown to outperform the best existing exome CNV method by a wide margin both in terms of sensitivity (92.0 versus 48.3%) and specificity (99.8 versus 70.5%). We also applied cnvCapSeq to a real capture sequencing cohort comprising a contiguous 358 kb region that contains the Complement Factor H gene cluster. In this dataset, cnvCapSeq identified 41 samples with CNV, including two with duplications, with a genotyping accuracy of 99%, as ascertained by quantitative real-time PCR.

Published
2014

11. Statistical methods for elucidating copy number variation in high-throughput sequencing studies

Author

Bellos, Evangelos, Coin, Lachlan, and Johnson, Michael

Subjects
eye diseases
Abstract

Copy number variation (CNV) is pervasive in the human genome and has been shown to contribute significantly to phenotypic diversity and disease aetiology. High-throughput sequencing (HTS) technologies have allowed for the systematic investigation of CNV at an unprecedented resolution. HTS studies offer multiple distinct features that can provide evidence for the presence of CNV. We have developed an integrative statistical framework that jointly analyses multiple sequencing features at the population level to achieve sensitive and precise discovery of CNV. First, we applied our framework to low-coverage whole-genome sequencing experiments and used data from the 1000 Genomes Project to demonstrate a substantial improvement in CNV detection accuracy over existing methods. Next, we extended our approach to targeted HTS experiments, which offer improved cost-efficiency by focusing on a predetermined subset of the genome. Targeted HTS involves an enrichment step that introduces non-uniformity in sequencing coverage across target regions and thus hinders CNV identification. To that end, we designed a customized normalization procedure that counteracts the effects of enrichment bias and enhances the underlying CNV signal. Our extended framework was benchmarked on contiguous capture datasets, where it was shown to outperform competing strategies by a wide margin. Capture sequencing can also generate large amounts of data in untargeted genomic regions. Although these off-target results can be a valuable source of CNV evidence, they are subject to complex enrichment patterns that confound their interpretation. Therefore, we developed the first normalization strategy that can adapt to the highly heterogeneous nature of off-target capture and thus facilitate CNV investigation in untargeted regions. All in all, we present a generalized CNV detection toolset that has been shown to achieve robust performance across datasets and sequencing platforms and can therefore provide valuable insight into the prevalence and impact of CNV. Open Access

Published
2014
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12. Population-haplotype models for mapping and tagging structural variation using whole genome sequencing

Author

Loizidou, Eleni, Prokopenko, Inga, Johnson, Michael, Coin, Lachlan, Bellos, Evangelos, Medical Research Council (Great Britain), and GlaxoSmithKline

Abstract

The scientific interest in copy number variation (CNV) is rapidly increasing, mainly due to the evidence of phenotypic effects and its contribution to disease susceptibility. Single nucleotide polymorphisms (SNPs) which are abundant in the human genome have been widely investigated in genome-wide association studies (GWAS). Despite the notable genomic effects both CNVs and SNPs have, the correlation between them has been relatively understudied. In the past decade, next generation sequencing (NGS) has been the leading high-throughput technology for investigating CNVs and offers mapping at a high-quality resolution. We created a map of NGS-defined CNVs tagged by SNPs using the 1000 Genomes Project phase 3 (1000G) sequencing data to examine patterns between the two types of variation in protein-coding genes. To investigate potential relationships between CNV-tagging SNPs and various phenotypes, we used SNPs reported for disease/phenotype associations from the GWAS catalog. Moreover, we applied our method to DIAGRAM consortium and Northern Finland Birth Cohort (NFBC) data. Our analysis replicated existing CNV-tagging SNPs but also revealed novel relationships between them in almost all the datasets we analysed. We have developed a statistical framework under a population perspective for a fast and accurate CNV detection. Using 202 drug-target genes defined in collaboration with GlaxoSmithKline (GSK), we applied our framework to the 1000G data. We calculated summary statistics based on the detected CNV calls including the allele frequency (AF) for each of the 26 populations of the 1000G. In addition, we visualised our results using UCSC genome browser visualisation tracks for all 202 regions and successfully benchmarked our CNV calls by comparing them to a gold standard set of the 1000G CNVs. Overall in this thesis, we present detailed maps of CNVs and CNV-tagging SNPs to enhance existing knowledge of their impact on human genome. Open Access

Published
2018

13. Integrated management systems: moving from function to organisation/ decision view

Author

Konstantinos Kirytopoulos, Evangelos Bellos, Vrassidas Leopoulos, Dimitra Voulgaridou, Leopoulos, Vrassidas, Voulgaridou, Dimitra, Bellos, Evangelos, and Kirytopoulos, Konstantinos

Subjects
Decision support system, Process management, chemical industries, Decision engineering, Computer science, Strategy and Management, Evidential reasoning approach, Intelligent decision support system, General Decision Sciences, General Business, Management and Accounting, R-CAST, companies, quality, Business decision mapping, Management system, Operations management, Business and International Management, Decision analysis
Abstract

PurposeThe integration of management systems is a common need nowadays, thus several paradigms exist in the bibliography for relevant efforts. However, the basic effort seems to be mainly at the direction of aligning processes and documents, taking into account only one of four typical views of organisations' modelling (the function view). Since the function view has been widely studied, this paper aims to focus on the organisation/decision view.Design/methodology/approachThe proposed approach focuses on the integrated management system (IMS) with respect to the organisation/decision view and offers a control mechanism which guarantees that requirements from all standards will be taken into consideration, while it proposes the use of a well‐known multi‐criteria decision making technique to support the decision makers. The paper focuses on the organisation/decision view, illustrated through a real case from the chemical industry.FindingsIt is concluded that the integration of management sub‐systems into one IMS should be done with respect to each one of the four enterprise modelling views, namely function, information, resource and organisation/decision view.Research limitations/implicationsThe proposed approach is general and can be applied to many integrated systems where decisions have to be taken. However, the selection of the analytic network process as a decision support tool implies that the decision involves both qualitative and quantitative criteria. In cases where only qualitative or only quantitative criteria exist, another decision support tool may be superior.Originality/valueThe originality of the paper stems from the consideration of the organisation/decision view rather than the function view that mostly appears in literature.

Published
2010

14. An MCDA approach for project selection in public sector

Author

Bellos, Evangelos, Voulgaridou, D, Kirytopoulos, Konstantinos, Panopoulos, D, and 5th Scientific Conference on Project Management, CCI - NTUA Greece 29-31 May, 2010

Subjects
project selection, public sector, multicriteria decision analysis, ANP
Abstract

Effective and efficient selection of projects is a crucial issue for every organization and should be aligned with its vision and strategies. The decision making process is highly complex, especially for public organisations, as it encompasses various, often conflicting criteria. Moreover they have to consider a much larger picture than private organisations and many scholars argue that public investment decisions fall into the category of constrained optimisation problems. The present study develops and proposes an approach for the prioritization of public projects, based on the Analytic Network Process (ANP), which is further validated through a real case example concerning the project selection process of a Greek municipality. The results indicate that social and political criteria dominate the decision making process, while the ANP documents the results in such way that they can be communicated to various stakeholders, ensuring public trust and establishing a system of transparency in public administration.

Published
2010

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