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2. Clinical Symptoms, Laboratory Parameters and Long-Term Follow-up in a National DADA2 Cohort

Author

Andriessen, Marie Valérie E., Legger, G. Elizabeth, Bredius, Robbert G. M., van Gijn, Marielle E., Hak, A. Elisabeth, Muller, Petra C. E. Hissink, Kamphuis, Sylvia, Klouwer, Femke C. C., Kuijpers, Taco W., Leavis, Helen L., Nierkens, Stefan, Rutgers, Abraham, van der Veken, Lars T., van Well, Gijs T. J., Mulders-Manders, Catharina M., and van Montfrans, Joris M.

Published
2023
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5. Management of adult-onset Still's disease: evidence- and consensus-based recommendations by experts.

Author

Leavis, Helen L, Daele, Paul L A van, Mulders-Manders, Catharina, Michels, Renée, Rutgers, Abraham, Legger, Elizabeth, Bijl, Marc, Hak, Elisabeth A, Lam-Tse, Wai-Kwan, Bonte-Mineur, Femke, Fretter, Peter, Simon, Anna, Paassen, Pieter van, Goes, Marlies C van der, Flendrie, Marcel, Vercoutere, Ward, Lieshout, Antoine W T van, Leek, Arjen, Vastert, Sebastiaan J, and Tas, Sander W

Subjects
*RHEUMATOID arthritis diagnosis, *BIOTHERAPY, *RHEUMATOID arthritis treatment, *CONSENSUS (Social sciences), *WORLD Wide Web, *RESEARCH funding, *QUESTIONNAIRES, *METHOTREXATE, *TREATMENT effectiveness, *DESCRIPTIVE statistics, *EVIDENCE-based medicine, *DELPHI method, *RHEUMATOLOGISTS, *GLUCOCORTICOIDS, *EVALUATION
Abstract

Objectives Adult-onset Still's disease (AOSD) is a rare condition characterized by fevers, rash, and arthralgia/arthritis; most doctors treating AOSD in the Netherlands treat <5 patients per year. Currently, there is no internationally accepted treatment guideline for AOSD. The objectives of this study were to conduct a Delphi panel aimed at reaching consensus about diagnostic and treatment strategies for patients with AOSD and to use the outcomes as a basis for a treatment algorithm. Methods The Delphi panel brought together 18 AOSD experts: rheumatologists, internists and paediatricians. The Delphi process consisted of three rounds. In the first two rounds, online lists of questions and statements were completed. In the third round, final statements were discussed during a virtual meeting and a final vote took place. Consensus threshold was set at 80%. Two targeted literature searches were performed identifying the level of evidence of the consensus-based statements. Results Consensus was reached on 29 statements, including statements related to diagnosis and diagnostic tests, definition of response and remission, the therapy, the use of methotrexate and tapering of treatment. The panel consented on reduction of the use of glucocorticoids to avoid side effects, and preferred the use of biologics over conventional treatment. The role of IL-1 and IL-6 blocking agents was considered important in the treatment of AOSD. Conclusion In this Delphi panel, a high level of consensus was achieved on recommendations for diagnosis and therapy of AOSD that can serve as a basis for a treatment guideline. [ABSTRACT FROM AUTHOR]

Published
2024
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8. Management of adult-onset Still's disease: evidence- and consensus-based recommendations by experts

Author

Leavis, Helen L, primary, van Daele, Paul L A, additional, Mulders-Manders, Catharina, additional, Michels, Renée, additional, Rutgers, Abraham, additional, Legger, Elizabeth, additional, Bijl, Marc, additional, Hak, Elisabeth A, additional, Lam-Tse, Wai-Kwan, additional, Bonte-Mineur, Femke, additional, Fretter, Peter, additional, Simon, Anna, additional, van Paassen, Pieter, additional, van der Goes, Marlies, additional, Flendrie, Marcel, additional, Vercoutere, Ward, additional, van Lieshout, Antoine W T, additional, Leek, Arjen, additional, Vastert, Sebastiaan J, additional, and Tas, Sander W, additional

Published
2023
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9. Neurological phenotype of adenosine deaminase 2 deficient patients: a cohort study.

Author

Verschoof, Merelijne A., van Meenen, Laura C. C., Andriessen, M. Valérie E., Brinkman, Daniëlle M. C., Kamphuis, Sylvia, Kuijpers, Taco W., Leavis, Helen L., Legger, G. Elizabeth, Mulders‐Manders, Catharina M., de Pagter, Anne P. J., Rutgers, Abraham, van Well, Gijs T. J., Coutinho, Jonathan M., Hak, A. Elisabeth, van Montfrans, Joris M., and Klouwer, Femke C. C.

Subjects
ADENOSINE deaminase, TRANSIENT ischemic attack, ISCHEMIC stroke, HEMORRHAGIC stroke, TUMOR necrosis factors, STROKE
Abstract

Background and purpose: Patients with adenosine deaminase 2 (ADA2) deficiency can present with various neurological manifestations due to vasculopathies and autoinflammation. These include ischaemic and hemorrhagic stroke, but less clearly defined neurological symptoms have also been reported. Methods: In this cohort study, patients with confirmed ADA2 deficiency from seven university hospitals in the Netherlands were included. The frequency and recurrence rates of neurological manifestations before and after initiation of tumor necrosis factor α (TNF‐α) inhibiting therapy were analyzed. Results: Twenty‐nine patients were included with a median age at presentation of 5 years (interquartile range 1–17). Neurological manifestations occurred in 19/29 (66%) patients and were the presenting symptom in 9/29 (31%) patients. Transient ischaemic attack (TIA)/ischaemic stroke occurred in 12/29 (41%) patients and was the presenting symptom in 8/29 (28%) patients. In total, 25 TIAs/ischaemic strokes occurred in 12 patients, one after initiation of TNF‐α inhibiting therapy and one whilst switching between TNF‐α inhibitors. None was large‐vessel occlusion stroke. Two hemorrhagic strokes occurred: one aneurysmatic subarachnoid hemorrhage and one spontaneous intracerebral hemorrhage. Most neurological symptoms, including cranial nerve deficits, vertigo, ataxia and seizures, were caused by TIAs/ischaemic strokes and seldom recurred after initiation of TNF‐α inhibiting therapy. Conclusions: Neurological manifestations, especially TIA/ischaemic stroke, are common in patients with ADA2 deficiency and frequently are the presenting symptom. Because it is a treatable cause of young stroke, for which antiplatelet and anticoagulant therapy are considered contraindicated, awareness amongst neurologists and pediatricians is important. Screening for ADA2 deficiency in young patients with small‐vessel ischaemic stroke without an identified cause should be considered. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Neurological phenotype of adenosine deaminase 2 deficient patients: a cohort study

Author

Verschoof, Merelijne A., primary, van Meenen, Laura C. C., additional, Andriessen, M. Valérie E., additional, Brinkman, Daniëlle M. C., additional, Kamphuis, Sylvia, additional, Kuijpers, Taco W., additional, Leavis, Helen L., additional, Legger, G. Elizabeth, additional, Mulders‐Manders, Catharina M., additional, de Pagter, Anne P. J., additional, Rutgers, Abraham, additional, van Well, Gijs T. J., additional, Coutinho, Jonathan M., additional, Hak, A. Elisabeth, additional, van Montfrans, Joris M., additional, and Klouwer, Femke C. C., additional

Published
2023
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11. Leflunomide/hydroxychloroquine combination therapy targets type I IFN-associated proteins in patients with Sjögren’s syndrome that show potential to predict and monitor clinical response

Author

Hamkour, Safae, primary, van der Heijden, Eefje HM, additional, Lopes, Ana P, additional, Blokland, Sofie L M, additional, Bekker, Cornelis P J, additional, Van Helden-Meeuwsen, Cornelia G, additional, Versnel, Marjan A, additional, Kruize, Aike A, additional, Radstake, Timothy RDJ, additional, Leavis, Helen L, additional, Hillen, Maarten R, additional, and van Roon, Joel AG, additional

Published
2023
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15. Chronische anemie en onverklaarde ontsteking

Author

van Daele, Paul L.A., van der Made, Caspar I., Leavis, Helen L., Hak, A. E.Liesbeth, Potjewijd, Judith, Rutgers, Abraham Bram, Transplantation Immunology Groningen, Internal Medicine, and Immunology

Subjects
Male, Inflammation, Anemia/diagnosis, Mutation, Humans, Anemia, Macrocytic, Middle Aged, Aged
Abstract

Achtergrond Het VEXAS-syndroom is een auto-inflammatoire ziekte die ontstaat door een verworven of somatische mutatie in het UBA1-gen. Deze X-gebonden aandoening komt vrijwel alleen voor bij mannen en openbaart zich pas op oudere leeftijd. Casus Wij beschrijven een patiënt met het VEXAS-syndroom bij wie in eerste instantie niet de juiste diagnose werd gesteld. Nadat de diagnose was gesteld op basis van genetisch onderzoek, behandelden wij de patiënt met prednisolon en de IL-6-remmer tocilizumab. Conclusie Bij mannen vanaf de middelbare leeftijd die een multisystemisch inflammatoir ziektebeeld laten zien zonder infectie, moet de diagnose ‘VEXAS-syndroom’ worden overwogen, zeker wanneer er sprake is van een bijkomende macrocytaire anemie. De diagnose kan eenvoudig worden gesteld op basis van gericht onderzoek naar mutaties in UBA1. De behandeling bestaat vooral uit toediening van immunosuppressiva. De mortaliteit is hoog.

Published
2023

16. Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19

Author

Bradbury, Charlotte A., Lawler, Patrick R., Stanworth, Simon J., McVerry, Bryan J., McQuilten, Zoe, Higgins, Alisa M., Mouncey, Paul R., Al-Beidh, Farah, Rowan, Kathryn M., Berry, Lindsay R., Lorenzi, Elizabeth, Zarychanski, Ryan, Arabi, Yaseen M., Annane, Djillali, Beane, Abi, Van Bentum-Puijk, Wilma, Bhimani, Zahra, Bihari, Shailesh, Bonten, Marc J. M., Brunkhorst, Frank M., Buzgau, Adrian, Buxton, Meredith, Carrier, Marc, Cheng, Allen C., Cove, Matthew, Detry, Michelle A., Estcourt, Lise J., Fitzgerald, Mark, Girard, Timothy D., Goligher, Ewan C., Goossens, Herman, Haniffa, Rashan, Hills, Thomas, Huang, David T., Horvat, Christopher M., Hunt, Beverley J., Ichihara, Nao, Lamontagne, Francois, Leavis, Helen L., Linstrum, Kelsey M., Litton, Edward, Marshall, John C., McAuley, Daniel F., McGlothlin, Anna, McGuinness, Shay P., Middeldorp, Saskia, Montgomery, Stephanie K., Morpeth, Susan C., Murthy, Srinivas, Neal, Matthew D., Nichol, Alistair D., Parke, Rachael L., Parker, Jane C., Reyes, Luis, Saito, Hiroki, Santos, Marlene S., Saunders, Christina T., Serpa-Neto, Ary, Seymour, Christopher W., Shankar-Hari, Manu, Singh, Vanessa, Tolppa, Timo, Turgeon, Alexis F., Turner, Anne M., van de Veerdonk, Frank L., Green, Cameron, Lewis, Roger J., Angus, Derek C., McArthur, Colin J., Berry, Scott, Derde, Lennie P. G., Webb, Steve A., Gordon, Anthony C., Depuydt, Pieter, De Waele, Jan, De Bus, Liesbet, Fierens, Jan, Vermassen, Joris, REMAP-CAP Investigators, University of Bristol [Bristol], University Health Network, University of Toronto, University of Oxford, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Monash University [Melbourne], Imperial College London, University of Manitoba [Winnipeg], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), University Medical Center [Utrecht], St. Michael's Hospital, 215522, CS-2016-16-011, RP-2015-06-18, National Institutes of Health, NIH, U.S. Department of Defense, DOD, National Institute of General Medical Sciences, NIGMS, National Institute of Neurological Disorders and Stroke, NINDS, Gordon and Betty Moore Foundation, GBMF, Medtronic, Baxter International, Medical Center, University of Pittsburgh, CancerCare Manitoba Foundation, CCMF, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD, Wellcome Trust, WT, Health Research Board, HRB: CTN 2014-012, Horizon 2020 Framework Programme, H2020: 101003589, LAM Therapeutics, Canadian Institutes of Health Research, IRSC: 158584, Medical Research Council, MRC, National Institute for Health and Care Research, NIHR, European Commission, EC, National Heart and Lung Institute, NHLI, Queen's University Belfast, QUB: US8962032, National Health and Medical Research Council, NHMRC: APP1101719, National Medical Research Council, NMRC, Health Research Council of New Zealand, HRC: 16/631, Ministère des Affaires Sociales et de la Santé: PHRC-20-0147, Innovate UK, Horizon 2020, Pharmaceuticals Bayer, Swedish Orphan Biovitrum, NIHR Imperial Biomedical Research Centre, BRC, Minderoo Foundation, Funding/Support: This study was funded by the following: the Platform for European Preparedness Against (Re-)Emerging Epidemics (PREPARE) consortium of the European Union, FP7-HEALTH-2013-INNOVATION-1 (grant 602525), the Rapid European COVID-19 Emergency Research Response (RECOVER) consortium of the European Union’s Horizon 2020 Research and Innovation Programme (grant 101003589), the Australian National Health and Medical Research Council (grant APP1101719), the Health Research Council of New Zealand (grant 16/631), the Canadian Institute of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program (grant 158584), the NIHR and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (grant CTN 2014-012), the University of Pittsburgh Medical Center (UPMC) Learning While Doing Program, the Translational Breast Cancer Research Consortium, the French Ministry of Health (grant PHRC-20-0147), the Minderoo Foundation, and the Wellcome Trust Innovations Project (grant 215522). Dr Shankar-Hari is funded by an NIHR clinician scientist fellowship (grant CS-2016-16-011) and Dr Gordon is funded by an NIHR research professorship (grant RP-2015-06-18)., The REMAP-CAP platform is supported by the Australian and New Zealand Intensive Care Society Clinical Trials Group, the Canadian Critical Care Clinical Trials Group, the Irish Critical Care Clinical Trials Network, the UK Critical Care Research Group and the International Forum of Acute Care Trialists., REMAP-CAP was supported in the Netherlands by the Research Collaboration Critical Care the Netherlands, reported receipt of personal fees from Lilly, BMS-Pfizer, Bayer, Amgen, Novartis, Janssen, Portola, Ablynx, and Grifols. Dr Lawler reported receipt of personal fees from Novartis, CorEvitas, and Brigham and Women’s Hospital and royalties from McGraw-Hill Publishing. Dr McVerry reported receipt of grants from the National Heart, Lung, and Blood Institute and Bayer Pharmaceuticals and personal fees from Boehringer Ingelheim. Dr L. Berry reported being an employee of Berry Consultants, Berry Consultants receives payments for the statistical analysis and design of REMAP-CAP. Dr Lorenzi reported being an employee of Berry Consultants, Berry Consultants receives payments for the statistical analysis and design of REMAP-CAP. Dr Zarychanski reported receipt of grants from the Canadian Institutes of Health Research, LifeArc, Research Manitoba, the CancerCare Manitoba Foundation, Peter Munk Cardiac Centre, and the Thistledown Foundation and research operating support as the Lyonel G. Israels Research Chair in Hematology. Dr Bonten reported membership in international study steering committees, advisory boards, and independent data safety and monitoring committees funded by Janssen Vaccines, Merck Sharp & Dohme, AstraZeneca, Pfizer, and Sanofi Pasteur (all reimbursements to UMC Utrecht). Dr Brunkhorst reported receipt of grants from Jena University Hospital. Dr Buxton reported receipt of a gift from the Breast Cancer Research Foundation and contracts with Amgen and Eisai. Dr Carrier reported receipt of grants from BMS-Pfizer and personal fees from Bayer, Sanofi, Servier, Leo Phama, and BMS-Pfizer to his institution. Dr Cove reported receipt of grants from the National Medical Research Council and personal fees from Baxter and Medtronic. Dr Estcourt reported receipt of grants from the UK National Institute for Health Research (NIHR) and the European Union Horizon 2020 Research and Innovation Programme. Dr Haniffa reported receipt of grants from the UK Research and Innovation/Medical Research Council African Critical Care Registry Network. Dr Horvat reported receipt of grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke. Dr Ichihara reported being affiliated with the Department of Healthcare Quality Assessment, University of Tokyo, which is a social collaboration supported by the National Clinical Database, Johnson & Johnson, and Nipro Corporation. Dr Marshall reported receipt of personal fees from AM Pharma and Critical Care Medicine. Dr McAuley reported receipt of personal fees from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Lilly, Vir Biotechnology, Faron Pharmaceutical, and SOBI and grants from the NIHR, the Wellcome Trust, Innovate UK, the UK Medical Research Council, and the Northern Ireland Health and Social Care Research and Development Division, in addition, Dr McAuley had a Queen’s University Belfast patent for novel treatment for inflammatory disease (US8962032), was co-director of research at the Intensive Care Society until June 2021, and was director of the Efficacy and Mechanisms Evaluation Program for the UK Medical Research Council/NIHR. Dr Middeldorp reported receipt of personal fees from Daiichi Sankyo, Bayer, Pfizer, Boehringer Ingelheim, Portola/Alexion, AbbVie, BMS-Pfizer, Sanofi, and Viatris, all paid to his institution, and grants from Daiichi Sankyo, Bayer, Pfizer, and Boehringer Ingelheim. Dr Neal reported equity in Haima Therapeutics, receipt of personal fees from Janssen Pharma and Haemonetics, and receipt of grants from Instrumentation Laboratory, the National Institutes of Health, and the Department of Defense. Dr Nichol reported receipt of personal fees from AM Pharma, paid to his university, and grants from Baxter. Dr Parke reported receipt of grants from Fisher and Paykel Healthcare NZ. Dr Serpa-Neto reported receipt of personal fees from Drager and Endpoint Health. Dr Seymour reported receipt of grants from the Gordon and Betty Moore Foundation and the National Institutes of Health/National Institute of General Medical Sciences. Dr Lewis reported being senior medical scientist at Berry Consultants, Berry Consultants receives payments for the statistical analysis and design of REMAP-CAP. Dr S. Berry reported being an employee with an ownership role at Berry Consultants, Berry Consultants receives payments for the statistical analysis and design of REMAP-CAP. Dr Derde reported being a coordinating committee member for the European Clinical Research Alliance on Infectious Diseases, a member of the Dutch Intensivists Task Force on Acute Infectious Threats, a member of the International Scientific Advisory Board for Sepsis Canada, and a member of the Dutch Academy of Sciences’ Pandemic Preparedness Plan committee. Dr Gordon reported receipt of personal fees from 30 Respiratory, paid to his institution. No other disclosures were reported., European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020), European Project: 602525,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,PREPARE(2014), Investigators, REMAP-CAP Writing Committee for the REMAP-CAP, Vascular Medicine, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, and Intensive Care Medicine

Subjects
Adult, Male, Platelet Aggregation Inhibitors/adverse effects, Critical Illness, [SDV]Life Sciences [q-bio], Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Hemorrhage, Aspirin/adverse effects, Hemorrhage/chemically induced, INFECTION, Humans, COAGULOPATHY, Aspirin, Anticoagulants, COVID-19, Bayes Theorem, Venous Thromboembolism, General Medicine, Middle Aged, Respiration, Artificial, COVID-19 Drug Treatment, Critical Illness/mortality, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Purinergic P2Y Receptor Antagonists/adverse effects, Purinergic P2Y Receptor Antagonists, COVID-19/complications, Female, Human medicine, Anticoagulants/adverse effects, Platelet Aggregation Inhibitors, Venous Thromboembolism/drug therapy
Abstract

Contains fulltext : 248713.pdf (Publisher’s version ) (Closed access) IMPORTANCE: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. OBJECTIVE: To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). INTERVENTIONS: Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. MAIN OUTCOMES AND MEASURES: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. RESULTS: The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm). CONCLUSIONS AND RELEVANCE: Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.

Published
2022

17. Soluble Signal Inhibitory Receptor on Leukocytes-1 Is Released from Activated Neutrophils by Proteinase 3 Cleavage

Author

von Richthofen, Helen J., primary, Westerlaken, Geertje H.A., additional, Gollnast, Doron, additional, Besteman, Sjanna, additional, Delemarre, Eveline M., additional, Rodenburg, Karlijn, additional, Moerer, Petra, additional, Stapels, Daphne A.C., additional, Andiappan, Anand K., additional, Rötzschke, Olaf, additional, Nierkens, Stefan, additional, Leavis, Helen L., additional, Bont, Louis J., additional, Rooijakkers, Suzan H.M., additional, and Meyaard, Linde, additional

Published
2023
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21. Air pollution from livestock farms and the oropharyngeal microbiome of COPD patients and controls

Author

van Kersen, Warner, primary, Bossers, Alex, additional, de Steenhuijsen Piters, Wouter A.A., additional, de Rooij, Myrna M.T., additional, Bonten, Marc, additional, Fluit, Ad C., additional, Heederik, Dick, additional, Paganelli, Fernanda L., additional, Rogers, Malbert, additional, Viveen, Marco, additional, Bogaert, Debby, additional, Leavis, Helen L., additional, and Smit, Lidwien A.M., additional

Published
2022
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22. Heterozygous Variants in the DNA-binding Domain of c-Myb May Affect Normal B/T Cell Development

Author

Smits, Bas M., primary, Hartley, Taila, additional, Dünnebach, Ester, additional, Bartels, Marije, additional, Boycott, Kim M., additional, Kernohan, Kirstin D., additional, Dyment, David A., additional, Giltay, Jacques C., additional, Haddad, Elie, additional, Jarinova, Olga, additional, van Montfrans, Joris, additional, van Royen-Kerkhof, Annet, additional, van der Veken, Lars T., additional, de Witte, Moniek, additional, Nierkens, Stefan, additional, Pham-Huy, Anne, additional, and Leavis, Helen L., additional

Published
2022
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24. Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin

Author

Spaan, András N., primary, Neehus, Anna-Lena, additional, Laplantine, Emmanuel, additional, Staels, Frederik, additional, Ogishi, Masato, additional, Seeleuthner, Yoann, additional, Rapaport, Franck, additional, Lacey, Keenan A., additional, Van Nieuwenhove, Erika, additional, Chrabieh, Maya, additional, Hum, David, additional, Migaud, Mélanie, additional, Izmiryan, Araksya, additional, Lorenzo, Lazaro, additional, Kochetkov, Tatiana, additional, Heesterbeek, Dani A. C., additional, Bardoel, Bart W., additional, DuMont, Ashley L., additional, Dobbs, Kerry, additional, Chardonnet, Solenne, additional, Heissel, Søren, additional, Baslan, Timour, additional, Zhang, Peng, additional, Yang, Rui, additional, Bogunovic, Dusan, additional, Wunderink, Herman F., additional, Haas, Pieter-Jan A., additional, Molina, Henrik, additional, Van Buggenhout, Griet, additional, Lyonnet, Stanislas, additional, Notarangelo, Luigi D., additional, Seppänen, Mikko R. J., additional, Weil, Robert, additional, Seminario, Gisela, additional, Gomez-Tello, Héctor, additional, Wouters, Carine, additional, Mesdaghi, Mehrnaz, additional, Shahrooei, Mohammad, additional, Bossuyt, Xavier, additional, Sag, Erdal, additional, Topaloglu, Rezan, additional, Ozen, Seza, additional, Leavis, Helen L., additional, van Eijk, Maarten M. J., additional, Bezrodnik, Liliana, additional, Blancas Galicia, Lizbeth, additional, Hovnanian, Alain, additional, Nassif, Aude, additional, Bader-Meunier, Brigitte, additional, Neven, Bénédicte, additional, Meyts, Isabelle, additional, Schrijvers, Rik, additional, Puel, Anne, additional, Bustamante, Jacinta, additional, Aksentijevich, Ivona, additional, Kastner, Daniel L., additional, Torres, Victor J., additional, Humblet-Baron, Stéphanie, additional, Liston, Adrian, additional, Abel, Laurent, additional, Boisson, Bertrand, additional, and Casanova, Jean-Laurent, additional

Published
2022
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26. Immunogenicity of the mRNA-1273 COVID-19 vaccine in adult patients with inborn errors of immunity

Author

van Leeuwen, Leanne P.M., primary, GeurtsvanKessel, Corine H., additional, Ellerbroek, Pauline M., additional, de Bree, Godelieve J., additional, Potjewijd, Judith, additional, Rutgers, Abraham, additional, Jolink, Hetty, additional, van de Veerdonk, Frank, additional, van Gorp, Eric C.M., additional, de Wilt, Faye, additional, Bogers, Susanne, additional, Gommers, Lennert, additional, Geers, Daryl, additional, Bruns, Anke H.W., additional, Leavis, Helen L., additional, van Haga, Jelle W., additional, Lemkes, Bregtje A., additional, van der Veen, Annelou, additional, de Kruijf-Bazen, S.F.J., additional, van Paassen, Pieter, additional, de Leeuw, Karina, additional, van de Ven, Annick A.J.M., additional, Verbeek-Menken, Petra H., additional, van Wengen, Annelies, additional, Arend, Sandra M., additional, Ruten-Budde, Anja J., additional, van der Ent, Marianne W., additional, van Hagen, P. Martin, additional, Sanders, Rogier W., additional, Grobben, Marloes, additional, van der Straten, Karlijn, additional, Burger, Judith A., additional, Poniman, Meliawati, additional, Nierkens, Stefan, additional, van Gils, Marit J., additional, de Vries, Rory D., additional, and Dalm, Virgil A.S.H., additional

Published
2022
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27. Soluble signal inhibitory receptor on leukocytes-1 is released from activated neutrophils by proteinase 3 cleavage

Author

von Richthofen, Helen J., primary, Westerlaken, Geertje H.A., additional, Gollnast, Doron, additional, Besteman, Sjanna, additional, Delemarre, Eveline M., additional, Rodenburg, Karlijn, additional, Moerer, Petra, additional, Stapels, Daphne A.C., additional, Andiappan, Anand K., additional, Rötzschke, Olaf, additional, Nierkens, Stefan, additional, Leavis, Helen L., additional, Bont, Louis J., additional, Rooijakkers, Suzan H.M., additional, and Meyaard, Linde, additional

Published
2022
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30. Clinical features and immune-related protein patterns of anti-MDA5 positive clinically amyopathic dermatomyositis Dutch patients

Author

Hensgens, Marjolein P M, primary, Delemarre, Eveline M, additional, Drylewicz, Julia, additional, Voortman, Mareye, additional, Krol, Roline M, additional, Dalm, Virgil A S H, additional, Miedema, Jelle R, additional, Wiertz, Ivo, additional, Grutters, Jan, additional, Limper, Maarten, additional, Nierkens, Stefan, additional, and Leavis, Helen L, additional

Published
2022
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31. Adult-onset autoinflammation caused by somatic mutations in UBA1: A Dutch case series of patients with VEXAS

Author

van der Made, Caspar I., primary, Potjewijd, Judith, additional, Hoogstins, Annemiek, additional, Willems, Huub P.J., additional, Kwakernaak, Arjan J., additional, de Sevaux, Ruud G.L., additional, van Daele, Paul L.A., additional, Simons, Annet, additional, Heijstek, Marloes, additional, Beck, David B., additional, Netea, Mihai G., additional, van Paassen, Pieter, additional, Elizabeth Hak, A., additional, van der Veken, Lars T., additional, van Gijn, Marielle E., additional, Hoischen, Alexander, additional, van de Veerdonk, Frank L., additional, Leavis, Helen L., additional, and Rutgers, Abraham, additional

Published
2022
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34. The oropharyngeal microbiome of COPD patients and controls in a livestock dense area

Author

van Kersen, Warner, primary, Bossers, Alex, additional, De Steenhuijsen Piters, Wouter A.A., additional, De Rooij, Myrna M.T., additional, Oldenwening, Marieke, additional, Bonten, Marc, additional, Fluit, Ad C., additional, Heederik, Dick, additional, Paganelli, Fernanda L., additional, Rogers, Malbert, additional, Viveen, Marco, additional, Willems, Rob, additional, Bogaert, Debby, additional, Leavis, Helen L., additional, and Smit, Lidwien A.M., additional

Published
2021
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35. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report

Author

Gordon, Anthony C., Mouncey, Paul R., Al-Beidh, Farah, Rowan, Kathryn M., Nichol, Alistair D., Arabi, Yaseen M., Annane, Djillali, Beane, Abi, van Bentum-Puijk, Wilma, Berry, Lindsay R., Bhimani, Zahra, Bonten, Marc J.M., Bradbury, Charlotte A., Brunkhorst, Frank M., Buzgau, Adrian, Cheng, Allen C., Detry, Michelle A., Duffy, Eamon J., Estcourt, Lise J., Fitzgerald, Mark, Goossens, Herman, Haniffa, Rashan, Higgins, Alisa M., Hills, Thomas E., Horvat, Christopher M., Lamontagne, Francois, Lawler, Patrick R., Leavis, Helen L., Linstrum, Kelsey M., Litton, Edward, Lorenzi, Elizabeth, Marshall, John C., Mayr, Florian B., McAuley, Danny, McGlothlin, Anna, McGuinness, Shay P, McVerry, Bryan J., Montgomery, Stephanie K., Morpeth, Susan C., Murthy, Srinivas, Orr, Katrina, Parke, Rachael L., Parker, Jane C., Patanwala, Asad E., Pettilä, Ville, Rademaker, Emma, Santos, Marlene S., Saunders, Christina T., Seymour, Christopher W., Shankar-Hari, Manu, Sligl, Wendy I., Turgeon, Alexis F., Turner, Anne M., van de Veerdonk, Frank L., Zarychanski, Ryan, Green, Cameron, Lewis, Roger J., Angus, Derek C., McArthur, Colin J., Berry, Scott, Webb, Steve A., and Derde, Lennie P.G.

Subjects
medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, COVID-19, Odds ratio, Intensive care unit, law.invention, Coronavirus, Sarilumab, chemistry.chemical_compound, Tocilizumab, chemistry, Interquartile range, law, Intensive care, Internal medicine, Interleukin-6 receptor, Medicine, business
Abstract

BackgroundThe efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.MethodsWe evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours of commencing organ support in an intensive care unit, were randomized to receive either tocilizumab (8mg/kg) or sarilumab (400mg) or standard care (control). The primary outcome was an ordinal scale combining in-hospital mortality (assigned −1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with pre-defined triggers to declare superiority, efficacy, equivalence or futility.ResultsTocilizumab and sarilumab both met the pre-defined triggers for efficacy. At the time of full analysis 353 patients had been assigned to tocilizumab, 48 to sarilumab and 402 to control. Median organ support-free days were 10 (interquartile range [IQR] −1, 16), 11 (IQR 0, 16) and 0 (IQR −1, 15) for tocilizumab, sarilumab and control, respectively. Relative to control, median adjusted odds ratios were 1.64 (95% credible intervals [CrI] 1.25, 2.14) for tocilizumab and 1.76 (95%CrI 1.17, 2.91) for sarilumab, yielding >99.9% and 99.5% posterior probabilities of superiority compared with control. Hospital mortality was 28.0% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab and 35.8% (142/397) for control. All secondary outcomes and analyses supported efficacy of these IL-6 receptor antagonists.ConclusionsIn critically ill patients with Covid-19 receiving organ support in intensive care, treatment with the IL-6 receptor antagonists, tocilizumab and sarilumab, improved outcome, including survival. (ClinicalTrials.govnumber:NCT02735707)

Published
2021

38. Targeted Proteomics Reveals Inflammatory Pathways that Classify Immune Dysregulation in Common Variable Immunodeficiency

Author

Berbers, Roos-Marijn, primary, Drylewicz, Julia, additional, Ellerbroek, Pauline M., additional, van Montfrans, Joris M., additional, Dalm, Virgil A. S. H., additional, van Hagen, P. Martin, additional, Keller, Baerbel, additional, Warnatz, Klaus, additional, van de Ven, Annick, additional, van Laar, Jaap M., additional, Nierkens, Stefan, additional, and Leavis, Helen L., additional

Published
2020
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39. Epidemic and nonepidemic multidrug-resistant Enterococcus faecium

Author

Leavis, Helen L., Willems, Rob J.L., Top, Janetta, Spalburg, Emile, Mascini, Ellen M., Fluit, Ad C., Hoepelman, Andy, de Neeling, Albert J., and Bonten, Mark J.M.

Subjects
Drug resistance -- Physiological aspects, Drug resistance -- Genetic aspects, Enterococcal infections -- Genetic aspects, Enterococcal infections -- Development and progression, Enterococcal infections -- Care and treatment
Abstract

The epidemiology of vancomycin-resistant Enterococcus faecium (VREF) in Europe is characterized by a large community reservoir. In contrast, nosocomial outbreaks and infections (without a community reservoir) characterize VREF in the [...]

Published
2003

40. Implementation of Early Next-Generation Sequencing for Inborn Errors of Immunity: A Prospective Observational Cohort Study of Diagnostic Yield and Clinical Implications in Dutch Genome Diagnostic Centers.

Author

Elsink, Kim, Huibers, Manon M. H., Hollink, Iris H. I. M., Simons, Annet, Zonneveld-Huijssoon, Evelien, van der Veken, Lars T., Leavis, Helen L., Henriet, Stefanie S. V., van Deuren, Marcel, van de Veerdonk, Frank L., Potjewijd, Judith, Berghuis, Dagmar, Dalm, Virgil A. S. H., Vermont, Clementien L., van de Ven, Annick A. J. M., Lambeck, Annechien J. A., Abbott, Kristin M., van Hagen, P. Martin, de Bree, Godelieve J., and Kuijpers, Taco W.

Subjects
NUCLEOTIDE sequencing, CHILD patients, COHORT analysis, IMMUNOLOGIC diseases, GENETIC testing, GENETIC disorder diagnosis, MOLECULAR diagnosis
Abstract

Objective: Inborn errors of immunity (IEI) are a heterogeneous group of disorders, affecting different components of the immune system. Over 450 IEI related genes have been identified, with new genes continually being recognized. This makes the early application of next-generation sequencing (NGS) as a diagnostic method in the evaluation of IEI a promising development. We aimed to provide an overview of the diagnostic yield and time to diagnosis in a cohort of patients suspected of IEI and evaluated by an NGS based IEI panel early in the diagnostic trajectory in a multicenter setting in the Netherlands. Study Design: We performed a prospective observational cohort study. We collected data of 165 patients with a clinical suspicion of IEI without prior NGS based panel evaluation that were referred for early NGS using a uniform IEI gene panel. The diagnostic yield was assessed in terms of definitive genetic diagnoses, inconclusive diagnoses and patients without abnormalities in the IEI gene panel. We also assessed time to diagnosis and clinical implications. Results: For children, the median time from first consultation to diagnosis was 119 days versus 124 days for adult patients (U=2323; p=0.644). The median turn-around time (TAT) of genetic testing was 56 days in pediatric patients and 60 days in adult patients (U=1892; p=0.191). A definitive molecular diagnosis was made in 25/65 (24.6%) of pediatric patients and 9/100 (9%) of adults. Most diagnosed disorders were identified in the categories of immune dysregulation (n=10/25; 40%), antibody deficiencies (n=5/25; 20%), and phagocyte diseases (n=5/25; 20%). Inconclusive outcomes were found in 76/165 (46.1%) patients. Within the patient group with a genetic diagnosis, a change in disease management occurred in 76% of patients. Conclusion: In this cohort, the highest yields of NGS based evaluation for IEI early in the diagnostic trajectory were found in pediatric patients, and in the disease categories immune dysregulation and phagocyte diseases. In cases where a definitive diagnosis was made, this led to important disease management implications in a large majority of patients. More research is needed to establish a uniform diagnostic pathway for cases with inconclusive diagnoses, including variants of unknown significance. [ABSTRACT FROM AUTHOR]

Published
2021
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41. Low IgA Associated With Oropharyngeal Microbiota Changes and Lung Disease in Primary Antibody Deficiency

Author

Berbers, Roos-Marijn, primary, Mohamed Hoesein, Firdaus A. A., additional, Ellerbroek, Pauline M., additional, van Montfrans, Joris M., additional, Dalm, Virgil A. S. H., additional, van Hagen, P. Martin, additional, Paganelli, Fernanda L., additional, Viveen, Marco C., additional, Rogers, Malbert R. C., additional, de Jong, Pim A., additional, Uh, Hae-Won, additional, Willems, Rob J. L., additional, and Leavis, Helen L., additional

Published
2020
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42. Behçet's Disease Under Microbiotic Surveillance? A Combined Analysis of Two Cohorts of Behçet's Disease Patients

Author

van der Houwen, Tim B., primary, van Laar, Jan A. M., additional, Kappen, Jasper H., additional, van Hagen, Petrus M., additional, de Zoete, Marcel R., additional, van Muijlwijk, Guus H., additional, Berbers, Roos-Marijn, additional, Fluit, Ad C., additional, Rogers, Malbert, additional, Groot, James, additional, Hazelbag, C. Marijn, additional, Consolandi, Clarissa, additional, Severgnini, Marco, additional, Peano, Clelia, additional, D'Elios, Mario M., additional, Emmi, Giacomo, additional, and Leavis, Helen L., additional

Published
2020
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45. Roux-Y Gastric Bypass and Sleeve Gastrectomy directly change gut microbiota composition independent of operation type

Author

Paganelli, Fernanda L., primary, Luyer, Misha, additional, Hazelbag, C. Marijn, additional, Uh, Hae-Won, additional, Rogers, Malbert R.C., additional, Adriaans, Danielle, additional, Berbers, Roos-Marijn, additional, Hendrickx, Antoni P.A., additional, Viveen, Marco C., additional, Groot, James A., additional, Bonten, Marc J. M., additional, Fluit, Ad C., additional, Willems, Rob J.L., additional, and Leavis, Helen L., additional

Published
2018
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49. A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease

Author

Aeschlimann, Florence A, primary, Batu, Ezgi D, additional, Canna, Scott W, additional, Go, Ellen, additional, Gül, Ahmet, additional, Hoffmann, Patrycja, additional, Leavis, Helen L, additional, Ozen, Seza, additional, Schwartz, Daniella M, additional, Stone, Deborah L, additional, van Royen-Kerkof, Annet, additional, Kastner, Daniel L, additional, Aksentijevich, Ivona, additional, and Laxer, Ronald M, additional

Published
2018
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50. Identification of a novel genomic island specific to hospital-acquired clonal complex 17 Enterococcus faecium isolates

Author

Heikens, Esther, van Schaik, Willem, Leavis, Helen L., Bonten, Marc J.M., and Willems, Rob J.L.

Subjects
Carbohydrate metabolism -- Analysis, Enterococcus -- Genetic aspects, Enterococcus -- Physiological aspects, Polymerase chain reaction -- Usage, Biological sciences
Abstract

The [delta][rho]-Web model, PCR, and dot blotting methods are used to identify anomalous GeCs in the genome of Enterococcus faecium DO, a clonal complex 17 (CC17) E. faecium strains that might contribute towards increased fitness and enhanced survival of CC17 E. faecium. A genomic island identified in CC17 E. faecium tentatively encoding a metabolic pathway involved in carbohydrate transport and metabolism might provide a competitive advantage over the E. faecium microbiota.

Published
2008

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