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101. Early Methicillin-resistant Staphylococcus Aureus (MRSA) Therapy in Cystic Fibrosis (CF) (STAR-Too)

Author

CF Therapeutics Development Network Coordinating Center, Seattle Children's Hospital, Washington University School of Medicine, University of Washington, University of Colorado, Denver, Baylor College of Medicine, University of Alabama at Birmingham, Cook Children's Medical Center, University of Michigan, University of Florida, University of Texas Southwestern Medical Center, Children's Hospital Medical Center, Cincinnati, St. Louis Children's Hospital, and Marianne Muhlebach, MD, Professor, Pediatric Pulmonolgy

Published
2017

103. Multicenter Perioperative Opioid Pharmacogenetic Study

Author

Baylor College of Medicine, Ochsner Health System, Children's Hospital Colorado, Children's Hospital Los Angeles, C.S. Mott Children's Hospital, St. Christopher's Hospital for Children, St. Louis Children's Hospital, Boston Children's Hospital, Seattle Children's Hospital, Ann & Robert H Lurie Children's Hospital of Chicago, University of Wisconsin, Madison, University of Miami, Johns Hopkins University, Stanford University, Phoenix Children's Hospital, University of Michigan, University of Utah, and Shanghai Children's Hospital

Published
2017

107. Managing Inflammatory Bowel Disease (Managing IBD)

Author

National Institutes of Health (NIH), Seattle Children's Hospital, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and Rona Levy, Professor

Published
2015

108. The CRISIS Prevention Study (CRISIS)

Author

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Seattle Children's Hospital, Children's Hospital Los Angeles, Arkansas Children's Hospital Research Institute, Children's Hospital of Michigan, University of Pittsburgh, Children's National Research Institute, University of California, Los Angeles, Harborview Injury Prevention and Research Center, and Michael Dean, Data Coordinating Center Principal Investigator

Published
2013

112. Early Orthodontic Intervention Under Medicaid

Author

National Institute of Dental and Craniofacial Research (NIDCR), Northwest and Alaska Center on Oral Health Disparities, Washington State Department of Social and Health Services, Seattle Children's Hospital, and Gregory King, DMD, PhD

Published
2010

117. [F-18]-fluorodeoxy-D-glucose???positron emission tomography response is associated with outcome for extremity osteosarcoma in children and young adults

Author

Department of Medical Oncology, University of Michigan, Ann Arbor, Michigan, Department of Pediatrics, Seattle Children's Hospital, Seattle, Washington ; Fax: (206) 987-3946 ; Seattle Children's Hospital, 4800 Sandpoint Way, Mailstop: B-6553, Seattle, WA 98105-0371, Departments of Orthopedics and Radiology, University of Washington Medical Center, Seattle, Washington, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, Hawkins, Douglas S., Conrad, Ernest U., Butrynski, James E., Schuetze, Scott M., Eary, Janet F., Department of Medical Oncology, University of Michigan, Ann Arbor, Michigan, Department of Pediatrics, Seattle Children's Hospital, Seattle, Washington ; Fax: (206) 987-3946 ; Seattle Children's Hospital, 4800 Sandpoint Way, Mailstop: B-6553, Seattle, WA 98105-0371, Departments of Orthopedics and Radiology, University of Washington Medical Center, Seattle, Washington, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, Hawkins, Douglas S., Conrad, Ernest U., Butrynski, James E., Schuetze, Scott M., and Eary, Janet F.

Abstract

BACKGROUND: Response to neoadjuvant chemotherapy is 1 of the most powerful prognostic factors for extremity osteosarcoma. [F-18]-fluorodeoxy-D-glucose???positron emission tomography (FDG-PET) is a noninvasive imaging modality that is used to predict histopathologic response. To determine the prognostic value of FDG-PET response for progression-free survival (PFS) in osteosarcoma, the authors of this report reviewed the University of Washington Medical Center experience. METHODS: Forty patients with extremity osteosarcoma were evaluated by FDG-PET. All patients received neoadjuvant and adjuvant chemotherapy. FDG-PET standard uptake values (SUVs) before neoadjuvant chemotherapy (SUV1) and after neoadjuvant chemotherapy (SUV2) were analyzed and correlated with histopathologic response. RESULTS: The median SUV1 was 6.8 (range, 3.0-24.1), the median SUV2 was 2.3 (range, 1.2-12.8), and the median SUV2 to SUV1 ratio (SUV2:1), was 0.36 (range, 0.12-1.10). A good FDG-PET response was defined as anSUV2 <2.5 or an SUV2:1 ???0.5. FDG-PET responses according to SUV2 and SUV2:1 were concordant with histologic response in 58% and 68% of patients, respectively. SUV2 was associated with outcome (4-year PFS, 73% for SUV2 <2.5 vs 39% for SUV2 ???2.5; P = .021). Both the initial disease stage and the histologic response were associated with outcome. CONCLUSIONS: FDG-PET imaging of extremity osteosarcoma was correlated only partially with a histologic response to neoadjuvant chemotherapy. An SUV2 <2.5 was associated with improved PFS. Future prospective studies are warranted to determine whether FDG-PET imaging may be used as a predictor of outcome independent of initial disease stage. Cancer 2009. ?? 2009 American Cancer Society.

Published
2009

118. The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: Phase 2 methodological report

Author

University of Michigan, Ann Arbor, Boston University School of Medicine, Boston, Massachusetts, Medical University of Vienna, Vienna, Austria ; Dr. Aletaha has received consulting fees, speaking fees, and/or honoraria from Abbott, Bristol-Myers Squibb, UCB, Schering-Plough, Wyeth, and Roche (less than $10,000 each)., Arthritis Research UK, Chesterfield, UK, Ministry of Health, Auckland, New Zealand ; Dr. Naden has received consulting fees from the American College of Rheumatology in regard to the methodology of developing weighted scoring systems (more than $10,000)., University of Pittsburgh, Pittsburgh, Pennsylvania, Johns Hopkins University, Baltimore, Maryland ; Dr. Bingham has received consulting fees, speaking fees, and/or honoraria from UCB, Roche, Genentech, Celgene, and Merck Serono (less than $10,000 each); he has received research and/or educational grant support from Bristol-Myers Squibb, Genentech, UCB, Centocor, Abbott, and Amgen., California Pacific Medical Center and University of California, San Francisco ; Dr. Birnbaum has received consulting fees, speaking fees, and/or honoraria from Amgen, Pfizer, Centocor, Abbott, and UCB (less than $10,000 each)., Charit?? Hospital???University Medicine Berlin, Free University and Humboldt University, Berlin, Germany ; Dr. Burmester has received consulting fees, speaking fees, and/or honoraria from Abbott, Bristol-Myers Squibb, Pfizer, UCB, and Roche (less than $10,000 each)., Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada ; Dr. Bykerk has received consulting fees, speaking fees, and/or honoraria from Amgen, Wyeth, Abbott, Schering-Plough, Roche, Bristol-Myers Squibb, and UCB (less than $10,000 each); her spouse is employed by Genzyme and owns stock in the company., National Jewish Medical and Research Center, Denver, Colorado ; Dr. Cohen has received consulting fees, speaking fees, and/or honoraria from UCB, Genentech, Bristol-Myers Squibb, and Human Genome Sciences (less than $10,000 each)., Lapeyronie Hospital and Montpellier I University, Montpellier, France ; Dr. Combe has received consulting fees, speaking fees, and/or honoraria from Abbott, Bristol-Myers Squibb, Pfizer, Roche, Schering-Plough, and Merck, Sharpe, and Dohme (less than $10,000 each)., Brigham and Women's Hospital and Harvard University, Boston, Massachusetts, Cochin Hospital, Assistance Publique H??pitaux de Paris, and Paris-Descartes University, Paris, France, University of Leeds and NIHR Leeds Biomedical Research Unit, Leeds, UK ; Dr. Emery has received consulting fees, speaking fees, and/or honoraria from Pfizer, Abbott, Centocor, UCB, Roche, Bristol-Myers Squibb, and Merck, Sharpe, and Dohme (less than $10,000 each)., School of Medicine, Catholic University of the Sacred Heart, Rome, Italy ; Dr. Ferraccioli holds a patent for T cell receptor clonotype analysis (PCT/IB 2008/053152 NP)., Erasmus Medical Center and University of Rotterdam, Rotterdam, The Netherlands, University of Colorado School of Medicine, Denver, Leiden University Medical Center, Leiden, The Netherlands ; Dr. Huizinga has received consulting fees, speaking fees, and/or honoraria from Schering-Plough, Bristol-Myers Squibb, UCB, Biotest AG, Wyeth/Pfizer, Novartis, Roche, Sanofi-Aventis, Abbott, and Axis-Shield (less than $10,000 each)., University of California, San Diego ; Dr. Kavanaugh has conducted clinical research for Amgen, Abbott, Bristol-Myers Squibb, UCB, Roche, Centocor, Genentech, and Sanofi-Aventis., UMassMemorial Medical Center and University of Massachusetts Medical School, Worcester ; Dr. Kay has received consulting fees from Array BioPharma, Bristol-Myers Squibb, Celgene, Centocor, Genentech, Roche, UCB, and Sanofi-Aventis (less than $10,000 each)., David Geffen School of Medicine at University of California, Los Angeles ; Dr. Khanna has received consulting fees, speaking fees, and/or honoraria from UCB and Abbott (less than $10,000 each)., Diakonhjemmet Hospital, Oslo, Norway, Swedish Medical Center and University of Washington, Seattle ; Dr. Mease has received consulting fees, speaking fees, and/or honoraria from Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Centocor, Roche, Genentech, UCB, Pfizer, Novartis, and Eli Lilly (less than $10,000 each)., McGill University Health Centre and McGill University, Montreal, Quebec, Canada ; Dr. M??nard has received unrestricted educational and research grants as well as consulting and speaking fees from Abbott, Amgen, Inova, Merck, Pfizer, Roche, Schering-Plough, UCB, and Wyeth (less than $10,000 each) and investigator-initiated research grants from Bristol-Myers Squibb, EuroImmun AG, and Roche (more than $10,000 each); he owns stock or stock options in Merck; and he has a license agreement with EuroImmun AG for an anti-Sa enzyme-linked immunosorbent assay., University of Pittsburgh, Pittsburgh, Pennsylvania ; Dr. Moreland has received consulting fees, speaking fees, and/or honoraria from Biogen Idec, Centocor, Pfizer, Takeda, KaloBios, ChemoCentryx, UCB, Genentech, Incyte, and Eli Lilly (less than $10,000 each)., University of North Carolina, Chapel Hill, New York University Hospital for Joint Diseases, New York, New York ; Dr. Pincus has received consulting fees, speaking fees, and/or honoraria from Amgen, Abbott, Bristol-Myers Squibb, Centocor, UCB, Wyeth, and Genentech (less than $10,000 each) and investigator-initiated research grants from Amgen, Bristol-Myers Squibb, UCB, and Centocor., Seattle Children's Hospital, Seattle, Washington, Medical University of Vienna, Vienna, Austria, Institute of Rheumatology, Warsaw, Poland ; Dr. Stanislawska-Biernat has received speaking fees from Abbott and Pfizer (less than $10,000 each)., University of Manchester, Manchester, UK, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands, UMassMemorial Medical Center and University of Massachusetts Medical School, Worcester, Institute of Rheumatology, Prague, Czech Republic ; Dr. Vencovsk?? has received speaking fees from Pfizer, UCB, Abbott, Roche, and Merck, Sharpe, and Dohme (less than $10,000 each)., National Data Bank for Rheumatic Diseases and University of Kansas, Wichita, Women's College Hospital and University of Toronto, Toronto, Ontario, Canada ; Department of Medicine, Women's College Hospital, 76 Grenville Street, 8th Floor, Room 815, Toronto, Ontario M5S 1B2, Canada, Neogi, Tuhina, Aletaha, Daniel, Silman, Alan J., Naden, Raymond L., Felson, David T., Aggarwal, Rohit, Bingham, Clifton O., Birnbaum, Neal S., Burmester, Gerd R., Bykerk, Vivian P., Cohen, Marc D., Combe, Bernard, Costenbader, Karen H., Dougados, Maxime, Emery, Paul, Ferraccioli, Gianfranco, Hazes, Johanna M. W., Hobbs, Kathryn, Huizinga, Tom W. J., Kavanaugh, Arthur, Kay, Jonathan, Khanna, Dinesh, Kvien, Tore K., Laing, Timothy, Liao, Katherine, Mease, Philip, M??nard, Henri A., Moreland, Larry W., Nair, Raj, Pincus, Theodore, Ringold, Sarah, Smolen, Josef S., Stanislawska-Biernat, Ewa, Symmons, Deborah, Tak, Paul P., Upchurch, Katherine S., Vencovsk??, Jir??, Wolfe, Frederick, Hawker, Gillian, University of Michigan, Ann Arbor, Boston University School of Medicine, Boston, Massachusetts, Medical University of Vienna, Vienna, Austria ; Dr. Aletaha has received consulting fees, speaking fees, and/or honoraria from Abbott, Bristol-Myers Squibb, UCB, Schering-Plough, Wyeth, and Roche (less than $10,000 each)., Arthritis Research UK, Chesterfield, UK, Ministry of Health, Auckland, New Zealand ; Dr. Naden has received consulting fees from the American College of Rheumatology in regard to the methodology of developing weighted scoring systems (more than $10,000)., University of Pittsburgh, Pittsburgh, Pennsylvania, Johns Hopkins University, Baltimore, Maryland ; Dr. Bingham has received consulting fees, speaking fees, and/or honoraria from UCB, Roche, Genentech, Celgene, and Merck Serono (less than $10,000 each); he has received research and/or educational grant support from Bristol-Myers Squibb, Genentech, UCB, Centocor, Abbott, and Amgen., California Pacific Medical Center and University of California, San Francisco ; Dr. Birnbaum has received consulting fees, speaking fees, and/or honoraria from Amgen, Pfizer, Centocor, Abbott, and UCB (less than $10,000 each)., Charit?? Hospital???University Medicine Berlin, Free University and Humboldt University, Berlin, Germany ; Dr. Burmester has received consulting fees, speaking fees, and/or honoraria from Abbott, Bristol-Myers Squibb, Pfizer, UCB, and Roche (less than $10,000 each)., Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada ; Dr. Bykerk has received consulting fees, speaking fees, and/or honoraria from Amgen, Wyeth, Abbott, Schering-Plough, Roche, Bristol-Myers Squibb, and UCB (less than $10,000 each); her spouse is employed by Genzyme and owns stock in the company., National Jewish Medical and Research Center, Denver, Colorado ; Dr. Cohen has received consulting fees, speaking fees, and/or honoraria from UCB, Genentech, Bristol-Myers Squibb, and Human Genome Sciences (less than $10,000 each)., Lapeyronie Hospital and Montpellier I University, Montpellier, France ; Dr. Combe has received consulting fees, speaking fees, and/or honoraria from Abbott, Bristol-Myers Squibb, Pfizer, Roche, Schering-Plough, and Merck, Sharpe, and Dohme (less than $10,000 each)., Brigham and Women's Hospital and Harvard University, Boston, Massachusetts, Cochin Hospital, Assistance Publique H??pitaux de Paris, and Paris-Descartes University, Paris, France, University of Leeds and NIHR Leeds Biomedical Research Unit, Leeds, UK ; Dr. Emery has received consulting fees, speaking fees, and/or honoraria from Pfizer, Abbott, Centocor, UCB, Roche, Bristol-Myers Squibb, and Merck, Sharpe, and Dohme (less than $10,000 each)., School of Medicine, Catholic University of the Sacred Heart, Rome, Italy ; Dr. Ferraccioli holds a patent for T cell receptor clonotype analysis (PCT/IB 2008/053152 NP)., Erasmus Medical Center and University of Rotterdam, Rotterdam, The Netherlands, University of Colorado School of Medicine, Denver, Leiden University Medical Center, Leiden, The Netherlands ; Dr. Huizinga has received consulting fees, speaking fees, and/or honoraria from Schering-Plough, Bristol-Myers Squibb, UCB, Biotest AG, Wyeth/Pfizer, Novartis, Roche, Sanofi-Aventis, Abbott, and Axis-Shield (less than $10,000 each)., University of California, San Diego ; Dr. Kavanaugh has conducted clinical research for Amgen, Abbott, Bristol-Myers Squibb, UCB, Roche, Centocor, Genentech, and Sanofi-Aventis., UMassMemorial Medical Center and University of Massachusetts Medical School, Worcester ; Dr. Kay has received consulting fees from Array BioPharma, Bristol-Myers Squibb, Celgene, Centocor, Genentech, Roche, UCB, and Sanofi-Aventis (less than $10,000 each)., David Geffen School of Medicine at University of California, Los Angeles ; Dr. Khanna has received consulting fees, speaking fees, and/or honoraria from UCB and Abbott (less than $10,000 each)., Diakonhjemmet Hospital, Oslo, Norway, Swedish Medical Center and University of Washington, Seattle ; Dr. Mease has received consulting fees, speaking fees, and/or honoraria from Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Centocor, Roche, Genentech, UCB, Pfizer, Novartis, and Eli Lilly (less than $10,000 each)., McGill University Health Centre and McGill University, Montreal, Quebec, Canada ; Dr. M??nard has received unrestricted educational and research grants as well as consulting and speaking fees from Abbott, Amgen, Inova, Merck, Pfizer, Roche, Schering-Plough, UCB, and Wyeth (less than $10,000 each) and investigator-initiated research grants from Bristol-Myers Squibb, EuroImmun AG, and Roche (more than $10,000 each); he owns stock or stock options in Merck; and he has a license agreement with EuroImmun AG for an anti-Sa enzyme-linked immunosorbent assay., University of Pittsburgh, Pittsburgh, Pennsylvania ; Dr. Moreland has received consulting fees, speaking fees, and/or honoraria from Biogen Idec, Centocor, Pfizer, Takeda, KaloBios, ChemoCentryx, UCB, Genentech, Incyte, and Eli Lilly (less than $10,000 each)., University of North Carolina, Chapel Hill, New York University Hospital for Joint Diseases, New York, New York ; Dr. Pincus has received consulting fees, speaking fees, and/or honoraria from Amgen, Abbott, Bristol-Myers Squibb, Centocor, UCB, Wyeth, and Genentech (less than $10,000 each) and investigator-initiated research grants from Amgen, Bristol-Myers Squibb, UCB, and Centocor., Seattle Children's Hospital, Seattle, Washington, Medical University of Vienna, Vienna, Austria, Institute of Rheumatology, Warsaw, Poland ; Dr. Stanislawska-Biernat has received speaking fees from Abbott and Pfizer (less than $10,000 each)., University of Manchester, Manchester, UK, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands, UMassMemorial Medical Center and University of Massachusetts Medical School, Worcester, Institute of Rheumatology, Prague, Czech Republic ; Dr. Vencovsk?? has received speaking fees from Pfizer, UCB, Abbott, Roche, and Merck, Sharpe, and Dohme (less than $10,000 each)., National Data Bank for Rheumatic Diseases and University of Kansas, Wichita, Women's College Hospital and University of Toronto, Toronto, Ontario, Canada ; Department of Medicine, Women's College Hospital, 76 Grenville Street, 8th Floor, Room 815, Toronto, Ontario M5S 1B2, Canada, Neogi, Tuhina, Aletaha, Daniel, Silman, Alan J., Naden, Raymond L., Felson, David T., Aggarwal, Rohit, Bingham, Clifton O., Birnbaum, Neal S., Burmester, Gerd R., Bykerk, Vivian P., Cohen, Marc D., Combe, Bernard, Costenbader, Karen H., Dougados, Maxime, Emery, Paul, Ferraccioli, Gianfranco, Hazes, Johanna M. W., Hobbs, Kathryn, Huizinga, Tom W. J., Kavanaugh, Arthur, Kay, Jonathan, Khanna, Dinesh, Kvien, Tore K., Laing, Timothy, Liao, Katherine, Mease, Philip, M??nard, Henri A., Moreland, Larry W., Nair, Raj, Pincus, Theodore, Ringold, Sarah, Smolen, Josef S., Stanislawska-Biernat, Ewa, Symmons, Deborah, Tak, Paul P., Upchurch, Katherine S., Vencovsk??, Jir??, Wolfe, Frederick, and Hawker, Gillian

Abstract

Objective The American College of Rheumatology and the European League Against Rheumatism have developed new classification criteria for rheumatoid arthritis (RA). The aim of Phase 2 of the development process was to achieve expert consensus on the clinical and laboratory variables that should contribute to the final criteria set. Methods Twenty-four expert RA clinicians (12 from Europe and 12 from North America) participated in Phase 2. A consensus-based decision analysis approach was used to identify factors (and their relative weights) that influence the probability of ???developing RA,??? complemented by data from the Phase 1 study. Patient case scenarios were used to identify and reach consensus on factors important in determining the probability of RA development. Decision analytic software was used to derive the relative weights for each of the factors and their categories, using choice-based conjoint analysis. Results The expert panel agreed that the new classification criteria should be applied to individuals with undifferentiated inflammatory arthritis in whom at least 1 joint is deemed by an expert assessor to be swollen, indicating definite synovitis. In this clinical setting, they identified 4 additional criteria as being important: number of joints involved and site of involvement, serologic abnormality, acute-phase response, and duration of symptoms in the involved joints. These criteria were consistent with those identified in the Phase 1 data-driven approach. Conclusion The consensus-based, decision analysis approach used in Phase 2 complemented the Phase 1 efforts. The 4 criteria and their relative weights form the basis of the final criteria set.

Published
2010

119. Intermediate follow-up following intravascular stenting for treatment of coarctation of the aorta

Author

Children's Hospital of Michigan, Wayne State University, Detroit, Michigan ; Children's Hospital of Michigan, 3901 Beaubien Blvd, Detroit, MI 48201, University of California at San Francisco, Division of Cardiology, San Francisco, California, Instituto Dante Pazzanese de Cardiologia, Sao Paulo, SP, Brazil, The Congenital Heart Institute at Miami, Children's Hospital and Arnold Palmer Women and Children's Hospital, Orlando, Florida, Children's Hospital of Omaha, University of Nebraska Creighton University, Omaha, Nebraska, Children's Hospital of Michigan, Wayne State University, Detroit, Michigan, Guy's Hospital, London, England, Columbus Children's Hospital, Ohio State University, Columbus, Ohio, Children's Hospital of Mississippi, University of Mississippi/Jackson, Mississipi, University of Chicago, Division of Cardiology, Chicago, Illinois, Mayo Clinic, Rochester, Minnesota, Cardiovascular Center Bethanien, Frankfurt, Germany, Children's Hospital of Iowa, University of Iowa, Iowa City, Iowa, Medical University of South Carolina, Division of Cardiology, Charleston, South Carolina, Children's Memorial Hospital, Northwestern University, Lincoln Park, Illinois, Duke Children's Heart Program, Duke University, Durham, North Carolina, Seattle Children's Hospital, University of Washington, Seattle, Washington, Babies and Children's Hospital of New York, Columbia Presbyterian, New York, New York, Forbes, Thomas J., Moore, Phillip, Pedra, Carlos A. C., Zahn, Evan M., Nykanen, David, Amin, Zahid, Garekar, Swati, Teitel, David, Qureshi, Shakeel A., Cheatham, John P., Ebeid, Makram R., Hijazi, Ziyad M., Sandhu, Satinder, Hagler, Donald J., Sievert, Horst, Fagan, Thomas E., Ringwald, Jeremy, Du, Wei, Tang, Liwen, Wax, David F., Rhodes, John, Johnston, Troy A., Jones, Thomas K., Turner, Daniel R., Pass, Robert, Torres, Alejandro, Hellenbrand, William E., Children's Hospital of Michigan, Wayne State University, Detroit, Michigan ; Children's Hospital of Michigan, 3901 Beaubien Blvd, Detroit, MI 48201, University of California at San Francisco, Division of Cardiology, San Francisco, California, Instituto Dante Pazzanese de Cardiologia, Sao Paulo, SP, Brazil, The Congenital Heart Institute at Miami, Children's Hospital and Arnold Palmer Women and Children's Hospital, Orlando, Florida, Children's Hospital of Omaha, University of Nebraska Creighton University, Omaha, Nebraska, Children's Hospital of Michigan, Wayne State University, Detroit, Michigan, Guy's Hospital, London, England, Columbus Children's Hospital, Ohio State University, Columbus, Ohio, Children's Hospital of Mississippi, University of Mississippi/Jackson, Mississipi, University of Chicago, Division of Cardiology, Chicago, Illinois, Mayo Clinic, Rochester, Minnesota, Cardiovascular Center Bethanien, Frankfurt, Germany, Children's Hospital of Iowa, University of Iowa, Iowa City, Iowa, Medical University of South Carolina, Division of Cardiology, Charleston, South Carolina, Children's Memorial Hospital, Northwestern University, Lincoln Park, Illinois, Duke Children's Heart Program, Duke University, Durham, North Carolina, Seattle Children's Hospital, University of Washington, Seattle, Washington, Babies and Children's Hospital of New York, Columbia Presbyterian, New York, New York, Forbes, Thomas J., Moore, Phillip, Pedra, Carlos A. C., Zahn, Evan M., Nykanen, David, Amin, Zahid, Garekar, Swati, Teitel, David, Qureshi, Shakeel A., Cheatham, John P., Ebeid, Makram R., Hijazi, Ziyad M., Sandhu, Satinder, Hagler, Donald J., Sievert, Horst, Fagan, Thomas E., Ringwald, Jeremy, Du, Wei, Tang, Liwen, Wax, David F., Rhodes, John, Johnston, Troy A., Jones, Thomas K., Turner, Daniel R., Pass, Robert, Torres, Alejandro, and Hellenbrand, William E.

Abstract

Background : We report a multiinstitutional study on intermediate-term outcome of intravascular stenting for treatment of coarctation of the aorta using integrated arch imaging (IAI) techniques. Methods and Results : Medical records of 578 patients from 17 institutions were reviewed. A total of 588 procedures were performed between May 1989 and Aug 2005. About 27% (160/588) procedures were followed up by further IAI of their aorta (MRI/CT/repeat cardiac catheterization) after initial stent procedures. Abnormal imaging studies included: the presence of dissection or aneurysm formation, stent fracture, or the presence of reobstruction within the stent (instent restenosis or significant intimal build-up within the stent). Forty-one abnormal imaging studies were reported in the intermediate follow-up at median 12 months (0.5–92 months). Smaller postintervention of the aorta (CoA) diameter and an increased persistent systolic pressure gradient were associated with encountering abnormal follow-up imaging studies. Aortic wall abnormalities included dissections ( n = 5) and aneurysm ( n = 13). The risk of encountering aortic wall abnormalities increased with larger percent increase in CoA diameter poststent implant, increasing balloon/coarc ratio, and performing prestent angioplasty. Stent restenosis was observed in 5/6 parts encountering stent fracture and neointimal buildup ( n = 16). Small CoA diameter poststent implant and increased poststent residual pressure gradient increased the likelihood of encountering instent restenosis at intermediate follow-up. Conclusions : Abnormalities were observed at intermediate follow-up following IS placement for treatment of native and recurrent coarctation of the aorta. Not exceeding a balloon:coarctation ratio of 3.5 and avoidance of prestent angioplasty decreased the likelihood of encountering an abnormal follow-up imaging study in patients undergoing intravascular stent placement for the treatment of coarctation of the aorta. We r

Published
2007

120. De novo and biallelic DEAF1 variants cause a phenotypic spectrum

Author

Elysa J. Marco, Heather C Mefford, Stacey McGee, Christèle Dubourg, Edmund Cauley, Randi J Hagerman, Maria J. Nabais Sá, Bert B.A. de Vries, Rüdiger Lorenz, Elizabeth E. Palmer, Michael J. Parker, Arjan P.M. de Brouwer, Hester Y. Kroes, M. Chiara Manzini, Abbey A. Scott, Tara Montgomery, Naama Orenstein, Jeanne Amiel, Delphine Héron, Leonie A. Menke, Jonathan Berg, Sylvie Odent, Rachel Harrison, Philip J. Jensik, Rani Sachdev, Miranda Splitt, Tyler Mark Pierson, Jan Maarten Cobben, Ehsan Ghayoor Karimiani, Anneke T. Vulto-vanSilfhout, Roberto Colombo, Nayana Lahiri, Julian A. Martinez-Agosto, Evan P. McNeil, Boris Keren, John M. Graham, Chanika Phornphutkul, Reza Maroofian, Radboud University Medical Center [Nijmegen], Southern Illinois University [Carbondale] (SIU), Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, St George's, University of London, Geisel School of Medicine at Dartmouth, University Medical Center [Utrecht], University of California [Davis] (UC Davis), University of California, Nottingham University Hospitals NHS Trust, Northern Genetics Service, Newcastle University [Newcastle], University of New South Wales [Sydney] (UNSW), Department of Pediatrics [Seattle, WA, USA] (Division of Genetic Medicine), University of Washington [Seattle]-Seattle Children’s Hospital, University of California [Los Angeles] (UCLA), Tel Aviv University [Tel Aviv], University of Dundee, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Amsterdam [Amsterdam] (UvA), Cedars-Sinai Medical Center, The George Washington University (GW), Fondazione 'Policlinico Universitario A. Gemelli' [Rome], CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Warren Alpert Medical School of Brown University, University of California (UC), Nottingham University Hospitals NHS Trust (NUH), Department of Pediatrics [Seattle, WA, USA], Tel Aviv University (TAU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), General Paediatrics, Paediatric Genetics, Amsterdam Reproduction & Development (AR&D), Sheffield Children's Hospital, St George‘s, University of London, University of Washington [Seattle]-Seattle Children’s Hospital [Seattle, WA, USA], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], George Washington University (GW), and AMS - Sports

Subjects
Adult, Male, Microcephaly, Adolescent, phenotype, Developmental Disabilities, genotype, [SDV]Life Sciences [q-bio], Mutation, Missense, Biology, Young Adult, 03 medical and health sciences, Neurodevelopmental disorder, All institutes and research themes of the Radboud University Medical Center, Genotype, medicine, Humans, Exome, Language Development Disorders, Autistic Disorder, Allele, Child, Alleles, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, Genetics, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], 030305 genetics & heredity, medicine.disease, Phenotype, neurodevelopmental disorder, Human genetics, DEAF1, DNA-Binding Proteins, intellectual disability, Child, Preschool, Speech delay, Autism, Female, medicine.symptom, Transcription Factors
Abstract

International audience; Purpose To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. Methods We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype–phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. Results The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001). Conclusion We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients. © 2019, American College of Medical Genetics and Genomics.

Published
2019
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121. NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly

Author

Sonal Mahida, Elliott H. Sherr, Elodie Lacaze, William B. Dobyns, Kosuke Izumi, Hilde Peeters, Marielle Alders, Catherine Nowak, Dawn L. Earl, Richard M. Gronostajski, Ryan J. Dean, Megan T. Cho, Anouck Schneider, Siren Berland, Patricia Blanchet, Laurence Faivre, Martin Zenker, Ina Schanze, Caitlin J. Bridges, Daniela T. Pilz, Sangamitra Boppudi, Ilse Wieland, Jens Bunt, Avni Santani, Jessica Douglas, Elaine H. Zackai, Muriel Holder-Espinasse, Linda J. Richards, Jean Baptiste Rivière, Tania Attié-Bitach, Timothy J. Edwards, Vincent Gatinois, Jacques Puechberty, Jonathan W. C. Lim, Ghayda Mirzaa, Sian Morgan, Phillis Lakeman, Steven Boogert, Samuel Huth, Marion Gérard, Denny Schanze, Florence Petit, Xiaonan Zhao, Eyal Reinstein, David Geneviève, Bronwyn Kerr, Dian Donnai, Constance Smith-Hicks, Brieana Fregeau, Amsterdam Reproduction & Development (AR&D), ACS - Pulmonary hypertension & thrombosis, Human Genetics, Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] (OVGU), Queensland Brain Institute, University of Queensland [Brisbane], University of Amsterdam [Amsterdam] (UvA), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Embryology and genetics of human malformation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Haukeland University Hospital, University of Bergen (UiB), GeneDx [Gaithersburg, MD, USA], University of Washington [Seattle], Seattle Children’s Hospital, University of Manchester [Manchester], Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, FHU TRANSLAD (CHU de Dijon), University of California [San Francisco] (UC San Francisco), University of California (UC), Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Lille, Children’s Hospital of Philadelphia (CHOP ), Département de génétique (groupe hospitalier le Havre), Groupe Hospitalier du Havre, Kennedy Krieger Institute [Baltimore], University Hospital of Wales (UHW), University Hospitals Leuven [Leuven], University of Glasgow, Sackler Faculty of Medicine, Tel Aviv University (TAU), Perelman School of Medicine, University of Pennsylvania, This work was supported by grants from the National Healthand Medical Research Council Australia (GNT1100443 to L.J.R.), the French Ministry of Health (PHRC national 2008/2008-A00515-50), Regional Council of Burgundy/Dijon University hospital (PARI 2012), The Genesis Foundation for Children, the US National Institutes of Health under NINDS grants(1R01NS092772 and 234567890 to W.B.D., 1R01NS058721 toW.B.D. and E.H.S., and K08NS092898 to G.M.M.), and Jordan’s Guardian Angels (G.M.M.). J.W.C.L. was supported by an International Postgraduate Research Scholarship and UQ Centennial Scholarship. R.M.G. was supported by NYSTEM grants (C026714,C026429, and C030133). R.J.D. was supported by Brain Injured Children’s Aftercare Recovery Endeavours (BICARE) Fellowship.L.J.R. was supported by an NHMRC Principal Research Fellowship(GNT1005751). M.Z. was supported by a grant from the GermanMinistry of Education and Research (BMBF) (GeNeRARe01GM1519A). We acknowledge the Linkage Infrastructure, Equipment and Facilities (LIEF) grant (LE100100074) awarded to the Queensland Brain Institute for the Slide Scanner and the facilities of the National Imaging Facility (NIF) at the Centre for Advanced Imaging, University of Queensland, used in the animal experiments., European Project: 270259,EC:FP7:ICT,FP7-ICT-2009-6,TBICARE(2011), Institute of Human Genetics (University Hospital Magdeburg), University Hospital of the Otto von Guericke University of Magdeburg, Department of Clinical Genetics, Academic Medical Centre, Amsterdam, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Bergen (UIB), Seattle Children's Research Institute, Department of Neurology (University of California : San Francisco), University of California [San Francisco] (UCSF), University of California-University of California, Department of Medical Genetics, HMNC Brain Health, Seattle Children’s Hospital [Seattle, WA, USA], Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Université de Lorraine (UL), Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Pediatrics (Perelman School of Medicine), University of Pennsylvania [Philadelphia], Regional Genetic Service, St Mary's Hospital, Manchester, Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Department of Pediatrics [Seattle, WA, USA] (Division of Genetic Medicine), University of Washington [Seattle]-Seattle Children’s Hospital [Seattle, WA, USA], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales, Center for Human Genetics, University Hospitals Leuven, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille 2 - Faculté de Médecine -Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Medical Genetics Institute, Meir Medical Center, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA], University of Pennsylvania [Philadelphia]-Perelman School of Medicine, Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, School of Computer Science and Technology, Northwestern Polytechnical University [Xi'an] (NPU), Department of Biochemistry and Developmental Genomics Group, University at Buffalo [SUNY] (SUNY Buffalo), State University of New York (SUNY)-State University of New York (SUNY)-Center of Excellence in Bioinformatics and Life Sciences, Institute of Human Genetics, University Hospital Magdeburg, université de Bourgogne, LNC, Evidence based Diagnostic and Treatment Planning Solution for Traumatic Brain Injuries - TBICARE - - EC:FP7:ICT2011-02-01 - 2014-07-31 - 270259 - VALID, Otto-von-Guericke University [Magdeburg] (OVGU), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of California, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University Hospital of Wales [Cardiff, UK], and Tel Aviv University [Tel Aviv]

Subjects
Male, 0301 basic medicine, chromosome 9p23, Medical and Health Sciences, Corpus Callosum, Cohort Studies, Mice, 2.1 Biological and endogenous factors, Megalencephaly, Aetiology, Child, Agenesis of the corpus callosum, Genetics (clinical), Pediatric, Genetics & Heredity, Cerebral Cortex, Mice, Knockout, Genetics, Single Nucleotide, nuclear factor I, Biological Sciences, NFIB, NFIX, developmental delay, Mental Health, Codon, Nonsense, NFIA, intellectual disability, Child, Preschool, chromosome 9p22.3, Neurological, Speech delay, Female, medicine.symptom, Haploinsufficiency, Adult, Adolescent, Knockout, Intellectual and Developmental Disabilities (IDD), [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, macrocephaly, Polymorphism, Single Nucleotide, Article, Young Adult, 03 medical and health sciences, Rare Diseases, Behavioral and Social Science, medicine, megalencephaly, Animals, Humans, Polymorphism, Codon, Preschool, Neurosciences, Macrocephaly, medicine.disease, Brain Disorders, haploinsufficiency, NFI Transcription Factors, 030104 developmental biology, Nonsense, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, agenesis of the corpus callosum
Abstract

The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:103 issue:5 pages:752-768 ispartof: location:United States status: published

Published
2018
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123. Early-phase clinical trial eligibility and response evaluation criteria for refractory, relapsed, or progressive neuroblastoma: A consensus statement from the National Cancer Institute Clinical Trials Planning Meeting

Author

Julie R. Park, Judith G. Villablanca, Barbara Hero, Brian H. Kushner, Keith Wheatley, Klaus H. Beiske, Ruth L. Ladenstein, Sylvain Baruchel, Margaret E. Macy, Lucas Moreno, Nita L. Seibel, Andrew D. Pearson, Katherine K. Matthay, Dominique Valteau‐Couanet, Institut Català de la Salut, [Park JR] Seattle Children’s Hospital, Seattle, Washington, USA. Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA. [Villablanca JG] Children’s Hospital Los Angeles, Los Angeles, California, USA. Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. [Hero B] Children’s Hospital, University of Cologne, Cologne, Germany. [Kushner BH] Memorial Sloan Kettering Cancer Center, New York, New York, USA. [Wheatley K] University of Birmingham, Birmingham, UK. [Beiske KH] Department of Pathology, Oslo University Hospital, Oslo, Norway. [Moreno L] Servei d'Hematologia i Oncologia Pediàtriques, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Cancer Research, Consensus, Neuroblastoma - Tractament, neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::neoplasias neuroepiteliales::tumores neuroectodérmicos primitivos::tumores neuroectodérmicos primitivos periféricos::neuroblastoma [ENFERMEDADES], Presa de decisions, diagnóstico::pronóstico::resultado del tratamiento [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Other subheadings::/therapy [Other subheadings], Diagnosis::Prognosis::Treatment Outcome [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Psychological Phenomena::Mental Processes::Thinking::Decision Making::Consensus [PSYCHIATRY AND PSYCHOLOGY], National Cancer Institute (U.S.), United States, Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neoplasms, Neuroepithelial::Neuroectodermal Tumors, Primitive::Neuroectodermal Tumors, Primitive, Peripheral::Neuroblastoma [DISEASES], 3-Iodobenzylguanidine, Neuroblastoma, Treatment Outcome, Oncology, Avaluació de resultats (Assistència sanitària), Humans, fenómenos psicológicos::procesos mentales::pensamiento::toma de decisión::consenso [PSIQUIATRÍA Y PSICOLOGÍA], Child, Otros calificadores::/terapia [Otros calificadores]
Abstract

Consensus criteria; Early phase; Neuroblastoma Criteris de consens; Fase inicial; Neuroblastoma Criterios de consenso; Fase inicial; Neuroblastoma Background International standardized criteria for eligibility, evaluable disease sites, and disease response assessment in patients with refractory, progressive, or relapsed high-risk neuroblastoma enrolled in early-phase clinical trials are lacking. Methods A National Cancer Institute–sponsored Clinical Trials Planning Meeting was convened to develop an international consensus to refine the tumor site eligibility criteria and evaluation of disease response for early-phase clinical trials in children with high-risk neuroblastoma. Results Standardized data collection of patient and disease characteristics (including specified genomic data), eligibility criteria, a definition of evaluable disease, and response evaluations for primary and metastatic sites of disease were developed. Eligibility included two distinct patient groups: progressive disease and refractory disease. The refractory disease group was subdivided into responding persistent disease and stable persistent disease to better capture the clinical heterogeneity of refractory neuroblastoma. Requirements for defining disease evaluable for a response assessment were provided; they included requirements for biopsy to confirm viable neuroblastoma and/or ganglioneuroblastoma in those patients with soft tissue or bone disease not avid for iodine-123 meta-iodobenzylguanidine. Standardized evaluations for response components and time intervals for response evaluations were established. Conclusions The use of international consensus eligibility, evaluability, and response criteria for early-phase clinical studies will facilitate the collection of comparable data across international trials and promote more rapid identification of effective treatment regimens for high-risk neuroblastoma. National Cancer Institute Pediatric and Adolescent Solid Tumor Steering Committee; Alex's Lemonade Stand Foundation for Childhood Cancer; Ben Towne Foundation; EVAN Foundation; Cancer Research UK Institute of Cancer Research, Grant/Award Number C347/A15403; National Institute for Health Research Research Methods Programme/Institute of Cancer Research Biomedical Research Centre.

Published
2022

125. Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations

Author

Danielle J. Owen, David FitzPatrick, Nina Mann, Stuart B. Bauer, Ilona Krey, Heather C Mefford, Jacob Zyskind, Roger Fick, Ana C. Onuchic-Whitford, Floor A. M. Duijkers, Etienne Coyaud, Simon E. Fisher, Juliann M. Savatt, Richard P. Lifton, Isabel Ottlewski, Amelie T. van der Ven, Peter J. Hulick, Nancy Rodig, Michelle A. Baum, Marielle Alders, Elysa J. Marco, Konrad Platzer, Ghaleb Daouk, Hadas Ityel, Eva H. Brilstra, Ian A. Glass, Heiko Reutter, Adda L. Graham-Paquin, Makiko Nakayama, Michael A. J. Ferguson, Amy Kolb, Weining Lu, Florian Buerger, Prabha Senguttuvan, Marcia Ferguson, Ronen Schneider, Isabelle Thiffault, Hila Milo Rasouly, Verena Klämbt, Tobias Bartolomaeus, Evan Chen, Mao Youying, Amar J. Majmundar, Jia Rao, Carrie Costin, Dina Ahram, Ali G. Gharavi, Lot Snijders Blok, Avram Z. Traum, Franziska Kause, Konstantin Deutsch, Arianna Vino, Dervla M. Connaughton, Antonie D. Kline, Deborah R. Stein, Daanya Salmanullah, Maxime Bouchard, Estelle M.N. Laurent, Audrey Squire, Daniel G. MacArthur, Kristen M. Laricchia, Asaf Vivante, Thomas M. Kitzler, Jonathan St-Germain, Brian Raught, Heidi L. Rehm, Ellen van Binsbergen, Chen Han Wilfred Wu, Caroline M. Kolvenbach, Monkol Lek, Selvin Kumar, Jing Chen, Mustafa K. Khokha, Ankana Daga, Hong Xu, Andrew D. Sharrocks, N. V. Shcherbakova, Simone Sanna-Cherchi, Inna S. Povolotskaya, Tze Y Lim, Johanna M. Rieke, Katrina M. Dipple, Gabriel C. Dworschak, Michael J. Somers, Tobias Hermle, Stefan Kohl, Steve Seltzsam, Victoria Y. Voinova, Shirlee Shril, Ingrid M. Wentzensen, Daw Yang Hwang, Velibor Tasic, Shrikant Mane, Jonathan Marquez, Friedhelm Hildebrandt, Rufeng Dai, Paulien A Terhal, Loai A. Eid, Thomas D. Challman, Boston Children's Hospital, Harvard Medical School [Boston] (HMS), University of Western Ontario (UWO), Fudan University [Shanghai], University of Manchester [Manchester], Yale University [New Haven], McGill University = Université McGill [Montréal, Canada], Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University Health Network, University of Toronto, Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft, Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], Radboud University Medical Center [Nijmegen], Brigham & Women’s Hospital [Boston] (BWH), Tel Aviv University (TAU), University of Amsterdam [Amsterdam] (UvA), Universität Leipzig, University Medical Center [Utrecht], Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA] (ADMI), GeneDx [Gaithersburg, MD, USA], University of Akron, University of Washington [Seattle], William Harvey Research Institute, Barts and the London Medical School, University of Edinburgh, Mary Bridge Childrens Hospital [Tacoma, WA, USA], NorthShore University HealthSystem [Evanston, IL, USA], Institute of Child Health [Tamil Nadu, India] (Hospital for Children), Boston University [Boston] (BU), Cortica Healthcare [San Rafael, CA, USA], Moscow Medical Institute of Health Ministry [Moscow, Russia], Pirogov Russian National Research Medical University, Dr. Mehta's Hospitals [Tamil Nadu, India], Seattle Children’s Hospital, Children's Mercy Hospital [Kansas City], University of Missouri [Kansas City] (UMKC), University of Missouri System, Neuro Spinal Hospital [Dubai, UAE], University Children’s Hospital [Skopje, Macédoine], Columbia University [New York], University Hospital Bonn, Massachusetts General Hospital [Boston], Rockefeller University [New York], Yale School of Medicine [New Haven, Connecticut] (YSM), Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Radboud university [Nijmegen], Tel Aviv University [Tel Aviv], Universität Leipzig [Leipzig], Pirogov Russian National Research Medical University [Moscow, Russia], Yale University School of Medicine, INSERM, Université de Lille, Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192, and SALZET, Michel

Subjects
0301 basic medicine, Male, Morpholino, Xenopus, 030232 urology & nephrology, Endogenous retrovirus, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], transcription regulator, Interactome, Epigenesis, Genetic, Morpholinos, Pathogenesis, ZNF198, Mice, 0302 clinical medicine, whole-exome sequencing, Child, Urinary Tract, Genetics (clinical), Exome sequencing, Genetics, Mice, Knockout, ZMYM2, genetic kidney disease, Forkhead Transcription Factors, FOXP1, 3. Good health, Pedigree, extra-renal features, DNA-Binding Proteins, Child, Preschool, Larva, syndromic CAKUT, Female, Protein Binding, Neuroinformatics, Heterozygote, Biology, Article, Amphibian Proteins, 03 medical and health sciences, Exome Sequencing, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Gene silencing, Animals, Humans, Family, Transcription factor, FIM, Infant, Repressor Proteins, 030104 developmental biology, genomic analysis, Case-Control Studies, Urogenital Abnormalities, congenital anomalies of the kidney and urinary tract, Mutation, Transcription Factors
Abstract

International audience; Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CA-KUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpho-lino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and cranio-facial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endoge-nous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.

Published
2020
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126. International Consensus for the Dosing of Corticosteroids in Childhood-Onset Systemic Lupus Erythematosus With Proliferative Lupus Nephritis

Author

Chalhoub, Nathalie E., Wenderfer, Scott E., Levy, Deborah M., Rouster-Stevens, Kelly, Aggarwal, Amita, Savani, Sonia I., Ruth, Natasha M., Arkachaisri, Thaschawee, Qiu, Tingting, Merritt, Angela, Onel, Karen, Goilav, Beatrice, Khubchandani, Raju P., Deng, Jianghong, Fonseca, Adriana R., Ardoin, Stacy P., Ciurtin, Coziana, Kasapcopur, Ozgur, Jelusic, Marija, Huber, Adam M., Ozen, Seza, Klein-Gitelman, Marisa S., Appenzeller, Simone, Cavalcanti, André, Fotis, Lampros, Lim, Sern Chin, Silva, Rodrigo M., Miramontes, Julia Ramírez, Rosenwasser, Natalie L., Saad-Magalhaes, Claudia [UNESP], Schonenberg-Meinema, Dieneke, Scott, Christiaan, Silva, Clovis A., Enciso, Sandra, Terreri, Maria T., Torres-Jimenez, Alfonso-Ragnar, Trachana, Maria, Al-Mayouf, Sulaiman M., Devarajan, Prasad, Huang, Bin, Brunner, Hermine I., Abulaban, Khalid, Aguiar, Cassyanne, Ahn, Sun-Young, Akoghlanian, Shoghik, Al-Abrawi, Safiya, Aljaberi, Najla, Alperin, Risa, Angeles-Han, Sheila, Ardalan, Kaveh, Bader-Meunier, Brigitte, Balboni, Imelda, Barbar-Smiley, Fatima, Baxter, Sarah, Beary, John, Boneparth, Alexis, Brakeman, Paul, Bridges, John, Burgos-Vargas, Ruben, Cabral, David A., Cameto, Juan, Carter, Caitlin, Chang, Joyce, Chédeville, Gaëlle, Chhakchhuak, Christine, Chiraseveenuprapund, Peter, Cifuentes Alvarado, Mayra, Concannon, Anthony, Cooper, Jennifer, Cron, Randy, De Carvalho, Luciana Martins, De Quattro, Kimberly, De Ranieri, Deirdre, Dizon, Brian, Donnelly Wrigley, Catherine, Duong, Minh Dien, Eberhard, Anne, Ede, Kaleo, Edelheit, Barbara, Edens, Cuoghi, Espada, Graciela, Farhey, Yolanda, Flores, Francisco, Fritz, Deborah, Ganguli, Suhas, Gilbert, Mileka, Gittar, Patsy, Greenbaum, Larry, Grom, Alexei, Gulati, Gaurav, Harry, Onengiya, Hayward, Kristen, Henrickson, Michael, Hersh, Aimee, Hiraki, Linda, Hiskey, Megan, Hoffmann, Sarah, Hollander, Matthew, Hom, Christine, Houk, Lawrence, Houk, J. Brian, Hsieh, Elena W.Y., Hsu, Joyce, Jensen, Paul, Joos, Rik, Jurado, Rosario, Jusan Fiorot, Fernanda, Kallash, Mahmoud, Kamphuis, Sylvia, Keltsev, Vladimir, Khanna, Surabhi, Kim, Susan, Kimseng, Karen Joy, Knight, Andrea, Kunder, Rebecca, Lai, Jamie, Laskin, Benjamin, Lewandowski, Laura, Lim, Lily, Linda, Wagner-Weiner, Lo, Mindy, Lovell, Daniel, Luggen, Michael, Madison, Jacqueline, Mansuri, Asif, Martin, Lorena, Mason, Sherene, Miller, Michael, Mina, Rina, Mohammed, Abdul, Moncrieffe, Halima, Moorthy, Lakshmi, Morgan, Esi, Mosquera, Angela, Muntel, Emily, Muscal, Eyal, Myones, Barry, Nocton, James, Ogbu, Ekemini, Okamura, Daryl, Olson, Judyann, Orrock, Janet, Paim-Marques, Luciana, Pain, Clare, Park, Catherine, Patel, Pooja, Pereira, Maria, Prado, Rogerio do, Radhakrishna, Suhas, Rheault, Michelle, Ridgway, William, Riskalla, Mona, Ronis, Tova, Sadun, Rebecca, Sagcal-Gironella, Anna Carmela, Santos, Maria carolina, Schikler, Kenneth, AL Suwairi, Wafaa, Siddiqi, Nabeela, Silva, Marco Felipe, Singh-Grewal, Davinder, Smitherman, Emily, Smolewska, Elzbieta, Son, Mary Beth, Srinivasalu, Hemalatha, Sule, Sangeeta, Susic, Gordana, Syed, Reema, Thatayatikom, Akaluck, Ting, Tracy, Toth, Mary, Turnier, Jessica, Vashisht, Priyanka, Vega Fernandez, Patricia, Velasquez, Monica, von Scheven, Emily, Wahezi, Dawn, Ware, Avis, Wu, Eveline, Yan, Jacqueline, Yildirim-Toruner, Cagri, Zamparo, Celso, Zhang, Yujuan, Lawson, Erica, Graduate School, Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Inflammatory diseases, University of Cincinnati College of Medicine, Baylor College of Medicine, The Hospital for Sick Children and The University of Toronto, Emory University and Children's Healthcare of Atlanta, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Medical University of South Carolina, KK Women's and Children's Hospital, Cincinnati Children's Hospital Medical Center, Hospital for Special Surgery, Albert Einstein College of Medicine, SRCC Children's Hospital, Capital Medical University and National Center for Children's Health, Universidade Federal do Rio de Janeiro (UFRJ), Nationwide Children's Hospital, University College London, Istanbul University-Cerrahpasa, University of Zagreb School of Medicine, IWK Health Centre and Dalhousie University, Hacettepe University, Northwestern University Feinberg School of Medicine and Ann & Robert H. Lurie Children's Hospital of Chicago, Universidade Estadual de Campinas (UNICAMP), Universidade Federal de Pernambuco (UFPE), National and Kapodistian University of Athens, University Teknologi MARA, Instituto Mexicano del Seguro Social, University of Washington and Seattle Children's Hospital, Universidade Estadual Paulista (UNESP), Amsterdam University Medical Center, Red Cross War Memorial Children's Hospital and University of Cape Town, Universidade de São Paulo (USP), Hospital de la Beneficencia Española, Universidade Federal de São Paulo (UNIFESP), National Medical Center La Raza, Aristotle University of Thessaloniki, King Faisal Specialist Hospital and Research Center and Alfaisal University, and University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center

Subjects
Male, medicine.medical_specialty, Adolescent, medicine.drug_class, Immunology, Lupus nephritis, Renal function, Article, Rheumatology, childhood-onset systemic lupus erythematosus, corticosteroids, lupus nephritis, treatment, Internal medicine, Biopsy, Immunology and Allergy, Medicine, Humans, Lupus Erythematosus, Systemic, Dosing, Age of Onset, Child, Glucocorticoids, Retrospective Studies, Kidney, Proteinuria, medicine.diagnostic_test, business.industry, food and beverages, medicine.disease, Lupus Nephritis, Clinical trial, medicine.anatomical_structure, Corticosteroid, Female, medicine.symptom, business
Abstract

Made available in DSpace on 2022-04-28T19:49:00Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-02-01 Arthritis Foundation Institute of Clinical and Translational Sciences Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institute of Diabetes and Digestive and Kidney Diseases National Center for Advancing Translational Sciences Objective: To develop a standardized steroid dosing regimen (SSR) for physicians treating childhood-onset systemic lupus erythematosus (SLE) complicated by lupus nephritis (LN), using consensus formation methodology. Methods: Parameters influencing corticosteroid (CS) dosing were identified (step 1). Data from children with proliferative LN were used to generate patient profiles (step 2). Physicians rated changes in renal and extrarenal childhood-onset SLE activity between 2 consecutive visits and proposed CS dosing (step 3). The SSR was developed using patient profile ratings (step 4), with refinements achieved in a physician focus group (step 5). A second type of patient profile describing the course of childhood-onset SLE for ≥4 months since kidney biopsy was rated to validate the SSR-recommended oral and intravenous (IV) CS dosages (step 6). Patient profile adjudication was based on majority ratings for both renal and extrarenal disease courses, and consensus level was set at 80%. Results: Degree of proteinuria, estimated glomerular filtration rate, changes in renal and extrarenal disease activity, and time since kidney biopsy influenced CS dosing (steps 1 and 2). Considering these parameters in 5,056 patient profile ratings from 103 raters, and renal and extrarenal course definitions, CS dosing rules of the SSR were developed (steps 3–5). Validation of the SSR for up to 6 months post–kidney biopsy was achieved with 1,838 patient profile ratings from 60 raters who achieved consensus for oral and IV CS dosage in accordance with the SSR (step 6). Conclusion: The SSR represents an international consensus on CS dosing for use in patients with childhood-onset SLE and proliferative LN. The SSR is anticipated to be used for clinical care and to standardize CS dosage during clinical trials. University of Cincinnati College of Medicine Baylor College of Medicine The Hospital for Sick Children and The University of Toronto Emory University and Children's Healthcare of Atlanta Sanjay Gandhi Postgraduate Institute of Medical Sciences Medical University of South Carolina KK Women's and Children's Hospital Cincinnati Children's Hospital Medical Center Hospital for Special Surgery Albert Einstein College of Medicine SRCC Children's Hospital Capital Medical University and National Center for Children's Health Universidade Federal do Rio de Janeiro Nationwide Children's Hospital University College London Cerrahpasa Medical School Istanbul University-Cerrahpasa University of Zagreb School of Medicine IWK Health Centre and Dalhousie University Hacettepe University Northwestern University Feinberg School of Medicine and Ann & Robert H. Lurie Children's Hospital of Chicago University of Campinas Hospital das Clínicas da Universidade Federal de Pernambuco National and Kapodistian University of Athens University Teknologi MARA Instituto Mexicano del Seguro Social University of Washington and Seattle Children's Hospital São Paulo State University Amsterdam University Medical Center Red Cross War Memorial Children's Hospital and University of Cape Town Universidade de São Paulo Hospital de la Beneficencia Española Universidade Federal de São Paulo National Medical Center La Raza Aristotle University of Thessaloniki King Faisal Specialist Hospital and Research Center and Alfaisal University University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center São Paulo State University CNPq: 303422/2015-7 FAPESP: FAPESP 2015/03756-4 National Institute of Arthritis and Musculoskeletal and Skin Diseases: P30-AR-076316 National Institute of Diabetes and Digestive and Kidney Diseases: P50-DK-096418 National Institute of Arthritis and Musculoskeletal and Skin Diseases: R34-AR-071651 National Center for Advancing Translational Sciences: T32-AR-050958

Published
2021

128. Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy

Author

Rhonda E. Schnur, Fabio Sirchia, Olga Levchenko, Caroline Nava, Jane Juusola, Sarah Verheyen, Marketa Vlckova, Lindsay Rhodes, Gregory M. Cooper, Darina Prchalova, Thomas Courtin, Øystein L. Holla, David Kronn, Akemi J. Tanaka, E. Martina Bebin, Tara Funari, Miroslava Hancarova, Ennio Del Giudice, Nicolas Guex, Astrid Eisenkölbl, Dawn L. Earl, Toshiki Takenouchi, Ursula Gruber-Sedlmayr, Sedlácek Z, Sofia Douzgou, Heidelis A. Seebacher, Gerarda Cappuccio, Jasmin Blatterer, Anna Mikhaleva, Dian Donnai, Wendy K. Chung, Else Merckoll, Natasha J Brown, Elizabeth A. Sellars, Stefan Mundlos, Susan M. Hiatt, Giuliana Giannuzzi, Sinje Geuer, Giuseppina Vitiello, Séverine Lorrain, Alexandre Reymond, David J. Amor, Nicolas Chatron, Julien Delafontaine, Martine Doco, Kristian Tveten, Cecilie F. Rustad, Sylvain Pradervand, Delphine Héron, Alfredo Brusco, Elena L. Dadali, Nicola Brunetti-Pierri, Boris Keren, Yuri A. Zarate, Crystle Lee, Joel Charrow, Binnaz Yalcin, Heidi Taska-Tench, Elin Tønne, Tomoko Uehara, Alexander Lavrov, Jennifer Norman, Norine Voisin, Anna C.E. Hurst, Victoria R. Sanders, Ganka Douglas, Diana Johnson, Kenjiro Kosaki, Université de Lausanne = University of Lausanne (UNIL), Cooper Medical School of Rowan University [Camden] (CMSRU), Manchester University NHS Foundation Trust (MFT), University of Manchester [Manchester], HudsonAlpha Institute for Biotechnology [Huntsville, AL], Oslo University Hospital [Oslo], Victorian Clinical Genetics Services [Melbourne, VIC, Australia] (VCGS), Murdoch Children's Research Institute (MCRI), University of Melbourne, Seattle Children’s Hospital, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme [ CHU Pitié-Salpêtrière AP-HP] (GRC : DIA), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Research Centre for Medical Genetics [Moscow, Russia] (RCMG), Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, Medical University of Graz, Sheffield Children's NHS Foundation Trust, University of Arkansas at Little Rock, Charles University [Prague] (CU), University Hospital Motol [Prague], University of Alabama at Birmingham [ Birmingham] (UAB), Università degli studi di Torino = University of Turin (UNITO), Azienda Ospedalerio - Universitaria Città della Salute e della Scienza di Torino = University Hospital Città della Salute e della Scienza di Torino, University of Naples Federico II = Università degli studi di Napoli Federico II, Ann & Robert H. Lurie Children's Hospital of Chicago, Swiss Institute of Bioinformatics [Lausanne] (SIB), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), GeneDx [Gaithersburg, MD, USA], Johannes Kepler University Linz [Linz] (JKU), Telemark Hospital Trust [Skien, Norway], New York Medical College (NYMC), Integris Pediatric Neurology [Oklahoma City, OK, USA] (IPN), Institute for Maternal and Child Health - IRCCS 'Burlo Garofolo' [Trieste], Keio University School of Medicine [Tokyo, Japan], Columbia University [New York], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Dupuis, Christine, Voisin, N., Schnur, R. E., Douzgou, S., Hiatt, S. M., Rustad, C. F., Brown, N. J., Earl, D. L., Keren, B., Levchenko, O., Geuer, S., Verheyen, S., Johnson, D., Zarate, Y. A., Hancarova, M., Amor, D. J., Bebin, E. M., Blatterer, J., Brusco, A., Cappuccio, G., Charrow, J., Chatron, N., Cooper, G. M., Courtin, T., Dadali, E., Delafontaine, J., Del Giudice, E., Doco, M., Douglas, G., Eisenkolbl, A., Funari, T., Giannuzzi, G., Gruber-Sedlmayr, U., Guex, N., Heron, D., Holla, O. L., Hurst, A. C. E., Juusola, J., Kronn, D., Lavrov, A., Lee, C., Lorrain, S., Merckoll, E., Mikhaleva, A., Norman, J., Pradervand, S., Prchalova, D., Rhodes, L., Sanders, V. R., Sedlacek, Z., Seebacher, H. A., Sellars, E. A., Sirchia, F., Takenouchi, T., Tanaka, A. J., Taska-Tench, H., Tonne, E., Tveten, K., Vitiello, G., Vlckova, M., Uehara, T., Nava, C., Yalcin, B., Kosaki, K., Donnai, D., Mundlos, S., Brunetti Pierri, N., Chung, W. K., and Reymond, A.

Subjects
Male, Models, Molecular, Hypertrichosis, [SDV]Life Sciences [q-bio], Mesomelic Dysplasia, Transcriptome, Mice, Gene Frequency, Missense mutation, Child, Zebrafish, Genetics (clinical), Genetics, Brain Diseases, 0303 health sciences, biology, Protein Stability, 030305 genetics & heredity, AFF3, AFF4, horseshoe kidney, intellectual disability, mesomelic dysplasia, Nuclear Proteins, Syndrome, Phenotype, Ubiquitin ligase, [SDV] Life Sciences [q-bio], Child, Preschool, Female, Transcriptional Elongation Factors, Adolescent, Mutation, Missense, Osteochondrodysplasias, Article, Evolution, Molecular, Young Adult, 03 medical and health sciences, medicine, Animals, Humans, Amino Acid Sequence, Fused Kidney, 030304 developmental biology, Epilepsy, Infant, Horseshoe kidney, biology.organism_classification, medicine.disease, biology.protein
Abstract

International audience; The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3-and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.

Published
2021
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129. Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway

Author

Martin A. Weber, Louise Devisme, Przemyslaw Szafranski, Fernando Scaglia, Megan K. Dishop, Eric Bieth, Claire Beneteau, Bruce Bennetts, Chantal Missirian, David Mowat, Sébastien Küry, Mark H. Lipson, Jennifer N. Dines, Justyna A. Karolak, James R. Lupski, Iben Bache, Amanda S. Freed, Véronique Secq, Bertrand Isidor, Gwenaelle André, Linda Pons, Anne Chun Hui Tsai, Qian Liu, Maria Orsaria, Claudia Gonzaga-Jauregui, Francesco Vetrini, Wendy K. Chung, Nicolas Joram, Jelena Martinovic, Marie Vincent, Cornelius F. Boerkoel, Arie van Haeringen, Tina M. Bartell, Gail H. Deutsch, Olivier Pichon, John A. Phillips, Marie Denis-Musquer, Zeynep Tümer, Tomasz Gambin, Nicolas Chassaing, Thomas Besnard, Edwina J. Popek, Arnaud Molin, Andrew J. Gifford, Zeynep Coban Akdemir, Benjamin Cogné, Kathleen A. Leppig, Galen M. Schauer, Catherine Mercer, Catherine Ward-Melver, Chester W. Brown, Jean Michel Liet, Dominique Carles, Madeleine Joubert, Lara Chalabreysse, Cédric Le Caignec, Damien Sanlaville, Tiphaine Bihouée, Heather C Mefford, Jean P. Pfotenhauer, Pawel Stankiewicz, Massimiliano Don, Anna F. Lee, Jérémie Mortreux, Katrina M. Dipple, Florence Petit, Katie Golden-Grant, Stéphane Bézieau, Shalini N. Jhangiani, Dorothy K. Grange, Laurent Pasquier, Daryl A. Scott, Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biomolécules et biotechnologies végétales (BBV EA 2106), Université de Tours, Division of Genetic Medicine [Seattle], University of Washington [Seattle], Laboratoire de dynamique des systèmes neuroendocriniens, Institut National de la Santé et de la Recherche Médicale (INSERM), Copenhagen University Hospitals, Clinical genetic clinic, Copenhagen University Hospital, Service de Pathologie, Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Femme-Enfant-Adolescent, Service de foetopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Service d'anatomie pathologique, CHU Bordeaux [Bordeaux], Université Bordeaux Segalen - Bordeaux 2, Service de Génétique [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle de Pathologie, Centre de Biologie Pathologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Institut National de la Santé et de la Recherche Médicale (INSERM), service hospitalier d'anatomie et cytologie pathologique humaine, APHM, Marseille, Assistance Publique - Hôpitaux de Marseille (APHM), Laboratoire de génétique chromosomique [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence des anomalies du développement [Lyon], Hospices Civils de Lyon (HCL), Service de Génétique, Hospices Civils de Lyon (HCL)-Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Groupe Hospitalier Est, University of Missouri [Columbia], University of Missouri System, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Baylor College of Medicine (BCM), Baylor University, Poznan University of Medical Sciences [Poland] (PUMS), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Seattle Children’s Hospital, Institute of Mother and Child, Baylor College of Medecine, Kaiser Permanente, Phoenix Children's Hospital, Sydney Children's hospital, The University of Sydney, Prince of Wales Hospital, University of British Columbia (UBC), Akron Children's Hospital, University of Copenhagen = Københavns Universitet (UCPH), AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Lille, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Sant’Antonio General Hospital, Università degli Studi di Udine - University of Udine [Italie], Université de Lyon, The University of Tennessee Health Science Center [Memphis] (UTHSC), University of Colorado [Colorado Springs] (UCCS), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Regeneron Pharmaceuticals [Tarrytown], University of Missouri [Columbia] (Mizzou), University Hospital Southampton NHS Foundation Trust, Universiteit Leiden, University of Copenhagen = Københavns Universitet (KU), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), and Leiden University

Subjects
0301 basic medicine, Lung Diseases, Male, Pathology, Organogenesis, 030105 genetics & heredity, Fibroblast growth factor, T-box transcription factor 4, Infant, Newborn, Diseases, Lung, Genetics (clinical), lacrimoauriculodentodigital (LAAD) syndrome, respiratory system, Hypoplasia, 3. Good health, Pedigree, medicine.anatomical_structure, lung hypoplasia, Paternal Inheritance, Female, Maternal Inheritance, Signal Transduction, medicine.medical_specialty, DNA Copy Number Variations, 17q23.1q23.2 recurrent deletion, neonatal lung disease, Gestational Age, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 5p12 deletion, Genetics, medicine, Humans, Lung hypoplasia, Receptor, Fibroblast Growth Factor, Type 2, Enhancer, [SDV.GEN]Life Sciences [q-bio]/Genetics, FGF10, Infant, Newborn, medicine.disease, 030104 developmental biology, Gene Expression Regulation, Dysplasia, aplasia of lacrimal and salivary glands, T-Box Domain Proteins, Fibroblast Growth Factor 10
Abstract

International audience; Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping similar to 2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

Published
2019
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130. A comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum

Author

François Nosten, Amy J. Conway, Samantha J. Barnes, Chiara Andolina, Steven P. Maher, Richard Thomson-Luque, Naresh Singh, Alison Roth, Silas A. Davidson, David E. Lanar, Brice Campo, Swamy R. Adapa, Benoît. Witkowski, Victor Chaumeau, Ratawan Ubalee, Stefan H. I. Kappe, Mélanie Rouillier, Amélie Vantaux, Stephen A. Kaba, Sebastian A. Mikolajczak, John H. Adams, Rays H. Y. Jiang, Dennis E. Kyle, Malina A. Bakowski, Case W. McNamara, Noah Sather, Caitlin A. Cooper, University of South Florida [Tampa] (USF), University of Georgia [USA], Armed Forces Research Institute of Medical Sciences [Bangkok] (AFRIMS), University of Oxford [Oxford], Mahidol University [Bangkok], Walter Reed Army Institute of Research, Malaria Molecular Epidemiology, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), California Institute for Biomedical Research - calibr, Scripps Research Institute, Medicines for Malaria Venture [Geneva] (MMV), Seattle Children’s Hospital, and Funding support was provided by Bill and Melinda Gates Foundation (OPP1023643 to J.H.A., OPP1023601 to D.E.K), Medicines for Malaria Venture (RD/16/1082 and RD/15/022 to D.E.K., RD/2017/0042 to B.W. and A.V.), the Georgia Research Alliance (D.E.K.), and National Institutes of Health (R01AI064478, BAA-NIAID-DAIT-NIHAI2013164 to J.H.A.).

Subjects
0301 basic medicine, Science, 030231 tropical medicine, Plasmodium vivax, General Physics and Astronomy, MESH: Sporozoites, Parasite load, Article, General Biochemistry, Genetics and Molecular Biology, MESH: Hepatocytes, 03 medical and health sciences, 0302 clinical medicine, Immune system, parasitic diseases, medicine, MESH: Animals, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, lcsh:Science, MESH: Mice, MESH: Plasmodium falciparum, MESH: Schizonts, MESH: Humans, Multidisciplinary, biology, Drug discovery, MESH: Malaria, Falciparum, MESH: Malaria, Vivax, Plasmodium falciparum, General Chemistry, biology.organism_classification, medicine.disease, MESH: Antimalarials, Virology, MESH: Plasmodium vivax, 3. Good health, 030104 developmental biology, Ion homeostasis, Drug development, lcsh:Q, MESH: Disease Models, Animal, Malaria, MESH: Liver
Abstract

Malaria liver stages represent an ideal therapeutic target with a bottleneck in parasite load and reduced clinical symptoms; however, current in vitro pre-erythrocytic (PE) models for Plasmodium vivax and P. falciparum lack the efficiency necessary for rapid identification and effective evaluation of new vaccines and drugs, especially targeting late liver-stage development and hypnozoites. Herein we report the development of a 384-well plate culture system using commercially available materials, including cryopreserved primary human hepatocytes. Hepatocyte physiology is maintained for at least 30 days and supports development of P. vivax hypnozoites and complete maturation of P. vivax and P. falciparum schizonts. Our multimodal analysis in antimalarial therapeutic research identifies important PE inhibition mechanisms: immune antibodies against sporozoite surface proteins functionally inhibit liver stage development and ion homeostasis is essential for schizont and hypnozoite viability. This model can be implemented in laboratories in disease-endemic areas to accelerate vaccine and drug discovery research., Currently available platforms to study liver stage of Plasmodium species have limitations. Here, the authors show that primary human hepatocyte cultures in 384-well format support hypnozoite and other liver stage development and are suitable for drug and antibody screens.

Published
2018
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131. 794 Postzygotic dominant-negative mutations of RHOA cause a mosaic neuroectodermal syndrome

Author

V. Carmignac, Didier Bessis, Paul Kuentz, Arthur Sorlin, Yannis Duffourd, Laurence Faivre, Veronica A. Kinsler, S.S. Kholmanskikh, F. Faravelli, J.-B. Rivière, Satyamaanasa Polubothu, Pierre Vabres, William B. Dobyns, M. E. Ross, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Cornell University [New York], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Seattle Children's Hospital, and University College of London [London] (UCL)

Subjects
Genetics, 0303 health sciences, RHOA, biology, Dominant negative, Cell Biology, Dermatology, Gene Therapy, Biochemistry, 3. Good health, Genetic Disease, 03 medical and health sciences, 0302 clinical medicine, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, biology.protein, Gene Regulation, Molecular Biology, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, 030304 developmental biology
Abstract

IF 6.448 (2017); International audience

Published
2018
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132. De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

Author

Kury, S., Woerden, G.M. van, Besnard, T., Onori, M.P., Latypova, X., Towne, M.C., Cho, M.T., Prescott, T.E., Ploeg, M.A., Sanders, S., Stessman, H.A.F., Pujol, A., Distel, ben, Robak, L.A., Bernstein, J.A., Denomme-Pichon, A.S., Lesca, G., Sellars, E.A., Berg, J., Carre, W., Busk, O.L., Bon, B.W.M. van, Waugh, J.L., Deardorff, M., Hoganson, G.E., Bosanko, K.B., Johnson, D.S., Dabir, T., Holla, O.L., Sarkar, A., Tveten, K., Bellescize, J. de, Braathen, G.J., Terhal, P.A., Grange, D.K., Haeringen, A. van, Lam, C., Mirzaa, G., Burton, J., Bhoj, E.J., Douglas, J., Santani, A.B., Nesbitt, A.I., Helbig, K.L., Andrews, M.V., Begtrup, A., Tang, S., Gassen, K.L.I. van, Juusola, J., Foss, K., Enns, G.M., Moog, U., Hinderhofer, K., Paramasivam, N., Lincoln, S., Kusako, B.H., Lindenbaum, P., Charpentier, E., Nowak, C.B., Cherot, E., Simonet, T., Ruivenkamp, C.A.L., Hahn, S., Brownstein, C.A., Xia, F., Schmitt, S., Deb, W., Bonneau, D., Nizon, M., Quinquis, D., Chelly, J., Rudolf, G., Sanlaville, D., Parent, P., Gilbert-Dussardier, B., Toutain, A., Sutton, V.R., Thies, J., Peart-Vissers, L.E.L.M., Boisseau, P., Vincent, M., Grabrucker, A.M., Dubourg, C., Tan, W.H., Verbeek, N.E., Granzow, M., Santen, G.W.E., Shendure, J., Isidor, B., Pasquier, L., Redon, R., Yang, Y.P., State, M.W., Kleefstra, T., Cogne, B., Petrovski, S., Retterer, K., Eichler, E.E., Rosenfeld, J.A., Agrawal, P.B., Bezieau, S., Odent, S., Elgersma, Y., Mercier, S., Undiagnosed Dis Network, GEM HUGO, Deciphering Dev Dis Study, Service de génétique médicale [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Neuroscience [Rotterdam, the Netherlands], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Expertise Center for Neurodevelopmental Disorders [Rotterdam, the Netherlands] (ENCORE), Genomics Program and Division of Genetics [Boston, USA], Harvard Medical School [Boston] (HMS)-Boston Children's Hospital-The Manton Center for Orphan Disease Research, Gene Discovery Core [Boston, MA, USA] ( The Manton Center for Orphan Disease Research), Harvard Medical School [Boston] (HMS)-Boston Children's Hospital, GeneDx [Gaithersburg, MD, USA], Department of Medical Genetics [Skien, Norway], Telemark Hospital Trust [Skien, Norway], Department of Psychiatry [San Francisco, CA, USA], University of California [San Francisco] (UCSF), University of California-University of California, Department of Genome Sciences [Seattle] (GS), University of Washington [Seattle], Department of Pharmacology [Omaha, NE, USA], Creighton University Medical School [Omaha, NE, USA], Neurometabolic Diseases Laboratory [Barcelona, Spain], Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Centre for Biomedical Research on Rare Diseases [Barcelona, Spain] (CIBERER), Hospital Sant Joan de Déu [Barcelona], Institució Catalana de Recerca i Estudis Avançats (ICREA), Department of Medical Biochemistry [Amsterdam, the Netherlands] (Academic Medical Center), University of Amsterdam [Amsterdam] (UvA), Department of Molecular and Human Genetics [Houston, USA], Baylor College of Medecine, Department of Pediatrics [Stanford], Stanford Medicine, Stanford University-Stanford University, Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Service de Génétique [HCL, Lyon] (Centre de Référence des Anomalies du Développement), Hospices civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), 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), Section of Genetics and Metabolism [Little Rock, AR, USA], University of Arkansas for Medical Sciences (UAMS), Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Laboratoire de Génétique Moléculaire & Génomique [CHU Rennes], CHU Pontchaillou [Rennes], Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Pediatrics [Philadelphia, PA, USA] (Division of Genetics), Children’s Hospital of Philadelphia (CHOP ), Department of Pediatrics [Chicago, IL, USA] (College of Medicine), University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Sheffield Children's NHS Foundation Trust, Northern Ireland Regional Genetics Centre [Belfast, UK], Belfast City Hospital-Belfast Health and Social Care Trust, Nottingham Regional Genetics Service [Nottingham, UK], City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], Département d'Epilepsie, Sommeil et Neurophysiologie Pédiatrique [HCL, Lyon], Hospices Civils de Lyon (HCL), Department of Genetics [Utrecht, the Netherlands], University Medical Center [Utrecht], Department of Pediatrics [Saint Louis, MO, USA] (Division of Genetics and Genomic Medicine), Washington University in Saint Louis (WUSTL), Department of Clinical Genetics [Leiden, the Netherlands], Leiden University Medical Center (LUMC), Department of Pediatrics [Seattle, WA, USA] (Division of Genetic Medicine), University of Washington [Seattle]-Seattle Children’s Hospital, Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, The Center for Applied Genomics [Philadelphia, PA, USA], Division of Human Genetics [Philadelphia, PA, USA], Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA], University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA] (Perelman School of Medicine), Division of Clinical Genomics [Aliso Viejo, CA, USA], Ambry Genetics [Aliso Viejo, CA, USA], Division of Neurology [Philadelphia, PA, USA], Institute of Human Genetics [Heidelberg, Germany], Universität Heidelberg [Heidelberg], University of Heidelberg, Medical Faculty, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Service de Neurologie [CHU Strasbourg], Hôpital de Hautepierre [Strasbourg]-Centre Hospitalier Universitaire de Strasbourg (CHU de Strasbourg ), Département de génétique médicale en pédiatrie [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de Génétique [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de Génétique [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Department of Biological Sciences [Limerick, Ireland], University of Limerick (UL), Bernal Institute [Limerick, Ireland], Howard Hughes Medical Institute [Seattle], Howard Hughes Medical Institute (HHMI), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de Génétique Clinique [CHU Rennes] (Réseau de Génétique et Génomique Médicale), Hôpitaux Universitaires du Grand Ouest, The Wellcome Trust Sanger Institute [Cambridge], Department of Medicine [Melbourne, Australia], University of Melbourne-Austin Health, Division of Newborn Medicine [Boston, MA, USA], Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Neurosciences, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Univ Angers, Okina, University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), 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), Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], Universiteit Leiden-Universiteit Leiden, Department of Pediatrics [Seattle, WA, USA], University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, Universität Heidelberg [Heidelberg] = Heidelberg University, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Amsterdam Gastroenterology Endocrinology Metabolism, Medical Biochemistry, and Bernardo, Elizabeth

Subjects
0301 basic medicine, Male, de novo mutations, AMPAR, medicine.disease_cause, Inbred C57BL, Mice, 0302 clinical medicine, Intellectual disability, CAMK2A, Exome, Phosphorylation, Genetics (clinical), Genetics, Neurons, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Brain, Phenotype, NMDAR, intellectual disability, Female, Signal transduction, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Signal Transduction, Glutamic Acid, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Article, Cell Line, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Journal Article, Animals, Humans, Protein kinase A, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], synaptic plasticity, medicine.disease, Mice, Inbred C57BL, CAMK2, CAMK2B, 030104 developmental biology, HEK293 Cells, Synaptic plasticity, Calcium-Calmodulin-Dependent Protein Kinase Type 2, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Contains fulltext : 182539.pdf (Publisher’s version ) (Closed access) Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.

Published
2017
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133. A Unified Approach to Diffusion Direction Sensitive Slice Registration and 3-D DTI Reconstruction From Moving Fetal Brain Anatomy

Author

Mads Fogtmann, Teresa Chapman, Sharmishtaa Seshamani, Christopher D. Kroenke, Xi Cheng, Colin Studholme, Jakob Wilm, François Rousseau, Biomedical Image Computing Group, Department of Pediatrics, Bioengineering and Radiology (University of Washington) (BICG), Advanced Imaging Research Center, Portland, Department of Radiology (Seattle Children's Hospital), DTU Informatics, Technical University of Denmark [Lyngby] (DTU), Département lmage et Traitement Information (IMT Atlantique - ITI), IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Laboratoire de Traitement de l'Information Medicale (LaTIM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Rousseau, François, Danmarks Tekniske Universitet = Technical University of Denmark (DTU), IMT Atlantique (IMT Atlantique), and Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-IMT Atlantique (IMT Atlantique)

Subjects
Point spread function, [SPI] Engineering Sciences [physics], Computer science, Image registration, Iterative reconstruction, Article, 030218 nuclear medicine & medical imaging, Fetal brain, White matter, [SPI]Engineering Sciences [physics], 03 medical and health sciences, Fetus, Imaging, Three-Dimensional, 0302 clinical medicine, Pregnancy, Prenatal Diagnosis, Motion estimation, medicine, Humans, Computer vision, Electrical and Electronic Engineering, Image resolution, ComputingMilieux_MISCELLANEOUS, [SPI.SIGNAL] Engineering Sciences [physics]/Signal and Image processing, Radiological and Ultrasound Technology, medicine.diagnostic_test, business.industry, Orientation (computer vision), Brain, Magnetic resonance imaging, Anatomy, Computer Science Applications, Diffusion Tensor Imaging, medicine.anatomical_structure, Female, Artificial intelligence, Deconvolution, business, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Algorithms, 030217 neurology & neurosurgery, Software, Diffusion MRI, Interpolation
Abstract

This paper presents an approach to 3-D diffusion tensor image (DTI) reconstruction from multi-slice diffusion weighted (DW) magnetic resonance imaging acquisitions of the moving fetal brain. Motion scatters the slice measurements in the spatial and spherical diffusion domain with respect to the underlying anatomy. Previous image registration techniques have been described to estimate the between slice fetal head motion, allowing the reconstruction of 3D a diffusion estimate on a regular grid using interpolation. We propose Approach to Unified Diffusion Sensitive Slice Alignment and Reconstruction (AUDiSSAR) that explicitly formulates a process for diffusion direction sensitive DW-slice-to-DTI-volume alignment. This also incorporates image resolution modeling to iteratively deconvolve the effects of the imaging point spread function using the multiple views provided by thick slices acquired in different anatomical planes. The algorithm is implemented using a multi-resolution iterative scheme and multiple real and synthetic data are used to evaluate the performance of the technique. An accuracy experiment using synthetically created motion data of an adult head and an experiment using synthetic motion added to sedated fetal monkey dataset show a significant improvement in motion-trajectory estimation compared to current state-of-the-art approaches. The performance of the method is then evaluated on challenging but clinically typical in utero fetal scans of four different human cases, showing improved rendition of cortical anatomy and extraction of white matter tracts. While the experimental work focuses on DTI reconstruction (second-order tensor model), the proposed reconstruction framework can employ any 5-D diffusion volume model that can be represented by the spatial parameterizations of an orientation distribution function.

Published
2014
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134. Global Asthma Network survey suggests more national asthma strategies could reduce burden of asthma

Author

Abdullah Yousef, Omar Al Omari, Darren Dookeeram, Sanela Domuz Vujnovic, Jing-Long Huang, Kevin Mortimer, NEUSA WANDALSEN, Pascual Chiarella, Maria Cheraghi, William Checkley, Neil Pearce, Emilija Vlaski, Julia Warnberg, Sandra Nora González-Díaz, Gerald Haidinger, Guy Marks, Arzu Yorgancıoglu, Mehran Karimi, Evans Amukoye, Sergio Bonini, Andrei Shpakou, Stefania La Grutta, Stefano Bonini, Nuha El Sharif, Yue Leon GUO, Heather Zar, Roberto Garcia-Almaraz, AlessanRSS Reis, Department of Paediatrics: Child and Youth Health, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand, Skin and Allergy Hospital, Helsinki University Hospital, Finland, Selroos Medical Consulting (Semeco AB), Angelholm, Sweden, University of Auckland, Auckland, New Zealand, Joensuu, Finland, International Union Against Tuberculosis and Lung Disease (The Union), Paris, France, International Union Against Tuberculosis and Lung Disease (The Union), Taipei City, Taiwan, The Epidemiological Laboratory for Public Health and Research, Khartoum, Sudan, Virgen de la Arrixaca’ University Children’s Hospital, Murcia, Spain, University of Santiago de Chile (USACH), Santiago, Chile, University of New South Wales, Sydney, Australia, London School, of Hygiene and Tropical Medicine, London, United Kingdom, St George’s, University of London, London, United Kingdom, Mother Theresa University, Hospital of Tirana, Tiranë, Albania, CHU Mustapha, Wilaya of Algiers, Algeria, Saad Dahlab University, Blida, Algeria, Programa Provincial Asma Infantil de Mendoza, Mendoza, Argentina, Hospital San Bernardo, Salta, Argentina, Asthma and Allergy Foundation, Buenos Aires, Argentina, 'Arabkir' Joint Medical Centre, Yerevan, Armenia, Mater Children’s Hospital, Brisbane, Australia, Hunter Medical Research Institute and Newcastle Children’s Hospital, Newcastle, Australia, Adelaide University, Adelaide, Australia, Medical University Vienna, Urfahrumgebung, Austria, Children’s Hospital Schwarzach, Salzburg, Austria, Yanka Kupala State University of Grodno, Grodno, Belarus, University of Antwerp, Antwerp, Belgium, Université d’Abomey-Calavi, Cotonou, Benin, Department of Health, Santa Cruz, Bolivia, School of Applied Health Sciences, Prijedor, Bosnia and Herzegovina, Universidade Estadual de Feira de Santana, Feira de Santana, Brazil, Federal University of Minas Gerais, Belo Horizonte, Brazil, Instituto de Medicina Integral, Recife, Brazil, Universidad Federal, Porto Alegre, Brazil, Rio de Janeiro State University (UERJ), Rio de Janeiro, Brazil, Federal University of Pelotas, Pelotas, Brazil, Passo Fundo University, Passo Fundo, Brazil, University of Parana, Curitiba, Brazil, Universidade Federal de São Paulo, São Paulo South, Brazil, Faculdade de Medicina do ABC, Santo André, Brazil, University Hospital ‘Alexandrovska’, Medical University, Sofia, Bulgaria, Université Poly Technique-BOBO, Bobo-Dioulasso, Burkina Faso, University of Douala, Douala, Cameroon, Yaounde Jamot Hospital, Bafoussam, Cameroon, University of Saskatchewan, Saskatoon, Canada, University of Toronto, Ontario, Canada, Princess Elizabeth Hospital, Guernsey, United Kingdom, Universidad Austral de Chile, Valdivia, Chile, Training Hospital for Peking University, Beijing, China, Anhui Chest Hospital, Hefei, China, The Union, Tayuan, China, Fundación Santa Fe de Bogotá, Bogotá, Colombia, Universidad Industrial de Santander, Bucaramanga, Colombia, Universidad Libre de Cali, Cali, Colombia, University of Kinshasa, Kinshasa, Congo, University of Costa Rica, Costa Rica, Rijeka Clinical Hospital Centre, Rijeka, Croatia, Cyprus International Institute for Environmental & Public Health, Nicosia, Cyprus, University of Copenhagen, Copenhagen, Denmark, AXXIS-Med, ical Centre SEAICA, Quito, Ecuador, Universidad San Francisco de Quito, Esmeraldas, Ecuador, Cairo University, Cairo, Egypt, Ministry of Health, Alexandria, Egypt, Universidad Dr Jose Matias Delgado, San Salvador, El Salvador, Health Consultancy Centre, Mekelle, Ethiopia, The Faroese Hospital System, Faroe Islands, Ministry of Health, Suva, Fiji, Helsinki University Hospital, Helsinki, Finland, Medical School Saint-Antoine, West Marne, Créteil, France, Aix Marseille University, Marseille, France, University of Bordeaux, Bordeaux, France, Medical School Saint-Antoine, French Polynesia, Center of Allergy & Immunology, Tbilisi, Kutaisi, Georgia, Ludwig Maximilians University, Munich, Germany, Komfo Anokye Teaching Hospital (KATH), Kumasi, Ghana, FHI 360 Ghana Country Office, Accra, Ghana, National Kapodistrian University of Athens, Athens, Greece, University of Thessaloniki, Thessaloniki, Greece, Old Dominion University, Grenada, The Chinese University of Hong Kong, Hong Kong, University of Szeged, Szeged, Hungary, King George’s Medical University, Lucknow, India, Apollo Hospitals, Chennai, India, Institute of Child Health, Kolkata, India, KPC Medical College and Hospital, Kolkata, India, Consultant Pediatrician, Mumbai, India, P.D. Hinduja Hospital and Medical Research Centre, Mumbai, India, Indira Gandhi Institute of Child Health, Bangalore, India, Maharaja Agrasen Medical College, Bikaner, India, All India Institute, of Medical Sciences, New Delhi, India, Asthma Bhawan, Jaipur, India, Postgraduate Institute of Medical Education and Research, Chandigarh, India, Pushpagiri Medical College, Kottayam, India, Christian Medical College Hospital, Vellore, India, Padjajaran University, Bandung, Indonesia, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran, Shahid Sadoughi Medical University, Yazd, Iran, National Research Institute of Tuberculosis and Lung Diseases, Birjand, Bushehr, Rasht, Tehran, Zanjan, Iran, Royal College of Surgeons Medical School, Ireland, Israel Center for Disease Control, Israel, Via Ugo de Carolis 59, Ascoli Piceno, Italy, Rome E Health Authority, Roma, Italy, Institute of Biomedicine and Molecular Immunology, Palermo, Italy, Local Health Authority, Empoli, Italy, Azienda Provinciale per I Servizi Sanitari, Trento, Italy, University of the West Indies, Kingston, Jamaica, National Hospital Organization Fukuoka Hospital, Fukuoka, Japan, Dokkyo Medical University, Tochigi, Japan, Jordon University of Science and Technology, Amman, Jordan, Jerash University, Jerash, Jordan, Kenya Medical Research Institute (KEMRI), Nairobi, Kenya, Moi University College of Health Sciences, Eldoret, Kenya, University of Ulsan, Seoul, South Korea, Al-Amiri Hospital, Kuwait, Riga Stradins University, Riga, Latvia, Ministry of Health, Tripoli, Libyan Arab Jamahiriya, University Children’s Clinic, Skopje, North Macedonia, Liverpool School of Tropical Medicine, Blantyre, Malawi, University of Malaya, Klang Valley, Malaysia, Université de Bamako, Bamako, Mali, University of Malta, Malta, Hospital Infantil de México, Mexico City North, Mexico, Hospital Infantil de Tamaulipas, Ciudad Victoria, Mexico, Hospital Universitario, Monterrey, Mexico, Hospital Civil De Guadalajara Juan I Menchaca, Guadalajara, Mexico, Universidad Autonoma of San Luis Potosí, San Luis Potosí, Mexico, Centro de Investigacion de Enfermedades Alergicas y Respiratorias, Mexicali, Mexico, Universiteit Utrecht, Utrecht, Netherlands, Medical School Saint-Antoine, New Caledonia, France, Hawke’s Bay District Health Board, Hawke’s Bay, New Zealand, Massey University, Wellington, New Zealand, Waikato District Health Board, Waikato, New Zealand, University of Otago, Otago, New Zealand, Whakatane Hospital, Bay of Plenty, New Zealand, University of Otago, Christchurch, New Zealand, University National Autonomous of Nicaragua, Matagalpa, Nicaragua, Obafemi Awolowo University, Ife, Nigeria, University of Ibadan, Ibadan, Nigeria, Ahmad Sani Yariman Bakura Specialist Hospital, Gusau, Nigeria, University of Maiduguri Teaching Hospital, Maiduguri, Nigeria, Paelon Memorial Clinic, Lagos, Nigeria, Niue Foou Hosptial, Niue Island, Niue, Norwegian Institute of Public Health, Oslo, Tromsø, Norway, Sultan Qaboos University, Al-Khod, Oman, The Allergy & Asthma Institute, Islamabad, Pakistan, Ministry of Health, Palau, Al Quds University, North Gaza, Ramallah, Palestine, Hospital Materno Infantil Jose Domingo de Obaldia, David-Panamá, Panama, Johns Hopkins University, Tumbes, Puno, Peru, Universidad Peruana de Ciencias Aplicadas, UPC, Lima, Peru, Adventist Medical Center Manila, Metro Manila, Philippines, Jagiellonian University, Kraków, Poland, Hospital CUR Descobertas, Lisboa, Portugal, Medical School Saint-Antoine, Reunion Island, France, University of Medicine & Pharmacy IULIU Hatieganu, Cluj-Napoca, Romania, The Siberian State Medical University, Tomsk, Russian Federation, Novosibirsk State Medical University, Novosibirsk, Russian Federation, Moto’otua Hospital/National Health Services, Apia, Samoa, King Khaled University, Abha, Saudi Arabia, University of Dammam/King Fahd Hospital of the University, Alkhobar, Saudi Arabia, Université Cheikh Anta DIOP, Dakar, Senegal, Primary Health Care, Novi Sad, Serbia, The Health Centre of Indjija, Indjija, Serbia, Children’s Hospital for Lung Diseases and Tuberculosis, Belgrade, Serbia, Connaught Teaching Hospital, Freetown, Sierra Leone, National University of Singapore, Singapore, Singapore, University of Pretoria, Pretoria, South Africa, University of Pretoria, Polokwane, Ekurhuleni, South Africa, University of Cape Town, Cape Town, South Africa, Center Public Health Castellon, Castellón, Spain, Universidad Autonoma de Barcelona, Barcelona, Spain, Centro de Salud de La Ería, Asturias, Spain, ‘Virgen de la Arrixaca’ University Children’s Hospital, Cartagena, Spain, Universidad del País Vasco UPV/EHU, Bilbao, Spain, Donostia Hospital, San Sebastián, Spain, Fundacion Maria Jose Jove, La Coruña, Spain, Sección de Neumología y Alergia Infantil, Madrid, Spain, Valencia University-CIBERESP, Valencia, Spain, Servicio Andaluz de Salud, Sevilla, Spain, Delegation at Cadiz of Andalusian Regional Health Ministry, Cádiz, Spain, University of Málaga, Málaga, Spain, Central Chest Clinic Colombo, Colombo, Sri Lanka, Teaching Hospital Peradeniya, Peradeniya, Sri Lanka, Ministry of Health, Gadarif, Sudan, National Center for Research and Training in Chronic Respiratory Diseases-Tishreen University, Lattakia, Syrian Arab Republic, National Taiwan University, Tainan, Taiwan, Chang Gung University, Taipei, Taiwan, Chiang Mai University, Chiang Mai, Thailand, Prapokklao Hospital, Chantaburi, Thailand, Khon Kaen University, Khon Kaen, Thailand, Mahidol University, Bangkok, Thailand, Medical Research Council Unit, Fajara, Gambia, CHU Tokoin, Lome, Togo, Ministry of Health, Tokelau, Vaiola Hospital, Nuku’alofa, Tonga, Sangre Grande Hospital, Trinidad and Tobago, Abderrahmen Mami Hospital, Ariana, Tunisia, Celal Bayar University School of Medicine, Ankara, Turkey, Princess Margaret Hospital, Funafuti, Tuvalu, Mulago Hospital & Complex, Kampala, Uganda, Ivan Horbachevsky Ternopil State Medical University, Ternopil, Ukraine, University of Sharjah, Sharjah, United Arab Emirates, University of Birmingham and Heartlands Hospital, Birmingham, United Kingdom, Old Dominion University, Virginia, United States, Parkview Hospital, Fort Wayne, United States, Seattle Children’s Hospital, Seattle, United States, University of North Carolina at Chapel Hill, North Carolina, United States, Hospital Pereira Rossell, Montevideo, Uruguay, Vila Central Hospital, Port Vila, Vanuatu, University Medical Centre, Ho Chi Minh, Viet Nam, University Teaching Hospital, Lusaka, Zambia, and Ministry of Health and Child Care, Zimbabwe

Subjects
Pulmonary and Respiratory Medicine, Gerontology, Adult, Allergy, Immunology, Community Networks, Global Burden of Disease, 03 medical and health sciences, 0302 clinical medicine, Cost of Illness, Wheeze, Environmental health, Surveys and Questionnaires, Cost of illness, Prevalence, Immunology and Allergy, Medicine, Humans, 030212 general & internal medicine, Disease management (health), Child, Asthma, business.industry, Disease Management, General Medicine, medicine.disease, 3. Good health, respiratory tract diseases, 030228 respiratory system, medicine.symptom, business
Abstract

Background Several countries or regions within countries have an effective national asthma strategy resulting in a reduction of the large burden of asthma to individuals and society. There has been no systematic appraisal of the extent of national asthma strategies in the world. Methods The Global Asthma Network (GAN) undertook an email survey of 276 Principal Investigators of GAN centres in 120 countries, in 2013–2014. One of the questions was: “Has a national asthma strategy been developed in your country for the next five years? For children? For adults?”. Results Investigators in 112 (93.3%) countries answered this question. Of these, 26 (23.2%) reported having a national asthma strategy for children and 24 (21.4%) for adults; 22 (19.6%) countries had a strategy for both children and adults; 28 (25%) had a strategy for at least one age group. In countries with a high prevalence of current wheeze, strategies were significantly more common than in low prevalence countries (11/13 (85%) and 7/31 (22.6%) respectively, p Interpretation In 25% countries a national asthma strategy was reported. A large reduction in the global burden of asthma could be potentially achieved if more countries had an effective asthma strategy.

Published
2017

135. Accuracy of nasal nitric oxide measurement as a diagnostic test for primary ciliary dyskinesia a systematic review and meta-analysis

Author

Shapiro, A.J. and Josephson, M. and Rosenfeld, M. and Yilmaz, O. and Davis, S.D. and Polineni, D. and Guadagno, E. and Leigh, M.W. and Lavergne, V., Division of Pediatric Respiratory Medicine, Montreal Children's Hospital, McGill University, Health Centre Research Institute, 1001 Boulevard Décarie, BRC.5016, Montreal, QC H4A 3J1, Canada, Division of Pediatric Pulmonology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, United States, Division of Pediatric Pulmonology, Seattle Children's Hospital, Regional Medical Center, University of Washington, Seattle, WA, United States, Department of Pediatric Allergy and Pulmonology, Faculty of Medicine, Celal Bayar University, Manisa, Turkey, Section of Pediatric Pulmonology, Allergy and Sleep Medicine, Department of Pediatrics, Riley Children's Hospital, Indiana University, School of Medicine, Indianapolis, IN, United States, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Kansas, Kansas City, KS, United States, Medical Library, McConnell Resource Center, McGill University, Health Centre, Montreal, QC, Canada, Division of Pediatric Pulmonology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States, and Department of Medical Biology, Sacré-Coeur Hospital, University of Montreal, Montreal, QC, Canada

Abstract

Rationale: Primary ciliary dyskinesia (PCD) is a rare disorder causing chronic otosinopulmonary disease, generally diagnosed through evaluation of respiratory ciliary ultrastructure and/or genetic testing. Nasal nitric oxide (nNO) measurement is used as a PCD screening test because patients with PCD have lownNOlevels, but its value as a diagnostic test remains unknown. Objectives: To perform a systematic review to assess the utility of nNO measurement (index test) as a diagnostic tool compared with the reference standard of electron microscopy (EM) evaluation of ciliary defects and/or detection of biallelic mutations in PCD genes. Data Sources: Ten databases were searched for reference sources from database inception through July 29, 2016. Data Extraction: Study inclusion was limited to publications with rigorous nNO index testing, reference standard diagnostic testing with EM and/or genetics, and calculable diagnostic accuracy information for cooperative patients (generally >5 yr old) with high suspicion of PCD. Synthesis: Meta-analysis provided a summary estimate for sensitivity and specificity and a hierarchical summary receiver operating characteristic curve. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess study quality, and Grading of Recommendations Assessment, Development, and Evaluation was used to assess the certainty of evidence. In 12 study populations (1,344 patients comprising 514 with PCD and 830 without PCD), using a reference standard of EM alone or EM and/or genetic testing, summary sensitivity was 97.6% (92.7-99.2) and specificity was 96.0% (87.9-98.7), with a positive likelihood ratio of 24.3 (7.6-76.9), a negative likelihood ratio of 0.03 (0.01-0.08), and a diagnostic odds ratio of 956.8 (141.2-6481.5) for nNO measurements. After studies using EM alone as the reference standard were excluded, the seven studies using an extended reference standard of EM and/or genetic testing showed a summary sensitivity of nNO measurements of 96.3% (88.7-98.9) and specificity of 96.4% (85.1-99.2), with a positive likelihood ratio of 26.5 (5.9-119.1), a negative likelihood ratio of 0.04 (0.01-0.12), and a diagnostic odds ratio of 699.3 (67.4-7256.0). Certainty of the evidence was graded as moderate. Conclusions: nNO is a sensitive and specific test for PCD in cooperative patients (generally>5 yr old) with high clinical suspicion for this disease. With a moderate level of evidence, this meta-analysis confirms that nNO testing using velum closure maneuvers has diagnostic accuracy similar to EM and/or genetic testing for PCD when cystic fibrosis is ruled out. Thus, low nNO values accompanied by an appropriate clinical phenotype could be used as a diagnostic PCD test, though EM and/or genetics will continue to provide confirmatory information. Copyright © 2017 by the American Thoracic Society.

Published
2017

136. Evaluation of the fetal QT interval using non-invasive fetal ECG technology

Author

Joachim Behar, Julien Oster, Terrence Chun, Reza Sameni, Douglas Y. Mah, Gari D. Clifford, Alisa Niksch, Tingting Zhu, Jessica Harrop, Cassandre Tanner, James A Greenberg, Adam Wolfberg, Jay Ward, Department of Engineering Science [Oxford], Institute of Biomedical Engineering [Oxford] (IBME), University of Oxford-University of Oxford, Technion - Israel Institute of Technology [Haifa], Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Tufts University School of Medicine [Boston], Boston Children's Hospital, Seattle Children's Hospital, Brigham and Women's Hospital [Boston], College of electrical and computer engineering, Shiraz University (Shiraz University ), Mindchild Medical, Emory University [Atlanta, GA], UL, IADI, and University of Oxford [Oxford]-University of Oxford [Oxford]

Subjects
Mean squared error, Physiology, 0206 medical engineering, Biomedical Engineering, Biophysics, 02 engineering and technology, Signal-To-Noise Ratio, QT interval, 03 medical and health sciences, Electrocardiography, 0302 clinical medicine, Signal-to-noise ratio, Physiology (medical), Medicine, Humans, Fetal Monitoring, Fetus, 030219 obstetrics & reproductive medicine, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, business.industry, 020601 biomedical engineering, Term (time), Fetal ecg, medicine.anatomical_structure, Scalp, Feasibility Studies, Female, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Biomedical engineering
Abstract

International audience; Non-invasive fetal electrocardiography (NI-FECG) is a promising alternative continuous fetal monitoring method that has the potential to allow morphological analysis of the FECG. However, there are a number of challenges associated with the evaluation of morphological parameters from the NI-FECG, including low signal to noise ratio of the NI-FECG and methodological challenges for getting reference annotations and evaluating the accuracy of segmentation algorithms. This work aims to validate the measurement of the fetal QT interval in term laboring women using a NI-FECG electrocardiogram monitor. Fetal electrocardiogram data were recorded from 22 laboring women at term using the NI-FECG and an invasive fetal scalp electrode simultaneously. A total of 105 one-minute epochs were selected for analysis. Three pediatric electrophysiologists independently annotated individual waveforms and averaged waveforms from each epoch. The intervals measured on the averaged cycles taken from the NI-FECG and the fetal scalp electrode showed a close agreement; the root mean square error between all corresponding averaged NI-FECG and fetal scalp electrode beats was 13.6 ms, which is lower than the lowest adult root mean square error of 16.1 ms observed in related adult QT studies. These results provide evidence that NI-FECG technology enables accurate extraction of the fetal QT interval.

Published
2016
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137. Weaver Syndrome-Associated EZH2 Protein Variants Show Impaired Histone Methyltransferase Function in Vitro

Author

Ana S A Cohen, Valentina Milano, Natália Tkachenko, M I Van Allen, Damian B. Yap, Chieko Chijiwa, María A Ramos-Arroyo, M. E. Suzanne Lewis, Katelin N. Townsend, Margaret L. McKinnon, Mélanie Fradin, Colin J. D. Ross, Jieqing Xu, William B. Dobyns, William T. Gibson, David D. Weaver, University of British Columbia (UBC), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Institute for Health Research, Centro Hospitalar do Porto, Policlinico Universitario 'A. Gemelli', Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University of Washington [Seattle], Seattle Children's Hospital, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indiana University System-Indiana University System, Contract grant sponsors: Canadian Institutes of Health Research (CIHR MOP-119595) Government of Canada through the Canadian Institutes of Health Research. Grant Number: CIHR MOP-119595, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Jonchère, Laurent

Subjects
0301 basic medicine, Male, Histone methyltransferase activity, Mutant, macromolecular substances, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Craniofacial Abnormalities, 03 medical and health sciences, Histone H3, Genetics, medicine, Congenital Hypothyroidism, Humans, childhood cancer, Abnormalities, Multiple, Enhancer of Zeste Homolog 2 Protein, EZH2, Genetics (clinical), Research Articles, Weaver syndrome, H3K27, biology, histone methyltransferase, Infant, Newborn, Polycomb Repressive Complex 2, Infant, Methylation, Histone-Lysine N-Methyltransferase, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Histone methyltransferase, biology.protein, Histone Methyltransferases, Female, PRC2, Hand Deformities, Congenital, Research Article
Abstract

International audience; Weaver syndrome (WS) is a rare congenital disorder characterized by generalized overgrowth, macrocephaly, specific facial features, accelerated bone age, intellectual disability, and susceptibility to cancers. De novo mutations in the enhancer of zeste homolog 2 (EZH2) have been shown to cause WS. EZH2 is a histone methyltransferase that acts as the catalytic agent of the polycomb-repressive complex 2 (PRC2) to maintain gene repression via methylation of lysine 27 on histone H3 (H3K27). Functional studies investigating histone methyltransferase activity of mutant EZH2 from various cancers have been reported, while WS-associated mutations remain poorly characterized. To investigate the role of EZH2 in WS, we performed functional studies using artificially-assembled PRC2 complexes containing mutagenized human EZH2 that reflected the codon changes predicted from patients with WS. We found that WS-associated amino acid alterations reduce the histone methyltransferase function of EZH2 in this in vitro assay. Our results support the hypothesis that WS is caused by constitutional mutations in EZH2 that alter the histone methyltransferase function of PRC2. However, histone methyltransferase activities of different EZH2 variants do not appear to correlate directly with the phenotypic variability between WS patients and individuals with a common c.553G\textgreaterC (p.Asp185His) polymorphism in EZH2. This article is protected by copyright. All rights reserved

Published
2016
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138. Patch-based augmentation of Expectation-Maximization for brain MRI tissue segmentation at arbitrary age after premature birth

Author

Vann Chau, François Rousseau, Averi E. Kitsch, Colin Studholme, Kenneth J. Poskitt, Mengyuan Liu, Dennis W. W. Shaw, Steven P. Miller, Biomedical Image Computing Group, Department of Pediatrics, Bioengineering and Radiology (University of Washington) (BICG), Center for Brain and Mental Health (The Hospital for Sick Children), Department of Pediatrics (University of Toronto), Department of Pediatrics (University of British Columbia), Département Image et Traitement Information (ITI), Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne-Institut Mines-Télécom [Paris] (IMT), Laboratoire de Traitement de l'Information Medicale (LaTIM), Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Mines-Télécom [Paris] (IMT), and Department of Radiology (Seattle Children's Hospital)

Subjects
Male, Computer science, Cognitive Neuroscience, Neuroimaging, Brain tissue, Article, 030218 nuclear medicine & medical imaging, White matter, 03 medical and health sciences, 0302 clinical medicine, Atlas (anatomy), Expectation–maximization algorithm, medicine, Image Processing, Computer-Assisted, Humans, Segmentation, medicine.diagnostic_test, Tissue segmentation, business.industry, Infant, Newborn, Brain, Magnetic resonance imaging, Pattern recognition, Anatomy, medicine.disease, Magnetic Resonance Imaging, medicine.anatomical_structure, Neurology, Premature birth, Female, Artificial intelligence, business, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, 030217 neurology & neurosurgery, Algorithms, Infant, Premature
Abstract

International audience; Accurate automated tissue segmentation of premature neonatal magnetic resonance images is a crucial task for quantification of brain injury and its impact on early postnatal growth and later cognitive development. In such studies it is common for scans to be acquired shortly after birth or later during the hospital stay and therefore occur at arbitrary gestational ages during a period of rapid developmental change. It is important to be able to segment any of these scans with comparable accuracy. Previous work on brain tissue segmentation in premature neonates has focused on segmentation at specific ages. Here we look at solving the more general problem using adaptations of age specific atlas based methods and evaluate this using a unique manually traced database of high resolution images spanning 20 gestational weeks of development. We examine the complimentary strengths of age specific atlas-based Expectation-Maximization approaches and patch-based methods for this problem and explore the development of two new hybrid techniques, patch-based augmentation of Expectation-Maximization with weighted fusion and a spatial variability constrained patch search. The former approach seeks to combine the advantages of both atlas- and patch-based methods by learning from the performance of the two techniques across the brain anatomy at different developmental ages, while the latter technique aims to use anatomical variability maps learnt from atlas training data to locally constrain the patch-based search range. The proposed approaches were evaluated using leave-one-out cross-validation. Compared with the conventional age specific atlas-based segmentation and direct patch based segmentation, both new approaches demonstrate improved accuracy in the automated labeling of cortical gray matter, white matter, ventricles and sulcal cortical-spinal fluid regions, while maintaining comparable results in deep gray matter.

Published
2016
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139. Baraitser-Winter cerebrofrontofacial syndrome : Delineation of the spectrum in 42 cases

Author

Sara Osimani, Andrew E. Fry, Koenraad Devriendt, Débora Romeo Bertola, Marjan M. Nezarati, Han G. Brunner, Grazia M.S. Mancini, Jorge L. Juncos, Pirayeh Eftekhari, Nataliya Di Donato, Marjolijn C.J. Jongmans, Laurence Faivre, Gilles Morin, Małgorzata J.M. Nowaczyk, Didier Lacombe, Zeichi-Seide Roseli, Conny M. A. van Ravenswaaij, Daniela Melis, Julien Masliah-Planchon, William B. Dobyns, Alexander Hoischen, Hatice Koçak Eker, Marlies Kempers, Andreas Rump, Vera Uliana, Victoria Mok Siu, Fabienne Giuliano, Nicole Philip, Beate Albrecht, Omar A Abdul-Raman, Alain Verloes, Mirjam Klaus, Angela E. Lin, Massimiliano Rossi, Albert David, Bregje W.M. van Bon, Jeanette C. Ramer, Ludivine Templin, Séverine Drunat, Yves Sznajer, Vincent Procaccio, Jean-Baptiste Rivière, Mary Ella M Pierpont, Francesca Faravelli, Judith Allanson, Leina Guion Almeida, Daniela T. Pilz, Cristina Rusu, Nicolas Chassaing, Charles Marques Lourenço, Bruce H. Wainer, Valérie Drouin-Garraud, Hôpital Robert Debré, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Universitätsklinikum Carl Gustav Carus, Université Paris Diderot - Paris 7 (UPD7), Radboud University Medical Centre [Nijmegen, The Netherlands], University of Mississippi Medical Center (UMMC), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Children's Hospital of Eastern Ontario [Ottawa, Canada], Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre hospitalier universitaire de Nantes (CHU Nantes), University Hospital Gasthuisberg, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Rouen, Normandie Université (NU), Ospedale Galliera, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire de Nice (CHU Nice), University of São Paulo (USP), Emory University School of Medicine, Emory University [Atlanta, GA], CHU Bordeaux [Bordeaux], Massachusetts General Hospital [Boston], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Università degli studi di Napoli Federico II, University of Western Ontario (UWO), CHU Amiens-Picardie, McMaster University [Hamilton, Ontario], Pennsylvania State University (Penn State), Penn State System, Hôpital de la Timone [CHU - APHM] (TIMONE), University of Minnesota [MN, USA], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Cliniques Universitaires Saint-Luc [Bruxelles], University Hospital Groningen, University Hospital of Wales [Cardiff, UK], Seattle Children’s Hospital, Clinical Genetics, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Ethical, Legal, Social Issues in Genetics (ELSI), and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Subjects
Male, Microcephaly, Pathology, Craniofacial abnormality, [SDV]Life Sciences [q-bio], Medizin, GYRAL MALFORMATIONS, Craniofacial Abnormalities, FUNCTIONAL DIVERSITY, 0302 clinical medicine, Ptosis, Gene Order, Genetics(clinical), Hypertelorism, Non-U.S. Gov't, Child, Genetics (clinical), Arthrogryposis, Dystonia, 0303 health sciences, Research Support, Non-U.S. Gov't, Anatomy, 3. Good health, Phenotype, Child, Preschool, Female, medicine.symptom, Abnormalities, Multiple, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, medicine.medical_specialty, APPARENTLY UNDESCRIBED SYNDROME, Adolescent, Lissencephaly, Biology, Research Support, Article, 03 medical and health sciences, Young Adult, SDG 3 - Good Health and Well-being, medicine, Genetics, Journal Article, Humans, Abnormalities, Multiple, Preschool, 030304 developmental biology, SHALLOW ORBITS, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], GAMMA-ACTIN, Pachygyria, Facies, medicine.disease, IRIS COLOBOMA, Actins, BETA-ACTIN, Amino Acid Substitution, Genetic Loci, Mutation, FACIAL SYNDROME, 030217 neurology & neurosurgery, MENTAL-RETARDATION, GROWTH-RETARDATION
Abstract

International audience; Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode beta- and gamma-actins. We present detailed phenotypic descriptions and neuroimaging on 36 patients analyzed by our group and six cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33 ACTB). The major clinical anomalies are striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows. Iris or retinal coloboma is present in many cases, as is sensorineural deafness. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Reduction of shoulder girdle muscle bulk and progressive joint stiffness is common. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Progressive, severe dystonia was seen in one family. Intellectual disability and epilepsy are variable in severity and largely correlate with CNS anomalies. One patient developed acute lymphocytic leukemia, and another a cutaneous lymphoma, indicating that actinopathies may be cancer-predisposing disorders. Considering the multifaceted role of actins in cell physiology, we hypothesize that some clinical manifestations may be partially mutation specific. Baraitser-Winter cerebrofrontofacial syndrome is our suggested designation for this clinical entity.European Journal of Human Genetics advance online publication, 23 July 2014; doi:10.1038/ejhg.2014.95.

Published
2015
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140. Recombinant Erwinia asparaginase (JZP458) in ALL/LBL: complete follow-up of the Children's Oncology Group AALL1931 study.

Author

Maese L, Loh ML, Choi MR, Agarwal S, Aoki E, Liang Y, Lin T, Girgis S, Chen C, Roller S, Chandrasekaran V, Iannone R, Silverman LB, Raetz EA, and Rau RE

Subjects
Humans, Child, Child, Preschool, Female, Adolescent, Male, Follow-Up Studies, Infant, Antineoplastic Agents therapeutic use, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Asparaginase therapeutic use, Asparaginase adverse effects, Asparaginase administration & dosage, Erwinia enzymology, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Recombinant Proteins therapeutic use, Recombinant Proteins administration & dosage
Abstract

Abstract: Children's Oncology Group study AALL1931 investigated the efficacy and safety of recombinant Erwinia asparaginase (JZP458) in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma and hypersensitivity reactions/silent inactivation to Escherichia coli-derived asparaginases. Each pegylated Escherichia coli asparaginase dose remaining in a patient's treatment plan was replaced by intramuscular (IM) or IV JZP458 (6 doses) administered Monday/Wednesday/Friday (MWF). Three IM cohorts (1a [25 mg/m2 MWF], n = 33; 1b [37.5 mg/m2 MWF], n = 83; 1c [25/25/50 mg/m2 MWF], n = 51) and 1 IV cohort (25/25/50 mg/m2 MWF, n = 62) were evaluated. The proportion (95% confidence interval [CI]) of patients maintaining nadir serum asparaginase activity (NSAA) levels of ≥0.1 IU/mL at the last 72 (primary end point) and 48 hours during course 1 was 90% (95% CI, 81-98) and 96% (95% CI, 90-100) in IM cohort 1c, respectively, and 40% (95% CI, 26-54) and 90% (95% CI, 82-98) in the IV cohort. Population pharmacokinetic modeling results were comparable with observed data, predicting the vast majority of patients would maintain therapeutic NSAA levels when JZP458 is administered IM or IV 25 mg/m2 every 48 hours, or IM 25/25/50 mg/m2 MWF, or with mixed IM and IV administration (IV/IV/IM 25/25/50 mg/m2 MWF). Drug discontinuation occurred in 23% and 56% of patients in the IM and IV cohorts, respectively; 13% and 33% because of treatment-related adverse events (mainly allergic reactions and pancreatitis). JZP458 achieves therapeutic NSAA levels via multiple IM and IV dosing schedules based on combined observed and modeled data with a safety profile consistent with other asparaginases. This trial was registered at www.ClinicalTrials.gov as #NCT04145531., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Published
2025
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141. Spatial and spectral changes in cortical surface potentials during pinching versusthumb and index finger flexion.

Author

Kerezoudis P, Jensen MA, Huang H, Ojemann JG, Klassen BT, Ince NF, Hermes D, and Miller KJ

Subjects
Humans, Adult, Male, Female, Brain Mapping methods, Young Adult, Epilepsy physiopathology, Fingers physiology, Electrocorticography methods, Motor Cortex physiology, Movement physiology
Abstract

Electrocorticographic (ECoG) signals provide high-fidelity representations of sensorimotor cortex activation during contralateral hand movements. Understanding the relationship between independent and coordinated finger movements along with their corresponding ECoG signals is crucial for precise brain mapping and neural prosthetic development. We analyzed subdural ECoG signals from three adult epilepsy patients with subdural electrode arrays implanted for seizure foci identification. Patients performed a cue-based task consisting of thumb flexion, index finger flexion or a pinching movement of both fingers together. Broadband power changes were estimated using principal component analysis of the power spectrum. All patients showed significant increases in broadband power during each movement compared to rest. We created topological maps for each movement type on brain renderings and quantified spatial overlap between movement types using a resampling metric. Pinching exhibited the highest spatial overlap with index flexion, followed by superimposed index and thumb flexion, with the least overlap observed for thumb flexion alone. This analysis provides practical insights into the complex overlap of finger representations in the motor cortex during various movement types and may help guide more nuanced approaches to brain-computer interfaces and neural prosthetics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Published
2025
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142. Intracerebroventricular B7-H3-targeting CAR T cells for diffuse intrinsic pontine glioma: a phase 1 trial.

Author

Vitanza NA, Ronsley R, Choe M, Seidel K, Huang W, Rawlings-Rhea SD, Beam M, Steinmetzer L, Wilson AL, Brown C, Beebe A, Lindgren C, Gustafson JA, Wein A, Holtzclaw S, Hoeppner C, Goldstein HE, Browd SR, Hauptman JS, Lee A, Ojemann JG, Crotty EE, Leary SES, Perez FA, Wright JN, Alonso MM, Dun MD, Foster JB, Hurst D, Kong A, Thomsen A, Orentas RJ, Albert CM, Pinto N, Annesley C, Gardner RA, Ho O, Pattabhi S, Gust J, Wendler JP, Park JR, and Jensen MC

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a fatal central nervous system (CNS) tumor that confers a median survival of 11 months. As B7-H3 is expressed on pediatric CNS tumors, we conducted BrainChild-03, a single-center, dose-escalation phase 1 clinical trial of repetitive intracerebroventricular (ICV) dosing of B7-H3-targeting chimeric antigen receptor T cells (B7-H3 CAR T cells) for children with recurrent or refractory CNS tumors and DIPG. Here we report results from Arm C, restricted to patients with DIPG. The primary objectives were to assess feasibility and tolerability, which were both met. Secondary objectives included assessments of CAR T cell distribution and survival. A total of 23 patients with DIPG enrolled, and 21 were treated with repeated doses of ICV B7-H3 CAR T cells using intra-patient dose-escalation regimens without previous lymphodepletion. Concurrent tumor-directed therapy, including re-irradiation, was not allowed while on protocol therapy. We delivered a total of 253 ICV doses and established the highest planned dose regimen, DR4, which escalated up to 10 × 10 7 cells per dose, as the maximally tolerated dose regimen. Common adverse events included headache, fatigue and fever. There was one dose-limiting toxicity (intratumoral hemorrhage) during DR2. For all treated patients (n = 21), the median survival from their initial CAR T cell infusion was 10.7 months and the median survival from diagnosis was 19.8 months with 3 patients still alive at 44, 45 and 52 months from diagnosis. Ultimately, this completed first-in-human trial shows that repetitive ICV dosing of B7-H3 CAR T cells in pediatric and young adult patients with DIPG is tolerable, including multiyear repeated dosing, and may have clinical efficacy that warrants further investigation on a multisite phase 2 trial. ClinicalTrials.gov registration: NCT04185038 ., Competing Interests: Competing interests: N.A.V. holds equity in and serves as the Scientific Advisory Board Chair for BrainChild Bio, Inc. J.A.G. holds equity in BrainChild Bio, Inc. R.J.O. receives research support from Lentigen Technology, a Miltenyi Biotec company, and is a consultant for Umoja Biopharma. R.A.G. is an inventor and receives royalties on patents related to CAR T cell technologies that are licensed to Juno Therapeutics, a Bristol Myers Squibb company, and serves as a consultant to Moonlight Bio. M.C.J. holds equity in and is the Chief Scientific Officer of BrainChild Bio, Inc. M.C.J. holds equity in, is a Board Observer for and serves as a member of the Joint Steering Committee of Umoja Biopharma, Inc. N.A.V., J.A.G., J.B.F., J.R.P. and M.C.J. are inventors on issued and pending patents related to CAR T cell therapies. The other authors declare no competing interests., (© 2025. The Author(s).)

Published
2025
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143. Phosphoribosyl pyrophosphate synthetase 1 ( PRPS1 ) associated retinal degeneration: an international study.

Author

Uner OE, Elsharawi R, Reynolds M, Bacci GM, Bargiacchi S, Birch DG, Chen FK, Jain N, Heath Jeffery RC, Lamey TM, Mustafi D, da Palma MM, Sallum JMF, Torres Soto M, Jones K, Yang P, Pennesi ME, and Everett LA

Abstract

Introduction: Phosphoribosyl pyrophosphate synthetase 1 ( PRPS1 ) is an X-linked gene critical for nucleotide metabolism. Pathogenic PRPS1 variants cause three overlapping phenotypes: Arts syndrome (severe neurological disease), Charcot-Marie-Tooth type 5 [CMTX5] (peripheral neuropathy), and non-syndromic sensorineural hearing loss (SNHL). Each may be associated with retinal dystrophy. Multicenter phenotypic studies are limited., Methods: A multicenter retrospective clinical case series of 15 patients from 12 pedigrees with PRPS1 -associated retinal degeneration is presented., Results: Of 15 patients, 11 (73.3%) were female. Mean age of ocular disease onset was 8.5 years (range, 0.5-35 years). Many were diagnosed with Leber congenital amaurosis prior to genetic testing ( n = 5). Five patients had clinical diagnoses of CMTX5 and Arts syndrome, two had isolated ocular disease, and one was asymptomatic. Mean initial VA (LogMAR) was 0.74, 0.74, 0.83, and 0.85 for isolated ocular disease, CMTX5, Arts, and SNHL, respectively. Ten patients were hyperopic and eight had asymmetric VA. Macular atrophy ( n = 13), optic atrophy ( n = 13), bone spicules ( n = 10), and parafoveal outer retinal atrophy (n = 12) were common findings. Electroretinogram showed delayed and attenuated photopic and scotopic responses ( n = 10). Median follow-up of 2.9 years (range, 1.5-11.6 years) in six patients showed retinal disease progression in two patients., Discussion: PRPS1 -associated retinal degeneration predominantly manifests as a bilateral asymmetric cone and rod dystrophy, commonly associated with hyperopia and optic atrophy.

Published
2025
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144. CANAIRI: the Collaboration for Translational Artificial Intelligence Trials in healthcare.

Author

McCradden MD, London AJ, Gichoya JW, Sendak M, Erdman L, Stedman I, Oakden-Rayner L, Akrout I, Anderson JA, Farmer LA, Greer R, Goldenberg A, Ho Y, Joshi S, Louise J, Mamdani M, Mazwi ML, Mohamud A, Palmer LJ, Peperidis A, Pfohl SR, Rickard M, Semmler C, Singh K, Singh D, Soremekun S, Tikhomirov L, van der Vegt AH, Verspoor K, and Liu X

Abstract

Competing Interests: Competing interests: S.R.P. is an employee of Google and may own stock as a part of a standard compensation package.

Published
2025
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146. Concordance of whole-genome long-read sequencing with standard clinical testing for Prader-Willi and Angelman syndromes.

Author

Paschal CR, Zalusky MPG, Beck AE, Gillentine MA, Narayanan J, Damaraju N, Goffena J, Storz SHR, and Miller DE

Abstract

Current clinical testing approaches for individuals with suspected imprinting disorders are complex, often requiring multiple tests performed in a stepwise fashion to make a precise molecular diagnosis. We investigated whether whole-genome long-read sequencing (LRS) could be used as a single data source to simultaneously evaluate copy number variants (CNVs), single nucleotide variants (SNVs), structural variants (SVs), and differences in methylation in a cohort of individuals known to have either Prader-Willi or Angelman syndrome. We evaluated 25 individuals sequenced to an average depth of coverage of 36x on an Oxford Nanopore PromethION. A custom one-page report was generated that could be used to assess copy number, SNVs, and methylation patterns at select CpG sites within the 15q11.2-q13.1 region and prioritize candidate pathogenic variants in UBE3A. After training with three positive controls, three analysts blinded to the known clinical diagnosis arrived at the correct molecular diagnosis for 22 out of 22 cases (20 true positive, 2 negative controls). Our findings demonstrate the utility of LRS as a single, comprehensive data source for complex clinical testing, offering potential benefits such as reduced testing costs, increased diagnostic yield, and shorter turnaround times in the clinical laboratory., (Copyright © 2025. Published by Elsevier Inc.)

Published
2025
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147. ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip.

Author

Lee JJY, Tao R, You Z, Haldipur P, Erickson AW, Farooq H, Hendriske LD, Abeysundara N, Richman CM, Wang EY, Das Gupta N, Hadley J, Batts M, Mount CW, Wu X, Rasnitsyn A, Bailey S, Cavalli FMG, Morrissy S, Garzia L, Michealraj KA, Visvanathan A, Fong V, Palotta J, Suarez R, Livingston BG, Liu M, Luu B, Daniels C, Loukides J, Bendel A, French PJ, Kros JM, Korshunov A, Kool M, Chico Ponce de León F, Perezpeña-Diazconti M, Lach B, Singh SK, Leary SES, Cho BK, Kim SK, Wang KC, Lee JY, Tominaga T, Weiss WA, Phillips JJ, Dai S, Zadeh G, Saad AG, Bognár L, Klekner A, Pollack IF, Hamilton RL, Ra YS, Grajkowska WA, Perek-Polnik M, Thompson RC, Kenney AM, Cooper MK, Mack SC, Jabado N, Lupien M, Gallo M, Ramaswamy V, Suva ML, Suzuki H, Millen KJ, Huang LF, Northcott PA, and Taylor MD

Abstract

Transcription factors are frequent cancer driver genes, exhibiting noted specificity based on the precise cell of origin. We demonstrate that ZIC1 exhibits loss-of-function (LOF) somatic events in group 4 (G4) medulloblastoma through recurrent point mutations, subchromosomal deletions and mono-allelic epigenetic repression (60% of G4 medulloblastoma). In contrast, highly similar SHH medulloblastoma exhibits distinct and diametrically opposed gain-of-function mutations and copy number gains (20% of SHH medulloblastoma). Overexpression of ZIC1 suppresses the growth of group 3 medulloblastoma models, whereas it promotes the proliferation of SHH medulloblastoma precursor cells. SHH medulloblastoma ZIC1 mutants show increased activity versus wild-type ZIC1, whereas G4 medulloblastoma ZIC1 mutants exhibit LOF phenotypes. Distinct ZIC1 mutations affect cells of the rhombic lip in diametrically opposed ways, suggesting that ZIC1 is a critical developmental transcriptional regulator in both the normal and transformed rhombic lip and identifying ZIC1 as an exquisitely context-dependent driver gene in medulloblastoma., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Published
2025
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148. Factors associated with treatment response in chronic nonbacterial osteomyelitis at a single center: a retrospective cohort study.

Author

Nowicki KD, Rogers ND, Keeter CL, Donaldson NJ, Soep JB, and Zhao Y

Subjects
Humans, Retrospective Studies, Female, Male, Child, Child, Preschool, Chronic Disease, Treatment Outcome, Adolescent, Osteomyelitis drug therapy, Osteomyelitis diagnosis, Anti-Inflammatory Agents, Non-Steroidal therapeutic use
Abstract

Background: NSAIDs are commonly used as first line therapy in chronic nonbacterial osteomyelitis (CNO) but are not effective for all patients. The objective of this study was to identify clinical variables associated with NSAID monotherapy response versus requiring second-line medication in a single-center cohort of patients with CNO., Methods: The charts of children with CNO who attended a CNO clinic at a quaternary care center between 1/1/05 and 7/31/21 were retrospectively reviewed. Patients were divided into 3 groups: NSAID-short (NSAID monotherapy for 3 to < 7 months), NSAID-long (NSAID monotherapy for ≥ 7 months), or second-line treatment. Patients were also categorized by which bodily regions were affected by CNO. Multiple linear and logistic regression models were constructed to predict total NSAID monotherapy days and the odds of needing second-line treatment, respectively. These models were optimized using variable combinations that minimized multicollinearity and maximized predictive power, as indicated by minimized AIC values., Results: One-hundred-sixty-four patients fulfilled inclusion criteria. Thirty-two patients were in the NSAID-short group, 62 in the NSAID-long group, and 70 in the second-line treatment group. Comparing the two NSAID groups showed that patients with unifocal disease at diagnosis required 47% fewer days of NSAIDs than those with multifocal disease. Results from logistic regression indicated that for each additional region affected, the odds of needing second line treatment increased by 1.94 times (p = 0.01) and that patients with symmetric bone lesions were 6.86 times more likely to require second-line treatment (p < 0.001)., Conclusions: Patients with unifocal CNO involvement at diagnosis were more likely to require shorter NSAID treatment. Patients with more regions affected and those with symmetric bone lesions were more likely to require second-line treatment., Competing Interests: Declarations. Ethics approval and consent to participate: This retrospective chart review study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Institutional Review Board of record of records, the Colorado Multiple Institutional Review Board (COMIRB) approved the collection of data for this study (#12–1557 and #13–0099). Informed consent and assent were obtained from all individual participants enrolled in this study after January 1, 2018 as data was collected prospectively (although prospective data was not included in this report), but consent was waived for those patients enrolled prior to January 1, 2018 given the retrospective nature of data collection for these patients. Consent for publication: Not applicable. Competing interests: YD received research funding from Bristol-Myers Squibb, Rheumatology Research Foundation, Consortium for Technology & Innovation in Pediatrics, Childhood Arthritis & Rheumatology Research Alliance, royalties from UpToDate and consulting fees from Novartis in 2020., (© 2025. The Author(s).)

Published
2025
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149. Developing Benchmarking Metrics for Appropriate Ordering of Vitamin D, Thyroid Testing, and Iron Workups.

Author

Liao HC, Saitman A, and Dickerson J

Subjects
Humans, Pilot Projects, Thyrotropin blood, Thyrotropin analysis, Thyroxine blood, Benchmarking, Vitamin D blood, Vitamin D analogs & derivatives, Thyroid Function Tests standards, Thyroid Function Tests statistics & numerical data, Thyroid Function Tests methods, Iron blood, Iron administration & dosage
Abstract

Background: Laboratory stewardship programs are increasingly adopted to enhance test utilization and improve patient care. Despite their potential, implementation within complex healthcare systems remains challenging. Benchmarking metrics helps institutions compare their performance against peers or best practices. However, the application in laboratory stewardship is underrepresented in the literature., Methods: The PLUGS (Patient-centered Laboratory Utiliazation Guidance Services) Informatics Working Group developed guidelines to address common test utilization issues. Metrics were based on data that are easily retrievable and calculable. Three key benchmarks were chosen for a pilot study: the ratio of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D test orders, the ratio of thyroid-stimulating hormone (TSH) to free thyroxine (FT4) test orders, and the percentage of iron workup orders after an initial low mean corpuscular volume (MCV). Institutions analyzed their own data and we established optimal benchmarks through inter-laboratory comparisons., Results: Nine laboratories evaluated vitamin D testing, with 2 implementing stewardship interventions beforehand. A benchmark of 50:1 was established, where a higher ratio indicates intentional ordering of 1,25-dihydroxyvitamin D. Nine laboratories evaluated thyroid testing, with 3 implementing interventions. The benchmark of 3.5:1 was established, with a higher ratio suggesting judicious TSH ordering. Seven laboratories evaluated iron workups, proposing a benchmark of 50% as a starting metric. Intervention guidelines were provided for laboratories below the benchmarks to promote improvement., Conclusions: Benchmarking metrics provide a standardized framework for assessing and enhancing test utilization practices across multiple laboratories. Continued collaboration and refinement of benchmarking methodologies is essential in maximizing the impact of laboratory stewardship programs on patient safety and resource utilization., (© Association for Diagnostics & Laboratory Medicine 2025. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Published
2025
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150. Financial Analytics for Laboratory Stewardship: Using Data and Informatics to Increase Financial Returns for Labs and Decrease Financial Harm to Patients.

Author

Ibrahim KA and Astion ML

Subjects
Humans, Clinical Laboratory Services economics, Clinical Laboratory Services organization & administration, Clinical Laboratory Services statistics & numerical data, Laboratories, Clinical
Abstract

Background: As clinical laboratories struggle to maintain their financial footing and as patients face mounting out-of-pocket expenses for diagnostic testing, being able to perform financial analysis of laboratory stewardship efforts has become an increasingly important skill., Content: Understanding the revenue cycle as it relates to diagnostic testing is fundamental to selecting, designing, implementing, and evaluating laboratory stewardship interventions for maximum financial return. Leveraging the data and processes driving the revenue cycle can inform informatics-based interventions (such as clinical decision support) and allow deliberate financial analyses of stewardship-focused projects. For labs striving not only to ensure their own financial health but also to help their patients avoid financial toxicity, the most effective strategies often depend on developing productive partnerships with key players along the revenue cycle., Summary: Financial laboratory analytics is an emerging skill set that can power laboratory stewardship efforts and whose benefits accrue to patients, clinicians, laboratories, and health systems., (© Association for Diagnostics & Laboratory Medicine 2025. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Published
2025
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