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Träfflista för sökning "WFRF:(Hagopian William) srt2:(2010-2014)"

Sökning: WFRF:(Hagopian William) > (2010-2014)

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1.
  • Hagopian, William A, et al. (författare)
  • The Environmental Determinants of Diabetes in the Young (TEDDY): genetic criteria and international diabetes risk screening of 421 000 infants.
  • 2011
  • Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X. ; 12, s. 733-743
  • Tidskriftsartikel (refereegranskat)abstract
    • Hagopian WA, Erlich H, Lernmark Å, Rewers M, Ziegler AG, Simell O, Akolkar B, Vogt Jr R, Blair A, Ilonen J, Krischer J, She J, and the TEDDY Study Group. The Environmental Determinants of Diabetes in the Young (TEDDY): genetic criteria and international diabetes risk screening of 421 000 infants. Aims: The Environmental Determinants of Diabetes in the Young (TEDDY) study seeks to identify environmental factors influencing the development of type 1 diabetes (T1D) using intensive follow-up of children at elevated genetic risk. This study requires a cost-effective yet accurate screening strategy to identify the high-risk cohort. Methods: The TEDDY cohort was identified through newborn screening using human leukocyte antigen (HLA) class II genes based on criteria established with pre-TEDDY data. HLA typing was completed at six international centers using different genotyping methods that can achieve >98% accuracy. Results: TEDDY developed separate inclusion criteria for the general population (GP) and first-degree relatives (FDRs) of T1D patients. The FDR eligibility includes nine haplogenotypes (DR3/4, DR4/4, DR4/8, DR3/3, DR4/4b, DR4/1, DR4/13, DR4/9, and DR3/9) for broad HLA diversity, whereas the GP eligibility includes only the first four haplogenotypes with DRB1*0403 as an exclusion allele. TEDDY has screened 414 714 GP infants, of which 19 906 (4.8%) were eligible, whereas 1415 of the 6333 screened FDR infants (22.2%) were eligible. High-resolution confirmation testing of the eligible subjects indicated that the low-cost and low-resolution genotyping techniques employed at the screening centers yielded an accuracy of 99%. There were considerable variations in eligibility rates among the centers for GP (3.5-7.4%) and FDR (19-32%) subjects. The eligibility rates among US ethnic groups were 0.9, 1.3, 5.0, and 6.9% for Asians, Black, Caucasians, and Hispanics, respectively. Conclusions: Different low-cost and low-resolution genotyping methods are useful for the efficient and accurate identification of a high-risk cohort for follow-up based on the TEDDY HLA inclusion criteria (ClinicalTrials.gov NCT00279318).
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2.
  • Hagopian, William, et al. (författare)
  • Teplizumab Preserves C-Peptide in Recent-Onset Type 1 Diabetes
  • 2013
  • Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 62:11, s. 3901-3908
  • Tidskriftsartikel (refereegranskat)abstract
    • Protege was a phase 3, randomized, double-blind, parallel, placebo-controlled 2-year study of three intravenous teplizumab dosing regimens, administered daily for 14 days at baseline and again after 26 weeks, in new-onset type 1 diabetes. We sought to determine efficacy and safety of teplizumab immunotherapy at 2 years and to identify characteristics associated with therapeutic response. Of 516 randomized patients, 513 were treated, and 462 completed 2 years of follow-up. Teplizumab (14-day full-dose) reduced the loss of C-peptide mean area under the curve (AUC), a prespecified secondary end point, at 2 years versus placebo. In analyses of prespecified and post hoc subsets at entry, U.S. residents, patients with C-peptide mean AUC andgt;0.2 nmol/L, those randomized 6 weeks after diagnosis, HbA(1c) andlt;7.5% (58 mmol/mol), insulin use andlt;0.4 units/kg/day, and 8-17 years of age each had greater teplizumab-associated C-peptide preservation than their counterparts. Exogenous insulin needs tended to be reduced versus placebo. Antidrug antibodies developed in some patients, without apparent change in drug efficacy. No new safety or tolerability issues were observed during year 2. In summary, anti-CD3 therapy reduced C-peptide loss 2 years after diagnosis using a tolerable dose.
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3.
  • Larsson, Helena, et al. (författare)
  • Children followed in the TEDDY study are diagnosed with type 1 diabetes at an early stage of disease.
  • 2014
  • Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X. ; 15:2, s. 118-126
  • Tidskriftsartikel (refereegranskat)abstract
    • The Environmental Determinants of Diabetes in the Young (TEDDY) study is designed to identify environmental exposures triggering islet autoimmunity and type 1 diabetes (T1D) in genetically high-risk children. We describe the first 100 participants diagnosed with T1D, hypothesizing that (i) they are diagnosed at an early stage of disease, (ii) a high proportion are diagnosed by an oral glucose tolerance test (OGTT), and (iii) risk for early T1D is related to country, population, human leukocyte antigen (HLA)-genotypes and immunological markers.
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4.
  • Liu, Edwin, et al. (författare)
  • Risk of pediatric celiac disease according to HLA haplotype and country.
  • 2014
  • Ingår i: New England Journal of Medicine. - 0028-4793. ; 371:1, s. 42-49
  • Tidskriftsartikel (refereegranskat)abstract
    • The presence of HLA haplotype DR3-DQ2 or DR4-DQ8 is associated with an increased risk of celiac disease. In addition, nearly all children with celiac disease have serum antibodies against tissue transglutaminase (tTG).
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5.
  • Sherry, Nicole, et al. (författare)
  • Teplizumab for treatment of type 1 diabetes (Protege study): 1-year results from a randomised, placebo-controlled trial
  • 2011
  • Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 378:9790, s. 487-497
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve beta-cell function and decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the safety and efficacy of one such antibody, teplizumab. less thanbrgreater than less thanbrgreater thanMethods In this 2-year trial, patients aged 8-35 years who had been diagnosed with type 1 diabetes for 12 weeks or fewer were enrolled and treated at 83 clinical centres in North America, Europe, Israel, and India. Participants were allocated (2:1:1:1 ratio) by an interactive telephone system, according to computer-generated block randomisation, to receive one of three regimens of teplizumab infusions (14-day full dose, 14-day low dose, or 6-day full dose) or placebo at baseline and at 26 weeks. The Protege study is still underway, and patients and study staff remain masked through to study closure. The primary composite outcome was the percentage of patients with insulin use of less than 0.5 U/kg per day and glycated haemoglobin A(1c) (HbA(1c)) of less than 6-5% at 1 year. Analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00385697. less thanbrgreater than less thanbrgreater thanFindings 763 patients were screened, of whom 516 were randomised to receive 14-day full-dose teplizumab (n=209), 14-day low-dose teplizumab (n=102), 6-day full-dose teplizumab (n=106), or placebo (n=99). Two patients in the 14-day full-dose group and one patient in the placebo group did not start treatment, so 513 patients were eligible for efficacy analyses. The primary outcome did not differ between groups at 1 year: 19.8% (41/207) in the 14-day full-dose group; 13.7% (14/102) in the 14-day low-dose group; 20.8% (22/106) in the 6-day full-dose group; and 20.4% (20/98) in the placebo group. 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p=0.03). Across the four study groups, similar proportions of patients had adverse events (414/417 [99%] in the teplizumab groups vs 98/99 [99%] in the placebo group) and serious adverse events (42/417 [10%] vs 9/99 [9%]). The most common clinical adverse event in the teplizumab groups was rash (220/417 [53%] vs 20/99 [20%] in the placebo group). less thanbrgreater than less thanbrgreater thanInterpretation Findings of exploratory analyses suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in beta-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children.
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6.
  • Skoglund, Camilla, 1977- (författare)
  • Autoantibodies related to type 1 diabetes in children
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Type 1 diabetes is an autoimmune disease resulting from destruction of the insulin producing beta cells in the pancreas. The patients need life-long heavy treatment and still complications, both acute and later in life, are common. The incidence of type 1 diabetes has increased rapidly during the last decades, especially among young children. The disease can be predicted by genes predisposing type 1 diabetes, mainly human leukocyte antigen (HLA) genes, together with presence of autoantibodies to beta-cell antigens, where multiple autoantibodies confer the highest risk. A number of immune system intervention trials are now ongoing aiming to halt the progression of the inflammatory process in the beta cells.This thesis aimed to investigate the prevalence and levels of autoantibodies in healthy children and in children with type 1 diabetes. Another aim was to study different properties of one of these autoantibodies, such as to which epitopes the antibodies bind and the distribution of immunoglobulin (Ig)-G subclasses, after immunomodulatory treatment in children with type 1 diabetes.We found that positivity to autoantibodies against glutamic acid decarboxylase (GADA) and tyrosine phosphatase like protein islet antigen-2 (IA-2A) was associated with HLA risk genotypes in 5-year old children from the general population. HLA risk genotypes seemed important for persistence of autoantibodies and for development of type 1 diabetes, while emergence of autoantibodies, especially transient autoantibodies, seemed to be more influenced by environmental factors. Improved methods for detection of autoantibodies are needed, for prediction of diabetes and for identification of high-risk individuals suitable for prevention treatments. Therefore, an assay for measurement of insulin autoantibodies (IAA), based on surface plasmon resonance (SPR), was developed. The main advantages of this method are that there is no need for labelling and that it is time-saving compared to the traditionally used radioimmunoassay (RIA), but further development of the method is needed.Treatment with GAD-alum (Diamyd) in children with type 1 diabetes has shown to preserve residual insulin secretion. This clinical effect was accompanied by an increase in GADA levels. We investigated the epitope reactivity of GADA in both GAD-alum and placebo treated children, and found that binding to one of the tested epitopes was temporarily increased after injection of GAD-alum. This result suggests that the quality of GADA was, to some extent, transiently affected by the treatment. On the other hand, no changes in binding to epitopes associated with stiff person syndrome (SPS) were observed, which together with the lack of change in GAD65 enzyme activity further strengthens the safety of the treatment. We also observed that the distribution of IgG subclasses was changed by GAD-alum treatment, with a lower proportion of IgG1 and higher IgG3 and IgG4. Lower IgG1 and higher IgG4 suggest a temporary switch towards a protective Th2 immune response, which has previously been observed in the same individuals for other immunological markers.In conclusion, measurement of autoantibodies related to type 1 diabetes is an important tool for studying the autoimmune process in pre-diabetic and type 1 diabetic children. In addition to the use as markers of disease progression, the autoantibodies may be used for studying the effects of immunomodulatory treatments on the humoral immune response.
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7.
  • Vehik, Kendra, et al. (författare)
  • Methods, quality control and specimen management in an international multicentre investigation of type 1 diabetes: TEDDY
  • 2013
  • Ingår i: Diabetes/Metabolism Research & Reviews. - : Wiley. - 1520-7552. ; 29:7, s. 557-567
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundThe vast array and quantity of longitudinal samples collected in The Environmental Determinants of Diabetes in the Young study present a series of challenges in terms of quality control procedures and data validity. To address this, pilot studies have been conducted to standardize and enhance both biospecimen collection and sample obtainment in terms of autoantibody collection, stool sample preservation, RNA, biomarker stability, metabolic biomarkers and T-cell viability. Research Design and MethodsThe Environmental Determinants of Diabetes in the Young is a multicentre, international prospective study (n=8677) designed to identify environmental triggers of type 1 diabetes (T1D) in genetically at-risk children from ages 3months until 15years. The study is conducted through six primary clinical centres located in four countries. ResultsAs of May 2012, over three million biological samples and 250 million total data points have been collected, which will be analysed to assess autoimmunity status, presence of inflammatory biomarkers, genetic factors, exposure to infectious agents, dietary biomarkers and other potentially important environmental exposures in relation to autoimmunity and progression to T1D. ConclusionsDetailed procedures were utilized to standardize both data harmonization and management when handling a large quantity of longitudinal samples obtained from multiple locations. In addition, a description of the available specimens is provided that serve as an invaluable repository for the elucidation of determinants in T1D focusing on autoantibody concordance and harmonization, transglutaminase autoantibody, inflammatory biomarkers (T-cells), genetic proficiency testing, RNA lab internal quality control testing, infectious agents (monitoring cross-contamination, virus preservation and nasal swab collection validity) and HbA(1c) testing. Copyright (c) 2013 John Wiley & Sons, Ltd.
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