ORCID Profile
0000-0002-8033-6078
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Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.BONE.2014.07.034
Abstract: Most patients with juvenile Paget's disease (JPD) are homozygous for mutations in the gene TNFRSF11B that result in deficiency of osteoprotegerin (OPG) - a key regulator of bone turnover. So far, about 10 different OPG mutations have been described. The current study presents two novel OPG mutations in JPD patients. Patient 1 was diagnosed at the age of 9months when he presented with inability to sit up, slow growth, marked bone pain and very high levels of serum alkaline phosphatase. Patient 2 presented a milder phenotype. He was initially diagnosed with osteogenesis imperfecta, and although he had numerous fractures and bone deformity, he was still independently mobile at the age of 19years, when a diagnosis of JPD was confirmed. Sequence analysis of DNA s les from the patients determined two novel homozygous mutations in TNFSRF11B. Patient 1 (severe phenotype) had a large (245-251kbp) homozygous deletion beginning in intron 1 that resulted in loss of 4 of the 5 exons of TNFSRF11B, including the whole ligand-binding domain. Patient 2 had a homozygous missense mutation resulting in a Thr>Pro change in exon 2 of TNFSRF11B that is predicted to disrupt the OPG ligand-binding domain. Taken in conjunction with other published cases, these results are consistent with the hypothesis that the most severe phenotypes in JPD are seen in patients with major gene deletions or mutations affecting cysteine residues in the ligand-binding domain.
Publisher: The Endocrine Society
Date: 02-2016
DOI: 10.1210/JC.2015-2175
Publisher: Cold Spring Harbor Laboratory
Date: 19-04-2023
DOI: 10.1101/2023.04.18.23288756
Abstract: Heterogeneity exists in type 1 diabetes (T1D) development and presentation. Islet autoantibodies form the foundation for T1D diagnostic and staging efforts. We hypothesized that autoantibodies can be used to identify heterogeneity in T1D before, at, and after diagnosis, and in response to disease modifying therapies. at clinically relevant timepoints throughout T1D progression. We performed a systematic review assessing 10 years of original research studies examining relationships between autoantibodies and heterogeneity during disease progression, at the time of diagnosis, after diagnosis, and in response to disease modifying therapies in in iduals at risk for T1D or within 1 year of T1D diagnosis. 10,067 papers were screened. Out of 151 that met data extraction criteria, 90 studies characterized heterogeneity before clinical diagnosis. Autoantibody type/target was most commonly examined, followed by autoantibody number, titer, order of seroconversion, affinity, and novel islet autoantibodies/epitopes. Recurring themes included positive relationships of autoantibody number and specific types and titers with disease progression, differing clinical phenotypes based on the order of autoantibody seroconversion, and interactions with age and genetics. Overall, reporting of autoantibody assay performance was commonly included however, only 43% (65/151) included information about autoantibody assay standardization efforts. Populations studied were almost exclusively of European ancestry. Current evidence most strongly supports the application of autoantibody features to more precisely define T1D before clinical diagnosis. Our findings support continued use of pre-clinical staging paradigms based on autoantibody number and suggest that additional autoantibody features, particularly when considered in relation to age and genetic risk, could offer more precise stratification. Increased participation in autoantibody standardization efforts is a critical step to improving future applicability of autoantibody-based precision medicine in T1D. We performed a systematic review to ascertain whether islet autoantibodies, biomarkers of autoimmunity against insulin-producing cells, could aid in stratifying in iduals with different clinical presentations of type 1 diabetes. We found existing evidence most strongly supporting the application of these biomarkers to the period before clinical diagnosis, when certain autoantibody features (number, type) and the age when they develop, can provide important information for patients and care providers on what to expect for future type 1 diabetes progression.
Publisher: American Diabetes Association
Date: 14-09-2023
DOI: 10.2337/DC23-1096
Publisher: American Diabetes Association
Date: 13-11-2013
DOI: 10.2337/DC13-1074
Abstract: To assess effectiveness of inpatient hybrid closed-loop control (HCLC) followed by outpatient sensor-augmented pump (SAP) therapy initiated within 7 days of diagnosis of type 1 diabetes on the preservation of β-cell function at 1 year. Sixty-eight in iduals (mean age 13.3 ± 5.7 years 35% female, 92% Caucasian) were randomized to HCLC followed by SAP therapy (intensive group N = 48) or to the usual-care group treated with multiple daily injections or insulin pump therapy (N = 20). Primary outcome was C-peptide concentrations during mixed-meal tolerance tests at 12 months. Intensive-group participants initiated HCLC a median of 6 days after diagnosis for a median duration of 71.3 h, during which median participant mean glucose concentration was 140 mg/dL (interquartile range 134–153 mg/dL). During outpatient SAP, continuous glucose monitor (CGM) use decreased over time, and at 12 months, only 33% of intensive participants averaged sensor use ≥6 days/week. In the usual-care group, insulin pump and CGM use were initiated prior to 12 months by 15 and 5 participants, respectively. Mean HbA1c levels were similar in both groups throughout the study. At 12 months, the geometric mean (95% CI) of C-peptide area under the curve was 0.43 (0.34–0.52) pmol/mL in the intensive group and 0.52 (0.32–0.75) pmol/mL in the usual-care group (P = 0.49). Thirty-seven (79%) intensive and 16 (80%) usual-care participants had a peak C-peptide concentration ≥0.2 pmol/mL (P = 0.30). In new-onset type 1 diabetes, HCLC followed by SAP therapy did not provide benefit in preserving β-cell function compared with current standards of care.
Publisher: Elsevier BV
Date: 08-2021
Publisher: Mary Ann Liebert Inc
Date: 02-2015
Publisher: Springer Science and Business Media LLC
Date: 25-11-2019
Publisher: Mary Ann Liebert Inc
Date: 02-2014
Publisher: American Medical Association (AMA)
Date: 21-11-2017
Publisher: American Society for Clinical Investigation
Date: 08-11-2021
Publisher: Hindawi Limited
Date: 12-2022
DOI: 10.1111/PEDI.13441
Publisher: Springer Science and Business Media LLC
Date: 10-2023
Publisher: American Society for Clinical Investigation
Date: 20-09-2018
Publisher: Hindawi Limited
Date: 10-2018
DOI: 10.1111/PEDI.12737
Publisher: Springer Science and Business Media LLC
Date: 05-10-2023
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.JOCD.2007.12.003
Abstract: Osteoporosis in adults has been defined on the basis of densitometric criteria, but at present the term osteoporosis does not have a widely recognized definition in pediatrics. Consequently, the International Society for Clinical Densitometry (ISCD) 2007 Position Development Conference reviewed the literature describing the relationship between bone densitometric studies and fractures in apparently healthy children and adolescents, and prepared Official Positions regarding the definition of osteoporosis in children and adolescents. The ISCD Official Positions with respect to the above issues, as well as the rationale and evidence used to derive these positions, are presented here.
Publisher: Springer Science and Business Media LLC
Date: 02-08-2021
DOI: 10.1007/S00125-021-05523-2
Abstract: Accurate prediction of disease progression in in iduals with pre-symptomatic type 1 diabetes has potential to prevent ketoacidosis and accelerate development of disease-modifying therapies. Current tools for predicting risk require multiple blood s les taken during an OGTT. Our aim was to develop and validate a simpler tool based on a single blood draw. Models to predict disease progression using a single OGTT time point (0, 30, 60, 90 or 120 min) were developed using TrialNet data collected from relatives with type 1 diabetes and validated in independent populations at high genetic risk of type 1 diabetes (TrialNet, Diabetes Prevention Trial–Type 1, The Environmental Determinants of Diabetes in the Young [1]) and in a general population of Bavarian children who participated in Fr1da. Cox proportional hazards models combining plasma glucose, C-peptide, sex, age, BMI, HbA 1c and insulinoma antigen-2 autoantibody status predicted disease progression in all populations. In TrialNet, the AUC for receiver operating characteristic curves for models named M 60 , M 90 and M 120 , based on s ling at 60, 90 and 120 min, was 0.760, 0.761 and 0.745, respectively. These were not significantly different from the AUC of 0.760 for the gold standard Diabetes Prevention Trial Risk Score, which requires five OGTT blood s les. In TEDDY, where only 120 min blood s ling had been performed, the M 120 AUC was 0.865. In Fr1da, the M 120 AUC of 0.742 was significantly greater than the M 60 AUC of 0.615. Prediction models based on a single OGTT blood draw accurately predict disease progression from stage 1 or 2 to stage 3 type 1 diabetes. The operational simplicity of M 120 , its validity across different at-risk populations and the requirement for 120 min s ling to stage type 1 diabetes suggest M 120 could be readily applied to decrease the cost and complexity of risk stratification.
Publisher: American Diabetes Association
Date: 17-12-2014
DOI: 10.2337/DC14-1813
Abstract: We assessed whether type 1 diabetes (T1D) can be diagnosed earlier using a new approach based on prediction and natural history in autoantibody-positive in iduals. Diabetes Prevention Trial–Type 1 (DPT-1) and TrialNet Natural History Study (TNNHS) participants were studied. A metabolic index, the T1D Diagnostic Index60 (Index60), was developed from 2-h oral glucose tolerance tests (OGTTs) using the log fasting C-peptide, 60-min C-peptide, and 60-min glucose. OGTTs with Index60 ≥2.00 and 2-h glucose & mg/dL (Ind60+Only) were compared with Index60 & .00 and 2-h glucose ≥200 mg/dL (2hglu+Only) OGTTs as criteria for T1D. In iduals were assessed for C-peptide loss from the first Ind60+Only OGTT to diagnosis. Areas under receiver operating characteristic curves were significantly higher for Index60 than for the 2-h glucose (P & 0.001 for both DPT-1 and the TNNHS). As a diagnostic criterion, sensitivity was higher for Ind60+Only than for 2hglu+Only (0.44 vs. 0.15 in DPT-1 0.26 vs. 0.17 in the TNNHS) OGTTs. Specificity was somewhat higher for 2hglu+Only OGTTs in DPT-1 (0.97 vs. 0.91) but equivalent in the TNNHS (0.98 for both). Positive and negative predictive values were higher for Ind60+Only OGTTs in both studies. Postchallenge C-peptide levels declined significantly at each OGTT time point from the first Ind60+Only OGTT to the time of standard diagnosis (range −22 to −34% in DPT-1 and −14 to −27% in the TNNHS). C-peptide and glucose patterns differed markedly between Ind60+Only and 2hglu+Only OGTTs. An approach based on prediction and natural history appears to have utility for diagnosing T1D.
Publisher: Hindawi Limited
Date: 09-2014
DOI: 10.1111/PEDI.12180
Publisher: Massachusetts Medical Society
Date: 15-08-2019
Publisher: American Diabetes Association
Date: 09-04-2019
DOI: 10.2337/DB19-0057
Abstract: A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test–stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P & 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.
Publisher: American Chemical Society (ACS)
Date: 22-08-2018
Publisher: Hindawi Limited
Date: 12-2022
DOI: 10.1111/PEDI.13455
Publisher: S. Karger AG
Date: 2016
DOI: 10.1159/000443136
Abstract: b i Background: /i /b Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. b i Evidence: /i /b A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describes the strength of the recommendation and the quality of supporting evidence. b i Process: /i /b Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. b i Results: /i /b This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. b i Conclusion: /i /b Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.
Publisher: Hindawi Limited
Date: 12-2022
DOI: 10.1111/PEDI.13452
No related grants have been discovered for Linda DiMeglio.