Browsing by Author "Russell, William E."

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    Barriers to Screening: An Analysis of Factors Impacting Screening for Type 1 Diabetes Prevention Trials
    (Oxford University Press, 2023-01-11) Kinney, Mara; You, Lu; Sims, Emily K.; Wherrett, Diane; Schatz, Desmond; Lord, Sandra; Krischer, Jeffrey; Russell, William E.; Gottlieb, Peter A.; Libman, Ingrid; Buckner, Jane; DiMeglio, Linda A.; Herold, Kevan C.; Steck, Andrea K.; Pediatrics, School of Medicine
    Context: Participants with stage 1 or 2 type 1 diabetes (T1D) qualify for prevention trials, but factors involved in screening for such trials are largely unknown. Objective: To identify factors associated with screening for T1D prevention trials. Methods: This study included TrialNet Pathway to Prevention participants who were eligible for a prevention trial: oral insulin (TN-07, TN-20), teplizumab (TN-10), abatacept (TN-18), and oral hydroxychloroquine (TN-22). Univariate and multivariate logistic regression models were used to examine participant, site, and study factors at the time of prevention trial accrual. Results: Screening rates for trials were: 50% for TN-07 (584 screened/1172 eligible), 9% for TN-10 (106/1249), 24% for TN-18 (313/1285), 17% for TN-20 (113/667), and 28% for TN-22 (371/1336). Younger age and male sex were associated with higher screening rates for prevention trials overall and for oral therapies. Participants with an offspring with T1D showed lower rates of screening for all trials and oral drug trials compared with participants with other first-degree relatives as probands. Site factors, including larger monitoring volume and US site vs international site, were associated with higher prevention trial screening rates. Conclusions: Clear differences exist between participants who screen for prevention trials and those who do not screen and between the research sites involved in prevention trial screening. Participant age, sex, and relationship to proband are significantly associated with prevention trial screening in addition to key site factors. Identifying these factors can facilitate strategic recruitment planning to support rapid and successful enrollment into prevention trials.
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    IL-6 receptor blockade does not slow β cell loss in new-onset type 1 diabetes
    (American Society for Clinical Investigation, 2021) Greenbaum, Carla J.; Serti, Elisavet; Lambert, Katharina; Weiner, Lia J.; Kanaparthi, Sai; Lord, Sandra; Gitelman, Stephen E.; Wilson, Darrell M.; Gaglia, Jason L.; Griffin, Kurt J.; Russell, William E.; Raskin, Philip; Moran, Antoinette; Willi, Steven M.; Tsalikian, Eva; DiMeglio, Linda A.; Herold, Kevan C.; Moore, Wayne V.; Goland, Robin; Harris, Mark; Craig, Maria E.; Schatz, Desmond A.; Baidal, David A.; Rodriguez, Henry; Utzschneider, Kristina M.; Nel, Hendrik J.; Soppe, Carol L.; Boyle, Karen D.; Cerosaletti, Karen; Keyes-Elstein, Lynette; Long, S. Alice; Thomas, Ranjeny; McNamara, James G.; Buckner, Jane H.; Sanda, Srinath; ITN058AI EXTEND Study Team; Pediatrics, School of Medicine
    Background: IL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual β cell function in newly diagnosed type 1 diabetes patients. Methods: We conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6–17 years). Results: There was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4+ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated. Conclusion: Tocilizumab reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual β cell function in newly diagnosed individuals with type 1 diabetes.
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    The risk of progression to type 1 diabetes is highly variable in individuals with multiple autoantibodies following screening
    (Springer Verlag, 2020-03) Jacobsen, Laura M.; Bocchino, Laura; Evans-Molina, Carmella; DiMeglio, Linda; Goland, Robin; Wilson, Darrell M.; Atkinson, Mark A.; Aye, Tandy; Russell, William E.; Wentworth, John M.; Boulware, David; Geyer, Susan; Sosenko, Jay M.; Medicine, School of Medicine
    Aims/hypothesis: Young children who develop multiple autoantibodies (mAbs) are at very high risk for type 1 diabetes. We assessed whether a population with mAbs detected by screening is also at very high risk, and how risk varies according to age, type of autoantibodies and metabolic status. Methods: Type 1 Diabetes TrialNet Pathway to Prevention participants with mAbs (n = 1815; age, 12.35 ± 9.39 years; range, 1-49 years) were analysed. Type 1 diabetes risk was assessed according to age, autoantibody type/number (insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA], insulinoma-associated antigen-2 autoantibodies [IA-2A] or zinc transporter 8 autoantibodies [ZnT8A]) and Index60 (composite measure of fasting C-peptide, 60 min glucose and 60 min C-peptide). Cox regression and cumulative incidence curves were utilised in this cohort study. Results: Age was inversely related to type 1 diabetes risk in those with mAbs (HR 0.97 [95% CI 0.96, 0.99]). Among participants with 2 autoantibodies, those with GADA had less risk (HR 0.35 [95% CI 0.22, 0.57]) and those with IA-2A had higher risk (HR 2.82 [95% CI 1.76, 4.51]) of type 1 diabetes. Those with IAA and GADA had only a 17% 5 year risk of type 1 diabetes. The risk was significantly lower for those with Index60 <1.0 (HR 0.23 [95% CI 0.19, 0.30]) vs those with Index60 values ≥1.0. Among the 12% (225/1815) ≥12.0 years of age with GADA positivity, IA-2A negativity and Index60 <1.0, the 5 year risk of type 1 diabetes was 8%. Conclusions/interpretation: Type 1 diabetes risk varies substantially according to age, autoantibody type and metabolic status in individuals screened for mAbs. An appreciable proportion of older children and adults with mAbs appear to have a low risk of progressing to type 1 diabetes at 5 years. With this knowledge, clinical trials of type 1 diabetes prevention can better target those most likely to progress.