OBJECTIVE There are variable reports of risk of concordance for progression to islet autoantibodies and type 1 diabetes in identical twins after one twin is diagnosed. We examined development of positive autoantibodies and type 1 diabetes and the effects of genetic factors and common environment on autoantibody positivity in identical twins, nonidentical twins, and full siblings. RESEARCH DESIGN AND METHODS Subjects from the TrialNet Pathway to Prevention Study (N = 48,026) were screened from 2004 to 2015 for islet autoantibodies (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A], and autoantibodies against insulin [IAA]). Of these subjects, 17,226 (157 identical twins, 283 nonidentical twins, and 16,786 full siblings) were followed for autoantibody positivity or type 1 diabetes for a median of 2.1 years. RESULTS At screening, identical twins were more likely to have positive GADA, IA-2A, and IAA than nonidentical twins or full siblings (all P < 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more positive autoantibodies, and two or more positive autoantibodies (all P ≤ 0.03). Initially autoantibody-positive identical twins had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody-negative identical twins. In nonidentical twins, type 1 diabetes risk by 3 years was 72% for initially multiple autoantibody–positive, 13% for single autoantibody–positive, and 0% for initially autoantibody-negative nonidentical twins. Full siblings had a 3-year type 1 diabetes risk of 47% for multiple autoantibody–positive, 12% for single autoantibody–positive, and 0.5% for initially autoantibody-negative subjects. CONCLUSIONS Risk of type 1 diabetes at 3 years is high for initially multiple and single autoantibody–positive identical twins and multiple autoantibody–positive nonidentical twins. Genetic predisposition, age, and male sex are significant risk factors for development of positive autoantibodies in twins.
Abstract Objective We set forth to compare ethnicities for metabolic and immunological characteristics at the clinical diagnosis of type 1 diabetes (T1D) and assess the effect of ethnicity on beta-cell functional loss within 3 years after clinical diagnosis. Research Methods and Design We studied participants in TrialNet New Onset Intervention Trials (n = 624, median age = 14.4 years, 58% male, 8.7% Hispanic) and followed them prospectively for 3 years. Mixed meal tolerance tests (MMTT) were performed within 6 months following clinical diagnosis and repeated semiannually. Unless otherwise indicated, analyses were adjusted for age, sex, BMI Z-score, and diabetes duration. Results At T1D clinical diagnosis, Hispanics, compared with non-Hispanic whites (NHW), had a higher frequency of diabetic ketoacidosis (DKA) (44.7% vs 25.3%, OR = 2.36, P = 0.01), lower fasting glucose (97 vs 109 mg/dL, P = 0.02) and higher fasting C-peptide (1.23 vs 0.94 ng/mL, P = 0.02) on the first MMTT, and higher frequency of ZnT8 autoantibody positivity (n = 201, 94.1% vs 64%, OR = 7.98, P = 0.05). After exclusion of participants in experimental arms of positive clinical trials, C-peptide area under the curve (AUC) trajectories during the first 3 years after clinical diagnosis were not significantly different between Hispanics and NHW after adjusting for age, sex, BMI-z score, and DKA (n = 413, P = 0.14). Conclusion Despite differences in the metabolic and immunological characteristics at clinical diagnosis of T1D between Hispanics and NHW, C-peptide trajectories did not differ significantly in the first 3 years following clinical diagnosis after adjustment for body mass index and other confounders. These findings may inform the design of observational studies and intervention trials in T1D.
OBJECTIVE We tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals. RESEARCH DESIGN AND METHODS We studied the 1,244 TrialNet Pathway to Prevention study participants (T1D patients’ relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median [range] age at initial autoantibody determination 11.1 years [1.2–51.8], 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic utility of T1D GRS, age, sex, Diabetes Prevention Trial–Type 1 (DPT-1) Risk Score, positive autoantibody number or type, HLA DR3/DR4-DQ8 status, and race/ethnicity. We used recursive partitioning analyses to identify cut points in continuous variables. RESULTS Higher T1D GRS significantly increased the rate of progression to T1D adjusting for DPT-1 Risk Score, age, number of positive autoantibodies, sex, and ethnicity (hazard ratio [HR] 1.29 for a 0.05 increase, 95% CI 1.06–1.6; P = 0.011). Progression to T1D was best predicted by a combined model with GRS, number of positive autoantibodies, DPT-1 Risk Score, and age (7-year time-integrated AUC = 0.79, 5-year AUC = 0.73). Higher GRS was significantly associated with increased progression rate from single to multiple positive autoantibodies after adjusting for age, autoantibody type, ethnicity, and sex (HR 2.27 for GRS >0.295, 95% CI 1.47–3.51; P = 0.0002). CONCLUSIONS The T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives.
351 Intravenous ganciclovir (GCV) can reduce the incidence and severity of symptomatic CMV disease after lung transplantation (LT), but is expensive and requires prolonged vascular access. We have initiated a pilot study to determine whether similar benefit can be achieved using oral GCV. Methods: Recipients with D+ and/or R+ CMV serology were included. All pts received IV GCV (5mg/kg bid, adjusted for cr) post-LT d 8-21 followed by oral GCV (1000 mg tid, adjusted for cr) post-LT d 22-90. These pts were compared to a historical controls (n=37) who received three times weekly (TIW) IV GCV for 90 d. post-LT between 1993-96. Primary endpoints were asymptomatic CMV shedding (+ CMV culture on surveillance BAL), CMV antigenemia, and CMV disease (signs/symptoms of systemic illness or pneumonitis, + CMV culture, no alternative diagnosis). Results: To date, 21 consecutive pts have begun oral GCV; 14 pts (4M/10F, age 46.1±11.8 yr.) are >90 d. post-LT and are included in this report. Mean time since LT is 6.5±1.6 mos. (Table) There were no significant differences between the oral GCV and TIW IV GCV groups at 180 d. after LT. CMV shedding, antigenemia, and disease were unusual during prophylaxis, but emerged after oral or IV GCV was stopped. After stopping oral GCV, 2 pts developed definite CMV syndrome and 1 possible CMV pneumonitis; in each case, improvement was seen with IV GCV treatment. Conclusions: Oral GCV suppresses CMV shedding and disease during rx. Results to date indicate that outcomes at 6 mos. after LT are similar for oral and IV GCV. As with IV GCV, CMV shedding and disease may be observed after oral GCV is stopped.Table
A leadership development initiative for managers in eight county human service organizations is described, followed by evaluation results from an ongoing study with six years of data. Multiple methods included surveys of participants and their supervisors using a time series design with post-program and 12-month follow-ups. Factors measured included program satisfaction, the acquisition of skills, and improved functioning in terms of leadership and management performance. Program graduates and their supervisors were asked the same questions regarding changes in the graduates' performance as managers. Results show high participant satisfaction, numerous opportunities to apply new knowledge, and improved on-the-job performance.
This chapter examines the construction of a 'Spanish' past in California between 1880 and 1930 – best exemplified by the mission church craze sparked by the popular 1884 novel Ramona – in the context of adaptation to US statehood. It argues that the state's history was 'de-Mexicanized' in part by the internal Anglo migrants who moved there, as well as the elite and increasingly dispossessed Californios, who often highlighted their whiteness as a way to preserve their status, as well as their land. Although romanticized Spanish myths remained popular, this chapter also considers the 're-Mexicanization' of space, this time in Olvera Street in 1920s Los Angeles, coming at a moment of rising immigration from Mexico, resulting in an invented Mexican village in the heart of a historically Mexican neighborhood.
