Innate immune activity as a predictor of persistent insulin secretion and association with responsiveness to CTLA4-Ig treatment in recent-onset type 1 diabetes.

AIMS/HYPOTHESIS: The study aimed to determine whether discrete subtypes of type 1 diabetes exist, based on immunoregulatory profiles at clinical onset, as this has significant implications for disease treatment and prevention as well as the design and analysis of clinical trials. METHODS: Using a plasma-based transcriptional bioassay and a gene-ontology-based scoring algorithm, we examined local participants from the Children's Hospital of Wisconsin and conducted an ancillary analysis of TrialNet CTLA4-Ig trial (TN-09) participants. RESULTS: The inflammatory/regulatory balance measured during the post-onset period was highly variable. Notably, a significant inverse relationship was identified between baseline innate inflammatory activity and stimulated C-peptide AUC measured at 3, 6, 12, 18 and 24 months post onset among placebo-treated individuals (p ≤ 0.015). Further, duration of persistent insulin secretion was negatively related to baseline inflammation (p ≤ 0.012) and positively associated with baseline abundance of circulating activated regulatory T cells (CD4+/CD45RA-/FOXP3high; p = 0.016). Based on these findings, data from participants treated with CTLA4-Ig were stratified by inflammatory activity at onset; in this way, we identified pathways and transcripts consistent with inhibition of T cell activation and enhanced immunoregulation. Variance among baseline plasma-induced signatures of TN-09 participants was further examined with weighted gene co-expression network analysis and related to clinical metrics. Four age-independent subgroups were identified that differed in terms of baseline innate inflammatory/regulatory bias, rate of C-peptide decline and response to CTLA4-Ig treatment. CONCLUSIONS/INTERPRETATION: These data support the existence of multiple type 1 diabetes subtypes characterised by varying levels of baseline innate inflammation that are associated with the rate of C-peptide decline. DATA AVAILABILITY: Gene expression data files are publicly available through the National Center for Biotechnology Information Gene Expression Omnibus (accession number GSE102234).

Assessing the Diagnostic Accuracy of TI-RADS in Pediatric Thyroid Nodules: A Multi-institutional Review.

PURPOSE: Thyroid nodules are uncommon in children and adolescents but carry an increased risk of malignancy when present. The Thyroid Imaging Reporting and Data System (TI-RADS) is an adult-validated ultrasound-based risk assessment providing a prediction of malignant potential for thyroid nodules, thereby guiding recommendations for fine needle aspiration biopsy (FNAB). Minimal data exist regarding the applicability of TI-RADS to predict malignancy in pediatric thyroid nodules. This study aims to analyze the performance of TI-RADS for children and adolescents with thyroid nodules, hypothesizing that applying TI-RADS criteria would improve accuracy and reduce the number of recommended FNAB compared to American Thyroid Association (ATA) size criteria alone. METHODS: A multi-institutional retrospective analysis was conducted including patients ≤21 years with a thyroid nodule by sonographic thyroid imaging between 2015 and 2020. TI-RADS scores were assigned at each institution by a pediatric radiologist trained in thyroid imaging and TI-RADS criteria. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy of TI-RADS scoring were compared to existing ATA size-based recommendation for performing a FNAB. Accounting for relative size differences between adults and children, a novel PED TI-RADS category was developed and tested, recommending FNAB for thyroid nodules with a TI-RADS 3 and ≥ 1.5 cm, TI-RADS 4 and ≥ 1.0 cm, and TI-RADS 5 any feasible size. RESULTS: 291 nodules from 260 patients (median age 14.9 years, 78.8% female) were assessed using TI-RADS. Applying adult TI-RADS criteria resulted in recommendation of FNAB for 35.1% of nodules, in contrast to 76.6% recommended by ATA guidelines (p < 0.0001) (Table). Utilizing the adult TI-RADS score ≥3 as an FNAB indicator resulted in 100% sensitivity and 28.5% specificity, with 0 cases of missed malignant nodules on pathology. When novel PED TI-RADS criteria were applied, 88 patients would have been spared an unnecessary FNAB with improved sensitivity and accuracy over ATA criteria. CONCLUSIONS: The application of adult and PED TI-RADS scoring to thyroid nodules in pediatric patients enhances the accuracy of malignancy prediction compared to current American Thyroid Association size criteria alone. The utilization of PED TI-RADS scoring eliminated unnecessary biopsies in many children while not missing a single thyroid malignancy. LEVEL OF EVIDENCE: Level III.