Thyroid Nodules on Ultrasound in Children and Young Adults: Comparison of Diagnostic Performance of Radiologists' Impressions, ACR TI-RADS, and a Deep Learning Algorithm.

BACKGROUND. In current clinical practice, thyroid nodules in children are generally evaluated on the basis of radiologists' overall impressions of ultrasound images. OBJECTIVE. The purpose of this article is to compare the diagnostic performance of radiologists' overall impression, the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS), and a deep learning algorithm in differentiating benign and malignant thyroid nodules on ultrasound in children and young adults. METHODS. This retrospective study included 139 patients (median age 17.5 years; 119 female patients, 20 male patients) evaluated from January 1, 2004, to September 18, 2020, who were 21 years old and younger with a thyroid nodule on ultrasound with definitive pathologic results from fine-needle aspiration and/or surgical excision to serve as the reference standard. A single nodule per patient was selected, and one transverse and one longitudinal image each of the nodules were extracted for further evaluation. Three radiologists independently characterized nodules on the basis of their overall impression (benign vs malignant) and ACR TI-RADS. A previously developed deep learning algorithm determined for each nodule a likelihood of malignancy, which was used to derive a risk level. Sensitivities and specificities for malignancy were calculated. Agreement was assessed using Cohen kappa coefficients. RESULTS. For radiologists' overall impression, sensitivity ranged from 32.1% to 75.0% (mean, 58.3%; 95% CI, 49.2-67.3%), and specificity ranged from 63.8% to 93.9% (mean, 79.9%; 95% CI, 73.8-85.7%). For ACR TI-RADS, sensitivity ranged from 82.1% to 87.5% (mean, 85.1%; 95% CI, 77.3-92.1%), and specificity ranged from 47.0% to 54.2% (mean, 50.6%; 95% CI, 41.4-59.8%). The deep learning algorithm had a sensitivity of 87.5% (95% CI, 78.3-95.5%) and specificity of 36.1% (95% CI, 25.6-46.8%). Interobserver agreement among pairwise combinations of readers, expressed as kappa, for overall impression was 0.227-0.472 and for ACR TI-RADS was 0.597-0.643. CONCLUSION. Both ACR TI-RADS and the deep learning algorithm had higher sensitivity albeit lower specificity compared with overall impressions. The deep learning algorithm had similar sensitivity but lower specificity than ACR TI-RADS. Interobserver agreement was higher for ACR TI-RADS than for overall impressions. CLINICAL IMPACT. ACR TI-RADS and the deep learning algorithm may serve as potential alternative strategies for guiding decisions to perform fine-needle aspiration of thyroid nodules in children.

Role of GLP-1 Receptor Agonists in Pediatric Obesity: Benefits, Risks, and Approaches to Patient Selection.

PURPOSE OF REVIEW: Effective treatments for pediatric obesity are limited. Glucagon-like peptide-1 receptor (GLP-1R) agonists have emerged as therapeutic agents for obesity in adults and have shown benefits outside of weight loss. Here we explore the evidence for GLP-1R agonist use in pediatric obesity. RECENT FINDINGS: Emerging evidence suggests that GLP-1R agonists have a role in pediatric obesity treatment. A recently published, randomized, placebo-controlled trial found a greater reduction in BMI z-score (- 0.22 SDs) in adolescents receiving liraglutide compared with placebo. As in adults, gastrointestinal adverse effects were commonly seen. GLP-1R agonists appear to perform favorably compared with other approved pharmacological agents for pediatric obesity. However, heterogeneity in weight loss response, cost, side effects, and need for injections may limit their use in many pediatric patients. Rather than broadly applying this therapy if it is approved, we suggest careful patient selection and monitoring by clinicians pending further studies.

Ghrelin regulation of glucose metabolism.

Ghrelin and its receptor, the growth hormone secretagogue receptor 1a (GHSR1a), are implicated in the regulation of glucose metabolism via direct actions in the pancreatic islet, as well as peripheral insulin-sensitive tissues and the brain. Although many studies have explored the role of ghrelin in glucose tolerance and insulin secretion, a complete mechanistic understanding remains to be clarified. This review highlights the local expression and function of ghrelin and GHSR1a in pancreatic islets and how this axis may modulate insulin secretion from pancreatic ß-cells. Additionally, we discuss the effect of ghrelin on in vivo glucose metabolism in rodents and humans, as well as the metabolic circumstances under which the action of ghrelin may predominate.

Interaction of GLP-1 and Ghrelin on Glucose Tolerance in Healthy Humans.

Emerging evidence supports the importance of ghrelin to defend against starvation-induced hypoglycemia. This effect may be mediated by inhibition of glucose-stimulated insulin secretion as well as reduced insulin sensitivity. However, administration of ghrelin during meal consumption also stimulates the release of glucagon-like peptide 1 (GLP-1), an incretin important in nutrient disposition. The objective of this study was to evaluate the interaction between ghrelin and GLP-1 on parameters of glucose tolerance following a mixed-nutrient meal. Fifteen healthy men and women completed the study. Each consumed a standard meal on four separate occasions with a superimposed infusion of 1) saline, 2) ghrelin, 3) the GLP-1 receptor antagonist exendin(9-39) (Ex9), or 4) combined ghrelin and Ex9. Similar to previous studies, infusion of ghrelin caused glucose intolerance, whereas Ex9 had a minimal effect. However, combined ghrelin and Ex9 resulted in greater postprandial glycemia than either alone, and this effect was associated with impaired ß-cell function and decreased glucose clearance. These findings suggest that in the fed state, stimulation of GLP-1 mitigates some of the effect of ghrelin on glucose tolerance. This novel interaction between gastrointestinal hormones suggests a system that balances insulin secretion and glucose disposal in the fed and fasting states.

Acute administration of acyl, but not desacyl ghrelin, decreases blood pressure in healthy humans.

OBJECTIVE: To compare the effects of acyl ghrelin (AG) and desacyl ghrelin (DAG) on blood pressure (BP), heart rate (HR) and other autonomic parameters in healthy humans and to elucidate the hormonal mechanisms through which AG could exert its cardiovascular effects. DESIGN: Seventeen healthy participants underwent frequent monitoring of systolic (sBP) and diastolic blood pressure (dBP), HR, respiratory rate (RR) and body surface temperature (Temp) during continuous infusion of AG, DAG, combined AG + DAG or saline control before and during an IV glucose tolerance test on 4 separate days. Plasma catecholamines, renin and aldosterone levels were also measured. Differences in outcome measures between treatment groups were assessed using mixed-model analysis. RESULTS: Compared to the saline control, AG and combined AG + DAG infusions decreased sBP, dBP, mean arterial blood pressure (MAP), HR and Temp. In contrast, DAG infusion did not alter BP, RR or Temp, but did decrease HR. The AG and AG + DAG infusions also raised plasma aldosterone levels compared to saline (P < 0.001) without affecting renin or catecholamine levels. CONCLUSIONS: The decrease in BP, HR, RR and Temp with AG infusion suggests mediation through the autonomic nervous system. The lack of response to DAG suggests that these autonomic effects require activation of the ghrelin receptor.

An intracellular role for ABCG1-mediated cholesterol transport in the regulated secretory pathway of mouse pancreatic beta cells.

Cholesterol is a critical component of cell membranes, and cellular cholesterol levels and distribution are tightly regulated in mammals. Recent evidence has revealed a critical role for pancreatic beta cell-specific cholesterol homeostasis in insulin secretion as well as in beta cell dysfunction in diabetes and the metabolic response to thiazolidinediones (TZDs), which are antidiabetic drugs. The ATP-binding cassette transporter G1 (ABCG1) has been shown to play a role in cholesterol efflux, but its role in beta cells is currently unknown. In other cell types, ABCG1 expression is downregulated in diabetes and upregulated by TZDs. Here we have demonstrated an intracellular role for ABCG1 in beta cells. Loss of ABCG1 expression impaired insulin secretion both in vivo and in vitro, but it had no effect on cellular cholesterol content or efflux. Subcellular localization studies showed the bulk of ABCG1 protein to be present in insulin granules. Loss of ABCG1 led to altered granule morphology and reduced granule cholesterol levels. Administration of exogenous cholesterol restored granule morphology and cholesterol content and rescued insulin secretion in ABCG1-deficient islets. These findings suggest that ABCG1 acts primarily to regulate subcellular cholesterol distribution in mouse beta cells. Furthermore, islet ABCG1 expression was reduced in diabetic mice and restored by TZDs, implicating a role for regulation of islet ABCG1 expression in diabetes pathogenesis and treatment.