Tandy Aye, MD

Abstract

CONTEXT: Executive dysfunction is a well-recognized component of the cognitive phenotype of Klinefelter syndrome (KS), yet the neural basis of KS-associated cognitive weaknesses, and their association with testicular failure is unknown.OBJECTIVE: We investigated executive function, brain activation and pubertal development in adolescents with and without KS.METHODS: Forty-three adolescents with KS (mean age 12.3 2.3 years) and 41 typically developing males (mean age 11.9 1.8 years) underwent pubertal evaluation, behavioral assessment and completed functional magnetic resonance imaging (fMRI) as they performed an executive function task, the go/no-go task. Group differences in activation were examined. Associations among activation, executive function and pubertal development measures were tested in secondary analyses.RESULTS: Males with KS exhibited reduced executive function, as well as lower activation in brain regions subserving executive function, including the inferior frontal gyrus, anterior insula, dorsal anterior cingulate cortex and caudate nucleus. Secondary analyses indicated that the magnitude of activation differences in males with KS was associated with severity of pubertal developmental delay, as indexed by lower testosterone (t(36) = 2.285, p = 0.028) and lower testes volume (t(36) = 2.238, p = 0.031). Greater parent-reported attention difficulties were additionally associated with lower testicular volume (t(36) = -2.028, p = 0.050).CONCLUSION: These findings indicate a neural basis for executive dysfunction in KS and suggest alterations in pubertal development may contribute to increased severity of this cognitive weakness. Future studies that examine whether these patterns change with testosterone replacement therapy are warranted.

View details for DOI 10.1210/clinem/dgad487

View details for PubMedID 37595261

Abstract

BACKGROUND AND OBJECTIVES: Autism spectrum disorder (ASD) and gender dysphoria (GD) frequently cooccur. However, existing research has primarily used smaller samples, limiting generalizability and the ability to assess further demographic variation. The purpose of this study was to (1) examine the prevalence of cooccurring ASD and GD diagnoses among US adolescents aged 9 to 18 and (2) identify demographic differences in the prevalence of cooccurring ASD and GD diagnoses.METHODS: This secondary analysis used data from the PEDSnet learning health system network of 8 pediatric hospital institutions. Analyses included descriptive statistics and adjusted mixed logistic regression testing for associations between ASD and GD diagnoses and interactions between ASD diagnosis and demographic characteristics in the association with GD diagnosis.RESULTS: Among 919898 patients, GD diagnosis was more prevalent among youth with an ASD diagnosis compared with youth without an ASD diagnosis (1.1% vs 0.6%), and adjusted regression revealed significantly greater odds of GD diagnosis among youth with an ASD diagnosis (adjusted odds ratio = 3.00, 95% confidence interval: 2.72-3.31). Cooccurring ASD/GD diagnoses were more prevalent among youth whose electronic medical record-reported sex was female and those using private insurance, and less prevalent among youth of color, particularly Black and Asian youth.CONCLUSIONS: Results indicate that youth whose electronic medical record-reported sex was female and those using private insurance are more likely, and youth of color are less likely, to have cooccurring ASD/GD diagnoses. This represents an important step toward building services and supports that reduce disparities in access to care and improve outcomes for youth with cooccurring ASD/GD and their families.

View details for DOI 10.1542/peds.2023-061363

View details for PubMedID 37395084

Abstract

While the field of pediatric endocrinology, and the American Board of Pediatrics, continues expanding training to include gender-affirming care, many pediatric endocrinology fellowship programs do not have formal curriculum for this patient population. Members of the Pediatric Endocrine Society (PES) that have a special interest in transgender health designed a curriculum based on Endocrine Society practice guidelines to expand the knowledge of gender affirming care for medical trainees' and faculty.PES members designed a 5-part self-guided educational module series with embedded knowledge questions. Uniquely, medical ethical reflections were included within each module. Participants completed baseline demographic and baseline and follow-up knowledge surveys.Most participants were pediatric endocrinology fellows and 44 % percent (n = 21) completed all study components, including the follow up knowledge survey. Knowledge question data analysis demonstrated knowledge gained in medical management of pubertal youth and surgical interventions.This is the first medical education curriculum in gender-affirming care created by pediatric endocrinologists grounded in the Endocrine Society practice guidelines. This study demonstrates medical knowledge gained in caring for gender diverse youth and is the first to incorporate ethical considerations for this patient population. While initially designed for pediatric endocrinology trainees and faculty, this curriculum may be of great utility for any provider interested in caring for gender diverse youth.

View details for DOI 10.1016/j.endmts.2023.100131

View details for PubMedID 37501755

View details for PubMedCentralID PMC10373477

Abstract

Gonadotrophin-releasing hormone agonists (GnRHa) are used for puberty suppression in central precocious puberty (CPP) and gender dysphoria (GD). Guidelines on biochemical monitoring are not defined.To evaluate the utility of biochemical monitoring of GnRHa therapy in patients with CPP or GD.Retrospective chart review of patients 18 years or younger who received GnRHa therapy from 1/1/2018 to 3/2/2021.103 patients were evaluated, 43 with CPP and 60 with GD. Using thresholds of basal luteinizing hormone (LH) <2 IU/L and stimulated LH <4 IU/L, biochemical pubertal suppression occurred in all but two patients. Basal LH frequently remained above prepubertal range.Laboratory assessment for puberty suppression on GnRHa therapy may be unnecessary in CPP and GD patients monitored with physical exams.

View details for DOI 10.1159/000529733

View details for Web of Science ID 000937266800001

View details for PubMedID 36791687

View details for Web of Science ID 001008985201102

View details for Web of Science ID 001008985201229

Abstract

Type 1 diabetes (T1D) is associated with lower scores on tests of cognitive and neuropsychological function and alterations in brain structure and function in children. This proof-of-concept pilot study (ClinicalTrials.gov Identifier NCT03428932) examined whether MRI-derived indices of brain development and function and standardized IQ scores in adolescents with T1D could be improved with better diabetes control using a hybrid closed-loop insulin delivery system. Eligibility criteria for participation in the study included age between 14 and 17 years and a diagnosis of T1D before 8 years of age. Randomization to either a hybrid closed-loop or standard diabetes care group was performed after pre-qualification, consent, enrollment, and collection of medical background information. Of 46 participants assessed for eligibility, 44 met criteria and were randomized. Two randomized participants failed to complete baseline assessments and were excluded from final analyses. Participant data were collected across five academic medical centers in the United States. Research staff scoring the cognitive assessments as well as those processing imaging data were blinded to group status though participants and their families were not. Forty-two adolescents, 21 per group, underwent cognitive assessment and multi-modal brain imaging before and after the six month study duration. HbA1c and sensor glucose downloads were obtained quarterly. Primary outcomes included metrics of gray matter (total and regional volumes, cortical surface area and thickness), white matter volume, and fractional anisotropy. Estimated power to detect the predicted treatment effect was 0.83 with two-tailed, =0.05. Adolescents in the hybrid closed-loop group showed significantly greater improvement in several primary outcomes indicative of neurotypical development during adolescence compared to the standard care group including cortical surface area, regional gray volumes, and fractional anisotropy. The two groups were not significantly different on total gray and white matter volumes or cortical thickness. The hybrid closed loop group also showed higher Perceptual Reasoning Index IQ scores and functional brain activity more indicative of neurotypical development relative to the standard care group (both secondary outcomes). No adverse effects associated with study participation were observed. These results suggest that alterations to the developing brain in T1D might be preventable or reversible with rigorous glucose control. Long term research in this area is needed.

View details for DOI 10.1038/s41467-022-32289-x

View details for PubMedID 36042217

Abstract

Although 37.5-51% of transgender adults state they would've considered freezing gametes before gender-affirming therapy if offered and 24-25.8% of transgender adolescents express interest in having biological children, less than 5% of transgender adolescents have opted for fertility preservation. We sought to assess fertility preservation utilization in our multidisciplinary adolescent gender clinic. We also aimed to identify fertility preservation utilization and interest among non-binary adolescents and young adults. A retrospective review was conducted of patients seen in the Stanford Pediatric & Adolescent Gender Clinic from October 2015 through March 2019 who were >10 years of age at initial visit. All individuals with documented discussion of fertility preservation were offered referral for formal fertility preservation consultation but only 24% of patients accepted. Only 6.8% of individuals subsequently underwent fertility preservation (n = 9). Transfeminine adolescents are more likely to pursue fertility preservation than transmasculine adolescents (p = 0.01). The rate of fertility preservation in non-binary adolescents did not significantly differ from those in transfeminine adolescents (p = 1.00) or transmasculine adolescents (p = 0.31). Although only one non-binary individual underwent fertility preservation, several more expressed interest with 36% accepting referral (n = 4) and 27% being seen in consultation (n = 3). Despite offering fertility preservation with designated members of a gender clinic team, utilization remains low in transgender adolescents. Additionally, non-binary adolescents and their families are interested in fertility preservation and referrals should be offered to these individuals. Further studies and advocacy are required to continue to address fertility needs of transgender adolescents.

View details for DOI 10.1371/journal.pone.0265043

View details for PubMedID 35275955

Abstract

OBJECTIVE: To determine the relationship between level of supervision (LOS) ratings for the Common Pediatric Subspecialty Entrustable Professional Activities (EPAs) with their associated subcompetency milestones across subspecialties and by fellowship training year.METHODS: Clinical Competency Committees (CCCs) in 14 pediatric subspecialties submitted LOS ratings for 6 Common Subspecialty EPAs and subcompetency milestone levels mapped to these EPAs. We examined associations between these subcompetency milestone levels and LOS ratings across subspecialty training year by fitting per-EPA linear mixed effects models, regressing LOS rating on milestone level and on training year.RESULTS: CCCs from 211 pediatric fellowship programs provided data for 369 first, 336 second, and 331 third year fellows. Mean subcompetency milestone levels increased similarly among subspecialties for most EPAs compared with the reference, Adolescent Medicine. Mean subcompetency milestones mapped to each EPA and mean EPA LOS ratings generally increased by training year across all subspecialties.CONCLUSIONS: Subcompetency milestones levels mapped to each Common Subspecialty EPA and the EPA LOS ratings increase similarly across subspecialties and by training year, providing validity evidence for using EPA LOS to assess pediatric subspecialty trainee performance. This study supports the development of tools to facilitated the CCC evaluation process across all pediatric subspecialties.

View details for DOI 10.1016/j.acap.2021.12.019

View details for PubMedID 34936942

View details for DOI 10.1542/2021-053258

View details for Web of Science ID 000754891900017

Abstract

BACKGROUND AND OBJECTIVES: Entrustable Professional Activities (EPAs) were developed to assess pediatric fellows. We previously showed that fellowship program directors (FPDs) may graduate fellows who still require supervision. How this compares with their expectations for entrustment of practicing subspecialists is unknown.METHODS: We surveyed US FPDs in 14 pediatric subspecialties through the Subspecialty Pediatrics Investigator Network between April and August 2017. For each of 7 common pediatric subspecialty EPAs, we compared the minimum level of supervision that FPDs required for graduation with the level they expected of subspecialists for safe and effective practice using the Friedman rank sum test and paired t test. We compared differences between subspecialties using linear regression.RESULTS: We collected data from 660 FPDs (response rate 82%). For all EPAs, FPDs did not require fellows to reach the level of entrustment for graduation that they expected of subspecialists to practice (P < .001). FPDs expected the least amount of supervision for the EPAs consultation and handovers. Mean differences between supervision levels for graduation and practice were smaller for clinical EPAs (consultation, handovers, lead a team) when compared with nonclinical EPAs (quality improvement, management, lead the profession and scholarship; P = .001) and were similar across nearly all subspecialties.CONCLUSIONS: Fellowship graduates may need continued development of clinical and nonclinical skills in their early practice period, underscoring a need for continued assessment and mentoring. Graduation readiness must be based on clear requirements, with alignment of FPD expectations and regulatory standards, to ensure quality care for patients.

View details for DOI 10.1542/peds.2021-050196

View details for PubMedID 34667096

View details for Web of Science ID 000696303300157

View details for Web of Science ID 000696303300201

Abstract

PURPOSE: Entrustable professional activities (EPAs) are one approach to competency-based medical education (CBME), and 7 EPAs have been developed that address content relevant for all pediatric subspecialties. However, it is not known what level of supervision fellowship program directors (FPDs) deem necessary for graduation. The Subspecialty Pediatrics Investigator Network (SPIN) investigated FPD perceptions of the minimum level of supervision required for a trainee to successfully graduate.METHOD: In 2017, SPIN surveyed all FPDs of accredited fellowships for 14 subspecialties. For each EPA, the minimum supervision level for graduation (ranging from observation only to unsupervised practice) was set such that no more than 20% of FPDs would accept a lower level.RESULTS: The survey response rate was 82% (660/802). The minimum supervision level for graduation varied across the 7 EPAs from 2 (direct) to 4 (indirect for complex cases), with significant differences between EPAs. The percentage of FPDs desiring a lower minimum supervision level ranged from 3% to 17%. Compared with the 4 nonclinical EPAs (quality improvement, management, lead within the profession, scholarship), the 3 clinical EPAs (consultation, handover, lead a team) had higher minimum supervision graduation levels (P < .001), with less likelihood that an FPD would graduate a learner below their minimum level (P < .001).CONCLUSIONS: Consensus among FPDs across all pediatric subspecialties demonstrates the potential need for ongoing supervision for graduates in all 7 common pediatric subspecialty EPAs after fellowship. As CBME programs are implemented, processes and infrastructure to support new graduates are important considerations for leaders.

View details for DOI 10.1097/ACM.0000000000004091

View details for PubMedID 34183598

Abstract

OBJECTIVES: To examine main factors that influence the decision to choose pediatric endocrinology as a career among pediatric endocrinologists and assess their work satisfaction or stress level and suggested strategies to increase interest in subspecialty training in pediatric endocrinology.METHODS: A workforce survey was distributed among 1470 members of the Pediatric Endocrine Society.RESULTS: The response rate was 37.4%, with 550 members responding. The most common reasons for the respondents choosing pediatric endocrinology were intellectual stimulation (79%), exposure to endocrinology during residency (57%) or medical school (43%), and ability to establish relationships with patients with chronic disorders (54%). Of the respondents, 97% considered intellectual stimulation as the most favorable aspect of the specialty, and 84% considered financial compensation as the most unfavorable aspect of pediatric endocrinology. Majority (77%) were satisfied or very satisfied with their work environment. The mean work-related stress score (0 [none] to 10 [worst]) was 5.7, standard deviation was 2.1, and median was 6 (Q1, Q3: 4, 7). Increased financial compensation for the services and loan payment or forgiveness option were the top strategies suggested to enhance interest among residents for training in the subspecialty. One third (37%) felt that reducing the duration of the fellowship to 2 years would increase interest in training in pediatric endocrinology.CONCLUSION: The pediatric endocrinologists reported overall excellent career satisfaction, indicating the potential to attract high-quality doctors to the specialty. Improving reimbursement and loan forgiveness were the top strategies suggested for increasing interest in subspecialty training in pediatric endocrinology.

View details for DOI 10.1016/j.eprac.2020.12.003

View details for PubMedID 34132198

View details for Web of Science ID 000593119300207

View details for Web of Science ID 000593119300206

View details for DOI 10.1016/j.jpeds.2020.10.063

View details for PubMedID 33137317

View details for Web of Science ID 000544736900197

Abstract

Glucose is a primary fuel source to the brain, yet the influence of dysglycemia on neurodevelopment in children with type 1 diabetes remains unclear. We examined brain activation using functional MRI in 80 children with type 1 diabetes (mean age SD, 11.51.8 years; 46% female) and 47 children without diabetes ("control", mean age 11.81.5 years; 51% female) as they performed a visuospatial working memory (N-back) task. Results indicated that in both groups, activation scaled positively with increasing working memory load across many areas, including the frontoparietal cortex, caudate and cerebellum. Between groups, children with diabetes exhibited reduced performance on the N-back task relative to control children, as well as greater modulation of activation (i.e., showed greater a increase in activation with higher working memory load). Post-hoc analyses indicated that greater modulation was associated in the diabetes group with better working memory function and with an earlier age of diagnosis. These findings suggest that increased modulation may occur as a compensatory mechanism, helping in part to preserve working memory ability, and further, that children with an earlier onset require additional compensation. Future studies that test whether these patterns change as a function of improved glycemic control are warranted.

View details for DOI 10.2337/db20-0123

View details for PubMedID 32471809

Abstract

Objective Every year 500,000 youths in the U.S. with chronic disease turn 18 and eventually require transfer to adult subspecialty care. Evidence-based interventions on the organization of transfer of care are limited, although engagement and retention in adult clinic are considered appropriate outcomes. Sustained continuity of care improves patient satisfaction and reduces hospitalization. Methods We conducted a prospective non-randomized cohort study of patients with pediatric endocrine conditions, age 16-26 years, enrolled upon referral to the adult endocrine clinic of a physician trained in both adult and pediatric endocrinology (Med+Peds Endocrinologist). Patients differed based on whether their referral originated from another pediatric endocrinologist (traditional transfer) or if the Med+Peds Endocrinologist previously saw the patient in his pediatric endocrine clinic (guided transfer). Rather than relying on arbitrary age criteria, guided transfer to adult clinic occurred when physician and patient considered it appropriate. The primary outcome was show rate at the first and second adult visits. Results Of 36 patients, 21 were referred by another pediatric endocrinologist and 15 underwent guided transfer. For traditional transfer, show rate to the first and second visit was 38% compared to 100% in the guided transfer group (p = 0.0001). Subgroup analysis of 27 patients with diabetes revealed that both groups had similar initial HbA1c (p = 0.38) and the guided transfer group maintained HbA1c. Conclusions Most traditional transfers were unsuccessful. Guided transfer was significantly more effective, with every patient successfully transferring, and could be implemented with adult endocrinologists willing to see patients in the pediatric clinic.

View details for DOI 10.4158/EP-2019-0470

View details for PubMedID 32045296

Abstract

Objectives: Fellowship program directors (FPD) and Clinical Competency Committees (CCCs) both assess fellow performance. We examined the association of entrustment levels determined by the FPD with those of the CCC for 6 common pediatric subspecialty entrustable professional activities (EPAs), hypothesizing there would be strong correlation and minimal bias between these raters.Methods: The FPDs and CCCs separately assigned a level of supervision to each of their fellows for 6 common pediatric subspecialty EPAs. For each EPA, we determined the correlation between FPD and CCC assessments and calculated bias as CCC minus FPD values for when the FPD was or was not a member of the CCC. In addition, we examined the effect of program size, FPD understanding of EPAs, and subspecialty on the correlations. Data were obtained in fall 2014 and spring 2015.Results: A total of 1040 fellows were assessed in the fall and 1048 in the spring. In both periods and for each EPA, there was a strong correlation between FPD and CCC supervision levels (P<.001). The correlation was somewhat lower when the FPD was not a CCC member (P<.001). Overall bias in both periods was small.Conclusions: The correlation between FPD and CCC assignment of EPA supervision levels is strong. Although slightly weaker when the FPD is not a CCC member, bias is small, so this is likely unimportant in determining fellow entrustment level. The similar performance ratings of FPDs and CCCs support the validity argument for EPAs as competency-based assessment tools.

View details for DOI 10.1177/2382120520936613

View details for PubMedID 32844115

Abstract

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, 12.359.39years; range, 1-49years) 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, 60min glucose and 60min 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% 5year 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) 12.0years of age with GADA positivity, IA-2A negativity and Index60 <1.0, the 5year 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 5years. With this knowledge, clinical trials of type 1 diabetes prevention can better target those most likely to progress.

View details for DOI 10.1007/s00125-019-05047-w

View details for PubMedID 31768570

View details for DOI 10.2337/db19-1384-P

View details for Web of Science ID 000501366903267

View details for Web of Science ID 000462161200064

Abstract

Serum cortisol measurements after ACTH stimulation are currently used to evaluate for adrenal insufficiency in children. We aim to determine if salivary cortisol measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) can confirm or replace serum cortisol during high dose ACTH stimulation test to improve test compliance and interpretation. We also aim to gain preliminary understanding of normal ranges of salivary cortisol in normal children at am, bedtime, and midnight.Children aged 6-17 years meeting study criteria and tested for adrenal insufficiency were recruited to concomitantly collect saliva and serum samples during high dose ACTH stimulation test. Normal children aged 3-18 years were recruited to collect morning, bedtime, and midnight saliva samples. Salivary cortisol was measured using LC-MS/MS while serum cortisol was determined by an immunoassay.Salivary cortisol in normal children were higher at am and lower at bedtime and midnight (p value <0.0002 and <0.007, respectively). The midnight and bedtime levels were not sufficiently different (p value 0.36). Salivary cortisol during ACTH stimulation test positively and closely correlated with serum cortisol with 100% specificity and sensitivity when 18g/dL for serum and 500ng/dL for salivary cortisol were used as cutoff values respectively for adrenal sufficiency.Measurement of salivary cortisol by LC-MS/MS is less invasive, more convenient and better time controlled in busy pediatric clinic, therefore is better suited for young children to be used during high dose ACTH stimulation test to evaluate for adrenal insufficiency and to assist interpretation of test results by serum cortisol.

View details for DOI 10.1007/s12020-019-02084-8

View details for PubMedID 31535345

Abstract

We developed a system to suspend insulin pump delivery overnight when the glucose trend predicts hypoglycemia. This predictive low-glucose suspend (PLGS) system substantially reduces nocturnal hypoglycemia without an increase in morning ketosis. Evaluation of hypoglycemia risk factors that could potentially influence the efficacy of the system remains critical for understanding possible problems with the system and identifying patients that may have the greatest benefit when using the system.The at-home randomized trial consisted of 127 study participants with hemoglobin A1c (A1C) of 8.5% (mmol/mol) for patients aged 4-14 years and 8.0% for patient aged 15-45 years. Factors assessed included age, gender, A1C, diabetes duration, daily percentage basal insulin, total daily dose of insulin (units/kg-day), bedtime BG, bedtime snack, insulin on board, continuous glucose monitor (CGM) rate of change (ROC), day of the week, time system activated, daytime exercise intensity, and daytime CGM-measured hypoglycemia.The PLGS system was effective in preventing hypoglycemia for each factor subgroup. There was no evidence that the PLGS system was more or less effective in preventing hypoglycemia in any one subgroup compared with the other subgroups based on that factor. In addition, the effect of the system on overnight hyperglycemia did not differ in subgroups.The PLGS system tested in this study effectively reduced hypoglycemia without a meaningful increase in hyperglycemia across a variety of factors.

View details for PubMedID 27207890

Abstract

To compare the frequency of elevated morning blood ketone levels according to age in 4-14 year olds with type 1 diabetes following overnight use of an automated low glucose insulin suspension system, or following control nights when the system was not used.For 28 children ages 4-9 years and 54 youth ages 10-14 years, elevation of morning blood ketone levels was assessed using the Precision Xtra Ketone meter following 1155 and 2345 nights, respectively. Repeated measures logistic regression models were used to compare age groups for blood ketone level elevation following control nights (system not activated) and following intervention nights with and without insulin suspension.Elevated morning blood ketones (0.6 mmol/L) were present following 10% of 580 control nights in the 4-9 year olds compared with 2% of 1162 control nights in 10-14 year olds (P < 0.001). Likewise, the frequency was greater following intervention nights in the younger age group (13% of 575 nights vs 2% of 1183 nights, P < 0.001). A longer duration of pump suspension resulted in a higher percentage of mornings with elevated blood ketones in the younger age group (P = 0.002), but not in the older age group (P = 0.63). The presence of elevated morning ketone levels did not progress to ketoacidosis in any subject.Elevated morning blood ketones are more common in younger children with type 1 diabetes with or without nocturnal insulin suspension. Care providers need to be aware of the differences in ketogenesis in younger age children relative to various clinical situations.

View details for DOI 10.1111/pedi.12410

View details for PubMedID 27402452

Abstract

Prior studies examining beta-cell preservation in type 1 diabetes have predominantly assessed stimulated C-peptide concentrations approximately 10wk after diagnosis. We examined whether earlier assessments might aid in prediction of beta cell function over time.Using data from a multi-center randomized trial assessing the effect of intensive diabetes management initiated within 1wk of diagnosis, we assessed which clinical factors predicted 90-min mixed-meal tolerance test (MMTT) stimulated C-peptide values obtained 2 and 6wk after diagnosis. We also studied associations of these factors with C-peptide values at 1- and 2-year post-diagnosis. Data from intervention and control groups were pooled.Among 67 study participants (mean age 13.35.7yr, range 7.8-45.7yr) in multivariable analyses, C-peptide increased from baseline to 2wks and then 6wk. C-peptide levels at these times were significantly correlated with 1- and 2-yr C-peptide concentrations (all p<0.001), with the strongest observed associations between 6-wk C-peptide and the 1- and 2-yr values (r=0.66 and r=0.61, respectively). In multivariable analyses, greater baseline and 6-wk C-peptide, and older age independently predicted greater 1- and 2-yr C-peptide concentrations.C-peptide assessments close to diagnosis were predictive of subsequent C-peptide production. Our data demonstrate a clear increase in C-peptide over the initial 6wk after diabetes diagnosis followed by a plateau. Our data do not suggest that MMTT assessments performed closer to diagnosis than 6wk would improve prediction of subsequent residual beta cell function.

View details for DOI 10.1111/pedi.12271

View details for Web of Science ID 000379831900001

View details for PubMedID 25720763

Abstract

Decrements in cognitive function may already be evident in young children with type 1 diabetes (T1D). Here we report prospectively acquired cognitive results over 18 months in a large cohort of young children with and without T1D.A total of 144 children with T1D (mean HbA1c: 7.9%) and 70 age-matched healthy controls (mean age both groups 8.5 years; median diabetes duration 3.9 years; mean age of onset 4.1 years) underwent neuropsychological testing at baseline and after 18-months of follow-up. We hypothesized that group differences observed at baseline would be more pronounced after 18 months, particularly in those T1D patients with greatest exposure to glycemic extremes.Cognitive domain scores did not differ between groups at the 18 month testing session and did not change differently between groups over the follow-up period. However, within the T1D group, a history of diabetic ketoacidosis (DKA) was correlated with lower Verbal IQ and greater hyperglycemia exposure (HbA1c area under the curve) was inversely correlated to executive functions test performance. In addition, those with a history of both types of exposure performed most poorly on measures of executive function.The subtle cognitive differences between T1D children and nondiabetic controls observed at baseline were not observed 18 months later. Within the T1D group, as at baseline, relationships between cognition (Verbal IQ and executive functions) and glycemic variables (chronic hyperglycemia and DKA history) were evident. Continued longitudinal study of this T1D cohort and their carefully matched healthy comparison group is planned.

View details for DOI 10.1017/S1355617715001289

View details for PubMedID 26786245

Abstract

Early-onset type 1 diabetes may affect the developing brain during a critical window of rapid brain maturation. Structural MRI was performed on 141 children with diabetes (4-10 years of age at study entry) and 69 age-matched control subjects at two time points spaced 18 months apart. For the children with diabetes, the mean (SD) HbA1c level was 7.9 0.9% (63 9.8 mmol/mol) at both time points. Relative to control subjects, children with diabetes had significantly less growth of cortical gray matter volume and cortical surface area and significantly less growth of white matter volume throughout the cortex and cerebellum. For the population with diabetes, the change in the blood glucose level at the time of scan across longitudinal time points was negatively correlated with the change in gray and white matter volumes, suggesting that fluctuating glucose levels in children with diabetes may be associated with corresponding fluctuations in brain volume. In addition, measures of hyperglycemia and glycemic variation were significantly negatively correlated with the development of surface curvature. These results demonstrate that early-onset type 1 diabetes has widespread effects on the growth of gray and white matter in children whose blood glucose levels are well within the current treatment guidelines for the management of diabetes.

View details for DOI 10.2337/db15-1242

View details for PubMedID 26512024

Abstract

Nocturnal hypoglycemia can cause seizures and is a major impediment to tight glycemic control, especially in young children with type 1 diabetes. We conducted an in-home randomized trial to assess the efficacy and safety of a continuous glucose monitor-based overnight predictive low-glucose suspend (PLGS) system.In two age-groups of children with type 1 diabetes (11-14 and 4-10 years of age), a 42-night trial for each child was conducted wherein each night was assigned randomly to either having the PLGS system active (intervention night) or inactive (control night). The primary outcome was percent time <70 mg/dL overnight.Median time at <70 mg/dL was reduced by 54% from 10.1% on control nights to 4.6% on intervention nights (P < 0.001) in 11-14-year-olds (n = 45) and by 50% from 6.2% to 3.1% (P < 0.001) in 4-10-year-olds (n = 36). Mean overnight glucose was lower on control versus intervention nights in both age-groups (144 18 vs. 152 19 mg/dL [P < 0.001] and 153 14 vs. 160 16 mg/dL [P = 0.004], respectively). Mean morning blood glucose was 159 29 vs. 176 28 mg/dL (P < 0.001) in the 11-14-year-olds and 154 25 vs. 158 22 mg/dL (P = 0.11) in the 4-10-year-olds, respectively. No differences were found between intervention and control in either age-group in morning blood ketosis.In 4-14-year-olds, use of a nocturnal PLGS system can substantially reduce overnight hypoglycemia without an increase in morning ketosis, although overnight mean glucose is slightly higher.

View details for DOI 10.2337/dc14-3053

View details for PubMedID 26049549

Abstract

Hypoglycemia remains an impediment to good glycemic control, with nocturnal hypoglycemia being particularly dangerous. Information on major contributors to nocturnal hypoglycemia remains critical for understanding and mitigating risk.Continuous glucose monitoring (CGM) data for 855 nights were studied, generated by 45 subjects 15-45 years of age with hemoglobin A1c (HbA1c) levels of 8.0% who participated in a larger randomized study. Factors assessed for potential association with nocturnal hypoglycemia (CGM measurement of <60mg/dL for 30min) included bedtime blood glucose (BG), exercise intensity, bedtime snack, insulin on board, day of the week, previous daytime hypoglycemia, age, gender, HbA1c level, diabetes duration, daily basal insulin, and daily insulin dose.Hypoglycemia occurred during 221 of 885 (25%) nights and was more frequent with younger age (P<0.001), lower HbA1c levels (P=0.006), medium/high-intensity exercise during the preceding day (P=0.003), and the occurrence of antecedent daytime hypoglycemia (P=0.001). There was a trend for lower bedtime BG levels to be associated with more frequent nocturnal hypoglycemia (P=0.10). Bedtime snack, before bedtime insulin bolus, weekend versus weekday, gender, and daily basal and bolus insulin were not associated with nocturnal hypoglycemia.Awareness that HbA1c level, exercise, bedtime BG level, and daytime hypoglycemia are all modifiable factors associated with nocturnal hypoglycemia may help patients and providers decrease the risk of hypoglycemia at night. Risk for nocturnal hypoglycemia increased in a linear fashion across the range of variables, with no clear-cut thresholds to guide clinicians or patients for any particular night.

View details for DOI 10.1089/dia.2014.0342

View details for PubMedID 25761202

Abstract

Significant regional differences in gray and white matter volume and subtle cognitive differences between young diabetic and nondiabetic children have been observed. Here, we assessed whether these differences change over time and the relation with dysglycemia. Children ages 4 to <10 years with (n = 144) and without (n = 72) type 1 diabetes (T1D) had high-resolution structural MRI and comprehensive neurocognitive tests at baseline and 18 months and continuous glucose monitoring and HbA1c performed quarterly for 18 months. There were no differences in cognitive and executive function scores between groups at 18 months. However, children with diabetes had slower total gray and white matter growth than control subjects. Gray matter regions (left precuneus, right temporal, frontal, and parietal lobes and right medial-frontal cortex) showed lesser growth in diabetes, as did white matter areas (splenium of the corpus callosum, bilateral superior-parietal lobe, bilateral anterior forceps, and inferior-frontal fasciculus). These changes were associated with higher cumulative hyperglycemia and glucose variability but not with hypoglycemia. Young children with T1D have significant differences in total and regional gray and white matter growth in brain regions involved in complex sensorimotor processing and cognition compared with age-matched control subjects over 18 months, suggesting that chronic hyperglycemia may be detrimental to the developing brain.

View details for DOI 10.2337/db14-1445

View details for PubMedID 25488901

Abstract

Overnight hypoglycemia occurs frequently in individuals with type 1 diabetes and can result in loss of consciousness, seizure, or even death. We conducted an in-home randomized trial to determine whether nocturnal hypoglycemia could be safely reduced by temporarily suspending pump insulin delivery when hypoglycemia was predicted by an algorithm based on continuous glucose monitoring (CGM) glucose levels.Following an initial run-in phase, a 42-night trial was conducted in 45 individuals aged 15-45 years with type 1 diabetes in which each night was assigned randomly to either having the predictive low-glucose suspend system active (intervention night) or inactive (control night). The primary outcome was the proportion of nights in which 1 CGM glucose values 60 mg/dL occurred.Overnight hypoglycemia with at least one CGM value 60 mg/dL occurred on 196 of 942 (21%) intervention nights versus 322 of 970 (33%) control nights (odds ratio 0.52 [95% CI 0.43-0.64]; P < 0.001). Median hypoglycemia area under the curve was reduced by 81%, and hypoglycemia lasting >2 h was reduced by 74%. Overnight sensor glucose was >180 mg/dL during 57% of control nights and 59% of intervention nights (P = 0.17), while morning blood glucose was >180 mg/dL following 21% and 27% of nights, respectively (P < 0.001), and >250 mg/dL following 6% and 6%, respectively. Morning ketosis was present <1% of the time in each arm.Use of a nocturnal low-glucose suspend system can substantially reduce overnight hypoglycemia without an increase in morning ketosis.

View details for DOI 10.2337/dc13-2159

View details for Web of Science ID 000338020400022

View details for PubMedCentralID PMC4067393

Abstract

Overnight hypoglycemia occurs frequently in individuals with type 1 diabetes and can result in loss of consciousness, seizure, or even death. We conducted an in-home randomized trial to determine whether nocturnal hypoglycemia could be safely reduced by temporarily suspending pump insulin delivery when hypoglycemia was predicted by an algorithm based on continuous glucose monitoring (CGM) glucose levels.Following an initial run-in phase, a 42-night trial was conducted in 45 individuals aged 15-45 years with type 1 diabetes in which each night was assigned randomly to either having the predictive low-glucose suspend system active (intervention night) or inactive (control night). The primary outcome was the proportion of nights in which 1 CGM glucose values 60 mg/dL occurred.Overnight hypoglycemia with at least one CGM value 60 mg/dL occurred on 196 of 942 (21%) intervention nights versus 322 of 970 (33%) control nights (odds ratio 0.52 [95% CI 0.43-0.64]; P < 0.001). Median hypoglycemia area under the curve was reduced by 81%, and hypoglycemia lasting >2 h was reduced by 74%. Overnight sensor glucose was >180 mg/dL during 57% of control nights and 59% of intervention nights (P = 0.17), while morning blood glucose was >180 mg/dL following 21% and 27% of nights, respectively (P < 0.001), and >250 mg/dL following 6% and 6%, respectively. Morning ketosis was present <1% of the time in each arm.Use of a nocturnal low-glucose suspend system can substantially reduce overnight hypoglycemia without an increase in morning ketosis.

View details for DOI 10.2337/dc13-2159

View details for PubMedID 24804697

Abstract

The aim of this study was to assess cognitive functioning in children with type 1 diabetes (T1D) and examine whether glycemic history influences cognitive function. Neuropsychological evaluation of 216 children (healthy controls, n = 72; T1D, n = 144) ages 4-10 years across five DirecNet sites. Cognitive domains included IQ, Executive Functions, Learning and Memory, and Processing Speed. Behavioral, mood, parental IQ data, and T1D glycemic history since diagnosis were collected. The cohorts did not differ in age, gender or parent IQ. Median T1D duration was 2.5 years and average onset age was 4 years. After covarying age, gender, and parental IQ, the IQ and the Executive Functions domain scores trended lower (both p = .02, not statistically significant adjusting for multiple comparisons) with T1D relative to controls. Children with T1D were rated by parents as having more depressive and somatic symptoms (p < .001). Learning and memory (p = .46) and processing speed (p = .25) were similar. Trends in the data supported that the degree of hyperglycemia was associated with Executive Functions, and to a lesser extent, Child IQ and Learning and Memory. Differences in cognition are subtle in young children with T1D within 2 years of onset. Longitudinal evaluations will help determine whether these findings change or become more pronounced with time. (JINS, 2014, 20, 238-247).

View details for DOI 10.1017/S1355617713001434

View details for PubMedID 24512675

Abstract

To investigate whether type 1 diabetes affects white matter (WM) structure in a large sample of young children.Children (ages 4 to <10 years) with type 1 diabetes (n = 127) and age-matched nondiabetic control subjects (n = 67) had diffusion weighted magnetic resonance imaging scans in this multisite neuroimaging study. Participants with type 1 diabetes were assessed for HbA1c history and lifetime adverse events, and glucose levels were monitored using a continuous glucose monitor (CGM) device and standardized measures of cognition.Between-group analysis showed that children with type 1 diabetes had significantly reduced axial diffusivity (AD) in widespread brain regions compared with control subjects. Within the type 1 diabetes group, earlier onset of diabetes was associated with increased radial diffusivity (RD) and longer duration was associated with reduced AD, reduced RD, and increased fractional anisotropy (FA). In addition, HbA1c values were significantly negatively associated with FA values and were positively associated with RD values in widespread brain regions. Significant associations of AD, RD, and FA were found for CGM measures of hyperglycemia and glucose variability but not for hypoglycemia. Finally, we observed a significant association between WM structure and cognitive ability in children with type 1 diabetes but not in control subjects.These results suggest vulnerability of the developing brain in young children to effects of type 1 diabetes associated with chronic hyperglycemia and glucose variability.

View details for DOI 10.2337/dc13-1388

View details for PubMedID 24319123

View details for PubMedCentralID PMC3898758

Abstract

The ability to lie still in an MRI scanner is essential for obtaining usable image data. To reduce motion, young children are often sedated, adding significant cost and risk.We assessed the feasibility of using a simple and affordable behavioral desensitization program to yield high-quality brain MRI scans in sedation-free children.222 children (4-9.9years), 147 with type 1 diabetes and 75 age-matched non-diabetic controls, participated in a multi-site study focused on effects of type 1 diabetes on the developing brain. T1-weighted and diffusion-weighted imaging (DWI) MRI scans were performed. All children underwent behavioral training and practice MRI sessions using either a commercial MRI simulator or an inexpensive mock scanner consisting of a toy tunnel, vibrating mat, and video player to simulate the sounds and feel of the MRI scanner.205 children (92.3%), mean age 71.7years had high-quality T1-W scans and 174 (78.4%) had high-quality diffusion-weighted scans after the first scan session. With a second scan session, success rates were 100% and 92.5% for T1-and diffusion-weighted scans, respectively. Success rates did not differ between children with type 1 diabetes and children without diabetes, or between centers using a commercial MRI scan simulator and those using the inexpensive mock scanner.Behavioral training can lead to a high success rate for obtaining high-quality T1-and diffusion-weighted brain images from a young population without sedation.

View details for DOI 10.1007/s00247-013-2798-7

View details for PubMedID 24096802

View details for PubMedCentralID PMC3946760

Abstract

To investigate whether type 1 diabetes affects white matter (WM) structure in a large sample of young children.Children (ages 4 to <10 years) with type 1 diabetes (n = 127) and age-matched nondiabetic control subjects (n = 67) had diffusion weighted magnetic resonance imaging scans in this multisite neuroimaging study. Participants with type 1 diabetes were assessed for HbA1c history and lifetime adverse events, and glucose levels were monitored using a continuous glucose monitor (CGM) device and standardized measures of cognition.Between-group analysis showed that children with type 1 diabetes had significantly reduced axial diffusivity (AD) in widespread brain regions compared with control subjects. Within the type 1 diabetes group, earlier onset of diabetes was associated with increased radial diffusivity (RD) and longer duration was associated with reduced AD, reduced RD, and increased fractional anisotropy (FA). In addition, HbA1c values were significantly negatively associated with FA values and were positively associated with RD values in widespread brain regions. Significant associations of AD, RD, and FA were found for CGM measures of hyperglycemia and glucose variability but not for hypoglycemia. Finally, we observed a significant association between WM structure and cognitive ability in children with type 1 diabetes but not in control subjects.These results suggest vulnerability of the developing brain in young children to effects of type 1 diabetes associated with chronic hyperglycemia and glucose variability.

View details for DOI 10.2337/dc13-1388

View details for PubMedCentralID PMC3898758

Abstract

Abstract Background: Children with type 1 diabetes (T1D) spend 4-7h/day in school with very little supervision of their diabetes management. Therefore, families have become more dependent on technology, such as use of real-time continuous glucose monitoring (RT-CGM), to provide increased supervision of their diabetes management. We sought to assess the impact of RT-CGM use in the classroom/school environment. Subjects and Methods: Children with T1D using RT-CGM, their parents, and teachers completed a questionnaire about RT-CGM in the classroom/school environment. Results: The RT-CGM was tolerated well in the classroom/school environment. Seventy percent of parents, 75% of students, and 51% of teachers found RT-CGM useful in the classroom/school environment. The students found the device to be more disruptive than did their parents and teachers. However, all three groups agreed that RT-CGM increased their comfort with diabetes management at school. Conclusions: Our study suggests that RT-CGM is useful and not disruptive in the classroom/school environment. The development of education materials for teachers could further increase its acceptance in the classroom/school environment.

View details for DOI 10.1089/dia.2012.0314

View details for PubMedID 23530577

Abstract

Administration of insulin via a pen device may be advantageous over a vial and syringe system. Hofman and colleagues introduce a new insulin pen needle, the NovoTwist, to simplify injections to a small group of children and adolescents. Their overall preferences and evaluation of the handling of the needle are reported in the study. This new needle has the potential to ease administration of insulin via a pen device that may increase both the use of a pen device and adherence to insulin therapy.

View details for PubMedID 22226270

Abstract

This article reviews current pump and continuous glucose monitoring therapy and what will be required to integrate these systems into closed-loop control. Issues with sensor accuracy, lag time, and calibration are discussed as well as issues with insulin pharmacodynamics, which result in a delayed onset of insulin action in a closed-loop system. A stepwise approach to closed-loop therapy is anticipated, where the first systems will suspend insulin delivery based on actual or predicted hypoglycemia. Subsequent systems may control to range, limiting the time spent in hyperglycemia by mitigating the effects of a missed food bolus or underestimate of consumed carbohydrates, while minimizing the risk of hypoglycemia.

View details for DOI 10.1016/j.ecl.2010.05.005

View details for Web of Science ID 000282146100011

View details for PubMedID 20723823

View details for PubMedCentralID PMC2938733

Abstract

Metformin has been proffered as a therapy for adolescent obesity, although long-term controlled studies have not been reported.To test the hypothesis that 48 weeks of daily metformin hydrochloride extended release (XR) therapy will reduce body mass index (BMI) in obese adolescents, as compared with placebo.Multicenter, randomized, double-blind, placebo-controlled clinical trial.The 6 centers of the Glaser Pediatric Research Network from October 2003 to August 2007.Obese (BMI > or = 95th percentile) adolescents (aged 13-18 years) were randomly assigned to the intervention (n = 39) or placebo groups. Intervention Following a 1-month run-in period, subjects following a lifestyle intervention program were randomized 1:1 to 48 weeks' treatment with metformin hydrochloride XR, 2000 mg once daily, or an identical placebo. Subjects were monitored for an additional 48 weeks. Main Outcome Measure Change in BMI, adjusted for site, sex, race, ethnicity, and age and metformin vs placebo.After 48 weeks, mean (SE) adjusted BMI increased 0.2 (0.5) in the placebo group and decreased 0.9 (0.5) in the metformin XR group (P = .03). This difference persisted for 12 to 24 weeks after cessation of treatment. No significant effects of metformin on body composition, abdominal fat, or insulin indices were observed.Metformin XR caused a small but statistically significant decrease in BMI when added to a lifestyle intervention program.clinicaltrials.gov Identifiers: NCT00209482 and NCT00120146.

View details for PubMedID 20124139