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Background Diabetes is a risk factor for poor COVID‐19 outcomes, but pediatric patients with type 1 diabetes are poorly represented in current studies. Methods T1D Exchange coordinated a US type 1 diabetes COVID‐19 registry. Forty‐six diabetes centers submitted pediatric cases for patients with laboratory confirmed COVID‐19. Associations between clinical factors and hospitalization were tested with Fisher's Exact Test. Logistic regression was used to calculate odds ratios for hospitalization. Results Data from 266 patients with previously established type 1 diabetes aged, Highlights Outcomes for children with type 1 diabetes who experience COVID‐19 are currently unknown. We report 266 cases from US diabetes clinics of children with type 1 diabetes who had COVID‐19. Diabetic ketoacidosis was the major adverse outcome, and it was associated with higher A1c.

We evaluated COVID-19 outcomes in children and young adults with type 1 diabetes (T1D) to determine if those with comorbidities are more likely to experience severe COVID-19 compared to those without.This cross-sectional study included questionnaire data on patients25 years of age with established T1D and laboratory-confirmed COVID-19 from 52 sites across the US between April 2020 and October 2021. We examined patient factors and COVID-19 outcomes between those with and without comorbidities. Multivariate logistic regression analysis examined the odds of hospitalization among groups, adjusting for age, HbA1c, race and ethnicity, insurance type and duration of diabetes.Six hundred fifty-one individuals with T1D and COVID-19 were analyzed with mean age 15.8 (SD 4.1) years. At least one comorbidity was present in 31%, and more than one in 10%. Obesity and asthma were the most frequently reported comorbidities, present in 19% and 17%, respectively. Hospitalization occurred in 17% of patients and 52% of hospitalized patients required ICU level care. Patients with at least one comorbidity were almost twice as likely to be hospitalized with COVID-19 than patients with no comorbidities (Odds ratio 2.0, 95% CI: 1.3-3.1). This relationship persisted after adjusting for age, HbA1c, race and ethnicity (minority vs nonminority), insurance type (public vs. private), and duration of diabetes.Our findings show that comorbidities increase the risk for hospitalization with COVID-19 in children and young adults highlighting the need for tailored COVID-19 prevention and treatment strategies in T1D.

Hypoglycemia occurs frequently in children with type 1 diabetes (T1D). However, the relationship between fear of hypoglycemia (FOH) and use of diabetes technology with different insulin delivery systems has not been well studied. Similarly, little is known about the relationship of diabetes treatment satisfaction with advances in diabetes technology in the pediatric population. Caregivers of children 6-17 years with T1D (n=104, 84% female caregivers, median T1D duration 5.3 years, mean GMI 7.5 ± 0.7%, 93% insulin pump users, 92% CGM users) using any insulin delivery system (8% MDI, 0.05% pump alone, 31% sensor augmented pump, 23% predictive low glucose suspend, 38% hybrid closed loop) completed the Hypoglycemia Fear Survey - Parent (HFS-P) and the Diabetes Treatment Satisfaction Questionnaire - Parent (DTSQ-P). Youth 13-17 years (n=35, 56% males) also completed the HFS - Child (HFS-C) and DTSQ - Child (DTSQ-C). Linear regression was used to look for associations between HFS and DTSQ scores and clinical factors, and paired t-tests were used to compare scores between caregivers and youth. Female caregivers had higher mean HFS Worry and Behavior scores than male caregivers (Worry 1.4 ± 0.18 vs. 0.88 ± 0.16, p=0.004; Behavior 4.9 ± 0.39 vs. 3.9 ± 0.3, p=0.008). Longer duration of diabetes, duration of pump use, and duration of CGM use were all associated with higher mean HFS-C Worry scores, but not with HFS-P Worry scores. The use of different insulin delivery systems was not associated with any HFS scores. Caregivers had a higher mean HFS Behavior score (4.8 ± 0.29) than youth (2.2 ± 0.078) (p Disclosure F. Abdulhussein: None. J. C. Wong: Advisory Panel; Self; Provention Bio, Inc., Research Support; Self; Dexcom, Inc., Tandem Diabetes Care.

Previous studies have shown adolescents with T1D diagnosed prior to menarche have an older age of menarche compared with those diagnosed after menarche and to the general population, and menstrual irregularity in women with T1D is more common than in those without T1D, suggesting that T1D may be associated with reproductive abnormalities. In this study, multiple regression models were used to explore the relationship between clinical factors and markers of reproductive health in 3528 women >18 years (mean age 39±17 years) in the T1D Exchange Clinic Registry who had a 5-year follow-up. Average age of menarche was 13±2 years, and 13% reported irregular menstrual periods unrelated to pregnancy or menopause. Younger age at T1D diagnosis was significantly associated with older age at menarche (p=0.001) after adjustment for race/ethnicity, current BMI, and report of severe hypoglycemia (SH). Having an evaluation for infertility was reported by 6% of participants and was associated with lower mean hemoglobin A1c (A1c; OR 0.79, 95% CI 0.67-0.91 for a 1% increase in A1c) and current use of continuous glucose monitoring (CGM, OR 1.58, 95% CI 1.16-2.16). Seeking an infertility evaluation was not significantly associated with age at T1D diagnosis, autoantibody status, or current menstrual regularity. Additionally, having an abnormal infertility evaluation was not associated with mean A1c (OR 0.85, 95% CI 0.62-1.17) or current use of CGM (OR 1.62, 95% CI 0.91-2.91). There were also no factors that were both clinically and statistically significantly associated with miscarriage or problems conceiving a child. These results suggest that women with T1D who are likely to seek infertility evaluations may be more determined to maintain optimal glycemic control with technology such as CGM, or that concern about fertility may drive the decision to use CGM and lower A1c. This study highlights the need for prospective studies to assess the impact of T1D on fertility in women. Disclosure A. Erkin-Cakmak: None. R. Bailey: None. P. Calhoun: Stock/Shareholder; Self; Dexcom, Inc. H. Cakmak: None. J.C. Wong: Consultant; Self; pH Pharma. Research Support; Self; Dexcom, Inc. Funding The Leona M. and Harry B. Helmsley Charitable Trust (G-2016PG-T1D053)

The use of real-time continuous glucose monitoring (CGM) is on the rise in children with type 1 diabetes (T1D), but little is known about how caregivers respond to high and low sensor glucose (SG) values in a real-world setting. We previously reported results from a cross-sectional survey, distributed throughout the United States, of 169 caregivers of children with T1D using CGM. In the current study, 21 of these participants, who were also using insulin pumps, voluntarily contributed their device data anonymously through the Tidepool platform. Up to 90 days of CGM and pump data per participant were analyzed to determine how caregivers respond to SG levels below and above target range. The children had a mean age of 8.8 ± 3.0 years, were 60% female, were 15% ethnic minority or mixed ethnicity, and had an average hemoglobin A1c of 7.2% ± 0.8%. For these participants in a 90-day period, there were a total of 453,908 CGM values, or a mean of 7205 values per 30 days per participant (mean 2263 to 14,323 values per 30 days for each participant). The average SG was 171.7 ± 29.9 mg/dL, with 57.8% of sensor values between 70-180 mg/dL. The percentage of values in hypoglycemic range (180 mg/dL) was 39.3%. Per 30 days, participants had means of 26.6 ± 30.3 hypoglycemic and 73.7 ± 28.6 hyperglycemic events lasting at least 15 minutes. Glucose values were rarely entered into pumps within 5 minutes of having SG values outside of target range for at least 15 minutes and were entered for 2.7% ± 5.3% of hypoglycemic and 3.0% ± 3.5% of hyperglycemic episodes. In response to high SG lasting at least 15 minutes, an insulin bolus was given 4.7% ± 4.0% of the time within 5 minutes and 59.3% ± 36.8% of the time within 60 minutes. The variable response to hypo- and hyperglycemia suggests further interventions that decrease the need for caregivers to perform active tasks in response to CGM data may help ease management burden and improve time in target range. Disclosure H. Howell: None. B.J. Yeung: None. A. Nguyen: None. J.C. Wong: Consultant; Self; pH Pharma. Research Support; Self; Dexcom, Inc. Funding Dexcom, Inc. (IIS-2017-048)

OBJECTIVES: The primary objective was to investigate the mediating effects of diabetes management in the relationship between diabetes symptoms and generic health-related quality of life (HRQOL) in adolescents and young adults (AYAs) with type 1 diabetes. The secondary objective explored patient health communication and perceived treatment adherence barriers as mediators in a serial multiple mediator model. METHODS: The PedsQL 3.2 Diabetes Module 15-item diabetes symptoms summary score, 18-item diabetes management summary score, and PedsQL 4.0 generic core scales were completed in a 10-site national field test study by 418 AYA aged 13 to 25 years with type 1 diabetes. Diabetes symptoms and diabetes management were tested for bivariate and multivariate linear associations with overall generic HRQOL. Mediational analyses were conducted to test the hypothesized mediating effects of diabetes management as an intervening variable between diabetes symptoms and generic HRQOL. RESULTS: The predictive effects of diabetes symptoms on HRQOL were mediated in part by diabetes management. In predictive analytics models utilizing multiple regression analyses, demographic and clinical covariates, diabetes symptoms, and diabetes management significantly accounted for 53% of the variance in generic HRQOL (P < 0.001), demonstrating a large effect size. Patient health communication and perceived treatment adherence barriers were significant mediators in an exploratory serial multiple mediator model. CONCLUSIONS: Diabetes management explains in part the effects of diabetes symptoms on HRQOL in AYA with type 1 diabetes. Patient health communication to healthcare providers and perceived treatment adherence barriers further explain the mechanism in the relationship between diabetes symptoms and overall HRQOL.

Continuous glucose monitoring (CGM) improves glycemic outcomes in children with type 1 diabetes (T1D) and is recommended for regular use. However, it is unclear how families use CGM and if they are using it to its greatest potential. In this study, 193 caregivers of children with T1D using CGM (mean age 9.3±2.8 years, 44% female, 10% ethnic minority, 92% using insulin pump) were recruited throughout the United States by social media to complete a cross-sectional survey about their real-time CGM use. Many children (70%) wore the sensor “all of the time,” with 77% using CGM ≥22 of the last 30 days. Most caregivers (93%) had a CGM feature to see their child’s data remotely in real time; 87% of those who used this feature viewed their child’s data at least once a day when their child was not with them. Though nearly all knew about CGM alert functions, only 73% set alerts for hyperglycemia and 80% for hypoglycemia “all the time.” Frequent retrospective review of CGM data was less common, with only 64% uploading and reviewing data at least monthly. Since starting CGM, most caregivers reported a decrease in their child’s glycated hemoglobin (A1c) (64%) and reduced frequency and severity of hypoglycemia (78%) and hyperglycemia (72%). In regression analysis (adjusted for age, duration of T1D, gender, minority status, caregiver education, geographic region, and pump use), younger age was associated with decrease in A1c (OR 0.78, 95% CI 0.67, 0.92) and decrease in hyperglycemia (OR 0.70, 95% CI 0.58, 0.84). Longer duration of CGM use was associated with decrease in hypoglycemia (OR 2.0, 95% CI 1.0, 4.1). Seventy-two percent reported CGM is “essential,” and 53% felt the greatest benefit is seeing data in real time. In summary, caregivers utilize real-time CGM functions (remote monitoring, alerts) more frequently than they retrospectively review data. Future studies should focus on how caregivers use real-time and retrospective CGM data to make T1D management decisions in order to optimize use of the technology. Disclosure J.C. Wong: Advisory Panel; Self; Tidepool Project. Research Support; Self; Dexcom, Inc. F. Abdulhussein: None. B.J. Yeung: None. E.J. Velazquez: None. Funding Dexcom, Inc.

OBJECTIVE To assess the frequency of continuous glucose monitoring (CGM) device use, factors associated with its use, and the relationship of CGM with diabetes outcomes (HbA1c, severe hypoglycemia [SH], and diabetic ketoacidosis [DKA]). RESEARCH DESIGN AND METHODS Survey questions related to CGM device use 1 year after enrollment in the T1D Exchange clinic registry were completed by 17,317 participants. Participants were defined as CGM users if they indicated using real-time CGM during the prior 30 days. RESULTS Nine percent of participants used CGM (6% of children CONCLUSIONS CGM use is uncommon but associated with lower HbA1c in some age-groups, especially when used more frequently. Factors associated with discontinuation and infrequent use of retrospective analysis of CGM data should be considered in developing next-generation devices and education on CGM use.

Objective Severe hypoglycemia (SH) and diabetic ketoacidosis (DKA) are common serious acute complications of type 1 diabetes (T1D). The aim of this study was to determine the frequency of SH and DKA and identify factors related to their occurrence in the T1D Exchange pediatric and young adult cohort. Research design and methods The analysis included 13 487 participants in the T1D Exchange clinic registry aged 2 to

EWS-WT1 is a chimeric transcription factor resulting from fusion of the N-terminal domain of the Ewing sarcoma gene EWS to the three C-terminal zinc fingers of the Wilms tumor suppressor WT1. This translocation underlies desmoplastic small round cell tumor (DSRCT), which is noted for the abundance of reactive stroma surrounding islets of tumor cells, suggestive of paracrine signals contributing to tumor cell proliferation. Hybridization to high-density oligonucleotide microarrays can be used to identify targets of EWS-WT1. Expression of EWS-WT1 from a tetracycline-regulated promoter leads to the induction of growth-associated genes, of which the most remarkable is the beta-chain of the interleukin-2/15 receptor (IL-2/15Rbeta). Potent transcriptional activation by the chimeric protein maps to two bindings sites within the IL-2/15Rbeta promoter. Analysis of primary DSRCT tumor specimens demonstrates high levels of IL-2/15Rbeta within the tumor cells, along with expression of IL-2 and IL-15 by the abundant hyperplastic endothelial cells within the reactive stroma. Activation of this cytokine signaling pathway is consistent with the nuclear localization of its downstream effectors, phosphorylated STAT3 and STAT5. These observations suggest that the transcriptional induction of a cytokine receptor by a tumor-associated translocation product enables a proliferative response of epithelial cancer cells to ligands secreted by the surrounding stroma.

An important step in the diagnostic evaluation of a patient with recessive limb-girdle muscular dystrophy is the immunohistochemical analysis of the components of the sarcoglycan complex in a muscle biopsy specimen. Even though a primary mutation in any of the four sarcoglycan genes (alpha-, beta-,gamma-, delta-sarcoglycan) may cause secondary deficiencies in all the other sarcoglycan proteins, more specific immunohistochemical patterns have emerged with the potential to guide and abbreviate the necessary molecular genetic investigations. In gamma-sarcoglycan mutations, the pattern consists of absent or prominently reduced gamma-sarcoglycan immunoreactivity in combination with reduced but detectable immunoreactivity for the other components, with preservation of delta-sarcoglycan. In five consecutive patients, this pattern was able to predict primary gamma-sarcoglycan mutations. Five different mutations were found, including a recurrent novel splice mutation, a large deletion of the entire gene and a novel missense mutation (Leu90Ser). The mutation Cys283Tyr, previously restricted to Gypsy populations was found in compound heterozygosity with del521T, common in north Africa. The variety of known and novel mutations found indicates that the immunohistochemical profile of gamma-sarcoglycan mutations is not restricted to a particular mutation or type of mutation, but rather is a general reflection of the effect of gamma-sarcoglycan mutations on the composition of the sarcoglycan complex. Complete immunohistochemical analysis with all available sarcoglycan antibodies, therefore, is a useful tool to guide the molecular genetic investigations that are necessary to arrive at the correct genetic diagnosis in a given case.

Desmoplastic small round cell tumor (DSRCT) is defined genetically by the chimeric fusion of the Ewing's sarcoma and Wilms' tumor genes, generating a novel transcription factor, EWS-WT1. By using cells with inducible EWS-WT1 to screen high-density microarrays, we identified BAIAP3 as a transcriptional target of the chimera. The BAIAP3 promoter is specifically bound in vivo by the (−KTS) isoform of EWS-WT1, consistent with its activation in reporter assays. BAIAP3 encodes a protein implicated in regulated exocytosis, which is colocalized with a secreted growth factor within cytoplasmic organelles. Ectopic expression of BAIAP3 in tumor cells dramatically enhances growth in low serum and colony formation in soft agar. BAIAP3 therefore encodes a transcriptional target of an oncogenic fusion protein that implicates the regulated exocytotic pathway in cancer cell proliferation.