Matthew Benson

Introduction: In a cohort of families of school-age children (8–12.99 years old) with type 1 diabetes, we examined the stability of parent and child diabetes-related distress (DRD) over 6 months and the associations between parent and child DRD and child glycated hemoglobin (HbA1c) over time.Research design and methods: We recruited families from two large pediatric hospital systems in the USA and used validated measures of parent (Parent Problem Areas in Diabetes-Child, PPAID-C) and child (Problem Areas in Diabetes-Child, PAID-C) DRD and children’s HbA1c. We collected data at baseline and 6 months. We calculated minimal clinically important differences in PPAID-C and PAID-C to examine DRD stability and used a linear regression model to examine associations between PPAID-C and PAID-C scores and child HbA1c over time.Results: We recruited n=132 parent–child dyads (mean child age=10.23±1.5 years; 50% male, 86% non-Hispanic white). 60% of children and 55% of parents reported stable DRD levels, 20% of children and 14% of parents reported increasing DRD levels, and 20% of children and 31% of parents reported decreasing DRD levels from baseline to 6 months. In the regression model, child HbA1c and DRD scores at baseline significantly predicted child HbA1c 6 months later, β=0.013, t(157)=2.32, p=0.02.Conclusions: Across 6 months, DRD remained stable or increased in 80% of school-aged children and 69% of parents. Only child HbA1c and DRD at baseline predicted higher child HbA1c 6 months later. Our results suggest it may be valuable to screen families of school-age children for DRD routinely and to develop treatments to help them reduce DRD.

Background: Type 1 diabetes (T1D) management requires following a complex and constant regimen relying on child or caregiver behaviors, skills, and knowledge. Psychological factors such as diabetes distress (DD), depression, and burnout are pertinent considerations in the treatment of pediatric T1D. Approximately 40% of youth and 61% of caregivers experience DD. Implementation of DD screening as part of clinical best practice is recommended and may facilitate treatment referral, perhaps leading to improved health or well-being for youth with T1D and their caregivers. By building on existing institutional infrastructure when available, screening via digital health platforms (applications, or “apps”) may allow for timely screening of, and response to, DD. Objective: This work details the creation, implementation, and refinement of a process to screen for DD in youth and their caregivers in the context of routine T1D care using a digital health platform. Methods: DD screening was implemented in an outpatient endocrinology clinic over 1 year as part of a larger screen-to-treat trial for children aged 8‐12.99 years and their caregivers. Validated measures were sent via digital health platform to be completed prior to the clinic visit. Results were initially reviewed manually, but a digital best practice alert (BPA) was later built to notify staff of elevated scores. Families experiencing DD received resources sent via the digital health platform. For this secondary analysis, child demographics and glycated hemoglobin A_1c (HbA_1c) were collected. Results: During the screening period, absolute completion rates were 36.78% and 38.83%, with adjusted screening rates at 52.02% and 54.48%, for children and caregivers, respectively. A total of 21 children (mean HbA_1c 8.04%, SD 1.39%) and 26 caregivers (child mean HbA_1c 8.04%, SD 1.72%) reported elevated DD. Prior to BPA development, resources were sent to all but 1 family. After BPA implementation, all families were sent resources. Conclusions: Early findings indicate that DD education, screening, and response can be integrated via digital platforms in a freestanding outpatient endocrinology clinic, thereby facilitating timely treatment referral and provision of resources for those identified with distress. Notably, in the observed 1-year screening period, screening rates were low, and barriers to implementation were identified. While some implementation challenges were iteratively addressed, there is a need for future quality improvement initiatives to improve screening rates and the identification of, or response to, DD in our pediatric patients and their families.

Autosomal dominant hypocalcemia (ADH) is due to enhanced calcium-dependent signaling caused by heterozygous gain-of-function (GOF) variants in the CASR gene (ADH1) or in the GNA11 gene, encoding Gα11 (ADH2). Both ADH1 and ADH2 are associated with hypocalcemia and normal or inappropriately low levels of circulating PTH. ADH1 patients typically manifest hypercalciuria, while ADH2 is associated with short stature in approximately 42% of cases. We evaluated a 10-yr-old boy with hypoparathyroidism and short stature. Biochemical analyses revealed hypocalcemia, hyperphosphatemia, and inconsistent hypercalciuria. Genetic analyses revealed a de novo heterozygous p.Leu723Arg variant in CASR. We characterized the expression of recombinant WT and Leu723Arg calcium-sensing receptor (CaSR) proteins in HEK293 cells and assessed G protein activation in vitro by CaSR using bioluminescence resonance energy transfer. Transient expression studies showed the Leu723Arg variant was normally expressed but resulted in a significantly lower EC50 for extracellular calcium activation of G11 but not other G proteins (ie, Gi, Gq, Gs). The Leu723Arg substitution has a novel GOF phenotype that leads to biased CaSR activation of G11 signaling, suggesting that residue 723 specifies activation of G11 but not other G proteins. Similar studies of a previously described CaSR variant associated with hypoparathyroidism and short stature, Leu616Val, showed no changes in any G protein pathways, indicating it is likely to be a benign variant. Given the preferential activation of G11 by the Leu723Arg CaSR variant, we propose that the patient’s short stature shares a similar basis to that in patients with ADH2 due to GOF variants in GNA11.

Objective: This paper reports on the initial outcomes of a new mHealth intervention to reduce diabetes distress (DD) in families of school-age children living with type 1 diabetes (T1D) entitled, ‘Remedy to Diabetes Distress’ (R2D2). Methods: We randomized 34 families (mean child age = 10 ± 1.4 years; 53% male, 85% White, mean HbA1c = 7.24 ± 0.71%) to one of three delivery arms differing only by number of telehealth visits over a 10-week period: zero visits = self-guided (SG), three visits = enhanced self-guided (ESG), or eight visits = video visits (VV). All families had 24 × 7 access to digital treatment materials for 10 weeks. We examined the feasibility and acceptability of R2D2. We used the Problem Areas in Diabetes-Child (PPAIDC and PAIDC, parent and child, respectively) to examine treatment effects by time and delivery arm. We performed sensitivity analyses to characterize families who responded to R2D2. Results: It was feasible for families to access R2D2 mHealth content independently, though attendance at telehealth visits was variable. Parents and children reported high satisfaction scores. There were significant pre-post reductions in PPAIDC (p = 0.026) and PAIDC (p = 0.026) scores but no differences by delivery arm. There were no differences in child age, sex, race, or pre-treatment HbA1c for responders versus non-responders, though families who responded reported higher PPAID-C scores pre-treatment (p = 0.01) and tended to report shorter diabetes duration (p = 0.08). Conclusions: Initial results support the acceptability and treatment effects of R2D2 regardless of the frequency of adjunctive virtual visits. Characterizing responders may help to identify families who could benefit from R2D2 in the future.

Introduction Diabetes distress (DD) describes the unrelenting emotional and behavioral challenges of living with, and caring for someone living with, type 1 diabetes (T1D). We investigated associations between parent-reported and child-reported DD, T1D device use, and child glycated hemoglobin (HbA1c) in 157 families of school-age children. Research design and methods Parents completed the Parent Problem Areas in Diabetes-Child (PPAID-C) and children completed the Problem Areas in Diabetes-Child (PAID-C) to assess for DD levels. Parents also completed a demographic form where they reported current insulin pump or continuous glucose monitor (CGM) use (ie, user/non-user). We measured child HbA1c using a valid home kit and central laboratory. We used correlations and linear regression for our analyses. Results Children were 49% boys and 77.1% non-Hispanic white (child age (mean±SD)=10.2±1.5 years, T1D duration=3.8±2.4 years, HbA1c=7.96±1.62%). Most parents self-identified as mothers (89%) and as married (78%). Parents’ mean PPAID-C score was 51.83±16.79 (range: 16–96) and children’s mean PAID-C score was 31.59±12.39 (range: 11–66). Higher child HbA1c correlated with non-pump users (r=−0.16, pConclusions Our analyses suggest parent DD is a strong predictor of child HbA1c and is another modifiable treatment target for lowering child HbA1c.

Background: Rickets and vitamin D deficiency appeared to increase in Alaskan children starting in the 1990s. We evaluated the epidemiology of rickets and vitamin D deficiency in Alaska native (AN) children in 2001–2010. Methods: We analyzed 2001–2010 visits with rickets or vitamin D deficiency diagnosis for AN and American Indian children and the general US population aged Results: In AN children, annual rickets-associated hospitalization rate (2.23/100,000 children/year) was higher than the general US rate (1.23; 95% CI 1.08–1.39). Rickets incidence increased with latitude. Rickets/vitamin D deficiency cases were more likely to have malnutrition (OR 38.1; 95% CI 4.9–294), had similar breast-feeding prevalence, and were less likely to have received vitamin D supplementation (OR 0.23; 95% CI 0.1–0.87) than controls. Conclusions: Our findings highlight the importance of latitude, malnutrition, and lack of vitamin D supplementation as risk factors for rickets.

Richard Lifton and colleagues identify somatic and germline mutations in the CACNA1D calcium channel gene in aldosterone-producing adenomas and primary aldosteronism. Their functional studies show that these mutations result in channel activation at more hyperpolarized membrane potentials, implicating increased Ca2+ influx in disease pathogenesis. Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel gene KCNJ5 that result in cell depolarization and Ca2+ influx cause ∼40% of these tumors1. We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5. The altered residues lie in the S6 segments that line the channel pore. Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation. These effects are inferred to cause increased Ca2+ influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa2. We also identified de novo germline mutations at identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain-of-function Ca2+ channel mutations in APAs and primary aldosteronism.