Intergenerational protective anti-gut commensal immunoglobulin G originates in early life.

Maternal immunoglobulins of the class G (IgGs) protect offspring from enteric infection, but when, where, and how these antibodies are physiologically generated and confer protection remains enigmatic. We found that circulating IgGs in adult mice preferentially bind early-life gut commensal bacteria over their own adult gut commensal bacteria. IgG-secreting plasma cells specific for early-life gut bacteria appear in the intestine soon after weaning, where they remain into adulthood. Manipulating exposure to gut bacteria or plasma cell development before, but not after, weaning reduced IgG-secreting plasma cells targeting early-life gut bacteria throughout life. Further, the development of this anti-gut commensal IgG response coincides with the early-life interval in which goblet cell-associated antigen passages (GAPs) are present in the colon. Offspring of dams "perturbed" by B cell ablation or reduced bacterial exposure in early life were more susceptible to enteric pathogen challenge. In contrast to current concepts, protective maternal IgGs targeted translocating gut commensals in the offspring, not the enteric pathogen. These early-life events affecting anti-commensal IgG production have intergenerational effects for protection of the offspring.

Insulin Pump Utilization in 2017-2021 for More Than 22,000 Children and Adults With Type 1 Diabetes: A Multicenter Observational Study.

This large type 1 diabetes cohort study showed that insulin pump utilization has increased over time and that use differs by sex, insurance type, and race/ethnicity. Insulin pump use was associated with more optimal A1C, increased use of continuous glucose monitoring (CGM), and lower rates of diabetic ketoacidosis and severe hypoglycemia. People who used an insulin pump with CGM had lower rates of acute events than their counterparts who used an insulin pump without CGM. These findings highlight the need to improve access of diabetes technology through provider engagement, multidisciplinary approaches, and efforts to address health inequities.

Exploring the determinants of successful implementation of a preventive mental health and wellness intervention for Afghan refugee families: a qualitative analysis.

Many refugee children experience trauma in early childhood. Effective, tailored interventions are needed to improve refugee children's access to preventive mental health. We interviewed refugee-serving stakeholders and parents participating in an evidence-based preventive mental health and wellness intervention adapted for Afghan refugee children and families who may have experienced trauma. Interview guide development was informed by two implementation science frameworks: the Consolidated Framework for Implementation Research and the Model for Adaptation Design and Impact. A three-person team coded transcripts via rapid qualitative analysis, and the study team reached consensus on themes. Six refugee-serving facilitators and five refugee parents discussed key determinants of successful implementation. Themes included: (i) modeling cultural humility to promote communication about emotions; (ii) needed linguistic support and referral networks to avoid miscommunications and missed communications; (iii) bridging connections between children, families and schools; (iv) different takeaways, or differing goals and expectations between facilitators and participants; and (v) timely, specific cultural considerations to overcome participation barriers. Overall, we found key determinants of successful implementation of a preventive mental health and wellness intervention for refugee children and families included adaptations to enhance cultural humility and sensitivity to cultural context while strengthening communication among facilitators, children and families.

The Design of the Electronic Health Record in Type 1 Diabetes Centers: Implications for Metrics and Data Availability for a Quality Collaborative.

BACKGROUND: Systematic and comprehensive data acquisition from the electronic health record (EHR) is critical to the quality of data used to improve patient care. We described EHR tools, workflows, and data elements that contribute to core quality metrics in the Type 1 Diabetes Exchange Quality Improvement Collaborative (T1DX-QI). METHOD: We conducted interviews with quality improvement (QI) representatives at 13 T1DX-QI centers about their EHR tools, clinic workflows, and data elements. RESULTS: All centers had access to structured data tools, nine had access to patient questionnaires and two had integration with a device platform. There was significant variability in EHR tools, workflows, and data elements, thus the number of available metrics per center ranged from four to 17 at each site. Thirteen centers had information about glycemic outcomes and diabetes technology use. Seven centers had measurements of additional self-management behaviors. Centers captured patient-reported outcomes including social determinants of health (n = 9), depression (n = 11), transition to adult care (n = 7), and diabetes distress (n = 3). Various stakeholders captured data including health care professionals, educators, medical assistants, and QI coordinators. Centers that had a paired staffing model in clinic encounters distributed the burden of data capture across the health care team and was associated with a higher number of available data elements. CONCLUSIONS: The lack of standardization in EHR tools, workflows, and data elements captured resulted in variability in available metrics across centers. Further work is needed to support measurement and subsequent improvement in quality of care for individuals with type 1 diabetes.

Gut microbiota induces weight gain and inflammation in the gut and adipose tissue independent of manipulations in diet, genetics, and immune development.

Obesity and the metabolic syndrome are complex disorders resulting from multiple factors including genetics, diet, activity, inflammation, and gut microbes. Animal studies have identified roles for each of these, however the contribution(s) specifically attributed to the gut microbiota remain unclear, as studies have used combinations of genetically altered mice, high fat diet, and/or colonization of germ-free mice, which have an underdeveloped immune system. We investigated the role(s) of the gut microbiota driving obesity and inflammation independent of manipulations in diet and genetics in mice with fully developed immune systems. We demonstrate that the human obese gut microbiota alone was sufficient to drive weight gain, systemic, adipose tissue, and intestinal inflammation, but did not promote intestinal barrier leak. The obese microbiota induced gene expression promoting caloric uptake/harvest but was less effective at inducing genes associated with mucosal immune responses. Thus, the obese gut microbiota is sufficient to induce weight gain and inflammation.

An "All-Data-on-Hand" Deep Learning Model to Predict Hospitalization for Diabetic Ketoacidosis in Youth With Type 1 Diabetes: Development and Validation Study.

BACKGROUND: Although prior research has identified multiple risk factors for diabetic ketoacidosis (DKA), clinicians continue to lack clinic-ready models to predict dangerous and costly episodes of DKA. We asked whether we could apply deep learning, specifically the use of a long short-term memory (LSTM) model, to accurately predict the 180-day risk of DKA-related hospitalization for youth with type 1 diabetes (T1D). OBJECTIVE: We aimed to describe the development of an LSTM model to predict the 180-day risk of DKA-related hospitalization for youth with T1D. METHODS: We used 17 consecutive calendar quarters of clinical data (January 10, 2016, to March 18, 2020) for 1745 youths aged 8 to 18 years with T1D from a pediatric diabetes clinic network in the Midwestern United States. The input data included demographics, discrete clinical observations (laboratory results, vital signs, anthropometric measures, diagnosis, and procedure codes), medications, visit counts by type of encounter, number of historic DKA episodes, number of days since last DKA admission, patient-reported outcomes (answers to clinic intake questions), and data features derived from diabetes- and nondiabetes-related clinical notes via natural language processing. We trained the model using input data from quarters 1 to 7 (n=1377), validated it using input from quarters 3 to 9 in a partial out-of-sample (OOS-P; n=1505) cohort, and further validated it in a full out-of-sample (OOS-F; n=354) cohort with input from quarters 10 to 15. RESULTS: DKA admissions occurred at a rate of 5% per 180-days in both out-of-sample cohorts. In the OOS-P and OOS-F cohorts, the median age was 13.7 (IQR 11.3-15.8) years and 13.1 (IQR 10.7-15.5) years; median glycated hemoglobin levels at enrollment were 8.6% (IQR 7.6%-9.8%) and 8.1% (IQR 6.9%-9.5%); recall was 33% (26/80) and 50% (9/18) for the top-ranked 5% of youth with T1D; and 14.15% (213/1505) and 12.7% (45/354) had prior DKA admissions (after the T1D diagnosis), respectively. For lists rank ordered by the probability of hospitalization, precision increased from 33% to 56% to 100% for positions 1 to 80, 1 to 25, and 1 to 10 in the OOS-P cohort and from 50% to 60% to 80% for positions 1 to 18, 1 to 10, and 1 to 5 in the OOS-F cohort, respectively. CONCLUSIONS: The proposed LSTM model for predicting 180-day DKA-related hospitalization was valid in this sample. Future research should evaluate model validity in multiple populations and settings to account for health inequities that may be present in different segments of the population (eg, racially or socioeconomically diverse cohorts). Rank ordering youth by probability of DKA-related hospitalization will allow clinics to identify the most at-risk youth. The clinical implication of this is that clinics may then create and evaluate novel preventive interventions based on available resources.

The Development and Initial Validation of Items to Assess Parent Fear of Nighttime Hypoglycemia.

OBJECTIVE: Parents of youth with type 1 diabetes (T1D) are fearful their children will experience nighttime hypoglycemia. Currently, the Hypoglycemia Fear Survey for Parents (HFS-P) lacks items that specifically assess parents' nighttime fear. This study aimed to fill this gap by rigorously identifying new items to specifically assess parent fear of nighttime hypoglycemia and then examine the psychometric properties of the revised Hypoglycemia Fear Survey for Parents including Nighttime Fear (HFS-P-NF). METHODS: For Phase 1, we recruited 10 pediatric diabetes providers and 15 parents/caregivers of youth with T1D to generate items related to fear of nighttime hypoglycemia. For Phase 2, we recruited an additional 20 parents/caregivers to pilot-test the newly generated items. For Phase 3, we recruited another 165 parents/caregivers to evaluate structural validity via confirmatory factor analyses, reliability, and content validity of the revised HFS-P-NF. RESULTS: In Phase 1, we generated 54 items. In Phase 2, we removed 34 items due to violations of distributional normality and nonsignificant correlations. In Phase 3, a four-factor model reflecting behaviors maintaining high glucose, helplessness, negative social consequences, and nighttime worries was the best fitting model for the HFS-P-NF. The new items demonstrated strong internal consistency (α = 0.96) and strong to moderate relationships with criterion and content validity measures. CONCLUSION: The current study provides initial evidence of validity and reliability for new items on the HFS-P-NF that broadened the conceptualization of parent fear of nighttime hypoglycemia. These findings are important to clinicians who may consider screening for parent fear of nighttime hypoglycemia more comprehensively.

The gut microbiota of people with asthma influences lung inflammation in gnotobiotic mice.

The gut microbiota in early childhood is linked to asthma risk, but may continue to affect older patients with asthma. Here, we profile the gut microbiota of 38 children (19 asthma, median age 8) and 57 adults (17 asthma, median age 28) by 16S rRNA sequencing and find individuals with asthma harbored compositional differences from healthy controls in both adults and children. We develop a model to aid the design of mechanistic experiments in gnotobiotic mice and show enterotoxigenic Bacteroides fragilis (ETBF) is more prevalent in the gut microbiota of patients with asthma compared to healthy controls. In mice, ETBF, modulated by community context, can increase oxidative stress in the lungs during allergic airway inflammation (AAI). Our results provide evidence that ETBF affects the phenotype of airway inflammation in a subset of patients with asthma which suggests that therapies targeting the gut microbiota may be helpful tools for asthma control.

Effect of Tight Glycemic Control on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial.

Importance: Near normalization of glucose levels instituted immediately after diagnosis of type 1 diabetes has been postulated to preserve pancreatic beta cell function by reducing glucotoxicity. Previous studies have been hampered by an inability to achieve tight glycemic goals. Objective: To determine the effectiveness of intensive diabetes management to achieve near normalization of glucose levels on preservation of pancreatic beta cell function in youth with newly diagnosed type 1 diabetes. Design, Setting, and Participants: This randomized, double-blind, clinical trial was conducted at 6 centers in the US (randomizations from July 20, 2020, to October 13, 2021; follow-up completed September 15, 2022) and included youths with newly diagnosed type 1 diabetes aged 7 to 17 years. Interventions: Random assignment to intensive diabetes management, which included use of an automated insulin delivery system (n = 61), or standard care, which included use of a continuous glucose monitor (n = 52), as part of a factorial design in which participants weighing 30 kg or more also were assigned to receive either oral verapamil or placebo. Main Outcomes and Measures: The primary outcome was mixed-meal tolerance test-stimulated C-peptide area under the curve (a measure of pancreatic beta cell function) 52 weeks from diagnosis. Results: Among 113 participants (mean [SD] age, 11.8 [2.8] years; 49 females [43%]; mean [SD] time from diagnosis to randomization, 24 [5] days), 108 (96%) completed the trial. The mean C-peptide area under the curve decreased from 0.57 pmol/mL at baseline to 0.45 pmol/mL at 52 weeks in the intensive management group, and from 0.60 to 0.50 pmol/mL in the standard care group (treatment group difference, -0.01 [95% CI, -0.11 to 0.10]; P = .89). The mean time in the target range of 70 to 180 mg/dL, measured with continuous glucose monitoring, at 52 weeks was 78% in the intensive management group vs 64% in the standard care group (adjusted difference, 16% [95% CI, 10% to 22%]). One severe hypoglycemia event and 1 diabetic ketoacidosis event occurred in each group. Conclusions and Relevance: In youths with newly diagnosed type 1 diabetes, intensive diabetes management, which included automated insulin delivery, achieved excellent glucose control but did not affect the decline in pancreatic C-peptide secretion at 52 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT04233034.

Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial.

Importance: In preclinical studies, thioredoxin-interacting protein overexpression induces pancreatic beta cell apoptosis and is involved in glucotoxicity-induced beta cell death. Calcium channel blockers reduce these effects and may be beneficial to beta cell preservation in type 1 diabetes. Objective: To determine the effect of verapamil on pancreatic beta cell function in children and adolescents with newly diagnosed type 1 diabetes. Design, Setting, and Participants: This double-blind, randomized clinical trial including children and adolescents aged 7 to 17 years with newly diagnosed type 1 diabetes who weighed 30 kg or greater was conducted at 6 centers in the US (randomized participants between July 20, 2020, and October 13, 2021) and follow-up was completed on September 15, 2022. Interventions: Participants were randomly assigned 1:1 to once-daily oral verapamil (n = 47) or placebo (n = 41) as part of a factorial design in which participants also were assigned to receive either intensive diabetes management or standard diabetes care. Main Outcomes and Measures: The primary outcome was area under the curve values for C-peptide level (a measure of pancreatic beta cell function) stimulated by a mixed-meal tolerance test at 52 weeks from diagnosis of type 1 diabetes. Results: Among 88 participants (mean age, 12.7 [SD, 2.4] years; 36 were female [41%]; and the mean time from diagnosis to randomization was 24 [SD, 4] days), 83 (94%) completed the trial. In the verapamil group, the mean C-peptide area under the curve was 0.66 pmol/mL at baseline and 0.65 pmol/mL at 52 weeks compared with 0.60 pmol/mL at baseline and 0.44 pmol/mL at 52 weeks in the placebo group (adjusted between-group difference, 0.14 pmol/mL [95% CI, 0.01 to 0.27 pmol/mL]; P = .04). This equates to a 30% higher C-peptide level at 52 weeks with verapamil. The percentage of participants with a 52-week peak C-peptide level of 0.2 pmol/mL or greater was 95% (41 of 43 participants) in the verapamil group vs 71% (27 of 38 participants) in the placebo group. At 52 weeks, hemoglobin A1c was 6.6% in the verapamil group vs 6.9% in the placebo group (adjusted between-group difference, -0.3% [95% CI, -1.0% to 0.4%]). Eight participants (17%) in the verapamil group and 8 participants (20%) in the placebo group had a nonserious adverse event considered to be related to treatment. Conclusions and Relevance: In children and adolescents with newly diagnosed type 1 diabetes, verapamil partially preserved stimulated C-peptide secretion at 52 weeks from diagnosis compared with placebo. Further studies are needed to determine the longitudinal durability of C-peptide improvement and the optimal length of therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT04233034.

Patient Demographics and Clinical Outcomes Among Type 1 Diabetes Patients Using Continuous Glucose Monitors: Data From T1D Exchange Real-World Observational Study.

BACKGROUND: The benefits of Continuous Glucose Monitoring (CGM) on glycemic management have been demonstrated in numerous studies; however, widespread uptake remians limited. The aim of this study was to provide real-world evidence of patient attributes and clinical outcomes associated with CGM use across clinics in the U.S. based T1D Exchange Quality Improvement (T1DX-QI) Collaborative. METHOD: We examined electronic Health Record data from eight endocrinology clinics participating in the T1DX-QI Collaborative during the years 2017-2019. RESULTS: Among 11,469 type 1 diabetes patients, 48% were CGM users. CGM use varied by race/ethnicity with Non-Hispanic Whites having higher rates of CGM use (50%) compared to Non-Hispanic Blacks (18%) or Hispanics (38%). Patients with private insurance were more likely to use CGM (57.2%) than those with public insurance (33.3%) including Medicaid or Medicare. CGM users had lower median HbA1c (7.7%) compared to nonusers (8.4%). Rates of diabetic ketoacidosis (DKA) and severe hypoglycemia were significantly higher in nonusers compared to CGM users. CONCLUSION: In this real-world study of patients in the T1DX-QI Collaborative, CGM users had better glycemic control and lower rates of DKA and severe hypoglycemia (SH) events, compared to nonusers; however, there were significant sociodemographic disparities in CGM use. Quality improvement and advocacy measures to promote widespread and equitable CGM uptake have the potential to improve clinical outcomes.

Novel expansion of a well-established antimicrobial stewardship program: Enhancing program efficiency and reach.

OBJECTIVE: To evaluate efficiency and impact of a novel antimicrobial stewardship program (ASP) prospective-audit-with-feedback (PAF) review process using the Cerner Multi-Patient Task List (MPTL). DESIGN: Retrospective cohort study. SETTING: A 367-bed free-standing, pediatric academic medical center. METHODS: The ASP PAF review process expanded to monitor all systemic and inhaled antibiotics through use of the MPTL on July 23, 2020. Average number of daily ASP reviews, absolute number of monthly interventions, and time to conduct ASP reviews were compared between the preimplementation period and the postimplementation period following expansion. Antibiotic days of therapy (DOT) per 1,000 patient days for overall and select antibiotics were compared between periods. ASP intervention characteristics were assessed. RESULTS: Average daily ASP reviews significantly increased following program expansion (9 vs 14 reviews; P < .0001), and the absolute number of ASP interventions each month also increased (34 vs 52 interventions; P ≤ .0001). Time to conduct daily ASP reviews increased in the postimplementation period (1.03 vs 1.32 hours). Overall antibiotic DOT per 1,000 patient days significantly decreased in the postimplementation period (457.9 vs 427.9; P < .0001) as well as utilization of select, narrow-spectrum antibiotics such as ampicillin and clindamycin. Intervention type and antibiotics were similar between periods. The ASP documented 128 "nonantibiotic interventions" in the postimplementation period, including culture and/or susceptibility testing (32.8%), immunizations (25.8%), and additional diagnostic testing (22.7%). CONCLUSIONS: Implementation of an ASP PAF review process using the MPTL allowed for efficient expansion of a pre-existing ASP and a decrease in overall antibiotic utilization. ASP documentation was enhanced to fully track the impact of the program.

Cash-Only INcentives to promote insulin DOSE engagement: A protocol paper for the pilot randomized controlled trial of COIN2DOSE.

BACKGROUND: Most adolescents with type 1 diabetes (T1D) do not achieve a glycated hemoglobin (HbA1c) <7.0%, which is the current clinical target. mHealth can offer a scalable and age-appropriate delivery method for behavioral interventions to lower adolescents' HbA1c levels, while applying established behavior change and behavioral economics theories can enhance scientific rigor. METHODS: We aim to conduct a pilot randomized clinical trial of a novel mHealth intervention called Coin2Dose (Cash-Only INcentives To promote insulin DOSE engagement), in a sample of youth with T1D: 1) to obtain measures of feasibility and acceptability and 2) to examine preliminary efficacy versus a standard care control group based on differences in youth's daily BOLUS scores, HbA1c levels, and Time in Range (TIR) at post-intervention and 3-month post-intervention follow-up. This pilot RCT is already registered in http://ClinicalTrials.gov (NCT#05280184). RESULTS: Our pilot will recruit youth with T1D 11-17 years-old who use an insulin pump or Bluetooth connected insulin pen and have an average daily BOLUS score ≤2.5. Youth randomized to Coin2Dose will receive the intervention for 12 weeks followed by a 12-week maintenance period. The pilot is scheduled to start July 2022 and to conclude in 2025. DISCUSSION: At the conclusion of the pilot, we will have information about the feasibility and acceptability of two different behavioral economic incentive structures for improving BOLUS scores. The work is anticipated to progress to final efficacy trial. We will disseminate study results through presentations at local, national, and international conferences and through peer-reviewed diabetes and psychology journals.

Impact of diabetes status and related factors on COVID-19-associated hospitalization: A nationwide retrospective cohort study of 116,370 adults with SARS-CoV-2 infection.

AIMS: We examined diabetes status (no diabetes; type 1 diabetes [T1D]; type 2 diabetes [T2D]) and other demographic and clinical factors as correlates of coronavirus disease 2019 (COVID-19)-related hospitalization. Further, we evaluated predictors of COVID-19-related hospitalization in T1D and T2D. METHODS: We analyzed electronic health record data from the de-identified COVID-19 database (December 2019 through mid-September 2020; 87 US health systems). Logistic mixed models were used to examine predictors of hospitalization at index encounters associated with confirmed SARS-CoV-2 infection. RESULTS: In 116,370 adults (>=18 years old) with COVID-19 (93,098 no diabetes; 802 T1D; 22,470 T2D), factors that independently increased risk for hospitalization included diabetes, male sex, public health insurance, decreased body mass index (BMI; <25.0-29.9 kg/m2), increased BMI (>25.0-29.9 kg/m2), vitamin D deficiency/insufficiency, and Elixhauser comorbidity score. After further adjustment for concurrent hyperglycemia and acidosis in those with diabetes, hospitalization risk was substantially higher in T1D than T2D and in those with low vitamin D and elevated hemoglobin A1c (HbA1c). CONCLUSIONS: The higher hospitalization risk in T1D versus T2D warrants further investigation. Modifiable risk factors such as vitamin D deficiency/insufficiency, BMI, and elevated HbA1c may serve as prognostic indicators for COVID-19-related hospitalization in adults with diabetes.

Adjusted Cutoff Scores Increase Sensitivity of Depression Screening Measures in Adolescents With Type 1 Diabetes.

OBJECTIVE: To measure the acceptability and diagnostic accuracy of commonly used depression screening measures to determine ideal cutoff scores that sensitively identify depressive disorders in adolescents with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: One hundred adolescents (12-17 years old) completed a reference standard, semistructured diagnostic interview and both long and short versions of five commonly used depression screening measures in the United States. To assess feasibility and acceptability, we used screener completion time and participant ratings, respectively. We used descriptive statistics, area under the receiver operating characteristic (ROC) curve analyses, and paired-sample area differences under the ROC curve to assess each measure's diagnostic validity against our reference standard and to determine ideal cutoff scores for this sample. RESULTS: Adolescents had a mean age of 15.0 ± 1.7 years, time since T1D diagnosis of 6.0 ± 4.1 years, and glycated hemoglobin (HbA1c) of 8.9 ± 1.8%. Sixty percent of adolescents were male, 15% endorsed a current depressive disorder, and 15% endorsed lifetime suicidality. Measures demonstrated low sensitivity (0.33-0.67) to detect current depressive disorders using preexisting cutoff scores. However, adjusted cutoff scores increased sensitivity and reduced false negatives. All depression screening measures demonstrated "good" to "excellent" predictive validity, and the Children's Depression Inventory-2 Short version demonstrated significantly greater diagnostic accuracy than the Patient Health Questionnare-2 item version for adolescents. CONCLUSIONS: Clinics should consider using screening measures with the greatest diagnostic accuracy as identified in this study and adjusting measure cutoff scores to increase sensitivity and reduce false negatives.

Pilot Wellness Program With Adapted Social-Emotional Learning and COVID-19 Curriculum for Refugee Youth.

Refugee children are less likely than their non-refugee peers to receive timely diagnoses and treatment for mental and/or behavioral health problems, despite facing multiple risk factors including potential exposure to trauma during premigration, migration, and postmigration experiences. Social-Emotional Learning offers preventive mental health education for children through well-established, evidenced-based curricula. Although there are clear benefits of Social-Emotional Learning curricula, which can help children achieve long-term success emotionally and academically, Social-Emotional Learning curricula are not easily accessible for refugee children, often because of language and socioeconomic barriers. In this pilot study, we evaluated the feasibility and acceptability of an adapted Social-Emotional Learning program that included culturally specific, multilingual, trauma-informed wellness, and physical education during the COVID-19 pandemic: EMPOWER (Emotions Program Outside the Clinic With Wellness Education for Refugees). We used the Intervention Mapping framework which guided the (1) planning, (2) program development, and (3) mixed-method evaluation of the feasibility and acceptability of the EMPOWER pilot. We found that this adaptation was well-received by Afghan refugee families and that COVID-19 safety measures were well-understood after participation. Challenges emerged around videoconferencing connectivity and around finding a common language for discussing emotions. Future iterations of the program and evaluations will require continued partnerships with community members and organizations. As we continue and expand EMPOWER, we aim to evaluate short-term improvement in Social-Emotional Learning competence as well as long-term mental and behavioral health outcomes for children and their families.

Targeted Activation of G-Protein Coupled Receptor-Mediated Ca2+ Signaling Drives Enhanced Cartilage-Like Matrix Formation.

Intracellular calcium ([Ca2+]i) signaling is a critical regulator of chondrogenesis, chondrocyte differentiation, and cartilage development. Calcium (Ca2+) signaling is known to direct processes that govern chondrocyte gene expression, protein synthesis, cytoskeletal remodeling, and cell fate. Control of chondrocyte/chondroprogenitor Ca2+ signaling has been attempted through mechanical and/or pharmacological activation of endogenous Ca2+ signaling transducers; however, such approaches can lack specificity and/or precision regarding Ca2+ activation mechanisms. Synthetic signaling platforms permitting precise and selective Ca2+ signal transduction can improve dissection of the roles that [Ca2+]i signaling plays in chondrocyte behavior. One such platform is the chemogenetic DREADD (designer receptor exclusively activated by designer drugs) hM3Dq, which activates [Ca2+]i signaling via the Gαq-PLCß-IP3-ER pathway upon clozapine N-oxide (CNO) administration. We previously demonstrated hM3Dq's ability to precisely and synthetically initiate robust [Ca2+]i transients and oscillatory [Ca2+]i signaling in chondrocyte-like ATDC5 cells. Here, we investigate the effects that long-term CNO stimulatory culture have on hM3Dq [Ca2+]i signaling dynamics, proliferation, and protein deposition in 2D ATDC5 cultures. Long-term culturing under repeated CNO stimulation modified the temporal dynamics of hM3Dq [Ca2+]i signaling, increased cell proliferation, and enhanced matrix production in a CNO dose- and frequency-dependent manner, and triggered the formation of cell condensations that developed aligned, anisotropic neotissue structures rich in cartilaginous proteoglycans and collagens, all in the absence of differentiation inducers. This study demonstrated Gαq-G-protein coupled receptor (GPCR)-mediated [Ca2+]i signaling involvement in chondroprogenitor proliferation and cartilage-like matrix production, and it established hM3Dq as a powerful tool for elucidating the role of GPCR-mediated Ca2+ signaling in chondrogenesis and chondrocyte differentiation. Impact statement Targeted activation of intracellular calcium signaling has gained attention as a cartilage tissue engineering adjuvant approach. In the present study, we demonstrated that activation of hM3Dq, an engineered chemogenetic activator of the Gαq-pathway and IP3-mediated intracellular calcium signaling, drives accelerated development of mesenchyme-like cell condensations and cartilaginous neotissue formation in chondrocyte-like cell cultures in vitro and does so without the requirement of differentiation factors/inducers. These outcomes highlight the potential of targeted/synthetic Gαq-pathway activation, specifically using novel chemogenetic approaches, to enhance the study of chondrocyte physiology and improve cartilage tissue engineering approaches.

Factors Associated With Achieving Target A1C in Children and Adolescents With Type 1 Diabetes: Findings From the T1D Exchange Quality Improvement Collaborative.

The optimal care of type 1 diabetes involves consistent glycemic management to avoid short- and long-term complications. However, despite advancements in diabetes technology and standards, achieving adequate glycemic levels in children and adolescents remains a challenge. This study aimed to identify factors associated with achieving the recommended A1C target of <7% from the United States-based multicenter T1D Exchange Quality Improvement Collaborative cohort, including 25,383 children and adolescents living with type 1 diabetes.