Safety and prescribing recommendations for verapamil in newly diagnosed pediatric type 1 diabetes (T1D): The CLVer experience.

Objectives: To report the safety and side effects associated with taking verapamil for beta-cell preservation in children with newly-diagnosed T1D. Research Design and Methods: Eighty-eight participants aged 8.5 to 17.9 years weighing ≥ 30 kg were randomly assigned to verapamil (N = 47) or placebo (N = 41) within 31 days of T1D diagnosis and followed for 12 months from diagnosis, main CLVer study. Drug dosing was weight-based with incremental increases to full dosage. Side effect monitoring included serial measurements of pulse, blood pressure, liver enzymes, and electrocardiograms (ECGs). At study end, participants were enrolled in an observational extension study (CLVerEx), which is ongoing. No study drug is provided during the extension, but participants may use verapamil if prescribed by their diabetes care team. Results: Overall rates of adverse events were low and comparable between verapamil and placebo groups. There was no difference in the frequency of liver function abnormalities. Three CLVer participants reduced or discontinued medication due to asymptomatic ECG changes. One CLVerEx participant (18 years old), treated with placebo during CLVer, who had not had a monitoring ECG, experienced complete AV block with a severe hypotensive episode 6 weeks after reaching his maximum verapamil dose following an inadvertent double dose on the day of the event. Conclusions: The use of verapamil in youth newly-diagnosed with T1D appears generally safe and well tolerated with appropriate monitoring. We strongly recommend monitoring for potential side effects including an ECG at screening and an additional ECG once full dosage is reached.ClinicalTrials.gov number: NCT04233034.

Effect of 48 Months of Closed-Loop Insulin Delivery on Residual C-Peptide Secretion and Glycemic Control in Newly Diagnosed Youth With Type 1 Diabetes: A Randomized Trial.

OBJECTIVE: We evaluated the effect of long-term intensive metabolic control with hybrid closed-loop (CL) on residual C-peptide secretion and glucose control compared with standard insulin therapy in youth with type 1 diabetes over 48 months. RESEARCH DESIGN AND METHODS: Following the 24-month primary phase of a multicenter, randomized, parallel trial of 96 newly diagnosed youth aged 10 to 16.9 years, participants were invited to an extension phase using treatment allocated at randomization. They continued with hybrid CL using the Cambridge algorithm or standard insulin therapy (control) until 48 months after diagnosis. Analysis was by intention-to-treat. RESULTS: At 24 months after diagnosis, 81 participants (mean ± SD age 14 ± 2 years) continued in the extension phase (47 CL, 34 control). There was no difference in fasting C-peptide corrected for fasting glucose at 48 months between groups (CL: 5 ± 9 vs. control: 6 ± 14 pmol/L per mmol/L; mean adjusted difference -2 [95% CI -7, 4; P = 0.54]). Central laboratory HbA1c remained lower in the CL group by 0.9% (10 mmol/mol [95% CI 0.2, 1.5; 3, 17 mmol/mol); P = 0.009). Time in target range of 3.9 to 10.0 mmol/L was 12 percentage points (95% CI 3, 20; P = 0.008) higher in the CL group compared with control. There were 11 severe hypoglycemic events (6 CL, 5 control) and 7 diabetic ketoacidosis events (3 CL, 4 control) during the extension phase. CONCLUSIONS: Improved glycemic control was sustained over 48 months after diagnosis with CL insulin delivery compared with standard therapy in youth with type 1 diabetes. This did not appear to confer a protective effect on residual C-peptide secretion.

Outcomes of isolated medial tibial plateau fractures by fracture morphology.

PURPOSE: To identify a cohort of isolated medial tibial plateau fractures treated with surgical fixation and to categorize them by Moore and Wahlquist classifications in order to determine the rate of complications with each fracture morphology and the predictive value of each classification system. We hypothesized there would be high rates of neurovascular injury, compartment syndrome, and complications overall with a higher incidence of neurovascular injury in Moore type III rim avulsion fractures and Wahlquist type C fractures that enter the plateau lateral to the tibial spines. METHODS: Patients who presented to six Level I trauma centers between 2010 and 2021 who underwent surgical fixation for isolated medial tibial plateau fractures were retrospectively reviewed. Data including demographics, radiographs, complications, and functional outcomes were collected. RESULTS: One hundred and fifty isolated medial tibial plateau fractures were included. All patients were classified by the Wahlquist classification of medial tibial plateau fractures, and 139 patients were classifiable by the Moore classification of tibial plateau fracture-dislocations. Nine percent of fractures presented with neurovascular injury: 5 % with isolated vascular injury and 6 % with isolated nerve injury. There were no significant differences in neurovascular injury by fracture type (Wahlquist p = 0.16, Moore p = 0.33). Compartment syndrome developed in two patients (1.3 %). The average final range of motion was 0.8-122° with no difference by Wahlquist or Moore classifications (p = 0.11, p = 0.52). The overall complication rate was 32 % without differences by fracture morphology. The overall rate of return to the operating room (OR) was 25 %. CONCLUSIONS: Isolated medial tibial plateau fractures often represent fracture-dislocations of the knee and should receive a meticulous neurovascular exam on presentation with a high suspicion for neurovascular injury. No specific fracture pattern was found to be predictive of neurovascular injuries, complications, or final knee range of motion. Patients should be counseled pre-operatively regarding high rates of return to the OR after the index surgery.

Multicenter Evaluation of Ultra-Rapid Lispro Insulin with Control-IQ Technology in Adults, Adolescents, and Children with Type 1 Diabetes.

Objective: To evaluate the safety and explore the efficacy of use of ultra-rapid lispro (URLi, Lyumjev) insulin in the Tandem t:slim X2 insulin pump with Control-IQ 1.5 technology in children, teenagers, and adults living with type 1 diabetes (T1D). Methods: At 14 U.S. diabetes centers, youth and adults with T1D completed a 16-day lead-in period using lispro in a t:slim X2 insulin pump with Control-IQ 1.5 technology, followed by a 13-week period in which URLi insulin was used in the pump. Results: The trial included 179 individuals with T1D (age 6-75 years). With URLi, 1.7% (3 participants) had a severe hypoglycemia event over 13 weeks attributed to override boluses or a missed meal. No diabetic ketoacidosis events occurred. Two participants stopped URLi use because of infusion-site discomfort, and one stopped after developing a rash. Mean time 70-180 mg/dL increased from 65% ± 15% with lispro to 67% ± 13% with URLi (P = 0.004). Mean insulin treatment satisfaction questionnaire score improved from 75 ± 13 at screening to 80 ± 11 after 13 weeks of URLi use (mean difference = 6; 95% confidence interval 4-8; P < 0.001), with the greatest improvement reported for confidence avoiding symptoms of high blood sugar. Mean treatment-related impact measure-diabetes score improved from 74 ± 12 to 80 ± 12 (P < 0.001), and mean TRIM-Diabetes Device (score improved from 82 ± 11 to 86 ± 12 (P < 0.001). Conclusions: URLi use in the Tandem t:slim X2 insulin pump with Control-IQ 1.5 technology was safe for adult and pediatric participants with T1D, with quality-of-life benefits of URLi use perceived by the study participants. Clinicaltrials.gov registration: NCT05403502.

CellMag-CARWash: A High Throughput Droplet Microfluidic Device for Live Cell Isolation and Single Cell Applications.

The recent push toward understanding an individual cell's behavior and identifying cellular heterogeneity has created an unmet need for technologies that can probe live cells at the single-cell level. Cells within a population are known to exhibit heterogeneous responses to environmental cues. These differences can lead to varied cellular states, behavior, and responses to therapeutics. Techniques are needed that are not only capable of processing and analyzing cellular populations at the single cell level, but also have the ability to isolate specific cell populations from a complex sample at high throughputs. The new CellMag-Coalesce-Attract-Resegment Wash (CellMag-CARWash) system combines positive magnetic selection with droplet microfluidic devices to isolate cells of interest from a mixture with >93% purity and incorporate treatments within individual droplets to observe single cell biological responses. This workflow is shown to be capable of probing the single cell extracellular vesicle (EV) secretion of MCF7 GFP cells. This article reports the first measurement of ß-Estradiol's effect on EV secretion from MCF7 cells at the single cell level. Single cell processing revealed that MCF7 GFP cells possess a heterogeneous response to ß-Estradiol stimulation with a 1.8-fold increase relative to the control.

Increasing and sustaining discharges by noon - a multi-year process improvement project.

High hospital occupancy degrades emergency department performance by increasing wait times, decreasing patient satisfaction, and increasing patient morbidity and mortality. Late discharges contribute to high hospital occupancy by increasing emergency department (ED) patient length of stay (LOS). We share our experience with increasing and sustaining early discharges at a 650-bed academic medical center in the United States. Our process improvement project followed the Institute of Medicine Model for Improvement of successive Plan‒Do‒Study‒Act cycles. We implemented multiple iterative interventions over 41 months. As a result, the proportion of discharge orders before 10 am increased from 8.7% at baseline to 22.2% (p < 0.001), and the proportion of discharges by noon (DBN) increased from 9.5% to 26.8% (p < 0.001). There was no increase in balancing metrics because of our interventions. RA-LOS (Risk Adjusted Length Of Stay) decreased from 1.16 to 1.09 (p = 0.01), RA-Mortality decreased from 0.65 to 0.61 (p = 0.62) and RA-Readmissions decreased from 0.92 to 0.74 (p < 0.001). Our study provides a roadmap to large academic facilities to increase and sustain the proportion of patients discharged by noon without negatively impacting LOS, 30-day readmissions, and mortality. Continuous performance evaluation, adaptability to changing resources, multidisciplinary engagement, and institutional buy-in were crucial drivers of our success.

Weight Gain and Glycemic Control in Adults with Type 1 Diabetes in the T1D Exchange Registry.

Aim: The impact of weight gain on insulin dosage and glycemic control in adults with type 1 diabetes (T1D) aged 25 years and older was investigated in the T1D Exchange Registry participants. Methods: Participants were categorized into four groups based on their change in weight from T1D Exchange registry enrollment to year 5: stable weight (-5 to <5 lb), gained 5 to <10 lb, gained 10 to <20 lb, or gained ≥20 lb. Those who lost >5 lb were excluded. The primary outcomes were glucose control, as measured by glycosylated hemoglobin (HbA1c), and total daily insulin dose (TDD) at year 5. Linear regression models were used to evaluate the association between weight gain, HbA1c, and TDD. Results: There were 1969 participants included in the analyses. The mean ± standard deviation age was 45 ± 13 years, 57% were female, and 92% were White non-Hispanic. For those with an enrollment HbA1c <8.0%, the mean HbA1c at year 5 was higher for those who gained ≥20 lb compared to those with a stable weight of -5 to <5 lb (7.4% ± 1.1% vs. 7.2% ± 0.8%, respectively; P = 0.005). For this cohort, the mean TDD at year 5 increased from 49 ± 25 to 61 ± 29 U for those who gained ≥20 lb, while decreased from 45 ± 27 to 44 ± 25 U for those with stable weight of -5 to <5 lb (P < 0.001). Among participants with an enrollment HbA1c ≥9.0%, the mean HbA1c at year 5 was statistically insignificant at 8.4% ± 1.3% for those who gained ≥20 lb compared to 9.2% ± 1.7% for those with a stable weight of -5 to <5 lb (P = 0.09). Conclusion: Significant weight gain in adults with T1D who had good to adequate glycemic control was associated with modest deterioration in glucose control despite an increase in TDD. Worsening glucose control may indicate insulin resistance related to weight gain despite significantly increased insulin dosage which was insufficient to maintain adequate glycemic control.

Does local fat thickness correlate with post-operative infection in open reduction and internal fixation of acetabulum fractures?

PURPOSE: Obesity is an epidemic which increases risk of many surgical procedures. Previous studies in spine and hip arthroplasty have shown that fat thickness measured on preoperative imaging may be as or more reliable in assessment of risk of post-operative infection and/or wound complications than body mass index (BMI). We hypothesized that, similarly, increased local fat thickness at the surgical site is a predictor of wound complication in acetabulum fracture surgery. METHODS: Patients who underwent open reduction and internal fixation (ORIF) of an acetabulum fracture through a Kocher-Langenbeck (K-L) approach at a single institution from 2013 to 2020 were identified. Pre-operative CT scans were used to measure fat thickness from the skin to the greater trochanter in line with the surgical approach. Post-operative infections and wound complications were recorded and associated with fat thickness and BMI. RESULTS: 238 patients met inclusion criteria. 12 patients had either infection or a wound complication (5.0%). There was no significant association with BMI or preoperative fat thickness on post-operative infection or wound complication (p-value 0.73 and 0.86). CONCLUSIONS: There is no statistically significant association of post-operative infection or wound complications in patients with increased soft tissue thickness or increased BMI. ORIF of acetabulum fractures through a K-L approach can be performed safely in patients with large subcutaneous fat thickness and high BMI with low risk of infection or wound complications.

Quantifying climate change impacts on future water resources and salinity transport in a high semi-arid watershed.

High salinity mobilization and movement from salt-laden deposits in semi-arid landscapes impair soils and water resources worldwide. Semi-arid regions worldwide are expected to experience rising temperatures and lower precipitation, impacting water supply and spatio-temporal patterns of salinity loads and affecting downstream water quality. This study quantifies the impact of future climate on hydrologic fluxes and salt loads in the Gunnison River Watershed (GRW) (14,608 km2), Colorado, using the APEX-MODFLOW-Salt hydro-chemical watershed model and three different CMIP5 climate models projection downscaled by Multivariate Adaptive Constructed Analogs (MACA) for the period 2020-2099. The APEX-MODFLOW-Salt model accounts for the reactive transport of major salt ions (SO42-, Cl-, CO32-, HCO3-, Ca2+, Na+, Mg2+, and K+) to streams via surface runoff, rainfall erosional runoff, soil lateral flow, quick return flow and groundwater-stream exchange. Model results are analyzed for spatial and temporal trends in water yield and salt loading pathways. Although streamflow is primarily derived from surface runoff (65%), the predominant source of salt loads is the aquifer (73%) due to elevated concentrations of groundwater salt. Annual salt loading from the watershed is 582 Mkg, approximately 10% of the salt load in the Colorado River measured at Lee's Ferry, AZ. For future climate scenarios, annual salt loads from the watershed increased between 4.1% and 9.6% from the historical period due to increased salt loading from groundwater and quick return flow. From the results, applying the APEX-MODFLOW-Salt model with downscaled future climate forcings can be a helpful modeling framework for investigating hydrology and salt mobilization, transport, and export in historical and predictive settings for salt-affected watersheds.

Performance of Dietary Behaviors in Chronic Community-Dwelling Stroke Survivors: A Mixed-Methods Study.

In order to gain a better understanding of post-stroke dietary behaviors (e.g., selecting, accessing, and preparing healthy foods) among chronic, community-dwelling stroke survivors, we conducted a mixed-methods study consisting of a quantitative online survey (n = 63) and follow-up focus groups with a subset of participants (n = 7). Perceived performance, assistance required, adaptive equipment and compensatory strategies used, and sources of education and training were examined. Results demonstrated (1) diminished post-stroke performance for most dietary behaviors (e.g., grocery shopping, meal preparation), (2) an increased desire to eat healthily to prevent recurrent stroke, (3) variable use of adaptive equipment and compensatory strategies, and (4) limited healthcare-based dietary behavior education and training. These results suggest that stroke survivors could benefit from increased dietary behavior intervention to improve dietary behavior performance. Findings can be used to guide clinical intervention and design future research studies.

Accessible and Generalizable in Vitro Luminescence Assay for Detecting GPCR Activation.

G protein-coupled receptors (GPCRs) serve critical physiological roles as the most abundant family of receptors. Here, we describe the design of a generalizable and cell lysate-based method that leverages the interaction between an agonist-activated GPCR and a conformation-specific binder to reconstitute split nanoluciferase (NanoLuc) in vitro. This tool, In vitro GPCR split NanoLuc ligand Triggered Reporter (IGNiTR), has broad applications. We have demonstrated IGNiTR's use with three Gs-coupled GPCRs, two Gi-coupled GPCRs and three classes of conformation-specific binders: nanobodies, miniG proteins, and G protein peptidomimetics. As an in vitro method, IGNiTR enables the use of synthetic G protein peptidomimetics and provides easily scalable and portable reagents for characterizing GPCRs and ligands. We tested three diverse applications of IGNiTR: (1) proof-of-concept GPCR ligand screening using dopamine receptor D1 IGNiTR; (2) detection of opioids for point-of-care testing; and (3) characterizing GPCR functionality during Nanodisc-based reconstitution processes. Due to IGNiTR's unique advantages and the convenience of its cell lysate-based format, this tool will find extensive applications in GPCR ligand detection, screening, and GPCR characterization.

A retrospective review of the rate of septic knee arthritis after retrograde femoral nailing for traumatic femoral fractures at a single academic institution.

Background: Retrograde intramedullary nailing of the femur is a popular treatment option for femoral shaft fractures. However, this requires accessing the intramedullary canal through the knee, posing a risk of intra-articular infection. The purpose of this study was to examine the rate of intra-articular infection of the knee after retrograde nailing of femoral shaft fractures. Methods: All patients who underwent retrograde intramedullary nailing for femoral shaft fractures between June 2004 and December 2017 at a level 1 trauma center were reviewed. Six months of follow-up or documented fracture union was required. Records were reviewed for documentation of septic arthritis of the ipsilateral knee during the follow-up period. Results: A total of 294 fractures, including 217 closed and 77 open injuries, were included. Eighteen had an associated ipsilateral traumatic arthrotomy; 188 cases had an associated ipsilateral lower extremity fracture. No cases of septic arthritis were identified. Conclusion: There were no cases of septic arthritis in 294 fractures treated with retrograde intramedullary nailing. Retrograde nailing appears safe for risk of postoperative septic arthritis of the knee even in the face of open fractures and traumatic wounds.

The Effects of an Acute Bout of Aerobic or Resistance Exercise on Nonexercise Physical Activity.

Introduction/Purpose: A reduction in nonexercise physical activity (NEPA) after exercise may reduce the effectiveness of exercise interventions on weight loss in adults with overweight or obesity. Aerobic exercise (AEx) and resistance exercise (REx) may have different effects on NEPA. The purpose of this secondary analysis was to examine the effect of a single bout of AEx or REx on NEPA and sedentary behavior in inactive adults with overweight or obesity. Methods: Adults with overweight or obesity (n = 24; 50% male; age, 34.5 ± 1.5 yr; body mass index, 28.5 ± 0.9 kg·m-2) not meeting current physical activity guidelines completed a single 45-min bout of AEx, REx, or a sedentary control on different days in random order. After each condition, participants' NEPA was recorded for 84 h by accelerometer. Time spent sedentary and in light, moderate, and vigorous physical activity; steps; metabolic equivalent of task (MET)-hours; and sit-to-stand transitions were calculated using activity count data. Results: No differences were observed in the percent of waking time spent sedentary and in light, moderate, and vigorous activity between conditions (P > 0.05). No differences were observed in steps, MET-hours, or sit-to-stand transitions between conditions (P > 0.05). NEPA responses were variable among individuals, with approximately half of participants reducing and half increasing NEPA over the 84 h after each exercise condition. Conclusion: NEPA was not reduced after an acute bout of AEx or REx in a sample of inactive adults with overweight or obesity.

Multiparametric, Label-Free Analysis of Microfluidic Droplets via a Dynamic Phase Grating Approach.

Droplet-based microfluidic systems possess many fundamental advantages as a platform for the analysis of chemical and biological species. However, whereas on-chip operations have rapidly developed over the past decades, approaches for analyzing target molecules within droplets have largely remained limited to methods requiring bulky and expensive instrumentation. In this work, we describe a droplet analysis approach whereby the droplet train itself is the sensing construct. Specifically, the droplet train is interrogated as a transmission phase grating, allowing high-throughput, label-free, solution-phase, and multi-parametric analysis of droplet contents. Importantly, three distinct properties of generated droplets can be simultaneously extracted using this conceptually simple and experimentally straightforward measurement approach. Under constant droplet generation conditions, measurement of droplet viscosity is achieved by monitoring changes in zero order to first order peak separation in the far-field diffraction pattern, with a sensitivity of 2.28 × 10-4 cSt per µm change in peak separation. In parallel, measurement of droplet refractive index (RI) is achieved by measuring changes in the ratio of the zero order to first order peak intensity, with a sensitivity of 2.14 × 10-4 RI units per unit change in a diffracted peak intensity ratio. Finally, droplet generation frequency is determined from the time-varying oscillation of the peak height ratio, yielding comparable results to an expensive high-speed camera commonly used for droplet imaging. Importantly, the experimental strategy for this approach is straightforward and does not require expensive instrumentation; therefore, it may find utility in affordable and portable analysis approaches applied to diverse droplet microfluidic assays.

Imaging Evaluation of the Living Liver Donor: A Systems-Based Approach.

Liver transplant is the definitive treatment of end-stage liver disease and early hepatocellular carcinoma. The number of liver transplant surgeries done is highly affected by the number and availability of deceased donor organs. Living donor liver transplantation has emerged as an alternative source of donors, increasing the availability of organs for transplant. Many factors must be considered when choosing living donor candidates to maintain a high level of donor safety and organ survival. To that end, potential donors undergo a rigorous pre-donation workup.

Periodontitis and cardiovascular risk factors in subjects with and without type 1 diabetes: A cross sectional analysis.

AIMS: This cross-sectional analysis explored the relationships between periodontal disease (PD) and subclinical CVD in a cohort of patients with type 1 diabetes and non-diabetic controls. METHODS: Data were collected from adults enrolled in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study or enrolled through the Barbara Davis Center for Diabetes Adult Clinic. A clinical periodontal exam measured attachment loss and probing depth. Brachial artery distensibility (brachD), carotid intima-media thickness (cIMT), and pulse wave velocity (PWV) were assessed as measures of subclinical cardiovascular structure and function. RESULTS: 144 participants with T1D and 148 non-diabetics were enrolled. Compared to non-diabetic controls, T1D participants had a higher probing depth (2.6 mm vs. 2.5 mm; p = 0.04), higher attachment loss (2.7 mm vs. 2.4 mm; p < 0.01), lower brachD (mean 5.8 vs. 6.4 mmHg; p < 0.01), a higher cIMT (mean 0.68 vs. 0.64 mm; p < 0.01), and a higher PWV (mean 8.3 vs. 7.8 m/s; p < 0.01). There were no significant associations between PD and CVD metrics. CONCLUSIONS: Periodontal and cardiovascular health was worse in participants with T1D compared to non-diabetics. No significant associations between PD measures and CVD were identified.

The impact of extensive agricultural water drainage on the hydrology of the Kleine Nete watershed, Belgium.

Agricultural water drainage can significantly lower groundwater levels and affect catchment hydrology. Therefore, building models with and without these features can indicate an adverse impact on the geohydrological process. Therefore, the standalone Soil Water Assessment Tool (SWAT+) model was initially developed to simulate streamflow at the Kleine Nete catchment outlet. Next, a physically based and spatially distributed groundwater module (gwflow) was integrated into the SWAT+ model and calibrated for stream discharge at the catchment outlet. Finally, the same model was calibrated for both streamflow and groundwater heads. These final model parameters are used to investigate the basin-wide hydrologic fluxes with and without including agricultural drainage systems in the model scheme. The result suggested that the standalone SWAT+ model poorly represented the stream discharge and attained low NSE values of 0.18 and 0.37 during the calibration and validation periods, respectively. Integrating the gwflow module to SWAT+ improved the model representation of stream discharge (NSE = 0.91 and 0.65 for calibration and validation periods, respectively) and groundwater heads. However, calibrating the model for only streamflow resulted in a high root mean square error (above 1 m) for groundwater head, and the seasonality is not captured. On the other hand, calibrating the coupled model for streamflow and hydraulic head reduced the root mean square error (below 0.5 m) and captured the seasonality of groundwater level fluctuations. Finally, drainage application resulted in a 50 % (from 33.04 mm to 16.59 mm) reduction in groundwater saturation excess flow and an 18.4 mm increment in drainage water to streams. To conclude, the new SWAT+gwflow model is more appropriate than the standalone SWAT+ model for the case study. Furthermore, calibrating the SWAT+gwflow model for streamflow and groundwater head has improved the model simulation, with implications for general coupled models where representing surface and groundwater in the calibration strategy is beneficial.

The Insulin-Only Bionic Pancreas Improves Glycemic Control in Non-Hispanic White and Minority Adults and Children With Type 1 Diabetes.

OBJECTIVE: We evaluated the performance of the iLet bionic pancreas (BP) in non-Hispanic White individuals (here referred to as "Whites") and in Black, Hispanic, and other individuals (here collectively referred to as "Minorities"). RESEARCH DESIGN AND METHODS: A multicenter, randomized controlled trial evaluated glycemic management with the BP versus standard of care (SC) in 161 adult and 165 pediatric participants with type 1 diabetes over 13 weeks. RESULTS: In Whites (n = 240), the mean baseline-adjusted difference in 13-week HbA1c between the BP and SC groups was -0.45% (95% CI -0.61 to -0.29 [-4.9 mmol/mol; -6.6 to -3.1]; P < 0.001), while this difference among Minorities (n = 84) was -0.53% (-0.83 to -0.24 [-6.0 mmol/mol; -9.2 to -2.8]; P < 0.001). In Whites, the mean baseline-adjusted difference in time in range between the BP and SC groups was 10% (95% CI 7-12; P < 0.001) and in Minorities was 14% (10-18; P < 0.001). CONCLUSIONS: The BP improves glycemic control in both Whites and Minorities and offers promise in decreasing health care disparities.

Mandibular advancement reduces pharyngeal collapsibility by enlarging the airway rather than affecting velopharyngeal compliance.

Mandibular advancement devices (MADs) are frequently prescribed for obstructive sleep apnea (OSA) patients, but approximately one third of patients experience no therapeutic benefit. Understanding the mechanisms by which MADs prevent pharyngeal collapse may help optimize MAD therapy. This study quantified the relative contributions of changes in airspace cross-sectional area (CSA) versus changes in velopharyngeal compliance in determining MAD efficacy. Sixteen patients with moderate to severe OSA (mean apnea-hypopnea index of 32 ± 15 events/h) underwent measurements of the velopharyngeal closing pressure (PCLOSE ) during drug induced sedated endoscopy (DISE) via stepwise reductions in nasal mask pressure and recording of the intraluminal pressure with a catheter. Airspace CSA was estimated from video endoscopy. Pharyngeal compliance was defined as the slope of the area-pressure relationship of the velopharyngeal airspace. MAD therapy reduced PCLOSE from a median of 0.5 cmH2 O pre-advancement to a median of -2.6 cmH2 O post-advancement (p = 0.0009), increased the minimal CSA at the velopharynx by approximately 20 mm2 (p = 0.0067), but did not have a statistically significant effect on velopharyngeal compliance (p = 0.23). PCLOSE had a strong correlation with CSA but did not correlate with velopharyngeal compliance. Our results suggest that MADs reduce velopharyngeal collapsibility by increasing airway size as opposed to affecting velopharyngeal compliance. This contradicts the speculation of previous literature that the effectiveness of MADs is partially due to a reduction in velopharyngeal compliance resulting from stretching of the soft palate. These findings suggest that quantification of velopharyngeal CSA pre- and post-MAD advancement has potential as a biomarker to predict the success of MAD therapy.

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.