Diagnostic Accuracy of Transient Elastography in Hepatosteatosis in Youth With Obesity.

Context: Steatotic liver disease is common but overlooked in childhood obesity; diagnostic methods are invasive or expensive. Objective: We sought to determine the diagnostic accuracy of vibration-controlled transient elastography (VCTE) compared with magnetic resonance imaging (MRI) in adolescents with obesity and high risk for hepatosteatosis. Methods: Baseline data in 3 clinical trials enrolling adolescents with obesity were included (NCT03919929, NCT03717935, NCT04342390). Liver fat was assessed using MRI fat fraction and VCTE-based controlled attenuation parameter (CAP). Hepatosteatosis was defined as MRI fat fraction ≥5.0%. The area under the receiver-operating characteristic curves (AUROCs) for CAP against MRI was calculated, and optimal CAP using the Youden index for hepatosteatosis diagnosis was determined. Results: Data from 82 adolescents (age 15.6 ± 1.4 years, body mass index 36.5 ± 5.9 kg/m2, 81% female) were included. Fifty youth had hepatosteatosis by MRI (fat fraction 9.3% ; 95% CI 6.7, 14.0), and 32 participants did not have hepatosteatosis (fat fraction 3.1%; 95% CI 2.2, 3.9; P < .001). The hepatosteatosis group had higher mean CAP compared with no hepatosteatosis (293 dB/m; 95% CI 267, 325 vs 267 dB/m; 95% CI 248, 282; P = .0120). A CAP of 281 dB/m had the highest sensitivity (60%) and specificity (74%) with AUROC of 0.649 (95% CI 0.51-0.79; P = .04) in the entire cohort. In a subset of participants with polycystic ovary syndrome (PCOS), a CAP of 306 dB/m had the highest sensitivity (78%) and specificity (52%) and AUROC of 0.678 (95% CI 0.45-0.90; P = .108). Conclusion: CAP of 281 dB/m has modest diagnostic performance for hepatosteatosis compared with MRI in youth with significant obesity. A higher CAP in youth with PCOS suggests that comorbidities might affect optimal CAP in hepatosteatosis diagnosis.

Recovery Trajectories in Children Requiring 3 or More Days of Invasive Ventilation.

OBJECTIVES: To characterize health-related quality of life (HRQL) and functional recovery trajectories and risk factors for prolonged impairments among critically ill children receiving greater than or equal to 3 days of invasive ventilation. DESIGN: Prospective cohort study. SETTING: Quaternary children's hospital PICU. PATIENTS: Children without a preexisting tracheostomy who received greater than or equal to 3 days of invasive ventilation, survived hospitalization, and completed greater than or equal to 1 postdischarge data collection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated 144 children measuring HRQL using proxy-report Pediatric Quality of Life Inventory and functional status using the Functional Status Scale (FSS) reflecting preillness baseline, PICU and hospital discharge, and 1, 3, 6, and 12 months after hospital discharge. They had a median age of 5.3 years (interquartile range, 1.1-13.0 yr), 58 (40%) were female, 45 (31%) had a complex chronic condition, and 110 (76%) had normal preillness FSS scores. Respiratory failure etiologies included lung disease ( n = 49; 34%), neurologic failure ( n = 23; 16%), and septic shock ( n = 22; 15%). At 1-month postdischarge, 68 of 122 (56%) reported worsened HRQL and 35 (29%) had a new functional impairment compared with preillness baseline. This improved at 3 months to 54 (46%) and 24 (20%), respectively, and remained stable through the remaining 9 months of follow-up. We used interaction forests to evaluate relative variable importance including pairwise interactions and found that therapy consultation within 3 days of intubation was associated with better HRQL recovery in older patients and those with better preillness physical HRQL. During the postdischarge year, 76 patients (53%) had an emergency department visit or hospitalization, and 62 (43%) newly received physical, occupational, or speech therapy. CONCLUSIONS: Impairments in HRQL and functional status as well as health resource use were common among children with acute respiratory failure. Early therapy consultation was a modifiable characteristic associated with shorter duration of worsened HRQL in older patients.

Zinc transporter 8 haploinsufficiency protects against beta cell dysfunction in type 1 diabetes by increasing mitochondrial respiration.

OBJECTIVE: Zinc transporter 8 (ZnT8) is a major humoral target in human type 1 diabetes (T1D). Polymorphic variants of Slc30A8, which encodes ZnT8, are also associated with protection from type 2 diabetes (T2D). The current study examined whether ZnT8 might play a role beyond simply being a target of autoimmunity in the pathophysiology of T1D. METHODS: The phenotypes of NOD mice with complete or partial global loss of ZnT8 were determined using a combination of disease incidence, histological, transcriptomic, and metabolic analyses. RESULTS: Unexpectedly, while complete loss of ZnT8 accelerated spontaneous T1D, heterozygosity was partially protective. In vivo and in vitro studies of ZnT8 deficient NOD.SCID mice suggested that the accelerated disease was due to more rampant autoimmunity. Conversely, beta cells in heterozygous animals uniquely displayed increased mitochondrial fitness under mild proinflammatory conditions. CONCLUSIONS: In pancreatic beta cells and immune cell populations, Zn2+ plays a key role as a regulator of redox signaling and as an independent secondary messenger. Importantly, Zn2+ also plays a major role in maintaining mitochondrial homeostasis. Our results suggest that regulating mitochondrial fitness by altering intra-islet zinc homeostasis may provide a novel mechanism to modulate T1D pathophysiology.

Femoral neck structural properties are altered in adults with type 1 diabetes.

AIMS: To determine differences in hip geometry in adults with type 1 diabetes (T1D) compared with healthy adults without diabetes. METHODS: In this cross-sectional study, 43 adults with T1D (mean age 56 years, 84 % female, 92 % White, mean duration of diabetes of 39 years, A1c of 7.8 %) and 40 adults without diabetes (mean age 60 years, 80 % female, 77 % white) who had hip dual-energy x-ray absorptiometry (DXA) scans from previous studies were included. Areal bone mineral density (aBMD) and measures of hip structural properties at the narrow neck, intertrochanteric and femoral shaft regions of the left proximal femur were analyzed between adults with T1D and controls using linear models controlled for age, sex, and body mass index. RESULTS: There were no significant differences in DXA-based aBMD at the hip (0.769 ± 0.132 vs. 0.900 ± 0.139 g/cm2, p = 0.07) or femoral neck (0.722 ± 0.116 vs. 0.849 ± 0.114 g/cm2, p = 0.09) regions between adults with T1D and controls. When controlling for age, sex, and BMI, DXA-based aBMD at the hip (0.880 ± 0.022 vs. 0.943 ± 0.020 g/cm2, p = 0.02) and femoral neck (0.750 ± 0.021 vs. 0.812 ± 0.020 g/cm2, p = 0.02) regions were significantly lower in adults with T1D than controls. Cortical thickness was significantly lower in all three hip regions in adults with T1D than in controls (narrow-neck: 0.169 ± 0.005 vs. 0.186 ± 0.005 cm, p = 0.011; intertrochanteric: 0.388 ± 0.013 vs. 0.425 ± 0.012 cm, p = 0.017; femoral shaft: 0.529 ± 0.017 vs. 0.586 ± 0.016 cm, p = 0.006). Moreover, adults with T1D had a smaller cross-sectional area at the narrow-neck (3.06 ± 0.09 vs. 3.32 ± 0.08 cm2, p = 0.015), a higher femoral shaft endocortical diameter (2.23 ± 0.07 vs. 2.02 ± 0.06 cm, p = 0.011), and higher buckling ratios (an indicator of cortical instability) at the intertrochanteric (9.22 ± 0.34 vs. 8.23 ± 0.32, p = 0.016) and femoral shaft (3.32 ± 0.15 vs. 2.89 ± 0.14, p = 0.016) regions. CONCLUSIONS: Adults with T1D have several significant differences in proximal femur morphology compared with controls. These morphological differences may adversely affect the mechanical integrity of the proximal femur, thereby contributing to an increased risk of fracture in the event of a fall.

Postdischarge health resource use in pediatric survivors of prolonged mechanical ventilation for acute respiratory illness.

We aimed to identify characteristics associated with postdischarge health resource use in children without medical complexity who survived an episode of prolonged mechanical ventilation for respiratory illness. We hypothesized that longer durations of mechanical ventilation, noncomplex chronic conditions, and severe acute respiratory distress syndrome (ARDS) would be associated with readmission or an Emergency Department (ED) visit. In this retrospective cohort, we evaluated children without a complex chronic condition who survived a respiratory illness requiring ≥3 days of mechanical ventilation and who had insurance eligibility within the Colorado All Payers Claims Database. We used insurance claims to characterize health resource use and multivariable logistic regression to identify characteristics associated with readmission or an ED visit during the postdischarge year. We evaluated 82 children, median age 12.8 months (interquartile range [IQR]: 4.0-24.1), 20 (24%) with a noncomplex chronic condition and 62 (76%) without any chronic conditions. Bronchiolitis (60%) and pneumonia/aspiration pneumonitis (17%) were the most common etiologies of respiratory failure and 47 (57%) patients had severe ARDS. Forty-six (56%) patients had an ED visit or readmission. Among the 18 readmitted patients, 16/18 (89%) readmissions were for respiratory illness. Forty (49%) patients had ≥2 outpatient pulmonary visits and 45 (55%) filled a pulmonary medication prescription. In analyses controlling for age, illness severity and mechanical ventilation duration, severe ARDS was predictive of ED visit or readmission (odds ratio [OR]: 5.53 [95% confidence interval [CI]: 1.79, 19.09]). Children who survive prolonged mechanical ventilation for respiratory disease experience high rates of postdischarge health resource use, particularly those surviving severe ARDS.

Identifying Long-Term Morbidities and Health Trajectories After Prolonged Mechanical Ventilation in Children Using State All Payer Claims Data.

OBJECTIVES: To identify postdischarge outcome phenotypes and risk factors for poor outcomes using insurance claims data. DESIGN: Retrospective cohort study. SETTING: Single quaternary center. PATIENTS: Children without preexisting tracheostomy who required greater than or equal to 3 days of invasive mechanical ventilation, survived the hospitalization, and had postdischarge insurance eligibility in Colorado's All Payer Claims Database. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used unsupervised machine learning to identify functional outcome phenotypes based on claims data representative of postdischarge morbidities. We assessed health trajectory by comparing change in the number of insurance claims between quarters 1 and 4 of the postdischarge year. Regression analyses identified variables associated with unfavorable outcomes. The 381 subjects had median age 3.3 years (interquartile range, 0.9-12 yr), and 147 (39%) had a complex chronic condition. Primary diagnoses were respiratory (41%), injury (23%), and neurologic (11%). We identified three phenotypes: lower morbidity (n = 300), higher morbidity (n = 62), and 1-year nonsurvivors (n = 19). Complex chronic conditions most strongly predicted the nonsurvivor phenotype. Longer PICU stays and tracheostomy placement most strongly predicted the higher morbidity phenotype. Patients with high but improving postdischarge resource use were differentiated by high illness severity and long PICU stays. Patients with persistently high or increasing resource use were differentiated by complex chronic conditions and tracheostomy placement. CONCLUSIONS: New morbidities are common after prolonged mechanical ventilation. Identifying phenotypes at high risk of postdischarge morbidity may facilitate prognostic enrichment in clinical trials.

Pulmonary surfactant protein B carried by HDL predicts incident CVD in patients with type 1 diabetes.

Atherosclerotic CVD is the major cause of death in patients with type 1 diabetes mellitus (T1DM). Alterations in the HDL proteome have been shown to associate with prevalent CVD in T1DM. We therefore sought to determine which proteins carried by HDL might predict incident CVD in patients with T1DM. Using targeted MS/MS, we quantified 50 proteins in HDL from 181 T1DM subjects enrolled in the prospective Coronary Artery Calcification in Type 1 Diabetes study. We used Cox proportional regression analysis and a case-cohort design to test associations of HDL proteins with incident CVD (myocardial infarction, coronary artery bypass grafting, angioplasty, or death from coronary heart disease). We found that only one HDL protein-SFTPB (pulmonary surfactant protein B)-predicted incident CVD in all the models tested. In a fully adjusted model that controlled for lipids and other risk factors, the hazard ratio was 2.17 per SD increase of SFTPB (95% confidence interval, 1.12-4.21, P = 0.022). In addition, plasma fractionation demonstrated that SFTPB is nearly entirely bound to HDL. Although previous studies have shown that high plasma levels of SFTPB associate with prevalent atherosclerosis only in smokers, we found that SFTPB predicted incident CVD in T1DM independently of smoking status and a wide range of confounding factors, including HDL-C, LDL-C, and triglyceride levels. Because SFTPB is almost entirely bound to plasma HDL, our observations support the proposal that SFTPB carried by HDL is a marker-and perhaps mediator-of CVD risk in patients with T1DM.

Renal SGLT mRNA expression in human health and disease: a study in two cohorts.

Pharmacological Na+-glucose linked cotransporter (SGLT)2 inhibition is being examined as a renal protection strategy in nondiabetic chronic kidney disease. We quantified renal SGLT mRNA expression in healthy controls (HC), glomerulonephritis (GN), and diabetic kidney disease (DKD) to identify differences in expression across a spectrum of renal diseases. mRNA expression of SGLT1 and SGLT2 in renal tubules and glomeruli, obtained using microdissection and microarray techniques, was evaluated in two large cohorts. The European Renal cDNA bank included HC, GN, and DKD (98 glomeruli and 93 tubulointerstitium). The Nephrotic Syndrome Study Network cohort included 124 adults with membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, and IgA nephropathy. Within the European Renal cDNA bank, SGLT2 tubular and glomerular log2 mRNA expression significantly differed across HC, GN, and DKD (P = 0.0009 and P = 0.0004), with the highest expression in HC. Within the Nephrotic Syndrome Study Network, there were no differences in SGLT log2 mRNA expression across GN subtypes. Tubular SGLT2 log2 mRNA expression positively correlated with estimated glomerular filtration rate (by the Modification of Diet in Renal Disease Study equation) and glycated hemoglobin (r = 0.33 and 0.34, P < 0.05) and inversely correlated with interstitial fibrosis (r = -0.21, P < 0.05). In conclusion, SGLT2 mRNA expression was lower in DKD compared with HC or GN and inversely related to interstitial fibrosis. The relationships between SGLT mRNA, protein expression, and transporter activity require further elucidation.

Prevalence, characteristics, and diabetes management in children with comorbid autism spectrum disorder and type 1 diabetes.

OBJECTIVE: To determine autism spectrum disorder (ASD) prevalence within our pediatric type 1 diabetes (T1D) clinic population and determine clinical characteristics and technology used by individuals with both ASD and T1D compared to matched controls with T1D alone and compared to our overall pediatric T1D clinic. METHODS: Medical chart review showed 30 individuals with both ASD and type 1 diabetes (ASD + T1D). Controls (n = 90) were matched for age, sex, race/ethnicity, and T1D duration. ASD + T1D was compared to both matched controls and the pediatric T1D clinical population. RESULTS: ASD prevalence in the pediatric T1D population was 1.16% (CI 0.96-1.26). Compared to the T1D clinic, ASD + T1D had more males (93% vs 52%; P < 0.0001), lower hemoglobin A1c (HbA1c) (8.2% vs 8.9%; 66 vs 74 mmol/mol; P = 0.006), and lower insulin pump (CSII) use (37% vs 56%; P < 0.0001). No differences were found between ASD + T1D and matched controls in HbA1c or blood glucose checks per day. The ASD + T1D group was less likely to use CSII than matched controls (37% vs 61%; P = 0.03). HbA1c did not change after CSII initiation in ASD + T1D, but increased for matched controls. CONCLUSIONS: Prevalence of ASD in the pediatric T1D population is comparable to the general population in Colorado. Individuals with ASD may experience barriers limiting CSII use, but achieve equivalent glycemic control compared to those without ASD. CSII may be more effective in maintaining lower HbA1c over time in those with ASD than in those without ASD.

Innate Immune Function and Organ Failure Recovery in Adults With Sepsis.

PURPOSE: Sepsis stimulates pro- and anti-inflammatory immune responses. The innate immune response is critical to organ injury repair. We tested for an association between innate immune function and organ function recovery in a prospective cohort of immune-competent adults with sepsis. METHODS: We conducted a prospective observational cohort study enrolling immune-competent adults with sepsis. We tested innate immune function by quantification of lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) α production capacity in whole blood samples on hospital days 1, 4, and 6. The primary outcome was organ function recovery on day 4 defined as a 4-point decrease in the composite cardiovascular and respiratory Sequential Organ Failure Assessment (SOFA) score components or a SOFA score ≤2. RESULTS: Patients with sepsis who recovered organ function by day 4 (n = 11) had similar baseline characteristics when compared to those with ongoing organ failure (n = 13). Tumor necrosis factor α production capacity was similar between the 2 groups on hospital days 1 and 4 but significantly different on day 6. Patients who regained organ function recovery had significantly higher TNF-α production capacity on day 6 ( P = .01), which persisted after adjustment for age, Acute Physiology and Chronic Health Evaluation III score, and steroid administration ( P = .03). There was no difference in TNF-α production capacity over time in those who survived to hospital discharge versus nonsurvivors. CONCLUSION: Increasing TNF-α production capacity is associated with improved organ failure recovery. Further studies are needed to evaluate a causal association between innate immune suppression and organ failure recovery as well as predictive accuracy for hospital survival. Impaired TNF-α production as a marker of sepsis-associated innate immune dysfunction may be a feasible target for immune stimulation to decrease time to organ failure recovery.

Sex-specific differences in insulin resistance in type 1 diabetes: The CACTI cohort.

OBJECTIVE: To test the hypothesis that multitissue deficits in insulin sensitivity are greater among women than men with type 1 diabetes compared to respective controls. RESEARCH DESIGN AND METHODS: Three-stage hyperinsulinemic-euglycemic clamps (4, 8, 40 mU/m2/min) were performed on 41 people with type 1 diabetes and 47 adults without diabetes (mean ±â€¯SD age 46 ±â€¯8). Infusions of [1-13C]palmitate, [1,1,2,3,3-2H2]glycerol, and [6,6-2H2]glucose isotope tracers were used to determine free fatty acid (FFA), glycerol, and glucose kinetics in 52 of these participants (25 M and 27 W). RESULTS: There was no difference in age or BMI by type 1 diabetes status in either sex. Free fatty acid rate of appearance (FFA Ra) was higher in both sexes with type 1 diabetes compared to those without diabetes during stages 1 and 2. The same was seen with glycerol for stages 1 and 2. During stage 3 glucose rate of disappearance (Rd) was lower in those with type 1 diabetes among both sexes. All had sex by type 1 diabetes interactions with greater deficits in insulin sensitivity in women. While there was no sex by diabetes interaction in regards to glucose rate of appearance (Ra), those with type 1 diabetes had a higher glucose Ra than those without diabetes. CONCLUSIONS: We found that type 1 diabetes affected adipose and skeletal muscle insulin sensitivity to a greater extent in women than in men, perhaps contributing to the greater relative increase in cardiovascular risk in women with type 1 diabetes.

Ambulatory glucose profile analysis of the juvenile diabetes research foundation continuous glucose monitoring dataset-Applications to the pediatric diabetes population.

BACKGROUND: Increased continuous glucose monitor (CGM) use presents both the benefit and burden of increased data for clinicians to rapidly analyze. The ambulatory glucose profile (AGP) is an evolving a universal software report for CGM data analysis. OBJECTIVES/HYPOTHESES: We utilized the Juvenile Diabetes Research Foundation-CGM dataset to evaluate the AGP across a broad spectrum of patients to show how AGP can be used clinically to assist with CGM-related decision making. We hypothesized that AGP metrics would be different across age and HbA1c strata. SUBJECTS: AGPs were generated from the JDRF-CGM trial dataset for all periods during which there were ≥10 days of CGM coverage in the 2 weeks adjacent to an HbA1c measurement yielding 1101 AGPs for 393 unique subjects. METHODS: AGPs were stratified by age group (8-14, 15-24, and ≥25 years) and HbA1c (within or above target for age) and compared for between group differences in AGP metrics via two-factor ANOVA. Glycemic differences between time periods were analyzed via segmented regression analysis. RESULTS: Glucose exposure (average and estimated A1c) and variability (standard deviation and interquartile range) were different between the low and high HbA1c levels. Within a given HbA1c level all age groups were significantly different from each other with older patients having lower averages with less variability than younger patients. CONCLUSIONS: AGP analysis of the JDRF-CGM data highlights significant differences in glycemic profiles between pediatric and adult age groups and between well and less well-controlled patient populations.

Factors associated with peritoneal dialysis catheter complications in children.

BACKGROUND/PURPOSE: Peritoneal dialysis (PD) is a common method of renal replacement therapy for children. However, placement of PD catheters has risk, and some are never used. METHODS: We conducted a retrospective chart review of children with a PD catheter placed between 2000 and 2014. Logistic regression analyses were used to identify covariates associated with complications. RESULTS: We identified 175 children with PD catheters. 110 complications developed in 80 children (45.7%). Complications including unexpected return to the operating room and peritonitis increased as the length of time a catheter was in place increased. Children who weighed <12.4 kg had 3.2 times greater odds of developing a leak (95% CI 1.21-8.63, p=0.02). Twelve children never used their PD catheters, 9 with acute kidney injury (AKI) who recovered from their disease more quickly than expected. No covariate was associated with nonuse. CONCLUSIONS: Complications with PD catheters are common and increase the longer catheters are in place. Lower weight children are at greater risk of PD catheter leak. Decreased initial volumes of dialysate in smaller children may mitigate this risk. Nonuse may be reduced if dialysis is permitted the day of placement for children with AKI.