High-fat diet (HFD) feeding impairs interscapular brown adipose tissue (iBAT) mitochondrial function, leading to lipid accumulation and insulin resistance. To evaluate HFD-induced metabolic impairments in iBAT lipid metabolism using 1H-MRS and to determine whether chronic cold exposure can restore mitochondrial lipid oxidation. Male Wistar rats (n = 20) were fed either chow diet (CD) or HFD for eight weeks followed by maintained thermoneutral or cold-exposed conditions for two weeks. Lipid content in iBAT was quantified by localized 1H-MRS on 7 Tesla (Bruker), using 72-mm volume transmit coil and a 2 × 2 phased array receive only cardiac coil and water suppressed PRESS sequence. Systemic insulin sensitivity and mRNA expression of functional genes were quantified to assess thermogenesis, lipolysis, fatty acid oxidation, and mitochondrial functions. At thermoneutrality, HFD-fed animals showed increased iBAT lipid fraction (75.3 ± 2

Skeletal muscle (SM) is an integral organ component in the pathophysiology of many acute and chronic diseases. But is there a 'gold' standard or accepted reference method for quantifying the amount and composition of human SM mass? Exploring that question led us to recognize the existence of a SM measurement paradigm that divides methods into two broad categories, in vitro and in vivo. In vitro methods quantify SM mass, weighing intact muscles as part of whole cadaver evaluations, only 51 of which are reported in medical literature with no recent additions. In vivo methods are used to evaluate SM in vivo, and two tiers were revealed in our analyses. An upper tier that included three methods considered 'reference' approaches for their accuracy and precision: computed tomography, magnetic resonance imaging and dual-energy X-ray absorptiometry. A lower in vivo method tier included bioimpedance analysis, three-dimensional imaging, several approaches involving creatine metabolism, ultrasound and anthropometry. A feature common to all of the lower tier methods is their need for calibration or validation against reference approaches in the upper in vivo method tier. A critical review of the three in vivo reference methods in the upper tier revealed widely variable SM volume/mass acquisition protocols, image analysis methods and applied terminology. Some reports espouse an upper tier reference method as the 'gold' standard while providing minimal details of exactly how and what was measured, thus making replication in follow-up studies difficult. Any technical issues related to an in vivo reference method are propagated to the in vivo methods in the lower tier that are calibrated or validated against them. Our review of in vivo reference methods of quantifying SM mass and composition led us to two broad recommendations. First, published reports including these reference methods should provide enough details related to acquisition and analysis protocols so that readers can replicate their findings. Second, an effort should be made to apply precise terminology in published reports in order to avoid confusion on exactly what was measured; suggestions are made on definitions of commonly used terms when referring to body composition compartments. Lastly, because there is no consensus on what constitutes a 'gold' standard for SM measurement, we suggest expert groups convene in the future to recommend optimum approaches and working guidelines for quantifying muscle mass and composition in vivo.

Performance assessments of quantitative determinations of proton density fat fraction (PDFF) have largely focused on the range between 0 and 50

INTRODUCTION:To examine whether within-person changes in total, regional and organ fat were associated with within-person changes in type 2 diabetes (T2D)-related biomarkers following interventions. METHODS:A secondary analysis from a randomised trial among Latino youth (30 males, 25 females) aged 12-16 years with obesity. The study sample combined participants randomised to either lifestyle intervention (N = 39) or usual care (N = 16). Total body composition was assessed by DEXA. Hepatic and pancreatic fat fractions were assessed using MRI. T2D risk factors included insulin sensitivity, beta-cell function and post-challenge glucose. RESULTS:Significant changes in %body fat, lean mass, insulin sensitivity and 2-h glucose were observed. Changes in fat mass were associated with changes in insulin sensitivity (β = -0.45, p < 0.001), while changes in lean mass were associated with changes in 2-h glucose concentrations (β = -0.50, p = 0.02). No association between changes in total, regional, or organ fat and beta cell function were noted. CONCLUSIONS:Our study revealed that within-person changes in fat mass and lean mass were associated with increased insulin sensitivity and reduced 2-h glucose concentrations, respectively, among high-risk Latino youth. The impact of reductions in regional and organ fat deposition on T2D risk factors warrants further examination.

The role of MRI to estimate liver iron concentration (LIC) for identifying patients with iron overload and guiding the titration of chelation therapy is increasingly established for routine clinical practice. However, the existence of multiple MRI-based LIC quantification techniques limits standardization and widespread clinical adoption. In this article, we review the existing and widely accepted MRI-based LIC estimation methods at 1.5 T and 3 T: signal intensity ratio (SIR) and relaxometry (R2 and R2*) and discuss the basic principles, acquisition and analysis protocols, and MRI-LIC calibrations for each technique. Further, we provide an up-to-date information on MRI vendor implementations and available offline commercial and free software for each MRI-based LIC quantification approach. We also briefly review the emerging and advanced MRI techniques for LIC estimation and their current limitations for clinical use. Lastly, we discuss the implications of MRI-based LIC measurements on clinical use and decision-making in the management of patients with iron overload. Some of the key highlights from this review are as follows: 1) Both R2 and R2* can estimate accurate and reproducible LIC, when validated acquisition parameters and analysis protocols are applied, 2) Although the Ferriscan R2 method has been widely used, recent consensus and guidelines endorse R2*-MRI as the most accurate and reproducible method for LIC estimation, 3) Ongoing efforts aim to establish R2*-MRI as the standard approach for quantifying LIC, and 4) Emerging R2*-MRI techniques employ radial sampling strategies and offer improved motion compensation and broader dynamic range for LIC estimation. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Background: Infant feeding patterns have been linked with obesity risk in childhood, but associations with precise measures of body fat distribution are unclear. Objective: We examined associations of infant feeding practices with abdominal fat and hepatic fat trajectories in childhood. Methods: This study included 356 children in the Healthy Start Study, a prospective prebirth cohort in Colorado. Infant feeding practices were assessed by postnatal interviews and categorized as any human milk <6 mo compared with >= 6 mo; complementary foods introduced <= 4 mo compared with >4 mo; soda introduced <18 mo compared with >18 mo. Abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) areas and hepatic fat (%) were assessed by magnetic resonance imaging in early and middle childhood (median 5 and 9 y old, respectively). We examined associations of infant feeding with adiposity trajectories across childhood using linear mixed models. Results: In the sample of children, 67% consumed human milk >= 6 mo, 75% were introduced to complementary foods at >4 mo, and 81% were introduced to soda at >18 mo. We did not find any associations between duration of any human milk consumption and childhood adiposity trajectories. Early introduction to complementary foods (<= 4 mo) was associated with faster rates of change for SAT and VAT during childhood (Slope [95% CI]: 15.1 [10.7,19.4] cm(2)/y for SAT; 2.5 [1.9,2.9] cm(2)/y for VAT), compared with introduction at >4 mo (5.5 [3.0,8.0] cm(2)/y and 1.6 [1.3,1.9] cm(2)/y, respectively). Similarly, early introduction to soda (<18 mo) was associated with faster rates of change for all 3 outcomes during childhood (Slope [95% CI]: 20.6 [15.0,26.1] cm(2)/y for SAT, 2.7 [2.0,3.3] cm(2)/y for VAT, 0.3 [0.1,0.5] %/year for hepatic fat) compared with delayed introduction (5.4 [2.8,8.0] cm(2)/y, 1.7 [1.3, 2.0] cm(2)/y, -0.1 [-0.2,0.0] %/y, respectively). Conclusions: The timing of introduction and quality of complementary foods in infancy was associated with rates of abdominal and hepatic fat accrual during childhood. Experimental studies are needed to assess underlying mechanisms.

OBJECTIVE:Performance assessments of quantitative determinations of proton density fat fraction (PDFF) have largely focused on the range between 0 and 50%. We evaluate PDFF in a two-site phantom study across the full 0-100% PDFF range. MATERIALS AND METHODS:We used commercially available 3D chemical-shift-encoded water-fat MRI sequences from three MRI system vendors at 1.5T and 3T and conducted the study across two sites. A spherical phantom housing 18 vials spanning the full 0-100% PDFF range was used. Data at each site were acquired using default parameters to determine same-day and different-day intra-scanner repeatability, and inter-system and inter-site reproducibility, in addition to linear regression between reference and measured PDFF values. RESULTS:Across all systems, results demonstrated strong linearity and minimal bias. For 1.5T systems, a pooled slope of 0.99 with a 95% confidence interval (CI) of 0.981-0.997 and a pooled intercept of 0.61% PDFF with a 95% CI of 0.17-1.04 were obtained. Results for pooled 3T data included a slope of 1.00 (95% CI 0.995-1.005) and an intercept of 0.69% PDFF (95% CI 0.39-0.97). Inter-site and inter-system reproducibility coefficients ranged from 2.9 to 6.2 (in units of PDFF), while intra-scanner same-day and different-day repeatability ranged from 0.6 to 7.8. DISCUSSION:PDFF across the 0-100% range can be reliably estimated using current commercial offerings at 1.5T and 3T.

Obesity is a well-established risk factor for type 2 diabetes (T2D) in youth. However, the contribution that organ fat plays to the pathophysiology of T2D among high-risk youth is sparsely documented. The purpose of this study was to determine the independent associations between hepatic and pancreatic fat fractions with insulin sensitivity and beta-cell function among Latino youth with obesity and prediabetes. This cross-sectional analysis involved 117 Latino adolescent boys (n=70) and girls (n=47), mean (±SD) age:14±1 years, fasting glucose: 102±8mg/dL, 2-hour glucose: 144±30mg/dL, and with obesity (BMI percentile: 98.52±1.13). Total body composition was assessed by DEXA, while hepatic and pancreatic fat contents were assessed using quantitative fat fraction magnetic resonance imaging at 3 Tesla. T2D risk factors included insulin sensitivity (Matsuda index) and beta-cell function (product of insulin sensitivity and insulinogenic index), estimated from a multi-sample 2-hour oral glucose tolerance test. Associations between organ fat and T2D risk factors were examined using Pearson correlation and multiple linear regression, adjusting for age, sex, and total body fat percentage (BF%). Insulin sensitivity significantly correlated with only BF% (r =-0.236, p=0.015), fat mass (r=-0.227, p=0.020), and hepatic fat fraction (r=-0.255, p=0.024), whereas beta-cell function significantly correlated with only BF% (r=-0.241, p=0.013). In multiple regression models, hepatic fat fraction (B= -0.045, p=0.041, Δr2=.034) but not pancreatic fat fraction (B= 0.058, p=0.179, Δr2= .015) was independently associated with insulin sensitivity, whereas neither measure of organ fat was associated with beta-cell function (each Δr2 <.01, each p>.38). Hepatic fat content was an independent predictor of insulin sensitivity among Latino youth with prediabetes. Further studies are needed to understand how adiposity contributes to beta-cell dysfunction among high-risk youth. Disclosure E.O.Owolabi: None. M.Olson: Advisory Panel; Rhythm Pharmaceuticals, Inc. H.H.Hu: None. A.Pena: None. K.A.Pituch: None. S.Bailey: None. W.C.Knowler: None. G.Q.Shaibi: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107579, F31DK125037)

Objective To test the hypothesis that cerebral blood flow (CBF) assessed with arterial spin labelling (ASL) MRI is increased and standardised neurological examination is altered in infants with neonatal opioid withdrawal syndrome (NOWS) compared with those without. Design Prospective cohort study. Setting Level IV neonatal intensive care unit and outpatient primary care centre. Participants Infants with NOWS receiving pharmacological treatment and unexposed controls matched for gestational age at birth and post-menstrual age at MRI. Main outcomes CBF assessed by ASL on non-sedated 3-Tesla MRI and standardised Hammersmith Neonatal Neurological Examination (HNNE) within 14 days of birth. Results Thirty infants with NOWS and 31 control infants were enrolled and included in the final analysis. Global CBF across the brain was higher in the NOWS group compared with controls (14.2 mL/100 g/min±5.5 vs 10.7 mL/100 g/min±4.3, mean±SD, Cohen’s d=0.72). HNNE total optimality score was lower in the NOWS group compared with controls (25.9±3.6 vs 28.4±2.4, mean±SD, Cohen’s d=0.81). A penalised logistic regression model including both CBF and HNNE items discriminated best between the two groups. Conclusions Increased cerebral perfusion and neurological examination abnormalities characterise infants with NOWS compared with those without intrauterine drug exposure and suggest prenatal substance exposure affects fetal brain development. Identifying neurological and neuroimaging characteristics of infants with NOWS can contribute to understanding mechanisms underlying later outcomes and to designing potential new treatments. This prospective cohort study found that 30 infants with neonatal opioid withdrawal syndrome had higher global cerebral blood flow and more neurological exam abnormalities than 31 unexposed controls. Follow-up to determine these infants’ neurodevelopmental courses is required.

Radiographic bone age assessment by automated software is precise and instantaneous. The aim of this study was to evaluate the accuracy of an automated tool for bone age assessment. We compared a total of 586 bone age radiographs from 451 patients, which had been assessed by three radiologists from 2013 to 2018, with bone age analysis by BoneXpert, using the Greulich and Pyle method. We made bone age comparisons in different patient groups based on gender, diagnosis and race, and in a subset with repeated bone age studies. We calculated Spearman correlation (r) and accuracy (root mean square error, or R2). Bone age analyses by automated and manual assessments showed a strong correlation (r=0.98; R2=0.96; P<0.0001), with the mean bone age difference of 0.12±0.76 years. Bone age comparisons by the two methods remained strongly correlated (P<0.0001) when stratified by gender, common endocrine conditions including growth disorders and early/precocious puberty, and race. In the longitudinal analysis, we also found a strong correlation between the automated software and manual bone age over time (r=0.7852; R2=0.63; P<0.01). Automated bone age assessment was found to be reliable and accurate in a large cohort of pediatric patients in a clinical practice setting in North America.

Purpose Obesity in youth increases the risk for type 2 diabetes (T2D) and elevated abdominal adipose tissue and organ fat may be particularly deleterious. The purpose of this study was to examine associations among measures of adiposity including total, visceral, and organ fat (hepatic and pancreatic) and whether these measures were independently associated with glycemia in Latino youth at risk for diabetes. Methods Latino adolescents (47 boys and 32 girls, 13.7 +/- 1.4 years) with obesity (BMIz 2.3 +/- 0.3) were assessed for total fat by DXA and visceral and organ fat by 3 T magnetic resonance imaging. Glycemic indicators included HbA1c, fasting glucose (FG), and 2-h glucose (2-HrG) following an oral glucose tolerance test. Pearson correlations and stepwise linear regression analyses controlling for age and sex were used to examine independent associations between adiposity and glycemia. Results Total fat was associated with visceral (r = 0.66, p = 0.001) and hepatic fat (r = 0.34, p < 0.01) while visceral fat was associated with hepatic (r = 0.42, p < 0.001) and pancreatic fat (r = 0.36, p < 0.001). In stepwise linear regression analysis, hepatic and pancreatic fat were significant predictors of FG, explaining 4.7% and 5.2% of the variance, respectively (total R-2 = 0.14, p = 0.02). Hepatic fat was the only significant predictor of 2-HrG explaining 9.9% of the variance in the model (total R-2 = 0.12, p = 0.03). No measure of adiposity was retained as a significant predictor of HbA1c. Conclusion Hepatic and pancreatic fat were the only adiposity measures independently associated with glycemia but the small amount of variance explained underscores the need for additional T2D biomarkers in high risk youth.

Background Proton density fat fraction (PDFF) estimated by using chemical shift-encoded (CSE) MRI is an accepted imaging biomarker of hepatic steatosis. This work aims to promote standardized use of CSE MRI to estimate PDFF. Purpose To assess the accuracy of CSE MRI methods for estimating PDFF by determining the linearity and range of bias observed in a phantom. Materials and Methods In this prospective study, a commercial phantom with 12 vials of known PDFF values were shipped across nine U.S. centers. The phantom underwent 160 independent MRI examinations on 27 1.5-T and 3.0-T systems from three vendors. Two three-dimensional CSE MRI protocols with minimal T1 bias were included: vendor and standardized. Each vendor's confounder-corrected complex or hybrid magnitude-complex based reconstruction algorithm was used to generate PDFF maps in both protocols. The Siemens reconstruction required a configuration change to correct for water-fat swaps in the phantom. The MRI PDFF values were compared with the known PDFF values by using linear regression with mixed-effects modeling. The 95% CIs were calculated for the regression slope (ie, proportional bias) and intercept (ie, constant bias) and compared with the null hypothesis (slope = 1, intercept = 0). Results Pooled regression slope for estimated PDFF values versus phantom-derived reference PDFF values was 0.97 (95% CI: 0.96, 0.98) in the biologically relevant 0%-47.5% PDFF range. The corresponding pooled intercept was -0.27% (95% CI: -0.50%, -0.05%). Across vendors, slope ranges were 0.86-1.02 (vendor protocols) and 0.97-1.0 (standardized protocol) at 1.5 T and 0.91-1.01 (vendor protocols) and 0.87-1.01 (standardized protocol) at 3.0 T. The intercept ranges (absolute PDFF percentage) were -0.65% to 0.18% (vendor protocols) and -0.69% to -0.17% (standardized protocol) at 1.5 T and -0.48% to 0.10% (vendor protocols) and -0.78% to -0.21% (standardized protocol) at 3.0 T. Conclusion Proton density fat fraction estimation derived from three-dimensional chemical shift-encoded MRI in a commercial phantom was accurate across vendors, imaging centers, and field strengths, with use of the vendors' product acquisition and reconstruction software. © RSNA, 2021 See also the editorial by Dyke in this issue.

Objective This study aimed to examine whether total, regional, and organ fat predicts bone marrow adipose tissue (BMAT) fat content and to explore whether BMAT fat content differs by sex among Latino youth. Methods Latino youth (n = 86; age 13.6 [1.4] years, 62% male) with obesity (BMI percentile = 98.5% [1.2%]) underwent a dual-energy x-ray absorptiometry scan to assess body composition and a magnetic resonance imaging scan to determine abdominal adiposity, liver fat, and vertebral BMAT fat content in the thoracic (average of T8-T12) and lumbar (average of L1-L5) spine. Results Male youth exhibited significantly greater thoracic (male youth = 30.8% [1.4%] vs. female youth = 24.5% [2.1%], p = 0.027) and lumbar (male youth = 36.3% [1.5%] vs. female youth = 30.2% [2.2%], p = 0.038) BMAT fat content compared with female youth. Visceral adipose tissue was a significant predictor of thoracic (beta = 0.434, t[86] = 3.016, p = 0.003) and lumbar (beta = 0.389, t[86] = 2.677, p = 0.009) BMAT fat content, explaining 8.9% and 6.9% of the variance, respectively. Liver fat was a significant predictor of both thoracic (beta = 0.487, t[86] = 4.334, p < 0.001) and lumbar (beta = 0.436, t[86] = 3.793, p < 0.001) BMAT fat content, explaining 17.6% and 13.8% of the variance, respectively. Conclusions Male youth had significantly greater thoracic and lumbar BMAT fat content than female youth. Greater BMAT fat content is associated with greater liver fat and visceral adipose tissue among youth with obesity. Further investigation of the mechanistic underpinnings of BMAT may help to differentiate its metabolic and bone-related functions.

Pediatric imaging use and payment trends in accountable care organizations (ACOs) are seldom studied but are important for health policy decisions and resource allocation. To evaluate patterns of advanced imaging use and associated payments over a 7-year period at a large ACO in the USA serving a Medicaid population. We reviewed paid claims data from 2011 through 2017 from an ACO, analyzing the MRI, CT and US use trends and payments from emergency department (ED) and outpatient encounters. We defined “utilization rate” as the number of advanced imaging procedures per 100 enrolled children per calendar year. Average yearly utilization and payments trends were analyzed using Pearson correlation. Across 7 years, 186,552 advanced imaging procedures were performed. The average overall utilization rate was 6.99 (95% confidence interval [CI]: 6.9–7.1). In the ED this was 2.7 (95% CI: 2.6–2.8) and in outpatients 4.3 (95% CI: 4.2–4.3). The overall utilization rate grew by 0.7% yearly (P=0.077), with US growing the most at 4.0% annually (P=0.0005), especially in the ED in the US, where it grew 10.8% annually (P=0.000019). The overall payments were stable from 2011 to 2017, with outpatient MRI seeing the largest payment decrease at 1.8% (P=0.24) and ED US showing the most growth at 3.3% (P=0.00016). Head CT and abdominal US were the two most common procedures. Over the study period, advanced imaging utilization at this large pediatric ACO serving the Medicaid population increased, especially with US use in the ED. Overall payments related to advanced imaging remained stable over this period.

Introduction: Lipid peroxidation and inflammation are pivotal pathological processes involved in the progression of NAFLD, a prelude to cardiovascular disease. Lifestyle intervention is the cornerstone approach for preventing cardiometabolic disease among high-risk populations, yet studies have not examined the mechanisms by which lifestyle intervention may mediate changes in liver fat in youth. Hypothesis: Lifestyle intervention will decrease hepatic fat fraction (HFF), tumor necrosis alpha (TNF)-α, and malondialdehyde (MDA)-protein adducts. Methods: Latino youth with obesity (n=26, age 13.9±1.3, BMI% 98.1±1.1) and prediabetes completed a 6-month lifestyle intervention that included nutrition education (1 d/wk) and physical activity (3 d/wk). HFF was measured by MRI before and after intervention. Fasting serum samples were collected for measurement of lipid peroxidation, measured by MDA-protein adducts, and inflammation, measured by TNF-α. Repeated measures ANOVA models were used to examine the effect of lifestyle intervention on HFF, MDA-protein adducts, and TNF-α. Data are presented as Mean±SE. Results: The intervention led to significant decreases in HFF (from 7.0±1.1% to 5.4±0.7%, p=0.027) and TNF-α (from 1.7±1.0 to 1.5±0.1 pg/mL, p=0.050), but not MDA-protein adducts (from 266.4±28.4 to 253.8±29.3 pmol/mL, p=0.105). However, there was significant heterogeneity in changes in HFF whereby those with the greatest response (n=14) decreased HFF by -44.0% while non-responders (n=12) increased HFF by 67.5%. HFF responders exhibited significantly greater reductions in MDA-protein adducts (from 256.2±39.4 to 228.1±40.0 pmol/mL, Δ-10.1%) compared to HFF non-responders (from 278.4±42.5 to 283.7±43.2 pmol/mL, Δ2.0%; p=0.023). TNF-α was reduced in HFF responders (from 1.8±0.2 to 1.5±0.1 pg/mL, Δ-17.8%) compared to HFF non-responders (from 1.5±0.2 to 1.5±0.1 pg/mL, Δ-4.4%) but was not significant (p=0.231). Conclusions: Reductions in HFF through lifestyle changes were associated with greater reductions in markers of lipid peroxidation, but not inflammation. The effect of lifestyle intervention on HFF may be mediated by markers that extend beyond traditional clinical risk factors among high-risk youth.

OBJECTIVE:The role of brown adipose tissue (BAT) in infant metabolism remains poorly understood, primarily because of the inherent limitation of positron emission tomography/computed tomography imaging to measure BAT, which is not suitable for infants. The aims of this method development study were to assess the feasibility, intra-rater reliability, interscan repeatability, and physiological relevance of measuring BAT in infants using magnetic resonance imaging (MRI). METHODS:A total of 10 nonsedated infants (mean age, 22.6 [1.3] days old) completed two 3-T MRI exams using chemical-shift-encoded water-fat scans 6.2 (2.8) days apart. Candidate BAT voxels in the supraclavicular region were identified based on fat signal fraction (FSF). The volumes of BAT depots were manually traced, and FSF was calculated. Whole-body fat mass was determined using dual-energy x-ray absorptiometry. RESULTS:Images were successfully obtained from 19 of 20 (95%) attempted scans. The mean BAT volume was 5.41 (SD 1.1) cm3 , and the mean FSF was 16.41% (SD 3.3%). Intra-rater analysis showed good reliability with no systemic bias (proportional bias for volume: p = 0.19; FSF: p = 0.30). Test-retest for interscan repeatability was good (intraclass correlation coefficients for volume: 0.92, p = 0.001 and intraclass correlation coefficients for FSF: 0.93, p < 0.001). FSF was inversely related to fat-free mass (r = -0.69, p = 0.03). CONCLUSIONS:This method development study supports the use of MRI to obtain reliable and quantitative measurements of BAT volume in infants.