Brain Volumes and Abnormalities in Adults Born Preterm at Very Low Birth Weight.

OBJECTIVES: To assess radiographic brain abnormalities and investigate volumetric differences in adults born preterm at very low birth weight (<1500 g), using siblings as controls. STUDY DESIGN: We recruited 79 adult same-sex sibling pairs with one born preterm at very low birth weight and the sibling at term. We acquired 3-T brain magnetic resonance imaging from 78 preterm participants and 72 siblings. A neuroradiologist, masked to participants' prematurity status, reviewed the images for parenchymal and structural abnormalities, and FreeSurfer software 6.0 was used to conduct volumetric analyses. Data were analyzed by linear mixed models. RESULTS: We found more structural abnormalities in very low birth weight participants than in siblings (37% vs 13%). The most common finding was periventricular leukomalacia, present in 15% of very low birth weight participants and in 3% of siblings. The very low birth weight group had smaller absolute brain volumes (-0.4 SD) and, after adjusting for estimated intracranial volume, less gray matter (-0.2 SD), larger ventricles (1.5 SD), smaller thalami (-0.6 SD), caudate nuclei (-0.4 SD), right hippocampus (-0.4 SD), and left pallidum (-0.3 SD). We saw no volume differences in total white matter (-0.04 SD; 95% CI, -0.13 to 0.09). CONCLUSIONS: Preterm very low birth weight adults had a higher prevalence of brain abnormalities than their term-born siblings. They also had smaller absolute brain volumes, less gray but not white matter, and smaller volumes in several gray matter structures.

Effects of Evolocumab on the Postprandial Kinetics of Apo (Apolipoprotein) B100- and B48-Containing Lipoproteins in Subjects With Type 2 Diabetes.

OBJECTIVE: Increased risk of atherosclerotic cardiovascular disease in subjects with type 2 diabetes is linked to elevated levels of triglyceride-rich lipoproteins and their remnants. The metabolic effects of PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors on this dyslipidemia were investigated using stable-isotope-labeled tracers. Approach and Results: Triglyceride transport and the metabolism of apos (apolipoproteins) B48, B100, C-III, and E after a fat-rich meal were investigated before and on evolocumab treatment in 13 subjects with type 2 diabetes. Kinetic parameters were determined for the following: apoB48 in chylomicrons; triglyceride in VLDL1 (very low-density lipoprotein) and VLDL2; and apoB100 in VLDL1, VLDL2, IDL (intermediate-density lipoprotein), and LDL (low-density lipoprotein). Evolocumab did not alter the kinetics of apoB48 in chylomicrons or apoB100 or triglyceride in VLDL1. In contrast, the fractional catabolic rates of VLDL2-apoB100 and VLDL2-triglyceride were both increased by about 45%, which led to a 28% fall in the VLDL2 plasma level. LDL-apoB100 was markedly reduced by evolocumab, which was linked to metabolic heterogeneity in this fraction. Evolocumab increased clearance of the more rapidly metabolized LDL by 61% and decreased production of the more slowly cleared LDL by 75%. ApoC-III kinetics were not altered by evolocumab, but the apoE fractional catabolic rates increased by 45% and the apoE plasma level fell by 33%. The apoE fractional catabolic rates was associated with the decrease in VLDL2- and IDL-apoB100 concentrations. CONCLUSIONS: Evolocumab had only minor effects on lipoproteins that are involved in triglyceride transport (chylomicrons and VLDL1) but, in contrast, had a profound impact on lipoproteins that carry cholesterol (VLDL2, IDL, LDL). Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02948777.

Effects of liraglutide on the metabolism of triglyceride-rich lipoproteins in type 2 diabetes.

AIM: To elucidate the impact of liraglutide on the kinetics of apolipoprotein (apo)B48- and apoB100-containing triglyceride-rich lipoproteins in subjects with type 2 diabetes (T2D) after a single fat-rich meal. MATERIALS AND METHODS: Subjects with T2D were included in a study to investigate postprandial apoB48 and apoB100 metabolism before and after 16 weeks on l.8 mg/day liraglutide (n = 14) or placebo (n = 4). Stable isotope tracer and compartmental modelling techniques were used to determine the impact of liraglutide on chylomicron and very low-density lipoprotein (VLDL) production and clearance after a single fat-rich meal. RESULTS: Liraglutide reduced apoB48 synthesis in chylomicrons by 60% (p < .0001) and increased the triglyceride/apoB48 ratio (i.e. the size) of chylomicrons (p < .001). Direct clearance of chylomicrons, a quantitatively significant pathway pretreatment, decreased by 90% on liraglutide (p < .001). Liraglutide also reduced VLDL1 -triglyceride secretion (p = .017) in parallel with reduced liver fat. Chylomicron-apoB48 production and particle size were related to insulin sensitivity (p = .015 and p < .001, respectively), but these associations were perturbed by liraglutide. CONCLUSIONS: In a physiologically relevant setting that mirrored regular feeding in subjects with T2D, liraglutide promoted potentially beneficial changes on postprandial apoB48 metabolism. Using our data in an integrated metabolic model, we describe how the action of liraglutide in T2D on chylomicron and VLDL kinetics could lead to decreased generation of remnant lipoproteins.

Natural Course of Nonalcoholic Fatty Liver Disease and Type 2 Diabetes in Patients With Human Immunodeficiency Virus With and Without Combination Antiretroviral Therapy-associated Lipodystrophy: A 16-Year Follow-up Study.

BACKGROUND: Abnormal glucose metabolism and nonalcoholic fatty liver disease (NAFLD) are common in patients with human immunodeficiency virus (HIV+ patients), but longitudinal data are lacking. We determined the natural course of NAFLD (liver fat [LFAT]) and type 2 diabetes mellitus (T2DM) in HIV+ patients with and without lipodystrophy (LD+ and LD-, respectively) during a 16-year longitudinal study. METHODS: LFAT (by proton magnetic resonance spectroscopy) and clinical characteristics were measured in 41 HIV+ patients at baseline and after 16 years. Liver fibrosis was estimated by measuring liver stiffness using transient elastography (TE) and magnetic resonance elastography (MRE) at 16 years. We also longitudinally studied 28 healthy subjects. RESULTS: During follow-up, the HIV+ patients gained more body fat (8.6% ± 0.7%) than the control patients (4.5% ± 0.6%, P < .001). Features of insulin resistance increased significantly in the HIV+ patients but not the control patients. A significant proportion (20%, P < .01 vs 0% at baseline) of the HIV+ but none of the control patients developed T2DM. LFAT was significantly higher at baseline in the LD+ (4.3 [1.9-11.8]) than the LD- (1.0 [0.5-1.5]; P < .001) HIV+ patients. LFAT remained stable during follow-up in all groups. At follow-up, liver stiffness measured with TE was similar among all HIV, LD+, LD-, and control patients and between the LD+ and LD- patients measured with MRE. Advanced fibrosis by MRE was observed in 3 of LD+ and none of LD- patients. CONCLUSIONS: During 16 years of follow-up, progression of NAFLD is rare compared to development of T2DM in HIV+ patients.

Plasma metabolites reveal distinct profiles associating with different metabolic risk factors in monozygotic twin pairs.

BACKGROUND: Obesity is related to a myriad of cardiometabolic outcomes, each of which may have a specific metabolomic signature and a genetic basis. We identified plasma metabolites associating with different cardiometabolic risk factors (adiposity, cholesterol, insulin resistance, and inflammation) in monozygotic (MZ) twins. Additionally, we assessed if metabolite profiling can identify subgroups differing by cardiometabolic risk factors. METHODS: We quantified 111 plasma metabolites (Acquity UPLC-triple quadrupole mass spectrometry), and measured blood lipids, HOMA index, CRP, and adiposity (BMI, %bodyfat by DEXA, fat distribution by MRI) in 40 MZ twin pairs (mean BMI 27.9 kg/m2, age 30.7). We determined associations among individuals (via linear regression) between metabolites and clinical phenotypes, and assessed, with within-twin pair analysis, if these associations were free from genetic confounding. We also performed cluster analysis to identify distinct subgroups based on subjects' metabolite profiles. RESULTS: We identified 42 metabolite-phenotype associations (FDR < 0.05), 19 remained significant after controlling for shared factors within the twin pairs. Aspartate, propionylcarnitine, tyrosine hexanoylcarnitine, and deoxycytidine associated positively with two or more adiposity measures. HDL cholesterol (HDL-C) associated negatively and BMI positively with the most numbers of metabolites; 12 were unique for HDL-C and 3 for BMI. Metabolites associating with HDL-C had the strongest effect size. Metabolite profiling revealed two distinct subgroups of individuals, differing by 32 metabolites (p < 0.05), and by total and LDL cholesterol (LDL-C). Forty-two metabolites predicted subgroup membership in correlation with total cholesterol and 45 metabolites predicted subgroup membership in correlation with LDL-C. CONCLUSIONS: Different fat depots share metabolites associating with general adiposity. BMI and HDL-C associated with the most pronounced and specific metabolomic signature. Metabolomics profiling can be used to identify distinct subgroups of individuals that differ by cholesterol measures. Most of the observed metabolite-phenotype associations are free of confounding by genetics and environmental factors shared by the co-twins.

Liraglutide treatment improves postprandial lipid metabolism and cardiometabolic risk factors in humans with adequately controlled type 2 diabetes: A single-centre randomized controlled study.

AIMS: Patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) exhibit considerable residual risk for cardiovascular disease (CVD). There is, therefore, increasing interest in targeting postprandial lipid metabolism and remnant cholesterol. Treatment with the glucagon-like peptide 1 (GLP-1) analogue liraglutide reduces CVD risk by mechanisms that remain unexplained in part. Here we investigated the effects of liraglutide intervention on ectopic fat depots, hepatic lipogenesis and fat oxidation, postprandial lipid metabolism and glycaemia in humans with type 2 diabetes. METHODS: The effect of liraglutide was investigated in 22 patients with adequately controlled type 2 diabetes. Patients were randomly allocated, in a single-blind fashion, to either liraglutide 1.8 mg or placebo once daily for 16 weeks. Because liraglutide is known to promote weight loss, the study included dietary counselling to achieve similar weight loss in the liraglutide and placebo groups. Cardiometabolic responses to a high-fat mixed meal were measured before and at the end of the liraglutide intervention. RESULTS: Weight loss at Week 16 was similar between the groups: -2.4 kg (-2.5%) in the liraglutide group and -2.1 kg (-2.2%) in the placebo group. HBA1c improved by 6.4 mmol/mol (0.6%) in the liraglutide group (P = 0.005). Liver fat decreased in both groups, by 31% in the liraglutide group and by 18% in the placebo group, but there were no significant changes in the rate of hepatic de novo lipogenesis or ß-hydroxybutyrate levels, a marker of fat oxidation. We observed significant postprandial decreases in triglycerides only in plasma, chylomicrons and VLDL, and remnant particle cholesterol after treatment in the liraglutide group. Fasting and postprandial apoCIII concentrations decreased after liraglutide intervention and these changes were closely related to reduced glycaemia. In relative importance analysis, approximately half of the changes in postprandial lipids were explained by reductions in apoCIII concentrations, whereas less than 10% of the variation in postprandial lipids was explained by reductions in weight, glycaemic control, liver fat or postprandial insulin responses. CONCLUSIONS: Intervention with liraglutide for 16 weeks produces multiple improvements in cardiometabolic risk factors that were not seen in the placebo group, despite similar weight loss. Of particular importance was a marked reduction in postprandial atherogenic remnant particles. The underlying mechanism may be improved glycaemic control, which leads to reduced expression of apoCIII, a key regulator of hypertriglyceridaemia in hyperglycaemic patients.

Role of apolipoprotein C-III overproduction in diabetic dyslipidaemia.

AIMS: To investigate how apolipoprotein C-III (apoC-III) metabolism is altered in subjects with type 2 diabetes, whether the perturbed plasma triglyceride concentrations in this condition are determined primarily by the secretion rate or the removal rate of apoC-III, and whether improvement of glycaemic control using the glucagon-like peptide-1 analogue liraglutide for 16 weeks modifies apoC-III dynamics. MATERIALS AND METHODS: Postprandial apoC-III kinetics were assessed after a bolus injection of [5,5,5-2 H3 ]leucine using ultrasensitive mass spectrometry techniques. We compared apoC-III kinetics in two situations: in subjects with type 2 diabetes before and after liraglutide therapy, and in type 2 diabetic subjects with matched body mass index (BMI) non-diabetic subjects. Liver fat content, subcutaneous abdominal and intra-abdominal fat were determined using proton magnetic resonance spectroscopy. RESULTS: Improved glycaemic control by liraglutide therapy for 16 weeks significantly reduced apoC-III secretion rate (561 ± 198 vs. 652 ± 196 mg/d, P = 0.03) and apoC-III levels (10.0 ± 3.8 vs. 11.7 ± 4.3 mg/dL, P = 0.035) in subjects with type 2 diabetes. Change in apoC-III secretion rate was significantly associated with the improvement in indices of glucose control (r = 0.67; P = 0.009) and change in triglyceride area under the curve (r = 0.59; P = 0.025). In line with this, the apoC-III secretion rate was higher in subjects with type 2 diabetes compared with BMI-matched non-diabetic subjects (676 ± 208 vs. 505 ± 174 mg/d, P = 0.042). CONCLUSIONS: The results reveal that the secretion rate of apoC-III is associated with elevation of triglyceride-rich lipoproteins in subjects with type 2 diabetes, potentially through the influence of glucose homeostasis on the production of apoC-III.

Minimal volume ventilation during robotically assisted mitral valve surgery.

INTRODUCTION: A minimal volume ventilation method for robotically assisted mitral valve surgery is described in this study. In an attempt to reduce postoperative pulmonary dysfunction, 40 of 174 patients undergoing robotically assisted mitral valve surgery were ventilated with a small tidal volume during cardiopulmonary bypass. METHODS: After propensity score matching, 31 patients with minimal volume ventilation were compared with 54 patients with no ventilation. Total ventilation time, PaO2/FiO2 ratio, arterial lactate concentration, and the rate of unilateral pulmonary edema in the matched minimal ventilation and standard treatment groups were evaluated. RESULTS: Patients in the minimal ventilation group had shorter ventilation times, 12.0 (interquartile range: 9.9-15.0) versus 14.0 (interquartile range: 12.0-16.3) hours (p = 0.036), and lower postoperative arterial lactate levels, 0.99 (interquartile range: 0.81-1.39) versus 1.28 (interquartile range: 0.99-1.86) mmol/L (p = 0.01), in comparison to patients in the standard treatment group. There was no difference in postoperative PaO2/FiO2 ratio levels or in the rate of unilateral pulmonary edema between the groups. CONCLUSION: Minimal ventilation appeared beneficial in terms of total ventilation time and blood lactatemia, while there was no improvement in arterial blood gas measurements or in the rate of unilateral pulmonary edema. The lower postoperative arterial lactate levels may suggest improved lung perfusion among patients in the minimal volume ventilation group. The differences in the ventilation times were in fact small, and further studies are required to confirm the possible advantages of the minimal volume ventilation method in robotically assisted cardiac surgery.

Personal model-assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD.

To elucidate the molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome-scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD+ and glutathione (GSH) in subjects with high HS Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD+ repletion on the development of NAFLD, we added precursors for GSH and NAD+ biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof-of-concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment.

Mitochondria-related transcriptional signature is downregulated in adipocytes in obesity: a study of young healthy MZ twins.

AIMS/HYPOTHESIS: Low mitochondrial activity in adipose tissue is suggested to be an underlying factor in obesity and its metabolic complications. We aimed to find out whether mitochondrial measures are downregulated in obesity also in isolated adipocytes. METHODS: We studied young adult monozygotic (MZ) twin pairs discordant (n = 14, intrapair difference ΔBMI ≥ 3 kg/m2) and concordant (n = 5, ΔBMI < 3 kg/m2) for BMI, identified from ten birth cohorts of 22- to 36-year-old Finnish twins. Abdominal body fat distribution (MRI), liver fat content (magnetic resonance spectroscopy), insulin sensitivity (OGTT), high-sensitivity C-reactive protein, serum lipids and adipokines were measured. Subcutaneous abdominal adipose tissue biopsies were obtained to analyse the transcriptomics patterns of the isolated adipocytes as well as of the whole adipose tissue. Mitochondrial DNA transcript levels in adipocytes were measured by quantitative real-time PCR. Western blots of oxidative phosphorylation (OXPHOS) protein levels in adipocytes were performed in obese and lean unrelated individuals. RESULTS: The heavier (BMI 29.9 ± 1.0 kg/m2) co-twins of the discordant twin pairs had more subcutaneous, intra-abdominal and liver fat and were more insulin resistant (p < 0.01 for all measures) than the lighter (24.1 ± 0.9 kg/m2) co-twins. Altogether, 2538 genes in adipocytes and 2135 in adipose tissue were significantly differentially expressed (nominal p < 0.05) between the co-twins. Pathway analysis of these transcripts in both isolated adipocytes and adipose tissue revealed that the heavier co-twins displayed reduced expression of genes relating to mitochondrial pathways, a result that was replicated when analysing the pathways behind the most consistently downregulated genes in the heavier co-twins (in at least 12 out of 14 pairs). Consistently upregulated genes in adipocytes were related to inflammation. We confirmed that mitochondrial DNA transcript levels (12S RNA, 16S RNA, COX1, ND5, CYTB), expression of mitochondrial ribosomal protein transcripts and a major mitochondrial regulator PGC-1α (also known as PPARGC1A) were reduced in the heavier co-twins' adipocytes (p < 0.05). OXPHOS protein levels of complexes I and III in adipocytes were lower in obese than in lean individuals. CONCLUSIONS/INTERPRETATION: Subcutaneous abdominal adipocytes in obesity show global expressional downregulation of oxidative pathways, mitochondrial transcripts and OXPHOS protein levels and upregulation of inflammatory pathways. DATA AVAILABILITY: The datasets analysed and generated during the current study are available in the figshare repository, https://dx.doi.org/10.6084/m9.figshare.3806286.v1.

Use of HOMA-IR to diagnose non-alcoholic fatty liver disease: a population-based and inter-laboratory study.

AIMS/HYPOTHESIS: Recent European guidelines for non-alcoholic fatty liver disease (NAFLD) call for reference values for HOMA-IR. In this study, we aimed to determine: (1) the upper limit of normal HOMA-IR in two population-based cohorts; (2) the HOMA-IR corresponding to NAFLD; (3) the effect of sex and PNPLA3 genotype at rs738409 on HOMA-IR; and (4) inter-laboratory variations in HOMA-IR. METHODS: We identified healthy individuals in two population-based cohorts (FINRISK 2007 [n = 5024] and the Programme for Prevention of Type 2 Diabetes in Finland [FIN-D2D; n = 2849]) to define the upper 95th percentile of HOMA-IR. Non-obese individuals with normal fasting glucose levels, no excessive alcohol use, no known diseases and no use of any drugs were considered healthy. The optimal HOMA-IR cut-off for NAFLD (liver fat ≥5.56%, based on the Dallas Heart Study) was determined in 368 non-diabetic individuals (35% with NAFLD), whose liver fat was measured using proton magnetic resonance spectroscopy (1H-MRS). Samples from ten individuals were simultaneously analysed for HOMA-IR in seven European laboratories. RESULTS: The upper 95th percentiles of HOMA-IR were 1.9 and 2.0 in healthy individuals in the FINRISK (n = 1167) and FIN-D2D (n = 459) cohorts. Sex or PNPLA3 genotype did not influence these values. The optimal HOMA-IR cut-off for NAFLD was 1.9 (sensitivity 87%, specificity 79%). A HOMA-IR of 2.0 corresponded to normal liver fat (<5.56% on 1H-MRS) in linear regression analysis. The 2.0 HOMA-IR measured in Helsinki corresponded to 1.3, 1.6, 1.8, 1.8, 2.0 and 2.1 in six other laboratories. The inter-laboratory CV% of HOMA-IR was 25% due to inter-assay variation in insulin (25%) rather than glucose (5%) measurements. CONCLUSIONS/INTERPRETATION: The upper limit of HOMA-IR in population-based cohorts closely corresponds to that of normal liver fat. Standardisation of insulin assays would be the first step towards definition of normal values for HOMA-IR.

Frontal Cortex Myo-Inositol Is Associated with Sleep and Depression in Adolescents: A Proton Magnetic Resonance Spectroscopy Study.

AIM: This study used proton magnetic resonance spectroscopy (1H MRS) to evaluate the neurochemistry of the frontal cortex in adolescents with symptoms of sleep and depression. METHODS: Nineteen non-medicated adolescent boys (mean age 16.0 years; 9 clinical cases with depression/sleep symptoms and 10 healthy controls) underwent 1H MRS at 3 T. MR spectra were acquired from the anterior cingulate cortex (ACC), the dorsolateral prefrontal cortex, and frontal white matter. Concentrations of N-acetyl aspartate, total creatine, choline-containing compounds, total glutamine plus glutamate, and myo-inositol (mI) were compared in the 2 subgroups, and correlated with sleep and clinical measures in the total sample. Sleep was assessed with self-report questionnaires and ambulatory polysomnography recordings. RESULTS: Concentrations of mI were lower in both frontal cortical regions among the depressed adolescents than in controls. No statistically significant differences in other metabolite concentrations were observed between the subgroups. Frontal cortex mI concentrations correlated negatively with depression severity, subjective daytime sleepiness, insomnia symptoms, and the level of anxiety, and correlated positively with total sleep time and overall psychosocial functioning. The correlations between mI in the ACC and total sleep time as well as daytime sleepiness remained statistically significant when depression severity was controlled in the analyses. CONCLUSION: Lower frontal cortex mI may indicate a disturbed second messenger system. Frontal cortical mI may thus be linked to the pathophysiology of depression and concomitant sleep symptoms among maturing adolescents. Short sleep and daytime sleepiness may be associated with frontal cortex mI independently from depression.

31Phosphorus magnetic resonance spectroscopy of the liver for evaluating inflammation and fibrosis in autoimmune hepatitis.

BACKGROUND: Liver biopsy is the gold standard in evaluating inflammation and fibrosis in autoimmune hepatitis. AIMS: In search of non-invasive follow-up tools in autoimmune hepatitis, we evaluated 31phosphorus magnetic resonance spectroscopy (31P MRS). METHODS: Twelve consecutive AIH patients (mean age 42.8 years, 10 women) underwent liver biopsy, routine laboratory liver function tests, which were compared to findings in 31P MRS and transient elastography (TE). RESULTS: Phosphoenolpuryvate (PEP) correlated with the grade of inflammation (r = 0.746, p = .005) and thromboplastin time (r = 0.592, p = .043). It also differentiated patients with active inflammation from patients without (t = 3.781, p = .009). There was no correlation between PEP and aminotransferase or immunoglobulin G levels. The phosphoethanolamine (PE)/phosphocholine (PC) ratio, PE/glyserophosphoethanolamine (GPE) ratio and PC/[total phosphomonoester (PME) + phosphodiester (PDE)] ratios correlated with immunoglobulin G (r = 0.764, p = .006; r = 0.618, p = .043; and r= -0.636, p = .035, respectively). PME/PDE and PE/GPE correlated with fibrosis (r = 0.668, p = .018 and r = 0.604, p = .037). PE/GPE also differentiated F3 from F0-2 patients (t = 3.810, p = .003). Phosphorus metabolites did not correlate with TE results and TE did not correlate with liver histology or laboratory parameters. CONCLUSIONS: 31P MRS seems to detect active inflammation and advanced fibrosis in AIH patients. TE was ineffective in fibrosis quantification.

Eye Movements of Radiologists Reflect Expertise in CT Study Interpretation: A Potential Tool to Measure Resident Development.

Purpose To establish potential markers of visual expertise in eye movement (EM) patterns of early residents, advanced residents, and specialists who interpret abdominal computed tomography (CT) studies. Materials and Methods The institutional review board approved use of anonymized CT studies as research materials and to obtain anonymized eye-tracking data from volunteers. Participants gave written informed consent. Early residents (n = 15), advanced residents (n = 14), and specialists (n = 12) viewed 26 abdominal CT studies as a sequence of images at either 3 or 5 frames per second while EMs were recorded. Data were analyzed by using linear mixed-effects models. Results Early residents' detection rate decreased with working hours (odds ratio, 0.81; 95% confidence interval [CI]: 0.73, 0.91; P = .001). They detected less of the low visual contrast (but not of the high visual contrast) lesions (45% [13 of 29]) than did specialists (62% [18 of 29]) (odds ratio, 0.39; 95% CI: 0.25, 0.61; P < .001) or advanced residents (56% [16 of 29]) (odds ratio, 0.55; 95% CI: 0.33, 0.93; P = .024). Specialists and advanced residents had longer fixation durations at 5 than at 3 frames per second (specialists: ß = .01; 95% CI: .004, .026; P = .008; advanced residents: ß = .04; 95% CI: .03, .05; P < .001). In the presence of lesions, saccade lengths of specialists shortened more than those of advanced (ß = .02; 95% CI: .007, .04; P = .003) and of early residents (ß = .02; 95% CI: .008, 0.04; P = .003). Irrespective of expertise, high detection rate correlated with greater reduction of saccade length in the presence of lesions (ß = -.10; 95% CI: -.16, -.04; P = .002) and greater increase at higher presentation speed (ß = .11; 95% CI: .04, .17; P = .001). Conclusion Expertise in CT reading is characterized by greater adaptivity in EM patterns in response to the demands of the task and environment. © RSNA, 2016 Online supplemental material is available for this article.

Kinetic and Related Determinants of Plasma Triglyceride Concentration in Abdominal Obesity: Multicenter Tracer Kinetic Study.

OBJECTIVES: Patients with obesity and diabetes mellitus have increased risk of cardiovascular disease. A major cause is an atherogenic dyslipidemia related primarily to elevated plasma concentrations of triglyceride-rich lipoproteins. The aim of this study was to clarify determinants of plasma triglyceride concentration. We focused on factors that predict the kinetics of very-low density lipoprotein 1 (VLDL1) triglycerides. APPROACH AND RESULTS: A multicenter study using dual stable isotopes (deuterated leucine and glycerol) and multicompartmental modeling was performed to elucidate the kinetics of triglycerides and apoB in VLDL1 in 46 subjects with abdominal obesity and additional cardiometabolic risk factors. Results showed that plasma triglyceride concentrations were dependent on both the secretion rate (r=0.44, P<0.01; r=0.45, P<0.01) and fractional catabolism (r=0.49, P<0.001; r=0.55, P<0.001) of VLDL1-triglycerides and VLDL1-apoB. Liver fat mass was independently and directly associated with secretion rates of VLDL1-triglycerides (r=0.56, P<0.001) and VLDL1-apoB (r=0.53, P<0.001). Plasma apoC-III concentration was independently and inversely associated with the fractional catabolisms of VLDL1-triglycerides (r=0.48, P<0.001) and VLDL1-apoB (r=0.51, P<0.001). CONCLUSIONS: Plasma triglyceride concentrations in abdominal obesity are determined by the kinetics of VLDL1 subspecies, catabolism being mainly dependent on apoC-III concentration and secretion on liver fat content. Reduction in liver fat and targeting apoC-III may be an effective approach for correcting triglyceride metabolism atherogenic dyslipidemia in obesity.

Metabolome and fecal microbiota in monozygotic twin pairs discordant for weight: a Big Mac challenge.

Postprandial responses to food are complex, involving both genetic and environmental factors. We studied postprandial responses to a Big Mac meal challenge in monozygotic co-twins highly discordant for body weight. This unique design allows assessment of the contribution of obesity, independent of genetic liability. Comprehensive metabolic profiling using 3 analytical platforms was applied to fasting and postprandial serum samples from 16 healthy monozygotic twin pairs discordant for weight (body mass index difference >3 kg/m(2)). Nine concordant monozygotic pairs were examined as control pairs. Fecal samples were analyzed to assess diversity of the major bacterial groups by using 5 different validated bacterial group specific denaturing gradient gel electrophoresis methods. No differences in fecal bacterial diversity were detected when comparing co-twins discordant for weight (ANOVA, P<0.05). We found that within-pair similarity is a dominant factor in the metabolic postprandial response, independent of acquired obesity. Branched chain amino acids were increased in heavier as compared with leaner co-twins in the fasting state, but their levels converged postprandially (paired t tests, FDR q<0.05). We also found that specific bacterial groups were associated with postprandial changes of specific metabolites. Our findings underline important roles of genetic and early life factors in the regulation of postprandial metabolite levels.

Impact of non-alcoholic fatty liver disease on liver volume in humans.

AIM: Knowledge of liver volume is needed in the preoperative screening of liver transplant donors and in pharmacokinetic studies. In previous studies, bodyweight, surface area, age and sex have been identified as predictors of total liver volume, but the impact of non-alcoholic fatty liver disease (NAFLD) independent of body size on liver volume has not been determined. We examined whether and to what extent liver fat due to NAFLD influences liver volume. METHODS: We quantified the percentage of liver fat by proton magnetic resonance spectroscopy ((1) H-MRS) and liver total, lean and fat volumes using magnetic resonance imaging (MRI) in 112 subjects (62 women, 50 men), who were characterized with respect to metabolic parameters associated with NAFLD. RESULTS: Of the subjects, 45% had NAFLD (liver fat 12.5 ± 4.5% vs 1.8 ± 1.6%, NAFLD vs no NAFLD, P < 0.001). Total liver volume was 29% higher in subjects with NAFLD (1.91 ± 0.45 L) than in those with no NAFLD (1.49 ± 0.31 L, P < 0.001). In multiple linear regression analysis, the percentage of liver fat and bodyweight independently explained variation in total liver volume (r(2) = 0.42, P < 0.001). The r-values for the relationship between metabolic parameters and the total liver fat volume were not significantly better than those between metabolic parameters and the percentage of liver fat. CONCLUSION: Both bodyweight and NAFLD increase liver volume independent of each other. Measurement of liver fat by (1) H-MRS allows accurate quantification of NAFLD and calculation of total liver volume.

Measuring short-term liver metabolism non-invasively: postprandial and post-exercise ¹H and ³¹P MR spectroscopy.

OBJECT: The objective of this study was to determine the effects of a standardized fat rich meal and subsequent exercise on liver fat content by ¹H MRS and on liver adenosine triphosphate (ATP) content by ³¹P MRS in healthy subjects. MATERIALS AND METHODS: Hepatic ¹H and proton decoupled ³¹P MRS were performed on nine healthy subjects on a clinical 3.0 T MR imager three times during a day: after (1) an overnight fast, (2) a following standardized fat rich meal and (3) a subsequent exercise session. Blood parameters were followed during the day to serve as a reference to MRS. RESULTS: Liver fat content increased gradually over the day (p = 0.0001) with an overall increase of 30 %. Also γ-NTP changed significantly over the day (p = 0.005). γ-NTP/tP decreased by 9 % (p = 0.019, post hoc) from the postprandial to the post-exercise state. CONCLUSION: Our study shows that in vivo MRS can depict short lived physiological changes; entering of fat into liver cells and consumption of ATP during exercise can be measured non-invasively in healthy subjects. The physiological state may have an impact on fat and energy metabolite levels. Hepatic ¹H and ³¹P MRS studies should be performed under standardized conditions.

Cardiac steatosis and left ventricular function in men with metabolic syndrome.

BACKGROUND: Ectopic accumulation of fat accompanies visceral obesity with detrimental effects. Lipid oversupply to cardiomyocytes leads to cardiac steatosis, and in animal studies lipotoxicity has been associated with impaired left ventricular (LV) function. In humans, studies have yielded inconclusive results. The aim of the study was to evaluate the role of epicardial, pericardial and myocardial fat depots on LV structure and function in male subjects with metabolic syndrome (MetS). METHODS: A study population of 37 men with MetS and 38 men without MetS underwent cardiovascular magnetic resonance and proton magnetic spectroscopy at 1.5 T to assess LV function, epicardial and pericardial fat area and myocardial triglyceride (TG) content. RESULTS: All three fat deposits were greater in the MetS than in the control group (p <0.001). LV diastolic dysfunction was associated with MetS as measured by absolute (471 mL/s vs. 667 mL/s, p = 0.002) and normalized (3.37 s⁻¹ vs. 3.75 s⁻¹, p = 0.02) LV early diastolic peak filling rate and the ratio of early diastole (68% vs. 78%, p = 0.001). The amount of epicardial and pericardial fat correlated inversely with LV diastolic function. However, myocardial TG content was not independently associated with LV diastolic dysfunction. CONCLUSIONS: In MetS, accumulation of epicardial and pericardial fat is linked to the severity of structural and functional alterations of the heart. The role of increased intramyocardial TG in MetS is more complex and merits further study.

Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation, and gut microbiota in a twin study.

Nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide riboside (NR) has emerged as a promising compound to improve obesity-associated mitochondrial dysfunction and metabolic syndrome in mice. However, most short-term clinical trials conducted so far have not reported positive outcomes. Therefore, we aimed to determine whether long-term NR supplementation boosts mitochondrial biogenesis and metabolic health in humans. Twenty body mass index (BMI)-discordant monozygotic twin pairs were supplemented with an escalating dose of NR (250 to 1000 mg/day) for 5 months. NR improved systemic NAD+ metabolism, muscle mitochondrial number, myoblast differentiation, and gut microbiota composition in both cotwins. NR also showed a capacity to modulate epigenetic control of gene expression in muscle and adipose tissue in both cotwins. However, NR did not ameliorate adiposity or metabolic health. Overall, our results suggest that NR acts as a potent modifier of NAD+ metabolism, muscle mitochondrial biogenesis and stem cell function, gut microbiota, and DNA methylation in humans irrespective of BMI.