Although parenteral nutrition (PN) is life-sustaining, it is associated with many complications including parenteral nutrition-associated liver disease (PNALD) and central line-associated bloodstream infections (CLASBIs), which carry a high morbidity and mortality and impose a burden on the health care system. Evidence has emerged that the dose and composition of intravenous lipid products may alter the incidence of PNALD. However, other patient and PN-related factors, such as prematurity, birth weight, and gastrointestinal anatomy and function, are important. To improve neonatal care, future research on optimizing the content of PN and decreasing the incidence IFALD and CLASBIs is required.

Intrauterine growth restriction is linked to decreased lean body mass and insulin resistance. The mammalian target of rapamycin (mTOR) regulates muscle mass and glucose metabolism; however, little is known about maternal dietary restriction and skeletal muscle mTOR in offspring. We hypothesized that early dietary restriction would decrease skeletal muscle mass and mTOR in the suckling rat. To test this hypothesis, ab libitum access to food or dietary restriction during gestation followed by postnatal cross-fostering to a dietary-restricted or ad libitum-fed rat dam during lactation generated 4 groups: control (CON), intrauterine dietary restricted (IUDR), postnatal dietary restricted (PNDR), and IUDR+PNDR (IPDR). At day 21, when compared to CON, the IUDR group demonstrated "catchup" growth, but no changes were observed in the mTOR pathway. Despite having less muscle mass than CON and IUDR (P < .001), in IPDR and PNDR rats mTOR remained unchanged. IPDR and PNDR (p)-tuberous sclerosis complex 2 was less than the IUDR group (P < .05). Downstream, IPDR's and PNDR's phosphorylated (p)-ribosomal s6 (rs6)/rs6 was less than that of CON (P < .05). However, male IPDR's and PNDR's p-mitogen activated protein kinase MAPK/MAPK was greater than CON (P < .05) without a change in p90 ribosomal s6 kinase (p90RSK). In contrast, in females, MAPK was unchanged, but IPDR p-p90RSK/p90RSK was less than CON (P = .01). In conclusion, IPDR and PNDR reduced skeletal muscle mass but did not decrease mTOR. In IPDR and PNDR, a reduction in tuberous sclerosis complex 2 may explain why mTOR was unchanged, whereas, in males, an increase in MAPK with a decrease in rs6 may suggest a block in MAPK signaling.

Non-cholesterol sterols are validated markers for fractional intestinal cholesterol absorption (cholestanol) and endogenous cholesterol synthesis (lathosterol). This study's objective was to evaluate markers for cholesterol synthesis and absorption in children exposed to two different intravenous lipid emulsions that rapidly change serum plant sterol concentrations as part of their parenteral nutrition (PN). Serum samples from two different studies were used: (1) nine PN-dependent children with intestinal failure associated liver disease (IFALD) whose soy-based, plant sterol-rich lipid (SO) was replaced with a fish-based, plant sterol-poor (FO) lipid; and (2) five neonates prescribed SO after birth. In the first study, samples were collected at baseline (prior to FO initiation) and after 3 and 6 months of FO. In study 2, samples were collected at 1 and 3 weeks of age. In study 1, a 7-fold reduction in campesterol, a 12-fold reduction in sitosterol, and a 15-fold reduction in stigmasterol was observed 6 months after switching to FO. Serum cholesterol concentrations did not change, but cholesterol-standardized lathosterol increased (3-fold) and cholesterol-standardized cholestanol decreased (2-fold). In study 2, after 3 weeks of SO, sitosterol and campesterol concentrations increased 4-5 fold. At the same time, cholesterol-standardized lathosterol increased 69% and cholesterol-standardized cholestanol decreased by 29%. Based on these finding we conclude that changes in serum plant sterol concentrations might have direct effects on endogenous cholesterol synthesis, although this needs to be confirmed in future studies. Moreover, we speculate that this changed synthesis subsequently affects intestinal cholesterol absorption.

Diet during pregnancy has long lasting consequences on the offspring, warranting a study on the impact of early exposure to a high fat diet on the adult offspring. We hypothesized that a prenatal n-6 enriched diet will have adverse metabolic outcomes on the adult offspring that may be reversed with a postnatal n-3 enriched diet. To test this hypothesis, we examined the adult offspring from three groups: (1) n-6 group: during gestation and lactation, dams consumed an n-6 polyunsaturated fatty acid enriched diet, (2) n-3 group: gestational n-6 diet was followed by an n-3 enriched diet during lactation, and (3) a control (CD) group that received standard diet throughout gestation and lactation. Offspring from all groups weaned to a control diet ad libitum. Beginning at postnatal day 2 (P < .03) and persisting at 360 days in males (P < .04), an increase in hypothalamic AgRP expression occurred in the n-6 and n-3 groups, with an increase in food intake (P = .01), and the n-3 group displaying lower body (P < .03) and brain (P < .05) weights. At 360 days, the n-6 and n-3 groups remained glucose tolerant and insulin sensitive, with increased phosphorylated-AMP-activated protein kinase (P < .05). n-6 group developed hepatic steatosis with reduced hepatic reflected as higher plasma microRNA-122 (P < .04) that targets pAMPK. We conclude that early life exposure to n-6 and n-3 led to hypothalamic AgRP-related higher food intake, with n-6 culminating in a fatty liver partially mitigated by postnatal n-3. While both diets preserved glucose tolerance and insulin sensitivity, postnatal n-3 displayed detrimental effects on the brain.

Background

There is evidence that microRNA (MIR) 122 is a biomarker for various liver diseases in adults and children. To date, MIR122 has not been explored in children with intestinal failure-associated liver disease (IFALD, or hyperbilirubinemia associated with prolonged parenteral nutrition).

Objectives

This study's purpose was to investigate changes in plasma miR-122, correlate miR-122 with serum liver function tests and enzymes, and investigate changes in whole blood transcripts including miR-122 targets in a group of children with IFALD who received pure intravenous fish oil (FO) as a treatment for cholestasis.

Methods

This was a prospective, observational study that enrolled children with IFALD who received intravenous FO (1 g/kg/d) and whose cholestasis resolved with FO. Plasma miR-122 was measured using reverse transcription-quantitative real-time PCR, and whole blood miR-122 targets were quantified using RNA sequencing.

Results

Fourteen subjects with median age 6 mo (IQR: 3-65 mo) were enrolled. RNA sequence data were available for 4 subjects. When compared with the start of FO, median miR-122 concentrations at 6 mo of FO therapy decreased [1.0 (IQR: 1.0-1.0) compared with 0.04 (IQR: 0.01-0.6), P = 0.009]. At the start of FO, miR-122 correlated with conjugated bilirubin (r = 0.56; P = 0.038). At ∼3 mo of FO, miR-122 correlated with conjugated bilirubin (r = 0.56; P = 0.045). Reactive oxygen species, heme metabolism, coagulation, adipogenesis, IL-6-Janus kinase-signal transducer and activator of transcription (JAK-STAT) 3, IL-2-STAT5, transforming growth factor-β, TNF-α, inflammatory response, mammalian target of rapamycin gene families (normalized enrichment scores < -1.4), and miR-122 target genes were significantly downregulated with FO.

Conclusions

In this small cohort of young children with IFALD, miR-122 decreased with FO therapy and correlated with conjugated bilirubin. Key pathways involving oxidation, inflammation, cellular differentiation, and nutrient regulation were downregulated. Data from this study provide information about IFALD and FO. This trial was registered at www.clinicaltrials.gov as NCT00969332.

Purpose

To develop a deep learning-based method for rapid liver proton-density fat fraction (PDFF) and R₂ * quantification with built-in uncertainty estimation using self-gated free-breathing stack-of-radial MRI.

Methods

This work developed an uncertainty-aware physics-driven deep learning network (UP-Net) to (1) suppress radial streaking artifacts because of undersampling after self-gating, (2) calculate accurate quantitative maps, and (3) provide pixel-wise uncertainty maps. UP-Net incorporated a phase augmentation strategy, generative adversarial network architecture, and an MRI physics loss term based on a fat-water and R₂ * signal model. UP-Net was trained and tested using free-breathing multi-echo stack-of-radial MRI data from 105 subjects. UP-Net uncertainty scores were calibrated in a validation dataset and used to predict quantification errors for liver PDFF and R₂ * in a testing dataset.

Results

Compared with images reconstructed using compressed sensing (CS), UP-Net achieved structural similarity index >0.87 and normalized root mean squared error <0.18. Compared with reference quantitative maps generated using CS and graph-cut (GC) algorithms, UP-Net achieved low mean differences (MD) for liver PDFF (-0.36%) and R₂ * (-0.37 s^-1 ). Compared with breath-holding Cartesian MRI results, UP-Net achieved low MD for liver PDFF (0.53%) and R₂ * (6.75 s^-1 ). UP-Net uncertainty scores predicted absolute liver PDFF and R₂ * errors with low MD of 0.27% and 0.12 s^-1 compared to CS + GC results. The computational time for UP-Net was 79 ms/slice, whereas CS + GC required 3.2 min/slice.

Conclusion

UP-Net rapidly calculates accurate liver PDFF and R₂ * maps from self-gated free-breathing stack-of-radial MRI. The pixel-wise uncertainty maps from UP-Net predict quantification errors in the liver.

Background

Infants with gastroschisis require operations and lengthy hospitalizations due to intestinal dysmotility. Dysbiosis may contribute to these problems. Little is known on the microbiome of gastroschisis infants.

Methods

The purpose of this study was to investigate the fecal microbiome in gastroschisis infants. Microbiome profiling was performed by sequencing the V4 region of the 16S rRNA gene. The microbiome of gastroschisis infants was compared with the microbiome of healthy controls, and the effects of mode of birth delivery, gestational age, antibiotic duration, and nutrition type on microbial composition and diversity were investigated.

Results

The microbiome of gastroschisis infants (n = 13) was less diverse (Chao1, P < .001), lacked Bifidobacterium (P = .001), and had increased Staphylococcus (P = .007) compared with controls (n = 83). Mode of delivery (R² = 0.04, P = .001), antibiotics duration ≥7 days (R² = 0.03, P = .003), age at sample collection (R² = 0.03, P = .009), and gestational age (R² = 0.02, P = .035) explained a small portion of microbiome variation. In gastroschisis infants, Escherichia-Shigella was the predominate genus, and those delivered via cesarean section had different microbial communities, predominantly Staphylococcus and Streptococcus, from those delivered vaginally. Although antibiotic duration contributed to the variation in microbiome composition, there were no significant differences in taxa distribution or α diversity by antibiotic duration or nutrition type.

Conclusion

The microbiome of gastroschisis infants is dysbiotic, and mode of birth delivery, antibiotic duration, and gestational age appear to contribute to microbial variation.

Background

MRI acquisition for pediatric pancreatic fat quantification is limited by breath-holds (BH). Full segmentation (FS) or small region of interest (ROI) analysis methods may not account for pancreatic fat spatial heterogeneity, which may limit accuracy.

Purpose

To improve MRI acquisition and analysis for quantifying pancreatic proton-density fat fraction (pPDFF) in children by investigating free-breathing (FB)-MRI, characterizing pPDFF spatial heterogeneity, and relating pPDFF to clinical markers.

Study type

Prospective.

Population

A total of 34 children, including healthy (N = 16, 8 female) and overweight (N = 18, 5 female) subjects.

Field strength and sequences

3 T; multiecho gradient-echo three-dimensional (3D) stack-of-stars FB-MRI, multiecho gradient-echo 3D Cartesian BH-MRI.

Assessment

A radiologist measured FS- and ROI-based pPDFF on FB-MRI and BH-MRI PDFF maps, with anatomical images as references. Regional pPDFF in the pancreatic head, body, and tail were measured on FB-MRI. FS-pPDFF, ROI-pPDFF, and regional pPDFF were compared, and related to clinical markers, including hemoglobin A1c.

Statistical tests

T-test, Bland-Altman analysis, Lin's concordance correlation coefficient (CCC), one-way analysis of variance, and Spearman's rank correlation coefficient were used. P < 0.05 was considered significant.

Results

FS-pPDFF and ROI-pPDFF from FB-MRI and BH-MRI had mean difference = 0.4%; CCC was 0.95 for FS-pPDFF and 0.62 for ROI-pPDFF. FS-pPDFF was higher than ROI-pPDFF (10.4% ± 6.4% vs. 4.2% ± 2.8%). Tail-pPDFF (11.6% ± 8.1%) was higher than body-pPDFF (8.9% ± 6.3%) and head-pPDFF (8.7% ± 5.2%). Head-pPDFF and body-pPDFF positively correlated with hemoglobin A1c.

Data conclusion

FB-MRI pPDFF is comparable to BH-MRI. Spatial heterogeneity affects pPDFF quantification. Regional measurements of pPDFF in the head and body were correlated with hemoglobin A1c, a marker of insulin sensitivity.

Evidence level

2 TECHNICAL EFFICACY: Stage 2.