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OBJECTIVE: The objective of the study was to compare neonatal morbidity and long-term neurodevelopmental outcome between very preterm infants with placental underperfusion and very preterm infants with histological chorioamnionitis. STUDY DESIGN: We measured the mental and motor development at age 2 and 7 years in 51 very preterm infants with placental underperfusion and 21 very preterm infants with histological chorioamnionitis. RESULTS: At 2 years, very preterm infants with placental underperfusion had poorer mental development than very preterm infants with histological chorioamnionitis (mean [SD] 90.8 [18.3] vs 104.1 [17.2], adjusted d = 1.12, P = .001). Motor development was not different between both groups (92.8 [17.2] vs 96.8 [8.7], adjusted d = 0.52, P = .12). At 7 years, large, although nonsignificant, effects were found for better mental and motor development and fewer behavioral problems in infants with histological chorioamnionitis. CONCLUSION: Placental pathology contributes to variance in mental development at 2 years and should be taken into account when evaluating neurodevelopmental outcome of very preterm infants. [ABSTRACT FROM AUTHOR]

Prevention of serious infections in preterm infants is a challenge, since prematurity and low birth weight often requires many interventions and high utility of devices. Furthermore, the possibility to administer enteral nutrition is limited due to immaturity of the gastrointestinal tract in the presence of a developing immune system. In combination with delayed intestinal bacterial colonisation compared with term infants, this may increase the risk for serious infections. Acidic and neutral oligosaccharides play an important role in the development of the immune system, intestinal bacterial colonisation and functional integrity of the gut. This trial aims to determine the effect of enteral supplementation of acidic and neutral oligosaccharides on infectious morbidity (primary outcome), immune response to immunizations, feeding tolerance and short-term and long-term outcome in preterm infants. In addition, an attempt is made to elucidate the role of acidic and neutral oligosaccharides in postnatal modulation of the immune response and postnatal adaptation of the gut.~Background~Background~In a double-blind placebo controlled randomised trial, 120 preterm infants (gestational age <32 weeks and/or birth weight <1500 gram) are randomly allocated to receive enteral acidic and neutral oligosaccharides supplementation (20%/80%) or placebo supplementation (maltodextrin) between day 3 and 30 of life. Primary outcome is infectious morbidity (defined as the incidence of serious infections). The role of acidic and neutral oligosaccharides in modulation of the immune response is investigated by determining the immune response to DTaP-IPV-Hib(-HBV)+PCV7 immunizations, plasma cytokine concentrations, faecal Calprotectin and IL-8. The effect of enteral acidic and neutral oligosaccharides supplementation on postnatal adaptation of the gut is investigated by measuring feeding tolerance, intestinal permeability, intestinal viscosity, and determining intestinal microflora. Furthermore, short-term and long-term outcome are evaluated.~Methods/design~Methods~Especially preterm infants, who are at increased risk for serious infections, may benefit from supplementation of prebiotics. Most studies with prebiotics only focus on the colonisation of the intestinal microflora. However, the pathways how prebiotics may influence the immune system are not yet fully understood. Studying the immune modulatory effects is complex because of the multicausal risk of infections in preterm infants. The combination of neutral oligosaccharides with acidic oligosaccharides may have an increased beneficial effect on the immune system. Increased insight in the effects of prebiotics on the developing immune system may help to decrease the (infectious) morbidity and mortality in preterm infants.~Discussion~Conclusions~Current Controlled Trials ISRCTN16211826.~Trial Registration~Background [ABSTRACT FROM AUTHOR]

OBJECTIVE: To study the effect of minimal enteral feeding (MEF) on intestinal permeability and feeding tolerance in preterm infants with intrauterine growth retardation (gestational age < 37 weeks, birth weight for gestational age p < 10). Furthermore, to determine whether fetal blood flow pulsatility or intestinal permeability predict feeding tolerance in these infants. DESIGN: Randomised controlled trial. METHODS: Within 48 hours of birth, infants were randomised to MEF or no enteral feeding (NEF) for five days in addition to parenteral feeding. Intestinal permeability was measured by the sugar absorption test before (SAT1) and after (SAT2) the study. The sugar absorption test measured the urinary lactulose/mannitol (LM) ratio after oral ingestion of a solution (375 mosm) containing mannitol and lactulose. Charts of all infants were assessed for measures of feeding tolerance. Fetal blood flow pulsatility index (U/C ratio) was measured within the seven days before birth. RESULTS: Of the 56 infants enrolled, 42 completed the study: 20 received MEF and 22 NEF. The decrease in LM ratio (LM ratio 1 - LM ratio 2) was not significantly different between the two groups (0.25 v 0.11; p = 0.14). Feeding tolerance, growth, and incidence of necrotising enterocolitis were not significantly different between the two groups. Neither the U/C nor the LM ratio 1 predicted feeding tolerance. CONCLUSIONS: The results suggest that MEF of preterm infants with intrauterine growth retardation has no effect on the decrease in intestinal permeability after birth. Neither fetal blood flow pulsatility nor intestinal permeability predicts feeding tolerance. [ABSTRACT FROM AUTHOR]

Objective: To determine the relation between intestinal permeability and birth weight, gestational age, postnatal age, and perinatal risk factors in neonates.Study Design: Intestinal permeability was measured by the sugar absorption test within two days of birth and three to six days later in preterm and healthy term infants. In the sugar absorption test, the urinary lactulose/mannitol ratio is measured after oral ingestion of a solution (375 mosm) of lactulose and mannitol.Results: A first sugar absorption test was performed in 116 preterm (26-36 weeks gestation) and 16 term infants. A second test was performed in 102 preterm and nine term infants. In the preterm infants, the lactulose/mannitol ratio was not related to gestational age (r = -0.09, p = 0.32) or birth weight (r = 0.07, p = 0.43). The median lactulose/mannitol ratio was higher if measured less than two days after birth than when measured three to six days later (0.427 and 0.182 respectively, p<0.001). The lactulose/mannitol ratio was higher in preterm infants than term infants if measured within the first 2 days of life (0.404 and 0.170 respectively, p < 0.001), but not different three to six days later (0.182 and 0.123 respectively, p = 0.08). In multiple regression analysis of perinatal risk factors, only umbilical arterial pH correlated with the lactulose/mannitol ratio in preterm infants less than 2 days of age (T = -1.98, p = 0.05).Conclusions: In preterm infants (26-36 weeks gestation), intestinal permeability is not related to gestational age or birth weight but is higher during the first 2 days of life than three to six days later. It is higher in preterm infants than in healthy term infants only if measured within two days of birth. This suggests rapid postnatal adaptation of the small intestine in preterm infants. [ABSTRACT FROM AUTHOR]

A preterm infant with mild respiratory insufficiency resulting from respiratory distress syndrome developed a pneumatocele after the start of nasal continuous positive airway pressure. Pneumonia was excluded by sputum and blood cultures. Treatment with high frequency oscillation ventilation resulted in complete recovery. [ABSTRACT FROM AUTHOR]

The assessment of newborn screening (NBS) algorithms' performance to ensure quality improvements is a continuous process: false-positive referrals can enable optimisations in the shorter term, but false-negative referrals are often only discovered many years after the screening has taken place [...].

Background: Limited evidence exists on the preferred feeding method when breastfeeding is not possible in late and moderate preterm (LMPT) infants. This RCT evaluates growth, safety, and tolerance of a concept infant formula (IF) with large, milk phospholipid-coated lipid droplets enriched in dairy lipids in LMPT infants with primary objective to demonstrate non-inferiority of daily weight gain from randomization to 3 months corrected age compared to a standard IF., Methods: LMPT infants were randomized before or around term equivalent age to either the concept (n = 21) or standard IF (n = 20). Forty-one breastfed (BF) infants served as reference., Results: Due to unintended low recruitment, non-inferiority in daily weight gain could not be demonstrated for the Concept compared to the Control group, but was compared to the BF group. Other outcomes were similar between the formula groups, except for an apparent larger head circumference gain in the Concept group. No apparent differences in growth and body composition outcomes were observed between the Concept and BF reference groups., Conclusion: This small-scale study suggests the concept IF is a safe alternative for parents who choose IF to feed their LMPT infant. Larger trials are needed to better determine impacts on head growth or body composition., Impact: In a small group of late and moderate preterm infants, growth from randomization until 3 months corrected age of infants fed with a concept infant formula with large, milk phospholipid-coated lipid droplets was not -significantly different from infants fed a standard infant formula. Infants in the Concept group had non-significant larger gain in head circumference compared to the Control group; larger trials are needed to confirm this finding. Both formulas were well-tolerated, with no differences in adverse events. The concept formula is potentially a safe alternative for parents of moderate to late preterm infants who choose to use formula milk., (© 2024. The Author(s).)

Small intestine (SI) maturation during early life is pivotal in preventing the onset of gut diseases. In this study we interrogated the milestones of SI development by gene expression profiling and ingenuity pathway analyses. We identified a set of cytokines as main regulators of changes observed across different developmental stages. Upon cytokines stimulation, with IFNγ as the most contributing factor, human fetal organoids (HFOs) increase brush border gene expression and enzyme activity as well as trans -epithelial electrical resistance. Electron microscopy revealed developed brush border and loss of fetal cell characteristics in HFOs upon cytokine stimulation. We identified T cells as major source of IFNγ production in the fetal SI lamina propria. Co-culture of HFOs with T cells recapitulated the major effects of cytokine stimulation. Our findings underline pro-inflammatory cytokines derived from T cells as pivotal factors inducing functional SI maturation in vivo and capable of modulating the barrier maturation of HFOs in vitro ., Competing Interests: J.-N.B. is an employee of DNAnexus. I.B.R. is an employee of Danone Nutricia Research., (© 2024 The Authors.)

Early life microbiota encompasses of a large percentage of Bifidobacterium, while it is not sufficiently understood how the Bifidobacterium population develops after infant's birth. Current study investigated the longitudinal changes in Bifidobacterium population during the first two years of life in 196 term born infants (1,654 samples) using 16S rRNA-23S rRNA internal transcribed spacer (ITS) sequence analysis. Throughout the first two years of life, Bifidobacterium breve, Bifidobacterium longum subsp. longum and Bifidobacterium adolescentis were most dominant and prevalent in the Bifidobacterium population, while B. breve had the highest relative abundance and prevalence during the first week of life and it was taken over by B. longum subsp. longum around two years after birth. Sampling time points, early antibiotic(s) exposure (effect only measurable within a month after birth), delivery mode (effect still detectable two-months after birth) and feeding mode (effect lasted until six months after birth), significantly contributed to the overall variation in the bifidobacterial population. From six months onwards, introducing of solid food and cessation of breastfeeding were accompanied with drastic changes in the composition in bifidobacterial population. Altogether, current study confirmed the effect of potential contributors to the longitudinal changes within the bifidobacterial population during the first two years of life. Registered at https://clinicaltrials.gov: NCT02536560.

Objective: The aim of this study was to explore differences in functional connectivity and network organization between very preterm born adolescents and term born controls and to investigate if these differences might explain the relation between preterm birth and adverse long-term outcome., Methods: Forty-seven very preterm born adolescents (53% males) and 54 controls (54% males) with matching age, sex and parental educational levels underwent high-density electroencephalography (EEG) at 13 years of age. Long-term outcome was assessed by Intelligence Quotient (IQ), motor, attentional functioning and academic performance. Two minutes of EEG data were analysed within delta, theta, lower alpha, upper alpha and beta frequency bands. Within each frequency band, connectivity was assessed using the Phase Lag Index (PLI) and Amplitude Envelope Correlation, corrected for volume conduction (AEC-c). Brain networks were constructed using the minimum spanning tree method., Results: Very preterm born adolescents had stronger beta PLI connectivity and less differentiated network organization. Beta AEC-c and differentiation of AEC-c based networks were negatively associated with long-term outcomes. EEG measures did not mediate the relation between preterm birth and outcomes., Conclusions: This study shows that very preterm born adolescents may have altered functional connectivity and brain network organization in the beta frequency band. Alterations in measures of functional connectivity and network topologies, especially its differentiating characteristics, were associated with neurodevelopmental functioning., Significance: The findings indicate that EEG connectivity and network analysis is a promising tool for investigating underlying mechanisms of impaired functioning., (Copyright © 2023 International Federation of Clinical Neurophysiology. All rights reserved.)

Background: Late and moderate preterm (LMPT) infants are at risk for adverse later life outcomes. We determined the association between feeding method at enrolment and growth and body composition of LMPT infants until 3 months corrected age (3mCA)., Methods: Infants born between 32 +0 and 36 +6 weeks of gestation (n = 107) were enrolled up to 4 weeks corrected age and stratified according to feeding at enrolment. We performed anthropometric measurements at enrolment, term equivalent age (TEA) and 3mCA, including skinfold measurements and body composition using dual X-ray absorptiometry (DEXA)., Results: Feeding method at enrolment was associated with fat mass (FM) (breast 554.9 g, mixed 716.8 g, formula 637.7 g, p = 0.048), lean body mass (LM) (2512 g, 2853 g, 2722 g, respectively, p = 0.009) and lean mass index (LMI) (10.6 kg/m 2 , 11.6 kg/m 2 ,11.2 kg/m 2 respectively, p = 0.008) at TEA, but not 3mCA. Breastfed infants demonstrated greater increase in LM (breast 1707 g, mixed 1536 g, formula 1384 g, p = 0.03) and LMI (1.23 kg/m 2 , 0.10 kg/m 2 , 0.52 kg/m 2 , respectively, p = 0.022) between TEA and 3mCA., Conclusions: Breastfed LMPT infants have lower FM and greater LM increase and LMI increase up to 3mCA compared to formula or mixed-fed infants. These findings stress the importance of supporting breastfeeding in this population., Impact: Infants born late and moderate preterm age who are exclusively breastfed soon after birth gain more lean mass up to 3 months corrected age compared to mixed- or formula-fed infants. Breastfed infants have lower lean and fat mass at term equivalent age compared to mixed- and formula-fed infants. This is the first study exploring this population's growth and body composition in detail at 3 months corrected age. Our results underline the importance of supporting mothers to initiate and continue breastfeeding at least until 3 months corrected age., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

White matter (WM) injury is the most common type of brain injury in preterm infants and is associated with impaired neurodevelopmental outcome (NDO). Currently, there are no treatments for WM injury, but optimal nutrition during early preterm life may support WM development. The main aim of this scoping review was to assess the influence of early postnatal nutrition on WM development in preterm infants. Searches were performed in PubMed, EMBASE, and COCHRANE on September 2022. Inclusion criteria were assessment of preterm infants, nutritional intake before 1 month corrected age, and WM outcome. Methods were congruent with the PRISMA-ScR checklist. Thirty-two articles were included. Negative associations were found between longer parenteral feeding duration and WM development, although likely confounded by illness. Positive associations between macronutrient, energy, and human milk intake and WM development were common, especially when fed enterally. Results on fatty acid and glutamine supplementation remained inconclusive. Significant associations were most often detected at the microstructural level using diffusion magnetic resonance imaging. Optimizing postnatal nutrition can positively influence WM development and subsequent NDO in preterm infants, but more controlled intervention studies using quantitative neuroimaging are needed. IMPACT: White matter brain injury is common in preterm infants and associated with impaired neurodevelopmental outcome. Optimizing postnatal nutrition can positively influence white matter development and subsequent neurodevelopmental outcome in preterm infants. More studies are needed, using quantitative neuroimaging techniques and interventional designs controlling for confounders, to define optimal nutritional intakes in preterm infants., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Otitis media (OM) is one of the most common diagnoses in preschool-age children. Its pathophysiology is poorly understood, but is associated with changes in the nasopharyngeal microbiome, immune system, and presence of allergies. These, in turn, can be affected by early-life antibiotic exposure. Therefore, this study aimed to determine if antibiotic treatment in the first week of life in children born at term was associated with acute otitis media (AOM) and otitis media with effusion (OME) in the first 4-6 years of life., Methods: A prospective birth cohort of 436 term-born infants was followed up at 4-6 years of age. Parents reported (recurrent) AOM and OME through online questionnaires, sent to parents of 418 eligible children. Doctors' diagnoses of AOM and OME were collected after additional informed consent. Multivariate logistic regression analyses were used to study the association between antibiotic exposure and AOM and OME., Results: Of the 436 infants, 151 infants received antibiotics in the first week of life. In total, 341 (82%) questionnaires were collected. The parental-reported prevalence was 45% (155/341) for AOM. Of these 155 children, 33 children also had OME (10% of the total cohort). Doctor's diagnoses were obtained from 308 (74%) children, of which 30% (91/308) had AOM. Of these 91 children, 12 children also had OME and 8 children had OME without a diagnosis of AOM (6% of the total obtained diagnoses). Antibiotic treatment in the first week of life was not significantly associated with parent-reported nor doctor-diagnosed (recurrent) AOM and OME in the first 4-6 years of life in the regression models., Conclusion: Antibiotic treatment in the first week of life was not associated with AOM and OME in the first 4-6 years of life in this prospective cohort of Dutch infants. More insight into the pathophysiology of OM is warranted to determine whether antibiotic-induced microbiome changes play a role in the susceptibility to OM., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Disruption of the developing microbiota by Caesarean birth or early exposure to antibiotics may impact long-term health outcomes, which can potentially be prevented by nutritional supplements. This systematic review aimed to summarise the evidence regarding the effects of prebiotics, probiotics and synbiotics on the intestinal microbiota composition of term infants born by Caesarean section or exposed to antibiotics in the first week of life., Methods: A systematic search was performed from inception to August 2022 in Medline and Embase. Two researchers independently performed title and abstract screening (n = 12,230), full-text screening (n = 46) and critical appraisal. We included randomised controlled trials which included term-born infants who were born following Caesarean section or who were exposed to postpartum antibiotics in the first week of life, pre-, pro- or synbiotics were administered &lt;6 weeks after birth and outcome(s) consisted of microbiota analyses., Results: Twelve randomised controlled trials investigating Caesarean born infants and one randomised controlled trial including infants exposed to antibiotics were included. Group sizes varied from 11 to 230 with 1193 infants in total. Probiotic (n = 7) or synbiotic (n = 3) supplementation significantly increased the abundance of the supplemented bacterial species (of the Bifidobacterium and Lactobacillus genus), and there was a decrease in Enterobacteriaceae, especially &lt;4 weeks of age. At phylum level, Actinobacteria (two studies), Proteobacteria (one study) and Firmicutes (one study) increased after probiotic supplementation. In three studies on prebiotics, two studies reported a significant increase in Bifidobacteria and one study found a significant increase in Enterobacteriaceae., Discussion: Prebiotic, probiotic and synbiotic supplements seem to restore dysbiosis after Caesarean section towards a microbial signature of vaginally born infants by increasing the abundance of beneficial bacteria. However, given the variety in study products and study procedures, it is yet too early to advocate specific products in clinical settings., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Carpay et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Caesarean section and early exposure to antibiotics disrupt the developing gastrointestinal microbiome, which is associated with long-term health effects., Objective: The aim of this systematic review was to summarise the impact of prebiotics, probiotics, or synbiotics supplementation on clinical health outcomes of term infants born by caesarean section or exposed to antibiotics in the first week of life., Design: A systematic search was performed in Medline and Embase from inception to August 2021. Title and abstract screening ( n  = 11,248), full text screening ( n  = 48), and quality assessment were performed independently by two researchers., Results: Six RCTs studying caesarean born infants were included, group sizes varied between 32-193 with in total 752 children. No studies regarding supplementation after neonatal antibiotic exposure were found. Three studies administered a probiotic, one a prebiotic, one a synbiotic, and one study investigated a prebiotic and synbiotic. Several significant effects were reported at follow-up varying between 10 days and 13 years: a decrease in atopic diseases ( n  = 2 studies), higher immune response to tetanus and polio vaccinations ( n  = 2), lower response to influenza vaccination ( n  = 1), fewer infectious diseases ( n  = 2), and less infantile colic ( n  = 1), although results were inconsistent., Conclusions: Supplementation of caesarean-born infants with prebiotics, probiotics, or synbiotics resulted in significant improvements in some health outcomes as well as vaccination responses. Due to the variety of studied products and the paucity of studies, no recommendations can be given yet on the routine application of prebiotics, probiotics, or synbiotics to improve health outcomes after caesarean section or neonatal antibiotic exposure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Kamphorst, Carpay, de Meij, Daams, Van Elburg and Vlieger.)

Objectives: Antibiotics may contribute to the development of functional gastrointestinal disorders (FGIDs). This study aimed to determine whether antibiotics during the first week of life, infantile colic in the first year of life, gut-associated immune markers at 1 year of age, and allergies at 4-6 years of age in term-born children were associated with a higher prevalence of FGIDs at 4-6 years of age., Methods: A prospective observational cohort of 436 term-born infants was followed up at the age of 4-6 years; 151 received broad-spectrum antibiotics (AB+), and 285 healthy controls (AB-). Validated Questionnaire On Pediatric Gastrointestinal Symptoms-Rome III and International Study of Asthma and Allergy in Childhood questionnaires were sent to parents of 418 available children. The independent t-test, chi-squared test or non-parametric test and logistic multivariate regression analyses were used., Results: In total, 340 of 418 (81%) questionnaires were completed. Only the presence of functional abdominal pain was significantly higher in AB+ than AB- (4% vs 0.4%, respectively, P  = 0.045). Children with food allergy fulfilled significantly more often the criteria for irritable bowel syndrome (IBS) and abdominal migraine (26% vs 9%, P  = 0.002 and 7% vs 1%, P  = 0.043, respectively) compared to non-allergic children. No differences in FGIDs existed at the age of 4-6 years between children with and without a history of infantile colic. There were significant differences in gut-associated immune markers between children with and without FGIDs., Conclusion: Antibiotics during the first week of life resulted in a higher risk for functional abdominal pain at 4-6 years. Furthermore, food allergy was associated with IBS and abdominal migraine at 4-6years., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Infants are frequently exposed to antibiotics (AB) in the first week of life for suspected bacterial infections. Little is known about the effect of AB on the developing intestinal microbiota. Therefore, we studied intestinal microbiota development with and without AB exposure in the first week of life in term born infants., Methods: We analysed the faecal microbiota from birth until 2.5 years of age by 16S rRNA gene amplicon sequencing in a cohort with 56 term born infants, exposed to AB in the first week of life (AB+) (AB for 2-3 days (AB2, n=20), AB for 7 days (AB7, n=36)), compared with 126 healthy controls (AB-). The effects of AB and duration were examined in relation to delivery and feeding mode., Results: AB+ was associated with significantly increased relative abundance of Enterobacteriaceae at 3 weeks and 1 year and a decrease of Bifidobacteriaceae , from 1 week until 3 months of age only in vaginally delivered, but not in C-section born infants. Similar deviations were noted in AB7, but not in AB2. After AB, breastfed infants had lower relative abundance of potentially pathogenic Enterobacteriaceae compared with formula fed infants and recovered 2 weeks faster towards controls., Conclusions: AB exposure in the first week of life alters faecal microbiota development with deviations in the relative abundance of individual taxa until 1 year of age. These alterations can have long-term health consequences, which emphasises the need for future studies aiming at restoring intestinal microbiota after AB administration., Competing Interests: Competing interests: This work and the PhD research by EVD was financed by a EU Joint Programming Initiative namely A Healthy Diet for a Healthy Life (JPIHDHL, http://www.healthydietforhealthylife.eu/) inconjunction with ZonMW and Danone Nutricia Research. GH is a full full-time employee of Chr Hansen A/S since January 2020. CB received a grant financed by JPI HDHL inconjunction with ZonMW and Danone Nutricia Research. RMvE was an employee at Danone Nutricia Research till 2020. JK is a full-time employee of Danone Nutricia., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Holder pasteurization (HoP) is the current recommended treatment for donor human milk. Although this method inactivates microbial contaminants, it also negatively affects various milk components. High-pressure processing (HPP, 400, 500, and 600 MPa), ultraviolet-C irradiation (UV-C, 2,430, 3,645, and 4,863 J/L) and thermoultrasonication (TUS, 1,080 and 1,620 kJ/L) were investigated as alternatives to thermal pasteurization (HoP). We assessed the effects of these methods on microbiological safety, and on concentration and functionality of immunoglobulin A, lactoferrin, lysozyme and bile salt-stimulated lipase, with LC-MS/MS-based proteomics and activity assays. HoP, HPP, TUS, and UV-C at 4863 J/L, achieved >5-log 10 microbial reduction. Native protein levels and functionality showed the highest reduction following HoP, while no significant reduction was found after less intense HPP and all UV-C treatments. Immunoglobulin A, lactoferrin, and lysozyme contents were also preserved after low intensity TUS, but bile salt-stimulated lipase activity was significantly reduced. This study demonstrated that HPP and UV-C may be considered as suitable alternatives to HoP, since they were able to ensure sufficient microbial inactivation while at the same time better preserving the bioactive components of donor human milk. In summary, our results provide valuable insights regarding the evaluation and selection of suitable processing methods for donor human milk treatment, which may replace HoP in the future., Competing Interests: JG is the founder and director of the Dutch National Human Milk Bank and member of the Dutch National Health Council. BS is as Science Director of Human Milk Research & Analytical Sciences an employee of Danone Nutricia Research, Utrecht, Netherlands. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kontopodi, Stahl, van Goudoever, Boeren, Timmermans, den Besten, Van Elburg and Hettinga.)

The association between prolonged antibiotic (AB) use in neonates and increased incidence of later life diseases is not yet fully understood. AB treatment in early life alters intestinal epithelial cell composition, functioning, and maturation, which could be the basis for later life health effects. Here, we investigated whether AB-induced changes in the neonatal gut persisted up to adulthood and whether early life AB had additional long-term consequences for gut functioning. Mice received AB orally from postnatal day 10 to 20. Intestinal morphology, permeability, and gene and protein expression at 8 weeks were analyzed. Our data showed that the majority of the early life AB-induced gut effects did not persist into adulthood, yet early life AB did impact later life gut functioning. Specifically, the proximal small intestine (SI) of adult mice treated with AB in early life was characterized by hyperproliferative crypts, increased number of Paneth cells, and alterations in enteroendocrine cell-specific gene expression profiles. The distal SI of adult mice displayed a reduced expression of antibacterial defense markers. Together, our results suggest that early life AB leads to structural and physiological changes in the adult gut, which may contribute to disease development when homeostatic conditions are under challenge.

Donor human milk is generally processed by holder pasteurization (HoP) at 62. 5°C for 30 min. This temperature-time combination is sufficient for eliminating pathogens in donor milk, but also negatively affects several bioactive milk components. Long heating up times may further affect the bioactive properties of pasteurized milk. High-Temperature-Short-Time (HTST), a treatment with shorter processing times (72°C for 15 sec), was investigated as a suitable alternative to HoP. In addition, pasteurization methods that follow the same temperature regime but with varying heating up times were compared. Human milk samples from four different donors were combined into one pool, which was then used to perform all analyses. The effects of these methods on the levels and functionality of immunoglobulin A, lactoferrin, lysozyme and bile salt-stimulated lipase, were evaluated with LC-MS/MS-based proteomics and activity assays, while the pasteurization efficacy was evaluated with an alkaline phosphatase test. HoP, a treatment with long processing times, times, caused the highest reduction in all proteins studied (reduced by 50-98%). Compounds such as lactoferrin and bile salt-stimulated lipase that are more sensitive to heat treatments were better retained with HTST, but their levels and functionality were still significantly lower than those of untreated donor milk (52 and 81% reduction of lactoferrin and bile salt-stimulated lipase activity, respectively). Our findings showed that a treatment with considerably shorter processing times, such as HTST, may reduce the thermal damage caused to the bioactive proteins compared to HoP, without affecting pasteurization efficacy. Since the vast majority of the donor human milk banks that are currently operating on a global level apply HoP to donor milk, our findings may provide relevant information for the optimization of donor milk processing., Competing Interests: JvG is the founder and director of the Dutch National Human Milk Bank and member of the Dutch National Health Council. BS is as Science Director of Human Milk Research and Analytical Sciences an employee of Danone Nutricia Research, Utrecht, Netherlands. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kontopodi, Boeren, Stahl, van Goudoever, van Elburg and Hettinga.)

Background: Docosahexaenoic acid (DHA) and arachidonic acid (AA) are important for fetal brain growth and development. Our aim was to evaluate the association between serum DHA and AA levels and brain volumes in extremely preterm infants., Methods: Infants born at <28 weeks gestational age in 2013-2015, a cohort derived from a randomized controlled trial comparing two types of parenteral lipid emulsions, were included (n = 90). Serum DHA and AA levels were measured at postnatal days 1, 7, 14, and 28, and the area under the curve was calculated. Magnetic resonance (MR) imaging was performed at term-equivalent age (n = 66), and volumes of six brain regions were automatically generated., Results: After MR image quality assessment and area under the curve calculation, 48 infants were included (gestational age mean [SD] 25.5 [1.4] weeks). DHA levels were positively associated with total brain (B = 7.966, p = 0.012), cortical gray matter (B = 3.653, p = 0.036), deep gray matter (B = 0.439, p = 0.014), cerebellar (B = 0.932, p = 0.003), and white matter volume (B = 3.373, p = 0.022). AA levels showed no association with brain volumes., Conclusions: Serum DHA levels during the first 28 postnatal days were positively associated with volumes of several brain structures in extremely preterm infants at term-equivalent age., Impact: Higher serum levels of DHA in the first 28 postnatal days are positively associated with brain volumes at term-equivalent age in extremely preterm born infants. Especially the most immature infants suffer from low DHA levels in the first 28 postnatal days, with little increase over time. Future research is needed to explore whether postnatal fatty acid supplementation can improve brain development and may serve as a nutritional preventive and therapeutic treatment option in extremely preterm infants., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background & Aims: Donor human milk (DHM) is recommended as the first alternative for preterm infants if their mother's own milk is not available or if the quantity is not sufficient. The most commonly used technique to eliminate microbial contaminants in DHM is holder pasteurization (HoP). However, the heating process during HoP partially destroys milk bioactive factors such as insulin. Therefore, innovative techniques have been developed as alternatives to HoP. The objective of this study was to determine the effect of HoP, high-temperature-short-time (HTST), thermoultrasonication (TUS), ultraviolet-C irradiation (UV-C), and high-pressure processing (HPP) on the insulin concentration in DHM., Methods: Milk samples from 28 non-diabetic mothers were collected. The milk samples were aliquoted and either left untreated or treated with HoP (62.5 °C; 30 min), HTST (72 °C; 15 s), TUS (60 W; 6 min), UV-C (4863 J/L), or HPP (500 MPa; 5 min)., Results: The mean insulin concentration in untreated milk was 79 ± 41 pmol/L. The mean insulin retention rate was 67% for HoP, 78% for HTST, 97% for TUS, 94% for UV-C, and 106% for HPP. The mean insulin concentration in milk treated with HoP was significantly lower compared to untreated milk (p = 0.01)., Conclusion: TUS, UV-C, and HPP preserve insulin in DHM. The insulin concentration in DHM is affected to a larger extent by HoP than by HTST. These results indicate that TUS, UV-C, and HPP may serve as alternatives to HoP., Competing Interests: Conflict of interest J.B.v.G. is member of the National Health Council, Chair of the Committee on Nutrition and Pregnancy, and Director of the Dutch National Human Milk Bank. He does not receive any honorarium for his services., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Parents commonly experience anxiety, worry, and psychological distress in caring for newborn infants, particularly those born preterm. Web-based therapist services may offer greater accessibility and timely psychological support for parents but are nevertheless labor intensive due to their interactive nature. Chatbots that simulate humanlike conversations show promise for such interactive applications., Objective: The aim of this study is to explore the usability and feasibility of chatbot technology for gathering real-life conversation data on stress, sleep, and infant feeding from parents with newborn infants and to investigate differences between the experiences of parents with preterm and term infants., Methods: Parents aged ≥21 years with infants aged ≤6 months were enrolled from November 2018 to March 2019. Three chatbot scripts (stress, sleep, feeding) were developed to capture conversations with parents via their mobile devices. Parents completed a chatbot usability questionnaire upon study completion. Responses to closed-ended questions and manually coded open-ended responses were summarized descriptively. Open-ended responses were analyzed using the latent Dirichlet allocation method to uncover semantic topics., Results: Of 45 enrolled participants (20 preterm, 25 term), 26 completed the study. Parents rated the chatbot as "easy" to use (mean 4.08, SD 0.74; 1=very difficult, 5=very easy) and were "satisfied" (mean 3.81, SD 0.90; 1=very dissatisfied, 5 very satisfied). Of 45 enrolled parents, those with preterm infants reported emotional stress more frequently than did parents of term infants (33 vs 24 occasions). Parents generally reported satisfactory sleep quality. The preterm group reported feeding problems more frequently than did the term group (8 vs 2 occasions). In stress domain conversations, topics linked to "discomfort" and "tiredness" were more prevalent in preterm group conversations, whereas the topic of "positive feelings" occurred more frequently in the term group conversations. Interestingly, feeding-related topics dominated the content of sleep domain conversations, suggesting that frequent or irregular feeding may affect parents' ability to get adequate sleep or rest., Conclusions: The chatbot was successfully used to collect real-time conversation data on stress, sleep, and infant feeding from a group of 45 parents. In their chatbot conversations, term group parents frequently expressed positive emotions, whereas preterm group parents frequently expressed physical discomfort and tiredness, as well as emotional stress. Overall, parents who completed the study gave positive feedback on their user experience with the chatbot as a tool to express their thoughts and concerns., Trial Registration: ClinicalTrials.gov NCT03630679; https://clinicaltrials.gov/ct2/show/NCT03630679., (©Jill Wong, Agathe C Foussat, Steven Ting, Enzo Acerbi, Ruurd M van Elburg, Chua Mei Chien. Originally published in JMIR Pediatrics and Parenting (https://pediatrics.jmir.org), 26.10.2021.)

Zinc deficiency (ZnD) has adverse health consequences such as stunted growth. Since young children have an increased risk of developing ZnD, it is important to determine its prevalence and associated factors in this population. However, only a few studies have reported on ZnD prevalence in young children from Western high-income countries. This study evaluated ZnD prevalence and associated factors, including dietary Zn intake, in healthy 1-3-year-old children from Western European, high-income countries. ZnD was defined as serum Zn concentration <9.9 µmol/L. A total of 278 children were included with a median age of 1.7 years (Q1-Q3: 1.2-2.3). The median Zn concentration was 11.0 µmol/L (Q1-Q3: 9.0-12.2), and ZnD prevalence was 31.3%. No significant differences were observed in the socio-economic characteristics between children with and without ZnD. Dietary Zn intake was not associated with ZnD. ZnD is common in healthy 1-3-year-old children from Western European countries. However, the use of currently available cut-off values defining ZnD in young children has its limitations since these are largely based on reference values in older children. Moreover, these values were not evaluated in relation to health consequences, warranting further research.

Background: Determining optimal nutritional regimens in extremely preterm infants remains challenging. This study aimed to evaluate the effect of a new nutritional regimen and individual macronutrient intake on white matter integrity and neurodevelopmental outcome., Methods: Two retrospective cohorts of extremely preterm infants (gestational age < 28 weeks) were included. Cohort B ( n = 79) received a new nutritional regimen, with more rapidly increased, higher protein intake compared to cohort A ( n = 99). Individual protein, lipid, and caloric intakes were calculated for the first 28 postnatal days. Diffusion tensor imaging was performed at term-equivalent age, and cognitive and motor development were evaluated at 2 years corrected age (CA) (Bayley-III-NL) and 5.9 years chronological age (WPPSI-III-NL, MABC-2-NL)., Results: Compared to cohort A, infants in cohort B had significantly higher protein intake (3.4 g/kg/day vs. 2.7 g/kg/day) and higher fractional anisotropy (FA) in several white matter tracts but lower motor scores at 2 years CA (mean (SD) 103 (12) vs. 109 (12)). Higher protein intake was associated with higher FA and lower motor scores at 2 years CA (B = -6.7, p = 0.001). However, motor scores at 2 years CA were still within the normal range and differences were not sustained at 5.9 years. There were no significant associations with lipid or caloric intake., Conclusion: In extremely preterm born infants, postnatal protein intake seems important for white matter development but does not necessarily improve long-term cognitive and motor development.

Background: Provision of donor human milk is handled by established human milk banks that implement all required measures to ensure its safety and quality. Detailed human milk banking guidelines on a European level are currently lacking, while the information available on the actual practices followed by the European human milk banks, remains limited. The aim of this study was to collect detailed data on the actual milk banking practices across Europe with particular emphasis on the practices affecting the safety and quality of donor human milk., Materials and Methods: A web-based questionnaire was developed by the European Milk Bank Association (EMBA) Survey Group, for distribution to the European human milk banks. The questionnaire included 35 questions covering every step from donor recruitment to provision of donor human milk to each recipient. To assess the variation in practices, all responses were then analyzed for each country individually and for all human milk banks together., Results: A total of 123 human milk banks completed the questionnaire, representing 85% of the European countries that have a milk bank. Both inter- and intra-country variation was documented for most milk banking practices. The highest variability was observed in pasteurization practices, storage and milk screening, both pre- and post-pasteurization., Conclusion: We show that there is a wide variability in milk banking practices across Europe, including practices that could further improve the efficacy of donor human milk banking. The findings of this study could serve as a tool for a global discussion on the efficacy and development of additional evidence-based guidelines that could further improve those practices., Competing Interests: The authors have declared that no competing interests exist.

Functionality of the gastrointestinal tract is essential for growth and development of newborns. Preterm infants have an immature gastrointestinal tract, which is a major challenge in neonatal care. This study aims to improve the understanding of gastrointestinal functionality and maturation during the early life of preterm infants by means of gastrointestinal enzyme activity assays and metaproteomics. In this single-center, observational study, preterm infants born between 24 and 33 weeks (n = 40) and term infants born between 37 and 42 weeks (n = 3), who were admitted to Isala (Zwolle, the Netherlands), were studied. Enzyme activity analyses identified active proteases in gastric aspirates of preterm infants. Metaproteomics revealed human milk, digestive and immunological proteins in gastric aspirates of preterm infants and feces of preterm and term infants. The fecal proteome of preterm infants was deprived of gastrointestinal barrier-related proteins during the first six postnatal weeks compared to term infants. In preterm infants, bacterial oxidative stress proteins were increased compared to term infants and higher birth weight correlated to higher relative abundance of bifidobacterial proteins in postnatal week 3 to 6. Our findings indicate that gastrointestinal and beneficial microbial proteins involved in gastrointestinal maturity are associated with gestational and postnatal age.

Rationale: Most of the preterm infants are born between 32 and 36 weeks of gestation (moderate to late preterm infants [MLPIs]). This comes with significant short- and long-term risks. Breastfeeding reduces many of these risks, but breastfeeding rates in MLPIs are lower than those in full-term infants. We performed a systematic review of studies identifying factors associated with successful breastfeeding in MLPIs and interventions to improve breastfeeding. Methods: Systematic search performed using PubMed April 24, 2020. In total, 11 articles describing barriers to breastfeeding in MLPIs and 6 articles about interventions to improve breastfeeding were included. Interventions were categorized according to different outcomes: breastfeeding initiation, continuation for 5 days to 6 weeks, and continuation ≥3 months. Because of heterogeneity in study characteristics, no meta-analysis was performed. Results: Breastfeeding rates were lower in those with lower socioeconomic status and single-parent households. Providing parents with more information and direct health care support significantly improved breastfeeding initiation. Cup feeding instead of bottle feeding had inconsistent effects on breastfeeding initiation and continuation. Continuous skin-to-skin contact did not affect breastfeeding initiation or continuation. Discussion: Risk groups for lower breastfeeding rates of MLPIs include mothers with lower socioeconomic status and single mothers. Interventions that may improve breastfeeding include cup feeding and providing parents with more information and health care support. Key limitations of included studies are lack of adequate adjustment for confounders and lack of blinding. However, this is the first systematic review identifying both risk groups and interventions to improve breastfeeding in MLPIs.

Background: The gut microbiota and the brain are connected through different mechanisms. Bacterial colonisation of the gut plays a substantial role in normal brain development, providing opportunities for nutritional neuroprotective interventions that target the gut microbiome. Preterm infants are at risk for brain injury, especially white matter injury, mediated by inflammation and infection. Probiotics, prebiotics and L-glutamine are nutritional components that have individually already demonstrated beneficial effects in preterm infants, mostly by reducing infections or modulating the inflammatory response. The NutriBrain study aims to evaluate the benefits of a combination of probiotics, prebiotics and L-glutamine on white matter microstructure integrity (i.e., development of white matter tracts) at term equivalent age in very and extremely preterm born infants., Methods: This study is a double-blind, randomised, controlled, parallel-group, single-center study. Eighty-eight infants born between 24 + 0 and < 30 + 0 weeks gestational age and less than 72 h old will be randomised after parental informed consent to receive either active study product or placebo. Active study product consists of a combination of Bifidobacterium breve M-16V, short-chain galacto-oligosaccharides, long-chain fructo-oligosaccharides and L-glutamine and will be given enterally in addition to regular infant feeding from 48 to 72 h after birth until 36 weeks postmenstrual age. The primary study outcome of white matter microstructure integrity will be measured as fractional anisotropy, assessed using magnetic resonance diffusion tensor imaging at term equivalent age and analysed using Tract-Based Spatial Statistics. Secondary outcomes are white matter injury, brain tissue volumes and cortical morphology, serious neonatal infections, serum inflammatory markers and neurodevelopmental outcome., Discussion: This study will be the first to evaluate the effect of a combination of probiotics, prebiotics and L-glutamine on brain development in preterm infants. It may give new insights in the development and function of the gut microbiota and immune system in relation to brain development and provide a new, safe treatment possibility to improve brain development in the care for preterm infants., Trial Registration: ISRCTN, ISRCTN96620855 . Date assigned: 10/10/2017.

Background: Over the past decades, the preterm birth rate has increased, mostly due to a rise in late and moderate preterm (LMPT, 32-36 weeks gestation) births. LMPT birth affects 6-7% of all births in the United Kingdom and is associated with increased morbidity risk after birth in infancy as well as in adulthood. Early life nutrition has a critical role in determining infant growth and development, but there are limited data specifically addressing LMPT infants, which was the rationale for the design of the current study. Objective: The Feeding Late and Moderate Infants and Growth Outcomes (FLAMINGO) study aims to improve understanding of the longitudinal growth, nutritional needs, and body composition of LMPT infants as well as their microbiome development and neurodevelopment. In addition, having a nested non-inferiority trial enables evaluation of the nutritional adequacy of a concept IMF with large milk phospholipid-coated lipid droplets comprising dairy and vegetable lipids. The primary outcome of this RCT is daily weight gain until 3 months corrected age. Methods: A total of 250 healthy LMPT infants (32+0-36+6 weeks gestational age) with birth weight 1.25-3.0 kg will be recruited to the cohort, of which 140 infants are anticipated to be enrolled in the RCT. During six visits over the first 2 years of life, anthropometry, body composition (using dual energy X-Ray absorptiometry), feeding behavior, and developmental outcomes will be measured. Saliva and stool samples will be collected for oral and gut microbiota assessment. Discussion: The FLAMINGO study will improve understanding of the longitudinal growth, body composition development, and feeding characteristics of LMPT infants and gain insights into their microbiome and neurodevelopment. Study Registration: www.isrctn.com; Identifier ISRCTN15469594., Competing Interests: MA-B is an employee of Danone. RMvE was previously an employee of Danone. NDE declares research funding from Danone Early Life Nutrition and Prolacta Biosciences US, and lecture honoraria from Nestle Nutrition Institute. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kakaroukas, Abrahamse-Berkeveld, Berrington, McNally, Stewart, Embleton and van Elburg.)

Background & Aims: The use of antibiotics (ABs) is a common practice during the first months of life. ABs can perturb the intestinal microbiota, indirectly influencing the intestinal epithelial cells (IECs), but can also directly affect IECs independent of the microbiota. Previous studies have focused mostly on the impact of AB treatment during adulthood. However, the difference between the adult and neonatal intestine warrants careful investigation of AB effects in early life., Methods: Neonatal mice were treated with a combination of amoxicillin, vancomycin, and metronidazole from postnatal day 10 to 20. Intestinal permeability and whole-intestine gene and protein expression were analyzed. IECs were sorted by a fluorescence-activated cell sorter and their genome-wide gene expression was analyzed. Mouse fetal intestinal organoids were treated with the same AB combination and their gene and protein expression and metabolic capacity were determined., Results: We found that in vivo treatment of neonatal mice led to decreased intestinal permeability and a reduced number of specialized vacuolated cells, characteristic of the neonatal period and necessary for absorption of milk macromolecules. In addition, the expression of genes typically present in the neonatal intestinal epithelium was lower, whereas the adult gene expression signature was higher. Moreover, we found altered epithelial defense and transepithelial-sensing capacity. In vitro treatment of intestinal fetal organoids with AB showed that part of the consequences observed in vivo is a result of the direct action of the ABs on IECs. Lastly, ABs reduced the metabolic capacity of intestinal fetal organoids., Conclusions: Our results show that early life AB treatment induces direct and indirect effects on IECs, influencing their maturation and functioning., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Infants born very preterm (<32 weeks of gestation) show distinct cognitive and motor problems throughout childhood. This study aims 1) to investigate differences in the structural connectome between very preterm born children and term born controls at school-age, and 2) to examine the relationship of the structural connectome with cognitive and motor problems. This study included 29 very preterm (12 males, mean age 8.6 years) and 52 term born peers (25 males, mean age 8.7 years). Wechsler Intelligence Scale for Children and Movement Assessment Battery for Children were used. Brain network measures of smallworldness, clustering coefficient and shortest path length based on fiber density of white matter tracts were determined from Diffusion Tensor Imaging data using probabilistic tractography. Smallworldness (F(1,79) = -2.09, p = .04, d = 0.52) and clustering coefficient (F(1,79) = -2.63, p = .01, d = 0.64) were significantly higher for very preterm children as compared to term peers. For Total Motor Impairment score and Manual Dexterity, there was a significant interaction between group and smallworldness (Beta = -10.81, p = .03 and Beta = -2.99, p = .004, respectively). Greater Total Motor Impairment and poorer Manual Dexterity were only significantly related to higher smallworldness in term controls (r = 0.35, p = .01 and r = 0.27, p = .04, respectively). Poorer Ball Skills were significantly related to higher smallworldness in both groups (Beta = -0.30, p = .03). This study clearly shows a more segregated network organization in very preterm children as compared to term peers. Importantly, motor problems go together with altered organization of the structural connectome in term born children, whereas this potential compensational process is only found for Ball Skills for very preterm children., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Human milk is the optimal diet for infant development, but infant milk formula (IMF) must be available as an alternative. To develop high-quality IMF, bovine milk processing is required to ensure microbial safety and to obtain a protein composition that mimics human milk. However, processing can impact the quality of milk proteins, which can influence gastro-intestinal (GI) tolerance by changing digestion, transit time and/or absorption. The aim of this study was to evaluate the impact of structural changes of proteins due to thermal processing on gastro-intestinal tolerance in the immature GI tract. Preterm and near-term piglets received enteral nutrition based on whey protein concentrate (WPC) either mildly pasteurized (MP-WPC) or extensively heated (EH-WPC). Clinical symptoms, transit time and gastric residuals were evaluated. In addition, protein coagulation and protein composition of coagulates formed during in vitro digestion were analyzed in more detail. Characterization of MP-WPC and EH-WPC revealed that mild pasteurization maintained protein nativity and reduced aggregation of β-lactoglobulin and α-lactalbumin, relative to EH-WPC. Mild pasteurization reduced the formation of coagulates during digestion, resulting in reduced gastric residual volume and increased intestinal tract content. In addition, preterm piglets receiving MP-WPC showed reduced mucosal bacterial adherence in the proximal small intestine. Finally, in vitro digestion studies revealed less protein coagulation and lower levels of β-lactoglobulin and α-lactalbumin in the coagulates of MP-WPC compared with EH-WPC. In conclusion, minimal heat treatment of WPC compared with extensive heating promoted GI tolerance in immature piglets, implying that minimal heated WPC could improve the GI tolerance of milk formulas in infants.

Very preterm birth is associated with attention deficits that interfere with academic performance. A better understanding of attention processes is necessary to support very preterm born children. This study examined voluntary and involuntary attentional control in very preterm born adolescents by measuring saccadic eye movements. Additionally, these control processes were related to symptoms of inattention, intelligence, and academic performance. Participants included 47 very preterm and 61 full-term born 13-years-old adolescents. Oculomotor control was assessed using the antisaccade and oculomotor capture paradigm. Very preterm born adolescents showed deficits in antisaccade but not in oculomotor capture performance, indicating impairments in voluntary but not involuntary attentional control. These impairments mediated the relation between very preterm birth and inattention, intelligence, and academic performance., (© 2019 The Authors. Child Development published by Wiley Periodicals, Inc. on behalf of Society for Research in Child Development.)

Gut organoids are stem cell derived 3D models of the intestinal epithelium that are useful for studying interactions between enteric pathogens and their host. While the organoid model has been used for both bacterial and viral infections, this is a closed system with the luminal side being inaccessible without microinjection or disruption of the organoid polarization. In order to overcome this and simplify their applicability for transepithelial studies, permeable membrane based monolayer approaches are needed. In this paper, we demonstrate a method for generating a monolayer model of the human fetal intestinal polarized epithelium that is fully characterized and validated. Proximal and distal small intestinal organoids were used to generate 2D monolayer cultures, which were characterized with respect to epithelial cell types, polarization, barrier function, and gene expression. In addition, viral replication and bacterial translocation after apical infection with enteric pathogens Enterovirus A71 and Listeria monocytogenes were evaluated, with subsequent monitoring of the pro-inflammatory host response. This human 2D fetal intestinal monolayer model will be a valuable tool to study host-pathogen interactions and potentially reduce the use of animals in research., (Copyright © 2020 Roodsant, Navis, Aknouch, Renes, van Elburg, Pajkrt, Wolthers, Schultsz, van der Ark, Sridhar and Muncan.)