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Objectives: Preventive measures against COVID-19 are essential for pregnant women. Pregnant women are particularly vulnerable to emerging infectious pathogens due to alterations in their physiology. We aimed to determine the optimum timing of vaccination to protect pregnant women and their neonates from COVID-19. Methods: A prospective observational longitudinal cohort study in pregnant women who received COVID-19 vaccination. We collected blood samples to evaluate levels of antispike, receptor binding domain and nucleocapsid antibodies against SARS-CoV-2 before vaccination and 15 days after the first and second vaccination. We determined the neutralizing antibodies from mother-infant dyads in maternal and umbilical cord blood at birth. If available, immunoglobulin A was measured in human milk. Results: We included 178 pregnant women. Median antispike immunoglobulin G levels increased significantly from 1.8 to 5431 binding antibody units/ml and receptor binding domain from 6 to 4466 binding antibody units/ml. Virus neutralization showed similar results between different weeks of gestation at vaccination (P >0.3). Conclusion: We advise vaccination in the early second trimester of pregnancy for the optimum balance between the maternal antibody response and placental antibody transfer to the neonate.

Human milk contains SARS-CoV-2-specific antibodies after COVID-19 vaccination. These milk antibodies decrease several months post-vaccination. Whether booster immunization restores human milk antibody levels, potentially offering prolonged passive immunity for the infant, remains unknown. In this prospective follow-up study, we investigated the longitudinal SARS-CoV-2-specific antibody response in human milk of 26 lactating women who received a COVID-19 booster dose of an mRNA-based vaccine. Moreover, we evaluated whether the booster-induced human milk antibody response differs for participants who received a similar or different vaccine type in their primary vaccination series. All participants (100%) who received a homologous booster vaccination showed SARS-CoV-2-specific immunoglobulin A (IgA) and immunoglobulin G (IgG) in their milk. Heterologous booster vaccination resulted in milk conversion for 9 (69%) and 13 (100%) participants for IgA and IgG respectively. Findings of this study indicate that both homologous and heterologous boosting schedules have the potential to enhance SARS-CoV-2-specific IgA and IgG in human milk.

Background It has been demonstrated that human milk from mothers who have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contains antibodies against the virus, which could play an important role in protecting the recipient infant against coronavirus disease 2019 (COVID-19). Seroconversion is measured frequently around the world, but the milk conversion rate is unknown. Research Aims To determine (1) the prevalence and (2) the dynamics of immunoglobulin A (IgA) antibodies against SARS-CoV-2 in human milk amongst lactating mothers in the Netherlands. Methods In this large prospective cohort study, lactating mothers ( N = 2312) were included between October 12, 2020 and February 24, 2021. Enzyme-linked immunosorbent assay was used to determine levels of IgA antibodies in human milk and immunoglobulin G (IgG) antibodies in serum against the ectodomain of the SARS-CoV-2 spike protein. Results A total of 691 (30.6%) participants had SARS-CoV-2 specific antibodies in human milk and/or serum. Of these participants, 524 (23.1%) had IgA antibodies against SARS-CoV-2 in human milk, and 356 (15.7%) had IgG antibodies against SARS-CoV-2 in serum. A total of 199 (8.8%) participants had antibodies in both human milk and serum. SARS-CoV-2 specific IgA antibodies in human milk remain present at least 10 months after a polymerase chain reaction confirmed infection. Conclusion The prevalence of IgA antibodies against SARS-CoV-2 in human milk was 23.1% in our cohort. This high prevalence of antibodies in human milk might lead to passive immunity in many breastfed infants and may serve as protection against COVID-19.

Infants may develop severe viral respiratory tract infections because their immune system is still developing in the first months after birth. Human milk provides passive humoral immunity during the first months of life. During the COVID-19 pandemic, circulation of common respiratory viruses was virtually absent due to the preventative measures resulting in reduced maternal exposure. Therefore, we hypothesized that this might result in lower antibody levels in human milk during the pandemic and, subsequently, decreased protection of infants against viral respiratory tract infections. We assessed antibody levels against respiratory syncytial virus (RSV), Influenza virus, and several seasonal coronaviruses in different periods of the COVID-19 pandemic in serum and human milk using a Luminex assay. IgG levels against RSV, Influenza, HCoV-OC43, HCoVHKU1, and HCoV-NL63 in human milk were reduced with a factor of 1.7 (P, 0.001), 2.2 (P, 0.01), 2.6 (P, 0.05), 1.4 (P, 0.01), and 2.1 (P, 0.001), respectively, since the introduction of the COVID-19 restrictions. Furthermore, we observed that human milk of mothers that experienced COVID-19 contained increased levels of IgG and IgA binding to other respiratory viruses. Passive immunity via human milk against common respiratory viruses was reduced during the COVID-19 pandemic, which may have consequences for the protection of breastfed infants against respiratory infections.

Background SARS-CoV-2-specific antibodies are secreted into human milk after women are vaccinated against COVID-19, which might protect the breastfed infant. Due to several reports of severe side-effects of the Oxford-AstraZeneca ChAdOx1 (AZD1222) vaccine against COVID-19, some lactating women followed a heterologous vaccination schedule consisting of the first dose of AZD1222 and a second dose of an mRNA-based vaccine. However, it is unclear whether this generates a significant SARS-CoV-2-specific antibody response in human milk. Main Issue To quantify the SARS-CoV-2-specific antibody response in human milk of two lactating women receiving a heterologous vaccination schedules: AZD1222 and mRNA-based vaccine (Pfizer-BioNTech [BNT162b2] and Moderna [mRNA-1273]). Management Both participants collected 16 samples of human milk longitudinally. SARS-CoV-2-specific Immunoglobulin A was measured using an enzyme-linked immunosorbent assay. Conclusion Based on our results, it could be suggested that heterologous vaccination with AZD1222 and an mRNA-based vaccine can elicit a significant SARS-CoV-2 specific IgA response in human milk.

ImportanceSARS-CoV-2-specific antibodies in human milk might protect the breastfed infant against COVID-19. One of the factors that may influence human milk antibodies is psychological stress, which is suggested to be increased in lactating women during the COVID-19 pandemic.ObjectiveTo determine whether psychological stress is increased in lactating women during the COVID-19 pandemic, and if maternal stress is associated with the level of SARS-CoV-2-specific antibodies in human milk.DesignPopulation-based prospective cohort study.SettingData collection took place in the Netherlands between October 2020 and February 2021.ParticipantsLactating women living in the Netherlands were eligible to participate in this study. In total, 2310 women were included.ExposuresStress exposure during the COVID-19 pandemic was determined using the Perceived Stress Scale (PSS) questionnaire and maternal lifetime stress was determined by the Life Stressor Checklist – revised (LSC-r) questionnaire.Main Outcome(s) and Measure(s)Stress experience during the COVID-19 pandemic was compared with a pre-pandemic cohort. SARS-CoV-2-specific antibodies in human milk were measured using an Enzyme-Linked Immunosorbent Assay (ELISA) with the Spike protein of SARS-CoV-2. The association between maternal stress and human milk antibodies was determined using a multiple regression model.ResultsThe PSS score of lactating mothers was not increased during the pandemic compared to the PSS score in the prepandemic cohort. Six hundred ninety-one participants had SARS-CoV-2-specific antibodies and were included in the regression models to assess the association between maternal stress and human milk antibodies. No association was found between PSS scores and human milk antibodies. In contrast, the LSC-r score was negatively associated with SARS-CoV-2-specific IgA in human milk (β = 0.98, 95% CI: 0.96–0.997, p = 0.03).Conclusions and RelevanceOur results suggest that lactating women in the Netherlands did not experience higher stress levels during the COVID-19 pandemic. Breastfed infants of mothers with high chronic stress levels receive lower amounts of antibodies through human milk, which possibly makes them more vulnerable to respiratory infections. This emphasizes the importance of psychological wellbeing during lactation.

The most abundant immunoglobulin present in the human body is IgA. It has the highest concentrations at the mucosal lining and in biofluids such as milk and is the second most abundant class of antibodies in serum. We assessed the structural diversity and clonal repertoire of IgA1-containing molecular assemblies longitudinally in human serum and milk from three donors using a mass spectrometry-based approach. IgA-containing molecules purified from serum or milk were assessed by the release and subsequent analysis of their Fab fragments. Our data revealed that serum IgA1 consists of two distinct structural populations, namely monomeric IgA1 (∼80%) and dimeric joining (J-) chain coupled IgA1 (∼20%). Also, we confirmed that IgA1 in milk is present solely as secretory (S)IgA, consisting of two (∼50%), three (∼33%) or four (∼17%) IgA1 molecules assembled with a J-chain and secretory component (SC). Interestingly, the serum and milk IgA1-Fab repertoires were distinct between monomeric, and J-chain coupled dimeric IgA1. The serum dimeric J-chain coupled IgA1 repertoire contained several abundant clones also observed in the milk IgA1 repertoire. The latter repertoire had little to no overlap with the serum monomeric IgA1 repertoire. This suggests that human IgA1s have (at least) two distinct origins; one of these produces dimeric J-chain coupled IgA1 molecules, shared in human serum and milk, and another produces monomeric IgA1 ending up exclusively in serum.

Variation in metabolite levels reflects individual differences in genetic and environmental factors. Here, we investigated the role of these factors in urinary metabolomics data in children. We examined the effects of sex and age on 86 metabolites, as measured on three metabolomics platforms that target amines, organic acids, and steroid hormones. Next, we estimated their heritability in a twin cohort of 1300 twins (age range: 5.7–12.9 years). We observed associations between age and 50 metabolites and between sex and 21 metabolites. The monozygotic (MZ) and dizygotic (DZ) correlations for the urinary metabolites indicated a role for non-additive genetic factors for 50 amines, 13 organic acids, and 6 steroids. The average broad-sense heritability for these amines, organic acids, and steroids was 0.49 (range: 0.25–0.64), 0.50 (range: 0.33–0.62), and 0.64 (range: 0.43–0.81), respectively. For 6 amines, 7 organic acids, and 4 steroids the twin correlations indicated a role for shared environmental factors and the average narrow-sense heritability was 0.50 (range: 0.37–0.68), 0.50 (range; 0.23–0.61), and 0.47 (range: 0.32–0.70) for these amines, organic acids, and steroids. We conclude that urinary metabolites in children have substantial heritability, with similar estimates for amines and organic acids, and higher estimates for steroid hormones.

Anelloviruses (AVs) are found in the vast majority of the human population and are most probably part of a healthy virome. These viruses infect humans in the early stage of life, however, the characteristics of the first colonizing AVs are still unknown. We screened a collection of 107 blood samples from children between 0.4 and 64.8 months of age for the presence of three AV genera: the Alpha-, Beta- and Gammatorquevirus. The youngest child that was positive for AV was 1.2 months old, and a peak in prevalence (100% of samples positive) was reached between the twelfth and eighteenth months of life. Intriguingly, the beta- and gammatorqueviruses were detected most at the early stage of life (up to 12 months), whereas alphatorqueviruses, the most common AVs in adults, increased in prevalence in children older than 12 months. To determine whether that order of colonization may be related to oral transmission and unequal presence of AV genera in breast milk, we examined 63 breast milk samples. Thirty-two percent of the breast milk samples were positive in a qPCR detecting beta- and gammatorqueviruses, while alphatorqueviruses were detected in 10% of the samples, and this difference was significant (p = 0.00654). In conclusion, we show that beta- and gammatorqueviruses colonize humans in the first months of life and that breastfeeding could play a role in AV transmission.

Background: Vaccination of lactating women against COVID-19 may protect not only themselves but also their breastfed infant through human milk. Therefore, it is important to gain insight into the human milk antibody response after immunization with the various vaccines that are currently widely used. The aim of this study is to determine and compare the antibody response in human milk following vaccination with mRNA- and vector-based vaccines up to over two months post-vaccination. Methods: This prospective cohort study was conducted in the Netherlands between January 06, 2021 and July 31, 2021. Participants were recruited through social media. Human milk samples were collected longitudinally during a period of 70 days from women receiving one of the four different severe acute respiratory coronavirus 2 (SARS-CoV-2) vaccines: Pfizer-BioNTech (BNT162b2), Moderna (mRNA-1273), Oxford/AstraZeneca (AZD1222) and Johnson&Johnson (Ad26.COV2.S). SARS-CoV-2-specific antibodies were measured using an enzyme-linked immunosorbent assay. The area under the curve (AUC) of the Immunoglobulins A (IgA) and G (IgG) antibody response was determined over 15 and 70 days following the first vaccination and compared between the different vaccines. Findings: This study enrolled 134 vaccinated lactating women of whom 97 participated the entire study period. In total, 1887 human milk samples were provided. The human milk antibody response differed between SARS-CoV-2 vaccines over the study period. The mean AUC of SARS-CoV-2-specific IgA, but not IgG, in human milk over 15 days was higher after vaccination with an mRNA-based vaccine than a vector-based vaccine (AUC with respect to ground [AUCg] ± the standard error of the mean [SEM] for IgA was 6·09 ± 0·89 in the BNT162b2 group, 7·48 ± 1·03 in the mRNA-1273 group, 4·17 ± 0·73 in the AZD1222 group, and 5·71 ± 0·70 in the Ad26.COV2.S group). Over a period of 70 days, the mean AUCg of both IgA and IgG was higher after vaccination with an mRNA-based vaccine than a vector-based vaccine (AUCg ± SEM for IgA was 38·77 ± 6·51 in the BNT162b2 group, 50·13 ± 7·41 in the mRNA-1273 group, 24·12 ± 5·47 in the AZD1222 group, and 28·15 ± 6·69 in the Ad26.COV2.S group; AUCg ± SEM for IgG was 40·43 ± 2·67 in the BNT162b2 group, 37·01 ± 2·38 in the mRNA-1273 group, 16·04 ± 5·09 in the AZD1222 group, and 10·44 ± 2·50 in the Ad26.COV2.S group). Interpretation: Overall, maternal vaccination during lactation with an mRNA-based vaccine resulted in higher SARS-CoV-2 antibody responses in human milk compared to vector-based vaccines. Therefore, vaccination with mRNA-based vaccines, preferably with the mRNA-1273 vaccine, might not only provide better immunological protection for the mother but also for her breastfed infant. Funding: Stichting Steun Emma Kinderziekenhuis and the Amsterdam Infection and Immunity Institute (grant 24175).

The most abundant immunoglobulin present in the human body is IgA1. It has the highest concentrations at the mucosal lining and in biofluids such as milk and is the second most abundant class of antibodies in serum. We assessed the structural diversity and clonal repertoire of IgA1-containing molecular assemblies longitudinally in human serum and milk from three donors using a mass spectrometry-based approach. IgA-containing molecules purified from serum or milk were assessed by the release and subsequent analysis of their Fab fragments. Our data revealed that serum IgA1 consists of two distinct structural populations, namely monomeric IgA1 (∼ 80%) and dimeric joining (J-) chain coupled IgA1 (∼ 20%). Also, we confirmed that IgA1 in milk is present solely as secretory (S)IgA, consisting of two (∼ 50%), three (∼ 33%) or four (∼ 17%) IgA1 molecules assembled with a J-chain and secretory component (SC). Interestingly, the serum and milk IgA1-Fab repertoires were distinct between monomeric, and J-chain coupled dimeric IgA1. The serum dimeric J-chain coupled IgA1 repertoire contained several abundant clones also observed in the milk IgA1 repertoire. The latter repertoire had little to no overlap with the serum monomeric IgA1 repertoire. This suggests that human IgA1s have (at least) two distinct origins; one of these produces dimeric J-chain coupled IgA1 molecules, shared in human serum and milk, and another produces monomeric IgA1 ending up exclusively in serum.

Objective Sex differences in disease susceptibility might be explained by sexual dimorphism in hypothalamic-pituitary-adrenal axis activity, which has been postulated to emerge during puberty. However, studies conducted thus far lacked an assessment of Tanner pubertal stage. This study aimed to assess the contribution of pubertal development to sexual dimorphism in cortisol production and metabolism. Methods Participants (n = 218) were enrolled from a population-based Netherlands Twin Register. At the ages of 9, 12 and 17 years, Tanner pubertal stage was assessed and early morning urine samples were collected. Cortisol metabolites were measured with GC-MS/MS and ratios were calculated, representing cortisol metabolism enzyme activities, such as A-ring reductases, 11β-HSDs and CYP3A4. Cortisol production and metabolism parameters were compared between sexes for pre-pubertal (Tanner stage 1), early pubertal (Tanner stage 2–3) and late-pubertal (Tanner stage 4–5) stages. Results Cortisol metabolite excretion rate decreased with pubertal maturation in both sexes, but did not significantly differ between sexes at any pubertal stage, although in girls a considerable decrease was observed between early and late-pubertal stage (P < 0.001). A-ring reductase activity was similar between sexes at pre- and early pubertal stages and was lower in girls than in boys at late-pubertal stage. Activities of 11β-HSDs were similar between sexes at pre-pubertal stage and favored cortisone in girls at early and late-pubertal stages. Cytochrome P450 3A4 activity did not differ between sexes. Conclusions Prepubertally, sexes were similar in cortisol parameters. During puberty, as compared to boys, in girls the activities of A-ring reductases declined and the balance between 11β-HSDs progressively favored cortisone. In addition, girls showed a considerable decrease in cortisol metabolite excretion rate between early and late-pubertal stages. Our findings suggest that the sexual dimorphism in cortisol may either be explained by rising concentrations of sex steroids or by puberty-induced changes in body composition.

Life-course experiences have been postulated to program hypothalamus–pituitary–adrenal (HPA) axis activity, suggesting that HPA axis activity is, at least partially, stable over time. Yet, there is paucity of data on the long-term stability of cortisol production and metabolism. We performed a prospective follow-up study in twins recruited from a nationwide register to estimate the stability of cortisol production and metabolism over time, and the contribution of genetic and environmental factors to this stability. In total, 218 healthy mono- and dizygotic twins were included. At the ages of 9, 12 and 17 years, morning urine samples were collected for assessment (by gas chromatography-tandem mass spectrometry) of cortisol metabolites, enabling the calculation of cortisol metabolite excretion rate and cortisol metabolism activity. Our results showed a low stability for both cortisol metabolite excretion rate (with correlations

SARS-CoV-2-specific antibodies are secreted into human milk of infected or vaccinated lactating women and might provide protection to the breastfed infant against COVID-19. Differences in antibody response after these types of exposure are unknown. In this longitudinal cohort study, we compared the antibody response in human milk following SARS-CoV-2 vaccination or infection. We analyzed 448 human milk samples of 28 lactating women vaccinated with the SARS-CoV-2 vaccine BNT162b2 as well as 82 human milk samples of 18 lactating women with a prior SARS-CoV-2 infection. The levels of SARS-CoV-2-specific IgA in human milk were determined over a period of 70 days both after vaccination and infection. The amount of SARS-CoV-2-specific IgA in human milk was similar after SARS-CoV-2 vaccination and infection. After infection, the variability in IgA levels was higher than after vaccination. Two participants with detectable IgA prior to vaccination were analyzed separately and showed higher IgA levels following vaccination compared to both groups. In conclusion, breastfed infants of mothers who have been vaccinated with the BNT162b2 vaccine receive human milk with similar amounts of SARS-CoV-2-specific antibodies compared to infants of previously infected mothers.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are being administered around the world; however, lactating women were excluded from SARS-CoV-2 vaccine trials. Therefore, knowledge about the effect of vaccination in this specific group is limited. This information is essential to empower lactating women to make a well-informed decision on their choice for vaccination. After natural infection, SARS-CoV-2 specific antibodies are present in human milk, which might offer protection for her newborn. The dynamics of these antibodies in human milk following vaccination remain to be elucidated. Research Aim To determine the effect of vaccination with BNT162b2 on the levels of SARS-CoV-2 specific IgA in human milk. Methods In this prospective longitudinal study, we included lactating women who received the BNT162b2 vaccine. Human milk samples were collected prior to vaccination and 3, 5, 7, 9, 11, 13, and 15 days after both vaccine doses. Samples were analyzed using enzyme-linked immunosorbent assay against the spike protein of SARS-CoV-2. Results In total, 366 human milk samples from 26 lactating women were analyzed. A biphasic response was observed, with SARS-CoV-2 specific immunoglobulin A (IgA) starting to increase between day 5 and 7 after the first dose of the vaccine. After the second dose, an accelerated IgA antibody response was observed. Conclusion After vaccination with the mRNA-based BNT162b2 vaccine, a SARS-CoV-2 specific antibody response was observed in human milk. The presence of SARS-CoV-2 specific IgA after vaccination is important as antibodies are transferred via human milk, and thereby might provide protection to infants against COVID-19.

Background Human milk contains antibodies against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) following Coronavirus Disease 2019 (COVID-19). These antibodies may serve as protection against COVID-19 in infants. However, the evolution of these human milk antibodies over time is unclear. Research Aim To elucidate the evolution of immunoglobulin A (IgA) against SARS-CoV-2 in human milk after a SARS-CoV-2 infection. Methods This longitudinal follow-up study included lactating mothers ( N = 24) who had participated in the COVID MILK study. To assess the evolution of SARS-CoV-2 antibodies, serum and human milk samples were collected 14–143 days after the onset of clinical symptoms related to COVID-19. Enzyme-Linked ImmunoSorbent Assay was used to detect antibodies against the ectodomain of the SARS-CoV-2 spike protein. Results SARS-CoV-2 antibodies remain present up to 5 months (143 days) in human milk after onset of COVID-19 symptoms. Overall, SARS-CoV-2 IgA in human milk seems to gradually decrease over time. Conclusion Human milk from SARS-CoV-2 convalescent lactating mothers contains specific IgA antibodies against SARS-CoV-2 spike protein up to at least 5 months post-infection. Passive viral immunity can be transferred via human milk and may serve as protection for infants against COVID-19.

Stress exposure during sensitive developmental periods lastingly affects brain function and cognition and increases vulnerability to psychopathology later in life, as established in various preclinical and clinical studies. Interestingly, similar patterns are seen in children who suffer from perinatal malnutrition. Stress and malnutrition can act closely aligned and stress and nutrition interact. There is emerging evidence that specific nutritional supplementation during various time windows may ameliorate the long-lasting effects of early-life stress, although possible mechanistic insights in this process are sparsely reported. Understanding how stress exposure in early-life influences brain development, and understanding the role of nutrition in this process, is essential for the development of effective (nutritional) therapies to improve long-term health in children exposed to early-life stress. This is especially important in the situation of preterm birth where both stress exposure and malnutrition are common. Here, we will discuss the programming effects of early-life stress, the possible underlying mechanisms, how nutrients impact on this process, and the promising role of nutrition in modulating (some of) the lasting consequences of early-life stress on brain function and health in adulthood.

Context Inter-individual differences in cortisol production and metabolism emerge with age and may be explained by genetic factors. Objective To estimate the relative contributions of genetic and environmental factors to inter-individual differences in cortisol production and metabolism throughout adolescence. Design Prospective follow-up study of twins. Setting Nationwide register. Participants 218 mono- and dizygotic twins (N = 109 pairs) born between 1995 amd 1996, recruited from the Netherlands Twin Register. Cortisol metabolites were determined in 213, 169, and 160 urine samples at the ages of 9, 12, and 17, respectively. Main outcome measures The total contribution of genetic factors (broad-sense heritability) and shared and unshared environmental influences to inter-individual differences in cortisol production and activities of 5α-reductase, 5β-reductase, and 11β-hydroxysteroid dehydrogenases and cytochrome P450 3A4. Results For cortisol production rate at the ages of 9, 12, and 17, broad-sense heritability was estimated as 42%, 30%, and 0%, respectively, and the remainder of the variance was explained by unshared environmental factors. For cortisol metabolism indices, the following heritability was observed: for the A-ring reductases (5α-and 5β-reductases), broad-sense heritability increased with age (to >50%), while for the other indices (renal 11β-HSD2, global 11β-HSD, and CYP3A4), the contribution of genetic factors was highest (68%, 18%, and 67%, respectively) at age 12. Conclusions The contribution of genetic factors to inter-individual differences in cortisol production decreased between 12 and 17y, indicative of a predominant role of individual circumstances. For cortisol metabolism, distinct patterns of genetic and environmental influences were observed, with heritability that either increased with age or peaked at age 12y.

Objective Sex-specific differences in hypothalamic–pituitary–adrenal axis activity might explain why male preterm infants are at higher risk of neonatal mortality and morbidity than their female counterparts. We examined whether male and female preterm infants differed in cortisol production and metabolism at 10 days post-partum. Design and methods This prospective study included 36 preterm born infants (18 boys) with a very low birth weight (VLBW) ( Results No differences between sexes were found for cortisol excretion rate, corticosteroid excretion rate or 11B-HSD activity. Interaction was observed between: sex and SNAPPE II score on 11B-HSD activity (P = 0.04) and sex and BPD on cortisol excretion rate (P = 0.04). Conclusion This study did not provide evidence for sex-specific differences in adrenocortical function in preterm VLBW infants on a group level. However, in an interaction model, sex differences became manifest under stressful circumstances. These patterns might provide clues for the male disadvantage in neonatal mortality and morbidity following preterm birth. However, due to the small sample size, the data should be seen as hypothesis generating.

BackgroundSince the outbreak of COVID-19, many put their hopes in the rapid development of effective immunizations. For now patient isolation, physical distancing and good hygiene are the sole measures for prevention. Processed breast milk with antibodies against SaRS-CoV-2 may serve as additional protection. We aimed to determine the presence and neutralization capacity of antibodies against SaRS-CoV-2 in breastmilk of mothers who have recovered from COVID-19.MethodsThis prospective case control study included lactating mothers, recovered from (suspected) COVID-19 and healthy controls. Serum and breastmilk was collected. To assess the presence of antibodies in breastmilk and serum, we used multiple complementary assays, namely ELISA with the SARS-CoV-2 spike protein, SARS-CoV-2 receptor binding domain (RBD) and with the SARS-CoV-2 nucleocapsid (N) protein for IgG and bridging ELISA with the SARS-CoV-2 RBD and N protein for total Ig. To assess the effect of pasteurization breastmilk was exposed to Holder Pasteurization and High Pressure Pasteurization.ResultsBreastmilk contained antibodies against SARS-CoV-2 using any of the assays in 24 out of 29 (83%) proven cases, in six out of nine (67%) suspected cases and in none of the 13 controls.In vitroneutralization of SARS-CoV-2 clinical isolate virus strain was successful in a subset of serum (13%) and milk samples (26%). Although after pasteurization of the milk SARS-CoV-2 antibodies were detected with both methods of pasteurization, virus neutralizing capacity of those antibodies was only retained with the HPP approach.ConclusionBreastmilk of mothers who recovered from COVID-19 contains significant amounts of IgA against SARS-CoV-2, both before and after pasteurization.Key PointsQuestionDoes breastmilk of mothers who have recovered from coronavirus disease 2019 (COVID-19) contain antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)?FindingsWe provide multiple lines of evidence on the presence of a variety of antibodies against SARS-CoV-2, with no such antibodies present in the controls. These antibodies are capable of neutralizing a clinical isolate of SARS-CoV-2in vitro. We furthermore show that high pressure pasteurization hardly affects antibody levels and efficacy.MeaningBreastmilk, obtained from mothers who have recovered from COVID-19, may serve as a safe and widely applicable preventive strategy for vulnerable high risk populations

Childhood obesity is associated with alterations in hypothalamus&ndash, pituitary&ndash, adrenal (HPA) axis activity. However, it is unknown whether these alterations are a cause or a consequence of obesity. This study aimed to explore the temporal relationship between cortisol production and metabolism, and body mass index (BMI). This prospective follow-up study included 218 children (of whom 50% were male), born between 1995 and 1996, who were assessed at the ages of 9, 12 and 17 years. Morning urine samples were collected for assessment of cortisol metabolites by gas chromatography-tandem mass spectrometry, enabling the calculation of cortisol metabolite excretion rate and cortisol metabolic pathways. A cross-lagged regression model was used to determine whether BMI at various ages during childhood predicted later cortisol production and metabolism parameters, or vice versa. The cross-lagged regression coefficients showed that BMI positively predicted cortisol metabolite excretion (p = 0.03), and not vice versa (p = 0.33). In addition, BMI predicted the later balance of 11&beta, hydroxysteroid dehydrogenase (HSD) activities (p = 0.07), and not vice versa (p = 0.55). Finally, cytochrome P450 3A4 activity positively predicted later BMI (p = 0.01). Our study suggests that changes in BMI across the normal range predict alterations in HPA axis activity. Therefore, the alterations in HPA axis activity as observed in earlier studies among children with obesity may be a consequence rather than a cause of increased BMI.

Background Since the outbreak of COVID-19, many put their hopes in the rapid development of effective immunizations. For now patient isolation, physical distancing and good hygiene are the sole measures for prevention. Processed breast milk with antibodies against SaRS-CoV-2 may serve as additional protection. We aimed to determine the presence and neutralization capacity of antibodies against SaRS-CoV-2 in breastmilk of mothers who have recovered from COVID-19. Methods This prospective case control study included lactating mothers, recovered from (suspected) COVID-19 and healthy controls. Serum and breastmilk was collected. To assess the presence of antibodies in breastmilk and serum, we used multiple complementary assays, namely ELISA with the SARS-CoV-2 spike protein, SARS-CoV-2 receptor binding domain (RBD) and with the SARS-CoV-2 nucleocapsid (N) protein for IgG and bridging ELISA with the SARS-CoV-2 RBD and N protein for total Ig. To assess the effect of pasteurization breastmilk was exposed to Holder Pasteurization and High Pressure Pasteurization. Results Breastmilk contained antibodies against SARS-CoV-2 using any of the assays in 24 out of 29 (83%) proven cases, in six out of nine (67%) suspected cases and in none of the 13 controls. In vitro neutralization of SARS-CoV-2 clinical isolate virus strain was successful in a subset of serum (13%) and milk samples (26%). Although after pasteurization of the milk SARS-CoV-2 antibodies were detected with both methods of pasteurization, virus neutralizing capacity of those antibodies was only retained with the HPP approach. Conclusion Breastmilk of mothers who recovered from COVID-19 contains significant amounts of IgA against SARS-CoV-2, both before and after pasteurization. Key Points Question Does breastmilk of mothers who have recovered from coronavirus disease 2019 (COVID-19) contain antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)? Findings We provide multiple lines of evidence on the presence of a variety of antibodies against SARS-CoV-2, with no such antibodies present in the controls. These antibodies are capable of neutralizing a clinical isolate of SARS-CoV-2 in vitro. We furthermore show that high pressure pasteurization hardly affects antibody levels and efficacy. Meaning Breastmilk, obtained from mothers who have recovered from COVID-19, may serve as a safe and widely applicable preventive strategy for vulnerable high risk populations

High rates of oxidative stress are common in preterm born infants and have short- and long-term consequences. The antioxidant properties of human milk limits the consequences of excessive oxidative damage. However, as the mother’s own milk it is not always available, donor milk may be provided as the best alternative. Donor milk needs to be pasteurized before use to ensure safety. Although pasteurization is necessary for safety reasons, it may affect the activity and concentration of several biological factors, including antioxidants. This literature review describes the effect of different pasteurization methods on antioxidant properties of human milk and aims to provide evidence to guide donor milk banks in choosing the best pasteurization method from an antioxidant perspective. The current literature suggests that Holder pasteurization reduces the antioxidant properties of human milk. Alternative pasteurization methods seem promising as less reduction is observed in several studies.

Homozygous mutations in NGLY1 were recently found to cause a condition characterized by a complex neurological syndrome, hypo‐ or alacrimia, and elevated liver transaminases. For yet unknown reasons, mortality is increased in patients with this condition. NGLY1 encodes the cytosolic enzyme N‐glycanase 1, which is responsible for the deglycosylation of misfolded N‐glycosylated proteins. Disruption of this process is hypothesized to lead to an accumulation of misfolded proteins in the cytosol. Here, we describe the disease course of a girl with a homozygous mutation in NGLY1, namely c.1837del (p.Gln613 fs). In addition to the previously described symptoms, at the age of 8 she presented with recurrent infections and hyperpigmentation, and, subsequently, a diagnosis of primary adrenal insufficiency was made. There are no previous reports describing adrenal insufficiency in such patients. We postulate that patients with NGLY1 deficiency may develop adrenal insufficiency as a consequence of impaired proteostasis, and the accompanying proteotoxic stress‐induced cell death, through defective Nrf1 function. We recommend an annual evaluation of adrenal function in all patients with NGLY1 mutations in order to prevent unnecessary deaths., Homozygous mutations in NGLY1 were recently found to cause a condition characterized by a complex neurological syndrome, hypo‐ or alacrimia, and elevated liver transaminases. For yet unknown reasons, mortality is increased in patients with this condition. We postulate that patients with NGLY1 mutations may develop adrenal insufficiency as a result of proteotoxic stress‐induced cell death, which could be an explanation for this increased mortality.

Background. The intestinal microbiota has increasingly been considered to play a role in the etiology of late-onset sepsis (LOS). We hypothesize that early alterations in fecal volatile organic compounds (VOCs), reflecting intestinal microbiota composition and function, allow for discrimination between infants developing LOS and controls in a preclinical stage.Methods. In 9 neonatal intensive care units in the Netherlands and Belgium, fecal samples of preterm infants born at a gestational age ≤30 weeks were collected daily, up to the postnatal age of 28 days. Fecal VOC were measured by high-field asymmetric waveform ion mobility spectrometry (FAIMS). VOC profiles of LOS infants, up to 3 days prior to clinical LOS onset, were compared with profiles from matched controls.Results. In total, 843 preterm born infants (gestational age ≤30 weeks) were included. From 127 LOS cases and 127 matched controls, fecal samples were analyzed by means of FAIMS. Fecal VOCs allowed for preclinical discrimination between LOS and control infants. Focusing on individual pathogens, fecal VOCs differed significantly between LOS cases and controls at all predefined time points. Highest accuracy rates were obtained for sepsis caused by Escherichia coli, followed by sepsis caused by Staphylococcus aureus and Staphylococcus epidermidis.Conclusions. Fecal VOC analysis allowed for preclinical discrimination between infants developing LOS and matched controls. Early detection of LOS may provide clinicians a window of opportunity for timely initiation of individualized therapeutic strategies aimed at prevention of sepsis, possibly improving LOS-related morbidity and mortality.