The second Newborn Sequencing in Genomic Medicine and Public Health study was a randomized, controlled trial of the effectiveness of rapid whole-genome or -exome sequencing (rWGS or rWES, respectively) in seriously ill infants with diseases of unknown etiology.Here we report comparisons of analytic and diagnostic performance. Of 1,248 ill inpatient infants, 578 (46%) had diseases of unknown etiology. 213 infants (37% of those eligible) were enrolled within 96 h of admission. 24 infants (11%) were very ill and received ultrarapid whole-genome sequencing (urWGS). The remaining infants were randomized, 95 to rWES and 94 to rWGS. The analytic performance of rWGS was superior to rWES, including variants likely to affect protein function, and ClinVar pathogenic/likely pathogenic variants (p < 0.0001). The diagnostic performance of rWGS and rWES were similar (18 diagnoses in 94 infants [19%] versus 19 diagnoses in 95 infants [20%], respectively), as was time to result (median 11.0 versus 11.2 days, respectively). However, the proportion diagnosed by urWGS (11 of 24 [46%]) was higher than rWES/rWGS (p ¼ 0.004) and time to result was less (median 4.6 days, p < 0.0001). The incremental diagnostic yield of reflexing to trio after negative proband analysis was 0.7% (1 of 147). In conclusion, rapid genomic sequencing can be performed as a first-tier diagnostic test in inpatient infants. urWGS had the shortest time to result, which was important in unstable infants, and those in whom a genetic diagnosis was likely to impact immediate management. Further comparison of urWGS and rWES is warranted because genomic technologies and knowledge of variant pathogenicity are evolving rapidly.

Human milk oligosaccharides (HMOs) are structurally diverse unconjugated glycans with a composition unique to each lactating mother. While HMOs have been shown to have an impact on the development of infant gut microbiota, it is not well known if HMOs also already affect milk microbial composition. To address this question, we analysed eleven colostrum samples for HMO content by high-pressure liquid chromatography and microbiota composition by quantitative PCR. Higher total HMO concentration was associated with higher counts of Bifidobacterium spp. (ρ=0.63, P=0.036). A distinctive effect was seen when comparing different HMO groups: positive correlations were observed between sialylated HMOs and Bifidobacterium breve (ρ=0.84, P=0.001), and non-fucosylated/non-sialylated HMOs and Bifidobacterium longum group (ρ=0.65, P=0.030). In addition to associations between HMOs and bifidobacteria, positive correlations were observed between fucosylated HMOs and Akkermansia muciniphila (ρ=0.70, P=0.017), and between fucosylated/sialylated HMOs and Staphylococcus aureus (ρ=0.75, P=0.007). Our results suggest that the characterised HMOs have an effect on specific microbial groups in human milk. Both oligosaccharides and microbes provide a concise inoculum for the compositional development of the infant gut microbiota.

Human milk oligosaccharides (HMOs) are complex carbohydrates that are highly abundant in and, in their complexity, unique to human milk. Accumulating evidence indicates that exposure to HMOs in the postnatal period affects immediate as well as long-term infant health and development. However, studies reported in the 1970s showed that HMOs already appear in maternal urine and blood during pregnancy and as early as the first trimester. In this pilot study we aimed to determine whether or not HMOs also appear in amniotic fluid. We enrolled women during pregnancy and collected their urine and amniotic fluid at birth as well as their milk 4 days postpartum. We analyzed the samples by high-performance liquid chromatography (HPLC) and mass spectrometry and identified several HMOs including 2′-fucosyllactose, 3-fucosyllactose, difucosyllactose, and 6′-sialyllactose to be present in different relative abundancies in all three tissues. This is the first report that HMOs appear in amniotic fluid and that the fetus is already exposed to HMOs in utero, warranting future research to investigate the immediate and long-term implications on fetal and infant health and development.

The addition of heliox to the standard practice of permissive hypercapnia facilitated improvement in gas exchange, which allowed a decrease in ventilator settings and oxygen exposure, both of which are known to contribute to lung injury in this population. A prospective trial is needed to more clearly define the acute and long-term impacts of this treatment.