Early-life gut microbiota development depends on a highly synchronized microbial colonization process in which diet is a key regulator. Microbiota transition toward a more adult-like state in toddlerhood goes hand in hand with the transition from a milk-based diet to a family diet. Microbiota development during the first year of life has been extensively researched; however, studies during toddlerhood remain sparse. Young children's requirement for micronutrients, such as dietary iron, is higher than adults. However, their intake is usually sub-optimal based on regular dietary consumption. The Child Health and Residence Microbes (CHaRM) study, conducted as an adjunct to the GUMLi (Growing Up Milk “Lite”) trial, was a double-blind randomized controlled trial to investigate the effects on body composition of toddler milk compared to unfortified standard cow's milk in healthy children between 1 and 2 years of age in Brisbane (Australia). In this trial, fortified milk with reduced protein content and added synbiotics [Bifidobacterium breve M-16V, short-chain galactooligosaccharides, and long-chain fructooligosaccharides (ratio 9:1)] and micronutrients were compared to standard unfortified cow's milk. In the present study, the effects of the intervention on the gut microbiota and its relationship with iron status in toddlers were investigated in a subset of 29 children (18 in the Active group and 11 in the Control group) who completed the CHaRM study. The toddler microbiota consisted mainly of members of the phyla Firmicutes, Bacteroidota, and Actinobacteriota. The abundance of the B. breve species was quantified and was found to be lower in the Control group than in the Active group. Analysis of blood iron markers showed an improved iron status in the Active group. We observed a positive correlation between Bifidobacterium abundance and blood iron status. PICRUSt, a predictive functionality algorithm based on 16S ribosomal gene sequencing, was used to correlate potential microbial functions with iron status measurements. This analysis showed that the abundance of predicted genes encoding for enterobactin, a class of siderophores specific to Enterobacteriaceae, is inversely correlated with the relative abundance of members of the genus Bifidobacterium. These findings suggest that healthy children who consume a young child formula fortified with synbiotics as part of a healthy diet have improved iron availability and absorption in the gut and an increased abundance of Bifidobacterium in their gut microbiome.

BACKGROUND:The impact of survivorship care plans (SCPs) on the proximal and distal outcomes of adult and childhood cancer survivors, and parent proxies, is unclear. This study aimed to determine the relationship between SCP receipt and these outcomes. METHODS:A cross-sectional survey of adult and childhood cancer survivors (and parent proxies for survivors aged younger than 16 years) across Australia and New Zealand was conducted. Multivariate regression models were fitted to measure the impact of SCP receipt on proximal (unmet information needs and propensity to engage with, and attend, cancer-related follow-up care) and distal outcomes (quality of life and satisfaction with cancer-related follow-up care) with control for cancer history and sociodemographic factors. RESULTS:Of 1123 respondents, 499 were adult cancer survivors and 624 were childhood cancer survivors (including 222 parent proxies). We found that SCP receipt was predictive of greater attendance at, and awareness of, cancer-related follow-up care (adult: odds ratio [OR], 2.46; 95% CI, 1.18-5.12; OR, 2.38; 95% CI, 1.07-5.29; child/parent: OR, 2.61; 95% CI, 1.63-4.17; OR, 1.63; 95% CI, 1.06-2.50; respectively). SCP receipt also predicted fewer unmet information needs related to "follow-up care required" and "possible late effects" (adult: OR, 0.44; 95% CI, 0.20-0.96; OR, 0.29; 95% CI, 0.13-0.64; child/parent: OR, 0.46; 95% CI, 0.30-0.72; OR, 0.57; 95% CI, 0.38-0.85; respectively). In terms of distal outcomes, SCP receipt predicted a better global quality of life for adult cancer survivors (β, 0.08; 95% CI, -0.01-7.93), proxy-reported health-related quality of life (β, 0.15; 95% CI, 0.44-7.12), and satisfaction with follow-up care for childhood cancer survivors (OR, 2.93; 95% CI, 1.64-5.23). CONCLUSIONS:Previous studies have shown little impact of SCPs on distal end points. Results suggest that SCPs may be beneficial to cancer survivors' proximal and distal outcomes.

Feeding plans and breastfeeding goals may require revision secondary to challenges related to feeding an infant with tongue-tie.

The relationship between the gut microbiota and brain function are receiving increasing research attention. Studies investigating gut microbiota and early childhood neurocognition are limited, particularly in longitudinal measurements. We examined cross-sectional relationships between gut microbiota of a cohort of otherwise healthy children using 16S rRNA sequencing and their cognitive development measured with Bayley's Scales of Infant Development III at 24 months of age (n = 43), and longitudinal relationships between gut microbiota composition at 12 months (n = 41) of age and neurodevelopment at 24 months of age. Associations between gut microbiota characteristics and cognitive development were observed both cross-sectionally and longitudinally, notably with butyrate producing bacteria among some children. Bacterial diversity varied between cross-sectional and longitudinal observations, where the gut microbiota community of children with lower cognitive scores had a trend toward higher alpha diversity, whereas, in the longitudinal observation, a trend toward reduced alpha diversity was observed. This study is limited by a small sample size and its exploratory nature. Yet, the study contributes to knowledge in the gut microbiota characteristics and early life neurodevelopment, a field of study which is underexplored, presenting opportunities for future larger specific studies.

This study's purpose was to determine the feasibility of a nurse coached walking intervention for informal caregivers of persons with dementia. Participants were randomly assigned to a nurse coached intervention or a control group. Five male and 27 female caregivers (n = 32) participated. Measures included steps, walked well-being, and perceived stress. For steps walked, each group experienced a statistical difference (p = .01 control; p = .02 intervention) and large effect size (0.90). Neither group had a statistical difference in well-being (p = .38 control; p = .08 intervention) or perceived stress (p = .56 control; p = .18 intervention). The intervention group achieved a large effect size in well-being (1.38) and moderate effect size in perceived stress (0.51). A 0.94 pedometer adherence, self-reported user ease with technology and 100% retention rate support feasibility. Many participants described feelings of loneliness and grief, but reported the pedometer motivated them to walk.

Objectives: The growing population of survivors of childhood brain tumors present the challenge of long-term quality of survival. The domains most affected by tumor and treatment are those implicated in development of typical intellectual functions: attention, working memory, and processing speed, with consequent effects upon function and quality of life. In this paper we present service evaluation data on the 12-month effect upon processing speed, visual and auditory attentional domains in 29 patients receiving methylphenidate aged 5-16 years (Mean=10.6). Methods: Patients received immediate-release methylphenidate and were converted to modified-release as appropriate. Mean optimal dose of immediate-release methylphenidate was 0.34 mg/kg per dose (range 0.2-0.67). Results: Patients showed a significant positive impact of methylphenidate on attention in all tests of selective visual attention from the Test of Everyday Attention for Children 2. A significant improvement was also shown on response time. Significant change was not found on psychometric measures of sustained auditory or visual attention, or selective auditory attention. Ratings of Health-Related Quality of Life showed a positive benefit of methylphenidate at 12 months. Side effects were minimal and not statistically significant. Conclusions: Survivors of childhood brain tumor with attentional and processing speed deficit show clinical benefit from methylphenidate.

Abstract MYC and MYCN are the most commonly amplified oncogenes in medulloblastoma. Their overall association with a poor prognosis has supported their adoption as high-risk disease biomarkers in trials. However, emerging evidence suggests that certain patients with MYN/MYCN focally-amplified tumours can achieve long-term survival and therefore may suffer unnecessary late-effects associated with intensified therapies. To investigate this heterogeneity, we characterised the molecular and clinico-pathological features of curated cohorts of MYC (n=64) and MYCN (n=95) amplified tumours, drawn from >1000 diagnostic cases, and assessed their associations with disease outcome. Within the MYCN-amplified cohort, survival was related to molecular group; patients with MYCNGrp3 or MYCNGrp4 tumours with no other clinico-pathological risk factors (subtotal resection (STR), metastatic disease, LCA pathology) were intermediate-risk (n=25;70% 5-year PFS). In contrast, a very-high-risk group was defined by positivity for MYCNSHH, STR and/or LCA (n=64;32% 5-year PFS). 22/35 assessable MYCNSHH harboured TP53 mutations; 9/12 with data were germline. MYCGrp3 represented the majority (46/58; 79%) of molecularly-grouped MYC-amplified tumours. Importantly, while radiotherapy receipt conferred a modest survival advantage, for MYC-amplified tumours with additional clinico-molecular risk factors (LCA, metastasis, STR, Grp3), survival was dismal, irrespective of radiotherapy receipt. A very-high-risk group of MYC-amplified tumours was identified (n=51;10% 5-year PFS), defined by positivity for ≥1 additional risk factors (STR, LCA and/or metastasis). Alternatively, membership of subgroups II/V defined a smaller, very-high-risk patient group (n=28;7% 5-year PFS). Long-term survival was seen in the majority of remaining MYC-amplified tumours negative for these specified features (61% 5-year PFS; high-risk). MYC and MYCN-amplified medulloblastomas are biologically heterogeneous with diverse clinical outcomes. Molecular subgroup assignment and established clinical features are critical for their improved stratification. Patient subgroups identified may be eligible for therapy de-escalation; in contrast, the very-high-risk patient groups are incurable using current therapies and urgently require novel experimental treatment strategies upfront.

Background: The growth and maturation of infants reflect their overall health and nutritional status. The purpose of this study is to examine the associations of prenatal and early postnatal factors with infant growth (IG). Methods: A data-driven model was constructed by structural equation modelling to examine the relationships between pre- and early postnatal environmental factors and IG at age 12 months. The IG was a latent variable created from infant weight and waist circumference. Data were obtained on 274 mother–child pairs during pregnancy and the postnatal periods. Results: Maternal pre-pregnancy BMI emerged as an important predictor of IG with both direct and indirect (mediated through infant birth weight) effects. Infants who gained more weight from birth to 6 months and consumed starchy foods daily at age 12 months, were more likely to be larger by age 12 months. Infant physical activity (PA) levels also emerged as a determinant. The constructed model provided a reasonable fit (χ2 (11) = 21.5, p < 0.05; RMSEA = 0.07; CFI = 0.94; SRMR = 0.05) to the data with significant pathways for all examined variables. Conclusion: Promoting healthy weight amongst women of child bearing age is important in preventing childhood obesity, and increasing daily infant PA is as important as a healthy infant diet.

The relationship of protein intake with insulin-like growth factor 1 (IGF-1) concentrations in well-nourished children during the second year of life is poorly understood. The aim of this study was to explore the effect of a reduced-protein Growing Up Milk Lite (GUMLi) or unfortified cow's milk (CM) on protein intake, growth, and plasma IGF-1 at 2 y. An exploratory analysis of a sub-sample of Auckland-based children (n = 79) in the GUMLi trial (a double-blind, randomised control trial, N = 160) completed in Auckland and Brisbane (2015–2017) was conducted. One-year old children were randomised to receive a reduced-protein GUMLi (1.7 g protein/100 mL) or a non-fortified CM (3.1 g protein/100 mL) for 12 months. Blood sampling and anthropometric measurements were made at 1 and 2 y. Diet was assessed using a validated food frequency questionnaire. Total protein intake (g/d) from all cow's milk sources was 4.6 g (95% CI: −6.7, −2.4; p < 0.005) lower in the GUMLi group after 12 months of the intervention, with a significant group-by-time interaction (p = 0.005). Length-for-age (LAZ) and weight-for-length (WLZ) z-scores did not differ between groups, however, mean body fat % (BF%) was 3.2% (95%CI: −6.2, −0.3; p = 0.032) lower in the GUMLi group at 2 y. There was no difference between the intervention groups in relation to IGF-1 and IGF-BP3 (p = 0.894 and 0.698, respectively), with no group-by-sex interaction. After combining the groups, IGF-1 concentration at 2 y was positively correlated with parameters of growth (all p < 0.05), total cow's milk intake (p = 0.032) after adjusting for sex, breastfeeding status, and gestation. Randomisation to a reduced protein GUMLi resulted in small reduction in %BF and lower total protein intakes but had no effect on growth. Plasma IGF-1 concentrations were independently associated with total protein intake from cow's milk at 2 y, highlighting a potential area of the diet to target when designing future protein-related nutrition interventions. Clinical Trial Registration: Australian New Zealand Clinical Trials Registry number: ACTRN12614000918628. Date registered: 27/08/2014.

Tumor recurrence developing from therapy resistance, immune escape and metastasis is the leading cause of death in medulloblastoma, the most frequent malignant pediatric brain tumor. Amplification of MYC genes is the most common genetic alteration in Group 3 and Group 4 subgroups that constitute two thirds of medulloblastoma. SOX9 is a transcription factor present in stem cells in the normal brain but is limited to rare, quiescent cells in medulloblastoma patients with MYC gene amplifications. By studying paired primary-recurrent patient samples and patient-derived xenografts we here identified significant accumulation of SOX9-positive cells in Group 3 and Group 4 relapses. To follow relapse at the single cell level we developed an inducible dual Tet model of MYC-driven MB, where MYC was re-directed from the treatment-sensitive bulk cells to resistant, dormant SOX9-positive cells by doxycycline. In this model, distant recurrent tumors and spinal metastases developed. SOX9 promoted immune escape, DNA repair suppression and was essential for recurrence. Tumor cell dormancy was non-hierarchical, migratory and depended on MYC suppression by SOX9 to promote relapse. By using computational modeling and treatment we also showed how doxorubicin and MGMT inhibitors were specifically targeting recurrent cells that could be of potential use in future treatments for patients affected by these fatal relapses.

The aim of this study was to explore the psychological outcomes of a mindfulness-based Internet-streamed yoga video in breast cancer survivors. A one-group, repeated-measures, purposive sample using a directed qualitative descriptive and convergent mixed-methods approach was used. Participants were recruited from breast oncology practices across 2 settings in the northeastern United States in April 2019. Education about the video was provided, and the link to the video was sent to participants. Demographic information, Knowing Participation in Change Short Form (KPCSF), Short Warwick-Edinburgh Mental Well-being Scale (WEMWBS), and the Generalized Anxiety Distress Scale (GAD-7) were obtained at baseline and at 2 and 4 weeks. A semistructured interview was conducted at 4 weeks. Thirty-five women (mean age = 56 years) participated. A one-group, repeated-measures analysis of variance indicated statistically significant changes occurred in all measures between week 0 and week 4: decreased GAD (t = −2.97, P = .004), improved WEMWBS (t = 2.52, P = .008), and increased KPC (t = 2.99, P = .004). Qualitative findings suggest the overall experience of the video was positive and the women would recommend its use to others. Improvements in all psychological measures were achieved with video use. Findings indicate an improvement in psychological measures and support the theory of Knowing Participation in Change. This work further contributes to accessible, flexible interventions available through the Internet and/or mobile applications aimed at improving breast cancer survivorship.

The present study investigates the proteomic content of milk-derived exosomes. A detailed description of the content of milk exosomes is essential to improve our understanding of the various components of milk and their role in nutrition.The exosomes used in this study were isolated as previously described and characterized by their morphology, particle concentration, and the presence of exosomal markers. Human and bovine milk exosomes were evaluated using Information-Dependent Acquisition (IDA) Mass Spectrometry. A direct comparison is made between their proteomic profiles.IDA analyses revealed similarities and differences in protein content. About 229 and 239 proteins were identified in the human and bovine milk exosome proteome, respectively, of which 176 and 186 were unique to each species. Fifty-three proteins were common in both groups. These included proteins associated with specific biological processes and molecular functions. Most notably, the 4 abundant milk proteins lactadherin, butyrophilin, perilipin-2, and xanthine dehydrogenase/oxidase were present in the top 20 list for both human and bovine milk exosomes.The milk exosome protein profiles we have provided are crucial new information for the field of infant nutrition. They provide new insight into the components of milk from both humans and bovines.

Background Optimal protein level in hypoallergenic infant formulas is an area of ongoing investigation. The aim was to evaluate growth of healthy term infants who received extensively hydrolyzed (EH) or amino acid (AA)-based formulas with reduced protein. Methods In this prospective, multi-center, double-blind, controlled, parallel group study, infants were randomized to receive a marketed EH casein infant formula at 2.8 g protein/100 kcal (Control) or one of two investigational formulas: EH casein formula at 2.4 g protein/100 kcal (EHF) or AA-based formula at 2.4 g total protein equivalents/100 kcal (AAF). Control and EHF each had 2 × 10 7 CFU Lactobacillus rhamnosus GG/100 kcal. Anthropometrics were measured and recall of formula intake, tolerance, and stool characteristics was collected at 14, 30, 60, 90, 120 days of age. Primary outcome was weight growth rate (g/day) between 14 and 120 days of age (analyzed by ANOVA). Medically confirmed adverse events were recorded throughout the study. Results No group differences in weight or length growth rate from 14 to 120 days were detected. With the exception of significant differences at several study time points for males, no group differences were detected in mean head circumference growth rates. However, mean achieved weight, length, and head circumference demonstrated normal growth throughout the study period. No group differences in achieved weight or length (males and females) and head circumference (females) were detected and means were within the WHO growth 25th and 75th percentiles from 14 to 120 days of age. With the exception of Day 90, there were no statistically significant group differences in achieved head circumference for males; means remained between the WHO 50th and 75th percentiles for growth at Days 14, 30, and 60 and continued along the 75th percentile through Day 120. No differences in study discontinuation due to formula were detected. The number of participants for whom at least one adverse event was reported was similar among groups. Conclusions This study demonstrated hypoallergenic infant formulas at 2.4 g protein/100 kcal were safe, well-tolerated, and associated with appropriate growth in healthy term infants from 14 to 120 days of age. Trial registration ClinicalTrials.gov, ClinicalTrials.gov Identifier: NCT01354366 . Registered 13 May 2011.

AbstractThe Eating Assessment in Toddlers FFQ (EAT FFQ) has been shown to have good reliability and comparative validity for ranking nutrient intakes in young children. With the addition of food items (n 4), we aimed to re-assess the validity of the EAT FFQ and estimate calibration factors in a sub-sample of children (n 97) participating in the Growing Up Milk – Lite (GUMLi) randomised control trial (2015–2017). Participants completed the ninety-nine-item GUMLi EAT FFQ and record-assisted 24-h recalls (24HR) on two occasions. Energy and nutrient intakes were assessed at months 9 and 12 post-randomisation and calibration factors calculated to determine predicted estimates from the GUMLi EAT FFQ. Validity was assessed using Pearson correlation coefficients, weighted kappa (κ) and exact quartile categorisation. Calibration was calculated using linear regression models on 24HR, adjusted for sex and treatment group. Nutrient intakes were significantly correlated between the GUMLi EAT FFQ and 24HR at both time points. Energy-adjusted, de-attenuated Pearson correlations ranged from 0·3 (fibre) to 0·8 (Fe) at 9 months and from 0·3 (Ca) to 0·7 (Fe) at 12 months. Weighted κ for the quartiles ranged from 0·2 (Zn) to 0·6 (Fe) at 9 months and from 0·1 (total fat) to 0·5 (Fe) at 12 months. Exact agreement ranged from 30 to 74 %. Calibration factors predicted up to 56 % of the variation in the 24HR at 9 months and 44 % at 12 months. The GUMLi EAT FFQ remained a useful tool for ranking nutrient intakes with similar estimated validity compared with other FFQ used in children under 2 years.

Abstract OBJECTIVE One of the most disabling side effects of treatment in survivors of brain tumours is the resultant reduction in level of processing speed and attention. This study aimed to evaluate intellectual and psychological benefit of short-acting methylphenidate to survivors of brain tumour. METHODS Paediatric BT patients attending a UK specialist treatment centre received assessment of cognitive performance. All patients identified with attentional difficulties were screened for contraindications to methylphenidate. Participants (N=23), mean age 11.09 years, completed a 6-month trial of methylphenidate. Measures of attention (Test of Everyday Attention for Children 2; SNAP-IV), side-effects (Stimulant Side-Effects Rating Scale), Health-Related Quality of Life (PEDS-QL), and experience of methylphenidate questionnaire (purpose-developed semi-structured questionnaire) were administered prior to medication and after six months. RESULTS Participants showed improvement in selective attention (t(18)=-5.4, p=<.001, d=.93) and processing speed (t(16)=-3.0, p=.01) at follow up. Family ratings of attention were significant (t(17)=14.46, p<.001, d=-1.19). Change in subjective measures of Health-Related Quality of Life (HRQoL) was also statistically significant as reported by children (t(16)=3.91, p=.001, d=-.99), and on a parental-report measure of child HRQoL (t(15)=-8.19, p<.001, d=-1.09). HRQoL measures show improvement to physical, academic, and emotional domains as reported by participants. CONCLUSIONS Paediatric BT survivors showed benefit from provision of methylphenidate in terms of reduced attentional and processing deficit, and in terms of emotional wellbeing. Treatment was well tolerated. Continued follow-up of the current participants in a longitudinal study aims to evidence longer-term benefit to participants.

Abstract Low grade gliomas (LGG), including pilocytic astrocytoma (PCA), are the commonest paediatric brain tumours and their behaviour is well understood, typically following a benign course. BRAF fusion is common, particularly in PCA of the cerebellum and optic pathway. Here we present two patients whose LGG behaved in an unusual fashion. The first patient who was treated 6 years previously on LGG2 with vincristine and carboplatin for a tectal plate lesion was identified on routine imaging to have local tumour progression and underwent completion staging. This showed a new enhancing soft tissue abnormality within the spinal cord at the level of L2. Due to radiological dubiety both lesions were biopsied for histological and molecular analysis, confirming LGG of the tectal plate and finding the spinal lesion to be a myxopapillary ependymoma. The second patient presented with acute hydrocephalus following a 2 year history of neurocognitive impairments. He was found to have a large, complex tumour centred in and expanding the bodies of both lateral ventricles with significant mass effect. Radiologically this was most in keeping with a central neurocytoma but histological analysis confirmed it to be a PCA with KIAA1549-BRAF fusion. The first case demonstrates the utility of molecular analysis in confirming two distinct tumour types in one patient, in a situation where metastasis would not be expected and would significantly alter treatment and prognosis. The second is an example of how imaging can be misleading in a KIAA1549-BRAF fused PCA presenting as an intraventricular mass.

Abstract BACKGROUND Whilst rates of survival following paediatric brain tumour have increased, quality of survival continues to present a significant challenge to children and their families. The neurocognitive impact of cranial radiotherapy (CRT) in childhood upon future intellectual development is well established. Both CRT and chemotherapy are associated with medium-term slowed speed of cognitive processing, attention, and memory impairment, and with longer-term failure to achieve pre-morbid intellectual potential and low Health-Related Quality of Life (HRQoL).Methylphenidate is a psychostimulant drug shown to be effective in alleviating some of the neurocognitive symptoms of cancer treatment, however the subjective experience of paediatric participants is not reported. AIM: The current study aimed to explore the subjective experience of HRQoL in paediatric neuro-oncology patients currently receiving methylphenidate. METHODS A retrospective audit was conducted on 12 paediatric neuro-oncology patients in receipt of methylphenidate. Both standardised and novel measures were used to assess aspects of HRQoL, specifically; social life, perceived independence, mood, confidence, school life, self-esteem, interpersonal relationships and fatigue levels. Data collected were analysed using Thematic Analysis. RESULTS Five key themes were identified; physical, emotional, social, academic and neuropsychological impact. CONCLUSION The current findings evidence the perception of patients that methylphenidate supported them to regain previously lost functionality. Methylphenidate has the potential to increase HRQoL in this population and to provide children with the opportunity to regain a sense of normality in their lives.

Immune-therapy is an attractive alternative therapeutic approach for targeting central nervous system (CNS) tumors and the constituency of the Tumor Immune Microenvironment (TIME) likely to predict patient response. Here, we describe the TIME of >6000 primarily pediatric CNS tumors using a deconvolution approach (methylCIBERSORT). We produce and validate a custom reference signature defining 11 non-cancer cell types to estimate relative proportions of infiltration in a panCNS tumor cohort spanning 80 subtypes. We group patients into three broad immune clusters associated with CNS tumor types/subtypes. In cohorts of medulloblastomas (n = 2325), malignant rhabdoid tumors (n = 229) and pediatric high-grade gliomas (n = 401), we show significant associations with molecular subgroups/subtypes, mutations, and prognosis. We further identify tumor-specific immune clusters with phenotypic characteristics relevant to immunotherapy response (i.e. Cytolytic score, PDL1 expression). Our analysis provides an indication of the potential future therapeutic and prognostic possibilities of immuno-methylomic profiling in pediatric CNS tumor patients that may ultimately inform approach to immune-therapy.