"I'd have no idea how to go about this " - a survey of Australian medical students' perspectives on their men's health education.

BACKGROUND: While there have been calls over the last 15 years for the inclusion of training in sex and gender-based medicine in medical school curricula and to sustain such improvements through a more gender responsive health system, little progress has been made. A related objective of the Australian National Men's Health Strategy (2020-30) is to improve practitioner core learning competencies in men's health as a critical step to reducing the burden of disease in men and disparities between men in health care access and outcomes. The aim of this study was therefore to obtain Australian medical student perspectives on the extent to which men's health and sex and gender-based medicine education is delivered in their curricula, their preparedness for engaging with men in clinical practice, and the men's health content they would have found useful during their training. METHODS: Eighty-three students (48% male) from 17 accredited medical schools, and in at least their fourth year of training, completed an online survey. The survey was co-designed by a multidisciplinary team of men's health researchers and clinicians, alongside a student representative. A mix of quantitative and qualitative survey items inquired about students' preparedness for men's health clinical practice, and coverage of men's health and sex- and gender-based medicine in their curricula. RESULTS: Most students reported minimal to no men's health coverage in their medical school education (65%). While few were offered optional men's health units (10.5%), the majority would have liked more formal training on the topic (78%). Accompanying qualitative findings substantiated a lack of preparedness among medical students to engage male patients, likely stemming from minimal coverage of men's health in their medical education. CONCLUSIONS: Australian medical students may feel underprepared for contemporary men's health clinical practice, as well as, albeit to a lesser extent, women's health clinical practice. There is a clear need and desire amongst medical students to enhance curricula with sex and gender-based medicine training.

A rapid review to inform the policy and practice for the implementation of chronic disease prevention and management programs for Aboriginal and Torres Strait Islander people in primary care.

BACKGROUND: More than 35% of Aboriginal and Torres Strait Islander adults live with cardiovascular disease, diabetes, or chronic kidney disease. There is a pressing need for chronic disease prevention and management among Aboriginal and Torres Strait Islander people in Australia. Therefore, this review aimed to synthesise a decade of contemporary evidence to understand the barriers and enablers of chronic disease prevention and management for Aboriginal and Torres Strait Islander People with a view to developing policy and practice recommendations. METHODS: We systematically searched for peer-reviewed published articles between January 2014 to March 2023 where the search was performed using subject headings and keywords related to "Aboriginal and Torres Strait Islander peoples," "Chronic Disease," and "Primary Health Care". Quality assessment for all included studies was conducted using the Aboriginal and Torres Strait Islander Quality Appraisal Tool. The data were extracted and summarised using a conventional content analysis approach and applying strength-based approaches. RESULTS: Database searches identified 1653 articles where 26 met inclusion criteria. Studies varied in quality, primarily reporting on 14 criteria of the Aboriginal and Torres Strait Islander Quality Appraisal Tool. We identified six key domains of enablers and barriers of chronic disease prevention and management programs and implied a range of policy and practice options for improvement. These include culturally acceptable and safe services, patient-provider partnerships, chronic disease workforce, primary health care service attributes, clinical care pathways, and accessibility to primary health care services. This review also identified the need to address social and cultural determinants of health, develop the Aboriginal and Torres Strait Islander and non-Indigenous chronic disease workforce, support multidisciplinary teams through strengthening clinical care pathways, and engage Aboriginal and Torres Strait Islander communities in chronic disease prevention and management program design and delivery. CONCLUSION: Enabling place-based partnerships to develop contextual evidence-guided strategies that align with community priorities and aspirations, with the provision of funding mechanisms and models of care through policy and practice reforms will strengthen the chronic disease prevention and management program for Aboriginal and Torres Strait Islander people.

GlycoNote with Iterative Decoy Searching and Open-Search Component Analysis for High-Throughput and Reliable Glycan Spectral Interpretation.

Mass spectrometry-based glycome analysis is a viable strategy for the compositional and functional exploration of glycosylation. However, the lack of generic tools for high-throughput and reliable glycan spectral interpretation largely hampers the broad usability of glycomic research. Here, we developed a generic and reliable glycomic tool, GlycoNote, for comprehensive and precise glycome analysis. GlycoNote supports interpretation of tandem-mass spectrometry glycomic data from any sample source, uses a novel target-decoy method with iterative decoy searching for highly reliable result output, and embeds an open-search component analysis mode for heterogeneity analysis of monosaccharides and modifications. We tested GlycoNote on several different large-scale glycomic datasets, including human milk oligosaccharides, N- and O-glycome from human cell lines, plant polysaccharides, and atypical glycans from Caenorhabditis elegans, demonstrating its high capacity for glycome analysis. An application of GlycoNote to the analysis of labeled and derived glycans further demonstrates its broad usability in glycomic studies. By enabling generic characterization of various glycan types and elucidation of component heterogeneity in glycomic samples, the freely available GlycoNote is a promising tool for facilitating glycomics in glycobiology research.

Meta-analysis of couple therapy in non-randomized clinical trial studies: Individual and couple level outcomes.

Couple therapy has outperformed control conditions in randomized clinical trials (RCTs). However, there have been some questions whether couple treatment in naturalistic settings is as effective as those with more rigorous controls. The current meta-analysis examined 48 studies of couple therapy in non-randomized clinical trials. The pre-post effect size was Hedge's g = 0.522 for relational outcomes and Hedge's g = 0.587 for individual outcomes. However, there was significant heterogeneity in the results. Several moderators explained some of the variance in these estimates. For relationship outcomes, studies who had older couples and longer length of relationship had better outcomes. Studies with a higher percentage of racial/ethnic minority (REM) couples and studies in Veteran Affairs Medical Centers (VAMC) had lower relational outcomes. For individual outcomes, studies that had more sessions, older couples, and VAMC had better outcomes. Studies with a higher percentage of REM couples also had worse individual outcomes. Trainee status was not consistently related to relational or individual outcomes. Implications for research and practice are provided.

A prospective cross-sectional study assessing teaching of interventional radiology across 20 Australian medical schools, endorsed by the Australian Medical Students Association.

BACKGROUND: Existing literature from around the world has shown that teaching of Interventional Radiology (IR) to medical students remains suboptimal. Despite calls for improvement at a "grass-roots" level, most IRs find that junior doctors have limited or no knowledge of IR, and thus reduced awareness of potential IR treatments for their patients or contemplating IR as a future career. The aim of this study was to survey current medical students to assess perception of whether a wider variety of medical schools are integrating IR into their curriculum, from universities all across Australia. This was a prospective cross-sectional study of members of the Australian Medical Students Association (AMSA) from across Australia. Students were given a 14-question survey of current university teaching and students' knowledge of the discipline of IR. The primary outcome was perception of current teaching and knowledge of IR. Secondary outcomes include awareness of technical, clinical, and other duties of IRs. RESULTS: Surveys were sent in a newsletter and posted on the AMSA Facebook page to their members. 82 responses were received via students from 20 out of 23 Australian medical schools. 61% of students described poor or no knowledge of IR. Teaching of IR was significantly worse than diagnostic radiology (p < 0.001), only 12% suggested that current IR teaching was adequate, and 99% suggested that IR teaching could be improved. Only 11% of students would consider a career in IR. CONCLUSIONS: Medical student perception of exposure to IR is poor compared to diagnostic radiology. Better awareness may lead to improved referral patterns for patients and more career interest in IR.

A narrative literature review of the impact of conscientious objection by health professionals on women's access to abortion worldwide 2013-2021.

Conscientious objection to provide abortion has been enshrined in laws and policies globally. Insufficient attention has been paid to the direct and indirect ways in which conscientious objection compromises women's access to a lawful abortion. Using a systematic search strategy, this narrative literature review synthesises the literature exploring conscientious objection's impact on women's access to abortion in a range of countries. This narrative literature review builds on an extensive literature review published by Chavkin et al. (2013. Conscientious objection and refusal to provide reproductive healthcare: A white paper examining prevalence, health consequences, and policy responses. International Journal of Gynecology & Obstetrics, 123, S41-S56. https://doi.org/10.1016/S0020-7292(13)60002-8). Searches were undertaken on the Medline (Ovid), Global Health, CINAHL, Scopus and Science Direct databases. Thirty six papers were included for thematic analysis. Conscientious objection to abortion was found to impact women's access to abortion at three main levels: the practitioner level, the healthcare system level and the sociocultural environment level. Conscientious objection was found to impact access directly through attempts by health professionals to restrict access, and indirectly by exacerbating pre-existing barriers to access. Further research is required to better quantify the extent to which this impacts women and whether interventions are effective in reducing the barriers that conscientious objection creates and exacerbates.

Human Milk Oligosaccharide Compositions Illustrate Global Variations in Early Nutrition.

BACKGROUND: Human milk oligosaccharides (HMOs) are an abundant class of compounds found in human milk and have been linked to the development of the infant, and specifically the brain, immune system, and gut microbiome. OBJECTIVES: Advanced analytical methods were used to obtain relative quantitation of many structures in approximately 2000 samples from over 1000 mothers in urban, semirural, and rural sites across geographically diverse countries. METHODS: LC-MS-based analytical methods were used to profile the compounds with broad structural coverage and quantitative information. The profiles revealed their structural heterogeneity and their potential biological roles. Comparisons of HMO compositions were made between mothers of different age groups, lactation periods, infant sexes, and residing geographical locations. RESULTS: A common behavior found among all sites was a decrease in HMO abundances during lactation until approximately postnatal month 6, where they remained relatively constant. The greatest variations in structural abundances were associated with the presence of α(1,2)-fucosylated species. Genomic analyses of the mothers were not performed; instead, milk was phenotyped according to the abundances of α(1,2)-fucosylated structures. Mothers from the South American sites tended to have higher proportions of phenotypic secretors [mothers with relatively high concentrations of α(1,2)-fucosylated structures] in their populations compared to the rest of the globe, with Bolivia at ∼100% secretors, Peru at ∼97%, Brazil at ∼90%, and Argentina at ∼85%. Conversely, the cohort sampled in Africa manifested the lowest proportion of secretors (South Africa ∼ 63%, the Gambia ∼ 64%, and Malawi ∼ 75%). Furthermore, we compared total abundances of HMOs in secretors compared with nonsecretors and found that nonsecretors have lower abundances of HMOs compared to secretors, regardless of geographical location. We also observed compositional differences of the 50+ most abundant HMOs between milk types and geographical locations. CONCLUSIONS: This study represents the largest structural HMO study to date and reveals the general behavior of HMOs during lactation among different populations.

Fucosylated Human Milk Oligosaccharide Foraging within the Species Bifidobacterium pseudocatenulatum Is Driven by Glycosyl Hydrolase Content and Specificity.

Human milk enriches members of the genus Bifidobacterium in the infant gut. One species, Bifidobacterium pseudocatenulatum, is found in the gastrointestinal tracts of adults and breastfed infants. In this study, B. pseudocatenulatum strains were isolated and characterized to identify genetic adaptations to the breastfed infant gut. During growth on pooled human milk oligosaccharides (HMOs), we observed two distinct groups of B. pseudocatenulatum, isolates that readily consumed HMOs and those that did not, a difference driven by variable catabolism of fucosylated HMOs. A conserved gene cluster for fucosylated HMO utilization was identified in several sequenced B. pseudocatenulatum strains. One isolate, B. pseudocatenulatum MP80, which uniquely possessed GH95 and GH29 α-fucosidases, consumed the majority of fucosylated HMOs tested. Furthermore, B. pseudocatenulatum SC585, which possesses only a single GH95 α-fucosidase, lacked the ability to consume the complete repertoire of linkages within the fucosylated HMO pool. Analysis of the purified GH29 and GH95 fucosidase activities directly on HMOs revealed complementing enzyme specificities with the GH95 enzyme preferring 1-2 fucosyl linkages and the GH29 enzyme favoring 1-3 and 1-4 linkages. The HMO-binding specificities of the family 1 solute-binding protein component linked to the fucosylated HMO gene cluster in both SC585 and MP80 are similar, suggesting differential transport of fucosylated HMO is not a driving factor in each strain's distinct HMO consumption pattern. Taken together, these data indicate the presence or absence of specific α-fucosidases directs the strain-specific fucosylated HMO utilization pattern among bifidobacteria and likely influences competitive behavior for HMO foraging in situ. IMPORTANCE Often isolated from the human gut, microbes from the bacterial family Bifidobacteriaceae commonly possess genes enabling carbohydrate utilization. Isolates from breastfed infants often grow on and possess genes for the catabolism of human milk oligosaccharides (HMOs), glycans found in human breast milk. However, catabolism of structurally diverse HMOs differs between bifidobacterial strains. This study identifies key gene differences between Bifidobacterium pseudocatenulatum isolates that may impact whether a microbe successfully colonizes an infant gut. In this case, the presence of complementary α-fucosidases may provide an advantage to microbes seeking residence in the infant gut. Such knowledge furthers our understanding of how diet drives bacterial colonization of the infant gut.

Associations of Human Milk Oligosaccharides and Bioactive Proteins with Infant Morbidity and Inflammation in Malawian Mother-Infant Dyads.

BACKGROUND: Human milk oligosaccharides (HMOs) and bioactive proteins likely benefit infant health, but information on these relations is sparse. OBJECTIVES: We aimed to examine associations of milk content of HMOs and bioactive proteins with incidence and longitudinal prevalence of infant morbidity (any illness, fever, diarrhea, acute respiratory infection, and loss of appetite) and markers of inflammation [C-reactive protein (CRP) and α-1-acid glycoprotein (AGP)]. These are secondary analyses of a randomized controlled trial. METHODS: Breast milk samples at 6 mo postpartum (n  = 659) were analyzed to quantify absolute abundance of HMOs, relative abundance of fucosylated HMOs, sialylated HMOs, and 51 individual HMOs, and concentrations of 6 bioactive proteins (lactalbumin, lactoferrin, lysozyme, antitrypsin, IgA, and osteopontin). We examined associations of these constituents with infant morbidity from 6 to 7 and 6 to 12 mo, and CRP and AGP at 6 and 18 mo, considering maternal secretor status [presence or absence of the functional enzyme encoded by the fucosyltransferase 2 gene (FUT2) ] and adjusting for covariates and multiple hypothesis testing. RESULTS: In secretors there were positive associations between total HMOs and longitudinal prevalence of fever (P = 0.032), between fucosylated HMOs and incidence of diarrhea (P = 0.026), and between lactoferrin and elevated CRP at 18 mo (P = 0.011). In nonsecretors, there were inverse associations between lactoferrin and incidence of fever (P  = 0.007), between osteopontin and longitudinal prevalence of lost appetite (P  = 0.038), and between fucosylated HMOs and incidence of diarrhea (P = 0.025), lost appetite (P = 0.019), and concentrations of AGP and CRP at 6 mo (P = 0.001 and 0.010); and positive associations between total HMOs and incidence of lost appetite (P = 0.024) and elevated CRP at 18 mo (P  = 0.026), between lactalbumin and incidence of diarrhea (P = 0.006), and between lactoferrin and elevated CRP at 18 mo (P = 0.015). CONCLUSIONS: Certain HMOs and bioactive proteins were associated with infant morbidity and inflammation, particularly in nonsecretors. Further research is needed to elucidate the causality of these relations.This trial was registered at clinicaltrials.gov as NCT01239693.

She Screened Positive for Depression at the First Prenatal Visit, What Really Happens Next?

The aim of this mixed-methods study was to evaluate how providers in a busy urban practice with universal depression screening and co-located behavioral health services responded to positive screens and to explore patient expectations and attitudes towards positive screens. Semi-structured interviews of 20 pregnant women were conducted within 10 days of a positive depression screen or endorsement of suicidal ideation on the Edinburgh Perinatal Depression Scale and health record documentation was reviewed. Qualitative data were entered into a meta-matrix and cross-case analysis was used to reduce the data and determine prominent patterns and themes. Most participants reported discussing their mood with their provider, appreciated the discussion and were satisfied with the plan. Most had documentation of a discussion by their provider. Only 4 of 9 participants who endorsed thoughts of self-harm had documentation of a discussion regarding their response. While nearly all women were recommended for psychotherapy, most did not receive it. Participants expected follow-up but few had discussion of mood documented at the second prenatal visit, independent of seeing the same provider. Co-located behavioral health did not guarantee that services were utilized. There is a need to incorporate tested integrated care approaches to improve assessments and linkage to effective depression treatment.

Associations of human milk oligosaccharides and bioactive proteins with infant growth and development among Malawian mother-infant dyads.

BACKGROUND: Human milk oligosaccharides (HMOs) and bioactive breast milk proteins have many beneficial properties. Information is sparse regarding associations between these milk constituents and infant growth and development in lower-income countries. OBJECTIVES: We aimed to examine associations of milk content of HMOs and bioactive proteins at 6 mo postpartum with infant growth and motor and cognitive development. These are secondary analyses of a randomized controlled trial in rural Malawi. METHODS: Breast milk samples were analyzed at 6 mo (n = 659) for general categories of HMOs (total HMOs, fucosylated HMOs, and sialylated HMOs), 51 individual HMOs, and 6 bioactive proteins (lactalbumin, lactoferrin, lysozyme, antitrypsin, IgA, and osteopontin). We examined associations of the relative abundances of HMOs and concentrations of bioactive proteins with infant growth from 6 to 12 mo [change in length-for-age (ΔLAZ), weight-for-age, weight-for-length, and head circumference z-scores] as well as ability to stand or walk alone at 12 mo, and motor and language skills, socioemotional development, executive function, and working memory at 18 mo. Analyses were adjusted for covariates and multiple hypothesis testing. RESULTS: Among all participants, there were inverse associations of IgA and lactoferrin concentrations with motor skills (P = 0.018 and P = 0.044), and a positive association of lactalbumin concentration with motor skills (P = 0.038). Among secretors only [fucosyltransferase 2 gene (FUT2) positive], there were positive associations of absolute abundance of HMOs with ΔLAZ (P = 0.035), and relative abundance of fucosylated and sialylated HMOs with language at 18 mo (P < 0.001 and P = 0.033, respectively), and inverse associations of osteopontin with standing and walking at 12 mo (P = 0.007 and 0.002, respectively). Relative abundances of several individual HMOs were associated with growth and development, mostly among secretors. CONCLUSIONS: Certain bioactive breast milk proteins and HMOs are associated with infant growth and motor and cognitive development. Further studies are needed to determine if a causal relation exists.This trial was registered at clinicaltrials.gov as NCT01239693.

BCATc modulates crosstalk between the PI3K/Akt and the Ras/ERK pathway regulating proliferation in triple negative breast cancer.

The cytosolic branched chain aminotransferase (BCATc) protein has been found to be highly expressed in breast cancer subtypes, including triple negative breast cancer (TNBC), compared with normal breast tissue. The catabolism of branched-chain amino acids (BCAAs) by BCATc leads to the production of glutamate and key metabolites which further drive the TCA cycle, important for cellular metabolism and growth. Upregulation of BCATc has been associated with increased cell proliferation, cell cycle progression and metastasis in several malignancies including breast, gliomas, ovarian and colorectal cancer but the underlying mechanisms are unclear. As nutrient levels of BCAAs, substrates of BCATc, regulate the PI3K/Akt pathway we hypothesized that increased expression of BCATc would contribute to tumour cell growth through upregulation of the insulin/IGF-1 signalling pathway. This pathway is known to potentiate proliferation and metastasis of malignant cells through the activation of PI3K/Akt and the RAS/ERK signalling cascades. Here we show that knockdown of BCATc significantly reduced insulin and IGF-1-mediated proliferation, migration and invasion of TNBC cells. An analysis of this pathway showed that when overexpressed BCATc regulates proliferation through the PI3K/Akt axis, whilst simultaneously attenuating the Ras/Erk pathway indicating that BCATc acts as a conduit between these two pathways. This ultimately led to an increase in FOXO3a, a key regulator of cell proliferation and Nrf2, which mediates redox homeostasis. Together this data indicates that BCATc regulates TNBC cell proliferation, migration and invasion through the IGF-1/insulin PI3K/Akt pathway, culminating in the upregulation of FOXO3a and Nrf2, pointing to a novel therapeutic target for breast cancer treatment.

Study protocol for a multisite randomised controlled trial of a rehabilitation intervention to reduce participation restrictions among female breast cancer survivors.

INTRODUCTION: Many breast cancer survivors report an inability to fully participate in activities of daily living after completing cancer treatment. Reduced activity participation is linked to negative consequences for individuals (eg, depression, reduced quality of life) and society (reduced workforce participation). There is currently a lack of evidence-based interventions that directly foster cancer survivors' optimal participation in life roles and activities. Pilot study data suggest rehabilitation interventions based on behavioural activation (BA) and problem-solving treatment (PST) can facilitate post-treatment role resumption among breast cancer survivors. METHODS AND ANALYSIS: This protocol describes a multisite randomised controlled trial comparing a 4-month long, nine-session BA and PST-informed rehabilitation intervention (BA/PS) against a time-matched, attention control condition. The overall objective is to assess the efficacy of BA/PS for enhancing breast cancer survivors' activity participation and quality of life over time. A total of 300 breast cancer survivors reporting participation restrictions after completing curative treatment for stage 1-3 breast cancer within the past year will be recruited across two sites (Dartmouth-Hitchcock Medical Center and University of Alabama at Birmingham). Assessments are collected on enrolment (T1) and 8 (T2), 20 (T3) and 44 (T4) weeks later. ETHICS AND DISSEMINATION: Study procedures are approved by the Committee for the Protection of Human Subjects at Dartmouth College, acting as the single Institutional Review Board of record for both study sites (STUDY 00031380). Results of the study will be presented at national meetings and submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03915548; Pre-results.

Persistence of Supplemented Bifidobacterium longum subsp. infantis EVC001 in Breastfed Infants.

Attempts to alter intestinal dysbiosis via administration of probiotics have consistently shown that colonization with the administered microbes is transient. This study sought to determine whether provision of an initial course of Bifidobacterium longum subsp. infantis (B. infantis) would lead to persistent colonization of the probiotic organism in breastfed infants. Mothers intending to breastfeed were recruited and provided with lactation support. One group of mothers fed B. infantis EVC001 to their infants from day 7 to day 28 of life (n = 34), and the second group did not administer any probiotic (n = 32). Fecal samples were collected during the first 60 postnatal days in both groups. Fecal samples were assessed by 16S rRNA gene sequencing, quantitative PCR, mass spectrometry, and endotoxin measurement. B. infantis-fed infants had significantly higher populations of fecal Bifidobacteriaceae, in particular B. infantis, while EVC001 was fed, and this difference persisted more than 30 days after EVC001 supplementation ceased. Fecal milk oligosaccharides were significantly lower in B. infantis EVC001-fed infants, demonstrating higher consumption of human milk oligosaccharides by B. infantis EVC001. Concentrations of acetate and lactate were significantly higher and fecal pH was significantly lower in infants fed EVC001, demonstrating alterations in intestinal fermentation. Infants colonized by Bifidobacteriaceae at high levels had 4-fold-lower fecal endotoxin levels, consistent with observed lower levels of Gram-negative Proteobacteria and Bacteroidetes. IMPORTANCE The gut microbiome in early life plays an important role for long-term health and is shaped in large part by diet. Probiotics may contribute to improvements in health, but they have not been shown to alter the community composition of the gut microbiome. Here, we found that breastfed infants could be stably colonized at high levels by provision of B. infantis EVC001, with significant changes to the overall microbiome composition persisting more than a month later, whether the infants were born vaginally or by caesarean section. This observation is consistent with previous studies demonstrating the capacity of this subspecies to utilize human milk glycans as a nutrient and underscores the importance of pairing a probiotic organism with a specific substrate. Colonization by B. infantis EVC001 resulted in significant changes to fecal microbiome composition and was associated with improvements in fecal biochemistry. The combination of human milk and an infant-associated Bifidobacterium sp. shows, for the first time, that durable changes to the human gut microbiome are possible and are associated with improved gut function.

Digestion of Human Milk Oligosaccharides by Bifidobacterium breve in the Premature Infant.

OBJECTIVE: The aim of this study was to measure consumption and absorption of human milk oligosaccharides (HMOs) in a cohort of premature infants treated with probiotic Bifidobacterium breve. METHODS: Twenty-nine premature infants (median gestational age 28 weeks, range 23-32 weeks) cared for in the neonatal intensive care unit of the King Edward and Princess Margaret Hospital in Perth, Australia, were treated with B breve at a dose of 1.66 billion organisms per day. Samples of feces, urine, and milk were obtained at initiation of the probiotic and again 3 weeks later. 16S ribosomal RNA from the feces was analyzed by next-generation sequencing. Quantitation of HMO content of the milk, urine, and feces was performed using nano-high-performance liquid chromatography-chip/time-of-flight mass spectrometry. RESULTS: There was heterogeneity in colonization with bifidobacteria. "Responders" received milk with higher percentages of fucosylated HMOs and had higher percentages of bifidobacteria and lower percentages of Enterobacteriaceae in their feces than "nonresponders." Several individual HMOs in the milk were associated with changes in fecal bifidobacteria over time. Changes over time in milk, fecal, and urine HMOs suggested heterogeneity among HMO structures in consumption by microbes in the gut lumen and absorption from the intestine. CONCLUSIONS: Colonization of the premature infant intestinal tract with probiotic B breve is influenced by prebiotic HMOs. B breve is a selective consumer of HMOs in the premature infant.

Lipid-Based Nutrient Supplements During Pregnancy and Lactation Did Not Affect Human Milk Oligosaccharides and Bioactive Proteins in a Randomized Trial.

BACKGROUND: Human milk oligosaccharides (HMOs) and bioactive proteins are beneficial to infant health. Recent evidence suggests that maternal nutrition may affect the amount of HMOs and proteins in breast milk; however, the effect of nutrient supplementation on HMOs and bioactive proteins has not yet been well studied. OBJECTIVE: We aimed to determine whether lipid-based nutrient supplements (LNSs) affect milk bioactive protein and HMO concentrations at 6 mo postpartum in women in rural Malawi. These are secondary outcomes of a previously published randomized controlled trial. METHODS: Women were randomly assigned to consume either an iron and folic acid capsule (IFA) daily from ≤20 wk gestation until delivery, followed by placebo daily from delivery to 6 mo postpartum, or a multiple micronutrient (MMN) capsule or LNS daily from ≤20 wk gestation to 6 mo postpartum. Breast milk concentrations of total HMOs, sialylated HMOs, fucosylated HMOs, lactoferrin, lactalbumin, lysozymes, antitrypsin, immunoglobulin A, and osteopontin were analyzed at 6 mo postpartum (n = 647). Between-group differences in concentrations and in proportions of women classified as having low concentrations were tested. RESULTS: HMO and bioactive protein concentrations did not differ between groups (P > 0.10 for all comparisons). At 6 mo postpartum, the proportions of women with low HMOs or bioactive proteins were not different between groups except for osteopontin. A lower proportion of women in the IFA group had low osteopontin compared with the LNS group after adjusting for covariates (OR: 0.5; 95% CI: 0.3, 0.9; P = 0.016). CONCLUSION: The study findings do not support the hypothesis that supplementation with an LNS or MMN capsule during pregnancy and postpartum would increase HMO or bioactive milk proteins at 6 mo postpartum among Malawian women. This trial was registered at clinicaltrials.gov as NCT01239693.

Growth and Morbidity of Gambian Infants are Influenced by Maternal Milk Oligosaccharides and Infant Gut Microbiota.

Human milk oligosaccharides (HMOs) play an important role in the health of an infant as substrate for beneficial gut bacteria. Little is known about the effects of HMO composition and its changes on the morbidity and growth outcomes of infants living in areas with high infection rates. Mother's HMO composition and infant gut microbiota from 33 Gambian mother/infant pairs at 4, 16, and 20 weeks postpartum were analyzed for relationships between HMOs, microbiota, and infant morbidity and growth. The data indicate that lacto-N-fucopentaose I was associated with decreased infant morbidity, and 3'-sialyllactose was found to be a good indicator of infant weight-for-age. Because HMOs, gut microbiota, and infant health are interrelated, the relationship between infant health and their microbiome were analyzed. While bifidobacteria were the dominant genus in the infant gut overall, Dialister and Prevotella were negatively correlated with morbidity, and Bacteroides was increased in infants with abnormal calprotectin. Mothers nursing in the wet season (July to October) produced significantly less oligosaccharides compared to those nursing in the dry season (November to June). These results suggest that specific types and structures of HMOs are sensitive to environmental conditions, protective of morbidity, predictive of growth, and correlated with specific microbiota.

Absolute Quantitation of Human Milk Oligosaccharides Reveals Phenotypic Variations during Lactation.

BACKGROUND: The quantitation of human milk oligosaccharides (HMOs) is challenging because of the structural complexity and lack of standards. OBJECTIVE: The objective of our study was to rapidly measure the absolute concentrations of HMOs in milk using LC-mass spectrometry (MS) and to determine the phenotypic secretor status of the mothers. METHODS: This quantitative method for measuring HMO concentration was developed by using ultraperformance LC multiple reaction monitoring MS. It was validated and applied to milk samples from Malawi (88 individuals; 88 samples from postnatal month 6) and the United States (Davis, California; 45 individuals, mean age: 32 y; 103 samples collected on postnatal days 10, 26, 71, or 120, repeated measures included). The concentrations of α(1,2)-fucosylated HMOs were used to determine the mothers' phenotypic secretor status with high sensitivity and specificity. We used Friedman's test and Wilcoxon's signed rank test to evaluate the change in HMO concentration during the course of lactation, and Student's t test was used to compare secretors and nonsecretors. RESULTS: A decrease (P < 0.05) in HMO concentration was observed during the course of lactation for the US mothers, corresponding to 19.3 ± 2.9 g/L for milk collected on postnatal day 10, decreasing to 8.53 ± 1.18 g/L on day 120 (repeated measures; n = 14). On postnatal day 180, the total concentration of HMOs in Malawi milk samples from secretors (6.46 ± 1.74 mg/mL) was higher (P < 0.05) than that in samples from nonsecretors (5.25 ± 2.55 mg/mL ). The same trend was observed for fucosylated species; the concentration was higher in Malawi milk samples from secretors (4.91 ± 1.22 mg/mL) than from nonsecretors (3.42 ± 2.27 mg/mL) (P < 0.05). CONCLUSIONS: HMOs significantly decrease during the course of lactation. Secretor milk contains higher concentrations of total and fucosylated HMOs than does nonsecretor milk. These HMO concentrations can be correlated to the health of breastfed infants in order to investigate the protective effects of milk components. The trials were registered at clinicaltrials.gov as NCT01817127 and NCT00524446.

A novel gene cluster allows preferential utilization of fucosylated milk oligosaccharides in Bifidobacterium longum subsp. longum SC596.

The infant intestinal microbiota is often colonized by two subspecies of Bifidobacterium longum: subsp. infantis (B. infantis) and subsp. longum (B. longum). Competitive growth of B. infantis in the neonate intestine has been linked to the utilization of human milk oligosaccharides (HMO). However, little is known how B. longum consumes HMO. In this study, infant-borne B. longum strains exhibited varying HMO growth phenotypes. While all strains efficiently utilized lacto-N-tetraose, certain strains additionally metabolized fucosylated HMO. B. longum SC596 grew vigorously on HMO, and glycoprofiling revealed a preference for consumption of fucosylated HMO. Transcriptomes of SC596 during early-stage growth on HMO were more similar to growth on fucosyllactose, transiting later to a pattern similar to growth on neutral HMO. B. longum SC596 contains a novel gene cluster devoted to the utilization of fucosylated HMO, including genes for import of fucosylated molecules, fucose metabolism and two α-fucosidases. This cluster showed a modular induction during early growth on HMO and fucosyllactose. This work clarifies the genomic and physiological variation of infant-borne B. longum to HMO consumption, which resembles B. infantis. The capability to preferentially consume fucosylated HMO suggests a competitive advantage for these unique B. longum strains in the breast-fed infant gut.