Classifying early infant feeding status from clinical notes using natural language processing and machine learning.

The objective of this study is to develop and evaluate natural language processing (NLP) and machine learning models to predict infant feeding status from clinical notes in the Epic electronic health records system. The primary outcome was the classification of infant feeding status from clinical notes using Medical Subject Headings (MeSH) terms. Annotation of notes was completed using TeamTat to uniquely classify clinical notes according to infant feeding status. We trained 6 machine learning models to classify infant feeding status: logistic regression, random forest, XGBoost gradient descent, k-nearest neighbors, and support-vector classifier. Model comparison was evaluated based on overall accuracy, precision, recall, and F1 score. Our modeling corpus included an even number of clinical notes that was a balanced sample across each class. We manually reviewed 999 notes that represented 746 mother-infant dyads with a mean gestational age of 38.9 weeks and a mean maternal age of 26.6 years. The most frequent feeding status classification present for this study was exclusive breastfeeding [n = 183 (18.3%)], followed by exclusive formula bottle feeding [n = 146 (14.6%)], and exclusive feeding of expressed mother's milk [n = 102 (10.2%)], with mixed feeding being the least frequent [n = 23 (2.3%)]. Our final analysis evaluated the classification of clinical notes as breast, formula/bottle, and missing. The machine learning models were trained on these three classes after performing balancing and down sampling. The XGBoost model outperformed all others by achieving an accuracy of 90.1%, a macro-averaged precision of 90.3%, a macro-averaged recall of 90.1%, and a macro-averaged F1 score of 90.1%. Our results demonstrate that natural language processing can be applied to clinical notes stored in the electronic health records to classify infant feeding status. Early identification of breastfeeding status using NLP on unstructured electronic health records data can be used to inform precision public health interventions focused on improving lactation support for postpartum patients.

Human milk derived fortifiers are associated with glucose, phosphorus, and calcium derangements.

OBJECTIVE: In 2017, our Level IV NICU switched from providing bovine-derived (BOV-fort) to human milk-derived fortifiers (HM-fort) and donor human milk (DHM) to premature infants born ≤ 30 weeks or ≤1250 g. Following this change, providers anecdotally observed increased hypoglycemia, hypercalcemia, and hyperphosphatemia. This study investigated potential laboratory differences between infants fed Bovine vs. Human milk derived fortifier. METHODS: Lab measurements from 402 infants (232 BOV-fort, 170 HM-fort) born between 2015 and 2019 were compared between groups. RESULTS: The proportion of infants ever having a blood glucose ≤ 45 mg/dL (p < 0.0001) was higher in the HM-fort group. The proportion of infants ever experiencing a phosphorus > 8.0 mg/dL were higher in the HM-fort group (p < 0.0001). The proportion of infants ever experiencing calcium > 11.4 mg/dL was higher in the HM-Fort group (p = 0.019). CONCLUSIONS: Provision of HM-Fort and DHM to extremely premature infants is associated with metabolic derangements.

Association between maternal stress and premature milk cortisol, milk IgA, and infant health: a cohort study.

Background: Maternal stress is pervasive in the neonatal intensive care unit (NICU). Maternal stress is associated with changes in human milk (HM) immunomodulatory agents, which may impact neonatal health. We sought to determine the association between maternal stress, HM immunoglobulin A (IgA) and cortisol, and to assess how these milk components correlate with infant immune and neurodevelopmental outcomes. We then compared how these associations persist over time. Methods: The study design involved a cohort study of exclusively breastfeeding mothers and their singleton moderately preterm (28-34 weeks) infants admitted to the NICU. We collected maternal serum, maternal saliva, and first-morning whole milk samples, and administered maternal stress questionnaires at 1 and 5 weeks postpartum. We analyzed the samples for HM IgA (using a customized immunoassay in skim milk) and for HM and salivary cortisol (using a chemiluminescent immunoassay). Infant illness was assessed using the Score for Neonatal Acute Physiology II (SNAP II) and SNAP II with Perinatal Extension (SNAPPE II), and infant neurodevelopment were assessed using the Test of Infant Motor Performance. We analyzed changes in HM IgA and cortisol over time using paired t-tests. Furthermore, we performed correlation and regression analyses after adjusting for gestational age (GA), corrected GA, and infant days of life. Results: In our study, we enrolled 26 dyads, with a mean maternal age of 28.1 years, consisting of 69% white, 19% Black, and 8% Hispanic. Cortisol: Salivary and HM cortisol were closely associated in week 1 but not in week 5. Though mean salivary cortisol remained stable over time [2.41 ng/mL (SD 2.43) to 2.32 (SD 1.77), p = 0.17], mean HM cortisol increased [1.96 ng/mL (SD 1.93) to 5.93 ng/mL (SD 3.83), p < 0.001]. Stress measures were inversely associated with HM cortisol at week 1 but not at week 5. IgA: HM IgA decreased over time (mean = -0.14 mg/mL, SD 0.53, p < 0.0001). High maternal stress, as measured by the Parental Stressor Scale: neonatal intensive care unit (PSS:NICU), was positively associated with HM IgA at week 5 (r = 0.79, P ≤ 0.001). Higher IgA was associated with a lower (better) SNAP II score at week 1 (r = -0.74, p = 0.05). No associations were found between maternal stress, salivary cortisol, HM cortisol, or HM IgA and neurodevelopment at discharge (as assessed using the TIMP score). Furthermore, these relationships did not differ by infant sex. Conclusion: Maternal stress showed associations with HM cortisol and HM IgA. In turn, HM IgA was associated with lower measures of infant illness.

Development of a head and neck lymphoedema specific quality of life tool: The Comprehensive Assessment of Lymphoedema Impact in the Head and Neck.

PURPOSE: To develop a head and neck lymphoedema (HNL) specific quality of life (QoL) instrument to assess physical, functional, and social/emotional impacts of HNL. METHODS: Instrument candidate items were reviewed by patients with HNL and clinicians and rated for importance, clarity, and invasiveness. The Content Validity Ratio was applied for item reduction. Three-step cognitive interviews were conducted with HNL patients to validate the items, survey format, and instructions. RESULTS: Initially, 130 candidate questions were developed. Following item reduction, 52 items progressed to three-step cognitive interviews. Following cognitive interviews, the Comprehensive Assessment of Lymphoedema Impact in Head and Neck (CALI-HaN) included 33 items; 1 global, 10 physical, 7 functional, and 15 emotional. CONCLUSIONS: Physical, functional, and socioemotional effects need to be considered when measuring QoL in patients with HNL. This study describes initial development of the CALI-HaN, an instrument that shows promise for clinical and research applications following future validation.

Awareness and experiences on core outcome set development and use amongst stakeholders from low- and middle- income countries: An online survey.

Harmonization of outcomes to be measured in clinical trials can reduce research waste and enhance research translation. One of the ways to standardize measurement is through development and use of core outcome sets (COS). There is limited involvement of low- and middle-income country (LMIC) stakeholders in COS development and use. This study explores the level of awareness and experiences of LMIC stakeholders in the development and use of COS. We conducted an online survey of LMIC stakeholders. Three existing COS (pre-eclampsia, COVID-19, palliative care) were presented as case scenarios, and respondents asked to state (with reason(s)) if they would or would not use the COS if they were working in that area. Quantitative data were analyzed descriptively while qualitative data were analyzed thematically. Of 81 respondents, 26 had COS experience, 9 of whom had been involved in COS development. Personal research interests and prevalence of disease are key drivers for initiation/participation in a given COS project. Most respondents would use the COS for pre-eclampsia (18/26) and COVID-19 (19/26) since the development process included key stakeholders. More than half of the respondents were not sure or would not use the palliative care COS as they felt stakeholder engagement was limited and it was developed for a different resource setting. Respondents reported that use of COS can be limited by (i) feasibility of measuring the outcomes in the COS, (ii) knowledge on the usefulness and availability of COS and (iii) lack of wide stakeholder engagement in the COS development process including having patients and carers in the development process. To ensure the development and use of COS in LMICs, collaborations are essential in awareness raising on COS utility, training, and COS development. The COS also needs to be made accessible in locally understandable languages and feasible to measure in LMICs.

To adopt or adapt an existing neonatal core outcome set in Kenya: a study protocol.

BACKGROUND: Development and use of core outcome set(s) (COS) in research can reduce research wastage by ensuring that a minimum set of outcomes are always reported on. Neonatal morbidity and mortality are a big burden in low- and middle-income countries (LMICs). Research is continuously being undertaken to reduce this burden. Currently, there is no COS for neonatal research in LMICs but there exists one for neonatal research in high-income countries (HICs). OBJECTIVES: To determine outcomes that are useful for neonatal care in Kenya to inform whether an existing COS should be adopted or adapted. To assess the feasibility of a routine data collection system to collect data of the agreed-on COS. METHODS: A review of existing literature on neonatal research in LMICs followed by a qualitative study of key stakeholders in neonatal care. To explore whether to adapt or adopt, in two hospitals, two focus group discussions with 6-8 parents/caregivers will be undertaken (one each in two hospitals). Key informant interviews will also be conducted with 6 health care providers in each of the hospitals. At the policy-making level, we will conduct 10 key informant interviews. Qualitative data will be analyzed thematically. A consensus meeting will be undertaken with key stakeholders, who will be presented with an overview of the COS developed for HICs, key findings from the literature, and the qualitative study to determine context-appropriate COS. The agreed-on outcomes will be counterchecked against the case records in the two hospitals. The feasibility of collecting the outcomes on a routine electronic research database, the Clinical Information Network that collects standardized data at admission and discharge, will be explored. The congruence (or not) of the outcomes will be documented and be used to enrich the discussion and provide a snapshot of the feasibility of the health information system to collect routine data on the COS. CONCLUSIONS: A COS for use in neonatal care in Kenya will help enhance outcome measurements and reporting not just in research but also in routine practice. This will enhance the comparability of interventions in trials and routine settings leading to reduced research wastage and likely improved quality of care. Additionally, the methodology used for this work can be adopted in other settings as a means of adopting or adapting an existing COS.

The effectiveness and acceptability of multimedia information when recruiting children and young people to trials: the TRECA meta-analysis of SWATs.

Background: The information provided to potential trial participants plays a crucial role in their decision-making. Printed participant information sheets for trials have received recurrent criticism as being too long and technical, unappealing and hard to navigate. An alternative is to provide information through multimedia (text, animations, video, audio, diagrams and photos). However, there is limited evidence on the effects of multimedia participant information on research recruitment rates, particularly in children and young people. Objectives: The study objectives were as follows: 1. to develop template multimedia information resources through participatory design, for use when recruiting children and young people to trials 2. to evaluate the multimedia information resources in a series of Studies Within A Trial, to test their effects on recruitment and retention rates, and participant decision-making, by comparing the provision of multimedia information resources instead of printed participant information sheets, and comparing the provision of multimedia information resources in addition to printed participant information sheets. Design: Two-phase study: 1. multimedia information resources development including qualitative study; user testing study; readability metrics; enhanced patient and public involvement 2. multimedia information resources' evaluation comprising Studies Within A Trial undertaken within host trials recruiting children and young people. Setting: United Kingdom trials involving patients aged under 18. Participants: Development phase: n = 120 (children and young people, parents, clinicians, trial personnel). Evaluation phase: n = 1906 (children and young people being asked to take part in trials). Interventions: Multimedia information resources (comprising text, audio, 'talking heads' video, trial-specific and trial-generic animations). Printed participant information sheets. Main outcome measures: Primary outcome: trial recruitment rate comparing multimedia information resource-only with printed participant information sheet-only provision. Secondary outcomes: trial recruitment rate comparing combined multimedia information resource and printed participant information sheet with printed participant information sheet-only provision; trial retention rate; quality of participant decision-making. Results for each trial were calculated and combined in a two-stage random-effects meta-analysis. Results: Phase 1 generated two multimedia information resource templates: (1) for children aged 6-11 years; (2) for children aged 12-18 years and parents. In the Phase 2 Studies Within A Trial the multimedia information resources improved trial recruitment, when compared to printed information alone [odds ratio (OR) = 1.54; 95% confidence interval (CI) 1.05 to 2.28; p = 0.03; I2 = 0%]. When printed participant information sheet-only provision was compared to combined multimedia information resource and printed participant information sheet provision, there was no effect on trial recruitment (OR = 0.89; 95% CI 0.53 to 1.50; I2 = 0%). There were no differences between multimedia information resource and printed participant information sheet on trial retention or participant decision-making quality. In a study within a hypothetical trial setting, multimedia information resource-only provision produced higher ratings of 'information was easy to understand' (Z = 3.03; p = 0.003) and 'I had confidence in decision-making' (Z = 2.00; p = 0.044) than printed participant information sheet-only provision. Limitations: It was not possible to include data from three Studies Within A Trial in the meta-analysis due to limited sample size, and questionnaire return rates were low, which reduced the strength of the findings. Conclusions: Use of multimedia information increased the rate of recruitment to trials involving children and young people compared to standard patient information sheets. Future work: There should be further evaluation of the effects of multimedia information on recruitment to trials involving children and young people. It would be valuable to assess any impacts of multimedia information resources on communication between trial recruiters, children and young people, and parents. Study registration: This trial is registered as TRECA ISRCTN 73136092 and Northern Ireland Hub for Trials Methodology Research SWAT Repository (SWAT 97). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 14/21/21) and is published in full in Health and Social Care Delivery Research; Vol. 11, No. 24. See the NIHR Funding and Awards website for further award information.

Clinical trials are important to National Health Service care, but it can be difficult to recruit enough people. We do not know enough about how to improve recruitment, especially when trying to recruit children and young people. People are normally told about a trial through printed information, which is often long and complex. Multimedia information (text, audio, cartoons and video) might be a better way of telling people. It is important to test whether multimedia interventions can help. One way of doing this is to run a 'Study Within A Trial' where people receive information in different ways. We created two multimedia interventions, one for parents and young people being asked for consent, and a simpler one for younger children. Some content applied to all trials, and some about the specific trial people were being asked to consider. We designed these by working closely with children and young people, parents and healthcare staff. We tested the multimedia information in six trials (although only three gave us enough data). Children, young people and their parents saw either standard printed information or our multimedia information. We then collected data on their decision-making, trial recruitment and whether people stayed in the trial. Children and young people who saw multimedia information were more likely to be recruited than those who received standard printed information. Once recruited to a trial, people given multimedia or printed information were similarly likely to remain in the trial. People's views on multimedia and printed information were also similar, but this finding could have been affected by small numbers of people returning questionnaires. Our study provides evidence that multimedia information can be used in trials with children and young people and that it increases the number of people who agree to take part, but further work is needed.

Bracing Adolescent Idiopathic Scoliosis (BASIS) study - night-time versus full-time bracing in adolescent idiopathic scoliosis: study protocol for a multicentre, randomized controlled trial.

Aims: Scoliosis is a lateral curvature of the spine with associated rotation, often causing distress due to appearance. For some curves, there is good evidence to support the use of a spinal brace, worn for 20 to 24 hours a day to minimize the curve, making it as straight as possible during growth, preventing progression. Compliance can be poor due to appearance and comfort. A night-time brace, worn for eight to 12 hours, can achieve higher levels of curve correction while patients are supine, and could be preferable for patients, but evidence of efficacy is limited. This is the protocol for a randomized controlled trial of 'full-time bracing' versus 'night-time bracing' in adolescent idiopathic scoliosis (AIS). Methods: UK paediatric spine clinics will recruit 780 participants aged ten to 15 years-old with AIS, Risser stage 0, 1, or 2, and curve size (Cobb angle) 20° to 40° with apex at or below T7. Patients are randomly allocated 1:1, to either full-time or night-time bracing. A qualitative sub-study will explore communication and experiences of families in terms of bracing and research. Patient and Public Involvement & Engagement informed study design and will assist with aspects of trial delivery and dissemination. Discussion: The primary outcome is 'treatment failure' (Cobb angle progression to 50° or more before skeletal maturity); skeletal maturity is at Risser stage 4 in females and 5 in males, or 'treatment success' (Cobb angle less than 50° at skeletal maturity). The comparison is on a non-inferiority basis (non-inferiority margin 11%). Participants are followed up every six months while in brace, and at one and two years after skeletal maturity. Secondary outcomes include the Scoliosis Research Society 22 questionnaire and measures of quality of life, psychological effects of bracing, adherence, anxiety and depression, sleep, satisfaction, and educational attainment. All data will be collected through the British Spine Registry.

Head and neck lymphedema and quality of life: the patient perspective.

PURPOSE: Head and neck lymphedema (HNL) is common after head and neck cancer (HNC). This study aimed to explore quality of life (QoL) in patients with HNL to guide the development of a patient-reported QoL measure. METHODS: We conducted semi-structured interviews with 22 HNC survivors with HNL. Interviews explored participants' experiences of living with HNL. Analysis of interview transcripts drew on qualitative content analysis to ensure themes were grounded in patient experience. RESULTS: Two main themes were established: "I want to live my life" and "It was like things were short-circuited." These themes encompassed the substantial disruption patients attributed to the HNL and their desire to normalize life. CONCLUSIONS: Understanding the impact of HNL on individual patients may be critical to optimizing treatment strategies to improve the physical burden of HNL and QoL. This study provides the framework for developing a patient-reported HNL QoL measure. IMPLICATIONS FOR CANCER SURVIVORS: The development of an HNL-specific QoL measure, grounded in the patient perspective, may provide cancer care teams with a tool to better understand HNL's impact on each patient to tailor patient-centered care and optimize QoL outcomes.

Untargeted Metabolomic Analysis of Lactation-Stage-Matched Human and Bovine Milk Samples at 2 Weeks Postnatal.

Epidemiological data demonstrate that bovine whole milk is often substituted for human milk during the first 12 months of life and may be associated with adverse infant outcomes. The objective of this study is to interrogate the human and bovine milk metabolome at 2 weeks of life to identify unique metabolites that may impact infant health outcomes. Human milk (n = 10) was collected at 2 weeks postpartum from normal-weight mothers (pre-pregnant BMI < 25 kg/m2) that vaginally delivered term infants and were exclusively breastfeeding their infant for at least 2 months. Similarly, bovine milk (n = 10) was collected 2 weeks postpartum from normal-weight primiparous Holstein dairy cows. Untargeted data were acquired on all milk samples using high-resolution liquid chromatography-high-resolution tandem mass spectrometry (HR LC-MS/MS). MS data pre-processing from feature calling to metabolite annotation was performed using MS-DIAL and MS-FLO. Our results revealed that more than 80% of the milk metabolome is shared between human and bovine milk samples during early lactation. Unbiased analysis of identified metabolites revealed that nearly 80% of milk metabolites may contribute to microbial metabolism and microbe-host interactions. Collectively, these results highlight untargeted metabolomics as a potential strategy to identify unique and shared metabolites in bovine and human milk that may relate to and impact infant health outcomes.

ACTivity as medicine In Oncology for Head and Neck (ACTIOHN): Protocol for a feasibility study investigating a patient-centred approach to exercise for people with head and neck cancer.

BACKGROUND AND AIM: Attempts at personalisation of exercise programmes in head and neck cancer (HaNC) have been limited. The main aim of the present study is to investigate the feasibility and acceptability of introducing a remotely delivered, fully personalised, collaborative, and flexible approach to prescribing and delivering exercise programmes into the HaNC usual care pathway. METHODS: This is a single arm, feasibility study. Seventy patients diagnosed with HaNC will be recruited from two regional HaNC centres in the United Kingdom. Patients will undertake an 8-week exercise programme designed and delivered by cancer exercise specialists. The exercise programme will start any time between the time of diagnosis and up to 8 weeks after completing treatment, depending on patient preference. The content of the exercise programme will be primarily based on patient needs, preferences, and goals, but guided by current physical activity guidelines for people with cancer. The primary outcome measure is retention to the study. Secondary quantitative outcomes are uptake to the exercise programme, different measures of exercise adherence, pre- and post-intervention assessments of fatigue (Multidimensional Fatigue Symptom Inventory-Short Form), quality of life (SF-36), physical activity levels (International Physical Activity Questionnaire-Short Form), and various components of physical fitness. The outcomes of the nested qualitative study are acceptability and feasibility of the intervention evaluated via interviews with patients, health care professionals, and the cancer exercise specialists. Intervention and participant fidelity will be determined using checklists and scrutiny of each patient's logbook and the cancer exercise specialists' meeting notes. Analysis of quantitative data will be via standard summary statistics. Qualitative data will be analysed using thematic analysis. EXPECTED RESULTS: This feasibility study will inform the design and conduct of a future randomised controlled trial. Success will be defined according to a traffic light system for identifying the appropriateness of progression to a randomised controlled trial. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number registry (ISRCTN82505455).

The Gut Microbiota Differ in Exclusively Breastfed and Formula-Fed United States Infants and are Associated with Growth Status.

BACKGROUND: Evidence regarding the effects of infant feeding type (exclusive breastfeeding compared with exclusive formula feeding) on the gut microbiota and how it impacts infant growth status is limited. OBJECTIVES: The primary objective was to compare gut microbiota by feeding type and characterize the associations between gut microbiota and infant growth status. METHODS: Stool samples from healthy, full-term infants (4-5 mo-old) who were either exclusively breastfed (BF) or exclusively formula-fed (FF) in Denver, CO, United States were collected, and fecal 16S ribosomal ribonucleic acid gene-based profiling was conducted. Length and weight were measured at the time of stool collection. Length-for-age z-score, weight-for-age z-scores (WAZ), and weight-for-length z-scores were calculated based on the World Health Organization standards. Associations between gut microbial taxa and anthropometric z-scores were assessed by Spearman's rank correlation test. RESULTS: A total of 115 infants (BF n = 54; FF n = 61) were included in this study. Feeding type (BF compared with FF) was the most significant tested variable on gut microbiota composition (P < 1 × 10-6), followed by mode of delivery and race. Significant differences were observed in α-diversity, ß-diversity, and relative abundances of individual taxa between BF and FF. BF infants had lower α-diversity than FF infants. Abundances of Bifidobacterium and Lactobacillus were greater in the breastfeeding group. FF infants had a higher relative abundance of unclassified Ruminococcaceae (P < 0.001), which was associated with a higher WAZ (P < 0.001) and length-for-age z-score (P < 0.01). Lactobacillus was inversely associated with WAZ (P < 0.05). CONCLUSIONS: Feeding type is the main driver of gut microbiota differences in young infants. The gut microbiota differences based on feeding type (exclusive breast- or formula feeding) were associated with observed differences in growth status. This trial was registered at clinicaltrials.gov as NCT02142647, NCT01693406, and NCT04137445.

Providing multimedia information to children and young people increases recruitment to trials: pre-planned meta-analysis of SWATs.

BACKGROUND: Randomised controlled trials are often beset by problems with poor recruitment and retention. Information to support decisions on trial participation is usually provided as printed participant information sheets (PIS), which are often long, technical, and unappealing. Multimedia information (MMI), including animations and videos, may be a valuable alternative or complement to a PIS. The Trials Engagement in Children and Adolescents (TRECA) study compared MMI to PIS to investigate the effects on participant recruitment, retention, and quality of decision-making. METHODS: We undertook six SWATs (Study Within A Trial) within a series of host trials recruiting children and young people. Potential participants in the host trials were randomly allocated to receive MMI-only, PIS-only, or combined MMI + PIS. We recorded the rates of recruitment and retention (varying between 6 and 26 weeks post-randomisation) in each host trial. Potential participants approached about each host trial were asked to complete a nine-item Decision-Making Questionnaire (DMQ) to indicate their evaluation of the information and their reasons for participation/non-participation. Odds ratios were calculated and combined in a meta-analysis. RESULTS: Data from 3/6 SWATs for which it was possible were combined in a meta-analysis (n = 1758). Potential participants allocated to MMI-only were more likely to be recruited to the host trial than those allocated to PIS-only (OR 1.54; 95% CI 1.05, 2.28; p = 0.03). Those allocated to combined MMI + PIS compared to PIS-only were no more likely to be recruited to the host trial (OR = 0.89; 95% CI 0.53, 1.50; p = 0.67). Providing MMI rather than PIS did not impact on DMQ scores. Once children and young people had been recruited to host trials, their trial retention rates did not differ according to intervention allocation. CONCLUSIONS: Providing MMI-only increased the trial recruitment rate compared to PIS-only but did not affect DMQ scores. Combined MMI + PIS instead of PIS had no effect on recruitment or retention. MMIs are a useful tool for trial recruitment in children and young people, and they could reduce trial recruitment periods.

Ecologies, synergies, and biological systems shaping human milk composition-a report from "Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN)" Working Group 2.

Human milk is universally recognized as the preferred food for infants during the first 6 mo of life because it provides not only essential and conditionally essential nutrients in necessary amounts but also other biologically active components that are instrumental in protecting, communicating important information to support, and promoting optimal development and growth in infants. Despite decades of research, however, the multifaceted impacts of human milk consumption on infant health are far from understood on a biological or physiological basis. Reasons for this lack of comprehensive knowledge of human milk functions are numerous, including the fact that milk components tend to be studied in isolation, although there is reason to believe that they interact. In addition, milk composition can vary greatly within an individual as well as within and among populations. The objective of this working group within the Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN) Project was to provide an overview of human milk composition, factors impacting its variation, and how its components may function to coordinately nourish, protect, and communicate complex information to the recipient infant. Moreover, we discuss the ways whereby milk components might interact such that the benefits of an intact milk matrix are greater than the sum of its parts. We then apply several examples to illustrate how milk is better thought of as a biological system rather than a more simplistic "mixture" of independent components to synergistically support optimal infant health.

Iron and DHA in Infant Formula Purchased in the US Fails to Meet European Nutrition Requirements.

Requirements for iron and docosahexaenoic acid (DHA) content of infant formula varies by country. Powdered full-term infant formula purchase data from all major physical stores in the US between 2017-2019 were obtained from CIRCANA, Inc. Iron and DHA composition and scoop sizes for each formula were obtained from manufacturers. The equivalent liquid ounces of prepared formula were calculated. Average iron and DHA content were compared between formula types and to both US and European formula composition requirements. These data represent 55.8 billion ounces of formula. The average iron content of all formula purchased was: 1.80 mg/100 kcal. This iron concentration is within the FDA regulations. However, it exceeds the maximum allowable iron concentration of infant formula (Stage 1) set by the European Commission of 1.3 mg/100 kcal. A total of 96% of formula purchased had an iron concentration of >1.3 mg/100 kcal. DHA is not a required ingredient in US formulas. The average DHA content of all formula purchased was: 12.6 mg/100 kcal. This DHA concentration is far below the minimum required DHA concentrations of infant formula (Stage 1) and follow-on formula (Stage 2) set by the European Commission of 20 mg/100 kcal. These are novel insights into the iron and DHA intake of formula-fed infants in the US. As international infant formulas have entered the US market due to the formula shortage, parents and providers need to be aware of regulatory differences in formula nutrient composition.

Effectiveness of lactation cookies on human milk production rates: a randomized controlled trial.

BACKGROUND: Expensive lactation cookies (LCs) are marketed as milk boosters; however, their effectiveness remains unknown. OBJECTIVES: The objective of this study was to evaluate the effectiveness of the 1-mo daily intake of LCs on changes in objective and subjective milk production and breastfeeding self-efficacy. METHODS: This is a 1-mo, randomized controlled trial among 18-45-y-old exclusively lactating parents of healthy, term, 2-mo-old infants living in the United States from March to December 2021. Participants (n = 176) were randomly assigned to eat daily 56.5 g of either LCs with "galactagogues" (oatmeal, brewer's yeast, flax seeds, and fenugreek) or conventional cookies containing similar weight, calories, and presentation but lacking galactagogues. The primary outcome was baseline-to-1-mo changes in human milk production rate (HMPR), measured with a validated milk expression protocol. Secondary outcomes included changes in perceived insufficient milk (PIM) and lactation self-efficacy scores. RESULTS: Among 176 randomly assigned participants (age: 31.3 ± 5.8 y; 71.0% self-identified as White, 15.3% Hispanic/Latin, 6.3% Black, and 4.0% Asian), 90 participants (51.1%) completed endline HMPR measures and 129 (73.3%) completed secondary outcomes. Imputed models showed a mean increase in HMPR of 5.8 ± 15.7 mL/h in control participants and 5.5 ± 17.6 mL/h in the LC participants after 1 mo of daily intake of the cookie. No significant differences were observed with adjusted linear mixed models on the multiply imputed data comparing baseline-to-endline changes in HMPR, PIM, or breastfeeding self-efficacy: mean (SE) difference-in-differences for HMPR, -0.33 (4.97), P = 0.948; PIM scores (range: 5-50), -0.52 (1.83), P = 0.775; and self-efficacy scores (range: 14-70), 0.31 (2.23), P = 0.888, respectively. CONCLUSIONS: This study found no evidence for the effect of consuming LCs on HMPR, PIM, or breastfeeding self-efficacy in exclusively breastfeeding parents with an overall adequate perceived milk supply. Recommendations to consume LCs for increasing objective or subjective milk supply may deliver false hope and unnecessary financial costs at a vulnerable time. TRIAL REGISTRATION NUMBER: This trial was registered at clinicaltrials.gov as NCT04805008.

Human milk-derived fortifiers are linked with feed extension due to Hypoglycemia in infants <1250 g or <30 weeks: a matched retrospective chart review.

OBJECTIVE: To investigate differences in hypoglycemia and extended feed prescriptions among premature infants provided bovine-derived human milk fortifiers (Bov-fort) with mother's milk or formula vs human milk-derived human milk fortifiers (HM-fort) with mother's milk or donor human milk. STUDY DESIGN: This was a retrospective chart review (n = 98). Infants receiving HM-fort were matched with infants receiving Bov-fort. Blood glucose values and feed orders were retrieved from the electronic medical record. RESULTS: Prevalence of ever having blood glucose <60 mg/dL was 39.1% in the HM-fort group vs. 23.9% in the Bov-fort group (p = 0.09). Blood glucose ≤45 mg/dL occurred in 17.4% of HM-fort vs 4.3% in Bov-fort (p = 0.07). Feeds were extended for any reason in 55% of HM-fort vs. 20% of Bov-fort (p < 0.01). Feed extension due to hypoglycemia occurred in 24% of HM-fort vs. 0% of Bov-fort (p < 0.01). CONCLUSION: Predominately HM-based feeds are associated with feed extension due to hypoglycemia. Prospective research is warranted to elucidate underlying mechanisms.

Complex and alternate consent pathways in clinical trials: methodological and ethical challenges encountered by underserved groups and a call to action.

BACKGROUND: Informed consent is considered a fundamental requirement for participation in trials, yet obtaining consent is challenging in a number of populations and settings. This may be due to participants having communication or other disabilities, their capacity to consent fluctuates or they lack capacity, or in emergency situations where their medical condition or the urgent nature of the treatment precludes seeking consent from either the participant or a representative. These challenges, and the subsequent complexity of designing and conducting trials where alternative consent pathways are required, contribute to these populations being underserved in research. Recognising and addressing these challenges is essential to support trials involving these populations and ensure that they have an equitable opportunity to participate in, and benefit from, research. Given the complex nature of these challenges, which are encountered by both adults and children, a cross-disciplinary approach is required. DISCUSSION: A UK-wide collaboration, a sub-group of the Trial Conduct Working Group in the MRC-NIHR Trial Methodology Research Partnership, was formed to collectively address these challenges. Members are drawn from disciplines including bioethics, qualitative research, trials methodology, healthcare professions, and social sciences. This commentary draws on our collective expertise to identify key populations where particular methodological and ethical challenges around consent are encountered, articulate the specific issues arising in each population, summarise ongoing and completed research, and identify targets for future research. Key populations include people with communication or other disabilities, people whose capacity to consent fluctuates, adults who lack the capacity to consent, and adults and children in emergency and urgent care settings. Work is ongoing by the sub-group to create a database of resources, to update NIHR guidance, and to develop proposals to address identified research gaps. CONCLUSION: Collaboration across disciplines, sectors, organisations, and countries is essential if the ethical and methodological challenges surrounding trials involving complex and alternate consent pathways are to be addressed. Explicating these challenges, sharing resources, and identifying gaps for future research is an essential first step. We hope that doing so will serve as a call to action for others seeking ways to address the current consent-based exclusion of underserved populations from trials.

Health and nutrition claims for infant formula: international cross sectional survey.

OBJECTIVES: To review available health and nutrition claims for infant formula products in multiple countries and to evaluate the validity of the evidence used for substantiation of claims. DESIGN: International cross sectional survey. SETTING: Public facing and healthcare professional facing company owned or company managed formula industry websites providing information about products marketed for healthy infants delivered at full term in 15 countries: Australia, Canada, Germany, India, Italy, Japan, Nigeria, Norway, Pakistan, Russia, Saudi Arabia, South Africa, Spain, the United Kingdom, and the United States in 2020-22. MAIN OUTCOME MEASURES: Number and type of claims made for each product and ingredient. References cited were reviewed and risk of bias was assessed for registered clinical trials using the Cochrane risk of bias tool, and for systematic reviews using the Risk Of Bias in Systematic reviews tool. RESULTS: 757 infant formula products were identified, each with a median of two claims (range from 1 (Australia) to 4 (US)), and 31 types of claims across all products. Of 608 products with ≥1 claims, the most common claim types were "helps/supports development of brain and/or eyes and/or nervous system" (323 (53%) products, 13 ingredients), "strengthens/supports a healthy immune system" (239 (39%) products, 12 ingredients), and "helps/supports growth and development" (224 (37%) products, 20 ingredients). 41 groups of ingredients were associated with ≥1claims, but many claims were made without reference to a specific ingredient (307 (50%) products). The most common groups of ingredients cited in claims were long chain polyunsaturated fatty acids (278 (46%) products, 9 different claims); prebiotics, probiotics, or synbiotics (225 (37%) products, 19 claims); and hydrolysed protein (120 (20%) products, 9 claims). 161/608 (26%) products with ≥1 claims provided a scientific reference to support the claim-266 unique references were cited for 24 different claim types for 161 products. The reference types most frequently cited were clinical trials (50%, 134/266) and reviews (20%, 52/266). 28% (38/134) of referenced clinical trials were registered, 14% (19/134) prospectively. 58 claims referred to 32 registered clinical trials, of which 51 claims (27 trials) related to a randomised comparison. 46 of 51 claims (90%) referenced registered clinical trial outcomes at high risk of bias, and all cited systematic reviews and pooled analyses, carried a high risk of bias. CONCLUSIONS: Most infant formula products had at least one health and nutrition claim. Multiple ingredients were claimed to achieve similar health or nutrition effects, multiple claims were made for the same ingredient type, most products did not provide scientific references to support claims, and referenced claims were not supported by robust clinical trial evidence.

Patient-centred outcomes following non-operative treatment or appendicectomy for uncomplicated acute appendicitis in children.

While non-operative treatment has emerged as an alternative to surgery for the treatment of uncomplicated acute appendicitis in children, comparative patient-centred outcomes are not well documented. We investigated these in a feasibility randomised trial. Of 57 randomised participants, data were available for 26. Compared with appendicectomy, children allocated to non-operative treatment reported higher short-term quality of life scores, shorter duration of requiring analgesia, more rapid return to normal activities and shorter parental absence from work. These preliminary data suggest differences exist in recovery profile and quality of life between these treatments that are important to measure in a larger RCT. Trial registration number is ISRCTN15830435.